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WO2007057768A2 - Sulfonyl derivatives - Google Patents

Sulfonyl derivatives Download PDF

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Publication number
WO2007057768A2
WO2007057768A2 PCT/IB2006/003287 IB2006003287W WO2007057768A2 WO 2007057768 A2 WO2007057768 A2 WO 2007057768A2 IB 2006003287 W IB2006003287 W IB 2006003287W WO 2007057768 A2 WO2007057768 A2 WO 2007057768A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
membered heterocycle
term
Prior art date
Application number
PCT/IB2006/003287
Other languages
French (fr)
Other versions
WO2007057768A3 (en
Inventor
Hengmiao Cheng
Stephan James Cripps
Jennifer Anne Lafontaine
Phuong Thi Quy Le
Jean Joo Matthews
Sajiv Krishnan Nair
Original Assignee
Pfizer Products 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.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2007057768A2 publication Critical patent/WO2007057768A2/en
Publication of WO2007057768A3 publication Critical patent/WO2007057768A3/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48Sulfur atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96Sulfur atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D265/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/281,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/301,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11- ⁇ -hsd-1).
  • Metabolic Syndrome e.g. raised blood pressure, decreased levels of HDL and increased levels of VLDL
  • VLDL VLDL
  • Obesity is an important factor in Metabolic Syndrome as well as in the majority (>80%) of type 2 diabetic, and omental fat appears to be of central importance.
  • Inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e.
  • 11- ⁇ -hsd-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
  • the invention relates to a compound of the formula (I):
  • n is 0 or 1 ;
  • R 1 is H, halo, CN, C r C 6 a!ky!, OR 7 , C r C 6 alkyl-OR 7 , NR 7 R 8 , C r C 6 alkyl-NR 7 R 8 , aryl, heterocycle, (C 1 -
  • R 2 and R 3 are each independently H, Ci-C 5 alkyl, (CR 7 R 8 ) m OR 9 wherein m is an integer from 0 -4, aryl, (C 1 -
  • C 4 alkyl)aryl or may together optionally cyclize to form a non-aromatic 4-6 membered heterocycle which is optionally further substituted with a C r C B alkyl;
  • R 4 is d-Cealkyl, CrC 6 alkyl-OR 7 , cycloalkyl, aryl, (4 to 10)-membered heterocycle, (C r C 4 alkyl)-cycloalkyl,
  • R 4 is optionally substituted with 1-4 R 6 groups
  • R 5 is H, C r C 6 alkyl, or cycloalkyl
  • R 6 is independently selected from the group consisting of halo, CN, CF 3 , CHF 2 , CH 2 F, trifluoromethoxy, OR 7 , CrCealkyl, d-Cealkenyl, C r C 6 alkynyl, (CR 7 R 8 ) P CONR S R 10 , (CR 7 R 8 ) P NRC(O)R 9 , (CR 7 R 8 ) P NR 9 R 10 ,
  • R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group of H, d-Cealkyl, cycloalkyl, aryl,
  • R 6 substituents can optionally be further substituted with 1-4 R 12 .
  • R 12 is independently selected from the group consisting of halo, CN, CF 3 , CHF 2 , CH 2 F, trifluoromethoxy,
  • R 13 , R 14 , R 15 , R 15 and R 17 are each independently selected from the group of H, C r C e alkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (Ci-C 4 alky))-cycloalkyl, (C 1 -C 4 alkyl)aryl, and (C- ⁇ -C 4 alkyl)- (4 to 10)-membered heterocycle.
  • n 0.
  • the invention relates to a compound of the formula (II):
  • R 1 is H, halo, CN, C r C 6 alkyl, OR 7 , C r C 6 alkyl-OR 7 , NR 7 R 8 , C r C 6 alkyl-NR 7 R 8 , aryl, heterocycle, (C 1 -
  • R 2 and R 3 together cyclize to form a non-aromatic 4-6 membered heterocycle which is optionally further substituted with a C r C 6 alkyl;
  • R 4 is C r C 6 alkyl, C r C 6 alkyl-OR 7 , cycloalkyl, aryl, (4 to 10)-membered heterocycle, (C r C 4 alkyl)-cycloalkyl,
  • R 4 is optionally substituted with 1-4 R 6 groups
  • R 5 is H, C r C 6 alkyl, or cycloalkyl
  • R 6 is independently selected from the group consisting of halo, CN, CF 3 , CHF 2 , CH 2 F, trifluoromethoxy, OR 7 , C r C 6 alkyl, C r C 6 alkenyl, d-C 6 alkynyl, (CR r R 8 ) p CONR 9 R 10 , (CR 7 R 8 ) P NRC(O)R 9 , (CR 7 R 8 ) P NR 9 R 1Q ,
  • R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group of H, C r C 6 alkyl, cycloalkyl, aryl,
  • R 6 substituents can optionally be further substituted with 1-4 R 12 .
  • R 12 is independently selected from the group consisting of halo, CN, CF 3 , CHF 2 , CH 2 F, trifluoromethoxy, OR 13 , d-C ⁇ alkyl, C r C 6 alkenyl, C r C 6 alkynyl, (CR 13 R 14 ) q CONR 15 R 16 , (CR 13 R 14 ) q NRC(O)R 1s , (CR 13 R 14 ) q NR 15 R 18 , (CR 13 R 14 ) q COR 15 , (CR 13 R 14 ) q CO 2 R 15 , cycloalkyl, aryl, (4 to 10)-membered heterocycle, (C r C 4 all ⁇ yl)-cycloalkyl, (CrC 4 alkyl)aryl, (C r C 4 alkyl)- (4 to 10)-membered heterocycle, (CR 13 R 14 ) q SO 2 R 15 , (CR 13 R 14 ) q SOR 1
  • R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from the group of H, C-pCgalkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (Ci-C 4 alkyl)-cycloalkyl, (Ci-C 4 alkyl)aryl, and (CrC 4 alkyl)- (4 to 10)-membered heterocycle.
  • n is 0 and R 2 and R 3 together cyclize to form a morpholine.
  • n is 0 and R 2 and R 3 together cyclize to form a pyrrolidine.
  • n is 0 and R 2 and R 3 together cyclize to form an azabicyclo[3.1.0]hexane.
  • n 1
  • n is 1 and R 2 and R 3 together cyclize to form a piperidine.
  • the invention relates to pharmaceutical compositions having an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable carrier.
  • the invention relates to methods for treating conditions that are mediated by the modulation of the 11- ⁇ -hsd-1 enzyme by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof.
  • the invention relates to methods for treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, viral diseases, ophthalmic disorders, inflammatory disorders, or diseases in which the liver is a target organ by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof.
  • the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof.
  • the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with latanoprost.
  • the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with a carbonic anhydrase inhibitor.
  • the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with an EP2 or EP4 agonist.
  • the invention relates to methods for treating diabetes by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with a PPAR agonist.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkyl groups of the invention include Ci-C 6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and so on.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkoxy as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
  • amino as used herein, is intended to include the -NH 2 radical, and any substitutions of the N atom.
  • heteroalkyl alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon (oxygen, nitrogen, sulfur, phosphorus or combinations thereof).
  • heteroalkyls, heteroalkenyls and heteroalkynyls include, e.g.
  • trifluoromethyl is meant to represent a -CF 3 group.
  • trifluoromethoxy is meant to represent a -OCF 3 group.
  • cyano as used herein, is meant to represent a -CN group.
  • OMs as used herein, is intended to mean, unless otherwise indicated is intended to mean methanesulfonate.
  • HOBt 1 -hydroxybenzotriazole is intended to mean, unless otherwise indicated is intended to mean 1 -hdroxybenzotriazole.
  • Me as used herein, unless otherwise indicated, is intended to mean means methyl.
  • MeOH as used herein, unless otherwise indicated, is intended to mean means methanol.
  • Et 2 O as used herein, unless otherwise indicated, is intended to mean means diethylether.
  • EtOH as used herein, unless otherwise indicated, is intended to mean means ethanol.
  • Et 3 N as used herein, unless otherwise indicated, is intended to mean means triethylamine.
  • EtOAc is ethyl acetate
  • TFA trifluoroacetic acid
  • TEA triethanolamine
  • HATU N,N,N',N'- tetramethyluronium hexafluorophosphate.
  • DIPEA diisopropyl ethyl amine
  • DCE diisopropyl ethyl amine
  • THF tetrahydrofuran
  • BHT butylated hydroxy toluene
  • Boc t-butoxycarbonyl
  • (Boc) 2 O is intended to mean di-tert-butyl dicarbonate.
  • CBZ 1 as used herein, unless otherwise indicated is intended to mean benzyloxycarbonyl.
  • NMM N-methyl- morpholine
  • MTBE tert-butyl methyl ether
  • DMAP 4- (dimethylamino)pyridine
  • EDC 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • TIOH thallium(l) hydroxide
  • TIOEt as used herein, unless otherwise indicated, is intended to mean thallium(l) ethoxide.
  • PCy 3 as used herein, is intended to mean tricyclohexylphosphine.
  • Pd 2 (dba) 3 is intended to mean tris(dibenzylideneacetone)dipalladium(0).
  • Pd(OAc) 2 is intended to mean palladium(ll) acetate.
  • Pd(PPh 3 ) 2 Cl 2 is intended to mean dichlorobis(triphenylphosphine)palladium(ll).
  • Pd(PPh 3 ) 4 as used herein, unless otherwise indicated, is intended to mean tetrakis(triphenylphophine)palladium(0).
  • Pd(dppf)CI 2 is intended to mean (1 ,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll), complex with dichloromethane (1:1 ).
  • Pd/C palladium on carbon
  • PyBOP as used herein, unless otherwise indicated, is intended to mean benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate.
  • DIEA as used herein unless otherwise indicated, is intended to mean N 1 N- diisopropylethylamine.
  • G6P glucose-6- phosphate
  • NIDDM non insulin dependent diabetes mellitus
  • NAHMDS sodium bis(trimethylsilyl)amide.
  • NADPH nicotinamide adenine dinucleotide phosphate, reduced form.
  • CD 3 OD is intended to mean deuteromethanol.
  • CD 3 CN is intended to mean deuteroacetonitrile.
  • DEAD is intended to mean diethyl azodicarboxylate.
  • DIAD diisopropyl azodicarboxylate
  • TsCH 2 NC is intended to mean tosylmethyl isocyanide.
  • CISO 3 H is intended to mean chlorosulfonic acid.
  • DMSO-d s or "DMSO-D 6 ,” as used herein, is intended to mean deuterodimethyl sulfoxide.
  • DME is intended to mean 1 ,2-dimethoxyethane.
  • DMF is intended to mean ⁇ /, ⁇ /-dimethylformamide.
  • DMSO dimethylsulfoxide
  • Dl deionized
  • KAc potassium acetate
  • mmol as used herein, is intended to mean millimole.
  • mm as used herein, is intended to mean millimeter.
  • min is intended to mean minute.
  • ⁇ l_ is intended to mean microliter.
  • ⁇ M is intended to mean micromolar.
  • ⁇ m is intended to mean micrometer.
  • M is intended to mean molar.
  • N is intended to mean normal.
  • nanometer is intended to mean nanometer.
  • nM is intended to mean nanoMolar.
  • wt/wt is intended to mean weight/weight.
  • v/v is intended to mean volume/volume.
  • UV ultraviolet
  • APCI-MS atmospheric pressure chemical ionization mass spectroscopy
  • HPLC high performance liquid chromatograph
  • LC liquid chromatograph
  • LCMS liquid chromatography mass spectroscopy
  • ELSD evaporative light scattering detection
  • MS mass spectroscopy
  • HRMS electrospray ionization
  • NA as used herein, unless otherwise indicated, is intended to mean not available.
