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US20100016393A1 - Novel hydrogen sulfate salt - Google Patents

Novel hydrogen sulfate salt Download PDF

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Publication number
US20100016393A1
US20100016393A1 US12/097,942 US9794206A US2010016393A1 US 20100016393 A1 US20100016393 A1 US 20100016393A1 US 9794206 A US9794206 A US 9794206A US 2010016393 A1 US2010016393 A1 US 2010016393A1
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Prior art keywords
compound
hydrogen sulfate
sulfate salt
salt
inhibitors
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Inventor
John DeMattei
Tsung-Hsun Chuang
Christopher John Squire
Ronald John Roberts
Gorkhn Sharma-Singh
Mohammed Pervez
James Gair Ford
Richard Anthony Storey
Paul Alfred Dickinson
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AstraZeneca R&D Alderley
AstraZeneca AB
Array Biopharma Inc
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AstraZeneca R&D Alderley
AstraZeneca AB
Array Biopharma Inc
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Application filed by AstraZeneca R&D Alderley, AstraZeneca AB, Array Biopharma Inc filed Critical AstraZeneca R&D Alderley
Priority to US12/097,942 priority Critical patent/US20100016393A1/en
Assigned to ARRAY BIOPHARMA, INC. reassignment ARRAY BIOPHARMA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEMATTEI, JOHN, CHUANG, TSUNG-HSUN
Assigned to ASTRAZENECA R&D ALDERLEY reassignment ASTRAZENECA R&D ALDERLEY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DICKINSON, PAUL ALFRED, FORD, JAMES GAIR, PERVEZ, MOHAMMED, ROBERTS, RONALD JOHN, SHARMA-SINGH, GORKHN, SQUIRE, CHRISTOPHER JOHN, STOREY, RICHARD ANTHONY
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DICKINSON, PAUL ALFRED, FORD, JAMES GAIR, PERVEZ, MOHAMMED, ROBERTS, RONALD JOHN, SHARMA-SINGH, GORKHN, SQUIRE, CHRISTOPHER JOHN, STOREY, RICHARD ANTHONY
Publication of US20100016393A1 publication Critical patent/US20100016393A1/en
Priority to US13/463,499 priority patent/US9156795B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2

Definitions

  • the present invention relates to a novel salt and, more particularly, to a novel salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (hereinafter referred to as “Compound 1”), which is a MEK inhibitor that is useful in the treatment and/or prophylaxis of proliferative disease states, such as cancer, in a mammal. More specifically, the present invention relates to a hydrogen sulfate salt of Compound 1 and to processes for the preparation of said salt.
  • compositions containing a hydrogen sulfate salt of Compound 1 and the use of the salt in the manufacture of medicaments for treatment and/or prophylaxis of proliferative disease states, such as cancer, in the human or animal body, and methods of treating proliferative disease states, such as cancer, in a mammal by administering a therapeutically effective amount of a hydrogen sulfate salt of Compound 1.
  • MAP kinase pathway a pathway that MAP kinase pathway.
  • Ras/Raf kinase pathway Active GTP-bound Ras results in the activation and indirect phosphorylation of Raf kinase.
  • Raf then phosphorylates MEK1 and 2 on two serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahn et al., Methods in Enzymology, 2001, 332:417-431).
  • Activated MEK then phosphorylates its only known substrates, the MAP kinases ERK1 and 2.
  • ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al., Methods in Enzymology 2001, 332:417-431).
  • ERK Phosphorylated ERK dimerizes and then translocates to the nucleus where it accumulates (Khokhlatchev et al., Cell 1998, 93:605-615). In the nucleus, ERK is involved in several important cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al., Molecular Cell, 2000, 6:1343-1354). Overall, treatment of cells with growth factors leads to the activation of ERK1 and 2 which results in proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74: 49-139).
  • bRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H., et al., Nature 2002, 417:949-954). These mutations in bRaf result in a constitutively active MAP kinase cascade. Studies of primary tumor samples and cell lines have also shown constitutive or overactivation of the MAP kinase pathway in cancers of pancreas, colon, lung, ovary and kidney (Hoshino, R., et al., Oncogene 1999, 18:813-822). Hence, there is a strong correlation between cancers and an overactive MAP kinase pathway resulting from genetic mutations.
  • MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies.
  • small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold et al., Nature - Medicine 1999, 5(7):810-816; Trachet et al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H., IBC 2 nd International Conference of Protein Kinases, Sep. 9-10, 2002), block static allodynia in animals (WO 01/05390) and inhibit growth of acute myeloid leukemia cells (Milella et al., J. Clin. Invest. 2001, 108 (6):851-859).
  • Inhibitors of the MEK are also described in WO 03/077914. 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide, or “Compound 1”, is exemplified in WO 03/077914 and possesses the following structural formula:
  • Compound 1 has been shown to possess inhibitory activity against MEK and therefore to be useful in the treatment of a hyperproliferative disease such as cancer.
  • WO 03/077914 discloses, in general terms, certain pharmaceutically acceptable salts of the compounds disclosed therein. Specifically, it is stated in WO 03/077914 that pharmaceutically acceptable salts of the compounds disclosed therein that possess a sufficiently basic moiety may form acid addition salts containing pharmaceutically acceptable anions, and a range of such anions are listed. Similarly, suitable salts of the compounds possessing an acidic moiety are to be formed by treatment of a compound with a basic compound and particularly an inorganic base.
  • the form of a pharmaceutically active compound which is used in medicaments is suitably one that provides for reasonable handling properties, which allow it to be processed and formulated.
  • salts do not form easily and/or are not stable, which is probably due to low pKa values.
  • the pKa value expresses the strength of acids and base, i.e., the tendency for an acid to lose a proton or a base to add a proton (Bronsted J. N., Rec. Trav. Chim. (1923) 47:718). This is particularly true for Compound 1.
  • the present invention provides a hydrogen sulfate salt (1:1 drug:H 2 SO 4 ) of Compound 1 and various forms thereof, all of which are included within the scope of the invention.
  • the salt may be in various forms, all of which are included within the scope of the invention. These forms include anhydrous forms as well as solvates. A further form may be produced by desolvating solvates. In a particular embodiment the salt is in the anhydrous form.
  • the present invention provides a method of using a hydrogen sulfate salt of Compound 1 as a medicament to treat a hyperproliferative disease or condition.
  • An additional aspect of the invention is the use of a hydrogen sulfate salt of Compound 1 in the preparation of a medicament for the treatment or prevention of a hyperproliferative disease or condition.
  • FIG. 1 shows the XRPD of the hydrogen sulfate salt of Compound 1
  • FIG. 2 shows the infrared spectrum of the hydrogen sulfate salt of Compound 1 obtained using the DRIFTS sampling technique
  • FIG. 3 shows the results of plasma concentration levels of Compound 1 following administration of 150 mg free base equivalent oral dispersion doses of Compound I (x) and the hydrogen sulfate salt to fasted dogs ( ⁇ ).
  • the present invention provides a hydrogen sulfate salt (1:1 drug to H 2 SO 4 ) of Compound 1 and various forms thereof, all of which are included within the scope of the invention.
  • the salt may be in various forms, all of which are included within the scope of the invention. These forms include anhydrous forms as well as solvates. A further form may be produced by desolvating solvates.
  • the salt is anhydrous hydrogen sulfate salt of Compound 1.
  • the present invention provides a hydrogen sulfate salt form of Compound 1 which shows unique physical and pharmaceutical properties that make it particularly suitable for use in medicaments.
  • salts of Compound 1 are crystalline.
  • the crystalline salts have been found to be better than the free base in terms in their handling properties from a manufacturing point of view, in particular their static and flow properties.
  • the formation of salts may provide a means of purification, as process impurities can be separated and salts are generally easier to isolate than the free base.
  • the hydrogen sulfate salt of Compound 1 is a crystalline salt, which has surprisingly been found to possess improved pharmaceutical properties when compared to the free base of Compound 1 and certain other salt forms of Compound 1.
