WO2010088000A2 - Composés antifibrotiques et leurs utilisations - Google Patents

Composés antifibrotiques et leurs utilisations Download PDF

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Publication number
WO2010088000A2
WO2010088000A2 PCT/US2010/000287 US2010000287W WO2010088000A2 WO 2010088000 A2 WO2010088000 A2 WO 2010088000A2 US 2010000287 W US2010000287 W US 2010000287W WO 2010088000 A2 WO2010088000 A2 WO 2010088000A2
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Prior art keywords
amino
substituted
acyl
thiophene
carboxamide
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PCT/US2010/000287
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English (en)
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WO2010088000A3 (fr
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Itzhak D. Goldberg
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Angion Biomedica Corp.
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Publication of WO2010088000A2 publication Critical patent/WO2010088000A2/fr
Publication of WO2010088000A3 publication Critical patent/WO2010088000A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • fibrosis Numerous diseases and conditions responsible for significant morbidity as well as mortality have as an underlying disease mechanism the inappropriate or excessive production of fibrous connective tissue, a process generally known as fibrosis.
  • diseases and conditions include fibrotic liver disease, cirrhosis, cardiac fibrosis and lung fibrosis including idiopathic pulmonary fibrosis.
  • numerous other conditions and diseases exhibit a fibrotic component, including but not limited to hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, heart failure and renal disease including renal fibrosis.
  • These conditions and diseases extract a major toll on the healths of afflicted individuals, and on the health care system. Means to affect the onset or progression of such conditions and diseases would be highly desirable.
  • a method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof:
  • R3 is Co- 4 alkyl
  • R4 is hydrogen, one or more hydroxyl groups or optionally substituted alkoxy groups
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R and R3 is hydrogen
  • R2 is and R3 is hydrogen and R4 is hydrogen.
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is
  • R3 is hydrogen; and the other substituents are as described above for Formula
  • R3 is Co ⁇ alkyl; and the other substituents are as described above for Formula (I).
  • the present invention is directed to a compound represented by
  • R3 is hydrogen; and the other variables are as described above for Formula (I).
  • the present invention is directed to a compound represented by
  • R3 is Co-.jalkyl; and the other variables are as described above for Formula (I).
  • the present invention is directed to a compound represented by
  • R3 is hydrogen; and the other variables are as described above for Formula (I).
  • the present invention is also directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition thereof:
  • Rl 1 is aryl, C3 -6 cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; amino; acyl; substituted acyl; acylCi -6 alkylsulf ⁇ nyl; acylCi -6 alkylsulfonyl; acyloxy; Ci.6alkylaminoC] -6 alkyl carbamoyloxy; aryl; cyano; heterocyclyl; C 2- 6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl- substituted aryl; C 2-6 alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci- ⁇ alkyl optionally substituted with halogen, amino, Ci -6 alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylCi- ⁇
  • R21 is hydrogen; lower alkyl optionally substituted with hydroxy, aryl or acyl; or cyclo(lower)alkyl;
  • R31 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; Ci- 6 alkyl optionally substituted with hvdroxy or C 1-6 alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci- ⁇ alkylthio; nitro; amino; acyl; substituted acyl; or C ⁇ cycloalkyloxy;
  • R41 is hydroxy; halogen; nitro; amino; protected amino; Ci -6 alkylamino; acyloxy; amino C 1-6 alkylamino; N-protected aminoCi- ⁇ alkylamino; d ⁇ alkoxy optionally substituted with hydroxy, aryl, substituted aryl, acyl, substituted acyl, amino, Ci -6 alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl or guanidino; Ci- ⁇ alkylthio optionally substituted with acyl, substituted acyl, amino, Ci -6 alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci -6 alkylsulfonyloxy, arylsulfonyloxy, arCi -6 alkoxy or substituted arCi ⁇ alkoxy; Ci.
  • R51 is hydrogen, Ci -6 alkyl, Ci -6 alkoxy or halogen; or together with R41 forms a fused aryl or heteroaryl ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O or S;
  • A is a single bond, O or NH
  • E is C Ci- ⁇ alkylene, C 2-6 alkenylene, — U — , ° ; or E is a group of the formula -G-J- in which G is Ci- ⁇ alkylene and
  • R61 _ l _ J is O or N , wherein R61 is hydrogen or N-protective group
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula II.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted aryl; and the other substituents are as described above for Formula II.
  • a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S; Rl 1 is optionally substituted aryl; and the other substituents are as described above for Formula II.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted heterocyclyl; and the other substituents are as described above for Formula II.
  • a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S; Rl 1 is optionally substituted heterocyclyl; and the other substituents are as described above for Formula II.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, Y is N, and the other substituents are as described above for Formula II.
  • a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S, Y is N, and the other substituents are as described above for Formula II.
  • the present invention is also directed to a method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition thereof:
  • Rl 2 is aryl, C 3 . 6 cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; protected amino, amino; acyl; substituted acyl; acylCi- ⁇ alkylsulfinyl; acyl d- ⁇ alkylsulfonyl; acyloxy; Ci. 6 alkylaminoCi- 6 alkyl carbamoyloxy; aryl; cyano; heterocyclyl; C 2 .
  • R22 is hydrogen; Ci- ⁇ alkyl optionally substituted with hydroxy, aryl or acyl; or C 3 - 6 cycloalkyl;
  • R32 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; optionally substituted with hydroxy or Ci -6 alkoxy; Ci -6 alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci -6 alkylthio; nitro; amino; acyl; substituted acyl; or Cs- ⁇ Cycloalkyloxy;
  • Al is a single bond, O, or NH
  • El is Ci- 6 alkylene, C 2-6 alkenylene, — ⁇ — ⁇ O . or El is a group of the formula -Gl-Jl- in which
  • O Gl is Ci- ⁇ alkylene or — ⁇ — and
  • R62 Jl is O or N , wherein R62 is hydrogen or N-protective group
  • Yl is aryl optionally substituted with 1-6 independent acyl, protected aminoCi -6 alkanoyl, protected amino and nitro, amino and nitro or diamino substituents; or Yl is a heterocyclyl optionally substituted with 1-6 halogen, acyl, Ci- ⁇ alkoxy, hydroxy, guanidino, mercapto, acylamino, amino, heterocyclyl, cyanoamino, Ci- 6 alkylamino, Ci. 6 alkylamino(Ci.
  • Ci -6 alkylamino substituted heterocyclyl
  • Ci -6 alkylhydrazino aryloxy, Q- ⁇ alkylthio, aryl, protected amino, N-protected Ci.6alkylamino(Ci. 6 alkyl)amino, N-protected aminoCi-6alkyl(N'- Ci-6alkyl)amino, aminoCi -6 alkyl(N- Ci -6 alkyl)amino, Ci -6 aUcylamino(Ci. 6 alkyl)(N- Ci.
  • Ci -6 alkyl)amino or Ci -6 alkoxy(Ci- 6 alkyl)amino substituents, or a Ci -6 alkyl substituent further optionally substituted with aryl, arCi -6 alkoxy, cyano, hydroxyimino, mercapto, Ci- 6 alkylamino, acyloxy, halogen, Ci ⁇ alkoxy, protected hydroxy, hydroxy, Ci -6 alkoxyaryl, protected amino, amino, heterocyclyl, or substituted heterocyclyl sub-substituents; provided that when Yl is phenyl optionally substituted with C h alky, or acyl, then Al is a single bond, and O f 2 El is - ⁇ N- .
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula (III).
  • the invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula (I), (II), or (III) in combination with a pharmaceutically acceptable carrier.
  • composition that is comprised of a pharmaceutically acceptable carrier and non-toxic therapeutically effective amount of a compound of Formula (I), (II) or (III) as described above (or a pharmaceutically acceptable salt or N-oxide thereof).
  • Non-limiting examples of compounds useful for the purposes herein include 3-
  • the aforementioned Formulae and compounds have anti- fibrotic activities and thus are useful for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis.
  • the diseases and conditions benefitted by treatment with an effective amount of a compound mentioned above or pharmaceutical composition thereof include but are not limited to fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, cardiac fibrosis, renal disease or lung (pulmonary) fibrosis.