  • RT room temperature
  • Celite ® as used herein, unless otherwise indicated, is intended to mean a white solid diatomite filter agent commercially available from World Minerals located in Los Angeles, California USA.
  • Ki is intended to mean values of enzyme inhibition constant.
  • Kj is intended to mean K, apparent.
  • IC 50 is intended to mean concentrations required for at least 50% enzyme inhibition.
  • cycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 9 carbon atoms, preferably 5-8 ring carbon atoms.
  • exemplary cycloalkyls include monocyclic rings having from 3-9 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • (4 to 10)-membered heterocyclyl includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms, respectively, in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is qui ⁇ olinyl.
  • non-aromatic heterocyclic groups are 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- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolin
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, fury], thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-2-yl (C-attached).
  • the 4 to 10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein the ring atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl.
  • a “solvate” is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.
  • the compounds of the present invention may have asymmetric carbon atoms. The carbon- carbon bonds of the compounds of the present invention may be depicted herein using a solid line
  • a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • Solutions of individual stereoisomeric compounds of the present invention may rotate plane- polarized light.
  • the use of either a "(+)" or “(-)” symbol in the name of a compound of the invention indicates that a solution of a particular stereoisomer rotates plane-polarized light in the (+) or (-) direction, as measured using techniques known to those of ordinary skill in the art.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
  • individual stereoisomeric compounds of the present invention may be prepared in enantiomerically enriched form by asymmetric synthesis.
  • Asymmetric synthesis may be performed using techniques known to those of skill in the art, such as the use of asymmetric starting materials that are commercially available or readily prepared using methods known to those of ordinary skill in the art, the use of asymmetric auxiliaries that may be removed at the completion of the synthesis, or the resolution of intermediate compounds using enzymatic methods.
  • the choice of such a method will depend on factors that include, but are not limited to, the availability of starting materials, the relative efficiency of a method, and whether such methods are useful for the compounds of the invention containing particular functional groups. Such choices are within the knowledge of one of ordinary skill in the art.
  • the derivative salts, prodrugs and solvates may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.
  • an optically pure compound is one that is enantiomerically pure.
  • the term "optically pure” is intended to mean a compound comprising at least a sufficient activity.
  • an optically pure amount of a single enantiomer to yield a compound having the desired pharmacological pure compound of the invention comprises at least 90% of a single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maieic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such as glucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citric acid or tartaric acid; amino acid, such as aspartic acid or glutamic acid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonic acid, such as p- toluenesulfonic acid or ethanesulfonic acid; and the like.
  • an inorganic acid such as hydrochloric acid; hydrobromic acid; sulfuric acid
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • derivatives, prodrugs, salts, or solvates that are solids
  • the derivatives, prodrugs, salts, and solvates used in the method of the invention may exist in different polymorph or crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
  • the derivative, salts, prodrugs and solvates used in the method of the invention may exist as tautomers, all of which are intended to be within the broad scope of the present invention.
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • Certain compounds may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds and mixtures thereof, are considered to be within the scope of the invention.
  • the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof.
  • the compounds may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those described 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 that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention 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.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the invention. Such compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, Le., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate,
  • Methodabolic syndrome means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • modulate refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/m 2 , and for females, as individuals whose body mass index is greater than 27.3 kg/m 2 .
  • the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
  • inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
  • terapéuticaally effective amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • amount . . . effective to lower blood glucose levels refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect.
  • Such a concentration typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being one example.
  • concentrations typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being one example.
  • insulin resistance refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
  • insulin resistance syndrome refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
  • NIDDM non insulin dependent diabetes mellitus
  • bioisosteric groups that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties.
  • Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al.,
  • the compounds of the present invention are modulators of 11- ⁇ -hsd-1.
  • the compounds of the present invention may modulate processes mediated by 11- ⁇ -hsd-1 , which refer to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the 11- ⁇ -hsd-1 inhibitors described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g.
  • ischemic heart disease and the like cell injury (e.g.) brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
  • inflammatory diseases e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, e
  • the compounds according to the present invention may be used in several indications which involve modulations of 11- ⁇ -hsd-1 enzyme.
  • the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical Endocrinology and Metabolism, 81 , 3441-3447) and may also be used disorders in the immune system (see Franchimont et al, "Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes", The Journal of Immunology 2000, Feb 15, vol 164 (4), pages 1768-74) and also in the above listed indications.
  • Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11- ⁇ -hsd-1 in the brain might increase satiety and therefore reduce food intake (Woods, S.C., et al., (1998), Science, 280:1378-1383).
  • Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and
  • glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A.W., (1999), Baillier's Clin. Endocrinol Metab., 13: 576-581).
  • HPA hypothalamo-pituitary-adrenal
  • the balance between the cell- mediated response and humoral responses is modulated by glucocorticoids.
  • a high glucocorticoid activity such as at a state of stress, is associated with a humoral response.
  • inhibition of the enzyme 11- ⁇ - hsd-1 has been suggested as a means of shifting the response towards a cell-based reaction.
  • 11- ⁇ -hsd-1 In the eye, expression of 11- ⁇ -hsd-1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris.
  • the distant isoenzyme 11 beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage.
  • 11- ⁇ -hsd-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
  • Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess.
  • Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, CH. , Cheng, S.L, and Kim, G.S., (1999) J. Endocrinol., 162: 371-379).
  • the negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11- ⁇ -hsd-1 in the glucocorticoid effect (Bellows, CG. , Ciaccia, A. and.
  • the compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (10 th Ed.). Assay
  • the inhibition constant, Ki was measured in a buffer containing 100 mM triethanolamine, 200 mM NaCI, 0.02% n-dodecyl ⁇ -maltoside, 5% glycerol, 5 mM ⁇ -mercaptoethanol, 1% DMSO, pH 8.0.
  • the activity of human 11b-hsd-1 is measured on a Corning 96-well plate for a total volume of 300 uL/well in the presence and absence of inhibitor. In each well, varying amounts of compounds are incubated with a fixed amount of 11b-hsd-1 (4 nM) and NADPH (500 uM) for 30 to 40 min at room temperature in the assay buffer.
  • the enzyme concentration was determined by titration using reversible tight-binding inhibitors.
  • the activity remaining after the pre-incubation period is measured by adding a fixed concentration of 3H-cortisone (200 nM) and the regeneration system constituted with 2 mM glucose- 6-phosphate, 1 U/mL glucose-6-phosphate dehydrogenase and 6 mM MgCI 2 .
  • the final concentration of cortisone in the assay buffer is lower than the K m value (328 nM).
  • the enzyme activity is quenched by mixing an aliquot of the assay buffer with an equal volume of DMSO in a second 96-well plate.
  • Vj, and V 0 are the rates of Cortisol formation in the presence and in the absence of inhibitor, respectively, I is the inhibitor concentration and E is the 11b-hsd-1 concentration in the assay buffer. All the concentrations reported are the final concentrations in the assay buffer
  • Glucose-6-Phosphate dehydrogenase was purchased from Sigma.
  • HEK293-11 ⁇ HSD1/GRE-Luciferase cell-based assay ECm determination Inhibition of 11 ⁇ HSD1 enzyme activity was measured using human kidney HEK293 stable transfected cells, over-expressing human 11 ⁇ HSD1 , and a reporter plasmid containing DNA sequences for specific recognition of glucocorticoid-activated glucocorticoid receptors (GRE), using a method similar to that described in Bujalska et al, Human 11 ⁇ -hydroxysteroid dehydrogenase: Studies on the stably transfected isoforms nd localization of the type 2 isozyme within renal tissue, Steroids, 62(1), 1991 , pp 77- 82 .
  • 11 ⁇ HSD1 is responsible for converting inactive into active glucocorticoids (cortisone to Cortisol, in humans).
  • Cortisol but not cortisone
  • GR glucocorticoid receptors
  • a compound with the capability of inhibiting 11 ⁇ HSD1 will reduce the luciferase signal, compare to cortisone control (enzyme substrate).
  • the compounds of the invention may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of 11- ⁇ -hsd-1 mediated diseases.
  • the compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs.
  • the compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets.
  • these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
  • a pharmaceutically acceptable enteric coating such as glyceryl monostearate or glyceryl distearate
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension.
  • excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan mono
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension, This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
  • 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.
  • the compounds may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and other glycerides.
  • topical use preparations for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
  • the compounds may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles.
  • Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight.
  • An exemplary dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
  • a compound of the invention may also be injected directly into the vitreous humor or aqueous humor.
  • a compound may be also be administered by well known, acceptable methods, such as subtenon and/or subconjunctival injections.
  • the macula is comprised primarily of retinal cones and is the region of maximum visual acuity in the retina.
  • a Tenon's capsule or Tenon's membrane is disposed on the sclera.
  • a conjunctiva covers a short area of the globe of the eye posterior to the limbus (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of the upper eyelid and lower eyelid, respectively.
  • the conjunctiva is disposed on top of Tenon's capsule.
  • the sclera and Tenon's capsule define the exterior surface of the globe of the eye.
  • age related macular degeneration choroid neovascularization, retinopathies (such as diabetic retinopathy, retinopathy of prematurity), retinitis, uveitis, cystoid macular edema (CME), glaucoma, and other diseases or conditions of the posterior segment of the eye
  • ARMD and CME it is most preferable to dispose the depot directly on the outer surface of the sclera, below Tenon's capsule, and generally above the macula.
  • the compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned subtenon or intravitreal injection.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form.
  • the solution or suspension may be prepared in its pure form and administered several times daily.
  • the present compositions, prepared as described above may also be administered directly to the cornea.
  • the composition is prepared with a muco-adhesive polymer which binds to cornea.
  • 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.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained- release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid- or gel-phase carriers or excipients.
  • suitable solid- or gel-phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • the compounds of the invention may be prepared according to U.S. Provisional Patent Application No. 60/569,362, the entirety of which is hereby incorporated by reference.
  • NMR data was acquired on a Bruker DRX 300 NMR Spectrometer ® using a broadband decoupling scheme to decouple the protons from the carbons.
  • the Bruker DRX 300 NMR Spectrometer ® is commercially available from Buker Biospin Corporation of Billercia, Massachusetts.
  • Purification Conditions included a Waters ® Bondapak column C18, 37-55 micron (particle size), 47x300 mm (column size) having a flow rate of 75 mL/min, a detector of UV 220 nm, where Buffer A is: 0.1 %HOAc in H 2 O and Buffer B is: 0.1%HOAc in CH 3 CN.
  • the Waters ® Bondapak column C18 is commercially available from Varian, Inc. of Palo Alto, California, USA.
  • the column was equilibrated in Buffer A for 20 min.
  • the sample was dissolved in 10 mL of DMSO, filtered, and injected onto the column.
  • the gradient was held at 100% in Buffer A for 5 min and then increased linearly to 90%Buffer A/10%Buffer B in 20 min and then held at 10% Buffer B for another 25 min.
  • the desired product came out at about 26 min during the isocratic hold of the gradient.
  • the fractions were checked, pooled, and lyophilized to afford a syrup.
  • Analytical LCMS Method Post-purification
  • the compound of formula D may be prepared by reacting a compound of formula C with R 4 SO 2 X wherein X is a leaving group such as Cl, Br, I, OMs, etc. in a suitable solvent (e.g. dichloromethane or DMF) advantageously, in the presence of a base (e.g. K 2 CO 3 , NaHCO 3 , Et 3 N), at a temperature ranging from about -78 degrees Celsius to the boiling point of the solvent, typically from O degrees Celsius about 100 degrees Celsius.