  • the dissolution rate of this crystalline salt, as well as its bioavailability has been found to be particularly high as compared to the free base and other salts, as illustrated in the examples hereinafter.
  • the enhanced bioavailability of the hydrogen sulfate salt of Compound 1 over the free base has been shown to be independent of the formulation used for administration.
  • the bioavailability of the free base and hydrogen sulfate forms have been compared herein when dosed in the same dispersion formulations, but similar differences in bioavailability were also observed for simple tablet formulations.
  • the present invention relates to a salt of Compound 1 which is a crystalline salt
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.
  • BCS Class 4 compounds normally have low bioavailability due to both low dissolution rate and permeability, and the limitation of permeability on absorption means that such salts would not usually be expected exert a substantial impact on absorption (See for example: Dressman et al. (2001) Pharm Tech. July: 68).
  • Suitable solvates of the hydrogen sulfate salt of Compound 1 are formed from a wide range of solvents, in particular organic solvents such as tetrahydrofuran (THF), acetonitrile (ACN), ethanol (EtOH) and methanol (MeOH).
  • organic solvents include esters such as C 1-6 alkyl esters, for example ethyl acetate, and ketones such as C 1-6 alkyl ketones, for example methyl ethyl ketone (2-butanone).
  • Preparation of the salt can be effected by reacting a slurry of Compound 1 in an organic solvent and water with sulfuric acid.
  • a 1:1 salt approximately 1 equivalent of sulfuric acid is used.
  • the invention provides a method for preparing a hydrogen sulfate salt of Compound 1, said method comprising:
  • the mole ratio of the amount of sulfuric acid to Compound 1 is suitably in the range of from 1.00:1 to 2:1, for example in a range from 1.05:1 to 1.15:1.
  • the sulfuric acid used is suitably in the form of concentrated sulfuric acid.
  • the mole ratio of sulfuric acid to Compound 1 is 1.10:1.0.
  • the amount of water added in step (i) is restricted to that necessary to ensure that the salt is formed.
  • the precise amounts used will depend upon the particular nature of the solvent, the concentration of the sulfuric acid etc., but typically, the water will be present in an amount of less than 20% v/v of the total liquid present, for example from 13-17% v/v.
  • the organic solvent used in step (i) is 2-butanone (methyl ethyl ketone), water is approximately 15% of the liquid volume, and the total amount of liquid used relative to Compound 1 is approximately 8 mL per gram of Compound 1.
  • step (i) addition of sulfuric acid in step (i) is carried out in a controlled manner, for example at a temperature below 10° C., and the remainder of step (i) is then carried out at elevated temperature, for example from 30-90° C., as a further example in a range between 55-75° C., and as a further example at about 65° C.
  • Suitable organic liquids include organic solvents in which Compound 1 and its salts are sparingly soluble.
  • the expression “sparingly soluble” means having a solubility less than 100 mL of solvent per gram of solute, for example between 30 and 100 mL of solvent per gram of solute.
  • These solvents include alkyl ketones, for example C 1-6 alkyl ketones such as 2-butanone, alcohols such as C 1-6 alcohols, for example methanol or ethanol, and esters such as C 1-6 alkyl esters, for example as ethyl acetate.
  • the organic solvent is methyl ethyl ketone (2-butanone).
  • the reaction mixture is filtered between steps (i) and (ii) to remove any extraneous material.
  • the residue is optionally washed, for example with a mixture of the organic liquid and water, and the desired salt crystallized from the filtrate, which may optionally be combined with the wash solution.
  • the hydrogen sulfate salt is recovered in step (ii) by cooling the reaction mixture, optionally with the addition of further organic liquid, so that the hydrogen sulfate salt is precipitated.
  • the further organic liquid may be the same organic liquid as used in step (i), or it may be a different organic liquid, provided this acts as an anti-solvent for the hydrogen sulfate salt of Compound 1. Seeding of the solution with crystals of the hydrogen sulfate salt of Compound 1 may assist in the precipitation process.
  • the filtrate prior to cooling, is first subjected to a distillation step to remove water and to ensure that the salt is recovered in an acceptable yield.