  • the disease or condition is liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis; scleroderma; systemic sclerosis; dermal fibrosis and idiopathic pulmonary fibrosis.
  • liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis,
  • the treatment is for wounds for acceleration of healing; reducing post-surgical scarring; reducing adhesion formation; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, and/or diabetes mellitus.
  • Figure 1 A-B show the expression of PDGFR ⁇ in epithelial cell lines, hepatic cells and fibroblasts
  • Figure 2 shows that PDGF stimulates lung fibroblast proliferation but not lung epithelial cell proliferation
  • Figure 3 shows in the bleomycin-induced lung fibrosis model that lung hydroxyproline content is significantly elevated
  • Figure 4 shows in the bleomycin-induced lung fibrosis model that phospho-PDGFR ⁇ (Tyr751) , lung hydroxyproline content is elevated compared to sham treated animals;
  • Figure 5 shows in the bleomycin-induced lung fibrosis model that lung weight is significantly reduced by treatment of animals by a compound of the invention
  • Figure 6 shows in the bleomycin-induced lung fibrosis model that interstitial collagen in lung tissue is significantly reduced by treatment with a compound of the invention
  • Figure 7 shows in the bleomycin-induced lung fibrosis model that lung hydroxyproline content of lung tissue is significantly reduced by treatment with a compound of the invention
  • Figure 8 shows in the bleomycin-induced lung fibrosis model that alpha SMA in lung tissue is significantly reduced by treatment with a compound of the invention
  • Figure 9 shows in the bleomycin-induced lung fibrosis model that phospho-PDGFR ⁇ in lung tissue is significantly reduced by treatment with a compound of the invention
  • Figure 10 shows that a compound of the invention inhibits both KDR and PDGFR kinase activity
  • Figures 11A-B show that a compound of the invention inhibits KDR signaling in endothelial cells (A) and PDGF signaling in hepatic stellate cells (B);
  • Figures 12A-B show that a compound of the invention significantly reduces liver weight (A) and hydroxyproline content of liver (B) in the TAA- induced liver fibrosis model.
  • Figures 13A-B show that a compound of the invention significantly reduces alpha SMA (A) and phospho-PDGFR ⁇ expression in liver (B) in the TAA- induced liver fibrosis model.
  • Figure 14 shows that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces dermal hydroxyproline content to a level not different that normal;
  • Figure 15 shows that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces skin collagen content
  • Figure 16 shows that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces dermal thickness
  • Figure 17 A-B show that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces alphaSMA and phospho-PDGFR in skin.
  • Co-4alkyl is used to mean an alkyl having 0-4 carbons - that is,
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • alkyl As used herein unless otherwise specified, “alkyl”, “alchemy”, and “alkynyl” includes straight or branched configurations. Lower alkyls, alkenyls, and alkynyls have 1-6 carbons. Higher alkyls, alkenyls, and alkynyls have more than 6 carbons.
  • aryl and “ar” are well known to chemists and include, for example, phenyl and naphthyl, as well as phenyl with one or more short alkyl groups (tolyl, xylyl, mesityl, cumenyl, di(t-butyl)phenyl).
  • substituted aryl is an aryl substituted with suitable substituents such as, for example, acyl, substituted acyl, N-protected piperazinylsulfonyl, piperazinylsulfonyl, N-Ci- 6 alkylpiperazinylsulfonyl, hydroxy heterocyclyl, halogen, nitro, amino, Q- 6 alkylamino, cyano, or Ci -6 alkoxy,
  • heterocyclyl is well known to chemists and contains at least one N, S or O hetero-ring atom, and includes saturated, unsaturated, partially saturated, mono or polycyclic heterocyclic groups such as, for example, pyrrolyl, pyrrolinyl, imidazoylyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolo-pyridazinyl, pyranyl
  • acyl includes for example, carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, aroyl, heterocyclylcarbonyl, and the like.
  • Esterified carboxy includes substituted or unsubstituted lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t- butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, dimethylaminopropoxycarbonyl, dimethylaminoethoxycarbonyl; substituted or unsubstituted aryloxycarbonyl such as phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl; substituted or unsubstituted ar(lower)alkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, 3-methoxy-4- nitrobenzyloxycarbonyl; and N-containing heterocyclyloxycarbony
  • halogen is fluorine, chlorine, bromine or iodine.
  • Ci -6 alkylhydrazino may be mono or
  • 2,2-di(Ci-6alkyl)hydrazino such as 2-methylhydrazino, 2,2-dimethylhydrazino, 2-ethylhydrazino, 2,2-diethylhydrazino, or the like.
  • Ci-ealkylaminoCi-ealkyl includes, for example, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl or the like.
  • Ci -6 alkanoyl includes substituted or unsubstituted alkanoyls such as formyl, acetyl, propionoyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like.
  • Aroyl includes benzoyl, naphthoyl, toluoyl, di(t-butyl)benzoyl and the like.
  • N-protective group in “protected amino”, includes substituted or unsubstituted lower alkanyl (such as, for example, formyl, acetyl, propionyl, trifluoroacetyl), phthaloyl, lower alkoxycarbonyl (such as tbutoxycarbonyl, t- amyloxycarbonyl), substituted or unsubstituted aralkyloxycarbonyl (such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl(benzenesulfonyl, tosyl). Phthaloyl, t-butoxycarbonyl or 9fluorenylmethoxycarbonyl are preferred.
  • hydroxyl-protective group' includes substituted or unsubstituted arylmethyl (for example, benzyl, lower alkoxy benzyl), acyl, or substituted silyl (for example, t-butyldiphenylsilyl).
  • alkyl includes straight and branched alkyl groups.
  • alkenyl alkynyl
  • alkynyl alkynyl
  • lower alkyl is used to indicate those alkyl groups (substituted, unsubstiruted, branched or unbranched) having 1-6 carbon atoms.
  • Lower alkenyl and “lower alkynyl” respectively include corresponding 1-6 carbon moieties.
  • the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20; 2-20; 3-20; 4-20; 5-20; 6-20; 7-20 or 8-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10; 2-10; 3-10; 4-10; 5-10; 6-10; 7-10 or 8-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8; 2-8; 3-8; 4-8; 5-8; 6-20 or 7-8 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6; 2-6; 3-6; 4-6 or 5-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4; 2-4 or 3-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • alicyclic refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to monocyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups.
  • alicyclic is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
  • Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH 2 - cyclopropyl, cyclobutyl, -CH 2 -cyclobutyl, cyclopentyl, -CH 2 -cyclopentyl, cyclohexyl, -CH 2 - cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
  • alkoxy refers to a saturated (i.e., O- alkyl) or unsaturated (i.e., O-alkenyl and O-alkynyl) group attached to the parent molecular moiety through an oxygen atom.
  • the alkyl group contains 1-20; 2-20; 3- 20; 4-20; 5-20; 6-20; 7-20 or 8-20 aliphatic carbon atoms.
  • the alkyl group contains 1-10; 2-10; 3-10; 4-10; 5-10; 6-10; 7-10 or 8-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8; 2-8; 3-8; 4-8; 5-8; 6-20 or 7-8 aliphatic carbon atoms.
  • the alkyl group contains 1-6; 2-6; 3-6; 4-6 or 5-6 aliphatic carbon atoms.
  • the alkyl group contains 1-4; 2-4 or 3-4 aliphatic carbon atoms.
  • the alkoxy group is optionally substituted with halogen, hydroxyl, O-alkyl, NO 2 , NH 2 , NH-alkyl, N- dialkyl, thioalkyl.
  • alkoxy examples include but are not limited to, methoxy, methoxyethanol, ethoxy, ethoxymethoxy, propoxy, isopropoxy, n-butoxy, /-butoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexoxy, and the like.
  • thioalkyl refers to a saturated (i.e., S-alkyl) or unsaturated (i.e., S-alkenyl and S-alkynyl) group attached to the parent molecular moiety through a sulfur atom.
  • the alkyl group contains 1-20 aliphatic carbon atoms.
  • the alkyl group contains 1-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms.
  • the alkyl group contains 1-6 aliphatic carbon atoms.
  • the alkyl group contains 1-4 aliphatic carbon atoms.
  • thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • alkylamino refers to a group having the structure -NHR' wherein R' is aliphatic or alicyclic, as defined herein.
  • aminoalkyl refers to a group having the structure NH 2 R'-, wherein R' is aliphatic or alicyclic, as defined herein.
  • the aliphatic or alicyclic group contains 1-20 aliphatic carbon atoms.
  • the aliphatic or alicyclic group contains 1-10 aliphatic carbon atoms.
  • the aliphatic or alicyclic group contains 1-6 aliphatic carbon atoms.
  • the aliphatic or alicyclic group contains 1-4 aliphatic carbon atoms.
  • R' is an alkyl, alkenyl, or alkynyl group containing 1-8 aliphatic carbon atoms.
  • alkylamino include, but are not limited to, methylamino, ethylamino, iso- propylamino and the like.
  • aromatic moiety refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • aromatic moiety refers to a planar ring having p-orbitals perpendicular to the plane of the ring at each ring atom and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer.
  • a mono- or polycyclic, unsaturated moiety that does not satisfy one or all of these criteria for aromaticity is defined herein as "non-aromatic", and is encompassed by the term “alicyclic”.
  • heteromatic moiety refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted; and comprising at least one heteroatom selected from O, S and N within the ring (i.e., in place of a ring carbon atom).
  • heteromatic moiety refers to a planar ring comprising at least one heteroatom, having p- orbitals perpendicular to the plane of the ring at each ring atom, and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer.
  • aromatic and heteroaromatic moieties may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties.
  • aromatic or heteroaromatic moieties and "aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic” are interchangeable.
  • Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl does not differ significantly from the common meaning of the term in the art, and refers to an unsaturated cyclic moiety comprising at least one aromatic ring.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl rings of 6-10 members are embodied herein.
  • heteroaryl does not differ significantly from the common meaning of the term in the art, and refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2
  • any two adjacent groups taken together may represent a 4, 5, 6, or 7-membered substituted or unsubstituted alicyclic or heterocyclic moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I
  • heteroaliphatic refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom.
  • a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms.
  • Heteroaliphatic moieties may be linear or branched, and saturated or unsaturated.
  • heterocycloalkyl refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include, but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring systems having 5-16 atoms wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), wherein the ring systems are optionally substituted with one or more functional groups, as defined herein.
  • heterocycloalkyl refers to a non-aromatic 5, 6, 7, 8, 9 or 10-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has O to 2 double bonds, each 6-membered ring has O to 2 double bonds and each 7-membered ring has O to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heterocyclic group
  • heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolid
  • a "substituted heterocycle, or heterocycloalkyl or heterocyclic” group refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2
  • any of the alicyclic or heterocyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • amino refers to a primary (-NH 2 ), secondary (-NHR x ), tertiary (-NR x R y ) or quaternary (-N + R x R y R 2 ) amine, where R x , R y and R z are independently an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein.
  • amino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.
  • acyl refers to a group having the general formula -
  • R is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein.
  • C 2-6 alkenylidene refers to a substituted or unsubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence "-" at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.
  • alkynyl encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups.
  • alicyclic encompass substituted and unsubstituted, and saturated and unsaturated groups.
  • cycloalkyl encompass both substituted and unsubstituted groups.
  • pharmaceutically acceptable derivative denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
  • Pharmaceutically acceptable derivatives thus include among others pro-drugs.
  • a pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety, which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species.
  • pro-drug is an ester, which is cleaved in vivo to yield a compound of interest.
  • Another example is an N-methyl derivative of a compound, which is susceptible to oxidative metabolism resulting in N-demethylation, particularly on the 1 position of the 3(5)-monosubstituted pyrazole derivatives of the invention.
  • Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
  • tautomerization refers to the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992).
  • tautomer refers to the compounds produced by the proton shift.
  • the present invention encompasses the tautomeric moieties like parasols, pyridones and enols, etc.
  • geometrical isomers refers to cis-trans isomerism, syn-anti or E/Z isomerism based on the Cahn-Ingold-Prelog system. See March's Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Sixth Edition, Wiley-Interscience, pages 182-195 (2007).
  • geometrical isomers refers to compounds having double bond with an E or Z configuration or cis-trans isomers of monocyclic or fused ring systems.
  • protecting group By the term “protecting group”, as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen and carbon protecting groups may be utilized.
  • oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM or MPM (p- methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t- butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz),
  • nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N- Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • isolated when applied to the compounds of the present invention, refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or (ii) produced, prepared or manufactured by the hand of man.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof; or purified versions thereof.
  • biological sample refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated).
  • the biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid.
  • the biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, seminal fluid, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g.
  • the biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ.
  • Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
  • Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates.
  • biological samples may be from any animal, plant, bacteria, virus, yeast, etc.
  • the term animal refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals.
  • the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig).
  • An animal may be a transgenic animal or a human clone.
  • the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
  • fibrosis Numerous diseases and conditions responsible for significant morbidity as well as mortality have as an underlying disease mechanism the inappropriate or excessive production of fibrous connective tissue, a process generally known as fibrosis. Such diseases and conditions include fibrotic liver disease, cirrhosis, cardiac fibrosis and lung fibrosis including idiopathic pulmonary fibrosis. In addition to these, numerous other conditions and diseases exhibit a fibrotic component, including but not limited to hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, heart failure and renal disease including renal fibrosis.
  • hepatic diseases and conditions include liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency).
  • Other conditions and diseases with a fibrotic component include damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; and renal failure.
  • anti-fibrotic compounds are useful for the treatment of wounds for acceleration of healing; reducing post-surgical scarring; reducing adhesion formation; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy; amyotrophic lateral sclerosis; scleroderma, systemic sclerosis and dermal fibrosis; and/or diabetes mellitus.
  • a method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof:
  • R3 is Co-4 alkyl
  • R4 is hydrogen, one or more hydroxyl groups or optionally substituted alkoxy groups
  • R2 is In yet another embodiment, R2 and R3 is hydrogen.
  • R2 is and R3 is hydrogen and R4 is hydrogen.
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • R3 is hydrogen; and the other substituents are as described above for
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2
  • R3 is hydrogen; and the other variables are as described above for Formula (I).
  • the present invention is also directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition thereof:
  • Rl 1 is aryl, C 3-6 cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; amino; acyl; substituted acyl; acylCi- 6 alkylsulfinyl; acylCi- 6 alkylsulfonyl; acyloxy; Ci- ⁇ alkylaminoCi-ealkyl carbamoyloxy; aryl; cyano; heterocyclyl; C 2-6 alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl- substituted aryl; C 2-6 alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci- 6 alkyl optionally substituted with halogen, amino, Ci- ⁇ aUcylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acyl, substituted acy
  • alkylamino N- acylCi- ⁇ alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci- 6 alkylhydrazinocarbonylamino, hydroxyimino, acylCi- ⁇ alkoxyimino, substituted acylCi- 6 alkoxyimino, acylCi- ⁇ alkoxy, guanidino or N-protected guanidino; or C 2-6 alkenyloxy optionally substituted with acyl or substituted acyl substituents;
  • R21 is hydrogen; lower alkyl optionally substituted with hydroxy, aryl or acyl; or cyclo(lower)alkyl;
  • R31 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; Ci -6 alkyl optionally substituted with hydroxy or Ci- ⁇ alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci -6 alkylthio; nitro; amino; acyl; substituted acyl; or C 3- 6cycloalkyloxy;
  • R41 is hydroxy; halogen; nitro; amino; protected amino; Ci -6 alkylamino; acyloxy; amino Ci- 6 alkylamino; N-protected aminoCi- ⁇ alkylamino; optionally substituted with hydroxy, aryl, substituted aryl, acyl, substituted acyl, amino, Ci -6 alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl or guanidino; d- ⁇ alkylthio optionally substituted with acyl, substituted acyl, amino, Ci- ⁇ alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci.