  • a suitable solvent e.g. dichloromethane or DMF
  • a base e.g. K 2 CO 3 , NaHCO 3 , Et 3 N
  • Compound of formula C can be prepared by removing the protecting group P in the compound of formula B.
  • the compound of formula B can be prepared by coupling the compound of formula A with a substituted or unsubstituted adamantyl-2-amine, following standard amide bond formation methods by a method known to those skilled in the art.
  • Compound formula A is an acid wherein P is a protecting functional group such as Boc or Cbz.
  • the compound of formula D can be prepared by coupling the compound of formula G with a substituted or unsubstituted adamantyl-2-amine following standard amide bond formation methods by a method known to those skilled in the art.
  • Compound of formula G may be prepared by treatment of compound of formula F, where R is an alkyl or cycloalkyl group, with a base such as NaOH, KOH, LiOH in a suitable solvent such as MeOH and water at an optimum temperature, typically ranging from room temperature to 60 degrees Celsius.
  • Compound of formula F may be prepared by reacting a compound of formula E with R 4 SO 2 X wherein X is a leaving group such as Cl, Br, I, OMs, etc.
  • a suitable solvent e.g. dichloromethane or DMF
  • a base e.g. K 2 CO 3 , NaHCO 3 , Et 3 N
  • a temperature ranging from about -78 degrees Celsius to the boiling point of the solvent, typically from O degrees Celsius about 100 degrees Celsius.
  • the compound of formula D can be prepared by treatment of the compound of formula F with a substituted or unsubstituted adamantyl-2-amine in a suitable solvent at a suitable temperature or in a suitable solvent in the presence of a Lewis acid such as AICI 3 .
  • a Lewis acid such as AICI 3 .
  • N-(tert-Butoxycarbonyl)-D-proline (43.6g, 202 mmol) was added to a slurry of 2-adamantylamine hydrochloride (38.3 g, 204 mmol), DMF (500 mL) and triethylamine (40.0 g, 395 mmol).
  • the resulting very thick suspension was stirred vigorously and cooled to 11 0 C.
  • the coupling reagent PyBOP (120.0 g, 230 mmol) in DMF (100 mL) was added while maintaining the temperature below 16 0 C and the heterogeneous reaction mixture was left in an ice-water bath overnight.
  • the reaction mixture was partitioned between water (3 L) and ethyl acetate:MTBE (1 :1.4 L). The aqueous layer was extracted with ethyl acetate:MTBE (1 :1 2x1 L). The combined organic layers were washed with brine (2x1 L) and dried over MgSO 4 , and filtered. The solvents were removed in vacuo and the product Ia was purified by chromatography (silica gel 50Og; eluted with hexanes:ethyl acetate, 3:1 ). Yield: 62.9 g.
  • Examples 2-14 Examples 2 through 14 were prepared using methods analogous to example 1 above except that the 2-chlorobenzenesulfonyl chloride was substituted with corresponding sulfonyl halide reagents. It is expected that examples 15 through 17 may also be prepared using methods analogous to example 1..
  • Examples 24 and 25 N-2-adamantyl-1- ⁇ [4-(aminocarbonyl)-2-chlorophenyl]sulfonyl ⁇ -D- prolinamide (24) and 4-( ⁇ (2R)-2-[(2-adamantylamino)carbonyl]pyrrolidin-1-yl ⁇ sulfonyl)-3- chlorobenzoic acid (25)
  • Example 26 through 29 were prepared using methods analogous to example 24 and 25 above.
  • Example 30 4-[(R)-2-(Adamantan-2-ylcarbamoyI)-pyrrolidine-1-sulfonyl]-benzoic acid methyl ester.
  • Example 31 N-2-adamantyl-1- ⁇ [4-(hydroxymethyI)phenyl]sulfonyl ⁇ -D-prolinamide.
  • lntermediate 33a ⁇ /-2-adamantyl-1-[(6-chloropyridin-3-yl)sulfonyl]-D-prolinamide
  • the sulfonamide was made using methods analogous to example 1 above, and was purified by trituration using methyl-t-butyl ether and CH 2 CI 2 .
  • piperidine analogs 34a and 34 were prepared in a manner similar to example 33 above, except that N-(tert-butoxycarbonyl)-D-proline was replaced with (3S)-1-(tert-butoxycarbonyl)piperidine-3- carboxylic acid.
  • Example 34 The title compound 34 was made by the same procedure as Example 19 and was purified by silica gel chromatography using 100% EtOAc. Examples 36 and 37:

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Abstract

The present invention relates to compounds, pharmaceutical compositions comprising these compounds and methods for treating a condition that is mediated by the modulation of the 11-β-hsd-1 enzyme.

Description

SULFONYL DERIVATIVES
This application claims the benefit of U. S. Provisional Application No. 60/863,542 filed October 30, 2006; U. S. Provisional Application No. 60/799,207 filed May 9, 2006; U. S. Provisional Application No. 60/753,759 filed December 23, 2005; and U. S. Provisional Application No. 60/738,154 filed November 18, 2005, the contents of which are hereby incorporated by reference in their entireties.
Field Of The Invention
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (11-β-hsd-1).
Background Of The Invention The role of 11-β-hsd-1 as an important regulator of local glucocorticoid effects and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692). The hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11- β-hsd-1 inhibitor carbenoxolone (Walker, B.R., et al. (1995) J. CHn. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (GΘPase) catalyzing the last common step of gluconeogenesis and glycogenosis. Finally, the blood glucose level and hepatic glucose production was reduced in mice having the 11-β-hsd-1 gene knocked-out. Data from this model also confirms that inhibition of 11-β-hsd-1 will not cause hypoglycemia, as predicted, since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, Y., et al., (1997) Proc. Natl. Acad. ScL USA 94: 14924-14929).
Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called Metabolic Syndrome (e.g. raised blood pressure, decreased levels of HDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes 49: 883-888, 2000). Obesity is an important factor in Metabolic Syndrome as well as in the majority (>80%) of type 2 diabetic, and omental fat appears to be of central importance. Inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, IJ. , Kumar, S., and Stewart, P.M. (1997; Lancet 349: 1210-1213). Recent data suggests that the levels of the glucocorticoid target receptors and the 11-β-hsd-1 enzymes determine the susceptibility to glaucoma (Stokes, J., et al., (2000) Invest. Ophthalmol., 41 :1629- 1638). Further, inhibition of 11-β-hsd-1 was recently presented as a novel approach to lower the intraocular pressure (Walker , E. A., et al, poster P3-698 at the Endocrine society meeting June 12-15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific inhibitor of 11-β-hsd-1 , was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11-β-hsd-1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11 beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11-β-hsd-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
Summary Of The Invention In one aspect, the invention relates to a compound of the formula (I):
Figure imgf000003_0001
(I) wherein; n is 0 or 1 ; R1 is H, halo, CN, CrC6a!ky!, OR7, CrC6alkyl-OR7, NR7R8, CrC6alkyl-NR7R8, aryl, heterocycle, (C1-
C4alkyl)aryl, (CrC4alkyl)heterocycle;
R2 and R3 are each independently H, Ci-C5alkyl, (CR7R8)mOR9 wherein m is an integer from 0 -4, aryl, (C1-
C4alkyl)aryl or may together optionally cyclize to form a non-aromatic 4-6 membered heterocycle which is optionally further substituted with a CrCBalkyl; R4 is d-Cealkyl, CrC6alkyl-OR7, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl,
(CrC4alkyl)aryl, or (CrC4alkyl)-(4 to 1Q)-membered heterocycle;
R4 is optionally substituted with 1-4 R6 groups;
R5 is H, CrC6alkyl, or cycloalkyl;
R6 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy, OR7, CrCealkyl, d-Cealkenyl, CrC6alkynyl, (CR7R8)PCONRSR10, (CR7R8)PNRC(O)R9, (CR7R8)PNR9R10,
(CR7R8JpCOR9, (CR7R8JpCO2R9, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cydoalkyl,
(CrC4alkyl)aryl, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR7R8)PSO2R9, (CRrR8)qSOR9,
(CR7R8)PSO2NR9R10, (CR7R8)pN R9SO2R10, O(CR7R8)paryl, (CR7R8)pNR9C(O)NR10R11, ,
(CR7R8JpNR9C(O)OR10, (CR7R8)POC(O)NR9R10, (CR7R8)POR9, O(CR7R8)p0R9, and O(CR7R8)PNR9R10, wherein p is an integer from 0-4;
R7, R8, R9, R10 and R11 are each independently selected from the group of H, d-Cealkyl, cycloalkyl, aryl,
(4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl, (CrC4alkyl)aryl, and (CrC4alkyl)-(4 to 1O)- membered heterocycle;
R6 substituents can optionally be further substituted with 1-4 R12. R12 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy,
OR13, CrC6alkyl, CrCealkenyl, CrCealkynyl, (CR13R14)qCONR15R16, (CR13R14)qNRC(O)R15, (CR13R14)qNR15R1B, (CR13R14X1COR15, (CR13R14)qCO2R15, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cyGloalkyl, (CrC4alkyl)aryt, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR13R14)qSO2R15, (CR13R14)qSOR15, (CR13R14)qSO2NR15R16, (CR13R14)qNR15SO2R16, O(CR13R14)qaryl, (CR13R14^NR15C(O)NR13R17, , (CR13R14)qNR15C(O)OR16, (CR13R14)qOC(O)NR15R16, (CR13R14)qOR15, O(CR13R14)qOR15, and O(CR13R14)qNR15R16 wherein q is an integer from 0 -4; and
R13, R14, R15, R15 and R17 are each independently selected from the group of H, CrCealkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (Ci-C4alky))-cycloalkyl, (C1-C4alkyl)aryl, and (C-ι-C4alkyl)- (4 to 10)-membered heterocycle.
In a further aspect of this embodiment, wherein R2 and R3 cyclize to form a 4-6 membered non-aromatic heterocycle. In a still further aspect of this invention, n is 0.
In another aspect, the invention relates to a compound of the formula (II):
Figure imgf000004_0001
(II) wherein; n is O oM;
R1 is H, halo, CN, CrC6alkyl, OR7, CrC6alkyl-OR7, NR7R8, CrC6alkyl-NR7R8, aryl, heterocycle, (C1-
C4alkyl)aryl, (Ci-C4alkyl)heterocycle;
R2 and R3 together cyclize to form a non-aromatic 4-6 membered heterocycle which is optionally further substituted with a CrC6alkyl; R4 is CrC6alkyl, CrC6alkyl-OR7, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl,
(CrC4alkyl)aryl, or (Ci-C4alkyl)-(4 to 10)-membered heterocycle;
R4 is optionally substituted with 1-4 R6 groups;
R5 is H, CrC6alkyl, or cycloalkyl;
R6 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy, OR7, CrC6alkyl, CrC6alkenyl, d-C6alkynyl, (CRrR8)pCONR9R10, (CR7R8)PNRC(O)R9, (CR7R8)PNR9R1Q,
(CR7R8)PCOR9, (CR7R8JpCO2R9, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (C-rQalkyO-cycloalkyl,
(Ci-C4alkyl)aryl, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR7R8)PSO2R9, (CR7R8)qSOR9,
(CR7R8)pSO2NR9R10, (CR7R8JpNR9SO2R10, O(CR7R8)paryl, (CR7R8)pNR9C(O)NR10R11, ,
(CR7R8VNR9C(O)OR10, (CR7R8)POC(O)NR9R10, (CR7R8)POR9, O(CR7R8)POR9, and O(CR7R8)PNR9R1Q, wherein p is an integer from 0-4;
R7, R8, R9, R10 and R11 are each independently selected from the group of H, CrC6alkyl, cycloalkyl, aryl,
(4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl, (Crdalkyljaryl, and (CrC4alkyl)-(4 to 10)- membered heterocycle;
R6 substituents can optionally be further substituted with 1-4 R12. - A -
R12 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy, OR13, d-Cβalkyl, CrC6alkenyl, CrC6alkynyl, (CR13R14)qCONR15R16, (CR13R14)qNRC(O)R1s, (CR13R14)qNR15R18, (CR13R14)qCOR15, (CR13R14)qCO2R15, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4all<yl)-cycloalkyl, (CrC4alkyl)aryl, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR13R14)qSO2R15, (CR13R14)qSOR1s, (CR13R14)qSO2NR15R16, (CR13R14)qNR15SO2R16, O(CR13R14)qaryl, (CR13R14)qNR15C(O)NR16R17, , (CR13R14)qNR15C(O)OR16, (CR13R14)qOC(O)NR15R18, (CR13R14)qOR15, O(CR13R14)qOR15, and O(CR13R14)qNR15R16 wherein q is an integer from 0 -4; and
R13, R14, R15, R16 and R17 are each independently selected from the group of H, C-pCgalkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (Ci-C4alkyl)-cycloalkyl, (Ci-C4alkyl)aryl, and (CrC4alkyl)- (4 to 10)-membered heterocycle.