  • the solvent is 2-butanone and the filtrate is distilled at atmospheric pressure.
  • the salt can be recovered from the resultant slurry for example by filtration.
  • the recovered material may then be dried for example at elevated temperature, for example of from 40-60° C., and as another example at about 50° C., until constant weight is achieved. If the product is a solvate with the organic liquid such as methanol, it may be de-solvated if desired at this time by heating.
  • the invention also includes isotopically-labeled compounds, which are identical to those recited in the present invention, 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, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • the hydrogen sulfate salt of Compound 1 and polymorphs thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of 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 widely used as a result of their ease of preparation and detectability.
  • Isotopically labeled salts of the present invention can generally be prepared by carrying out procedures disclosed in WO 03/077914 by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent during the preparation, or if desired, using an isotopically labeled sulfuric acid in the preparation of the salt.
  • the composition may be in a form suitable for oral administration (for example as tablets, lozenges, hard or soft capsules, emulsions, dispersible powders or granules, syrups, elixirs or oily or extemporaneously prepared aqueous suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder), for parenteral injection (for example as a sterile solution, suspension or emulsion for intravenous, subcutaneous, intramuscular, intravascular or infusion dosing), for topical administration (for example as creams, ointments, gels, oily solutions or suspensions or extemporaneously prepared aqueous suspensions), or for rectal administration (for example as a suppository).
  • the hydrogen sulfate salt of Compound 1 is administered orally.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • an effective dosage is in the range of about 0.01 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.7 to 7000 mg/day, preferably about 70 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • a unit dosage form such as a tablet or capsule will usually contain, for example 1-1000 mg of active ingredient, and preferably 5-420 mg of active ingredient. Preferably a daily dose in the range of 0.03-6 mg/kg is employed.
  • a hydrogen sulfate salt of Compound 1 as defined herein for use in a method of treatment or prophylaxis of the human or animal body by therapy is hydrogen sulfate salt of Compound 1 as defined herein for use as a medicament.
  • the present invention provides hydrogen sulfate salt of Compound as defined herein for use as a medicament for the treatment of disease states mediated through MEK, in particular proliferative disorders, or abnormal cell growth, such as cancer, in a warm-blooded mammal such as a human.
  • a further aspect of the invention provides the use of hydrogen sulfate salt of Compound 1 as defined herein in the manufacture of a medicament for use in the treatment of disease states mediated through the MEK, in particular proliferative disorders, or abnormal cell growth, such as cancer, in a warm-blooded mammal such as a human.
  • a method for treating disease states mediated through the MEK, in particular proliferative disorders, or abnormal cell growth, such as cancer, in a warm-blooded mammal, such as a human, in need of such treatment which comprises administering to said mammal an effective amount of an hydrogen sulfate salt of Compound 1 hydrogen sulfate salt as herein, or a pharmaceutical composition as defined herein.
  • proliferative disorders which may be treated using the salts or compositions of the invention, include hyperproliferative disorders in a mammal.
  • Particular cancers are brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological or thyroid cancer.
  • the compounds and compositions of the invention may also be used in the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • MEK mediated diseases which may be treated using the compounds, or compositions of the invention include pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced renal disease) or the treatment of pain in a mammal.
  • the compounds and compositions may also be used for the prevention of blastocyte implantation in a mammal, or for treating a disease related to vasculogenesis or angiogenesis in a mammal.
  • diseases may include tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scieroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • abnormal cell growth and “hyperproliferative disorder” are used interchangeably in this application and refer to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes, for example, the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or over expression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.
  • 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.
