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WO2009018233A1 - Dérivés de n-(arylamino)arylsulfonamide comprenant des polymorphes en tant qu'inhibiteurs de mek ainsi que compositions, procédés d'utilisation et procédés de préparation de ceux-ci - Google Patents

Dérivés de n-(arylamino)arylsulfonamide comprenant des polymorphes en tant qu'inhibiteurs de mek ainsi que compositions, procédés d'utilisation et procédés de préparation de ceux-ci Download PDF

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Publication number
WO2009018233A1
WO2009018233A1 PCT/US2008/071392 US2008071392W WO2009018233A1 WO 2009018233 A1 WO2009018233 A1 WO 2009018233A1 US 2008071392 W US2008071392 W US 2008071392W WO 2009018233 A1 WO2009018233 A1 WO 2009018233A1
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WIPO (PCT)
Prior art keywords
compound
composition
alkyl
additional embodiments
cancer
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Application number
PCT/US2008/071392
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English (en)
Inventor
Jean-Michel Vernier
Colin Edward Rowlings
Jean-Luc Girardet
Stuart Dimock
Barry Quart
Jeffrey N. Miner
Original Assignee
Ardea Biosciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40304796&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2009018233(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US11/830,733 external-priority patent/US8101799B2/en
Priority to AP2010005134A priority Critical patent/AP2817A/xx
Priority to CN2008801088296A priority patent/CN101808516B/zh
Priority to AU2008282338A priority patent/AU2008282338B2/en
Priority to KR1020157020493A priority patent/KR20150091434A/ko
Priority to EP08796733.7A priority patent/EP2184984A4/fr
Priority to NZ582929A priority patent/NZ582929A/en
Application filed by Ardea Biosciences, Inc. filed Critical Ardea Biosciences, Inc.
Priority to US12/671,287 priority patent/US8648116B2/en
Priority to BRPI0815659-0A2A priority patent/BRPI0815659A2/pt
Priority to EA201000268A priority patent/EA020624B1/ru
Priority to KR1020147017261A priority patent/KR20140098185A/ko
Priority to CA2693390A priority patent/CA2693390C/fr
Priority to JP2010520118A priority patent/JP2010535232A/ja
Priority to MX2010001244A priority patent/MX2010001244A/es
Publication of WO2009018233A1 publication Critical patent/WO2009018233A1/fr
Priority to MX2010011314A priority patent/MX2010011314A/es
Priority to US12/937,630 priority patent/US8808742B2/en
Priority to SG2013028378A priority patent/SG189784A1/en
Priority to CN2009801180672A priority patent/CN102131771A/zh
Priority to CA2720671A priority patent/CA2720671A1/fr
Priority to EA201001639A priority patent/EA201001639A1/ru
Priority to EP09732683A priority patent/EP2291350A4/fr
Priority to AU2009236325A priority patent/AU2009236325A1/en
Priority to PCT/US2009/040538 priority patent/WO2009129246A2/fr
Priority to BRPI0911297A priority patent/BRPI0911297A2/pt
Priority to KR1020107025394A priority patent/KR20110014149A/ko
Priority to JP2011505138A priority patent/JP2011518786A/ja
Priority to IL203296A priority patent/IL203296A/en
Priority to TNP2010000049A priority patent/TN2010000049A1/fr
Priority to MA32636A priority patent/MA31881B1/fr
Priority to IL208284A priority patent/IL208284A0/en
Priority to ZA2010/06944A priority patent/ZA201006944B/en
Priority to CO10128068A priority patent/CO6331425A2/es
Priority to MA33245A priority patent/MA32226B1/fr
Priority to EC2010010548A priority patent/ECSP10010548A/es
Priority to HK11101625.8A priority patent/HK1147396A1/xx
Priority to AU2015200390A priority patent/AU2015200390B2/en
Priority to PH12015501914A priority patent/PH12015501914A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
    • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
    • A01N41/04—Sulfonic acids; Derivatives thereof
    • A01N41/06—Sulfonic acid amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/28—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention concerns N-(2-arylamino) aryl sulfonamide compounds which are inhibitors of MEK including crystalline polymorphic forms which exhibit a specific powder x-ray diffraction profile and/or a specific differential scanning calorimetry profile.
  • This invention also concerns pharmaceutical compositions comprising the compounds described herein and methods of use of the compounds and compositions described herein, including the use in the treatment and/or prevention of cancer, hyperproliferative diseases and inflammatory conditions.
  • the invention also concerns methods of making the compunds and compositions described herein.
  • Oncogenes ⁇ genes that contribute to the production of cancers ⁇ are generally mutated forms of certain normal cellular genes ("proto-oncogenes").
  • Oncogenes often encode abnormal versions of signal pathway components, such as receptor tyrosine kinases, serine-threonine kinases, or downstream signaling molecules.
  • the central downstream signaling molecules are the Ras proteins, which are anchored on the inner surfaces of cytoplasmic membranes, and which hydrolyze bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP).
  • GTP guanosine triphosphate
  • GDP guanosine diphosphate
  • Ras alternates between an active "on” state with a bound GTP (hereafter “Ras. GTP”) and an inactive "off state with a bound GDP.
  • the active "on” state, Ras.GTP binds to and activates proteins that control the growth and differentiation of cells.
  • Ras.GTP leads to the activation of a cascade of serine/threonine kinases.
  • the Raf proteins activate "MEKl” and "MEK2,” abbreviations for mitogen-activated £RK- activating Mnases (where ERK is extracellular signal-regulated protein kinase, another designation for MAPK).
  • MEKl and MEK2 are dual-function serine/threonine and tyrosine protein kinases and are also known as MAP kinase kinases.
  • Ras.GTP activates Raf, which activates MEKl and MEK2, which activate MAP kinase (MAPK).
  • MAPK MAP kinase
  • Blockade of downstream Ras signaling as by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
  • the interaction of Raf and Ras is a key regulatory step in the control of cell proliferation.
  • MEK may also be activated by other upstream signal proteins such as MEK kinase or MEKKl and PKC.
  • Activated MAPK translocates and accumulates in the nucleus, where it can phosphorylate and activate transcription factors such as EBc-I and Sapla, leading to the enhanced expression of genes such as that for c-fos.
  • Raf and other kinases phosphorylate MEK on two neighboring serine residues, S 218 and S 222 in the case of MEKl . These phosphorylations are required for activation of MEK as a kinase.
  • MEK phosphorylates MAP kinase on two residues separated by a single amino acid: a tyrosine, Y 185 and a threonine, T 183 .
  • MEK appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins.
  • MEK's unusual specificity and its requirement for a strong interaction with MAP kinase prior to phosphorylation suggest that MEK's mechanism of action may differ sufficiently from the mechanisms of other protein kinases as to allow for selective inhibitors of MEK. Possibly, such inhibitors would operate through allosteric mechanisms rather than through the more usual mechanism involving blockage of an ATP binding site.
  • MEKl and MEK2 are validated and accepted targets for antiproliferative therapies, even when the oncogenic mutation does not affect MEK structure or expression. See, eg., U.S. Patent Publications 2003/0149015 by Barrett et al. and 2004/0029898 by Boyle et al.
  • Patent Publication 2005/004186 describes related compounds in which the 4-iodo substituent of the '030 patent is replaced by a very broad genus of moieties including alkyl, alkoxy, acyloxy, alkenyl, carbamoyl, carbamoylalkyl, carboxyl, carboxylalkyl, N- acylsulfonamido, and others.
  • U.S. Patent 6,469,004 and corresponding publication WO 00/42022 describe carboxylic and hydroxamic acid esters of a group of heterocyclo-condensed phenylene compounds, i.e., benzimidazoles, benzooxazoles, benzothiazoles, benzothiadiazoles, quinazolines, etc.
  • the heterocycles are 7-F-6-(4-iodo-phenylamino)-5 -carboxylic acid esters, carboxylic acid amides or hydroxamic acid esters.
  • More recent publication U.S. 2005/0026970 described similar compounds in which the 4-iodo substituent was replaced by a very broad genus of structures.
  • Patent Publication WO 02/06213 and corresponding U.S. Application Ser. No. 10/333,399 describe hydroxy-substituted acid esters of 1-oxamic acid- 2(4-halophenylamino)-3,4-difluorobenzene.
  • U.S. Patent No. 6,891,066 and corresponding publication WO 03/62191 describe similar compounds wherein the 4-halo substituent is replaced by a very broad genus of structures. Among the substituents in the 4-position were methyl, ethyl, ethynyl, and 2-hydroxyethyl. Specific related compounds are described in U.S. Patent No. 6,770,778.
  • Patent Publication WO 04/083167 published September 30, 2004, (in Japanese) discloses more than two thousand but provides NMR data for only 400 - 1-(N-substituted sulfonyl urea)-2(2,4-dihalophenylamino)-3,4-difluorobenzenes and asserts that they useful as MEK inhibitors. Data indicating inhibition of MEK were presented for a subgroup of just twelve.
  • these twelve compounds all contained one of the following groups: an N, N-disubstituted sulfonyl urea, N-piperazinesulfonamide, N-piperidinesulfonamide or N-pyrrolidinesulfonamide.
  • the MEK cascade has also been implicated in inflammatory diseases and disorders.
  • U.S. Application Publication No. 2006/0030610 to Koch et al. U.S. Application Publication No. 2006/0140872 to Furue et al.
  • inflammatory bowel diseases are Crohn's disease and ulcerative colitis.
  • MEKl and MEK2 are validated and accepted targets for anti-proliferative therapies, even when the oncogenic mutation does not affect MEK structure or expression. See, e.g., U.S. Patent Publications 2003/0149015 by Barrett et al. and 2004/0029898 by Boyle et al
  • Z is H or F
  • X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF 3 ;
  • G 1 is C 1 -C 6 alkyl optionally substituted with one amino, C r C 3 alkylamino, or dialkylamino group, said dialkylamino group comprising two C 1 -C 4 alkyl groups which may be identical or non-identical; or G 1 is a C 3 -C 8 diamino alkyl group;
  • R la is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C 1 - C 3 alkoxy, where said cyclopropoxy group or the C 1 - C 3 alkyl moieties of said C 1 - C 3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 - alkyl groups within said C 1 - C 4 alkoxy are optionally further substituted with a second OH group;
  • R 1b is CH(CH 3 )-C 1-3 alkyl or C 3 -C 6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH 3 , and CN;
  • R 10 is (CH ⁇ n O ro R 1 ; where m is 0 or 1 ; and where when m is 0, n is 1 or 2;
  • R' is C 1 -C 6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6 cycloalkyl;
  • R ld is C(A)(A')(B)-;
  • B is H or CM alkyl, optionally substituted with one or two OH groups;
  • a and A' are independently H or C ll4 alkyl, optionally substituted with one or two OH groups; or
  • R 2 and R 3 are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, M-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
  • R 4 is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, w-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoy
  • U and V are, independently, N, CR 2 or CR 3 ;
  • R 2 , R 3 and R 4 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, .sec-butyl, tert-buryl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, l,3,4-oxadiazol-2-yI, 5-methyl-l,3,4-oxadiazolyl, 1,3,4- thiadiazolyl, 5-methyl-l,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonyiamino, and methyls
  • R 5 and R 6 are, independently, H, F, Cl or methyl; Ar 2 is
  • U is -NH-, -NCH 3 - or -O-;
  • R 7 and R 8 are, independently, H, F, Cl, or methyl.
  • the invention provides a compound of formula I, selected from the compounds below:
  • the invention provides a compound of formula I, selected from:
  • the invention provides a compound of formula I, selected from:
  • the invention provides a composition comprising a compound of formula I, selected from those shown below, where the 2-OH carbon is in the R configuration, substantially free of the S- isomer.
  • the invention provides a composition comprising a compound of formula I, selected from those shown below, where the 2-OH carbon is in the S configuration, substantially free of the R- isomer.
  • this invention provides a compound of formula I, where Y is phenyl, pyridyl, or pyrazolyl.
  • this invention provides a compound of formula I, where Y is substituted phenyl, pyridyl, or pyrazolyl. In yet another subgeneric embodiment, this invention provides a compound of formula I, where Y is Br or I. In one subgeneric embodiment, this invention provides a compound of formula I, where G is 1-piperidyl, 2- piperidyl, 3-piperidyl, or 4-piperidyl. In another subgeneric embodiment, this invention provides a compound of formula I, where G is 1-piperazyl or 2-piperazyl. In another subgeneric embodiment, this invention provides a compound of formula I, where G is morpholyl.
  • this invention provides a compound of formula I, where G is N-methyl-2-aminoethyl. In one subgeneric embodiment, this invention provides a compound of formula I, where G is N-methyl-3-amino-n-propyl. In another subgeneric embodiment, this invention provides a compound of formula I, where G is (C ⁇ N-CH ⁇ HrNH-tCHz),,-, where n is 1, 2, or 3. In another subgeneric embodiment, this invention provides a compound of formula I, where G is (CH 3 CH 2 ) 2 N-CH 2 CH 2 -NH-(CH 2 ) n -, where n is 1 or 2.
  • this invention provides a compound of formula I, where G is 1 -piperidyl, 2-piperidyl, 3- piperidyl, or 4-piperidyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is 1-piperazyl or 2-piperazyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is morpholyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is N-methyl-2-aminoethyl; R 0 is H, halo, or methoxy; X is F; and Y is I
  • this invention provides a compound of formula I, where G is N- methyl-3-amino-n-propyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is (CH 3 ) 2 N-CH 2 CH 2 -NH-(CH 2 ) H -, where n is 1, 2, or 3; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is (CH 3 CH 2 ) 2 N-CH 2 CH 2 -NH-(CH 2 ) n -, where n is I or 2; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising a compound selected from:
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the compound is in the R configuration. In some embodiments, the compound is in the R configuration, substantially free of the S- isomer. In some embodiments, the compound is in the S configuration.
  • the compound is in the S configuration, substantially free of the R- isomer, In some embodiments, the compound is in the S configuration, substantially free of the R- isomer, In some
  • the compound is: F , In some embodiments, the compound is:
  • the invention also relates to a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyI) cyclopropane- 1 -sulfonamide (also referred to herein as "Compound A” and "N-(-)- ⁇ 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)
  • the powder x-ray diffraction pattern contains at least 50% of the peaks shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern contains at least 70% of the peaks shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern contains at least 90% of the peaks shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in FIG. S.
  • Compound A has been characterized as the "S" isomer by making the R and S-MTPA esters at the secondary alcohol and comparing the proton chemical shift difference. See, e.g., Dale, J.A.; Mosher, H.S., J. Am. Chem. Soc, 1973, 95, 512 and Ohtani et al., J. Am. Chem. Soc, 1991, 113, 4092.
  • the invention also relates to N-(R)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl) cyclopropane- 1 -sulfonamide (also referred to herein as "Compound B” and "N-(+)-(3,4-difIuoro-2-(2- fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide”):
  • Compound B has been characterized as the "R" isomer by making the R and S-MTPA esters at the secondary alcohol and comparing the proton chemical shift difference. See, e.g., Dale, J.A.; Mosher, H.S., J. Am. Chem. Soc, 1973, 95, 512 and Ohtani et al., J. Am. Chem. Soc, 1991, 113, 4092.
  • the invention also relates to a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-
  • iodophenylamino-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide exhibits a specific differential scanning calorimetry pattern.
  • the differential scannine calorimetry pattern is substantially the same as the differential scanning calorimetry pattern shown in FIG. 6.
  • the invention also relates to pharmaceutical compositions comprising an effective amount of crystalline polymorph form A ofN-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenyIamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide and a pharmaceutically acceptable carrier or vehicle.
  • 6-methoxyphenyl)-I-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide is useful for treating or preventing cancer or an inflammatory disease.
  • the invention further relates to methods for treating or preventing cancer or an inflammatory disease, comprising administering an effective amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-ciihydroxypropyl) cyclopropane-1 -sulfonamide to a subject in need thereof.
  • the present invention is directed to pharmaceutical compositions comprising effective amounts of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier.
  • Such compositions may contain adjuvants, excipients, and preservatives, agents for delaying absorption, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizing agents, other carriers, and other inert ingredients. Methods of formulation of such compositions are well-known in the art.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.002 to about 6 g/day. In further or additional embodiments the amount of compound of formula I is about 0.005 to about 5 g/day. fn further or additional embodiments the amount of compound of formula I is about 0.01 to about 5 g/day.
  • the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the pharmaceutical composition is for administration to a mammal.
  • the mammal is human.
  • the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant.
  • the pharmaceutical composition further comprises at least one therapeutic agent
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and antineoplastic agents.
  • the antineoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is taxol, bortezomib or both.
  • the pharmaceutical composition is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula I .
  • compositions and methods for using a composition comprising a compound selected from:
  • the 2-OH carbon on the compound is in the R configuration. In some embodiments, the 2-OH carbon on the compound is in the S configuration. In some embodiments, composition is substantially free of the S- isomer of the compound. In some embodiments, the composition is substantially free of the R- isomer of the compound. In some embodiments, the compound contains less than 10% of the S- isomer of the compound. In some embodiments, the compound contains less than 10% of the R- isomer of the compound. In some embodiments, the compound contains less than 5% of the S- isomer of the compound. In some embodiments, the compound contains less than 5% of the R- isomer of the compound. In some embodiments, the compound contains less than 1% of the S- isomer of the compound. In some embodiments, the compound contains less than 1% of the R- isomer of the compound.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • the composition allows for modified release of the compound. In some embodiments, the composition allows for sustained release of the compound. In some embodiments, the composition allows for delayed release of the compound. In some embodiments, the compound is present in an amount of about 1-50 mgs. In some embodiments, the compound is present in an amount of about 1-10 mgs. In some embodiments, the compound is present in an amount of about 10-20 mgs. In some embodiments, the compound is present in an amount of about 20-40 mgs. In some embodiments, the compound is present in an amount of about 40-50 mgs.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • compositions comprising: about 1-50 mg of a compound having the following structure wherein the composition allows for modified release of the drug.
  • the composition further comprises microcrystalline cellulose.
  • the composition further comprises croscarmellose sodium.
  • the composition further comprises sodium lauryl sulfate.
  • the composition further comprises magnesium stearate. Also provided here in are compositions comprising about lmg of a compound having the following structure:
  • the composition further comprises about 222.2mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4mg of magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • the composition further comprises about 10mg of a compound having the following structure F .
  • the composition further comprises about 213.2mg of microcrystalline cellulose.
  • the composition further comprises about 12.0mg of croscarmellose sodium.
  • the composition further comprises about 2.4mg of sodium lauryl sulfate.
  • the composition further comprises about 2.4mg of magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • the composition further comprises about 20mg of a compound having the following structure: the composition further comprises about 203.2mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4mg of magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • compositions and methods of treating cancer or inflammation with compositions comprising about 40mg of a compound having the following structure F .
  • the composition further comprises about 183.2mg of microcrystalline cellulose.
  • the composition further comprises about 12.0mg of croscarmellose sodium.
  • the composition further comprises about 2.4mg of sodium lauryl sulfate.
  • the composition further comprises about 2.4mg of magnesium stearate. Also provided herein are compositions and methods of treating cancer or inflammation with compositions
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 92.6% by weight of the composition.
  • the composition further comprises about 5% by weight croscarmellose sodium.
  • the composition further comprises about 1% by weight sodium lauryl sulfate.
  • the composition further comprises about 1% by weight magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • compositions and methods of treating cancer or inflammation with compositions comprising about 4,2% by weight of a compound having the following structure F , and about 95.8 % by weight of a pharmaceutically acceptable carrier or vehicle.
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 88.8% by weight of the composition.
  • the composition further comprises about 5% by weight croscarmellose sodium.
  • the composition further comprises about 1% by weight sodium lauryl sulfate.
  • the composition further comprises about 1% by weight magnesium stearate. Also provided herein are compositions and methods of treating cancer or inflammation with compositions
  • the pharmaceutically acceptable carrier or vehicle further comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises from about 1% to about 6% by weight croscarmellose sodium.
  • the composition further comprises from about 0.1% to about 2% by weight sodium lauryl sulfate.
  • the composition further comprises from about 0.25% to about 1.5% by weight magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • the composition further comprises about 222.2mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4mg of magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • the composition further comprises about 213.2mg of microcrystalline cellulose, In some embodiments, the composition further comprises about 12.0mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4mg of magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • compositions and methods of treating cancer or inflammation with compositions comprising about 20mg of a compound having the following structure: F .
  • the composition further comprises about 203.2mg of microcrystalline cellulose.
  • the composition further comprises about 12.0mg of croscarmellose sodium.
  • the composition further comprises about 2.4mg of sodium lauryl sulfate.
  • the composition further comprises about 2.4mg of magnesium stearate. Also provided herein are compositions and methods of treating cancer or inflammation with compositions
  • the composition further comprises about 183.2mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4mg of magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 92.6% by weight of the composition.
  • the composition further comprises about 5% by weight croscarmellose sodium.