In a further aspect of this embodiment, n is 0 and R2 and R3 together cyclize to form a morpholine.
In yet another aspect of this embodiment, n is 0 and R2 and R3 together cyclize to form a pyrrolidine.
In still another aspect of this embodiment, n is 0 and R2 and R3 together cyclize to form an azabicyclo[3.1.0]hexane.
In another alternative embodiment, n is 1.
In a further aspect of this embodiment, n is 1 and R2 and R3 together cyclize to form a piperidine.
Additional embodiments of the invention include compounds having the following structure:
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000006_0002
In another aspect, the invention relates to pharmaceutical compositions having an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable carrier.
In another aspect, the invention relates to methods for treating conditions that are mediated by the modulation of the 11-β-hsd-1 enzyme by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof. In another aspect, the invention relates to methods for treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, viral diseases, ophthalmic disorders, inflammatory disorders, or diseases in which the liver is a target organ by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof.
In another aspect, the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof.
In another aspect, the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with latanoprost.
In another aspect, the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with a carbonic anhydrase inhibitor. In a further aspect, the invention relates to methods for treating glaucoma by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with an EP2 or EP4 agonist.
In another aspect, the invention relates to methods for treating diabetes by administering to a mammal an effective amount of any of these compounds or pharmaceutically acceptable salts or solvates thereof, in combination with a PPAR agonist.
Definitions
The terms "comprising" and "including" as used herein, unless otherwise indicated, are used in their open, non-limiting sense. The term "alkyl," as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups of the invention include Ci-C6alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and so on.
The term "alkenyl," as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
The term "alkynyl," as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
The term "alkoxy," as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above. The term "amino," as used herein, is intended to include the -NH2 radical, and any substitutions of the N atom.
The term "azido", as used herein, is intended to mean N3.
The terms "halogen" and "halo," as used herein represent chlorine, fluorine, bromine or iodine. The terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl" include alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon (oxygen, nitrogen, sulfur, phosphorus or combinations thereof). Examples of heteroalkyls, heteroalkenyls and heteroalkynyls include, e.g. -(C1-C3 alkyl)-NRR, -(CrC3alkyl)-SR, -(C1-C3 alkyl)-SO2R, -(C1-C3 alkyl)- OR, -(C1-C3 alkyl)-PO2RR', -(C1-C3 alkyl)-PO3R, -(C1-C3 alkyl)-PO4 and the like, where R and R' are independently selected from H, alkyl, alkenyl, alkynyl and aryl but are not both H.
The term "trifluoromethyl," as used herein, is meant to represent a -CF3 group.
The term "trifluoromethoxy," as used herein, is meant to represent a -OCF3 group.
The term "cyano," as used herein, is meant to represent a -CN group. The term "OMs, " as used herein, is intended to mean, unless otherwise indicated is intended to mean methanesulfonate.
The term "HOBt," 1 -hydroxybenzotriazole is intended to mean, unless otherwise indicated is intended to mean 1 -hdroxybenzotriazole.
The term "Me," as used herein, unless otherwise indicated, is intended to mean means methyl. The term "MeOH," as used herein, unless otherwise indicated, is intended to mean means methanol.
The term "Et," as used herein, unless otherwise indicated, is intended to mean means ethyl.
The term "Et2O," as used herein, unless otherwise indicated, is intended to mean means diethylether. The term "EtOH," as used herein, unless otherwise indicated, is intended to mean means ethanol.
The term "Et3N," as used herein, unless otherwise indicated, is intended to mean means triethylamine.
The term "EtOAc," as used herein, unless otherwise indicated, is ethyl acetate.
The term "AIMe2CI," as used herein, unless otherwise indicated, is intended to mean dimethyl aluminum chloride.
The term "Ph," as used herein, unless otherwise indicated, is intended to mean phenyl.
The term "Ac," as used herein, unless otherwise indicated, is intended to mean means acetyl.
The term "TFA," as used herein, unless otherwise indicated, is intended to mean trifluoroacetic acid. The term "TEA," as used herein, unless otherwise indicated, is intended to mean triethanolamine.
The term "HATU," as used herein, unless otherwise indicated, is intended to mean N,N,N',N'- tetramethyluronium hexafluorophosphate.
The term "DIPEA," as used herein, unless otherwise indicated, is intended to mean diisopropyl ethyl amine. The term "DCE," as used herein, unless otherwise indicated, is intended to mean 1 ,2-dichloro ethane.
The term "THF," as used herein, unless otherwise indicated, is intended to mean tetrahydrofuran.
The term "BHT," as used herein, unless otherwise indicated, is intended to mean butylated hydroxy toluene. The term "Boc," as used herein, unless otherwise indicated, is intended to mean t-butoxycarbonyl.
The term "(Boc)2O," as used herein, unless otherwise indicated, is intended to mean di-tert-butyl dicarbonate. The term "CBZ1" as used herein, unless otherwise indicated is intended to mean benzyloxycarbonyl.
The term "nitro", as used herein, unless otherwise indicated is intended to mean NO2.
The term "NMM," as used herein, unless otherwise indicated is intended to mean N-methyl- morpholine. The term "MTBE," as used herein, unless otherwise indicated is intended to mean tert-butyl methyl ether.
The term "DMAP," as used herein, unless otherwise indicated is intended to mean 4- (dimethylamino)pyridine.
The term "EDC," as used herein, unless otherwise indicated is intended to mean 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
The term "TIOH," as used herein, unless otherwise indicated, is intended to mean thallium(l) hydroxide.
The term "TIOEt," as used herein, unless otherwise indicated, is intended to mean thallium(l) ethoxide. The term "PCy3," as used herein, is intended to mean tricyclohexylphosphine.
The term "Pd2(dba)3," as used herein, unless otherwise indicated, is intended to mean tris(dibenzylideneacetone)dipalladium(0).
The term "Pd(OAc)2," as used herein, unless otherwise indicated, is intended to mean palladium(ll) acetate. The term "Pd(PPh3)2Cl2," as used herein, unless otherwise indicated, is intended to mean dichlorobis(triphenylphosphine)palladium(ll).
The term "Pd(PPh3)4 " as used herein, unless otherwise indicated, is intended to mean tetrakis(triphenylphophine)palladium(0).
The term "Pd(dppf)CI2," as used herein, is intended to mean (1 ,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll), complex with dichloromethane (1:1 ).
The term "Pd/C," as used herein, unless otherwise indicated, is intended to mean palladium on carbon.
The term "PyBOP," as used herein, unless otherwise indicated, is intended to mean benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate. The term "DIEA," as used herein unless otherwise indicated, is intended to mean N1N- diisopropylethylamine.
The term "G6P," as used herein, unless otherwise indicated, is intended to mean glucose-6- phosphate. The term "NIDDM, as used herein, unless otherwise indicated, is intended to mean non insulin dependent diabetes mellitus.
The term "NAHMDS," as used herein unless otherwise indicated, is intended to mean sodium bis(trimethylsilyl)amide. The term "NADPH," as used herein, unless otherwise indicated, is intended to mean nicotinamide adenine dinucleotide phosphate, reduced form.
The term "CDCI3 or CHLORFORM-D," as used herein, is intended to mean deuterochloroform.
The term "CD3OD," as used herein, is intended to mean deuteromethanol.
The term "CD3CN," as used herein, is intended to mean deuteroacetonitrile. The term "DEAD," as used herein, is intended to mean diethyl azodicarboxylate.
The term "DIAD," as used herein, is intended to mean diisopropyl azodicarboxylate.
The term "TsCH2NC," as used herein, is intended to mean tosylmethyl isocyanide.
The term "CISO3H," as used herein, is intended to mean chlorosulfonic acid.
The term "DMSO-ds" or "DMSO-D6," as used herein, is intended to mean deuterodimethyl sulfoxide.
The term "DME," as used herein, is intended to mean 1 ,2-dimethoxyethane.
The term "DMF," as used herein, is intended to mean Λ/,Λ/-dimethylformamide.
The term "DMSO," as used herein, is intended to mean, unless otherwise indicated dimethylsulfoxide. The term "Dl," as used herein, is intended to mean deionized.
The term "KOAc," as used herein, is intended to mean potassium acetate.
The term "neat," as used herein, is meant to represent an absence of solvent.
The term "mmol," as used herein, is intended to mean millimole.
The term "eqv," as used herein, is intended to mean equivalent. The term "ml_," as used herein, is intended to mean milliliter.
The term "U," as used herein, is intended to mean units.
The term "mm," as used herein, is intended to mean millimeter.
The term "g," as used herein, is intended to mean gram.
The term "kg," as used herein, is intended to mean kilogram. The term "h," as used herein, is intended to mean hour.
The term "min," as used herein, is intended to mean minute.
The term "μl_," as used herein, is intended to mean microliter.
The term "μM," as used herein, is intended to mean micromolar.
The term "μm," as used herein, is intended to mean micrometer. The term "M," as used herein, is intended to mean molar.
The term "N," as used herein, is intended to mean normal.
The term "nm," as used herein, is intended to mean nanometer.
The term "nM," as used herein, is intended to mean nanoMolar.
The term "amu," as used herein, is intended to mean atomic mass unit. The term "0C," as used herein, is intended to mean Celsius.
The term "m/z " as used herein, is intended to mean, unless otherwise indicated, mass/charge ratio.
The term "wt/wt," as used herein, is intended to mean weight/weight. The term "v/v," as used herein, is intended to mean volume/volume.
The term "mL/min," as used herein, is intended to mean milliliter/minute.
The term "UV," as used herein, is intended to mean ultraviolet.
The term "APCI-MS," as used herein, is intended to mean atmospheric pressure chemical ionization mass spectroscopy. The term "HPLC," as used herein, is intended to mean high performance liquid chromatograph.
The term "LC," as used herein, is intended to mean liquid chromatograph.
The term "LCMS," as used herein, is intended to mean liquid chromatography mass spectroscopy.
The term "SFC," as used herein, is intended to mean supercritical fluid chromatography. The term "sat," as used herein, is intended to mean saturated.
The term "aq," as used herein, is intended to mean aqueous.
The term "ELSD," as used herein, is intended to mean evaporative light scattering detection.
The term "MS," as used herein, is intended to mean mass spectroscopy.
The term "HRMS (ESI)," as used herein, is intended to mean high resolution mass spectrometry (electrospray ionization).
The term "Anal.," as used herein, is intended to mean analytical.
The term "Calcd," as used herein, is intended to mean calculated.