  • alkylsulfonyloxy or arylsulfonyloxy aminoCi -6 alkylsulfonyl; N-protected aminoCi -6 alkylsulfonyl; Ci- ⁇ alkylaminosulfonyl; heterocyclylsulfonyl; aminoCi. 6 alkylsulfinyl; N-protected amino piperidyloxy; or N-protected piperidyloxy;
  • R51 is hydrogen, Ci -6 alkyl, Ci -6 alkoxy or halogen; or together with R41 forms a fused aryl or heteroaryl ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O or S;
  • A is a single bond, O or NH
  • E is C Ci -6 alkylene, C 2-6 alkenylene, — U — , ° ; or E is a group of the formula -G-J- in which G is C].6alkylene and R61
  • I J is O or N , wherein R61 is hydrogen or N-protective group
  • Y is CH or N.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula II.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted aryl; and the other substituents are as described above for Formula II.
  • a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S; Rl 1 is optionally substituted aryl; and the other substituents are as described above for Formula II.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted heterocyclyl; and the other substituents are as described above for Formula II.
  • a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S; Rl 1 is optionally substituted heterocyclyl; and the other substituents are as described above for Formula II.
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, Y is N, and the other substituents are as described above for Formula II.
  • a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S, Y is N, and the other substituents are as described above for Formula II.
  • the present invention is also directed to a method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition thereof:
  • Rl 2 is aryl, C 3- 6cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; protected amino, amino; acyl; substituted acyl; acylCi.6alkylsulfinyl; acyl Ci.6alkylsulfonyl; acyloxy; Ci-ealkylaminoCi- ⁇ alkyl carbamoyloxy; aryl; cyano; heterocyclyl; C 2- 6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl-substituted aryl; C 2-6 alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci -6 alkyl optionally substituted with halogen, amino, Ci -6 alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylCi_
  • alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acylCi- ⁇ alkylamino, N-protected acylCi- ⁇ alkylamino, N- acylCi -6 alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci.
  • R22 is hydrogen; Q ⁇ alkyl optionally substituted with hydroxy, aryl or acyl; or C 3- 6Cycloalkyl;
  • R32 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; optionally substituted with hydroxy or Ci -6 alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci. 6 alkylthio; nitro; amino; acyl; substituted acyl; or Cs ⁇ cycloalkyloxy; Al is a single bond, O, or NH;
  • El is Ci-6alkylene, C 2-6 alkenylene, — " — , ° ; or El is a group of the formula -Gl-Jl- in which
  • O Gl is C 1-6 alkylene or — " — and
  • R62 Jl is O or N , wherein R62 is hydrogen or N-protective group
  • Yl is aryl optionally substituted with 1-6 independent acyl, protected aminoCi -6 alkanoyl, protected amino and nitro, amino and nitro or diamino substituents; or Yl is a heterocyclyl optionally substituted with 1-6 halogen, acyl, Ci ⁇ alkoxy, hydroxy, guanidino, mercapto, acylamino, amino, heterocyclyl, cyanoamino, Ci- ⁇ alkylamino, Ci- ⁇ alkylaminoCCi-ealkylamino), substituted heterocyclyl, Ci -6 alkylhydrazino, aryloxy, C 1- ⁇ alkylthio, aryl, protected amino, N-protected Ci.
  • Ci -6 alkylamino(Ci -6 alkyl)amino N-protected aminoCi -6 alkyl(N'- Ci -6 alkyl)amino, aminoCi -6 alkyl(N- Ci- 6 alkyl)amino, Ci -6 alkylamino(Ci- 6alkyl)(N- C 1-6 alkyl)amino, or Ci -6 alkoxy(Ci -6 alkyl)amino substituents, or a Ci -6 alkyl substituent further optionally substituted with aryl, arCi -6 alkoxy, cyano, hydroxyimino, mercapto, Ci- ⁇ alkylamino, acyloxy, halogen, Ci ⁇ alkoxy, protected hydroxy, hydroxy, Ci_ 6 alkoxyaryl, protected amino, amino, heterocyclyl, or substituted heterocyclyl sub-substituents; provided that when Yl is phenyl optionally substituted with C
  • the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula (III).
  • a compound of Formula (III) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof wherein X is S, and the other substituents are as described above for Formula (III).
  • Co-4alkyl is used to mean an alkyl having 0-4 carbons - that is,
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • alkyl As used herein unless otherwise specified, “alkyl”, “alkenyl”, and “alkynyl” includes straight or branched configurations. Lower alkyls, alkenyls, and alkynyls have 1-6 carbons. Higher alkyls, alkenyls, and alkynyls have more than 6 carbons.
  • aryl and “ar” are well known to chemists and include, for example, phenyl and naphthyl, as well as phenyl with one or more short alkyl groups (tolyl, xylyl, mesityl, cumenyl, di(t-butyl)phenyl).
  • substituted aryl is an aryl substituted with suitable substituents such as, for example, acyl, substituted acyl, N-protected piperazinylsulfonyl, piperazinylsulfonyl, N-Ci- 6 alkylpiperazinylsulfonyl, hydroxy heterocyclyl, halogen, nitro, amino, Ci- ⁇ alkylamino, cyano, or Ci- ⁇ alkoxy,
  • heterocyclyl is well known to chemists and contains at least one N, S or O hetero-ring atom, and includes saturated, unsaturated, partially saturated, mono or polycyclic heterocyclic groups such as, for example, pyrrolyl, pyrrolinyl, imidazoylyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolo-pyridazinyl, pyranyl
  • acyl includes for example, carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, aroyl, heterocyclylcarbonyl, and the like.
  • Esterified carboxy includes substituted or unsubstituted lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t- butoxycarbonyl, hexyloxycarbonyl, 2iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, dimethylaminopropoxycarbonyl, dimethylaminoethoxycarbonyl; substituted or unsubstituted aryloxycarbonyl such as phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl; substituted or unsubstituted ar(lower)alkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, 3methoxy-4- nitrobenzyloxycarbonyl; and N-containing heterocyclyloxycarbony
  • halogen is fluorine, chlorine, bromine or iodine.
  • Ci -6 alkylhydrazino may be mono or
  • 2,2-di(Ci -6 alkyl)hydrazino such as 2-methylhydrazino, 2,2-dimethylhydrazino, 2-ethylhydrazino, 2,2-diethylhydrazino, or the like.
  • Ci-oalkylaminoCi-oalkyl includes, for example, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl or the like.
  • C 1-6 alkanoyl includes substituted or unsubstituted alkanoyls such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like.
  • Aroyl includes benzoyl, naphthoyl, toluoyl, di(t-butyl)benzoyl and the like.
  • N-protective group in “protected amino”, includes substituted or unsubstituted lower alkanyl (such as, for example, formyl, acetyl, propionyl, trifluoroacetyl), phthaloyl, lower alkoxycarbonyl (such as tbutoxycarbonyl, t- amyloxycarbonyl), substituted or unsubstituted aralkyloxycarbonyl (such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), 9fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl(benzenesulfonyl, tosyl). Phthaloyl, t-butoxycarbonyl or 9fluorenylmethoxycarbonyl are preferred.
  • hydroxy 1-protective group' includes substituted or unsubstituted arylmethyl (for example, benzyl, lower alkoxy benzyl), acyl, or substituted silyl (for example, t-butyldiphenylsilyl).
  • the above Formulas (I), (II), and (III) are shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formulas (I), (II), and (III) and pharmaceutically acceptable salts three of. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixture of stereoisomers.
  • the invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula (I), (II), or (III) in combination with a pharmaceutically acceptable carrier.
  • composition that is comprised of a pharmaceutically acceptable carrier and non-toxic therapeutically effective amount of a compound of Formula (I), (II) or (III) as described above (or a pharmaceutically acceptable salt or N-oxide thereof).
  • Non-limiting examples of compounds useful for the purposes herein include 3-
  • the aforementioned Formulae and compounds have anti- fibrotic activities and thus are useful for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis.
  • the diseases and conditions benefitted by treatment with an effective amount of a compound mentioned above or pharmaceutical composition thereof include but are not limited to fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, cardiac fibrosis, renal disease or lung (pulmonary) fibrosis.
  • the disease or condition is liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis and idiopathic pulmonary fibrosis.
  • liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepati
  • the treatment is for wounds for acceleration of healing; reducing postsurgical scarring; reducing adhesion formation; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, scleroderma, systemic sclerosis and dermal fibrosis and/or diabetes mellitus.