  • the composition further comprises about 1% by weight sodium lauryl sulfate.
  • the composition further comprises about 1% by weight magnesium stearate.
  • compositions and methods of treating cancer or inflammation with compositions are also provided herein.
  • compositions and methods of treating cancer or inflammation with compositions comprising about 4.2% by weight of a compound having the following structure F , and about 95.8 % by weight of a pharmaceutically acceptable carrier or vehicle.
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 88.8% by weight of the composition.
  • the composition further comprises about 5% by weight croscarmellose sodium.
  • the composition further comprises about 1% by weight sodium lauryl sulfate.
  • the composition further comprises about 1% by weight magnesium stearate. Also provided herein are compositions and methods of treating cancer or inflammation with compositions
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises from about 1% to about 6% by weight croscarmellose sodium.
  • the composition further comprises from about 0.1% to about 2% by weight sodium lauryl sulfate.
  • the composition further comprises from about 0.25% to about 1.5% by weight magnesium stearate.
  • a crystalline polymorph Form A of N-(-)-(3,4-difluoro-2-(2-fluoro-4-iodophenyIamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide that exhibits a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5 and compositions comprising this compound..
  • the crystalline polymorph Form A, wherein the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern shown in FIG. 5. In some embodiments, the crystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 143 °C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.
  • crystalline polymorph Form A of N-(-)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide that exhibits a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in FIG. 6 and compositions comprising this compound.
  • the crystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 143°C.
  • the crystalline polymorph of claim 67 or 68, wherein the crystalline polymorph is substantially free of water.
  • N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide made by a method comprising the step of crystallizing amorphous N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyI)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide and compositions comprising this compound,
  • the crystallization step comprises crystallizing from a mixture of ethyl acetate and heptane.
  • the mixture of ethyl acetate and heptane is in a ratio of from about 1 -4 parts ethyl acetate to about 2- 10 parts heptane . In some embodiments, the mixture of ethyl acetate and heptane is in a ratio of from about 2 parts ethyl acetate to about 5 parts heptane. Also provided herein are methods for inhibiting MEK enzymes comprising contacting said MEK enzyme with a compound or composition described herein, wherein the compound is present in an amount sufficient to inhibit said enzyme by at least 25%. In some embodiments, the MEK enzyme is MEK kinase. In some embodiments, said contacting occurs within a cell.
  • the MEK inhibitor is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, non-MEK kinase inhibitor therapy, chemotherapy, surgery, Glucocorticoid, methotrexate, biological response modifiers, or any combination thereof.
  • the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases and malignant diseases.
  • the MEK mediated disorder is a hyperproliferative disease.
  • the MEK mediated disorder is cancer, tumors, leukemias, neoplasms, or carcinomas.
  • the MEK mediated disorder is an inflammatory disease.
  • said inflammatory disease is rheumatoid arthritis or multiple sclerosis.
  • the proliferative disease is cancer, psoriasis, restenosis, disease, or atherosclerosis. In some embodiments, the proliferative disease is cancer.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B-leukemia, stomach cancer, mesothelioma or small cell lung cancer.
  • the method further comprises administering at least one therapeutic agent.
  • this step comprises the administration of at least one additional cancer therapy.
  • the additional therapy is radiation therapy, non-MEK kinase inhibitor therapy, chemotherapy, surgery, Glucocorticoid, methotrexate, biological response modifiers, or any combination thereof.
  • Also provided herein are methods for the treatment or prophylaxis of an inflammatory disease in an individual comprising administering to said individual an effective amount of a composition comprising a compound described herein.
  • the inflammatory disease is rheumatoid arthritis or multiple sclerosis.
  • cancer cells comprise brain, breast, lung, ovarian, pancreatic, prostate, renal, stomach or colorectal cancer cells.
  • Also provided herein are methods of inhibiting tumor size increase, reducing the size of a tumor, reducing tumor proliferation or preventing tumor proliferation in an individual comprising administering to said individual an effective amount of the compound or composition described herein to inhibit tumor size increase, reduce the size of a tumor, reduce tumor proliferation or prevent tumor proliferation.
  • the tumor occurs in the brain, breast, lung, ovaries, pancreas, prostate, kidney, stomach, colon or rectum.
  • Z is H or F
  • X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF 3 ;
  • G 1 is C 1 -C 6 alkyl optionally substituted with one amino, C 1 -C 3 alkylamino, or dialkylamino group, said dialkylamino group comprising two C 1 -C 4 alkyl groups which may be identical or non-identical; or
  • G 1 is a C 3 -C 8 diamino alkyl group
  • R la is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C 1 - C 3 alkoxy, where said cyclopropoxy group or the C 1 - C 3 alkyl moieties of said C 1 - C 3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 - alkyl groups within said C r C 4 alkoxy are optionally further substituted with a second OH group;
  • R 1b is CH(CH 3 )-C 1 . 3 alkyl or C 3 -C 6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH 3 , and CN; Ru is (CH 2 ) n O m R'; where m is 0 or 1; and where when m is 0, n is 1 or 2; when m is 1, n is 2 or 3;
  • R 1 is C 1 -C 6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6 cycloalkyl;
  • R 1d is C(A)(A 1 )(B)-;
  • B is H or C 1-4 alkyl, optionally substituted with one or two OH groups;
  • a and A' are independently H or C 1-4 alkyl, optionally substituted with one or two OH groups; or A and A', together with the carbon atom to which they are attached, form a 3- to 6- member saturated ring;
  • R 2 and R 3 are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, .sec-butyl, tert-b ⁇ ty ⁇ or methylsulfonyl;
  • U and V are, independently, N, CR 2 or CR 3 ;
  • R 2 , R 3 and R 4 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 ,
  • OCF 3 ethyl, w-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetar ⁇ ido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, l,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4- thiadiazolyl, 5-methyl-l : 3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, and methylsulfonyl;
  • R 5 and R 6 are, independently, H, F, Cl or methyl; Ar 2 is
  • U is -NH-, -NCH 3 - Or -O-;
  • R 7 and R 8 are, independently, H, F, Cl, or methyl.
  • the compound is selected from:
  • the compound is selected from F and ; where the 2-OH carbon is in the R configuration.
  • the compound of formula (I), or a pharmaceutical salt is selected from F and ; where the 2-OH carbon is in the R configuration.
  • the compound is . In some embodiments,
  • these methods further comprise administering at least one additional therapeutic agent.
  • at least one additional cancer therapy is performed.
  • the additional cancer therapy is radiation therapy, chemotherapy, surgery, or any combination thereof.
  • compositions are administered orally. In some embodiments, the composition is administered once a day or twice a day. In some embodiments, the composition is administered once a day for at least one week.
  • T ma ⁇ of the compound is achieved between 1 hour and 3 hours after administration of the composition to a fasted subject.
  • the compound upon administration to a subject, the compound reaches a C max between about 0.01 ⁇ g/ml to about 1.0 ⁇ g/ral on day 1. In some embodiments, upon administration to a subject, the compound reaches a C max between about 0.01 ⁇ g/ml to about 0.8 ⁇ g/ml on day 1. In some embodiments, upon administration to a subject, the compound reaches a C max between about 0.03 ⁇ g/ml to about 0.5 ⁇ g/ml on day 1.
  • the compound has an AUC between about 0.1 ⁇ g hr/mL to about 5.0 ⁇ g hr/mL from 0-12 hours. In some embodiments, the compound has an AUC between about 0.1 ⁇ g hr/mL to about 4.0 ⁇ g hr/mL. In some embodiments, the compound has an AUC between about 0.5 ⁇ g hr/mL to about 3.0 ⁇ g hr/mL. In some embodiments, the compound has a T a1J1x between 0.5 and 5.0 hours. In some embodiments, the compound has a T 1113x between 1.0 and 3.0 hours. In some embodiments, the compound has a T max between 1.0 and 2.5 hours.
  • the compound has a plasma concentration greater than about 0.01 mg/mL after 5 hours after a single dose. In some embodiments, the compound has a plasma concentration greater than about 0.01 mg/mL after 10 hours after a single dose. In some embodiments, the compound has a plasma concentration greater than about 0.01 mg/mL after 15 hours after a single dose.
  • the compound upon administration to a group of 10 subjects, the compound reaches a mean C raax between about 0.01 ⁇ g/ml to about 1.0 ⁇ g/ml on day 1. In some embodiments, upon administration to a group of 10 subjects, the compound reaches a mean C 018x between about 0.01 ⁇ g/ml to about 0.8 ⁇ g/ml on day 1. In some embodiments, upon administration to a group of 10 subjects, the compound reaches a mean C m8x between about 0.03 ⁇ g/ml to about 0.5 ⁇ g/ml on day 1. In some embodiments, the compound has a mean AUC between about 0.1 ⁇ g hr/mL to about 5.0 ⁇ g hr/mL.
  • the compound has a mean AUC between about 0.1 ⁇ g hr/mL to about 4.0 ⁇ g hr/mL. In some embodiments, the compound has a mean AUC between about 0.5 ⁇ g hr/mL to about 3.0 ⁇ g hr/mL. In some embodiments, the compound has a mean T max between 0.5 and 5.0 hours. In some embodiments, the compound has a mean T 1 - J1x between 1.0 and 3.0 hours. In some embodiments, the compound has a mean T max between 1.0 and 2.5 hours.
  • the tumor decreases in volume by at least about 25%. In some embodiments, after daily administration of the drug for 5 days, the tumor decreases in volume by at least about 50%. In some embodiments, after daily administration of the drug for 5 days, the tumor decreases in volume by at least about 20-70%. In some embodiments, after daily administration of the drug for 15 days, the tumor decreases in volume by at least about 25%. In some embodiments, after daily administration of the drug for 15 days, the tumor decreases in volume by at least about 50%. In some embodiments, after daily administration of the drug for 15 days, the tumor decreases in volume by at least about 20-70%.
  • the tumor decreases in volume by at least about 25%. In some embodiments, after daily administration of the drug for 30 days, the tumor decreases in volume by at least about 50%. In some embodiments, after daily administration of the drug for 30 days, the tumor decreases in volume by at least about 20-70%.
  • the tumor growth is inhibited by at least about 20%. In some embodiments, after administration of the drug, the tumor growth is inhibited by at least about 40%. In some embodiments, after administration of the drug, the tumor growth is inhibited by at least about 60%. In some embodiments, after administration of the drug, the tumor growth is inhibited by at least about 80%. In some embodiments, after administration of the drug, the tumor growth is inhibited by between about 20% to about 100%. In some embodiments, after administration of the drug, the tumor growth is substantially inhibited. In some embodiments, the composition is administered twice a day. In some embodiments, the composition is administered once a day. In some embodiments, the MEK inhibitor does not interfere with the coadministration of a second tumor suprressing agent.
  • the composition is in the form of a tablet, a capsule, a gel cap, a caplet, a pellet, or a bead.
  • the composition is in the form of a capsule or tablet dosage form has a total weight of about 50 mg to about 1000 mg.
  • the composition is in the form of a capsule or tablet has a total weight selected from the group consisting of 50 mg, 75mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, and 500 mg.
  • the composition is in the form of a capsule or tablet has a total weight of about 240 mg.
  • the composition further comprises at least one filler selected from microcrystalline cellulose, silicif ⁇ ed microcrystalline cellulose, lactose, a compressible sugar, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate, calcium carbonate, starch and a calcium silicate.
  • at least one filler selected from microcrystalline cellulose, silicif ⁇ ed microcrystalline cellulose, lactose, a compressible sugar, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate, calcium carbonate, starch and a calcium silicate.
  • the composition further comprises at least one disintegrant selected from croscarmellose sodium, sodium starch glycolate, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, betonite and veegum.
  • disintegrant selected from croscarmellose sodium, sodium starch glycolate, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, betonite and veegum.
  • the composition further comprises at least one lubricant selected from magnesium stearate, metallic stearates, talc, sodium stearyl fumarate and stearic acid.
  • the composition further comprises at least one wetting agent or surfactant selected from sodium lauryl sulfate, glycerol, sorbitan oleates, sorbitan stearates, polyoxyethylenated sorbitan laurate, pahmtate, stearate, oleate or hexaolate, polyoxyethylene stearyl alcohol and sorbitan monolaurate.
  • at least one wetting agent or surfactant selected from sodium lauryl sulfate, glycerol, sorbitan oleates, sorbitan stearates, polyoxyethylenated sorbitan laurate, pahmtate, stearate, oleate or hexaolate, polyoxyethylene stearyl alcohol and sorbitan monolaurate.
  • compositions in the form of a capsule or tablet and the capsule or tablet releases at least 60 percent of the drug within 30 minutes using U.S. Pharmacopeia (USP) Apparatus II at 50 rpm with 1% sodium lauryl sulfate in water as the dissolution medium In some embodiments, the composition is in the form of a capsule or tablet and the capsule or tablet releases about 60-100 percent of the drug within 30 minutes using U.S. Pharmacopeia (USP) Apparatus II at 50 rpm with 1% sodium lauryl sulfate in water as the dissolution medium.
  • the composition is in the form of a capsule or tablet and the capsule or tablet releases about 60-90 percent of the drug within 30 minutes using U.S. Pharmacopeia (USP) Apparatus II at 50 rpm with 1% sodium lauryl sulfate in water as the dissolution medium.
  • the composition is in the form of a capsule or tablet and the capsule or tablet releases about 60-80 percent of the drug within 30 minutes using U.S. PharmacopeiafJJSP) Apparatus II at 50 rpm with 1% sodium iauryl sulfate in water as the dissolution medium.
  • capsules or tablets each comprising from about 1 to about 50 mg of a compound described herein and having a USP acceptance value for content uniformity of less than about 15.
  • the invention relates to methods for treating or preventing cancer, comprising administering to a subject in need an effective amount of a pharmaceutical composition comprising a compound of formula (I), as described herein.
  • a pharmaceutical composition comprising a compound of formula (I), as described herein.
  • the compounds and compositions useful in these methods are as described by the genus of formula (I) or any sub-genus or species exemplified throughout the present application falling within formula (I).
  • the invention relates to methods for treating or preventing an inflammation disease, comprising administering to a subject in need an effective amount of a pharmaceutical composition comprising a compound of formula (I), as described herein.
  • the compounds and compositions useful in these methods are as described by the genus of formula (I) or any sub-genus or species exemplified throughout the present application falling within formula (I).
  • the invention relates to methods for treating or preventing ankylosing spondylitis, gout, tendonitis, bursitis or sciatica, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I), as described herein.
  • the compounds and compositions useful in these methods are as described by the genus of formula (I) or any sub-genus or species exemplified throughout the present application falling within formula (I).
  • the present invention is also directed to a method of treating a disease in an individual suffering from said disease comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the present invention is directed to a method of treating a disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof
  • the present invention is directed to a method of treating a disorder in a human, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof
  • the present invention is directed to a method of treating a hyperproliferative disorder in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof
  • the present invention is directed to a method of treating an inflammatory disease, condition, or disorder in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the present invention is directed to a method of treating a disorder or condition which is modulated by the MEK cascade in a mammal, including a human, comprising administering to said mammal an amount of the compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, effective to modulate said cascade.
  • the appropriate dosage for a particular patient can be determined, according to known methods, by those skilled in the art.
  • Inhibition of MEK Enzyme In other aspects, the present invention is directed to a method for inhibiting a MEK enzyme.
  • the method comprises contacting said MEK enzyme with an amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, sufficient to inhibit said enzyme, wherein said enzyme is inhibited.
  • the enzyme is at least about 1% inhibited.
  • the enzyme is at least about 2% inhibited.
  • the enzyme is at least about 3% inhibited.
  • the enzyme is at least about 4% inhibited.
  • the enzyme is at least about 5% inhibited.
  • the enzyme is at least about 10% inhibited.
  • the enzyme is at least about 20% inhibited. In further or additional embodiments the enzyme is at least about 25% inhibited. In further or additional embodiments the enzyme is at least about 30% inhibited. In further or additional embodiments the enzyme is at least about 40% inhibited. In further or additional embodiments the enzyme is at least about 50% inhibited. In further or additional embodiments the enzyme is at least about 60% inhibited. In further or additional embodiments the enzyme is at least about 70% inhibited. In further or additional embodiments the enzyme is at least about 75% inhibited. In further or additional embodiments the enzyme is at least about 80% inhibited. In further or additional embodiments the enzyme is at least about 90% inhibited. In further or additional embodiments the enzyme is essentially completely inhibited.
  • the MEK enzyme is MEK kinase. In further or additional embodiments the MEK enzyme is MEKl . In further or additional embodiments the MEK enzyme is MEK2. In further or additional embodiments the contacting occurs within a cell. In further or additional embodiments the cell is a mammalian cell. In further or additional embodiments the mammalian cell is a human cell. In further or additional embodiments, the MEK enzyme is inhibited with a composition comprising a pharmaceutically acceptable salt of a compound of formula I.
  • the present invention is directed to a method of treatment of a MEK mediated disorder in an individual suffering from said disorder comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the composition comprising a compound of formula I is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily, In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from the MEK mediated disorder is a mammal. In further or additional embodiments, the individual is a human.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, non-cancer hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, dry eye, closed angle glaucoma and wide angle glaucoma.
  • the MEK mediated disorder is an inflammatory disease.
  • the MEK mediated disorder is a hyperproliferative disease.
  • the MEK mediated disorder is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignant disease.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, renal cancer, colorectal cancer or leukemia.
  • the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method for achieving an effect in a patient comprising the administration of an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, to a patient, wherein the effect is selected from the group consisting of inhibition of various cancers, immunological diseases, and inflammatory diseases.
  • the effect is inhibition of various cancers.
  • the effect is inhibition of immunological diseases.
  • the effect is inhibition inflammatory diseases.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day.
  • the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method for degrading, inhibiting the growth of or killing a cancer cell comprising contacting said cell with an amount of a composition effective to degrade, inhibit the growth of or to kill said cell, the composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the cancer cells comprise brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer cells.
  • the composition is administered with at least one therapeutic agent.
  • the therapeutic agent is taxol, bortezomib or both.
  • the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents
  • the anti- neoplastic agents selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the cancer cells are degraded. In further or additional embodiments, 1% of the cancer cells are degraded.
  • 2% of the cancer cells are degraded. In further or additional embodiments, 3% of the cancer cells are degraded. In further or additional embodiments, 4% of the cancer cells are degraded. In further or additional embodiments, 5% of the cancer cells are degraded. In further or additional embodiments, 10% of the cancer ceils are degraded. In further or additional embodiments, 20% of the cancer cells are degraded. In further or additional embodiments, 25% of the cancer cells are degraded. In further or additional embodiments, 30% of the cancer cells are degraded. In further or additional embodiments, 40% of the cancer cells are degraded. In further or additional embodiments, 50% of the cancer cells are degraded. In further or additional embodiments, 60% of the cancer cells are degraded.
  • the aforementioned degradation occurs in one day, five days, ten days, one month, two months, six months or one year.
  • the cancer cells are killed. In further or additional embodiments, 1% of the cancer cells are killed. In further or additional embodiments, 2% of the cancer cells are killed. In further or additional embodiments, 3% of the cancer cells are killed. In further or additional embodiments, 4% of the cancer cells are killed. In further or additional embodiments, 5% of the cancer cells are killed. In further or additional embodiments, 10% of the cancer cells are killed. In further or additional embodiments, 20% of the cancer cells are killed. In further or additional embodiments, 25% of the cancer cells are killed. In further or additional embodiments, 30% of the cancer cells are killed. In further or additional embodiments, 40% of the cancer cells are killed. In further or additional embodiments, 50% of the cancer cells are killed.
  • the aforementioned cancer cell killing occurs in one day, five days, ten days, one month, two months, six months or one year.
  • the growth of the cancer cells is inhibited. In further or additional embodiments, the growth of the cancer cells is about 1% inhibited. In further or additional embodiments, the growth of the cancer cells is about 2% inhibited. In further or additional embodiments, the growth of the cancer cells is about 3% inhibited. In further or additional embodiments, the growth of the cancer cells is about 4% inhibited. In further or additional embodiments, the growth of the cancer cells is about 5% inhibited. In further or additional embodiments, the growth of the cancer cells is about 10% inhibited. In further or additional embodiments, the growth of the cancer cells is about 20% inhibited. In further or additional embodiments, the growth of the cancer cells is about 25% inhibited.
  • the growth of the cancer cells is about 30% inhibited. In further or additional embodiments, the growth of the cancer cells is about 40% inhibited. In further or additional embodiments, the growth of the cancer cells is about 50% inhibited. In further or additional embodiments, the growth of the cancer cells is about 60% inhibited. In further or additional embodiments, the growth of the cancer cells is about 70% inhibited. In further or additional embodiments, the growth of the cancer cells is about 75% inhibited. In further or additional embodiments, the growth of the cancer cells is about 80% inhibited. In further or additional embodiments, the growth of the cancer cells is about 90% inhibited. In further or additional embodiments, the growth of the cancer cells is about 100% inhibited.