The term "NA," as used herein, unless otherwise indicated, is intended to mean not available.
The term "RT," as used herein, unless otherwise indicated, is intended to mean room temperature.
The term "Celite®," as used herein, unless otherwise indicated, is intended to mean a white solid diatomite filter agent commercially available from World Minerals located in Los Angeles, California USA.
The term "Ki," as used herein, is intended to mean values of enzyme inhibition constant.
The term "Kj," app, as used herein, is intended to mean K, apparent. The term "IC50," as used herein, is intended to mean concentrations required for at least 50% enzyme inhibition.
The term "cycloalkyl", as used herein, unless otherwise indicated refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 9 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-9 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
Figure imgf000012_0001
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term "(4 to 10)-membered heterocyclyl", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms, respectively, in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quiπolinyl. Examples of non-aromatic heterocyclic groups are 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- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.Ojhexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, fury], thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-2-yl (C-attached). The 4 to 10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An example of a heterocyclic group wherein the ring atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4 to 10 membered heterocyclic are derived from, but not limited to, the following:
Figure imgf000013_0001
Unless otherwise indicated, the term "oxo" refers to =0.
A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine. The compounds of the present invention may have asymmetric carbon atoms. The carbon- carbon bonds of the compounds of the present invention may be depicted herein using a solid line
( ), a solid wedge ( ""^mm ), (J^ ) wavy line, or a dotted wedge ( -1111111HI ), The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. The use of a wavy line to depict bonds to asymmetric carbon atoms is meant to indicate the diastereomer is present. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
Solutions of individual stereoisomeric compounds of the present invention may rotate plane- polarized light. The use of either a "(+)" or "(-)" symbol in the name of a compound of the invention indicates that a solution of a particular stereoisomer rotates plane-polarized light in the (+) or (-) direction, as measured using techniques known to those of ordinary skill in the art.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
Alternatively, individual stereoisomeric compounds of the present invention may be prepared in enantiomerically enriched form by asymmetric synthesis. Asymmetric synthesis may be performed using techniques known to those of skill in the art, such as the use of asymmetric starting materials that are commercially available or readily prepared using methods known to those of ordinary skill in the art, the use of asymmetric auxiliaries that may be removed at the completion of the synthesis, or the resolution of intermediate compounds using enzymatic methods. The choice of such a method will depend on factors that include, but are not limited to, the availability of starting materials, the relative efficiency of a method, and whether such methods are useful for the compounds of the invention containing particular functional groups. Such choices are within the knowledge of one of ordinary skill in the art.
When the compounds of the present invention contain asymmetric carbon atoms, the derivative salts, prodrugs and solvates may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.
As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term "optically pure" is intended to mean a compound comprising at least a sufficient activity. Preferably, an optically pure amount of a single enantiomer to yield a compound having the desired pharmacological pure compound of the invention comprises at least 90% of a single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
If a derivative used in the method of the invention is a base, a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maieic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such as glucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citric acid or tartaric acid; amino acid, such as aspartic acid or glutamic acid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonic acid, such as p- toluenesulfonic acid or ethanesulfonic acid; and the like.
If a derivative used in the method of the invention is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative Examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. In the case of derivatives, prodrugs, salts, or solvates that are solids, it is understood by those skilled in the art that the derivatives, prodrugs, salts, and solvates used in the method of the invention, may exist in different polymorph or crystal forms, all of which are intended to be within the scope of the present invention and specified formulas. In addition, the derivative, salts, prodrugs and solvates used in the method of the invention may exist as tautomers, all of which are intended to be within the broad scope of the present invention.
The compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
Certain compounds may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
The subject invention also includes isotopically-labelled compounds, which are identical to those described 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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, 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 preferred in some circumstances, lsotopically labeled compounds of the invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the invention. Such compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, Le., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. The term "diseases in which the liver is a target organ", as used herein, unless otherwise indicated, means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria.
The term "Metabolic syndrome", as used herein, unless otherwise indicated means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.
The term "modulate" or "modulating", as used herein, refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
The term "obesity" or "obese", as used herein, refers generally to individuals who are at least about 20-30% over the average weight for his/her age, sex and height. Technically, "obese" is defined, for males, as individuals whose body mass index is greater than 27.8 kg/m2, and for females, as individuals whose body mass index is greater than 27.3 kg/m2. Those of skill in the art readily recognize that the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
The term "inflammatory disorders", as used herein, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
The phrase "amount . . . effective to lower blood glucose levels", as used herein, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect.
Such a concentration typically falls in the range of about 10 nM up to 2 μM; with concentrations in the range of about 100 nM up to 500 nM being one example. As noted previously, since the activity of different compounds may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.
The phrase "insulin resistance", as used herein, refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
The phrase "insulin resistance syndrome", as used herein, refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al.,
Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
Other aspects, advantages, and features of the invention will become apparent from the detailed description below.
Detailed Description Of The Invention
The compounds of the present invention are modulators of 11-β-hsd-1. The compounds of the present invention may modulate processes mediated by 11-β-hsd-1 , which refer to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the 11-β-hsd-1 inhibitors described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g.) brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
The compounds according to the present invention may be used in several indications which involve modulations of 11-β-hsd-1 enzyme. Thus, the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical Endocrinology and Metabolism, 81 , 3441-3447) and may also be used disorders in the immune system (see Franchimont et al, "Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes", The Journal of Immunology 2000, Feb 15, vol 164 (4), pages 1768-74) and also in the above listed indications. lnhibition of 11-β-hsd-1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1) an independent cardiovascular risk factor (Halleux, C. M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between glucocorticoid "activity" and cardiovascular risk factor suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B. R., et al., (1998), Hypertension 31 : 891-895; Fraser, R., et al., (1999), Hypertension, 33: 1364-1368).
Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11-β-hsd-1 in the brain might increase satiety and therefore reduce food intake (Woods, S.C., et al., (1998), Science, 280:1378-1383).
Inhibition of 11-β-hsd-1 in isolated murine pancreatic β-cells improves the glucose-stimulated insulin secretion (Davani, B., et al. (2000) J. Biol. Chem., Nov. 10, 2000; 275(45): 34841-4).
Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and
B.C.J. Sutter, (1979), Horm. Metab. Res. 11: 555-560). Thus, inhibition of 11-β-hsd-1 is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat.
Stress and glucocorticoids influence cognitive function (de Quervain, D.J.-F., B. Roozendaal, and J. L. McGaugh, (1998), Nature, 394: 787-790). The enzyme 11-β-hsd-1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., Edwards, C.R.W. and Seckl, J. R., (1996) Neuroscience 16: 65-70; Seckl, J.R., Front. Neuroendocrinol., (2000), 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11-β-hsd-1 inhibitor. Based the above and on the known effects of glucocorticoids in the brain, it may also be suggested that inhibiting 11-β-hsd-1 in the brain may result in reduced anxiety (Tranche, F., et al., (1999), Nature Genetics 23: 99-103). Thus, taken together, the hypothesis is that inhibition of 11-β-hsd-1 in the human brain would prevent reactivation of cortisone into Cortisol and protect against deleterious glucocorticoid- mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite (previous section).
The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A.W., (1999), Baillier's Clin. Endocrinol Metab., 13: 576-581). The balance between the cell- mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11-β- hsd-1 has been suggested as a means of shifting the response towards a cell-based reaction.
In certain disease states, including tuberculosis, lepra and psoriasis the immune reaction is biased towards a humoral response when in fact the appropriate response would be cell based. Temporal inhibition of 11-β-hsd-1 , local or systemic, might be used to push the immune system into the appropriate response (Mason, D., (1991), Immunology Today , 12: 57-60; Rook, et al., supra).
Recent data suggests that the levels of the glucocorticoid target receptors and the 11-β-hsd-1 enzymes determine the susceptibility to glaucoma (Stokes, J., et al., (2000) Invest. Ophthalmol., 41 :1629- 1638). Further, inhibition of 11-β-hsd-1 was recently presented as a novel approach to lower the intraocular pressure (Walker , E. A., et al, poster P3-698 at the Endocrine society meeting June 12-15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific inhibitor of 11-β-hsd-1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11-β-hsd-1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11 beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11-β-hsd-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, CH. , Cheng, S.L, and Kim, G.S., (1999) J. Endocrinol., 162: 371-379). The negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11-β-hsd-1 in the glucocorticoid effect (Bellows, CG. , Ciaccia, A. and. Heersche, J.N.M, (1998), Bone 23: 119-125). Other data suggest a role of 11-β-hsd-1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M.S., et al., (2000), Bone, 27:375-381 ). Taken together, these different data suggest that inhibition of 11-β-hsd-1 may have beneficial effects against osteoporosis by more than one mechanism working in parallel.
Bile acids inhibit 11 β-hydroxysteroid dehydrogenase type 2. This results in a shift in the overall body balance in favor of Cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani, C, Vogt, B., Odermatt, A., Dick, B. Frey, B.M., Frey, F.J., Nov. 2001 , J Clin Invest, 108(9): 1299-305. "Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis"). Reducing the activity of 11-β-hsd-1 in the liver by a selective inhibitor is predicted to reverse this imbalance, and acutely counter the symptoms such as hypertension, while awaiting surgical treatment removing the biliary obstruction.
The compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (10th Ed.). Assay
The inhibition constant, Ki, was measured in a buffer containing 100 mM triethanolamine, 200 mM NaCI, 0.02% n-dodecyl β-maltoside, 5% glycerol, 5 mM β-mercaptoethanol, 1% DMSO, pH 8.0. In a typical assay, the activity of human 11b-hsd-1 is measured on a Corning 96-well plate for a total volume of 300 uL/well in the presence and absence of inhibitor. In each well, varying amounts of compounds are incubated with a fixed amount of 11b-hsd-1 (4 nM) and NADPH (500 uM) for 30 to 40 min at room temperature in the assay buffer. The enzyme concentration was determined by titration using reversible tight-binding inhibitors. The activity remaining after the pre-incubation period is measured by adding a fixed concentration of 3H-cortisone (200 nM) and the regeneration system constituted with 2 mM glucose- 6-phosphate, 1 U/mL glucose-6-phosphate dehydrogenase and 6 mM MgCI2. The final concentration of cortisone in the assay buffer is lower than the Km value (328 nM). In each well, the enzyme activity is quenched by mixing an aliquot of the assay buffer with an equal volume of DMSO in a second 96-well plate. 15 uL of these final samples are loaded on a C-18A column, Varian Polaris (3 urn, 50 x 4.6 mm) connected to an Agilent 1100 HPLC with 96-well plate autosampler and a β-ram detector from IN/US System. 3H-Cortisone and 3H-cortisol are separated on the column using an isocratic mixture of 38%- 62% methanol-water. The area of 3H-cortisol is calculated and plotted versus time to determine a linear velocity. A Ki value was then determined using the following equation from J. F. Morrison (1969):
Figure imgf000021_0001
Where Vj, and V0 are the rates of Cortisol formation in the presence and in the absence of inhibitor, respectively, I is the inhibitor concentration and E is the 11b-hsd-1 concentration in the assay buffer. All the concentrations reported are the final concentrations in the assay buffer
See also Morrison, J. F., "Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight- binding inhibitors," Biochim Biophys Acta., 1969; 185: 269-86. [1 ,2-3H]-cortisone was purchased from American Radiolabeled Chemicals Inc. NADPH, Glucose-
6-Phosphate (G6P), and Glucose-6-Phosphate dehydrogenase was purchased from Sigma. HEK293-11βHSD1/GRE-Luciferase cell-based assay: ECm determination Inhibition of 11βHSD1 enzyme activity was measured using human kidney HEK293 stable transfected cells, over-expressing human 11 βHSD1 , and a reporter plasmid containing DNA sequences for specific recognition of glucocorticoid-activated glucocorticoid receptors (GRE), using a method similar to that described in Bujalska et al, Human 11β-hydroxysteroid dehydrogenase: Studies on the stably transfected isoforms nd localization of the type 2 isozyme within renal tissue, Steroids, 62(1), 1991 , pp 77- 82 . These sequences were fused to a luciferase reporter gene (Luc) allowing for quantification of 11βHSD1 enzyme modulation. 11 βHSD1 is responsible for converting inactive into active glucocorticoids (cortisone to Cortisol, in humans). Cortisol (but not cortisone) binds and activates glucocorticoid receptors (GR), which will result in activation of luciferase and production of light (assay readout). A compound with the capability of inhibiting 11βHSD1 will reduce the luciferase signal, compare to cortisone control (enzyme substrate).
