WO2005016883A2 - Derives d'acrylamide servant d'antagonistes de l'integrine vla-1, et leurs utilisations - Google Patents

Derives d'acrylamide servant d'antagonistes de l'integrine vla-1, et leurs utilisations Download PDF

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WO2005016883A2
WO2005016883A2 PCT/US2004/026653 US2004026653W WO2005016883A2 WO 2005016883 A2 WO2005016883 A2 WO 2005016883A2 US 2004026653 W US2004026653 W US 2004026653W WO 2005016883 A2 WO2005016883 A2 WO 2005016883A2
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phenyl
amino
carbonyl
piperidine
acryloyl
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PCT/US2004/026653
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WO2005016883A3 (fr
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Steven A. Boyd
Scott Miller
Allen Thomas
Rui Xu
Yvan Lehuerou
Indrani Gunawardana
Gan Zhang
Jason Demeese
Martin Mclaughlin
Matthew Yanik
Mark L. Lupher, Jr.
Irina C. Jacobson
Eugene D. Thorsett
Francine S. Farouz
Ramesh A. Kasar
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Icos Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds which are VLA-1 integrin antagonists. This invention also relates to compositions containing such compounds and methods of treatment using such compounds in treating diseases mediated, at least in part, by the VLA-1 integrin.
  • Integrins are heterodimeric cell surface proteins composed of two noncovalently linked poly- peptide chains, and ⁇ . Integrins are the major receptor for cell adhesion to extracellular matrix and play important roles in certain cell-cell and cell-matrix adhesion events. These integrin-medi- ated adhesion events are critical for both normal and pathophysiological processes during cell activation, migration, proliferation and differentiation. (for reviews see R.O. Hynes, 1992, Cell , 69: 11 ; T.A. Springer, 1994, Cell , 75:301; R.O. Hynes, 2002, Cell , 110 : 613 ) .
  • VLA-1 (very late antigen-1) is an integrin heterodi er composed of an alpha chain (CD49a, l) and a beta chain (CD29, ⁇ l) .
  • VLA-1 is one member of a family of four ⁇ l integrin molecules that have been shown to bind to the extracellular matrix proteins, collagen, and laminin.
  • the ⁇ l integrin collagen receptors include ⁇ l ⁇ l (VLA-1) , ⁇ 2 ⁇ l (VLA- 2), ⁇ lO ⁇ l, and ⁇ ll ⁇ l. These four collagen receptors share overlapping, but distinct, expression profiles. They also appear to have distinct ligand preferences in vi tro ( . Tulla et al., 2001, J Biol . Chem .
  • ⁇ l ⁇ l has been shown to bind more effectively to type IV collagen than type I collagen while ⁇ 2 ⁇ l binds to type I collagen better than to type IV collagen (S.K. Dickeson et al., 1999, J. Biol . Chem . , 274:32182).
  • VLA-1 is expressed on smooth muscle cells, microvascular endothelial cells, fibroblasts, osteo- blasts, and chondrocytes. In addition, VLA-1 is also expressed on activated cells of the immune system including effector T cells, acrophages, and NK cells (A.R. de Fougerolles et al., 2000, J. Clin . Invest . , 105: 121 ) ; however, it does not appear to be expressed on B cells or neutrophils. VLA-1 is expressed on T cells in various disease states including in the joints of arthritis patients (M.E. HemLer et al., 1986, J. Clin . Invest . , 78:696), lesions of giant cell arteritis patients (C.
  • Inhibiting VLA-1 function using ⁇ l null mice and/or blocking anti- ⁇ l antibodies has shown efficacy either prophylactically or therapeutically or both in several animal models of inflammatory disease including 1) delayed-type hypersensitivity as a model of general inflammatory disease (A.R. de Fougerolles et al., 2000, J. Clin. Invest., 105:121) ; 2) contact hypersensitivity as a model for skin allergic reactions (A.R. de Fougerolles et al., 2000, J Clin. Invest., 105:121); 3) anticollagen mAb-induced arthritis as a model of rheumatoid arthritis (A.R. de Fougerolles et al., 2000, J. Clin.
  • TNBS- and DSS- induced colitis as models of inflammatory bowel disease (S. Fiorucci et al., 2002, Immunity, 27:769; C.F. Krieglstein et al., 2002, J. Clin. Invest., 110:1113) .
  • VLA- 1 has been shown to mediate adhesion to and migration across collagen matrix. Therefore, VLA-1 expression may be critical for allowing the effector cells to enter the site of inflammation.
  • mAbs against ⁇ l have also been shown to block collagen- induced cytokine release, including release of TNF- ⁇ , a key mediator in arthritis (S. Miyake et al., 1994, Eur. J. Immunol., 24:2000) .