  • the present invention is directed to a method of reducing the size of a tumor, inhibiting tumor size increase, reducing tumor proliferation or preventing tumor proliferation in an individual, comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the size of a tumor is reduced.
  • the size of a tumor is reduced by at least 1%.
  • the size of a tumor is reduced by at least 2%.
  • the size of a tumor is reduced by at least 3%. In further or additional embodiments, the size of a tumor is reduced by at least 4%. In further or additional embodiments, the size of a tumor is reduced by at least 5%. In further or additional embodiments, the size of a tumor is reduced by at least 10%. In further or additional embodiments, the size of a tumor is reduced by at least 20%. In further or additional embodiments, the size of a tumor is reduced by at least 25%. In further or additional embodiments, the size of a tumor is reduced by at least 30%. In further or additional embodiments, the size of a tumor is reduced by at least 40%. In further or additional embodiments, the size of a tumor is reduced by at least 50%.
  • the size of a tumor is reduced by at least 60%. In further or additional embodiments, the size of a tumor is reduced by at least 70%. In further or additional embodiments, the size of a tumor is reduced by at least 75%. In further or additional embodiments, the size of a tumor is reduced by at least 80%. In further or additional embodiments, the size of a tumor is reduced by at least 85%. In further or additional embodiments, the size of a tumor is reduced by at least 90%. In further or additional embodiments, the size of a tumor is reduced by at least 95%. In further or additional embodiments, the tumor is eradicated. In some embodiments, the size of a tumor does not increase.
  • tumor proliferation is reduced. In some embodiments, tumor proliferation is reduced by at least 1 %. In some embodiments, tumor proliferation is reduced by at least 2 %. In some embodiments, tumor proliferation is reduced by at least 3 %. In some embodiments, tumor proliferation is reduced by at least 4 %. In some embodiments, tumor proliferation is reduced by at least 5 %. In some embodiments, tumor proliferation is reduced by at least 10 %. In some embodiments, tumor proliferation is reduced by at least 20 %. In some embodiments, tumor proliferation is reduced by at least 25 %. In some embodiments, tumor proliferation is reduced by at least 30 %.
  • tumor proliferation is reduced by at least 40 %. In some embodiments, tumor proliferation is reduced by at least 50 %. In some embodiments, tumor proliferation is reduced by at least 60 %. In some embodiments, tumor proliferation is reduced by at least 70 %. In some embodiments, tumor proliferation is reduced by at least 75 %. In some embodiments, tumor proliferation is reduced by at least 75 %. In some embodiments, tumor proliferation is reduced by at least 80 %. In some embodiments, tumor proliferation is reduced by at least 90 %. In some embodiments, tumor proliferation is reduced by at least 95 %. In some embodiments, tumor proliferation is prevented. In various embodiments, the aforementioned effects on cell proliferation occurs in one day, five days, ten days, one month, two months, six months or one year.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereo.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day.
  • the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human, In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method for the treatment or prophylaxis of a proliferative disease in an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the proliferative disease is cancer, psoriasis, restenosis, autoimmune disease, or atherosclerosis.
  • the proliferative disease is a hyperproliferative disease.
  • the proliferative disease is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignant disease.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, stomach cancer, head and neck cancer or leukemia.
  • the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • the cancer is brain cancer or adrenocortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, the cancer is pancreatic cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphona. In further or additional embodiments, the cancer is pre-B acute leukemia.
  • the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell lung cancer. In further embodiments, the cancer is stomach cancer. In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day, In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from the proliferative disease is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered. Inflammatory Diseases, the present invention is directed to a method for the treatment or prophylaxis of an inflammatory disease in an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the inflammatory disease is selected from chronic inflammatory diseases, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathy arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerosis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, allergies, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema or scleroderma.
  • chronic inflammatory diseases rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic
  • composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day.
  • the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower Hmit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from the inflammatory disease is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method for the treatment or prophylaxis of cancer in an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the cancer is brain cancer, breast cancer, stomach cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia.
  • the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, stomach cancer, colorectal cancer or leukemia.
  • the cancer is brain cancer or adrenocortical carcinoma.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is pancreatic cancer.
  • the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphona. In further or additional embodiments, the cancer is pre-B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is stomach cancer.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate.
  • dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human, In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • Figure 1 shows graphs of average tumor volume against time (days) in mice implanted with A375 Melanoma, Colo205 Colon Tumor, A431 Epidermoid Tumor or HT-29 Colon Tumor cells. Mice were dosed orally (25mg/kg, 50mg/kg or 100mg/kg), once a day, for 14 days.
  • Figure 2 shows a graph of % Tumor growth inhibition (%TGI) in A375 Xenograft mice dosed 50mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/kg BID.
  • %TGI % Tumor growth inhibition
  • Figure 3 shows a graph of plasma concentration (log nM) against pERK % inhibition in female nu/nu mice implanted with Colo205 tumor cells. Mice were given a single dose of 2.5, 5, 10, or 25 mg/kg.
  • Figure 4 shows a graph of plasma concentration (ng/mL) against time (hours) in humans after administration of a single dose 2mg (2 x lmg capsules), 4mg (4 x lmg capsules) or 6mg (6 x lmg capsules).
  • Figure 5 is a graph of a powder x-ray diffraction (PXRD) pattern of N-(S)-(3 ,4-difluoro-2 -(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide Form A, generated using a Inel XRG-3000 diffractometer.
  • the graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 ⁇ in degrees.
  • Figure 6 is a graph of a modulated Differential Scanning Caiorimetry (DSC) thermogram of N-(S)-(3,4-difluoro- 2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide Form A generated using a TA Instruments differential scanning calorimeter Q1000.
  • the graph plots the normalized heat flow in units of Watts/gram (W/g) versus the measured sample temperature in °C.
  • Figure 7 is a graph of the PXRD patterns of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxypheny I)-I -(2, 3 -dihydroxypropyl)cyclopropane-l -sulfonamide Form A (top) and N-(S)-(3,4-difluoro-2-(2-fluoro- 4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3-dihydroxypropyl)cycIopropane- 1 -sulfonamide amorphous (bottom), generated using a Inel XRG-3000 diffractometer.
  • the graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 ⁇ in degrees.
  • Figure 8 shows a Dynamic Vapor Sorption/Desorption (DVS) isotherm of N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)- 1 -(2,3-dihydroxypropyl)cyclopropane- 1 -sulfonamide Form A generated using a VTI SGA-100 Vapor Sorption Analyzer.
  • VPS Dynamic Vapor Sorption/Desorption
  • Figure 9 shows a Thermogravimetry (TG) thermogram of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide Form A) generated using a TA Instrument 2950 thermogravimetric analyzer.
  • TG Thermogravimetry
  • Figure 10(a) and Figure 10(b) show growth arrest of Log phase dividing A375 cells exposed to increasing concentrations of N-(S)-(3 ,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide. Cells were analyzed for ATP content. 100% growth arrest was determined using l ⁇ M N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane- 1 -sulfonamide.
  • Figure 11 shows a 48 hr AK assay in A375 cells.
  • Log phase dividing A375 cells were exposed to N-(S)-(3,4- difluoro-2 -(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2 ,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide and PD-325901 for 48 hr and analyzed for AK release.
  • Figure 13 A shows inhibition of growth of human colorectal carcinoma Colo205 cells, with GI 50 values at 6 nM and 11 nM respectively.
  • Figure 13B shows inhibition of growth of A375 cells with GI 50 values at 5 nM and 22 nM.
  • Figuresl4A and Figure 14B show the effect of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide on cell cycle progression, demonstrating that exposure of A375 cells to N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide causes arrest in the Gl phase of the cell cycle, indicated by the depletion of cells in both the G2 and S phases.
  • Figure ISA and Figure ISB show the effect of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide on the stomach cancer (gastric adenocarcinoma) cell line AGS after 3 days (Figure 15A) and 6 days ( Figure 15B).
  • the y axis is the cell number relative to vehicle and the x axis is uM of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide.
  • Figure 16 shows the mean liver weights in tumor bearing mice after treatment with N-(S)-(3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxvpropyl)cyclopropane-1-sulfonamide (2mg/kg, once daily, po; 10mg/kg, once daily, po and 50mg/kg, once daily, po).
  • Figure 17 shows liver tumor weights in tumor bearing mice after treaement with N-(S)-(3,4-difluoro-2-(2-fluoro- 4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyI)cyclopropane-l -sulfonamide (2mg/kg, once daily, po; 10mg/kg, once daily, po and 50mg/kg, once daily, po).
  • Figure 18 shows the average tumor weights in after treaement with N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide (2mg/kg; 10mg/kg; and 50mg/kg).
  • Figure 19 shows the inhibition of Hs746t Cell proliferation in a graph of cell number (relative to vehicle) vs concentration of N-(S)-(3 ,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2 ,3 - dihydroxypropyl)cyclopropane- 1 -sulfonamide.
  • Figure 20A depicts a graph comparing the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyI)- 1 -(2,3-dihydroxypropyl)cyclopropane- 1 -sulfonamide at day 5 of treatment of non-small cell lung cancer (NSCLC) MV522 cells.
  • NSCLC non-small cell lung cancer
  • Figure 20B is a graph demonstrating the respective apoptosis levels at increasing concentrations N-(S)-(3,4- difluoro-2 -(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide at day 5 of treatment of non-small cell lung cancer (NSCLC) H358 cells.
  • NSCLC non-small cell lung cancer
  • Figure 20C is a graph demonstrating the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2 ,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide at day 6 of treatment of non-small cell lung cancer (NSCLC) A549 cells.
  • NSCLC non-small cell lung cancer
  • Figure 20D is a graph demonstrating the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2 ,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide at day 5 of treatment of non-small cell lung cancer (NSCLC) H727 cells.
  • NSCLC non-small cell lung cancer
  • Figure 20E is a graph demonstrating the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fIuoro-4-iodophenylamino)-6-methoxypheny I)- 1 -(2 ,3 -dihydroxypropyljcyclopropane- 1 -sulfonamide at day
  • Figure 20F is a graph demonstrating the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxvpropyl)cyclopropane-1-sulfonamide at day
  • Figure 20G is a graph demonstrating the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxypheny I)- 1 -(2,3-dihydroxypropyl)cyclopropane- 1 -sulfonamide at day 5 of treatment of colon HUH7 Hepatoma cells.
  • Figure 20H is a graph depicting the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide at day 5 of treatment of Sarcoma U2-OS cells.
  • Figure 201 is a graph demonstrating the respective apoptosis levels at increasing concentrations of N-(S)-(3,4- difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide at day 5 of treatment of Glioma D37 cells.
  • Figure 21 shows the selectivity of Compound A towards MEKl and MEK2 against a pane of 205 enzymes at 10 ⁇ M.
  • Cell lines were Colo205, A375, A431 and HT-29.
  • Figure 22 is a graph showing the increases in paw volume in each of the treatment groups and the reduction in edema relative to vehicle control, after dosing the rats with 6, 20, 60, and 200 mg/kg of N-(S)-(3,4-difluoro-2-(2-fluoro- 4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide in Rat Carrageenan Paw Edema Model.
  • Figure 23 A shows inhibition of swelling in adjuvant induced arthritis model, in the acute phase for rats treated with 2, 6 and 20mg/kg of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane- 1 -sulfonamide.
  • Figure 23B shows inhibition of swelling in adjuvant induced arthritis model, in the delayed phase for rats treated with 2, 6 and 20mg/kg of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane- 1 -sulfonamide .
  • Figure 24 shows mean arthritic scores in Collagen- Antibody Induced- Arthritis (CAIA) Mice treated with 1, 3 & 10 mg/kg QD N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane- 1 -sulfonamide.
  • CAIA Collagen- Antibody Induced- Arthritis
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds. Where substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl includes optionally substituted alkyl.
  • the compounds presented herein may possess one or more stereocenters and each center may exist in the R or S configuration, or combinations thereof. Likewise, the compounds presented herein may possess one or more double bonds and each may exist in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible stereoisomers, regioisomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds presented herein include all separate configuration stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • bond or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , - CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc).
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons (except in those instances where macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA and the like).
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 . . . C 1 -C x .
  • a group designated as 11 C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the ranges C 1 -C 2 and C 1 -C 3 .
  • ' 1 C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iro-butyl, sec-butyl, and f-butyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
  • heteroatom or “hetero” as used herein, alone or in combination, refer to an atom other than carbon or hydrogen. Heteroatoms are may be independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • alkyl refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl- 1-butyl, 2-methy 1-3 -butyl, 2,2-dimethyl-1-propyl, 2-methyl-l -pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1-butyl, 3,3-dimethyl-l -butyl, 2-ethyl-I-butyl, n-butyl, isobutyl, sec-
  • C 1 -C 6 alkyl or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • the "alkyl” is substituted. Unless otherwise indicated, the “alkyl” is unsubstititued.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, or two to about six carbon atoms.
  • C 2 -C 6 alkenyl or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • the "alkenyl” is substituted. Unless otherwise indicated, the “alkenyl” is unsubstititued.
  • alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, or from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • the "alkynyl” is substituted. Unless otherwise indicated, the “alkynyl” is unsubstititued.
  • heteroalkyl refers to alkyl, alkenyl and alkynyl structures respectively, as described above, in which one or more of the skeletal chain carbon atoms (and any associated hydrogen atoms, as appropriate) are each independently replaced with a heteroatom (i.e.
  • haloalkyl refers to alkyl, alkenyl and alkynyl groups respectively, as defined above, in which one or more hydrogen atoms is replaced by fluorine, chlorine, bromine or iodine atoms, or combinations thereof.
  • two or more hydrogen atoms may be replaced with halogen atoms that are the same as each another (e.g. difluoromethyl); in other embodiments two or more hydrogen atoms may be replaced with halogen atoms that are not all the same as each other (e.g. 1-chloro-1-fluoro-1- iodoethyl).
  • Non-limiting examples of haloalkyl groups are fluoromethyl, chloromethyl and bromoethyl.
  • a non-limiting example of a haloalkenyl group is bromoethenyl.
  • a non-limiting example of a haloalkynyl group is chloroethynyl.
  • carbon chain refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl group, which is linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the "chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
  • cycle refers to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexane, pyridine, pyran and pyrimidine are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.
  • fused refers to cyclic structures in which two or more rings share one or more bonds.
  • cycloalkyl refers to a saturated, hydrocarbon monoradical ring, containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, though may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl).
  • a numerical range such as “C 3 -C 6 cycloalkyl” or “C 3-6 cycloalkyl” means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., is cyclopropyl, cyclobutyl, cyclopentyl or cyclohepty, although the present definition also covers the occurrence of the term " cycloalkyl " where no numerical range is designated.
  • the term includes fused, non-fused, bridged and spiro radicals.
  • a fused cycloalkyl may contain from two to four fused rings where the ring of attachment is a cycloalkyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. Examples include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo [2.2.1] heptyl and adamantyl ring systems. Illustrative examples include, but are not limited to the following moieties: O O - - and the like.
  • the "cycloalkyl” is substituted. Unless otherwise indicated, the “cycloalkyl” is unsubstititued.
  • the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • the terms include fused, non-fused, bridged and spiro radicals.
  • a fused non-aromatic heterocyclic radical may contain from two to four fused rings where the attaching ring is a non-aromatic heterocycle, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • Fused ring systems may be fused across a single bond or a double bond, as well as across bonds that are carbon-carbon, carbon-hetero atom or hetero atom-hetero atom.
  • the terms also include radicals having from three to about twelve skeletal ring atoms, as well as those having from three to about ten skeletal ring atoms. Attachment of a non-aromatic heterocyclic subunit to its parent molecule can be via a heteroatom or a carbon atom. Likewise, additional substitution can be via a heteroatom or a carbon atom.
  • an imidazolidine non-aromatic heterocycle may be attached to a parent molecule via either of its N atoms (imidazolidin-1-yl or imidazoiidin-3-yl) or any of its carbon atoms (imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl),
  • non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • Examples include, but are not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyr ⁇ olinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,
  • the terms also include all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • the "non-aromatic heterocyclyl” or “heteroalicyclyl” is substituted. Unless otherwise indicated, the “non-aromatic heterocyclyl” or “heteroalicyclyl” is unsubstititued.
  • aryl refers to an aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non-fused aryl rings.
  • a fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • aryl includes fused and non-fiised rings containing from six to about twelve ring carbon atoms, as well as those containing from six to about ten ring carbon atoms.
  • a non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a non-fused bi-aryl group includes biphenyl.
  • the "aryl” is substituted. Unless otherwise indicated, the "aryl" is unsubstititued.
  • heteroaryl refers to an aromatic monoradicals containing from about five to about twenty skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but not limited to these atoms and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • heteroaryl includes fused and non-fused heteroaryl radicals having at least one heteroatom.
  • heteroaryl also includes fused and non-fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms. Bonding to a heteroaryl group can be via a carbon atom or a heteroatom.
  • an imidazole group may be attached to a parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl).
  • a heteroaryl group may be further substituted via any or all of its carbon atoms, and/or any or all of its heteroatoms.
  • a fused heteroaryl radical may contain from two to four fused rings where the ring of attachment is a heteroaromatic ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • a non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and a non-fused bi- heteroaryl group includes bipyridinyl.
  • heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyL purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazoiinyl, quinoxalinyl, triazolyl,
  • heteroaryl is substituted. Unless otherwise indicated, the “heteroaryl” is unsubstititued.
  • heterocyclyl refers collectively to heteroalicyclyl and heteroaryl groups.
  • the number of carbon atoms in a heterocycle is indicated (e.g., C r C 6 heterocycle), at least one non-carbon atom (the heteroatom) must be present in the ring.
  • Designations such as “C 1 -C 6 heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring.
  • 4-6 membered heterocycle refers to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
  • a four, five, or six membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms.
  • those two or more heteroatoms can be the same or different from one another.
  • Non-aromatic heterocyclic groups include groups having only three atoms in the ring, while aromatic heterocyclic groups must have at least five atoms in the ring. Bonding (i.e.
  • heterocycle attachment to a parent molecule or further substitution) to a heterocycle can be via a heteroatom or a carbon atom.
  • heterocyclyl is substituted.
  • heterocycyl is unsubstititued.
  • halogen halo or halide as used herein, alone or in combination refer to fluoro, chloro, bromo and/or iodo.
  • amino refers to the monoradical -NH 2 .
  • alkylamino refers to the monoradical -NH(alkyl) where alkyl is as defined herein.
  • dialkylamino refers to the monoradical -N(alkyl)(alkyl) where each alkyl may be identical or non-identical and is as defined herein.
  • diamino alkyl refers to an alkyl group containing two amine groups, wherein said amine groups may be substituents on the alkyl group which may be amino, alkylamino, or dialkylamino groups, or wherein one or both of said amine groups may form part of an alkyl chain to form -alkylene-N(H or alkyl)-alkylene-N(H or alkyl or alkylene-)(H or alkyl or alkylene-).
  • hydroxy refers to the monoradical -OH.
  • cyano as used herein, alone or in combination, refers to the monoradical -CN.
  • cyanomethyl as used herein, alone or in combination, refers to the monoradical -CH 2 CN.
  • nitro refers to the monoradical -NO 2 .
  • oxy refers to the diradical -O-.
  • alkoxy refers to an alkyl ether radical, -O-alkyl, including the groups -O-aliphatic and -O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • sulfamide refers to the diradical group -NH-S(O) 2 -NH-.
  • reactant refers to a nucleophile or electrophile used to create covalent linkages. It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, the radical arylalkyl is attached to the structure in question by the alkyl group.
  • MEK inhibitor refers to a compound that exhibits an IC 50 with respect to MEK activity, of no more than about 100 ⁇ M or not more than about 50 ⁇ M, as measured in the Mekl kinase assay described generally herein.
  • IC 50 is that concentration of inhibitor which reduces the activity of an enzyme (e.g., MEK) to half-maximal level. Compounds described herein have been discovered to exhibit inhibition against MEK.
  • Compounds of the present invention preferably exhibit an IC 50 with respect to MEK of no more than about 10 ⁇ M, more preferably, no more than about 5 ⁇ M, even more preferably not more than about 1 ⁇ M, and most preferably, not more than about 200nM, as measured in the Mekl kinase assay described herein.
  • subject encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • effective amount refers to an amount of at least one agent or compound being administered that is sufficient to treat or prevent the particular disease or condition.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate "effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the terms "substantially free of water” and “substantially free of solvent” as used herein, refer to crystalline polymorph forms comprising less than 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1 or 2% by weight of water or solvent respectively.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
  • topical and rectal administration Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • the compounds and compositions described herein are administered orally.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutical composition refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • agonist refers to a molecule such as a compound, a drug, an enzyme activator or a hormone modulator which enhances the activity of another molecule or the activity of a receptor site.
  • antagonist refers to a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone modulator, which diminishes, or prevents the action of another molecule or the activity of a receptor site.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • module refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist and an antagonist.