Cells were plated in 384 Well Flat Bottom White Polystyrene TC-Treated Microplates, at 20,000 cell/well at a volume of 40 μl/well, in serum-free DME Medium. Plates were incubated at 37°C, 5% COZ overnight before addition of inhibitor compounds. Different concentrations of inhibitor compounds were added in 10% (v/v) dimethylsulfoxide (5 μL/well), followed by addition of 3 μM Cortisone (5 μL/well), and cells were incubated at 37°C (5% CO2) for six hours. At the end of the incubation, 25 μL/well SteadyLite HTS were added and plates were incubated 10min at room temp on shaker. Plates were then read on Top Count using 384HSD1 program. The concentration of inhibitor compound causing 50% inhibition of light signal was determined via a custom made Excel Macro. All results were compared to 100% activation control, i.e. cells treated only with cortisone (no inhibitors added). 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. In addition, those of ordinary skill in the art are familiar with formulation and administration techniques. Such topics would be discussed, e.g. in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, current edition, Pergamon Press; and Remington's Pharmaceutical Sciences, current edition, Mack Publishing, Co., Easton, Pa. These techniques can be employed in appropriate aspects and embodiments of the methods and compositions described herein. The following examples are provided for illustrative purposes only and are not meant to serve as limitations of the present invention.
The compounds of the invention may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of 11-β-hsd-1 mediated diseases. The compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs. The compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets. As is conventional in the art these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension, This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables. The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and other glycerides.
For topical use preparations, for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
The compounds may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight. An exemplary dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. To enhance the therapeutic activity of the present compounds they may be administered concomitantly with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like.
For administration to the eye, a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous humor or aqueous humor.
Further, a compound may be also be administered by well known, acceptable methods, such as subtenon and/or subconjunctival injections. As is well known in the ophthalmic art, the macula is comprised primarily of retinal cones and is the region of maximum visual acuity in the retina. A Tenon's capsule or Tenon's membrane is disposed on the sclera. A conjunctiva covers a short area of the globe of the eye posterior to the limbus (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of the upper eyelid and lower eyelid, respectively. The conjunctiva is disposed on top of Tenon's capsule. The sclera and Tenon's capsule define the exterior surface of the globe of the eye. For treatment of age related macular degeneration (ARMD), choroid neovascularization, retinopathies (such as diabetic retinopathy, retinopathy of prematurity), retinitis, uveitis, cystoid macular edema (CME), glaucoma, and other diseases or conditions of the posterior segment of the eye, it is preferable to dispose a depot of a specific quantity of an ophthaimically acceptable pharmaceutically active agent directly on the outer surface of the sclera and below Tenon's capsule. In addition, in cases of ARMD and CME it is most preferable to dispose the depot directly on the outer surface of the sclera, below Tenon's capsule, and generally above the macula.
The compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned subtenon or intravitreal injection. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Within particularly preferred embodiments of the invention, the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form. The solution or suspension may be prepared in its pure form and administered several times daily. Alternatively, the present compositions, prepared as described above, may also be administered directly to the cornea. Within preferred embodiments, the composition is prepared with a muco-adhesive polymer which binds to cornea. Thus, for example, 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.
A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained- release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention. For example, the synthesis of non- exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
Examples
The compounds of the invention may be prepared according to U.S. Provisional Patent Application No. 60/569,362, the entirety of which is hereby incorporated by reference.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to the characteristic protons in the titled compound are presented where appropriate. 1H NMR shift (δH) are given in parts per million (ppm) down field from an internal reference standard.
The invention will now be described in reference to the following EXAMPLES. These EXAMPLES are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner. Analysis and Purification Procedures for Final Products related to Methods A through F The crude reaction mixtures were analyzed by HPLC. Prior to purification, samples were filtered through Whatman® GF/F Unifilter (#7700-7210), commercially available from Whatman® of Clifton, New
Jersey USA. Purification of samples was performed by reverse phase HPLC. Fractions were collected in
23 mL pre-tared tubes and centrifugal evaporated to dryness. Dried product was weighed and dissolved in DMSO. Products were then analyzed and submitted for screening.
NMR data was acquired on a Bruker DRX 300 NMR Spectrometer® using a broadband decoupling scheme to decouple the protons from the carbons. The Bruker DRX 300 NMR Spectrometer® is commercially available from Buker Biospin Corporation of Billercia, Massachusetts. Analytical LCMS Method (Pre-purification) Column: Peeke Scientific® Hl-Q C-18, 50 x 4.6 mm, commercially available from Peeke Scientific® of Redwood City, CA, 5 μm, Eluent A: Water with 0.05% TFA, Eluent B: Acetonitrile with 0.05% TFA, Gradient: linear gradient of 0-100% B in 3.0 min, then 100% B for 0.5 min, then 100-0% B in 0.25 min, hold 100% A for 0.75 min, Flow: 2.25 mL/min, Column Temperature: 250C, Injection Amount: 15 μL of a 286 μM crude solution in methanol/DMSO/water 90/5/5, UV Detection: 260 and 210 nm, Mass Spectrometry: APCl, positive mode, mass scan range 111.6-1000 amu. Preparative LC Method (Gilson)
Column: Peeke Scientific® Hl-Q C18, 50 mm X 20 mm, 5 μm, Eluent A: 0.05% TFA in Water, Eluent B: 0.05% TFA in Acetonitrile, Pre-inject Equilibration: 0.50 min, Post-inject Hold: 0.16 min, Gradient: 0-100% B in 2.55 min, then ramp 100% back to 0% in 0.09 min, Flow: 50.0 mL/min, Column Temp: Ambient, Injection Amount: 1200 μL of filtered crude reaction mixture in DMSO, Detection: UV at 210 nm or 260 nm. Analytical LCMS Purification
Purification Conditions included a Waters® Bondapak column C18, 37-55 micron (particle size), 47x300 mm (column size) having a flow rate of 75 mL/min, a detector of UV 220 nm, where Buffer A is: 0.1 %HOAc in H2O and Buffer B is: 0.1%HOAc in CH3CN. The Waters® Bondapak column C18 is commercially available from Varian, Inc. of Palo Alto, California, USA.
The column was equilibrated in Buffer A for 20 min. The sample was dissolved in 10 mL of DMSO, filtered, and injected onto the column. The gradient was held at 100% in Buffer A for 5 min and then increased linearly to 90%Buffer A/10%Buffer B in 20 min and then held at 10% Buffer B for another 25 min. The desired product came out at about 26 min during the isocratic hold of the gradient. The fractions were checked, pooled, and lyophilized to afford a syrup. Analytical LCMS Method (Post-purification)
Column: Peeke Scientific® Hl-Q C-18, 50 x 4.6 mm, 5 μm, Eluent A: Water with 0.05% TFA, Eluent B: Acetonitrile with 0.05% TFA, Gradient: linear gradient of 0-100% B in 1.75 min, then 100% B for 0.35 min, then 100-50% B for 0.5 min, Flow: 3.00 mL/min, Column Temperature: 25 °C, Injection Amount: 15 μL of a 300 μM solution in methanol/DMSO 99/1 , UV Detection: 260 nm, Mass Spectrometry: APCI, positive mode, mass scan range 100-1000 amu, ELSD: gain=9, temp 40 0C, nitrogen pressure 3.5 bar. Scheme 1
Figure imgf000027_0001
B
Figure imgf000027_0002
Scheme 2
Figure imgf000027_0003
Figure imgf000027_0004
Scheme 3
Figure imgf000028_0001
Referring to Scheme 1 above, the compound of formula D may be prepared by reacting a compound of formula C with R4SO2X wherein X is a leaving group such as Cl, Br, I, OMs, etc. in a suitable solvent (e.g. dichloromethane or DMF) advantageously, in the presence of a base (e.g. K2CO3, NaHCO3, Et3N), at a temperature ranging from about -78 degrees Celsius to the boiling point of the solvent, typically from O degrees Celsius about 100 degrees Celsius. Compound of formula C can be prepared by removing the protecting group P in the compound of formula B. The compound of formula B can be prepared by coupling the compound of formula A with a substituted or unsubstituted adamantyl-2-amine, following standard amide bond formation methods by a method known to those skilled in the art. Compound formula A is an acid wherein P is a protecting functional group such as Boc or Cbz.
Referring to Scheme 2 above, the compound of formula D can be prepared by coupling the compound of formula G with a substituted or unsubstituted adamantyl-2-amine following standard amide bond formation methods by a method known to those skilled in the art. Compound of formula G may be prepared by treatment of compound of formula F, where R is an alkyl or cycloalkyl group, with a base such as NaOH, KOH, LiOH in a suitable solvent such as MeOH and water at an optimum temperature, typically ranging from room temperature to 60 degrees Celsius. Compound of formula F may be prepared by reacting a compound of formula E with R4SO2X wherein X is a leaving group such as Cl, Br, I, OMs, etc. in a suitable solvent (e.g. dichloromethane or DMF) advantageously, in the presence of a base (e.g. K2CO3, NaHCO3, Et3N), at a temperature ranging from about -78 degrees Celsius to the boiling point of the solvent, typically from O degrees Celsius about 100 degrees Celsius.