  • patients that can be treated with compounds or compositions of the present invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, non small cell lung cancer, bone cancer, CMML, pancreatic cancer, colorectal, skin cancer, cancer of the head and neck, melanoma (in particular cutaneous or intraocular melanoma), uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), ovarian cancer, multiple myeloma, hepatocellular carcinoma, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e
  • the hydrogen sulfate salt of Compound 1 may be applied as a sole therapy or may involve, in addition to the hydrogen sulfate salt of Compound 1, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to Compound 1 hydrogen sulfate salt may be surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may cover categories of therapeutic agent such as:
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/
  • vascular targeting agents for example combretastatin phosphate and compounds disclosed in WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213, and the vascular damaging agents described in International Patent Application Publication No. WO 99/02166, (for example N-acetylcolchinol-O-phosphate));
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, and exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, and cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, leuprorelin, and buserelin), inhibitors of 5 ⁇ -reductase (for example finasteride);
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene, and
  • anti-invasion agents for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanese;
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies, (for example the anti-erbb2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [C225]), and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors such as inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)) and erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as antimetabolites (for example antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, tegafur, purine and adenosine analogues, and cytosine arabinoside, hydroxyurea or, for example, one of the anti-metabolites specifically disclosed in European Patent Application No.
  • antimetabolites for example antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, tegafur, purine and adenosine analogues, and cytosine arabinoside, hydroxyurea
  • antimetabolites for example antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, tegafur, purine and adenosine analogues, and cytosine arabinoside, hydroxyurea
  • antitumour antibiotics for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, and mithramycin
  • platinum derivatives for example cisplatin, and carboplatin
  • alkylating agents for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, and thiotepa
  • antimitotic agents for example vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as tax
  • chemotherapeutic agent including:
  • biological response modifiers for example interferon
  • antibodies for example edrecolomab
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (x) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • a hydrogen sulfate salt of Compound 1 may be used in conjunction with an effective amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
  • anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix-metalloprotienase 9
  • COX-II cyclooxygenase II
  • useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Suitable MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.
  • MMP-2 and/or MMP-9 are used.
  • MMP-1, MMP-3, NMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13 are used.
  • MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
  • a further aspect of the present invention the hydrogen sulphate salt of Compound 1 in combination with any one of the anti tumour agents listed under (i)-(xi) herein above.
  • a further aspect of the present invention provides the hydrogen sulphate salt of Compound 1 in combination with one or more of the anti tumour agents listed under (i)-(xi) herein above.
  • a further aspect of the present invention provides the hydrogen sulphate salt of Compound 1 in combination with any one of the classes of anti-tumour agents listed under (i)-(xi) herein above.
  • kits comprising the hydrogen sulphate salt of Compound 1 in combination with an anti-tumour agent selected from one listed under (i)-(xi) herein above.
  • a kit comprising:
  • an anti-tumour agent selected from one listed under (i)-(xi) herein above; in a second unit dosage form;
  • Compound 1 has been found to have activity in the following assay.
  • N-terminal 6 His-tagged, constitutively active MEK1 (2-393) is expressed in E. coli and protein is purified by conventional methods (Ahn et al., Science 1994, 265:966-970).
  • the activity of MEK1 is assessed by measuring the incorporation of ⁇ - 33 P-phosphate from ⁇ - 33 P-ATP onto N-terminal His tagged ERK2, which is expressed in E. coli and is purified by conventional methods, in the presence of MEK1.
  • the assay is carried out in 96-well polypropylene plate.
  • the incubation mixture (100 ⁇ L) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl 2 , 5 mM ⁇ -glycerolphosphate, 100 ⁇ M sodium orthovanadate, 5 mM DTT, 5 nM MEK1, and 1 ⁇ M ERK2.
  • Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% DMSO. Reactions are initiated by the addition of 10 ⁇ M ATP (with 0.5 ⁇ Ci ⁇ - 33 P-ATP/well) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TCA is added to stop the reaction and precipitate the proteins.
  • Precipitated proteins are trapped onto glass fiber B filterplates, and excess labeled ATP washed off using a Tomtec MACH III harvestor. Plates are allowed to air-dry prior to adding 30 ⁇ L/well of Packard Microscint 20, and plates are counted using a Packard TopCount. In this assay, Compound 1 exhibited an IC 50 of less than 50 micromolar.
  • FTIR spectra were obtained on a Nicolet Magna 860 ESP FTIR Spectrometer in various ways including from a 2% w/w dispersion of this material in powdered KBr, using the DRIFTS sampling technique, over the 4,000-400 cm ⁇ 1 mid-infrared spectral region.