  • any one or more occurrences of aliphatic and/or heteroaliphatic may independently be substituted or unsubstituted, linear or branched, saturated or unsaturated; any one or more occurrences of alicyclic and/or heteroalicyclic may independently be substituted or unsubstituted, saturated or unsaturated; and any one or more occurrences of aryl and/or heteroaryl may independently be substituted or unsubstituted.
  • inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.
  • certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers.
  • this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
  • Compounds of the invention may be prepared by crystallization of compound of Formula (I), (II) and (III) under different conditions and may exist as one or a combination of polymorphs of compound of general formulas (I), (II) and (III) forming part of this invention.
  • different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques.
  • inventive compounds their derivatives, their tautomeric and geometrical isomeric forms, their stereoisomers, their positional isomer, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • Tautomeric forms of compounds of the present invention include, pyrazoles, pyridones and enols, etc.
  • geometrical isomers include E/Z isomers of compounds having double bonds and cis-trans isomers of monocyclic or fused ring systems, etc.
  • this invention provides novel compounds that have biological properties useful for the treatment of any of a number of conditions or diseases in which an anti- f ⁇ brotic agent has a therapeutically useful role.
  • compositions which comprise any one or more of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents.
  • additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved agent to treat the same or related indication, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder related to fibrosis.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood, or N-demethylation of a compound of the invention where R 1 is methyl.
  • the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut (peanut), corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents such as, for example, water or other solvents, so
  • liquid compositions or liquid formulations comprising compounds of the invention are provided that have increased solubility as compared to compounds of the invention dissolved in aqueous buffer such as phosphate-buffered saline.
  • aqueous buffer such as phosphate-buffered saline.
  • such liquid compositions with increased solubility are provided by a composition comprising polyethylene glycol, polysorbate or a combination thereof.
  • the polyethylene glycol is polyethylene glycol 300.
  • the polysorbate is polysorbate 80.
  • the polyethylene glycol is present at about 40% to about 60% (v/v).
  • the polysorbate is present at about 5% to about 15% (v/v).
  • the polyethylene glycol is present at about 50% (v/v).
  • the polysorbate is present at about 10% (v/v).
  • the polyethylene glycol is present at 50% (v/v) together with polysorbate 80 at 10% (v/v).
  • the balance of the solution can be a saline solution, a buffer or a buffered saline solution, such as phosphate-buffered saline.
  • the pH of the solution can be from about pH 5 to about pH 9, and in other embodiments, about from pH 6 to about pH 8.
  • the pH of the buffer is 7.4.
  • the compound of the invention is soluble at a concentration higher than in buffer alone, and can be present at about 0.8 to about 10 milligrams per milliliter of solution, or even higher.
  • compositions offer the preparation of convenient dosing solutions of practical volumes for single dose administration, by any route, in particular a parenteral route.
  • the route is intravenous, subcutaneous or intraperitoneal.
  • Such compositions with a higher solubility permit achievement of more elevated blood concentrations that provide efficacy when the threshold Cmax (maximal blood concentration after administration) should be achieved for optimal efficacy.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • solid dosage forms of compounds embodied herein are provided. In some embodiment, such solid dosage forms have improved oral bioavailability.
  • a formulation is prepared in a solid formulation comprising about 20% (w/w) compound of the invention, about 10-20% (w/w) GLUCIRE® 44/14, about 10-20% (w/w) vitamin E succinate (TPS), 0 to about 60% polyethylene glycol 400, 0 to about 40% Lubrizol, 0 to about 15% Cremophor RH 40 (w/w), and about 1% (w/w) BHT.
  • Formulations containing Cremophor RH 20 are liquid at room temperature but waxy solids at 4 C.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • solid dosage forms are provided.
  • such solid dosage forms provide a higher than about a 20% oral bioavailability.
  • compounds of the invention can be co-precipitated with one or more agents such as mannitol, a combination of mannitol and lactobionic acid, a combination of mannitol and gluconic acid, a combination of mannitol and methanesulfonic acid, a combination of microcrystalline cellulose and oleic acid or a combination of pregelatinized starch and oleic acid.
  • agents to aid in preparing formulations of inventive compound are merely illustrative and non-limiting.
  • Non-limiting examples of inventive compounds in such solid dosage forms include
  • the present invention encompasses pharmaceutically acceptable topical formulations of inventive compounds.
  • pharmaceutically acceptable topical formulation means any formulation which is pharmaceutically acceptable for intradermal administration of a compound of the invention by application of the formulation to the epidermis.
  • the topical formulation comprises a carrier system.
  • Pharmaceutically effective carriers include, but are not limited to, solvents (e.g., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals.
  • solvents e.g., alcohols, poly alcohols, water
  • creams e.g., lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals.
  • buffered solutions e.g., hypotonic or buffered saline
  • the topical formulations of the invention may comprise excipients.
  • Any pharmaceutically acceptable excipient known in the art may be used to prepare the inventive pharmaceutically acceptable topical formulations.
  • excipients that can be included in the topical formulations of the invention include, but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or additional therapeutic agents used in combination to the inventive compound.
  • Suitable preservatives include, but are not limited to, alcohols, quaternary amines, organic acids, parabens, and phenols.
  • Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
  • Suitable moisturizers include, but are not limited to, glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol.
  • Suitable buffering agents for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid buffers.
  • Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
  • Suitable skin protectants that can be used in the topical formulations of the invention include, but are not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.
  • the pharmaceutically acceptable topical formulations of the invention comprise at least a compound of the invention and a penetration enhancing agent.
  • a penetration enhancing agent means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption.
  • penetration enhancing agent means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption.
  • a wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I.
  • penetration agents for use with the invention include, but are not limited to, triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe- vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.
  • triglycerides e.g., soybean oil
  • aloe compositions e.g., aloe- vera gel
  • ethyl alcohol isopropyl alcohol
  • octolyphenylpolyethylene glycol oleic acid
  • polyethylene glycol 400 propylene glycol
  • the compositions may be in the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred.
  • Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • Formulations for intraocular administration are also included.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium.
  • penetration enhancing agents can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anti-inflammatory agent), or they may achieve different effects (e.g., control of any adverse effects).
  • one or more compounds of the invention may be formulated with at least one cytokine, growth factor or other biological, such as an interferon, e.g., alpha interferon, or with at least another small molecule compound.
  • interferon e.g., alpha interferon
  • pharmaceutical agents that may be combined therapeutically with compounds of the invention include: antivirals and antifibrotics such as interferon alpha, combination of interferon alpha and ribavirin, Lamivudine, Adefovir dipivoxil and interferon gamma; anticoagulants such as heparin and warfarin; antiplatelets e.g., aspirin, ticlopidine and clopidogrel; other growth factors involved in regeneration, e.g., VEGF and FGF and mimetics of these growth factors ; antiapoptotic agents; and motility and morphogenic agents.
  • the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., antiinflammatory and/or palliative).
  • additional therapeutically active ingredients e.g., antiinflammatory and/or palliative.
  • palliative refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative.
  • palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.
  • liver fibrosis is the scarring response of the liver to chronic liver injury; when fibrosis progresses to cirrhosis, morbid complications can develop.
  • end-stage liver fibrosis or cirrhosis is the seventh leading cause of death in the United States, and afflicts hundreds of millions of people worldwide; deaths from end-stage liver disease in the United States are expected to triple over the next 10-15 years, mainly due to the hepatitis C epidemic.
  • liver disease In addition to the hepatitis C virus, many other forms of chronic liver injury also lead to end-stage liver disease and cirrhosis, including other viruses such as hepatitis B and delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency).
  • viruses such as hepatitis B and delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wil
  • liver fibrosis has focused to date on eliminating the primary injury. For extrahepatic obstructions, biliary decompression is the recommended mode of treatment whereas patients with Wilson's disease are treated with zinc acetate.
  • interferon has been used as antiviral therapies with limited response: -20% when used alone or ⁇ 50% response when used in combination with ribavirin.
  • treatment with interferon with or without ribavirin is associated with numerous severe side effects including neutropenia, thrombocytopenia, anemia, depression, generalized fatigue and flu-like symptoms, which are sufficiently significant to necessitate cessation of therapy.