Referring to Scheme 3 above, the compound of formula D can be prepared by treatment of the compound of formula F with a substituted or unsubstituted adamantyl-2-amine in a suitable solvent at a suitable temperature or in a suitable solvent in the presence of a Lewis acid such as AICI3. Example 1: N-2-adamantyl-1 -[(2-chlorophenyl)sulfonyl]-D-prolinamide
Figure imgf000028_0002
lntermediate Ia: fert-butyl-(2/?)-2-[(2-adamantylamino)carbonyI]pyrrolidine-1-carboxylate
N-(tert-Butoxycarbonyl)-D-proline (43.6g, 202 mmol) was added to a slurry of 2-adamantylamine hydrochloride (38.3 g, 204 mmol), DMF (500 mL) and triethylamine (40.0 g, 395 mmol). The resulting very thick suspension was stirred vigorously and cooled to 11 0C. The coupling reagent PyBOP (120.0 g, 230 mmol) in DMF (100 mL) was added while maintaining the temperature below 16 0C and the heterogeneous reaction mixture was left in an ice-water bath overnight. The reaction mixture was partitioned between water (3 L) and ethyl acetate:MTBE (1 :1.4 L). The aqueous layer was extracted with ethyl acetate:MTBE (1 :1 2x1 L). The combined organic layers were washed with brine (2x1 L) and dried over MgSO4, and filtered. The solvents were removed in vacuo and the product Ia was purified by chromatography (silica gel 50Og; eluted with hexanes:ethyl acetate, 3:1 ). Yield: 62.9 g. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.28 - 1.40 (9 H, m) 1.48 (2 H, d, J=12.38 Hz) 1.65-1.72 (4 H, m) 1.72 - 1.83 (11 H, m) 1.93-2.01 (1 H, m) 2.02 - 2.13 (1 H, m) 3.22 - 3.29 (1 H, m) 3.75 - 3.85 (1 H, m) 4.17 - 4.25 (1 H, m) 7.62 (1 H, d, J=7.58 Hz); LCMS (M+1): 349. Intermediate Ib: N-2-adamantyl-D-prolinamide Deprotection of nitrogen in the non-aromatic ring proceeded by cooling ferf-Butyl-(2/?)-2-[(2- adamantylamino)carbonyl]pyrrolidine-1-carboxylate (62.9 g, 180 mmol) in CH2CI2 (400 mL) to 8 0C, and adding a solution of HCI (20.Og, 540mmol) in diethyl ether (700 mL). The resultant clear solution was stirred at rt for 2 d. The precipitated solid was filtered, washed with CH2CI2--Et2O (1:1 , 150 mL) and dried at 400C to give the desired product Ib as a white solid (46.2 g). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.51 (2 H, d, J=12.63 Hz) 1.69 (2 H, s) 1.74 - 2.01 (13 H, m) 2.26 - 2.35 (1 H, m) 3.22 (2 H, ddd, J=17.6, 11.4, 6.1 Hz) 3.87 (1 H, d, J=6.8 Hz) 4.19 - 4.27 (1 H, m) 8.29 - 8.37 (1 H, m) 8.47 (1 H, s) 9.36 (1 H, s); LCMS (M+1 ): 249. Example 1.: N-2-adamantyl-1-[(2-chlorophenyl)sulfonyl]-D-prolinamide
Sulfonyl amide formation proceeded by addition of a a solution of 2-chlorobenzensulfonyl chloride (147 mg, 0.695 mmol) in CH2CI2 (2 mL) to a solution of Λ/-2-adamantyl-D-prolinamide acetic acid salt (200 mg, 0.58 mmol) in anhydrous CH2CI2 (6 ml) and Et3N (0.4 mL) at rt. After the reaction mixture was stirred at rtfor 16 h, the reaction mixture was diluted with CH2CI2 (50 mL), washed with satd. aq. NaHCθ3 solution, and then dried with over K2CO3. After the organic layer was concentrated under reduced pressure, the residue was purified by reverse phase chromatography on Kromasil C8 column, elution with 0.1 % acetic acid in water and 0.1 % acetic acid in acetonitrile to provide the titled compound 1 (189 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.64 - 1.68 (m, 2 H) 1.80 - 2.16 (m, 16 H) 3.34 - 3.44 (m, 1 H) 3.56 - 3.60 (m, 1 H) 3.87 - 3.90 (m, 1 H) 4.57 (dd, J=8.34, 3.54 Hz, 1 H) 7.49 - 7.60 (m, 1 H) 7.60 - 7.70 (m, 3 H) 8.10 (d, J=8.08 Hz, 1 H). Examples 2-14: Examples 2 through 14 were prepared using methods analogous to example 1 above except that the 2-chlorobenzenesulfonyl chloride was substituted with corresponding sulfonyl halide reagents. It is expected that examples 15 through 17 may also be prepared using methods analogous to example 1.. Example 18: (3R)-N-2-adamantyl-4-[(2-chlorophenyl)sulfonyl]moφholine-3-carboxamide
Title compound 18 was prepared using methods analogous to example 1 above, except that N- (tert-butoxycarbonyl)-D-proline was substituted with (SRH^tert-butoxycarbonyOrmorpholine-S-carboxylic acid. Examples 19 -20:
It is expected that examples 19 and 20 may be prepared using methods analogous to example 18 above.
Example 21 : (IS^R^RJ-S-^-chlorophenylJsulfonylJ-W-^aSjδRJ-S-hydroxy^-adamantyll-a- azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000030_0001
Intermediate 21a: terf-butyl (1S,2R,5R)-2-({[(2s,5R)-5-hydroxy«2-adamantyl]amino}carbonyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate
(1r,4s)-4-aminoadamantan-1-ol (0.72 g, 4.30 mmol) was dissolved in DMF (10 ml_) and then added to (1 S,2R,5R)-3-(ferf-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.82g, 3.92 mmol), HATU (1.49 g, 3.92 mmol) and DIEA (1.41 mL, 8.62 ml.) then stirred for 12 h. The reaction mixture was diluted with EtOAc (40 mL) and partitioned between HCI (2 X 50 mL, 0.1 N) and saturated aqueous NaHCO3 (2 X 50 mL). The organic layer was dried over Na2SO4 and concentrated to give clear oil. Purification was through silica gel eluting with hexanes/EtOAc (1:1), combined purified fractions, and concentrated under high vacuum to afford product as white solid (0.89g, y = 60 %). LCMS (ESI): 377.2. Intermediate 21b: (1 S,2K,5R)-W-[(2s,5R)-5-hydroxy-2-adamantyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide te/f-butyl (1 S,2R,5R)-Λ/-[(2s,5f?)-5-hydroxy-2-adamantyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide was dissolved in dioxane (5 mL). To the solution, was added HCI aq. (6 N, 0.71 mL) and stirred for 3 h, concentrated. The residue was triturated with EtOAc (2 x 50 mL) and concentrated under high vacuum for 24 h. The solid was rinsed with EtOAc (10 mL), filtered and dried under high vacuum 2 h to afford product as a white powder (0.27 g, y = 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.51 (d, J=4.0 Hz, 1 H), 0.56 - 0.65 (m, 1 H), 1.24 - 1.40 (m, 3 H), 1.57 - 1.78 (m, 6 H), 1.85 - 2.14 (m, 6 H), 2.67 - 2.70 (m, 1 H), 3.26 - 3.37 (m, 2 H), 3.47 - 3.57 (m, 1 H)1 4.41 - 4.49 (m, 1 H), 8.55 (d, J=6.8 Hz, 1 H). LCMS (ESI): 277.1.
Example 21 : (1 S,2R,5R)-3-[(4-chlorophenyl)sulfonyl]-W-[(2s,5/?)-5-hydroxy-2-adamantyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide
(1S,2fi,5ft)-A/-[(2s,5R)-5-hydroxy-2-adamantyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.2 g, 0.6 mmol) was dissolved in methylene chloride (5 mL), followed by addition of pyridine (0.33 mL, 3.2 mmol) and 4-chlorobenzenesulfonyl chloride (0.16 g, 0.77 mmol) and stirring for 12 h. The reaction mixture was concentrated and then diluted with ethyl acetate (50 mL) and partitioned between 0.5 N HCI (2 X 30 mL), saturated aqueous NaHCO3 (2 X 30 mL) then dried over Na2SO4 and concentrated. Purification was through silica gel eluting with hexanes:EtOAc (1:3), combined purified fractions to give a foam. The foam was triturated with water (2 X 5 mL). The residue was dissolved in 2 mL methylene chloride followed by addition of 5 mL hexane to precipitate the product, which was decanted and dried under vacuum for 24 h to afford product 21 as a white solid (0.16 g, 59%). HPLC Rt: 2.973 (100%). Examples 22 - 23:
It is expected that examples 22 and 23 may be prepared using methods analogous to example 21 above.
Examples 24 and 25: N-2-adamantyl-1-{[4-(aminocarbonyl)-2-chlorophenyl]sulfonyl}-D- prolinamide (24) and 4-({(2R)-2-[(2-adamantylamino)carbonyl]pyrrolidin-1-yl}sulfonyl)-3- chlorobenzoic acid (25)
Figure imgf000031_0001
A suspension of LiOH (70 mg, 2.90 mmol) in water (3 mL) was added to a stirred solution of compound 7 (538 mg, 1.20 mmol)(see Example 8 in Table 1 below) in THF (6 mL) at rt. The solution was further stirred at rt for 15 h. Approximately one half of the solution was withdrawn from the reaction flask before allowing the reaction to stir for an additional 24 h at rt. The solution that was withdrawn from the reaction flask was concentrated in vacuo. The resulting aqueous solution was extracted with CH2CI2 (2x10 mL). The combined CH2CI2 extracts were dried over MgSO4 and concentrated in vacuo. The crude material thus obtained was purified by silica column using HPFC (eluant 0-5% CH3OH in CH2CI2) to afford amide 24 (67 mg) as a white solid.
Complete conversion to the amide was observed by LCMS after allowing the rest of the reaction to stir for an additional 24 h at rt. The reaction mixture was heated at 50 °C (bath temperature) for 3 d. The volatiles were evaporated in vacuo. The residual aqueous solution was diluted with water (10 mL) and acidified with 10% aqueous HCI to about pH 2, affording white precipitate. The solution was filtered, and the precipitate thus obtained was dried in vacuo to afford the desired acid 25 (255 mg, ~90% from nitrile) as a white solid. Example 26 - 29:
Examples 26 through 29 were prepared using methods analogous to example 24 and 25 above. Example 30: 4-[(R)-2-(Adamantan-2-ylcarbamoyI)-pyrrolidine-1-sulfonyl]-benzoic acid methyl ester.
Figure imgf000032_0001
27 30
Compound 27 (0.05 g, 0.12 mmol) was suspended in a mixture of benzene (1 mL) and MeOH (1 mL) at rt. The mixture was stirred rapidly at rt while trimethylsilyldiazomethane (0.12 mL, 0.24 mmol) was added dropwise over 1 min. After stirring for 2 h, the mixture was concentrated in vacuo to yield crude product as a yellow oil. The product was purified using medium pressure liquid chromatography (hexanes to 95% acetone/hexanes) to yield pure product 30 as a white solid (0.04 g, 77 %).
Example 31: N-2-adamantyl-1-{[4-(hydroxymethyI)phenyl]sulfonyl}-D-prolinamide.
Figure imgf000032_0002
Compound 27 (0.07 g, 0.15 mmol) was dissolved in THF (1 mL), and NaBH4 (0.01 g, 0.26 mmol) was added in one portion. The mixture was cooled to 0 0C, and a solution of iodine (0.04 g, 0.15 mmol) in THF (1 mL) was then added dropwise over 2 min. The mixture was allowed to slowly warm to rt. After 4 h, the mixture was quenched with Rochelle's salt, and the resulting the mixture was extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to yield the crude product as a red oil. The product was purified using medium pressure liquid chromatography (CH2CI2 to 10 % MeOH/CH2CI2) to yield pure product 30 as a white solid (0.04 g, 64 %). Example 32: N-2-adamantyl-1-{[3-(hydroxymethyl)phenyl]sulfonyl}-D-prolinamide
The title compound 32 was prepared using methods analogous to example 31 above- Example 33: /V-2-adamantyI-1-[(6-methylpyridin-3-yl)sulfonyl]-D-prolinamide
Figure imgf000032_0003
lntermediate 33a: Λ/-2-adamantyl-1-[(6-chloropyridin-3-yl)sulfonyl]-D-prolinamide
The sulfonamide was made using methods analogous to example 1 above, and was purified by trituration using methyl-t-butyl ether and CH2CI2.
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.62 - 2.06 (m, 17 H) 2.25 - 2.37 (m, 1 H) 3.11 - 3.25 (m, 1 H) 3.59 - 3.70 (m, 1 H) 3.97 - 4.13 (m, 2 H) 7.12 (d, J=8.08 Hz, 1 H) 7.54 (d, J=8.34 Hz, 1 H) 8.10 (dd,
J=8.34, 2.53 Hz, 1 H) 8.86 (d, J=2.53 Hz, 1 H) ; LRMS m/z calcd for (M + H)+ 424.2, found 424.2.