  • pharmaceutically acceptable derivative or prodrug refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of formula ⁇ , which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
  • a "prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of Formulas I.
  • the amino acid residues contemplated include but are not limited to the 20 naturally- occurring amino acids.
  • Suitable amino acids include 4-hydroxyproline, hydroxyzine, demosine, isodemosine, 3-methyl histidine, norvaline, ⁇ -alanine, ⁇ - aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are well known in the art.
  • prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N- Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.
  • Various forms of prodrugs are well known in the art. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
  • prodrugs include, but are not limited to, the following groups and combinations of these groups; amine derived prodrugs:
  • Hydroxy prodrugs include, but are not limited to acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfide containing esters.
  • pharmaceutically acceptable salt includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Compounds described may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorides, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,
  • metaphosphate methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, oxalates, palmoate, pectinate, persulfate, phenylacetates, phenylpropionates, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, propionates, phthalate, , phenylbutyrate, propanesulfonate, pyrophosphates, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate and xylenesulfonate.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethano ⁇ amme, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they may contain. Water or oil-soluble or dispersible products may be obtained by such quaternization. See, for example, Berge et al., supra. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • enhancement means to increase or prolong either in potency or duration a desired effect.
  • enhancing refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that at least one of the compounds described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that at least one of the compounds described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the compounds described herein will be co- administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different tunes in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds of the invention and the other agent(s) are administered in a single composition.
  • compounds of the invention and the other agent(s) are admixed in the composition.
  • the term "metabolite,” as used herein, refers to a derivative of a compound which is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • Z is H or F
  • X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF 3 ;
  • R 0 is H, F, Cl, Br, I, CH 3 NH-, (CHj) 2 N-, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, monosubstituted phenyl, O(C 1 -C 4 alkyl),
  • G 1 is C 1 -C 6 alkyl optionally substituted with one amino, C 1 -C 3 alkylamino, or dialkylamino group, said dialkylamino group comprising two C 1 -C 4 alkyl groups which may be identical or non-identical; or Gi is a C 3 -C 8 diamino alkyl group;
  • R la is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C r C 3 alkoxy, where said cyclopropoxy group or the C 1 - C 3 alkyl moieties of said C 1 - C 3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 - alkyl groups within said C r C 4 alkoxy are optionally further substituted with a second OH group; R lb is CH(CH 3 )-C 1 .
  • R 10 is (CH 2 ⁇ O m R'; where m is 0 or 1 ; and where when m is 0, n is 1 or 2; when m is l, n is 2 or 3;
  • R' is Ci-C 6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6 cycloalkyl;
  • R ld is C(A)(A 1 )(B)-;
  • B is H or CM alkyl, optionally substituted with one or two OH groups;
  • a and A' are independently H or C 1 . 4 alkyl, optionally substituted with one or two OH groups; or
  • R 2 and R 3 are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
  • R 4 is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, »-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoy
  • R 6 Is H, F, Cl or methyl; Ar 1 is
  • U and V are, independently, N, CR 2 or CR 3 ;
  • R 2 , R 3 and R 4 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, 5ec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazoI-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4- thiadiazolyl, 5-methyl-l,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrroIidinylcarbonylamino, and methyl
  • R 5 and R 6 are, independently, H, F, Cl or methyl; Ar 2 is
  • U is -NH-, -NCH 3 - or -O-;
  • R 7 and R 8 are, independently, H, F, Cl, or methyl.
  • the invention provides a compound of formula I, where G is Gi or G 2 . In other embodiments, G is G 1 . In further or additional embodiments, G is G 2 . In some embodiments, the invention provides a compound of formula I, where G is R 18 , R lb , R 10 , R ld , R le , Ar 1 , Ar 2 or Ar 3 . In further or additional embodiments, G is R 1a , R 1h , R lc , Rj d or R le . In further or additional embodiments, G is R Ja . In further or additional embodiments, G is R lb . In further or additional embodiments, G is R 1c . In further or additional embodiments, G is R ]d .
  • G is R le . In further or additional embodiments, G is Ar h Ar 2 or Ar 3 . In further or additional embodiments, G is Ar 1 . In further or additional embodiments, G is Ar 2 . In further or additional embodiments, G is Ar 3
  • Z is H. In some embodiments, Z is F. In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is CH 3 , In some embodiments, X is CH 2 OH. In some embodiments, X is CH 2 F. In some embodiments, X is CHF 2 . In some embodiments, X is CF 3 . In some embodiments, X is F, Cl, or CH 3 .
  • G is G 1 or G 2
  • X is F, Cl, or CH 3
  • G is G 1 or G 2
  • R 0 is F, Cl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl group and the C 1 -C 4 alkyl moiety of said C 1 -C 4 alkoxy group optionally substituted with F, Cl, OCH 3 , or OCH 2 CH 3 .
  • G is G 1 or G 2
  • R 0 is H, F, Cl, C r C 4 alkyl, methoxy, ethoxy, or 2-methoxy-ethoxy.
  • G 1 is N-methyl-2-aminoethyl.
  • G 2 is 1-piperidyl, 2-piperidyl, 3-piperidyl, or 4-piperidyl. In further or additional embodiments, G 2 is morpholyl, 1-piperazyl, or 2-piperazyl.
  • G is Ru, R 1b , R 10 , R 1d , R i e , Ar 1 , Ar 2 or Ar 3 and X is F, Cl, or CH 3 .
  • G is R la , R lb , R 10 , R ld , R I ⁇ AT I , Ar 2 or Ar 3 , X is F, Cl, or CH 3 and Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl
  • G is R la , R lb , R lc , R 1d , R 1 « Ar 1 , Ar 2 or Ar 3 , X is F, Cl, or CH 3 , Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl and Z is H or F
  • G is R la , R 1b , R lc , R 1d , R le , Ar 1 , Ar 2 or Ar 3 and R 0 is F, Cl, C 1 -C 4 alkyl or C 1 - C 4 alkoxy, said C 1 -C 4 alkyl group and the C 1 -C 4 alkyl moiety of said C 1 -C 4 alkoxy group optionally substituted with F, Cl, OCH 3 , or OCH 2 CH 3 .
  • G is R la , R ]b , R 10 , R 1d , R 1e , Axi, Ar 2 or Ar 3 and R 0 is H, F, Cl, C 1 -C 4 alkyl, methoxy, ethoxy, or 2- methoxy-ethoxy.
  • G is R la ; and Z is F. In further or additional embodiments, G is R la where R ]a is CH 3 , R 0 is H; and Y is Br, I, CF 3 , or CH 3 . In some embodiments, G is R lb and Z is F. In further or additional embodiments, G is R lb , Z is F, and R 0 is H, F, or OCH 3 . In further or additional embodiments, G is R lb , Z is F, R 0 is H, F, or OCH 3 , and X is F or CH 3 .
  • G is R lb , Z is F, R 0 is H, F, or OCH 3 , X is F or CH 3 and Y is Br, I or CH 3 .
  • G is R lb where R £b is C 3 -C 6 cycloalkyl.
  • G is R 1b where R lb is substituted C 3 -C 6 cycloalkyl.
  • G is R 1b where R !b is unsubstituted C 3 - C 6 cycloalkyl.
  • G is R lb where R lb is unsubstituted C 3 -C 6 cycloalkyl and R 0 is H. In further or additional embodiments, G is R lb where R [b is isopropyl or cyclopropyl.
  • G is R ]c , and Y is I, Br, CH 3 , or CF 3 .
  • G is R 10 , Y is I, Br, CH 3 , or CF 3 , and Z is F.
  • G is R 10 , Y is I, Br, CH 3 , or CF 3 , Z is F and m is zero.
  • G is R fd and R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert- butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino.
  • G is R ldj
  • R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, ⁇ -butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino and X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl.
  • G is R ]d
  • R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino
  • X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl
  • Y is I, Br, CI, or mono-, di- or tri- fluoromethyl.
  • G is R 1d
  • R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec- butyl, ir ⁇ -buty], tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino
  • X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl
  • Y is I, Br, Cl, or mono-, di- or tri- fluoromethyl
  • Z is H or F.
  • G is R ld and R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2- metnoxy- ethoxy.
  • G is R 1 d , R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2- methoxy-ethoxy and X is F, Cl, or CH 3 .
  • G is R ld , R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2- methoxy-ethoxy, X is F, Cl, or CH 3 and Y is I, Br, Cl, or mono-, di- or tri- fluoromethyl.
  • G is R ld , R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2- methoxy-ethoxy, X is F, Cl, or CH 3 , Y is I, Br, Cl, or mono-, di- or tri- fluoromethyl and Z is H or F.
  • G is R 1d and R 0 is H; X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl.
  • G is R 1d , R 0 is H; X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl and Y is I, Br, Cl, or mono-, di- or tri- fluoromethyl.
  • G is R 1d , R 0 is H; X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl, Y is I, Br, Cl, or mono-, di- or tri- fluoromethyl and Z is H or F.
  • G is R ld where R ld is C(A)(A') is C r C 6 cycloalkyl. In further or additional embodiments, G is R ld where R ld is C(A)(A 1 ) is C 1 -C 6 cycloalkyl and B is H.
  • G is R 1d where R ld is C(A)(A') is C 1 -C 6 cycloalkyl and B is methyl, ethyl, 2-hydroxyethyl, w-propyl, 3- hydroxypropyl, 2,3- dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 1-methyl-2-hydroxy ethyl, n-butyl, sec-butyl, isobutyl, or 2- hydroxymethyl-3 -hydroxy propyl.
  • G is R 1d where R ld is C(A)(A') is C 1 -C 6 cycloalkyl and B is 2,3- dihydroxypropyl or 3,4-dihydroxybutyl.
  • G is R ⁇ where R 1d is C(A)(A') is C 1 -C 6 cycloalkyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the R configuration.
  • G is R ld where R ld is C(A)(A') is C 1 -C 6 cycloalkyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the S configuration
  • G is R Jd where R 1d is C(A)(A') is C 1 -C 6 cycloalkyl and B is methyl, optionally substituted with one OH group, or C 2 -C 4 alkyl, optionally substituted with one or two OH groups.
  • G is R ]d where R ⁇ is C(A)(A') is C 1 -C 6 cycloalkyl and R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, (so-butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino.
  • G is R ]d where R 1d is C(A)(A') is C 1 -C 6 cycloalkyl and R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2- methoxy-ethoxy.
  • G is R 1(i where R ld is C(A)(A 1 ) is C r C 6 cycloalkyl and R 0 is H; X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl.
  • the invention provides a composition comprising a compound of formula I, where G is R ld where R 1d is C(A)(A') is C r C 6 cycloalkyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the R configuration, which is substantially free of the S isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R Jd where R ld is C(A)(A') is C 1 -C 6 cycloalkyl and B is 2,3-dihydroxypropyl, in which the chiral carbon in B is in the R configuration, which is substantially free of the S isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R, d where R 1d is C(A)(A') is C 1 -C 6 cycloalkyl and B is 3,4- dihydroxybutyl, in which the chiral carbon in B is in the R configuration, which is substantially free of the S isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R 1d where R ld is C(A)(A') is C 1 -C 6 cycloalkyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the S configuration, which is substantially free of the R isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R ld where R !d is C(A)(A') is C 1 - C 6 cycloalkyl and B is 2,3-dihydroxypropyl, in which the chiral carbon in B is in the S configuration, which is substantially free of the R isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R ld where R ld is C(A)(A') is C 1 -C 6 cycloalkyl and B is 3,4-dihydroxybutyl, in which the chiral carbon in B is in the S configuration, which is substantially free of the R isomer.
  • G is R 1d where R ld is C(A)(A') is cyclopropyl. In further or additional embodiments, G is R ld where R 1 d is C(A)(A 1 ) is cyclopropyl and B is H.
  • G is Ru where R ld is C(A)(A') is cyclopropyl and B is methyl, ethyl, 2-hydroxyethyl, n-propyl, 3- hydroxypropyl, 2,3- dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 1-methyl-2-hydroxy ethyl, n-butyl, sec-butyl, isobutyl, or 2- hydroxymethyl-3-hydroxy propyl.
  • G is R ld where R ld is C(A)(A 1 ) is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl.
  • G is R ld where R 1d is C(A)(A') is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the R configuration.
  • G is R ld where R ld is C(A)(A') is cyclopropyl and B is 2,3- dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the S configuration.
  • G is R ld where R ⁇ is C(A)(A') is cyclopropyl and B is methyl, optionally substituted with one OH group, or C 2 -C 4 alkyl, optionally substituted with one or two OH groups.
  • G is R ld where R ld is C(A)(A') is cyclopropyl and R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, wo-butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino.
  • G is R ld where R ⁇ is C(A)(A') is cyclopropyl and R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2- methoxy-ethoxy.
  • G is R [d where R ld is C(A)(A 1 ) is cyclopropyl and R 0 is H; X is F, Cl, CH 3 , or mono-, di- or tri- fluoromethyl.
  • the invention provides a composition comprising a compound of formula I, where G is R !d where R 1d is C(A)(A') is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the R configuration, which is substantially free of the S isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R ld where R 1d is C(A)(A') is cyclopropyl and B is 2,3-dihydroxypropyl, in which the chiral carbon in B is in the R configuration, which is substantially free of the S isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R ld where R ld is C(A)(A') is cyclopropyl and B is 3,4-dihydroxybutyl, in which the chiral carbon in B is in the R configuration, which is substantially free of the S isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R 1d where R ld is C(A)(A') is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral carbon in B is in the S configuration, which is substantially free of the R isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R ld where R ld is C(A)(A') is cyclopropyl and B is 2,3- dihydroxypropyl, in which the chiral carbon in B is in the S configuration, which is substantially free of the R isomer.
  • the invention provides a composition comprising a compound of formula I, where G is R 1d where R !d is C(A)(A') is cyclopropyl and B is 3,4-dihydroxybutyl, in which the chiral carbon in B is in the S configuration, which is substantially free of the R isomer.
  • G is R 1e and n is 1.
  • G is R 1 .
  • R 0 is H
  • R 4-6 are H
  • R 2 and R 3 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 , O CH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, jec-butyl, tert-b ⁇ tyl, and methylsulfonyl
  • X is F and Y is I.
  • G is Ar : where Ar 1 Is phenyl optionally substituted with one group selected from acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyI, 5 -methyl- 1,3,4- thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N- pyrrolidinylcarbonylamino, and methylsulfonyl, optionally substituted with 1-3 substituents selected independently from F, Cl, and CH 3 .
  • G is Ar 1 where Ar 1 Is phenyl optionally substituted with one group selected from acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5- methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyI, 5 -methyl- 1,3,4- thiadiazolyl, IH-tetrazolyl, N-morpholylcarbonylamino, N- morpholylsulfonyl, N- pyrrolidinylcarbonylamino, and methylsulfonyl, optionally substituted with 1-3 substituents selected independently from F, Cl, and CH 3 , R 0 is H, X is F, Cl, or methyl and Y is Br, I, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl
  • G is Ar 1 where Ar 1 is and where R 2 and R 3 are, independently, H, F, Cl, CH 3 , CF 3 , OCH 3 . In further or additional embodiments, G is Ar 1 where Ar 1
  • G is Ar 1 where Ar 1 Is phenyl or mono-substituted phenyl. In further or additional embodiments, G is Ar 1 where Ar t is phenyl or mono-substituted phenyl, X is F or CH 3 , Y is I, Br, or Cl, Z is F; and R 0 is F, methyl, ethyl, methoxy, or 2-methoxy-ethoxy.
  • G is Ar 1 where U is N or CR 2 and V is N. In further or additional embodiments, G is Ar 1 where U is N or CR 2 and V is CR. In further or additional embodiments, G is Ar 1 where U is N or CR 2 , V is CR, R 0 is H, X is F, Cl, or methyl and Y is Br, I, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, cyclopropyl, OCH 3 , OCH 2 CH 3 or SCH 3 .
  • G is Ar 2 where Ar 2 is where R 7 is H or methyl and R 8 is H, acetamido,
  • G is Ar 2 where Ar 2 is where R 7 is H or methyl, R 8 is
  • R 0 is H, X is F, Cl, or methyl, Y is Br, I, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, cyclopropyl, OCH 3 , OCH 2 CH 3 or SCH 3 and Z is F.
  • R 0 is H.
  • R 0 is H, X is F or Cl and Y is Br, I, CH 2 CH 3 or SCH 3
  • G is Ar 3 where U is -O-.
  • G is R 1a , where R u is defined as above. In further or additional embodiments, G is R 1a , and R c is H, where R ]a is defined as above. In further or additional embodiments, G is Rj a and R 0 is as defined above, other than H, and R 13 is defined as above. In further or additional embodiments, G is R Ia , where R u is methyl, monohalomethyl, C r C 3 alkoxymethyl, or cyclopropoxymethyl.
  • G is R 1 «, where R u is methyl, monohalomethyl, C 1 -C 3 alkoxymethyl, or cyclopropoxy methyl and where R 0 is F, CI, C 1 -C 3 alkyl, monochloro C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoro methoxy, or 2-methoxy-ethoxy.
  • R 0 is F, CI, C 1 -C 3 alkyl, monochloro C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoro methoxy, or 2-methoxy-ethoxy.
  • G is R] b , where R n , is defined as above.
  • G is Rn,, and R 0 is H, where R n , is defined as above.
  • G is R lb , R 0 is H and Z is F, where Rn is defined as above.
  • G is R 1b and R 0 is as defined above, other than H, and Ru, is defined as above.
  • G is R 1b , where R ⁇ is isopropyl, 2-butyl, 2-pentyI, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, all optionally substituted with 1 or 2 substituents selected independently from F, Cl, OH, and OCH 3 ; Y is Br, I, methyl, or trifluoromethyl.
  • G is R 1b , where R ]b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with 1 or 2 substituents selected independently from F 1 Cl, OH, and OCH 3 ; Y is Br, I, methyl, or trifluoromethyl; and R 0 is F, Cl, C 1 -C 3 alkyl, monochloro CpC 3 alkyl, C x -C 3 alkoxy, trifluoromethoxy, or 2-methoxy- ethoxy.
  • G is R ]b , where R ]b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, all optionally substituted with one Cl or with 1 or 2 OH groups; and Y is Br, I, methyl, or trifluoromethyl.
  • G is Rn, where R 1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, all optionally substituted with one Cl or with 1 or 2 OH groups; Y is Br, I, methyl, or trifluoromethyl; and R 0 is F, Cl, C 1 -C 3 alkyl, monochloro C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethoxy, or 2- methoxy-ethoxy.
  • G is R 1c , where R jc is defined as above, In further or additional embodiments, G is R 10 , and R 0 is H, where R !c is defined as above. In further or additional embodiments, G is R 1c and R 0 is as defined above, other than H, and R lc is defined as above.
  • G is R 10 , and R 0 is H, where R 1c is (CH 2 ⁇ O m R', where m is 0 or 1, n is 2 or 3 when m is 1, and n is 1 or 2 when m is 0, and R' is C 1 -C 6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6 cycloalkyl.
  • m is zero, n is 1 or 2, and R' is C 1 -C 4 alkyl, optionally substituted as described above.
  • m is 1, n is 2 or 3, and R' is C 1 -C 4 alkyl, optionally substituted as described above.
  • m is zero, n is 1 or 2, and R' is CrC 4 alkyl, optionally substituted with 1 -3 groups selected from OH, OCH 3 , Cl, and cyclopropyl.
  • G is R ⁇ , where R 1d is defined as above. In further or additional embodiments, G is R 1d , and R 0 is H, where R !d is defined as above. In further or additional embodiments, G is R ⁇ and R 0 is as defined above, other than H, and R ⁇ is defined as above.
  • G is R 1d , and R 0 is H, where R ⁇ is C(A)(A')(B)- where B, A, and A' are, independently, H or C 1-4 alkyl, optionally substituted with one or two OH groups or halogen atoms, or A and A 1 , together with the carbon atom to which they are attached, form a 3- to 6- member saturated ring, said ring optionally containing one or two heteroatoms selected, independently, from O, N, and S and optionally substituted with one or two groups selected independently from methyl, ethyl, fluoro, chloro, bromo and iodo.
  • G is R lB where R le is defined as above.
  • G is R le , and R 0 is H, where R !e is defined as above.
  • G is R 1 . and R 0 is as defined above, other than H, and R le is defined as above.
  • G is Ar 1 , where Ar 1 is defined as above. In further or additional embodiments, G is Ar 1 , and R 0 is H, where Ar 1 Is defined as above. In further or additional embodiments, G is Ar 1 and R 0 is as defined above, other than H, and Arjis defined as above.
  • G is Ar 2 , where Ar 2 is defined as above. In further or additional embodiments, G is Ar 2 , and R 0 is H, where Ar 2 defined as above. In further or additional embodiments, G is Ar 2 and R 0 is as defined above, other than H, and Ar 2 is defined as above. In further or additional embodiments, X is F, Cl, or CH 3 ; Y is I, Br, Cl, CF 3 or C 1 -C 3 alkyl, and Z is H or F.