  • the filter was washed with a mixture of 2-butanone (85 mL) and water (15 mL). The combined filtrates were heated to 72° C. before adding 2-butanone (500 mL) maintaining a temperature of between 60-72° C. The resulting mixture was distilled at atmospheric pressure (approximate distillation temperature 73-74° C.) until 500 mL of distillate had been collected.
  • 1,640-1,370 Includes the C ⁇ C aromatic ring stretching vibrations, the C ⁇ C and C ⁇ N stretching vibrations of the benzimidazole group, the O—H deformation vibration of the primary alcohol group and the aliphatic C—H deformation vibrations.
  • 1,506 Includes the CNH bending vibration of the secondary aromatic amine group.
  • 1,213 The aryl C—F stretching vibration.
  • 1,189 The asymmetric SO 3 ⁇ stretching vibration of the benzimidazole 1:1 sulfate salt group.
  • 1,100-1,000 Includes the C—O stretching vibration of the primary alcohol group and the aryl C—Br stretching vibration.
  • Step A 2,3,4-Trifluoro-5-nitro-benzoic acid: A 3 litre three neck round bottom flask was charged with 125 ml H 2 SO 4 . Fuming nitric acid was added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) was added in 5 g portions over 90 minutes. The dark brownish yellow solution was stirred for 60 minutes at which time the reaction was complete. The reaction mixture was poured into 1 litre of an ice:water mixture and extracted with diethyl ether (3 ⁇ 600 ml). The combined extracts were dried (MgSO 4 ) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 min after which time it was filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI ( ⁇ ) m/z 220 (M ⁇ 1) detected.
  • Step B 4-Amino-2,3-difluoro-5-nitro-benzoic acid: Ammonium hydroxide solution ( ⁇ 30% in water) (35 ml, 271 mmol) was added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0° C. with stirring. Upon completion of the ammonium hydroxide addition, the reaction mixture was warmed to room temperature with stirring. After 2.5 hours, the reaction mixture was cooled to 0° C. and concentrated HCl was carefully added until pH of reaction mixture was 0. The reaction mixture was diluted with water (30 ml) and extracted with diethyl ether (3 ⁇ 50 ml). The combined organic extracts were dried (MgSO 4 ) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI ( ⁇ ) m/z 217 (M ⁇ 1) detected.
  • Step C 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester: A 2 M solution of tetramethylsilane (TMS) diazomethane in hexanes (6.88 ml, 13.75 mmol) was added to a suspension of 4-amino-2,3-difluoro-5-nitrobenzoic acid (2.00 g, 9.17 mmol) in 25 ml of 4:1 Tetrahydrofuran (THF):MeOH at 0° C. under nitrogen atmosphere. Upon completion of addition, reaction mixture was warmed to room temperature. After 0.5 hours, excess TMS diazomethane was destroyed by the careful addition of acetic acid. The reaction was then concentrated under reduced pressure and dried in vacuo 1.95 g (92%) of pure desired product: MS APCI ( ⁇ ) m/z 231 (M ⁇ 1) detected.
  • TMS tetramethylsilane
  • Step D 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester: 4-Amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (23.48 g, 101.1 mmol) was suspended in xylenes (125 ml) and aniline (92 ml, 1011 mmol) was added. The reaction mixture was stirred at 125° C. for 16 hours under N 2 . The reaction mixture was cooled to room temperature and solids precipitated out of solution. The solids were collected by filtration and washed with xylenes and then diethyl ether. Recovered 22.22 g (72.78 mmol) of yellow solid which was pure desired product.
  • Step E 7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester: 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester (16.70 g, 54.71 mmol), formic acid (250 ml, 6.63 mol) and 20% Pd(OH) 2 /C (9.00 g, 16.91 mmol) in ethanol (250 mL) were stirred at 40° C. for two hours under N 2 and then at 95° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite rinsing with ethyl acetate.