  • Treatments for other chronic liver diseases such as hepatitis B, autoimmune hepatitis and Wilson's disease are also associated with many side effects, while primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease have no effective treatment other than liver transplantation.
  • the compounds of the invention are beneficial for the treatment of the foregoing conditions, and generally are antifibrotic agents for this and other organ or tissues.
  • liver IR injury to the liver is a major alloantigen-independent component affecting transplantation outcome, causing up to 10% of early organ failure, and leading to the higher incidence of both acute and chronic rejection.
  • surgeons are forced to consider cadaveric or steatotic grafts or other marginal livers, which have a higher susceptibility to reperfusion injury.
  • liver IR injury is manifested in clinical situations such as tissue resections (Pringle maneuver), and hemorrhagic shock.
  • the damage to the postischemic liver represents a continuum of processes that culminate in hepatocellular injury.
  • Ischemia activates Kupffer cells, which are the main sources of vascular reactive oxygen species (ROS) formation during the initial reperfiision period.
  • ROS vascular reactive oxygen species
  • intracellular generation of ROS by xanthine oxidase and in particular mitochondria may also contribute to liver dysfunction and cell injury during reperfiision.
  • Endogenous antioxidant compounds such as superoxide dismutase, catalase, glutathione, alphatocopherol, and beta- carotene, may all limit the effects of oxidant injury but these systems can quickly become overwhelmed by large quantities of ROS.
  • Cell death of hepatocytes and endothelial cells in this setting is characterized by swelling of cells and their organelles, release of cell contents, eosinophilia, karyolysis, and induction of inflammation, characteristic of oncotic necrosis. More recent reports indicate that liver cells also die by apoptosis, which is morphologically characterized by cell shrinkage, formation of apoptotic bodies with intact cell organelles and absence of an inflammatory response.
  • IR injury could significantly increase the number of patients that may successfully undergo liver transplantation.
  • Pharmacologic interventions that reduce cell death and/or enhance organ regeneration represent a therapeutic approach to improve clinical outcome in liver transplantation, liver surgery with vascular exclusion and trauma and can therefore reduce recipient/patient morbidity and mortality.
  • the compounds of the invention are beneficial for the treatment of the foregoing conditions.
  • Therapeutic strategies focus primarily on acute treatment to reduce injury in the ischemic penumbra, the region of reversibly damaged tissue surrounding an infarct.
  • Thrombolytic therapy has been shown to improve perfusion to the ischemic penumbra, but it must be administered within three hours of the onset of infarction.
  • Several neuroprotective agents that block specific tissue responses to ischemia are promising, but none have yet been approved for clinical use. While these therapeutic approaches limit damage in the ischemic penumbra, they do not address the underlying problem of inadequate blood supply due to occluded arteries.
  • An alternative strategy is to induce formation of collateral blood vessels in the ischemic region; this occurs naturally in chronic ischemic conditions, but stimulation of vascularization via therapeutic angiogenesis has potential therapeutic benefit.
  • CBF cerebral blood flow
  • Atherosclerosis comprises a fibrotic component, and compounds described herein are useful for prevention and treatment as well as intervention in the development of heart failure.
  • Renal Disease Chronic renal dysfunction is a progressive, degenerative disorder that ultimately results in acute renal failure and requires dialysis as an intervention, and renal transplantation as the only potential cure. Initiating conditions of renal dysfunction include ischemia, diabetes, underlying cardiovascular disease, or renal toxicity associated with certain chemotherapeutics, antibiotics, and radiocontrast agents. Most end-stage pathological changes include extensive fibrinogenesis, epithelial atrophy, and inflammatory cell infiltration into the kidneys.
  • Acute renal failure is often a complication of diseases including diabetes or renal ischemia, procedures such as heminephrectomy, or as a side effect of therapeutics administered to treat disease.
  • the widely prescribed anti-tumor drug c/s-diamminedichloroplatinum (cisplatin) for example, has side effects that include a high incidence of nephrotoxicity and renal dysfunction, mainly in the form of renal tubular damage that leads to impaired glomerular filtration.
  • Administration of gentamicin, an aminoglycoside antibiotic, or cyclosporin A, a potent immunosuppressive compound causes similar nephrotoxicity. The serious side effects of these effective drugs restrict their use.
  • the development of agents that protect renal function and enhance renal regeneration after administration of nephrotoxic drugs will be of substantial benefit to numerous patients, especially those with malignant tumors, and may allow the maximal therapeutic potentials of these drugs to be realized.
  • the compounds of the invention are beneficial for the treatment of the renal diseases mentioned above.
  • IPF Idiopathic pulmonary fibrosis
  • IPF accounts for a majority of chronic interstitial lung diseases, and has an estimated incidence rate of 10.7 cases for 100,000 per year, with an estimated mortality of 50-70%.
  • IPF is characterized by an abnormal deposition of collagen in the lung with an unknown etiology. Although the precise sequence of the pathogenic sequelae is unknown, disease progression involves epithelial injury and activation, formation of distinctive subepithelial fibroblast/myofibroblast foci, and excessive extracellular matrix accumulation.
  • Fibrosis is the final common pathway of a variety of lung disorders, and in this context, the diagnosis of pulmonary fibrosis implies the recognition of an advanced stage in the evolution of a complex process of abnormal repair. While many studies have focused on inflammatory mechanisms for initiating the fibrotic response, the synthesis and degradation the extracellular matrix represent the central event of the disease. It is this process that presents a very attractive site of therapeutic intervention.
  • IPF interstitial lung disease
  • idiopathic pulmonary fibrosis pulmonary fibrosis
  • Corticosteroids are the most frequently used antiinflammatory agents and have been the mainstay of therapy for IPF for more than four decades, but the efficacy of this approach is unproven, and toxicities are substantial. No studies have compared differing dosages or duration of corticosteroid treatment in matched patients.
  • Interferon gamma may be effective in the treatment of IPF in some patients but its role is controversial.
  • Literature indicated that IFN-gamma may be involved in small airway disease in silicotic lung. Others showed that IFN gamma mediates, bleomycin-induced pulmonary inflammation and fibrosis.
  • the compounds of the invention are beneficial for the treatment of the foregoing condition, among other fibrotic diseases.
  • Scleroderma also known as systemic sclerosis (SSc)
  • SSc systemic sclerosis
  • ECM extracellular matrix
  • SSc systemic sclerosis
  • Efficacy of the compounds of the invention on the aforementioned disorders and diseases or the potential to be of benefit for the prophylaxis or treatment thereof may be demonstrated in various studies, ranging from biochemical effects evaluated in vitro and effects on cells in culture, to in-vivo models of disease, wherein direct clinical manifestations of the disease can be observed and measured, or wherein early structural and/or functional events occur that are established to be involved in the initiation or progression of the disease.
  • the positive effects of the compounds of the invention have been demonstrated in a variety of such assays and models, for a number of diseases and disorders.
  • One skilled in the art can readily determine following the guidance described herein whether a compound of the invention has antifibrotic activity.
  • Hepatic Disease Antifibrotic Activity in Hepatic Stellate Cells.
  • Serum starved (activated) LX2 cells an immortalized human hepatic stellate cell line
  • LX2 cells an immortalized human hepatic stellate cell line
  • the rat model of thioacetamide (TAA)-induced liver fibrosis and the rat bile duct ligation model of fibrosis shows improvements by the compounds of the invention, in a panel of functional and histological tests: gross morphology, mass, portal pressure, presence of ascites, enzymes (AST, ALT), collagen content, interstitial fibrosis and alpha-smooth muscle actin and MMP-2.
  • mice are injected with a high dose of HgCl 2 (7 mg/kg, s.c.) and divided into treatment groups. Animals in the first group receive vehicle or a compound of the invention (1 mg/kg, i.p.) on the day of toxin injection and daily thereafter for 3 days, and are euthanized on day 4. Blood samples that are collected prior to HgCl 2 injection, on day 2 and on day 4 are analyzed for serum creatinine. In the second group, treatment with vehicle or compound begins on the day following toxin injection (i.e., 24h delayed treatment) and daily thereafter until day 6.