  • X is F, Cl, or CH 3 :
  • Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl
  • Z is H or F
  • X is F, Cl, or CH 3 :
  • Y is I, Br, Cl, CF 3 , or C r C 3 alkyl, Z is H or F, and R 0 is furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, or pyrazolyl.
  • X is F, Cl, or CH 3 :
  • Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl, Z is H or F, and
  • R 0 is F, Cl, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethoxy, or 2- methoxy-ethoxy.
  • R 1 d is cycloalkyl or 1-alkyl-cycloalkyl, in which the 1 -alkyl group is optionally substituted with one or two OH groups or with one or two halogen atoms.
  • R 0 is furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, or pyrazolyl; and Rm is cycloalkyl or 1-alkyl-cycloalkyl, in which the 1-alkyl group is optionally substituted with one or two OH groups or one or two halogen atoms.
  • R )d is cycloalkyl or 1-alkyl-cycloalkyl, in which the 1 -alkyl group is optionally substituted with one or two OH groups, and where Y is Br, I, methyl, or trifluoromethyl.
  • R ld is cycloalkyl or 1-alkyl-cycloalkyl, in which the 1 -alkyl group is optionally substituted with one or two fluorine or chlorine atoms, and where Y is Br, I, methyl, or trifluoromethyl.
  • R 1d is cycloalkyl or (1 -alley l)-cycloalkyl, in which the 1 -alkyl group is optionally substituted with one or two OH groups, and where R 0 ' is F, Cl, C 1 -C 3 alkyl, monochloro C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy.
  • R 1d is tetrahydrofuryl, tetrahydrothienyl, pyrrolidyl, piperidyl, piperazinyl, or morpholyl, each optionally substituted as described above, and where Y is Br, I, methyl, or trifluoromethyl.
  • R !d is oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidyl, piperidyl, piperazinyl, or morpholyl, each optionally substituted as described above, and where Y is Br, I, methyl, or trifluoromethyl.
  • R ld is cyclopropyl or 1-alkyl-cyclopropyl, in which the 1 -alkyl group is optionally substituted with one or two OH groups, and where R 0 ' is F, Cl, methyl, ethyl, chloromethyl, Q-C 2 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy.
  • R ld is 1-(monohydroxyalkyl) cycloalkyl.
  • R ld is 1-(monohydroxyalkyl) cycloalkyl, where R 0 ' is F, Cl, methyl, ethyl, chloromethyl, C 1 -C 2 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy.
  • R ld is 1- (dihydroxyalkyl) cycloalkyl.
  • R 1 d is 1-(dihydroxyalkyl) cycloalkyl, where R 0 ' is F, Cl, methyl, ethyl, chloromethyl, C 1 -C 2 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy.
  • U is CR 2 and V is N. In another more specific, subgeneric embodiment, U and V are both N. In a more specific, subgeneric embodiment, U is CR 2 and V is CR 3 .
  • this invention provides a compound of formula I, where G is Ar 1 and Ar 1 is phenyl or monosubstituted phenyl, R 0 is F, methyl, ethyl, C 1 -C 3 alkoxy, trifluoromethoxy, or 2-methoxy- ethoxy; X is F, Cl, or CH 3 ; Y is I; and Z is F.
  • this invention provides a compound of formula I, where G is Ai 1 , where Ar 1 is phenyl or monosubstituted phenyl, R 0 is halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, all such alkyl, cycloalkyl, alkenyl, and alkynyl groups optionally substituted with 1-3 substituents selected independently from halogen, OH, CN, cyanomethyl, nitro, phenyl, and trifluoromethyl; or R 0 is phenyl, OR 3 , furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, or pyrazolyl.
  • this invention provides a compound of formula I, where A is Ar 1 , where Ar 1 is phenyl or monosubstituted phenyl, R 0 is F, Cl, C 1 -C 3 alkyl, C r C 3 alkoxy, 2-methoxyethoxy, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, trifluoromethyl, phenyl, furyl, or thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, or pyrazolyl; X is F, Cl, or methyl; Y is I, Br, Cl, CF 3 , or C r C 3 alkyl; and Z is F.
  • this invention provides a compound of formula I, where G is Ar 1 , where Ar 1 is phenyl or monosubstituted phenyl, R 0 is H; X is F, Cl, or CH 3 ; Y is Br or I; and Z is F.
  • his invention provides a compound of formula I, where G is Ar 2 , where Ar 2 is 2-thienyl, 2-furyl, 3 -thienyl, 3 -furyl, 2-pyrrolyl, or 3 -pyrrolyl, all optionally substituted with methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen.
  • his invention provides a compound of formula I, where G is Ar 2 , where Ar 2 is 2-thienyl, 2-furyl, 3-thienyI, 3-furyl, 2-pyrrolyl, or 3- pyrrolyl, all optionally substituted with methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen; R 0 is other than H; X is F, Cl, or CH 3 : Y is I, Br, Cl, CF 3 , or C r C 3 alkyl, and Z is H or F.
  • this invention provides a compound of formula I, where G is Ar 2 , where Ar 2 is 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrolyl, or 3-pyrroIyl, all optionally substituted with methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen; R 0 is F, Cl, C 1 -C 3 alkyl, monochloro C 1 - C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethoxy, methyloxy-methoxy, or 2-methoxy-ethoxy; X is F, Cl, or CH 3 : Y is I, Br, Cl, CF 3 , or CpC 3 alkyl, and Z is H or F.
  • his invention provides a compound of formula I, where G is Ar 2 , where Ar 2 is 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrolyl, or 3-pyrrolyl, all optionally substituted with methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen; R 0 is H; X is F, Cl, or CH 3 : Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl, and Z is H or F.
  • his invention provides a compound of formula I, where G is Ar 2 , where Ar 2 is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, or pyrazolyl, all optionally substituted with methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen; R c is H or methoxy; X is F, Cl, or CH 3 : Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl, and Z is H or F.
  • the compound of formula (I), or a pharmaceutical salt thereof is selected from
  • the invention provides a compound of formula I, or a pharmaceutical salt thereof, selected
  • the invention provides a compound of formula I, or a pharmaceutical salt thereof, selected
  • the invention provides a composition comprising a compound of formula I, selected from those shown below, where the 2-OH carbon is in the R configuration, substantially free of the S- isomer.
  • the invention provides a composition comprising a compound of formula I, selected from those shown below, where the 2-OH carbon is in the S configuration, substantially free of the R- isomer.
  • this invention provides a compound of formula I, where Y is phenyl, pyridyl, or pyrazolyl. In another subgeneric embodiment, this invention provides a compound of formula I, where Y is substituted phenyl, pyridyl, or pyrazolyl. In yet another subgeneric embodiment, this invention provides a compound of formula I, where Y is Br or I. In one subgeneric embodiment, this invention provides a compound of formula I, where G is 1-piperidyl, 2- piperidyl, 3-piperidyl, or 4-piperidyl. In another subgeneric embodiment, this invention provides a compound of formula I, where G is 1-piperazyl or 2-piperazyl.
  • this invention provides a compound of formula I, where G is morpholyl. In another subgeneric embodiment, this invention provides a compound of formula I, where G is N-methyl-2-aminoethyl. In one subgeneric embodiment, this invention provides a compound of formula I, where G is N-methyl-3-amino-n-propyl. In another subgeneric embodiment, this invention provides a compound of formula I, where G is (CH 3 ) 2 N-CH 2 CH 2 -NH-(CH 2 ) O -, where n is 1, 2, or 3.
  • this invention provides a compound of formula I, where G is (CH 3 CH 2 ) 2 N-CH 2 CH 2 -NH-(CH 2 ) n -, where n is 1 or 2.
  • this invention provides a compound of formula I, where G is 1-piperidyl, 2-piperidyl, 3- piperidyl, or 4-piperidyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is 1-piperazyl or 2-piperazyl; R 0 is H, halo, or methoxy; X is F; and Y is I
  • this invention provides a compound of formula I, where G is morpholyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is N-methyl-2-aminoethyl; R 0 is H, halo, or methoxy; X is F; and Y is I
  • this invention provides a compound of formula I, where G is N- methyl-3-amino-n-propyl; R 0 is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is (CH 3 ) 2 N-CH 2 CH 2 -NH-(CH 2 ),, ⁇ where n is 1, 2, or 3; R° is H, halo, or methoxy; X is F; and Y is I.
  • this invention provides a compound of formula I, where G is ⁇ CH 3 CH 2 ) 2 N-CH 2 CH 2 -NH-(CH 2 ) n -, where n is 1 or 2; R" is H, halo, or methoxy; X is F; and Y is I.
  • the invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising a compound selected from the group consisting of:
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the compound is in the R configuration. In some embodiments, the compound is in the R configuration, substantially free of the S- isomer. In some embodiments, the compound is in the S configuration. In some embodiments, the compound is in the S configuration,
  • the compound is: . In some embodiments, the compound is: . In some
  • the compound is: . In some embodiments, the compound is:
  • the compound is:
  • Table 1 shows embodiments of this invention which are compounds of formula I, wherein R 0 is as defined herein, G is R 1a where R 1a is as defined in the table and X, Y and Z are defined in the table.
  • Table 2 shows embodiments of this invention which are compounds of formula I, wherein R 0 is as defined herein, G is R 1b where R lb is as defined in the table and X, Y and Z are defined in the table.
  • Table 3 shows embodiments of this invention which are compounds of formula I, wherein R 0 is as defined herein, G is R lc where R lc is as defined in the table and X, Y and Z are defined in the table.
  • Tables 4a and 4b show embodiments of this invention which are compounds of formula I, wheTe G - R ]d , Z is F, X is F and R 1d and R 0 are defined in the table. Each line in the table corresponds to five species which differ only at position Y.
  • Table 5a shows embodiments of this invention which are compounds of formula I, where G is Ar 1 , Ar 2 or R !d , and where R 0 is H, Z is F and G and X are defined in the table.
  • Table 5b shows embodiments of this invention which are compounds of formula I, where G is Ar 1 , Ar 2 or R ld , and where R 0 is H, Z is F and G and X are defined in the table.
  • the starting materials for the synthesis of the compounds as described herein may be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can be synthesized.
  • the compounds described herein, and other related compounds having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4* Ed., VoIs.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • Protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4- dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
  • AllyI blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • Protecting or blocking groups may be selected from:
  • Scheme I above illustrates a method for making the sulfonamide derivatives of formula VI.
  • 1 ,2 Diamine derivative (formula IV) can be easily prepared in two steps from the desired nitro derivatives (formula I).
  • Compounds of formula IV can be reacted with the sulfonyl chloride derivatives (formula V, see next scheme) to form the desired sulfonamide.
  • the 1,2 diamine derivatives IV can be protected to for an imidazolidone (formula VII), before being reacted with the corresponding sulfonyl chloride.
  • Deprotection of the 1 ,2 diamine VIII under basic conditions provided the desired material VI. II.
  • the general route to synthesis compound of general formula V is outlined below
  • Scheme II above shows one example of the preparation of complex sulfonyl chloride.
  • Compound XX can be synthesized from IX, alkylated, and converted to the potassium salt XII. Treatment of the salt with SOCl 2 or POCl 3 affords the desired compounds. Other more specific procedures to prepare unique sulfonyl chloride derivatives are reported in the experimental section.
  • Scheme III above illustrates the preparation of sulfonamide derivatives of general formula XIII.
  • these compounds can be easily obtained by reacting the compound VI with a boronic acid using a palladium catalyst under Suzuki conditions,
  • the compounds described herein may exist as geometric isomers.
  • the compounds described herein may possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • compounds may exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • the compounds described herein may possess one or more chiral centers and each center may exist in the R or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein.
  • the compounds described herein can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • Resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds described herein, or dissociable complexes may be used (e.g., crystalline diastereomeric salts).
  • Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chiral chromatography, or separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981, herein incorporated by reference in its entirety. Labeled compounds of formula I
  • isotopically-labeled compounds of formula I and methods of treating disorders.
  • the invention provides for methods of treating diseases, by administering isotopically-labeled compounds of formula I.
  • the isotopically-labeled compounds of formula I can be administered as pharmaceutical compositions.
  • compounds of formula I also include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, pharmaceutically acceptable salts, thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of formula I for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.
  • isotopes are often easily prepared and detectabilited. Further, substitution with heavier isotopes such as deuterium, i. e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be desirable in some circumstances.
  • isotopically labeled compounds and pharmaceutically acceptable salts thereof can generally be prepared by carrying out procedures described herein, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • compositions can be administered as pharmaceutical compositions.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Base addition salts can also be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like
  • inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, tumeric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-e
  • Solvates of compounds of formula I are solvates of compounds of formula I and methods of treating disorders.
  • the invention provides for methods of treating diseases, by administering solvates of compounds of formula I.
  • the solvates of compounds of formula I can be administered as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Polymorphs of compounds of formula I
  • polymorphs of compounds of formula I and methods of treating disorders.
  • the invention provides for methods of treating diseases, by administering polymorphs of compounds of formula I.
  • the polymorphs of compounds of formula I can be administered as pharmaceutical compositions.
  • the compounds described herein include all their crystalline forms, known as polymorphs.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs may have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the powder x-ray diffraction pattern contains at least about 50% of the peaks shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern contains at least about 70% of the peaks shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern contains at least about 90% of the peaks shown in FIG. 5. In some embodiments, the powder x-ray diffraction pattern is substantially the same the powder x-ray diffraction pattern shown in FIG. 5.
  • the invention also relates to a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyI) cyclopropane- 1 -sulfonamide that exhibits a specific differential scanning calorimetry pattern.
  • the specific differential scannin calorimetry patern is substantially the same as the differential scanning calorimetry pattern shown in FIG. 6.
  • the crystalline polymorph form A has a melting point onset as determined by differential scanning calorimetry at about 143°C.
  • the invention also relates to a polymorphic form of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide made by a method comprising the step of crystallizing amorphous N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide from a solvent.
  • the invention also relates to a polymorphic form of N-(S)-(3,4-difluoro-2- (2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide made by a method comprising the step of crystallizing amorphous N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide from a mixture of hexane and ethyl acetate.
  • the invention also relates to pharmaceutical compositions comprising an effective amount of crystalline polymorph form A of N-(S)-(3 ,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide and a pharmaceutically acceptable carrier or vehicle.
  • Other aspects of the invention relate to a pharmaceutical composition comprising the crystalline polymorph form A and at least one excipient or carrier.
  • (2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide is useful for treating or preventing cancer or an inflammatory disease.
  • the invention further relates to methods for treating or preventing cancer or an inflammatory disease, comprising administering an effective amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide to a subject in need thereof.
  • aspects of the invention relate to methods for the treatment or prophylaxis of an inflammatory disease comprising administering to a subject in need thereof an effective amount of the crystalline polymorph. Further aspects of the invention relate to methods for the treatment or prophylaxis of a proliferative disease comprising administering to a subject in need thereof an effective amount of the crystalline polymorph.
  • Prodrugs of compounds of formula I Also described herein are prodrugs of compounds of formula I and methods of treating disorders. For example, the invention provides for methods of treating diseases, by administering prodrugs of compounds of formula I. The prodrugs of compounds of formula I can be administered as pharmaceutical compositions.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound as described herein which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug a short peptide (polyamino acid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site- specific tissues.
  • the design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J. Physiol. ,
  • prodrug derivatives of compounds described herein can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of formula I with a suitable carbamylating agent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para- nitrophenyl carbonate, or the like.
  • a suitable carbamylating agent such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para- nitrophenyl carbonate, or the like.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. Indeed, some of the herein- described compounds may be a prodrug for another derivative or
  • prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in A dvanced Drug Delivery Reviews 1996, /P, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • the pharmaceutical compositions comprise an effective amount of a compound formula I, or a pharmaceutically acceptable salt, thereof. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof and at least one pharmaceutically acceptable carrier. In some embodiments the pharmaceutical compositions are for the treatment of disorders. In some embodiments the pharmaceutical compositions are for the treatment of disorders in a mammal. In some embodiments the pharmaceutical compositions are for the treatment of disorders in a human.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier.
  • Such compositions may contain adjuvants, excipients, and preservatives, agents for delaying absorption, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizing agents, other carriers, and other inert ingredients. Methods of formulation of such compositions are well-known in the art.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is hi the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.002 to about 6 g/day. In further or additional embodiments the amount of compound of formula I is about 0.005 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 5 g/day.
  • the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily.
  • the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the pharmaceutical composition is for administration to a mammal. In further or additional embodiments, the mammal is human.
  • the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant.
  • the pharmaceutical composition further comprises at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the antineoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is taxol, bortezomib or both.
  • the pharmaceutical composition is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula I.
  • the invention also relates to a composition comprising F .
  • the 2-OH carbon on the compound is in the R configuration.
  • composition is substantially free of the S- isomer of the compound.
  • the compound contains less than 10% of the S- isomer of the compound.
  • the compound contains less than 5% of the S- isomer of the compound.
  • the compound contains less than 1% of the S- isomer of the compound.
  • the compound is in the R configuration.
  • the 2-OH carbon on the compound is in the S configuration.
  • composition is substantially free of the R- isomer of the compound.
  • the compound contains less than 10% of the R- isomer of the compound.
  • the compound contains less than 5% of the R- isomer of the compound.
  • the compound contains less than 1% of the R- isomer of the compound.
  • the compound is in the S configuration.
  • the composition contains at least about 50% of a compound which exhibits a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the In some embodiments, the powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern shown in FIG. 5.
  • the composition contains at least about 75% of a compound which exhibits a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. S.
  • the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the In some embodiments, the powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern shown in FIG. 5,
  • the composition contains at least about 90% of a compound which exhibits a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the In some embodiments, the powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern shown in FIG. 5.
  • substantially all of the compound in the composition exhibits a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. S.
  • the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in FIG. 5.
  • the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the In some embodiments, the powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern shown in FIG. 5.
  • the crystalline polymorph present in the composition has a melting point onset as determined by differential scanning calorimetry at about 143°C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.
  • the composition contains at least about 50% of a compound which exhibits a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in FIG. 6.
  • the crystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 143°C.
  • the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.
  • the composition contains at least about 75% of a compound which exhibits a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in FIG. 6.
  • the crystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 143°C.
  • the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.
  • the composition contains at least about 90% of a compound which exhibits a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in FIG. 6.
  • the crystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 143 °C.
  • the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.
  • substantially all the compound in the composition exhibits a differential scanning calorimetry pattern substantiaily the same as the differential scanning calorimetry pattern shown in FIG. 6.
  • the crystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 143°C.
  • the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.
  • the polymorphic form of N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1 -sulfonamide made by a method comprising the step of crystallizing amorphous N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide.
  • the crystallization step comprises crystallizing from a mixture of ethyl acetate and heptane, for example, a mixture of ethyl acetate and heptane is in a ratio of from about 1-4 parts ethyl acetate to about 2-10 parts heptane or more specifically, a ratio of from about 2 parts ethyl acetate to about 5 parts heptane.
  • the compound is formulated for the immediate release of the compound. In some embodiments, the compound is formulated for the sustained release of the compound. In other embodiments, the compound is formulated for the extended release of the compound.
  • the composition is in a tablet dosage form. In other embodiments, the composition is in a cpasule dosage form.
  • the composition can be made into a capsule or tablet dosage form and a wide range of alternative compositions and manufacturing approaches can be used, References: (1) Remington, The Science and Practice of Pharmacy, 20* Edition, 2000, (2) Pharmaceutical Dosage Forms Tablets Volumes 1-3, 1989 and (3) Modern Pharmaceuticals 4 ⁇ Edition, 2002.
  • a range of manufacturing approaches can be employed including dry blending, wet granulation, roller compaction, extrusion, spheronization, coating, and spray drying processes. Soft gel formulation and manufacturing approaches are also possible.
  • the composition includes a filler or diluent.
  • the filler or diluent is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, compressible sugar, calcium phosphate, calcium sulfate, calcium carbonate, calcium silicate and starch.
  • the filler or diluent is microcrystalline cellulose.
  • the composition includes a disintegrant.
  • the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, methylceilulose, alginic acid, sodium alginate, starch derivatives, betonite and veegum.
  • the disintegrant is croscarmellose sodium.
  • the composition includes a lubricant.
  • the lubricant is selected from magnesium stearate, metallic stearates, talc, sodium stearyl fumarate and stearic acid.
  • the lubricant is magnesium stearate.
  • the composition includes a wetting agent or surfactant.
  • the wetting agent or surfactant is selected from sodium lauryl sulfate, glycerol, sorbitan oleates, sorbitan stearates, polyoxyethylenated sorbitan laurate, palmitate, stearate, oleate or hexaolate, polyoxyethylene stearyl alcohol and sorbitan monolaurate.
  • the wetting agent or surfactant is sodium lauryl sulfate.