  • Step F 6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester: 7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester (4.99 g, 17.51 mmol) was dissolved in N,N-dimethylformamide (275 ml). N-bromosuccinimide (3.15 g, 17.70 mmol) was added as a solid and the reaction mixture was stirred at room temperature under N 2 . After 30 minutes, the reaction mixture was quenched by the addition of aqueous saturated sodium bisulfite solution.
  • Step G 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester: 6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboyxlic acid methyl ester (6.38 g, 17.51 mmol), was dissolved in N,N-dimethylformamide (275 mL). N-chlorosuccinimide (2.36 g, 17.70 mmol) was added as a solid and the reaction mixture was stirred at room temperature under N 2 until the reaction is complete (5-6 days).
  • Step H 6-(4-Bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester and 6-(4-Bromo-2-chlorophenylamino)-7-fluoro-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester: A solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (150 mg, 0.38 mmol), iodomethane (28 ⁇ L, 0.45 mmol) and potassium carbonate (78 mg, 0.56 mmol) in dimethylformamide (1.5 mL) was stirred at 75° C.
  • Step I 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid: 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (56 mg, 0.14 mmol) was dissolved into 2:1 THF/water (3 mL) and NaOH (0.55 ml, 1.0 M aqueous solution, 0.55 mmol) was added. After stirring for two hours the reaction was reduced to one quarter initial volume via rotary evaporation and the remainder diluted to 50 ml with water.
  • aqueous solution was acidified to pH 2 by the addition of 1.0 M aqueous HCl and extracted with 1:1 tetrahydrofuran/ethyl acetate (3 ⁇ ), dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide 43 mg (79%) pure carboxylic acid as an off white solid.
  • Step J 6-(4-Bromo-2 chloro-phenylamino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboyxlic acid (2-vinyloxy-ethoxy)-amide: 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2.00 g, 5.0 mmol), O-(2-vinloxy-ethyl)-hydroxylamine (0.776 g, 7.5 mmol), HOBt (0.88 g, 6.5 mmol), triethylamine (1.61 mL, 2.3 mmol) and EDC1 (1.3 g, 6.5 mmol) were dissolved in dimethylformamide (52 mL), and stirred at room temperature for 48 hours.
  • Step K 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboyxlic acid (2-hydroxy-ethoxy)-amide: Hydrochloric acid (14 mL, 1.0 M aqueous solution, 14 mmol) was added to a suspension of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboyxlic acid (2-vinyloxyethoxy)-amide (2.18 g, 4.50 mmol) in ethanol (50 mL) and the reaction mixture allowed to stir for 24 hours.
  • Example 1 The product of Example 1 was subject to the following tests to determine its physical properties.
  • the X-ray powder diffraction spectra were determined by mounting a sample of the crystalline salt on Siemens single silicon crystal (SSC) wafer mounts and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 40 kV and 40 mA with a wavelength of 1.5406 angstroms. The collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 2 mm antiscatter slit and a 0.2 mm detector slit.
  • SSC Siemens single silicon crystal
  • the sample was exposed for 1 second per 0.02 degree 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode.
  • the running time was 31 minutes and 41 seconds.
  • the instrument was equipped with a scintillation counter as detector. Control and data capture was by means of a Dell Optiplex 686 NT 4.0 Workstation operating with Diffract+ software.
  • the dispersion was removed from the vial using the disposable syringe and dosed to the animal via a gavage tube positioned into the stomach.
  • Dogs were fed about 400 g of Special Diet Services Laboratory Diet A each day and allowed water ad libitum.
  • Whole blood (2 mL) in lithium heparin tubes were taken from the jugular vein immediately prior to dosing and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours.
  • the blood was centrifuged at 3000 rpm for 15 minutes and plasma was removed into plain blood tubes and the plasma stored at ⁇ 20° C. until analysis.
  • Plasma 50 mcL was analyzed for Compound 1 concentration. Two dogs were excluded from the analysis as they had vomited just after dosing. Mean plasma concentration profiles for Compound 1 seen after oral dosing are shown in FIG. 3 where the line represented by ⁇ illustrates a formulation which included the hydrogen sulfate salt of Compound 1, and the line represented by x shows the results of Compound 1 free base in the same formulation.

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