  • toxin injection i.e., 24h delayed treatment
  • mice are euthanized on day 7.
  • Blood samples collected prior to HgCl 2 injection, on day 4 and day 7 are analyzed for serum creatinine and BUN.
  • Serum creatinine, BUN, and development of tubular necrosis are measured to indicate positive clinical activity.
  • Protection against urethral obstruction The effects of the compounds of invention on renal injury secondary to ureteral obstruction are examined in a mouse model of transient unilateral renal artery occlusion.
  • Kidneys from mice subject to unilateral ureteral obstruction for 2 weeks are examined for histological evidence of injury and protection by compound treatment. Immunohistochemical staining is performed for fibronectin, proliferating cell nuclear antigen, and TUNEL (for an assessment of apoptosis).
  • Tri chrome staining is also performed to assess the extent of collagen formation as an indication of interstitial fibrosis.
  • Cerebral infarction / stroke Neuroprotective Effects in Brain Tissue. Cerebral infarction is induced in rats by middle cerebral artery occlusion (MCAO) for 24 hr. Test compound or vehicle is administered by i.p. at 2 mg/kg at -24, 0, and 8 hr. Sections of the brain are then examined for cell death by staining with a tetrazolium compound (2,3,5- Triphenyl-2H-tetrazolium chloride, or TTC). Normal rat brains exhibit a red staining due to TTC reduction whereas areas containing dead cells are white.
  • a tetrazolium compound (2,3,5- Triphenyl-2H-tetrazolium chloride, or TTC.
  • the Ashcroft scale is used to obtain a numerical fibrotic score with each specimen being scored independently by two histopathologists, and the mean of their individual scores considered as the fibrotic score. Lung weight and hydroxyproline content are also measured as a means to assess the extent of fibrosis.
  • Scleroderma A model is used in which bleomycin is subcutaneously injected into the skin is conducted in mice. Dermal hydroxyproline, dermal collagen, and dermal thickness are measures of the extent of pathology.
  • compounds of the invention exhibit activity generally as anti-fibrotic agents. More specifically, compounds of the invention demonstrate the ability to inhibit fibrosis. Thus, in certain embodiments, compounds of the invention are useful for the treatment of any of a number of conditions or diseases in which inhibitors of fibrosis have a therapeutically useful role, in particular antifibrotic activities.
  • the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it.
  • a subject including, but not limited to a human or animal
  • Subjects for which the benefits of the compounds of the invention are intended for administration include, in addition to humans, livestock, domesticated, zoo and companion animals.
  • this invention provides method for use of compounds that have biological properties useful for modulating the fibrotic process.
  • the inventive compounds are useful for the treatment of wounds for acceleration of healing (wound healing may be accelerated by promoting cellular proliferation, particularly of vascular cells), reducing post-surgical scarring, reducing adhesion formation such as from the consequences of surgery or infection, normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction, development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs, fibrotic diseases, hepatic disease including fibrosis and cirrhosis, lung fibrosis, renal failure, renal fibrosis, cerebral infarction (stroke), diabetes mellitus, and vascularization of grafted or transplanted tissues or organs.
  • wound healing may be accelerated by promoting cellular proliferation, particularly of vascular cells), reducing post-surgical scarring, reducing adhesion formation such as from the consequences of surgery or infection, normalization of my
  • Renal conditions for which compounds of the invention may prove useful include: radiocontrast nephropathy; fibrosis secondary to renal obstruction; indication for renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension.
  • Benefit in treatment of amyotrophic lateral sclerosis, diabetes mellitus and muscular dystrophy are also embodied herein.
  • a method for the treatment of disorders related to anti-fibrotic activity comprising administering a therapeutically effective amount of a compound of Formula (I), (II) or (III) as described herein, to a subject in need thereof.
  • the inventive method is used for the treatment of hepatic disease, stroke, myocardial infarction and other ischemic or f ⁇ brotic diseases.
  • Other diseases of interest include scleroderma, systemic sclerosis and dermal fibrosis.
  • agonists may be used to preserve organs and tissues identified for transplantation, and may be infused into the donor, perfused into the harvested organs and tissues or provided as a bath, and administered to the recipient.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for the treatment of conditions or diseases in which anti-fibrotics have a therapeutically useful role.
  • the expression "effective amount” as used herein refers to a sufficient amount of agent to modulate fibrosis and to exhibit a therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular therapeutic agent, its mode and/or route of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, subcutaneously, intradermally, intra-ocularly, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, preferably from about 0.
  • 1 mg/kg to about 10 mg/kg for parenteral administration or preferably from about 1 mg/kg to about 50 mg/kg, more preferably from about 10 mg/kg to about 50 mg/kg for oral administration, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dosages smaller than 0.001 mg/kg or greater than 50 mg/kg can be administered to a subject.
  • compounds are administered orally or parenterally.
  • compositions comprising one or more compounds of the invention may also contain other compounds or agents for which co-administration with the compound(s) of the invention is therapeutically advantageous.
  • pharmaceutical agents are used in the treatment of the diseases and disorders for which the compounds of the invention are also beneficial, any may be formulated together for administration.
  • Synergistic formulations are also embraced herein, where the combination of at least one compound of the invention and at least one other compounds act more beneficially than when each is given alone.
  • Non-limiting examples of pharmaceutical agents that may be combined therapeutically with compounds of the invention include (non-limiting examples of diseases or conditions treated with such combination are indicated in parentheses): antivirals and antifibrotics, such as interferon alpha (hepatitis B, and hepatitis C), combination of interferon alpha and ribavirin (hepatitis C), Lamivudine (hepatitis B), Adefovir dipivoxil (hepatitis B), interferon gamma (idiopathic pulmonary fibrosis, liver fibrosis, and fibrosis in other organs); anticoagulants, e.g.,heparin and warfarin (ischemic stroke); antiplatelets e.g., aspirin, ticlopidine and clopidogrel (ischemic stroke); other growth factors involved in regeneration, e.g., VEGF and FGF and mimetics of these growth factors; antiapoptotic agents; and motility and morphogenic agents.
  • the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention.
  • the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • kits are especially suited for the delivery of solid oral forms such as tablets or capsules.
  • Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • placebo dosages, or calcium dietary supplements can be included to provide a kit in which a dosage is taken every day.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • any available techniques can be used to make or prepare the inventive compounds or compositions including them.
  • a variety of solution phase synthetic methods such as those discussed in detail below may be used.
  • the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.
  • inventive compounds can be synthesized according to the methods described herein.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, “Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 “Chemistry of Carbon Compounds", vols.
  • the starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.
  • reaction mixtures are stirred using a magnetically driven stirrer bar.
  • An inert atmosphere refers to either dry argon or dry nitrogen.
  • Reactions are monitored either by thin layer chromatography, by proton nuclear magnetic resonance (NMR) or by high-pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.
  • reaction mixtures are cooled to room temperature or below then quenched, when necessary, with either water or a saturated aqueous solution of ammonium chloride.
  • Desired products are extracted by partitioning between water and a suitable water-immiscible solvent (e.g. ethyl acetate, dichloromethane, diethyl ether).
  • a suitable water-immiscible solvent e.g. ethyl acetate, dichloromethane, diethyl ether.
  • the desired product containing extracts are washed appropriately with water followed by a saturated solution of brine.
  • the extract is washed with a 10% solution of sodium sulphite in saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure.
  • the extract is washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had acidic character).
  • the extract is washed with 10% aqueous citric acid solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had basic character).
  • Post washing the desired product containing extracts are dried over anhydrous magnesium sulphate, and then filtered. The crude products are then isolated by removal of solvent(s) by rotary evaporation under reduced pressure, at an appropriate temperature (generally less than 45°C).
  • chromatographic purification refers to flash column chromatography on silica, using a single solvent or mixed solvent as eluent.
  • desired product containing elutes are combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45°C) to constant mass.
  • Compounds of Formula I described herein can be prepared following the guidance found in US Patent Nos. 6,949,563 and 7,101,893; Published U.S. Patent Application Nos. 2005/0154014, 2006/0247275 and 20070293426, and Garton et el., Cancer Res 2006 Jan 15 66(2): 1015-24, the entire contents of which are hereby incorporated by reference.