  • composition comprising:
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising: about 0.4% by weight of a compound of structure:
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 92.6% by weight of the composition.
  • the composition further comprises: about 5% by weight croscarmellose sodium; about 1% by weight sodium lauryl sulfate; and about 1% by weight magnesium stearate.
  • the invention also relates to a composition comprising: about 4.2% by weight of a compound of structure:
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 88.8% by weight of the composition.
  • the composition further comprises: about 5% by weight croscarmellose sodium; about 1% by weight sodium lauryl sulfate; and about 1% by weight magnesium stearate.
  • the invention also relates to a composition
  • a composition comprising: from about 2% to about 10% by weight of a compound of
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises: from about 1% to about 6% by weight croscarmellose sodium; from about 0.1% to about 2% by weight sodium lauryl sulfate; and from about 0.25% to about 1.5% by weight magnesium stearate.
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises: from about 1% to about 6% by weight croscarmellose sodium; and from about 0.25% to about 1.5% by weight magnesium stearate.
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising:
  • about 40mg of a compound of structure about 183.2mg of microcrystalline cellulose; about 12.0mg of croscarmellose sodium; about 2.4mg of sodium lauryl sulfate; and about 2.4mg of magnesium stearate.
  • the invention also relates to a composition
  • a composition comprising: about 0.4% by weight of a compound of structure:
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 92.6% by weight of the composition.
  • the composition further comprises: about 5% by weight croscarmellose sodium; about 1% by weight sodium lauryl sulfate; and about 1% by weight magnesium stearate.
  • the invention also relates to a composition
  • a composition comprising: about 4.2% by weight of a compound of structure:
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 88.8% by weight of the composition,
  • the composition further comprises: about 5% by weight croscarmellose sodium; about 1% by weight sodium lauryl sulfate; and about 1% by weight magnesium stearate.
  • the invention also relates to a composition
  • a composition comprising: from about 2% to about 10% by weight of a compound of
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises: from about 1% to about 6% by weight croscarmellose sodium; from about 0.1% to about 2% by weight sodium lauryl sulfate; and from about 0.25% to about 1.5% by weight magnesium stearate.
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises: from about 1% to about 6% by weight croscarmellose sodium; and from about 0.25% to about 1.5% by weight magnesium stearate.
  • the invention also relates to a composition
  • a composition comprising:
  • the invention also relates to a composition comprising: about 10mg of a compound of structure: about 213.2mg of microcrystalline cellulose; about 12,0mg of croscarmellose sodium; about 2.4mg of sodium lauryl sulfate; and about 2.4mg of magnesium stearate.
  • the invention also relates to a composition comprising: about 10mg of a compound of structure: about 213.2mg of microcrystalline cellulose; about 12,0mg of croscarmellose sodium; about 2.4mg of sodium lauryl sulfate; and about 2.4mg of magnesium stearate.
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising:
  • the invention also relates to a composition comprising: about 0.4% by weight of a compound of structure:
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 92.6% by weight of the composition.
  • the composition further comprises: about 5% by weight croscarmellose sodium; about 1% by weight sodium lauryl sulfate; and about 1% by weight magnesium stearate.
  • the invention also relates to a composition comprising: about 4.2% by weight of a compound of structure:
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is about 88.8% by weight of the composition.
  • the composition further comprises: about 5% by weight croscarmellose sodium; about 1% by weight sodium lauryl sulfate; and about 1% by weight magnesium stearate.
  • the invention also relates to a composition
  • a composition comprising: from about 2% to about 10% by weight of a compound of
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises: from about 1% to about 6% by weight croscarmellose sodium; from about 0.1% to about 2% by weight sodium lauryl sulfate; and from about 0.25% to about 1.5% by weight magnesium stearate.
  • the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose.
  • the microcrystalline cellulose is from about 85% to about 95% by weight of the composition.
  • the composition further comprises: from about 1% to about 6% by weight croscarmellose sodium; and from about 0.25% to about 1.5% by weight magnesium stearate.
  • compositions comprising an effective amount of a crystalline polymorph form A ofN-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide.
  • the pharmaceutical compositions comprise an effective amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are for the treatment of disorders.
  • the pharmaceutical compositions are for the treatment of disorders in a mammal.
  • the pharmaceutical compositions are for the treatment of disorders in a human.
  • the pharmaceutical compositions are for the treatment or prophylaxis of inflammatory diseases.
  • the pharmaceutical compositions are for the treatment or prophylaxis of proliferative diseases.
  • the present invention is directed to a method for achieving an effect in a patient comprising the administration of an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof, to a patient, wherein the effect is selected from the group consisting of inhibition of various cancers, immunological diseases, and inflammatory diseases.
  • the compound or pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that further comprises a pharmaceutically acceptable carrier or vehicle.
  • the effect is inhibition of various cancers.
  • the effect is inhibition of immunological diseases.
  • the effect is inhibition inflammatory diseases. Any of the compositions described and claimed herein may be used in the methods provided in this section.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, or surgery or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day.
  • the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • MEK protein kinase inhibitors further comprising a compound of formula I, wherein the compound of formula I is present in an amount of about 0.1 mg to about 200 mg.
  • the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 0.2 mg to about 100 mg.
  • the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 0.3 mg to about 90 mg.
  • the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 0.4 mg to about 80 mg.
  • the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 0.5 mg to about 70 mg. In other embodiments, the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 0.4 mg to about 80 mg. In other embodiments, the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 0.5 mg to about 70 mg. In other embodiments, the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 1 mg to about 60 mg.
  • the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 1.5 mg to about 50 mg. In other embodiments, the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 2 mg to about 45 mg. In other embodiments, the MEK protein kinase inhibitor comprises a compound of formula I and is present in an amout of about 2.5 mg to about 40 mg. In further embodiments, MEK protein kinase inhibitor further comprising the compound of formula I present in the dosage amounts provided herein is selected from the group consisting of:
  • MEK protein kinase inhibitors further comprising a compound of formula I, wherein the compound of formula I is present in an amount of about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, and/or about 13 mg, about 14 mg, or about 15 mg.
  • the compound of formula I present in the dosage is present in an amount of about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about
  • MEK protein kinase inhibitors further comprising a compound of formula I, wherein the compound of formula I is present in an amount of about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, or about 200 mg.
  • the dosage amounts provided herein is selected from the group consisting of: and
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method of treating a disease in an individual suffering from said disease comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the present invention is directed to a method of treating a disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof
  • the present invention is directed to a method of treating a disorder in a human, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the invention provides methods of inhibiting MEK activity by contacting MEK with an amount of a compound of formula I sufficient to inhibit the activity of MEK.
  • the invention provides methods of inhibiting MEK activity in a solution by contacting said solution with an amount of a compound of formula I sufficient to inhibit the activity of MEK in said solution.
  • the invention provides methods of inhibiting MEK activity in a cell by contacting said cell with an amount of a compound described herein sufficient to inhibit the activity of MEK in said cell.
  • the invention provides methods of inhibiting MEK activity in a tissue by contacting said tissue with an amount of a compound described herein sufficient to inhibit the activity of MEK in said tissue. In some embodiments, the invention provides methods of inhibiting MEK activity in an organism by contacting said organism with an amount of a compound described herein sufficient to inhibit the activity of MEK in said organism. In some embodiments, the invention provides methods of inhibiting MEK activity in an animal by contacting said animal with an amount of a compound described herein sufficient to inhibit the activity of MEK in said animal. In some embodiments, the invention provides methods of inhibiting MEK activity in a mammal by contacting said mammal with an amount of a compound described herein sufficient to inhibit the activity of MEK in said mammal. In some embodiments, the invention provides methods of inhibiting MEK activity in a human by contacting said human with an amount of a compound described herein sufficient to inhibit the activity of MEK in said human.
  • Compounds of formula I, and compositions containing a compound of formula I, and pharmaceutically acceptable salts, solvates, polymorphs, esters, amides, tautomers or prodrugs thereof, may modulate the activity of MEK enzymes; and, as such, are useful for treating diseases or conditions in which aberrant MEK enzyme activity contributes to the pathology and/or symptoms of a disease or condition.
  • the present invention is directed to a method of treating a disorder or condition which is modulated by the MEK cascade in a mammal, including a human, comprising administering to said mammal an amount of the compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, effective to modulate said cascade.
  • a mammal including a human
  • administering comprising administering to said mammal an amount of the compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, effective to modulate said cascade.
  • the appropriate dosage for a particular patient can be determined, according to known methods, by those skilled in the art.
  • the present invention is directed to a method for inhibiting a MEK enzyme,
  • the method comprises contacting said MEK enzyme with an amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof, sufficient to inhibit said enzyme, wherein said enzyme is inhibited.
  • the enzyme is at least about 1% inhibited.
  • the enzyme is at least about 2% inhibited.
  • the enzyme is at least about 3% inhibited.
  • the enzyme is at least about 4% inhibited.
  • the enzyme is at least about 5% inhibited.
  • the enzyme is at least about 10% inhibited. In further or additional embodiments the enzyme is at least about 20% inhibited. In further or additional embodiments the enzyme is at least about 25% inhibited. In further or additional embodiments the enzyme is at least about 30% inhibited. In further or additional embodiments the enzyme is at least about 40% inhibited. In further or additional embodiments the enzyme is at least about 50% inhibited. In further or additional embodiments the enzyme is at least about 60% inhibited. In further or additional embodiments the enzyme is at least about 70% inhibited. In further or additional embodiments the enzyme is at least about 75% inhibited. In further or additional embodiments the enzyme is at least about 80% inhibited.
  • the enzyme is at least about 90% inhibited, In further or additional embodiments the enzyme is essentially completely inhibited. In further or additional embodiments the MEK enzyme is MEK kinase. In further or additional embodiments the MEK enzyme is MEKl . In further or additional embodiments the MEK enzyme is MEK2. In further or additional embodiments the contacting occurs within a cell. In further or additional embodiments the cell is a mammalian cell. In further or additional embodiments the mammalian cell is a human cell. In further or additional embodiments, the MEK enzyme is inhibited with a composition comprising a pharmaceutically acceptable salt of a compound of formula I.
  • the present invention is directed to a method of treatment of a MEK mediated disorder in an individual suffering from said disorder comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the composition comprising a compound of formula I is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from the MEK mediated disorder is a mammal, In further or additional embodiments, the individual is a human.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, non-cancer hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, dry eye, closed angle glaucoma and wide angle glaucoma.
  • the MEK mediated disorder is an inflammatory disease.
  • the MEK mediated disorder is a hyperproliferative disease.
  • the MEK mediated disorder is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignant disease.
  • stomach cancer brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia.
  • the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the invention also relates to methods of modulating MEK activity by contacting MEK with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenyIamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide sufficient to modulate the activity of MEK.
  • Modulate can be inhibiting or activating MEK activity.
  • the invention provides methods of inhibiting MEK activity by contacting MEK with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenyIamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide sufficient to inhibit the activity of MEK.
  • the invention provides methods of inhibiting MEK activity in a solution by contacting said solution with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3 -dihydroxypropyl)cyclopropane-l -sulfonamide sufficient to inhibit the activity of MEK in said solution.
  • the invention provides methods of inhibiting MEK activity in a cell by contacting said cell with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide sufficient to inhibit the activity of MEK in said cell.
  • the invention provides methods of inhibiting MEK activity in a tissue by contacting said tissue with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyI)- 1 - (2, 3 -dihydroxypropyl)cyclopropane-l -sulfonamide sufficient to inhibit the activity of MEK in said tissue.
  • the invention provides methods of inhibiting MEK activity in an organism by contacting said organism with an amount of a crystalline polymorph form A of N- ⁇ S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide sufficient to inhibit the activity of MEK in said organism.
  • the invention provides methods of inhibiting MEK activity in an animal by contacting said animal with an ofamount a crystalline polymorph form A of N-(S)-(3 ,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-suIfonamide sufficient to inhibit the activity of MEK in said animal.
  • the invention provides methods of inhibiting MEK activity in a mammal by contacting said mammal with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide sufficient to inhibit the activity of MEK in said mammal.
  • the invention provides methods of inhibiting MEK activity in a human by contacting said human with an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide sufficient to inhibit the activity of MEK in said human.
  • the present invention is directed to a method for the treatment, prevention or prophylaxis of cancer in an individual comprising administering to said individual an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the compound or pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that further comprises a pharmaceutically acceptable carrier or vehicle,
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, stomach cancer, or leukemia.
  • the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, melanoma, thyroid cancer, or basal cell carcinoma, In further or additional embodiments, the cancer is brain cancer or adrenocortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer.
  • the cancer is pancreatic cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphona. In further or additional embodiments, the cancer is pre-B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell lung cancer.
  • the cancer is stomach cancer.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent,
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents, hi further or additional embodiments, the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the compound of formula I is administered in a single dose, once daily.
  • the compound of formula I is administered in multiple doses, more than once per day.
  • the compound of formula I is administered twice daily.
  • the compound of formula I is administered three times per day.
  • the compound of formula I is administered four times per day.
  • the compound of formula I is administered more than four times per day.
  • the individual suffering from cancer is a mammal.
  • the individual is a human.
  • an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • Abnormal Cell Growth Also described herein are compounds, pharmaceutical compositions and methods for inhibiting abnormal cell growth.
  • the abnormal cell growth occurs in a mammal.
  • Methods for inhibiting abnormal cell growth comprise administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof, wherein abnormal cell growth is inhibited.
  • Methods for inhibiting abnormal cell growth in a mammal comprise administering to the mammal an amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof, wherein the amounts of the compound, or salt, is effective in inhibiting abnormal cell growth in the mammal.
  • the methods comprise administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, or its salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof and the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art and can be used in combination with the compounds of the invention.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • Also described are methods for inhibiting abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof, in combination with radiation therapy, wherein the amounts of the compound, or its salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or a derivative thereof is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the administration of the compound of formula I in this combination therapy can be determined as described herein.
  • the invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
  • Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein.
  • useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24,1996), WO 96/27583 (published March 7,1996), European Patent Application No. 97304971.1 (filed July 8,1997), European Patent Application No.
  • MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
  • the present invention is directed to a method for degrading, inhibiting the growth of or killing a cancer cell comprising contacting said cell with an amount of a composition effective to degrade, inhibit the growth of or to kill said cell, the composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the cancer cells comprise brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer cells.
  • the composition is administered with at least one therapeutic agent.
  • the therapeutic agent is taxol, bortezomib or both.
  • the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
  • the anti-neoplastic agents selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the cancer cells are degraded. In further or additional embodiments, 1% of the cancer cells are degraded.
  • 2% of the cancer cells are degraded. In further or additional embodiments, 3% of the cancer cells are degraded. In further or additional embodiments, 4% of the cancer cells are degraded. In further or additional embodiments, 5% of the cancer cells are degraded. In further or additional embodiments, 10% of the cancer cells are degraded. In further or additional embodiments, 20% of the cancer cells are degraded. In further or additional embodiments, 25% of the cancer cells are degraded. In further or additional embodiments, 30% of the cancer cells are degraded. In further or additional embodiments, 40% of the cancer cells are degraded. In further or additional embodiments, 50% of the cancer cells are degraded. In further or additional embodiments, 60% of the cancer cells are degraded.
  • 70% of the cancer cells are degraded. In further or additional embodiments, 75% of the cancer cells are degraded, In further or additional embodiments, 80% of the cancer cells are degraded. In further or additional embodiments, 90% of the cancer cells are degraded. In further or additional embodiments, 100% of the cancer cells are degraded. In further or additional embodiments, essentially all of the cancer ceils are degraded.
  • the cancer cells are killed. In further or additional embodiments, 1% of the cancer cells are killed. In further or additional embodiments, 2% of the cancer cells are killed. In further or additional embodiments, 3% of the cancer cells are killed. In further or additional embodiments, 4% of the cancer cells are killed. In further or additional embodiments, 5% of the cancer cells are killed. In further or additional embodiments, 10% of the cancer cells are killed. In further or additional embodiments, 20% of the cancer cells are killed. In further or additional embodiments, 25% of the cancer cells are killed. In further or additional embodiments, 30% of the cancer cells are killed. In further or additional embodiments, 40% of the cancer cells are killed. In further or additional embodiments, 50% of the cancer cells are killed.
  • the growth of the cancer cells is inhibited. In further or additional embodiments, the growth of the cancer cells is about 1% inhibited. In further or additional embodiments, the growth of the cancer cells is about 2% inhibited. In further or additional embodiments, the growth of the cancer cells is about 3% inhibited.
  • the growth of the cancer cells is about 4% inhibited. In further or additional embodiments, the growth of the cancer cells is about 5% inhibited. In further or additional embodiments, the growth of the cancer cells is about 10% inhibited. In further or additional embodiments, the growth of the cancer cells is about 20% inhibited. In further or additional embodiments, the growth of the cancer cells is about 25% inhibited. In further or additional embodiments, the growth of the cancer cells is about 30% inhibited. In further or additional embodiments, the growth of the cancer celis is about 40% inhibited. In further or additional embodiments, the growth of the cancer cells is about 50% inhibited. In further or additional embodiments, the growth of the cancer cells is about 60% inhibited.
  • the growth of the cancer cells is about 70% inhibited. In further or additional embodiments, the growth of the cancer cells is about 75% inhibited. In further or additional embodiments, the growth of the cancer cells is about 80% inhibited. In further or additional embodiments, the growth of the cancer cells is about 90% inhibited. In further or additional embodiments, the growth of the cancer cells is about 100% inhibited. In further or additional embodiments, a composition comprising a pharmaceutically acceptable salt of a compound of formula I is used. Also described herein are methods for inhibiting abnormal cell growth. In some embodiments, the abnormal cell growth occurs in a mammal.
  • Methods for inhibiting abnormal cell growth comprise administering an effective amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide, wherein abnormal cell growth is inhibited.
  • Methods for inhibiting abnormal cell growth in a mammal comprise administering to the mammal an amount of a crystalline polymorph form A of N-(S)-(3 ,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-l -(2,3-dihydroxypropyl)cycIopropane- 1 - sulfonamide, wherein the amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l -sulfonamide is effective in inhibiting abnormal cell growth in the mammal.
  • the methods comprise administering an effective amount of a crystalline polymorph form A of N-(S)-(3 ,4-difluoro-2-(2 -fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3 -dihydroxypropyl)cyclopropane- 1 - sulfonamide in combination with an amount of a chemotherapeutic, wherein the amounts of the crystalline polymorph form A ofN-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide and of the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art and can be used in combination with the compounds and compositions of the invention.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • the methods for inhibiting abnormal cell growth in a mammal comprise administering to the mammal an amount of a crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenyIamino)-6- methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide in combination with radiation therapy, wherein the amount of crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1- (2,3-dihydroxypropyl)cyclopropane-l -sulfonamide in combination with the radiation therapy is effective in inhibiting abnormal cell growth.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the present invention is directed to a method of treating a hyperproliferative disorder in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the present invention is directed to a method for the treatment, prevention or prophylaxis of a proliferative disease in an individual comprising administering to said individual an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the compound or pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that further comprises a pharmaceutically acceptable carrier or vehicle.
  • the proliferative disease is cancer, psoriasis, restenosis, autoimmune disease, or atherosclerosis.
  • the proliferative disease is a hyperproliferative disease.
  • the proliferative disease is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignant disease.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, stomach cancer, colorectal cancer or leukemia.
  • the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, stomach cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia.
  • the cancer is brain cancer or adrenocortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, the cancer is pancreatic cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphona. In further or additional embodiments, the cancer is pre-B acute leukemia.
  • the cancer is chronic lymphocytic B-Seukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is stomach cancer.
  • the composition comprising a compound of formula I is administered in combination with an additional therapy.
  • the additional therapy is radiation therapy, chemotherapy, surgery or a combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and antineoplastic agents.
  • the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0,5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day.
  • the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
  • the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from the proliferative disease is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method of reducing the size of a tumor, inhibiting rumor size increase, reducing tumor proliferation or preventing tumor proliferation in an individual, comprising administering to said individual an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the compound or pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that further comprises a pharmaceutically acceptable carrier or vehicle.
  • the size of a tumor is reduced.
  • the size of a tumor is reduced by at least 1%.
  • the size of a tumor is reduced by at least 2%. In further or additional embodiments, the size of a tumor is reduced by at least 3%. In further or additional embodiments, the size of a tumor is reduced by at least 4%. In further or additional embodiments, the size of a tumor is reduced by at least 5%. In further or additional embodiments, the size of a tumor is reduced by at least 10%. In further or additional embodiments, the size of a tumor is reduced by at least 20%. In further or additional embodiments, the size of a tumor is reduced by at least 25%. In further or additional embodiments, the size of a tumor is reduced by at least 30%. In further or additional embodiments, the size of a tumor is reduced by at least 40%.