Example 33: Λ/-2-adamantyl-1 -[(6-methyIpyridin-3-yI)sulfonyl]-D-prolinamide
To a mixture of A/-2-adamantyl-1-[(6-chloropyridin-3-yl)sulfonyl]-D-prolinamide (200mg,
0.47mmol), trimethylboroxine (0.08mL, 0.57mmol), and cesium carbonate (308mg, 0.94mmol) in 1,4 dioxane (2ml_) was added [2-[(D-κN)methyl]phenyl-κC](tricyclohexylphosphine)(trifluoroacetato-κO-9SP-
4-3)-palladium, (Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M.
B.; Light, M. E. Organometallics 2003, 22, 987), (1 mg, 0.5wt%). The reaction mixture was radiated using the microwave at 175 0C for 20 min. The reaction mixture was then partitioned between H2O and EtOAc, and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried with sodium sulfate and filtered. The residue was purified by silica gel column chromatography using 100%
EtOAc to 10% (10% MeOH/CH2CI2)/EtOAc to give a yellow solid 33 (152 mg, 80% yield).
1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1.64 - 2.11 (m, 19 H) 2.22 - 2.35 (m, 1 H) 3.11 - 3.25 (m, 1
H) 3.59 - 3.68 (m, 2 H) 3.99 - 4.10 (m, 2 H) 7.36 (d, J=8.08 Hz, 1 H) 7.99 - 8.06 (m, 1 H) 8.96 (s, 1 H);
LRMS m /z calcd for (M + H)+ 404.2, found 404.2. Example 34: tert-Butyl (3S)-3-[(2-adamantylamino)carbonyl]piperidine-1-carboxylate and (3S)-N-2- adamantyIpiperidine-3-carboxamide
Figure imgf000033_0001
The piperidine analogs 34a and 34 were prepared in a manner similar to example 33 above, except that N-(tert-butoxycarbonyl)-D-proline was replaced with (3S)-1-(tert-butoxycarbonyl)piperidine-3- carboxylic acid.
Intermediate 34a: (3S)-Λ/-2-adamantyl-1 -[(6-chloropyridin-3-yl)sulfonyl]piperidine-3-carboxamide The sulfonamide 34a was made using by sulfonyl amide formation as in Example 33 above and was purified by column chromatography on silica gel with 50 - 80% EtOAc/hexanes. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.63 - 1.99 (m, 18 H) 2.42 - 2.53 (m, 1 H) 2.61 - 2.72 (m, 1 H) 2.79 - 2.89 (m, 1 H) 3.49 (d, J=11.37 Hz, 1 H) 3.59 (dd, J= 11.37, 3.03 Hz, 1 H) 4.05 (d, J=8.08 Hz, 1 H) 6.09 (d, J=7.58 Hz, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 7.99 (dd, J=8.08, 2.27 Hz, 1 H) 8.76 (d, J=2.53 Hz, 1 H) ; LRMS m/z calcd for (M + H)+ 438.2, found 438.2. Example 34: (3S)"/V-2-adamantyl-1-[(6-methylpyridin-3-yl)sulfonyl]piperidine-3-carboxamide
The title compound 34 was made by the same procedure as Example 19 and was purified by silica gel chromatography using 100% EtOAc. Examples 36 and 37:
Figure imgf000034_0001
36
Figure imgf000034_0002
37
A solution of N-2-adamantyl-1-[(3-cyano-4-fluorophenyl)sulfonyl]-D-prolinamide 9 (150 mg, 0.35 mmol) in TFA/conc. H2SO4 (0.5 mL, 4:1 v/v) was heated at 60 °C for 6 h. The reaction mixture was cooled to rt and poured into a ice-water. The aqueous solution was extracted with EtOAc, and the combined organics were washed with satd. NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The crude material thus obtained was purified by column chromatography using 0-5 % methanol in CH2CL2 to afford 36 (10 mg, 7%) and 37 (77 mg, 50%) as off-white solids.
The compounds listed in Table 1 are prepared according to the cited methods.
Figure imgf000034_0003
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations that would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

We claim:
1. A compound of formula (I):
Figure imgf000042_0001
(I) wherein; n is 0 or 1 ;
R1 is H, halo, CN, CrC6alkyl, OR7, CrC6alkyl-OR7, NR7R8, CrC6alkyl-NR7R8, aryl, heterocycle, (C1- C4alkyl)aryl, (CrGtalkylJheterocycle; R2 and R3 are each independently H, Ci-Cβalkyl, (CR7 R8)mOR9 wherein m is an integer from 0 -4, aryl, (C1- C4alkyl)aryl or may together optionally cyclize to form a non-aromatic 4-6 membered heterocycle which is optionally further substituted with a CrC6alkyl;
R4 is Ci-C6alkyl, CrCβalkyl-OR7, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (C1-C4alkyl)-cycloalkyl, (Ci-C4alkyl)aryl, or (Ci-C4alkyl)-(4 to 10)-membered heterocycle; R4 is optionally substituted with 1-4 R6 groups; R5 is H, Ci-Cβalkyl, or cycloalkyl;
R6 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy, OR7, CrC6alkyl, CrC6alkenyl, CrC6alkynyl, (CR7R8)PCONR9R10, (CR7R8)PN RC(O)R9, (CR7R8)PNR9R10, (CR7R8)PCOR9, (CR7R8)pCO2R9, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (Ci-C4alkyl)-cycloalkyl, (CrC4alkyl)aryl, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR7R8)PSO2R9, (CR7R8)qSOR9, (CR7R8JpSO2NR9R10, (CR7R8)PNR9SO2R10, O(CR7R8)paryl, (CR7R8)pNR9C(O)NR10R11, ,
(CR7R8)PNR9C(O)OR10, (CR7R8)POC(O)NR9R10, (CR7R8)POR9, O(CR7R8)POR9, and O(CR7R8)PNR9R10, wherein p is an integer from 0-4;
R7, R8, R9, R10 and R11 are each independently selected from the group of H, CrC6alkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl, (CrC4alkyl)aryl, and (CrC4alkyl)-(4 to 10)- membered heterocycle;
Rs substituents can optionally be further substituted with 1-4 R12.
R12 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy, OR13, d-Cβalkyl, CrC6alkenyl, CrC6alkynyl, (CR13R14)qCONR15R16, (CR13R14)qNRC(O)R15, (CR13R14)qNR15R15, (CR13R14)qCOR15, (CR13R14)qCO2R15, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycIoalkyl, (CrC4alkyl)aryl, (CrC4alkyl)- (4 to 10)-membered heterαcycle, (CR13R14)qSO2R15, (CR13R14)qSOR15, (CR13R14)qSO2NR15R16, (CR13R14)qNR15SO2R16, O(CR13R14)qaryl, (CR13R14)qNR15C(O)NR16R17, , (CR13R14)qNR16C(O)OR16, (CR13R14)qOC(O)NR16R16, (CR13R14)qOR15, O(CR13R14)qOR15, and O(CR13R14)qNR15R16 wherein q is an integer from 0 -4; and
R13, R14, R15, R16 and R17 are each independently selected from the group of H, CrC6alkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl, (Ci-C4alkyl)aryl, and (GrC4alkyl)- (4 to 10)-membered heterocycle.
2. The compound according to claim 1, wherein R2 and R3 cyclize to form a 4-6 membered non-aromatic heterocycle.
3. The compound according to claim 2 wherein n is 0.
4. A compound of formula (II):
Figure imgf000043_0001
(H) wherein; n is 0 or 1 ; R1 is H, halo, CN, CrCBalkyl, OR7, CrC6alkyl-OR7, NR7R8, CrCsa]kyl-NR7R8, aryl, heterocycle, (C1-
C4alkyl)aryl,
Figure imgf000043_0002
R2 and R3 together cyclize to form a non-aromatic 4-6 membered heterocycle which is optionally further substituted with a CrC6alkyl;
R4 is Ci-Cealkyl, C^Csalkyl-OR7, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (Ci-C4alkyl)-cycloalkyl, (CrC4alkyl)aryl, or (Ci-C4alkyl)-(4 to 10)-membered heterocycle;
R4 is optionally substituted with 1-4 R6 groups;
R5 is H, CrCBalkyl, or cycloalkyl;
R6 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy,
OR7, CrC6alkyl, CrC6alkenyl, CrC6alkynyl, (CR7R8)PCONR9R10, (CR7Rε)pNRC(O)R9, (CR7R8)PNR9R10, (CR7R8)pCOR9, (CR7R8)pCO2R9, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl,
(CrC4a[kyl)aryl, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR7R8)PSO2R9, (CR7R8)qSOR9,
(CR7R8)PSO2NR9R10, (CR7R8JpNR9SO2R10, O(CR7R8)paryl, (CR7R8)pNR9C(O)NR10R11, ,
(CR7R8VNR9C(O)OR10, (CR7R8)POC(O)NRSR10, (CR7R8)POR9, O(CR7R8)POR9, and O(CR7R8)PNR9R10, wherein p is an integer from 0-4; R7, R8, R9, R10 and R11 are each independently selected from ths group of H, CrC6alkyl, cycloalkyl, aryl,
(4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl, (CrC4alkyl)aryl, and (CrC4alkyl)-(4 to 10)- membered heterocycle;
R6 substituents can optionally be further substituted with 1-4 R12.
R12 is independently selected from the group consisting of halo, CN, CF3, CHF2, CH2F, trifluoromethoxy, OR13, CrC6alkyl, CrC6alkenyl, CrC6alkynyl, (CR13R14)qCONR15R16, (CR13R14)qNRC(O)R15,
(CR13R14)qNR15R16, (CR13R14)qCOR15, (CR13R14)qCO2R15, cycloalkyl, aryl, (4 to 10)-membered heterocycle,
(CrC4alkyl)-cycloalkyl, (CrC4alkyl)aryi, (CrC4alkyl)- (4 to 10)-membered heterocycle, (CR13R14)qSO2R15,
(CR13R14)qSOR15, (CR13R14)qSO2NR15R16, (CR13R14)qNR15SO2R16, O(CR13R14)qaryl,
(CR13R14)qNR15C(O)NR16R17, , (CR13R14)qNR15C(O)OR16, (CR13R14)qOC(O)NR15R16, (CR13R14)qOR15, O(CR13R14)qOR15, and O(CR13R14)qNR15R16 wherein q is an integer from 0 -4; and R13, R14, R15, R16 and R17 are each independently selected from the group of H, CrCealkyl, cycloalkyl, aryl, (4 to 10)-membered heterocycle, (CrC4alkyl)-cycloalkyl, (CrC4alkyl)aryl, and (C1-C4alkyl)- (4 to 10)-membered heterocycle.
5. The compound according to claim 4, wherein n is 0 and R2 and R3 together cyclize to form a morpholine.
6. The compound according to claim 4, wherein n is 0 and R2 and R3 together cyclize to form a pyrrolidine.
7. The compound according to claim 4, wherein n is 0 and R2 and R3 together cyclize to form an azabicyclo[3.1.0]hexane.
8. The compound according to claim 4, wherein n is 1.
9. The compound according to claim 8, wherein n is 1 and R2 and R3 together cyclize to form a piperidine.
10. A compound selected from
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000045_0002
11. A pharmaceutical composition comprising an effective amount of a compound according to any of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
12. A method of treating a condition that is mediated by the modulation of the 11-β-hsd-1 enzyme, the method comprising administering to a mammal an effective amount of a compound according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt or solvate thereof.
13. A method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, viral diseases, ophthalmic disorders, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to any of claims 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10,or a pharmaceutically acceptable salt or solvate thereof.
14. A method of treating glaucoma, the method comprising administering to a mammal an effective amount of a compound according to any of claims 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt or solvate thereof.
15. A method of treating diabetes, comprising administering to a mammal an effective amount of a compound according to any of claims 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt or solvate thereof, in combination with a PPAR agonist.
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