  • Compounds of Formula II can be prepared by following the guidance in 6,054,457, incorporated herein by reference in its entirety.
  • Compounds of Formula III can be prepared following the guidance of 6,316,482, incorporated herein by reference in its entirety.
  • Antifibrotic Activity of compounds of the invention in vitro and in vivo The antifibrotic effects of compounds of the invention in the immortalized human hepatic stellate cell line LX2 are determined. Serum starved LX2 cells are treated for 24 hours with compounds of the invention at doses ranging from 12 to 24 ug/ml. RNA is then isolated and real time PCR is performed to evaluate changes in collagen I mRNA. Results typically indicate a 70% to 90% decrease in collagen I mRNA expression in cells treated with instant compounds.
  • a rat model of thioacetamide (TAA)-induced liver fibrosis and the rat bile duct ligation model of fibrosis shows improvements by the compounds of the invention.
  • TAA thioacetamide
  • rats are treated with TAA (200 mg/kg) three times a week for 6 weeks, at which point they are sacrificed.
  • TAA thioacetamide
  • rats are subjected to bile duct ligation for 4 weeks and are sacrificed.
  • test compound is injected, i.p. daily, for the entire duration of fibrosis induction.
  • a panel of functional and histological tests are conducted: gross morphology, mass, portal pressure, presence of ascites, enzymes (AST, ALT), collagen content, interstitial fibrosis and alpha-smooth muscle actin and MMP-2.
  • Tissues are sectioned and are stained with modified Masson's Trichrome and are analyzed for interstitial fibrosis.
  • the Ashcroft scale is used to obtain a numerical fibrotic score with each specimen being scored independently by two histopathologists, and the mean of their individual scores are considered as the fibrotic score.
  • the other lung is analyzed for hydroxyproline content. Further experiments are described in the examples below.
  • Example 1 PDGFR as a target for anti-fibrotic therapeutics
  • PDGFR ⁇ was found to be predominantly expressed in mesenchymal lung and liver cell lines that the receptor is activated in the fibrotic lungs of mice treated with bleomycin.
  • Example 2 PDGF stimulates lung fibroblast proliferation but not lung epithelial cell proliferation.
  • PDGF-BB was found to stimulate the growth of the pulmonary fibroblast cell line HPF to a similar extent as serum (FCS) did, whereas proliferation of the epithelial cell line BEAS-2B was not stimulated by PDGF-BB (Figure 2). This is consistent with the observation that BEAS-2B cells do not express the PDGFR ⁇ , while the HPF cells have significant expression of the receptor. PDGF may therefore act primarily as a growth factor for mesenchymal fibroblast cells.
  • Example 3 PDGFR is activated in bleomycin-induced lung fibrosis.
  • Example 4 Compound of the invention prevents bleomycin-induced lung fibrosis in mice
  • Interstitial collagen - picosirius red staining and hydroxyproline content Interstitial deposition of collagen is a hallmark indicator of fibrosis.
  • the collagen level was determined by picosirius red stain followed by Bioquant quantitative analysis of histochemical lung sections. As shown in Figure 6, the picosirius red staining was markedly elevated in lungs from animals treated with bleomycin compared to non-treated controls.
  • picosirius red staining was markedly less in bleomycin exposed compound-treated animals compared to vehicle controls (p ⁇ 0.003). Similar results were obtained by determining the total hydroxyproline content of the right lungs from animals in the various treatment groups ( Figure 7). A highly significant correlation was found between the picosirius red signal and the hydroxyproline concentrations from the same animals (pO.OOOl; data not shown). These data indicate that the compound has strong therapeutic activity in preventing bleomycin-induced pulmonary fibrosis in mice.
  • ⁇ SMA expression is an important fibrotic marker protein expressed in response to various cytokines and fibrosis-inducing challenges.
  • ANG-3154 treatment we performed quantitative immunohistochemistry on section from normal, bleomycin-exposed animals and bleomycin exposed, compound treated animals.
  • Figure 8 bleomycin resulted in a marked elevation in ⁇ SMA expression. Bleomycin-exposed animals that were treated with compound; on the other hand, had significantly reduced ⁇ SMA expression compared to bleomycin treated animals.
  • Example 5 Compounds of the invention are inhibitors of PDGFR and KDR
  • Inhibiting PDGFR and KDR is potentially the most critical biochemical pathway for receptor-tyrosine kinase inhibitors as potential anti-f ⁇ brotic agents.
  • Inventive compounds inhibit KDR and PDGF kinase activity.
  • compounds were tested at various concentrations for ability to inhibit the kinase activity of recombinant enzymes.
  • the cytoplasmic kinase domains of KDR (residues 790-1356) and PDGFR ⁇ (residues 557-1106) expressed as GST fusion proteins in a baculovirus expression system were used.
  • Inventive compound inhibits KDR signaling in endothelial cells and PDGF signaling in hepatic stellate Cells
  • Example 7 Inventive compound prevents TAA-induced liver ⁇ brosis in mice
  • the thioacetamde (TAA)-induced liver fibrosis model was set up the evaluate compounds of the invention.
  • mice were treated with TAA at 200 mg/kg, IP, 3 times a week (Mon, Wed, and Fri) for 5 weeks. These mice were treated with compound orally, 5 times a week (Mon-Fri) for 4 weeks starting a week after TAA treatment.
  • Example 8 Inventive compound decreases dermal ⁇ brosis
  • mice C57BL/6 mice (Jackson Labs) were given 500 ug/ml of bleomycin (Sigma) in 100 ul and injected subcutaneously into the shaved backs of mice with a 27 gauge needle daily for three weeks.
  • mice were euthanized by CO2 inhalation on the day following final treatment.
  • the treated sites of truncal skin tissue ⁇ lcm area were harvested for histological analysis and 6mm diameter skin punch biopsies were taken for hydroxyproline content.
  • Dermal hydroxyproline content Hydroxyproline analyses was performed on skin punch biopsies (6mm) from each mouse according to the method as described by Woessner et al. Results were expressed as micrograms of hydroxyproline per 6mm diameter skin tissue. The efficiency of the hydrolysis was verified with rat tail collagen by comparison to standard hydroxyproline (Sigma).
  • Hydroxyproline was markedly elevated in bleomycin treated vehicle group compared to sham operated mice. Compound treatment decreased hydroxyproline content significantly (p ⁇ 0.001) to the bleomycin treated animals ( Figure 14).
  • Trichrome staining was markedly elevated in bleomycin treated sites when compared to sham operated controls. On the other hand, trichrome staining was markedly less in bleomycin exposed compound-treated animals compared to vehicle controls (p ⁇ 0.005) ( Figure 15).
  • Dermal Thickness Measurements Skin was removed from the interscapular region of the back, was fixed and embedded in paraffin, sectioned (4- ⁇ m thick), and stained with hematoxylin/eosin (H&E). The H&E stained cross-sections of skin was viewed under the microscope and photographed under (40 X). Photographs were taken using a microscope equipped with a computerized digital camera. Microscope was calibrated with markings on a Haemacytometer. The dermal thickness was determined by measuring the maximal distance between the epidermal-dermal junction with homogeneous collagen bundles with cellular infiltrates and the dermal subcutaneous fat junction at two different skin sections and 6 different fields for each mouse H&E stained sections. Dermal thickness was calculated from the haemacytometer calibration. The mean of each mice and each group was compared.
  • Sections were incubated with immunoglobulin G-peroxidase-conjugated secondary antibodies (Sigma) at a dilution of 1 :150, washed in PBS for 10 minutes, incubated with 0.5 mg/mL diaminobenzidine tetrahydrochloride 2-hydrate plus 0.05% H 2 O 2 for 10 minutes, and again washed in PBS.

Abstract

La présente invention concerne des composés ayant les formules (I), (II) et (III) : F et leurs dérivés pharmaceutiquement acceptables, comme il est décrit généralement et par classes et sous-classes ici, et elle concerne en outre des compositions pharmaceutiques les contenant, et des procédés pour les utiliser pour le traitement de l'un quelconque de nombreux états et maladies impliquant une fibrose et pour lesquels une activité antifibrotique est bénéfique.
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