  • the size of a tumor is reduced by at least 50%. In further or additional embodiments, the size of a tumor is reduced by at least 60%. In further or additional embodiments, the size of a tumor is reduced by at least 70%. In further or additional embodiments, the size of a tumor is reduced by at least 75%. In further or additional embodiments, the size of a tumor is reduced by at least 80%. In further or additional embodiments, the size of a tumor is reduced by at least 85%. In further or additional embodiments, the size of a tumor is reduced by at least 90%. In further or additional embodiments, the size of a tumor is reduced by at least 95%. In further or additional embodiments, the tumor is eradicated. In some embodiments, the size of a tumor does not increase.
  • tumor proliferation is reduced. In some embodiments, tumor proliferation is reduced by at least 1 %. In some embodiments, tumor proliferation is reduced by at least 2 %. In some embodiments, tumor proliferation is reduced by at least 3 %. In some embodiments, tumor proliferation is reduced by at least 4 %. In some embodiments, tumor proliferation is reduced by at least 5 %. In some embodiments, tumor proliferation is reduced by at least 10 %. In some embodiments, tumor proliferation is reduced by at least 20 %. In some embodiments, tumor proliferation is reduced by at least 25 %. In some embodiments, tumor proliferation is reduced by at least 30 %. In some embodiments, tumor proliferation is reduced by at least 40 %, In some embodiments, tumor proliferation is reduced by at least 50 %.
  • tumor proliferation is reduced by at least 60 %. In some embodiments, tumor proliferation is reduced by at least 70 %. In some embodiments, tumor proliferation is reduced by at least 75 %. In some embodiments, tumor proliferation is reduced by at least 75 %. In some embodiments, tumor proliferation is reduced by at least 80 %. In some embodiments, tumor proliferation is reduced by at least 90 %. In some embodiments, tumor proliferation is reduced by at least 95 %. In some embodiments, tumor proliferation is prevented. In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof.
  • the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent.
  • the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and antineoplastic agents.
  • the antineoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • the therapeutic agent is selected from taxol, bortezomib or both.
  • the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day.
  • the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day.
  • the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • the present invention is directed to a method for the treatment, prevention or prohylaxis of an inflammatory disease in an individual comprising administering to said individual an effective amount of compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof.
  • the compound or pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that further comprises a pharmaceutically acceptable carrier or vehicle.
  • the inflammatory disease is selected from chronic inflammatory diseases, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathies, ankylosing spondylitis, gout, tendonitis, bursitis, sciatica, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerosis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, allergies, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema or scleroderma.
  • chronic inflammatory diseases rheumatoid arthritis, rheumatoid arthritis, spond
  • the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day.
  • the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily.
  • the compound of formula I is administered in multiple doses, more man once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day.
  • the individual suffering from the inflammatory disease is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
  • Described herein are compounds of formula I or a pharmaceutically acceptable salt solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof. Also described, are pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof.
  • the compounds and compositions described herein may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • compositions comprising crystalline polymorph N-(S)-(3,4-difluoro-2- (2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1 -(2,3 -dihydroxypropyl)cyclopropane- 1 -sulfonamide (Form A).
  • the compounds and compositions described herein may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. Administration can be effected by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant, said implant made for example, out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • topical application such as creams or ointments, injection, catheter, or implant, said implant made for example, out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical, and rectal administration.
  • compounds described herein can be administered locally to the area in need of treatment. This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
  • site or former site
  • Those of ordinary skill in the art are familiar with formulation and administration techniques that can be employed with the compounds and methods of the invention, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient active ingredient
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which are useful for oral administration include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules or tablets can contain the active ingredient; in admixture with a filler such as microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose, dicalcium phosphate, or compressible sugar ; a binder such as hypromellose, povidone or starch paste; a disintegrant such as croscarmellose sodium, crospovidone or sodium starch glycolate; a surfactant such as sodium lauryl sulfate and/or lubricants and processing aides such as talc,magnesium stearate, stearic acid or colloidal silicion dioxide and, optionally, stabilizers.
  • a filler such as microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose,
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions are useful, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • Pharmaceutical preparations may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Pharmaceutical preparations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w or may comprise less than 5% w/w, or from 0.1% to 1% w/w of the formulation.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • compositions and compounds described herein may be used in any of the formulations discussed in this section, which is not intended to be limiting and should not be so construed.
  • the compounds or compositions described herein can be delivered in a vesicle, e.g., a liposome (see, for example,
  • a pump may be used (see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al. Surgery, 1980 88, 507; Saudek et al. N. Engl. J. Med 1989, 321, (574). Additionally, a controlled release system can be placed in proximity of the therapeutic target.
  • compositions described herein can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents; fillers such as microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose, dicalcium phosphate, or compressible sugar ; binders such as hypromellose, povidone or starch paste; disintegrants such as croscarmellose sodium, crospovidone or sodium starch glycolate; a surfactant such as sodium lauryl sulfate and/or lubricants and processing aides such as talc, sodium croscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and
  • the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • the capsule and tablet dosage forms may be prepared by various processing techniques including dry blending and wet granulation techniques. In the dry blending method of manufacture the drug substance may be incorporated into the dosage form by dry blending with the excipients followed by encapsulation into a capsule shell or compression into a tablet form.
  • the dry blending operation may be approached in a stepwise manner and include screening steps between the blending steps to facilitate formation of a uniform blend.
  • the drug substance may be added to the dry excipients and mixed prior to the addition of the binder solution or the drug substance may be dissolved and added as a solution as part of granulation.
  • the surfactant if used, may be added to the dry excipients or added to the binder solution and incorporated in a solution form.
  • Capsule dosage forms may also be manufactured by dissolving the drag substance in a material that can be filled into and is compatible with hard gelatin capsule shells that can be subsequently banded and sealed.
  • Capsule and tablet dosage forms may also be produced by dissolving the drug substance in a material such a molten form of a high molecular weight polyethylene glycol and cooling to a solid form, milling and incorporating this material into conventional capsule and tablet manufacturing processes.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin,
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Pharmaceutical compositions may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin.
  • the oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3 -butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the inhibitors with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • topical application can include mouth washes and gargles.
  • compositions may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. To be administered in the form of transdermal delivery, the dosage form will, of course, be continuous rather than intermittent throughout the dosage regimen. Doses
  • the amount of pharmaceutical compositions administered will firstly be dependent on the mammal being treated.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, sex, diet, weight, general health and response of the individual patient, the severity of the patient's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, time of administration, route of administration, the disposition of the composition, rate of excretion, drug combination, and the discretion of the prescribing physician.
  • the route of administration may vary depending on the condition and its severity.
  • the pharmaceutical composition may be in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g.
  • an effective amount to achieve the desired purpose is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the amount and frequency of administration of the compounds described herein, and if applicable other therapeutic agents and/or therapies, will be regulated according to the judgment of the attending clinician (physician) considering such factors as described above. Thus the amount of pharmaceutical composition to be administered may vary widely.
  • Administration may occur in an amount of between about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), or at least about 0.1 mg/kg of body weight per day.
  • a particular therapeutic dosage can include, e.g., from about 0.01 mg to about 7000 mg of compound, or, e.g., from about 0.05 mg to about 2500 mg.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, from about 1 mg to 300 mg, or 10 mg to 200 mg, according to the particular application.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.
  • the amount administered will vary depending on the particular IC 50 value of the compound used. In combinational applications in which the compound is not the sole therapy, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules, including lactose or milk sugar and high molecular weight polyethylene glycols.
  • active compound When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof may be administered as a sole therapy.
  • the compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof may also be administered in combination with another therapy or therapies.
  • N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide (Form A) which may be administered as a sole therapy.
  • Crystalline polymorph form A of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide may also be administered in combination with another therapy or therapies.
  • one of the side effects experienced by a patient upon receiving one of the compounds described herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the compound.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • Other therapies include, but are not limited to administration of other therapeutic agents, radiation therapy or both.
  • the compounds described herein need not be administered in the same pharmaceutical composition as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route.
  • the compounds/compositions may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition is well within the knowledge of the skilled clinician.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • therapeutic agents may include chemotherapeutic agents, such as anti-tumor substances, for example those selected from, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-p ⁇ atin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, an anti-metabolite disclosed in European Patent Application No.
  • chemotherapeutic agents such as anti-tumor substances, for example those selected from, mitotic inhibitors, for example vinblastine
  • alkylating agents for example cis-p ⁇ atin, carboplatin and cyclophosphamide
  • anti-metabolites for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, an anti-metabolite disclosed in European Patent Application No.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment.
  • compositions described herein may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound/composition.
  • the compound/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the compound/composition, and the chemotherapeutic agent and/or radiation, may not be important.
  • the compounds/compositions of the invention may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compounds/compositions of the invention.
  • This alternate administration may be repeated during a single treatment protocol.
  • the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
  • the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compounds/compositions of the invention followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
  • the practicing physician can modify each protocol for the administration of a compound/composition for treatment according to the individual patient's needs, as the treatment proceeds.
  • the attending clinician in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis.
  • combination therapies include use of the compounds of the invention with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present.
  • combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: aromatase inhibitors, antiestrogen, anti-androgen, corticosteroids, gonadorelin agonists, topoisomerase land 2 inhibitors, microtubule active agents, alkylating agents, nitrosoureas, antineoplastic antimetabolites, platinum containing compounds, lipid or protein kinase targeting agents, IMiDs, protein or lipid phosphatase targeting agents, anti-angiogenic agents, Akt inhibitors, IGF-I inhibitors, FGF3 modulators, mTOR inhibitors, Smac mimetics, HDAC inhibitors, agents that induce cell differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, IKK inhibitors, P38MAP
  • compounds according to the present invention may be administered with an agent selected from the group comprising: dacarbazine (DTIC), actinomycins C 2 , C 3 , D, and F b cyclophosphamide, melphalan, estramustine, maytansinol, rifamycin, streptovaricin, doxorubicin, daunorubicin, epirubicin, idarubicin, detorubicin, carminomycin, idarabicin, epirubicin, esorubicin, mitoxantrone, bleomycins A, A 2 , and B, camptothecin, Mnotecan.RTM., Topotecan.RTM., 9-aminocamptothecin, 10,11 - methylenedioxycamptothecin, 9-nitrocamptothecin, bortezomib, temozolomide
  • DTIC dacarbazine
  • compounds and pharmaceutically acceptable salts of the compounds according to the present invention may be administered with an agent selected from the group comprising: corticosteroids, non-steroidal anti-inflammatories, muscle relaxants and combinations thereof with other agents, anaesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, capsaicin, betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluoci t iolone acetononide, fluocinonide, halocinonide, clocortalone pi
  • IL 17 inactivating anti-bodies IL- 17 receptor antagonists/inhibitors, CTLA inhibitors, CD20 inhibitors, soluble VEGFR-I receptors, anti- VEGFR-I receptor antibodies, anti- VEGF antibodies, integrin receptor antagonist, Selectm inhibitors, P-selectin and E-selectin inhibitors, Phospholipase A2 Inhibitors , Lipoxygenase Inhibitors, RANKL and RANK antagonists/antibodies, Osteoprotegerin antagonists, Lymphotoxin inhibitors, B- lymphocyte stimulator, MCP-I inhibitors, MTF inhibitors, inhibitors of : CD2, CD3, CD4 , CD25 , CD40 and CD40 Ligand CDl 52 (CTLA4), Macrolide immunosuppressants, Selective inhibitors of nucleotide metabolism, Inhibitors of chemotaxis, CXC receptor and CXC ligand inhibitors, Chemokine Antagonists, leukocyte chemotaxi
  • compounds and pharmaceutically acceptable salts of the compounds according to the present invention may be administered with an agent selected from the group comprising: beta-blockers, carbonic anhydrase inhibitors, .alpha.- and .beta.-adrenergic antagonists including al-adrenergic antagonists, .alpha.2 agonists, miotics, prostaglandin analogs, corticosteroids, and immunosuppressant agents.
  • an agent selected from the group comprising: beta-blockers, carbonic anhydrase inhibitors, .alpha.- and .beta.-adrenergic antagonists including al-adrenergic antagonists, .alpha.2 agonists, miotics, prostaglandin analogs, corticosteroids, and immunosuppressant agents.
  • compounds pharmaceutically acceptable salts of the compounds according to the present invention may be administered with an agent selected from the group comprising: timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol, brinzolamide, dorzolamide, nipradilol, iopidine, brimonidine, pilocarpine, epinephrine, latanoprost, travoprost, bimatoprost, unoprostone, dexamethasone, prednisone, methylprednisolone, azathjoprine, cyclosporine, and immunoglobulins.
  • an agent selected from the group comprising: timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol, brinzolamide, dorzolamide, nipradilo
  • compounds pharmaceutically acceptable salts of the compounds according to the present invention may be administered with an agent selected from the group comprising: corticosteroids, immunosuppressants, prostaglandin analogs and antimetabolites.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: dexamethasome, prednisone, methylprednisolone, azathioprme, cyclosporine, immunoglobulins, latanoprost, travoprost, bimatoprost, unoprostone, infliximab, rutuximab, methotrexate, non-steroidal antiinflammatories, muscle relaxants and combinations thereof with other agents, anaesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin, betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, d
  • PDE4 inhibitors - similar mechanism to Ibudilast (AV-411) , CDC-801, JNK inhibitors - CC-401, Combination TNF/PDE4 inhibitors - CDC-998, ILl antagonists e.g.
  • Immunosuppressive agents iNOS inhibitors, NSAIDs, sPLA2 inhibitors, Colchicine, allopurinol, oxypurinol, Gold, Ridaura - Auranofin, febuxostat, Puricase, PEG-uricase formulations, Benzbromarone, Long-acting beta-2 agonists (LABAs), salmeterol (Serevent Diskus) and formoterol (Foradil), Leukotriene modifiers include montelukast (Singulair) and zafirlukast (Accolate). Inhaled cromolyn (Intal) or nedocromil (Tilade), Theophylline.
  • Short-acting beta-2 agonists Ipratropium (Atrovent), Immunotherapy-(AHergy-desensitization shots), Anti-IgE monoclonal antibodies - Xolair, Common DMARDs include hydroxychloroquine (PIaquenil), the gold compound auranofin (Ridaura), sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (Imuran), cyclosporine (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), Antibiotics, CD80 antagonists, costimulatory factor antagonists, Humax-CD20 (ofatumumab); CD20 antagonists, MEK inhibitors, ,NF kappa B inhibitors, anti B-cell antibodies, denosumab, mAb that specifically targets the
  • compounds and pharmaceutically acceptable salts of the compounds according to the present invention may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, protein tyrosine phosphatase- 1B (PTP-1B) inhibitors, GSK3 (glycogen synthase kinase-3) inhibitors, GLP-I (glucagon like peptide- 1), GLP-I analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, RXR ligands sodium-dependent glucose co-transporter inhibitors, glycogen phosphorylase A inhibitors, an AGE breaker, PPAR modulators, LXR and FXR modulators, non-glitazone type PPARS agonist, selective glucocorticoid antagonists, met
  • Described herein are methods of treating a disease in an individual suffering from said disease comprising administering to said individual an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof. Also described herein are methods of treating a disease or disorder in an individual suffering from said disease or disorder comprising administering to said individual an effective amount of N-(S)-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyI)-l -(2,3 -dihydroxypropyl)cyclopropane-l -sulfonamide (Form A).
  • the invention extends to the use of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxypheny I)-I -(2,3- dihydroxypropyl)cyclopropane-l -sulfonamide (Form A) in the manufacture of a medicament for treating a disease or disorder.
  • the invention relates to the prophylaxis or treatment of any disease or disorder in which MEK kinase plays a role including, without limitation: oncologic, hematologic, inflammatory, ophthalmologic, neurological, immunologic, cardiovascular, and dermatologic diseases as well as diseases caused by excessive or unregulated pro-inflammatory cytokine production including for example excessive or unregulated TNF, IL-I , IL-6 and IL-8 production in a human, or other mammal.
  • the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such cytokine-mediated diseases or disorders. Further, the invention extends to the administration to a human an effective amount of a MEK inhibitor for treating any such disease or disorder.
  • Diseases or disorders in which MEK kinase plays a role include, without limitation: dry eye, glaucoma, autoimmune diseases, inflammatory diseases, destructive-bone disorders, proliferative disorders, neurodegenerative disorders, viral diseases, allergies, infectious diseases, heart attacks, angiogenic disorders, reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase synthetase-2 (COX-2).
  • COX-2 prostaglandin endoperoxidase synthetase-2
  • the disease is a hyperproliferative condition of the human or animal body, including, but not limited to cancer, hyperplasias, restenosis, inflammation, immune disorders, cardiac hypertrophy, atherosclerosis, pain, migraine, angiogenesis-related conditions or disorders, proliferation induced after medical conditions, including but not limited to surgery, angioplasty, or other conditions.
  • said hyperproliferative condition is selected from the group consisting of hematologic and nonhematologic cancers.
  • said hematologic cancer is selected from the group consisting of multiple myeloma, leukemias, and lymphomas.
  • said leukemia is selected from the group consisting of acute and chronic leukemias.
  • said acute leukemia is selected from the group consisting of acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL).
  • said chronic leukemia is selected from the group consisting of chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).
  • said lymphoma is selected from the group consisting of Hodgkin's lymphoma and non-Hodgkin's lymphoma.
  • said hematologic cancer is multiple myeloma.
  • said hematologic cancer is of low, intermediate, or high grade.
  • said nonhematologic cancer is selected from the group consisting of: brain cancer, cancers of the head and neck, lung cancer, breast cancer, cancers of the reproductive system, cancers of the digestive system, pancreatic cancer, and cancers of the urinary system.
  • said cancer of the digestive system is a cancer of the upper digestive tract or colorectal cancer.
  • said cancer of the urinary system is bladder canceT or renal cell carcinoma.
  • said cancer of the reproductive system is prostate cancer.
  • cancers of oral cavity and pharynx include: cancers of oral cavity and pharynx, cancers of the respiratory system, cancers of bones and joints, cancers of soft tissue, skin cancers, cancers of the genital system, cancers of the eye and orbit, cancers of the nervous system, cancers of the lymphatic system, and cancers of the endocrine system.
  • these cancer s may be selected from the group consisting of: cancer of the tongue, mouth, pharynx, or other oral cavity; esophageal cancer, stomach cancer, or cancer of the small intestine; colon cancer or rectal, anal, or anorectal cancer; cancer of the liver, intrahepatic bile duct, gallbladder, pancreas, or other biliary or digestive organs; laryngeal, bronchial, and other cancers of the respiratory organs; heart cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, other non-epithelial skin cancer; uterine or cervical cancer; uterine corpus cancer; ovarian, vulvar, vaginal, or other female genital cancer; prostate, testicular, penile or other male genital cancer; urinary bladder cancer; cancer of the kidney; renal, pelvic, or urethral cancer or other cancer of the genito-urinary organs; thyroid cancer or other en
  • cancers which may be treated using the compounds and methods described herein include: adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lympban
  • Also described are methods for the treatment of a hyperproliferative disorder in a mammal that comprise administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate, or derivative thereof, in combination with an anti-tumor agent.
  • the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti- metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, anti- androgens, SHIP activators - AQX-MN100, Humax-CD20 (ofatumumab), CD20 antagonists, IL2-diptheria toxin fusions.
  • the disease to be treated using the compounds, compositions and methods described herein may be a hematologic disorder.
  • said hematologic disorder is selected from the group consisting of sickle cell anemia, myelodysplastic disorders (MDS), and myeloproliferative disorders.
  • said myeloproliferative disorder is selected from the group consisting of polycythemia vera, myelofibrosis and essential thrombocythemia.
  • the compounds, compositions and methods described herein may be useful as anti-inflammatory agents with the additional benefit of having significantly less harmful side effects.
  • the compounds, compositions and methods described herein are useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, ankylosing spondylitis, gout, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.
  • the compounds, compositions and methods described herein are also useful in treating osteoporosis and other related bone disorders.
  • These compounds, compositions and methods described herein are also useful to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
  • the compounds, compositions and methods described herein may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.
  • the compounds, compositions and methods described herein are also useful in organ transplant patients either alone or in combination with conventional immunomodulators.
  • the compounds, compositions and methods described herein are useful in the treatment of pruritis and vitaligo.
  • compounds, compositions and methods described herein are useful in treating the particular inflammatory disease rheumatoid arthritis.
  • inflammatory diseases which may be prevented or treated include, without limitation: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis.
  • respiratory system diseases may be prevented or treated including but not limited to chronic obstructive pulmonary disease, and pulmonary fibrosis.
  • MEK kinase inhibitors described herein are also associated with prostaglandin endoperoxidase synthetase-2 (COX-2) production.
  • Pro-inflammatory mediators of the cyclooxygenase pathway derived from arachidonic acid, such as prostaglandins are produced by inducible COX-2 enzyme. Regulation of COX-2 would regulate these pro-inflammatory mediators, which affect a wide variety of cells and are important and critical inflammatory mediators of a wide variety of
  • inflammatory mediators have been implicated in pain, such as in the sensitization of pain receptors, and edema.
  • additional MEK kinase-mediated conditions which may be prevented or treated include edema, analgesia, fever and pain such as neuromuscular pain, headache, dental pain, arthritis pain and pain caused by cancer.
  • the disease to be treated by the compounds, compositions and methods described herein may be an ophthalmologic disorder.
  • Ophthalmologic diseases and other diseases in which angiogenesis plays a role in pathogenesis may be treated or prevented and include, without limitation, dry eye (including Sjogren's syndrome), macular degeneration, closed and wide angle glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue.
  • the compounds, compositions and methods described herein are useful to treat glaucomatous retinopathy and/or diabetic retinopathy.
  • the compounds, compositions and methods described herein are also useful to treat post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery..
  • said ophthalmologic disorder is selected from the group consisting of dry eye, closed angle glaucoma and wide angle glaucoma.
  • the disease to be treated by the compounds, compositions and methods described herein may be an autoimmune disease.
  • Autoimmune diseases which may be prevented or treated include, but are not limited to: rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontal disease, temporomandibular joint disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft vs.
  • Inflammatory diseases which may be prevented or treated include, but are not limited to: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis.
  • compounds, compositions and methods described herein are useful in treating the particular autoimmune diseases rheumatoid arthritis and multiple sclerosis.
  • the disease to be treated by the compounds, compositions and methods described herein may be a dermatologic disorder.
  • said dermatologic disorder is selected from the group including, without limitation, melanoma, basel cell carcinoma, squamous cell carcinoma, and other non-epithelial skin cancer as well as psoriasis and persistent itch, and other diseases related to skin and skin structure, may be treated or prevented with MEK kinase inhibitors of this invention.
  • Metabolic diseases which may be treated or prevented include, without limitation, metabolic syndrome, insulin resistance, and Type 1 and Type 2 diabetes.
  • the compositions described herein may be useful to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.
  • the compounds, compositions and methods described herein are also useful in treating tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like.
  • diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including mya
  • the compounds, compositions and methods described herein may also be useful to treat allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis.
  • the disease to be treated by the compounds, compositions and methods described herein may be a cardiovascular condition.
  • said cardiovascular condition is selected from the group consisting of atherosclerosis, cardiac hypertrophy, idiopathic cardiomyopathies, heart failure, angiogenesis-related conditions or disorders, and proliferation induced after medical conditions, including, but not limited to restenosis resulting from surgery and angioplasty.
  • the disease to be treated by the compounds, compositions and methods described herein may be a neurological disorder.
  • said neurologic disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Alzheimer's dementia, and central nervous system damage resulting from stroke, ischemia and trauma.
  • said neurological disorder is selected from the group consisting of epilepsy, neuropathic pain, depression and bipolar disorders.
  • the disease to be treated by the compounds, compositions and methods described herein may cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS related AIDS-Related (e.g. Lymphoma and Kaposi's Sarcoma) or Viral-Induced cancer.
  • cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical
  • the compounds and compositions are for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
  • the disease to be treated by the compounds, compositions and methods described herein may pancreatitis, kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease), pain, a disease related to vasculogenesis or angiogenesis, tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, tendonitis, bursitis, sciatica, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer in a mammal.
  • kidney disease including proliferative glomerulonephritis and diabetes- induced renal disease
  • pain a disease related to va
  • the disease to be treated by the compounds, compositions and methods described herein may the prevention of blastocyte implantation in a mammal.
  • Patients that can be treated with the compounds described herein, or their pharmaceutically acceptable salts, solvate, polymorphs, esters, amides, tautomers, prodrugs, hydrates, or derivatives according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squam
  • kits for the treatment of disorders such as the ones described herein.
  • kits comprise a compound, compounds or compositions described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider..
  • Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
  • the compounds described herein can be utilized for diagnostics and as research reagents.
  • the compounds described herein can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues.
  • expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined.
  • analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.
  • the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals (eg dogs, cats), exotic animals and farm animals (eg horses), including mammals, rodents, and the like.
  • Procedure B To a stirred solution of the amine (1 eq) in anhydrous pyridine (5ml/mmole) was added the sulfonyl chloride (1 - 5 eq). The reaction mixture was stirred at 40 °C for 48 hours. The reaction mixture was partitioned with water and EtOAc. The organic layer was washed with brine, dried (MGSO 4 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica. Procedure C: Substitution of the iodo-atom:
  • Procedure D Synthesis of N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2- (alkylamino)ethanesulfonamide:
  • Step A 2.3 -Difluoro-N-( 2-fluoro-4-iodophenyl)-6-nitroaniline :
  • Step C N-(3.4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanesulfonamide:
  • N-fS j ⁇ difluoro-l-fl-fluoro- ⁇ iodophenylamino)phenyl)-1-methylcyclopropane-1-sulfonamide Step A: n-Butyl 3 -chloro-1-propanesulfonate:
  • Triethylamine (28 ml, 200 mmol) in CH 2 Cl 2 (50 ml) was slowly added to an ice-cooled solution of 3-chloro-1- propanesulfonyl chloride (36.6g, 200 mmol) and 1-butanol (18.4 g, 240 m mol) in CH 2 Cl 2 (250 ml) and stirring was continued for 16h.
  • the mixture was diluted with CH 2 Cl 2 (200 ml), washed (aqueous HCl) and dried (MgSO 4 ) and the solvent was evaporated to obtain the titled product 1 (40.85 g, 95%) in crude form as slightly yellow oil which was used for the next reaction without further purification.
  • Step B 1 -Butyl cyclopropanesulfonate: Solutions of 1-butyl 3-chloro-1-propanesulfonate (4.6 g, 21.39 mmol in 25 ml THF) and of butyllithium (14.7 ml,
  • Step E l-Methyl-cyclopropanesulfonylchloride:
  • Step F N-H .4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)- 1 -methylcyclopropane- 1 -sulfonamide:
  • Step A Butyl cyclopropanesulfonate:
  • Step B Butyl 1 -allylcyclopropane- 1 -sulfonate: To a solution of 1-butyl cyclopropanesulfonate (4.8 g, 24.9 mmol) in THF at -78°C was added simultaneously butyllithium solution (15.6 ml, 24.9 mmol, 1.6M, THF) and allyl iodide (24.9 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 hours at -78°C and 3 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue extracted with CH 2 Cl 2 (100 ml). The extract was washed with water, dried (MgSO 4 ) and evaporated.
  • Step C Potassium 1-allylcyclopropane-1-sulfonate :
  • Step D l-allylcyclopropane-l-sulfonyl chloride:
  • Step A 2-d -bromocycloproDyl)ethanol: To a solution of neat diethyl zinc (3.3 ml, 3.977 g, 30 mmol) in 100 ml anhydrous DCM was added very slowly trifluoroacetic acid (2.31 ml, 3.4188 g, 30 mmol) dropwise at 0°C.
  • Step C TBS protected 2-( " 1-chlorosulfonylcyclopropyl)ethanol: To a solution of the cyclopropyl bromide prepared in step B (1.1227 g, 4.04 mmol) in 15 ml anhydrous diethyl ether was added a 1.7 M solution oft-BuLi in pentane (4.8 ml, 8.16 mmol) at -78°C. The solution was stirred for 30 min at this temperature, and was then transferred via a transfer canola into a solution of freshly distilled sulfuryl chloride (0.65 ml, 1.029 g, 8.1 mmol) in 8 ml diethyl ether at -78°C.
  • Step D TB S-protected N-(3.4-difluoro-2-( " 2-fluoro-4-iodophenylamiao)phenyl ' )- 1 -( 2- hydroxyethyl)cyclopropane- 1 -sulfonamide:
  • Step E N-r3.4-difluoro-2-(2-fluoro-4-iodophenylamipo)phenyl)-1-(2-hydroxyethyl)cyclopropane-1- sulfonamide:

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Abstract

L'invention concerne des composés N-(arylamino)arylsulfonamide qui sont des inhibiteurs de MEK comprenant des formes polymorphes cristallines présentant un profil de diffraction aux rayons X sur poudre spécifique et/ou un profil de calorimétrie à balayage différentiel spécifique. La présente invention concerne également des compositions pharmaceutiques comprenant les composés et des procédés d'utilisation des composés et des compositions décrits ici, y compris l'utilisation dans le traitement et/ou la prévention du cancer, de maladies hyperprolifératives et d'affections inflammatoires. L'invention concerne également des procédés de préparation des composés et des compositions décrits ici.
PCT/US2008/071392 2005-07-21 2008-07-28 Dérivés de n-(arylamino)arylsulfonamide comprenant des polymorphes en tant qu'inhibiteurs de mek ainsi que compositions, procédés d'utilisation et procédés de préparation de ceux-ci WO2009018233A1 (fr)

Priority Applications (36)

Application Number Priority Date Filing Date Title
MX2010001244A MX2010001244A (es) 2007-07-30 2008-07-28 Derivados de n-(arilamino) sulfonamidas que incluyen polimorfos como inhibidores de mek asi como composiciones, metodos de uso y de preparacion de los mismos.
JP2010520118A JP2010535232A (ja) 2007-07-30 2008-07-28 Ｍｅｋの阻害剤としての多形体を含む、ｎ−（アリールアミノ）スルホンアミドの誘導体、および組成物、使用方法、ならびにその調製方法
US12/671,287 US8648116B2 (en) 2005-07-21 2008-07-28 Derivatives of N-(arylamino) sulfonamides including polymorphs as inhibitors of MEK as well as compositions, methods of use and methods for preparing the same
AU2008282338A AU2008282338B2 (en) 2007-07-30 2008-07-28 Derivatives of N-(arylamino) sulfonamides including polymorphs as inhibitors of MEK as well as compositions, methods of use and methods for preparing the same
KR1020157020493A KR20150091434A (ko) 2007-07-30 2008-07-28 다형체를 포함하는, ｍｅｋ의 억제제로서의 ｎ-(아릴아미노) 술폰아미드의 유도체 및 조성물, 사용 방법 및 이의 제조 방법
EP08796733.7A EP2184984A4 (fr) 2007-07-30 2008-07-28 Dérivés de n-(arylamino)arylsulfonamide comprenant des polymorphes en tant qu'inhibiteurs de mek ainsi que compositions, procédés d'utilisation et procédés de préparation de ceux-ci
NZ582929A NZ582929A (en) 2007-07-30 2008-07-28 Derivatives of n-(arylamino) sulfonamides including polymorphs as inhibitors of mek as well as compositions, methods of use and methods for preparing the same
AP2010005134A AP2817A (en) 2007-07-30 2008-07-28 Derivatives of n-(arylamino)sulfonamides includingpolymorphs as inhibitors of mek as well as compos itions, methods of use and methods for preparing the same
CN2008801088296A CN101808516B (zh) 2007-07-30 2008-07-28 作为mek抑制剂的包括多晶型物的n-(芳氨基)磺酰胺衍生物和组合物、其使用方法和制备方法
BRPI0815659-0A2A BRPI0815659A2 (pt) 2007-07-30 2008-07-28 Derivados de n-(arilamino) sulfonamidas incluindo polimorfos como inibidores de mek bem como composições, métodos de uso e métodos para preparar os mesmos
EA201000268A EA020624B1 (ru) 2007-07-30 2008-07-28 Кристаллическая полиморфная форма n-(-)-(3,4-дифтор-2-(2-фтор-4-йодфениламино)-6-метоксифенил)-l-(2,3-дигидроксипропил)циклопропан-1-сульфонамида и ее применение в качестве ингибитора mek
KR1020147017261A KR20140098185A (ko) 2007-07-30 2008-07-28 다형체를 포함하는, ｍｅｋ의 억제제로서의 ｎ-(아릴아미노) 술폰아미드의 유도체 및 조성물, 사용 방법 및 이의 제조 방법
CA2693390A CA2693390C (fr) 2007-07-30 2008-07-28 Derives de n-(arylamino)arylsulfonamide comprenant des polymorphes en tant qu'inhibiteurs de mek ainsi que compositions, procedes d'utilisation et procedes de preparation de ceux-ci
KR1020107025394A KR20110014149A (ko) 2008-04-14 2009-04-14 조성물 및 이것의 제조 및 사용 방법
BRPI0911297A BRPI0911297A2 (pt) 2008-04-14 2009-04-14 composição e métodos para preparo e uso das mesmas
AU2009236325A AU2009236325A1 (en) 2008-04-14 2009-04-14 Compositions and methods for preparing and using same
CN2009801180672A CN102131771A (zh) 2008-04-14 2009-04-14 组合物及其制备和使用方法
JP2011505138A JP2011518786A (ja) 2008-04-14 2009-04-14 調製及び使用のための組成物及び方法
SG2013028378A SG189784A1 (en) 2008-04-14 2009-04-14 Compositions and methods for preparing and using same
MX2010011314A MX2010011314A (es) 2008-04-14 2009-04-14 Composiciones y metodos de preparacion y uso de las mismas.
CA2720671A CA2720671A1 (fr) 2008-04-14 2009-04-14 Compositions et leurs procedes de preparation et d'utilisation
EA201001639A EA201001639A1 (ru) 2008-04-14 2009-04-14 Композиции и способы их получения и применения
EP09732683A EP2291350A4 (fr) 2008-04-14 2009-04-14 Compositions et leurs procédés de préparation et d utilisation
US12/937,630 US8808742B2 (en) 2008-04-14 2009-04-14 Compositions and methods for preparing and using same
PCT/US2009/040538 WO2009129246A2 (fr) 2008-04-14 2009-04-14 Compositions et leurs procédés de préparation et d'utilisation
IL203296A IL203296A (en) 2007-07-30 2010-01-13 History of n - (arylamino) sulfonamides including polymorphs as mek inhibitors as well as preparations, methods of use and methods of preparation thereof
TNP2010000049A TN2010000049A1 (en) 2007-07-30 2010-01-29 Derivatives of n-(arylamino) sulfonamides includig polymorphs as inhibitors of mek as well as compositions, methods of use and methods for preparing the same
MA32636A MA31881B1 (fr) 2007-07-30 2010-02-19 Dérivés de n-(arylamino)arylsulfonamide comprenant des polymorphes en tant qu'inhibiteurs de mek ainsi que compositions, procédés d'utilisation et procédés de préparation de ceux-ci
IL208284A IL208284A0 (en) 2008-04-14 2010-09-21 Compositions and methods for preparing and using same
ZA2010/06944A ZA201006944B (en) 2008-04-14 2010-09-29 Compositions and methods for preparing and using same
EC2010010548A ECSP10010548A (es) 2008-04-14 2010-10-14 Composiciones y metodos de preparacion y uso de las mismas
CO10128068A CO6331425A2 (es) 2008-04-14 2010-10-14 Composiciones que comprenden n-(3,4-difluoro-2-(2-fluoro-4-yodofenilamino)6-metoxifenil)-1-(2,3-dihidroxiproxipropil)ciclopropan-1-sulfamida
MA33245A MA32226B1 (fr) 2008-04-14 2010-10-14 Compositions et leurs procedes de preparation et d'utilisation
HK11101625.8A HK1147396A1 (en) 2007-07-30 2011-02-18 Derivatives of n-(arylamino) sulfonamides including polymorphs as inhibitors of mek as well as compositions, methods of use and methods for preparing the same
AU2015200390A AU2015200390B2 (en) 2007-07-30 2015-01-28 Derivatives of N-(arylamino) sulfonamides including polymorphs as inhibitors of MEK as well as compositions, methods of use and methods for preparing the same
PH12015501914A PH12015501914A1 (en) 2007-07-30 2015-08-28 Derivatives of n-(arylamino) sulfonamides including polymorphs as inhibitors of mek as well as compositions, methods of use and methods for preparing the same

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US11/830,733 2007-07-30
US11/830,733 US8101799B2 (en) 2005-07-21 2007-07-30 Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
US3446608P 2008-03-06 2008-03-06
US3446408P 2008-03-06 2008-03-06
US61/034,464 2008-03-06
US61/034,466 2008-03-06
US4488608P 2008-04-14 2008-04-14
US61/044,886 2008-04-14

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JP (3) JP2010535232A (fr)
KR (3) KR20150091434A (fr)
CN (2) CN103479604B (fr)
AP (1) AP2817A (fr)
AU (2) AU2008282338B2 (fr)
BR (1) BRPI0815659A2 (fr)
CA (1) CA2693390C (fr)
CO (1) CO6470808A2 (fr)
CR (1) CR11244A (fr)
DO (1) DOP2010000045A (fr)
EA (2) EA020624B1 (fr)
EC (1) ECSP109910A (fr)
HK (1) HK1147396A1 (fr)
HN (1) HN2010000203A (fr)
IL (1) IL203296A (fr)
MA (1) MA31881B1 (fr)
MX (1) MX2010001244A (fr)
NZ (1) NZ582929A (fr)
PH (1) PH12015501914A1 (fr)
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EP2848246A1 (fr) 2013-09-13 2015-03-18 Bayer Pharma Aktiengesellschaft Compositions pharmaceutiques contenant du refametinib
WO2015041534A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut P90rsk en combinaison avec raf/erk/mek
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US9987357B2 (en) 2013-02-04 2018-06-05 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a WNT pathway inhibitor
US10010507B1 (en) 2015-03-03 2018-07-03 Pharmacyclics Llc Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor
US10065968B2 (en) 2012-06-04 2018-09-04 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
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EP2291350A4 (fr) * 2008-04-14 2012-09-19 Ardea Biosciences Inc Compositions et leurs procédés de préparation et d utilisation
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CN102143943A (zh) * 2008-09-09 2011-08-03 弗·哈夫曼-拉罗切有限公司 酰基磺酰胺的多晶型物
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JP2013508318A (ja) * 2009-10-21 2013-03-07 バイエル・ファルマ・アクチェンゲゼルシャフト 置換されたベンゾスルホンアミド誘導体
US9579361B2 (en) 2010-01-12 2017-02-28 Oncomed Pharmaceuticals, Inc. Wnt antagonist and methods of treatment and screening
WO2012059041A1 (fr) 2010-11-02 2012-05-10 Centaurus Biopharma Co., Ltd. Nouveaux 6-arylaminopyridonecarboxamides comme inhibiteurs de mek
WO2013109142A1 (fr) 2012-01-16 2013-07-25 Stichting Het Nederlands Kanker Instituut Inhibition de la voie des mapk/erk et pdk combinée dans des cas de néoplasie
US10106548B2 (en) 2012-06-04 2018-10-23 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
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US10752634B2 (en) 2012-06-04 2020-08-25 Pharmacyclics Llc Crystalline forms of a brutons tyrosine kinase inhibitor
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US10961251B1 (en) 2012-06-04 2021-03-30 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
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US9987357B2 (en) 2013-02-04 2018-06-05 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a WNT pathway inhibitor
EP2848246A1 (fr) 2013-09-13 2015-03-18 Bayer Pharma Aktiengesellschaft Compositions pharmaceutiques contenant du refametinib
WO2015041534A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut P90rsk en combinaison avec raf/erk/mek
WO2015041533A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut Association de rock et de la voie mapk
WO2015156674A2 (fr) 2014-04-10 2015-10-15 Stichting Het Nederlands Kanker Instituut Méthode de traitement du cancer
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MX2010001244A (es) 2010-08-31
JP6309880B2 (ja) 2018-04-11
AU2015200390B2 (en) 2017-02-23
BRPI0815659A2 (pt) 2014-09-30
TN2010000049A1 (en) 2011-09-26
IL203296A (en) 2017-06-29
JP2010535232A (ja) 2010-11-18
ECSP109910A (es) 2010-04-30
NZ582929A (en) 2012-03-30
AP2817A (en) 2013-12-31
EP2184984A4 (fr) 2013-07-24
MA31881B1 (fr) 2010-12-01
KR20140098185A (ko) 2014-08-07
JP2017125021A (ja) 2017-07-20
SV2010003469A (es) 2010-04-30
KR20150091434A (ko) 2015-08-10
EA020624B1 (ru) 2014-12-30
EP2184984A1 (fr) 2010-05-19
DOP2010000045A (es) 2010-10-31
CN103479604A (zh) 2014-01-01
CA2693390A1 (fr) 2009-02-05
JP2015078199A (ja) 2015-04-23
EA201400552A1 (ru) 2014-09-30
CN103479604B (zh) 2016-08-10
KR20100092424A (ko) 2010-08-20
AU2008282338A1 (en) 2009-02-05
PH12015501914A1 (en) 2017-07-31
CR11244A (es) 2010-05-20
CN101808516B (zh) 2013-08-28
AP2010005134A0 (en) 2010-02-28
HN2010000203A (es) 2012-11-19
HK1147396A1 (en) 2011-08-12
EA032294B1 (ru) 2019-05-31
CN101808516A (zh) 2010-08-18
CA2693390C (fr) 2017-01-17
AU2008282338B2 (en) 2015-02-12
EA201000268A1 (ru) 2010-08-30
CO6470808A2 (es) 2012-06-29

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