  • MMP matrix metalloproteinase
  • VLA-1 provides a way of reducing inflammation through the synergistic
  • VLA-1 is an upstream regulator of multiple disease promoting factors
  • Fibrosis is a common response to chronic injury and represents a paradigm for the cycle of parenchymal wound healing in a variety of tissues (reviewed in R. Bataller and D.A. Brenner, 2001, Semin . Liver Dis . , 22:437; D. M. Bissell, 1998, J. Gastroenterol . , 33 : 295 ) .
  • this wound healing process can result in pathologic tissue scarring, which results from the progression of several defined steps.
  • an infiltrate consisting of inflammatory cells and platelets and resident "myofibroblasts" (identified as hepatic stellate cells in the liver and differentiated mesangial cells in the kidney) , accumulates at the site of injury.
  • the local extracellular matrix (ECM) is altered by de novo production of collagen by the myofibroblasts.
  • ECM extracellular matrix
  • the myofibroblasts migrate and align within the wound site and proliferate.
  • the myofibroblasts contract the collagen, forming the fibrotic scar which contributes to tissue dysfunction. It is generally believed that a similar process results in scarring within tissues of the liver, kidney, lung, and skin.
  • VLA-1 is expressed on myofibroblasts in vitro and in vivo and is believed to regulate their pathologic functions.
  • Alport syndrome is a genetic disorder characterized by progressive glomeruloneph- ritis resulting in fibrosis of the kidneys and ultimately kidney failure. Alport syndrome affects approximately 1 in 5000 people and is caused by mutations in the type IV collagen genes. This condition has been mimicked in mice by knocking out the gene of the ⁇ 3 chain of type IV collagen (Alport mouse) . Double knockout mice for both type IV collagen and ⁇ l integrin have a delayed onset and slowed progression of glomerular disease (D. Cosgrove et al., 2000, Am. J. Pathol . , 257:1649).
  • ⁇ l Ab blocks hepatic stellate cell adhesion to collagen and endothelin- stimulated hepatic stellate cell-mediated contrac- tion of collagen lattices in vitro
  • VLA-1 is the sole integrin utilized by contracting hepatic stellate cells in vivo (L . Racine-Sampson et al., 1997, J. Biol . Chem . , 272:30911) .
  • blocking anti- ⁇ l antibody has shown efficacy therapeutically in two independent models of fibrotic kidney disease (S. Kagami et al., 2002, Lab . Invest . , 82:1219; H.T. Cook et al., 2002, Am . J. Pa thol . , 252:1265) .
  • VLA-1 may also play a role in regulation of tumor vascularization (angiogenesis) and tumor cell metastasis in many forms of cancer.
  • VLA-1 may regulate tumor angiogenesis by two distinct mechanisms: 1) by regulating the proliferation potential of the vascular endothelial fibroblasts (A. Pozzi et al., 1998, J Cell . Biol . , 242:587; D.R. Senger et al., 2002, Am . J. Pa thol . , 160: 195 ) , and 2) by regulating the production of matrix metalloproteinase 9 which in turn regulates the activity of angiostatin, a potent angiogenesis inhibitor (A.
  • VLA-1 inhibitors there are only two descriptions for VLA-1 inhibitors in the patent literature, and both describe large molecular weight polypeptides .
  • the first is a mAb to VLA-1 (WO 02/083854 A2) and the second is a disintegrin isolated from cobra venom (WO 02/22571 A2) . Therefore, there still exists a need in the art for low molecular weight antagonists, specific inhibitors of VLA-1-dependent cell adhesion that have improved pharmacokinetic and pharmacodynamic properties such as oral bioavail- ability and significant duration of action.
  • Such compounds would prove to be useful for the treat- ment, prevention, or suppression of various pathologies mediated by VLA-1 binding and cellular adhesion, migration, activation, or differentiation.
  • the present invention provides acrylamide compounds which are antagonists to the VLA-1 integrin.
  • this invention is directed to a compound of Formula I:
  • A together with the nitrogen atom bound thereto, form a 4-8 membered heterocyclic group containing 1 to 2 nitrogen atoms, wherein said heterocyclic group may optionally be substituted with 1 to 3 additional substituents each independently selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, alkylsulfanyl, and halo, wherein the one or more alkyl and substituted alkyl substituents, if present, may be attached to either a carbon or a nitrogen atom in said heterocyclic group, wherein the one or more hydroxy, alkoxy, alkylsulfanyl, and halo substituents, if present, may not be attached to a nitrogen atom in said heterocyclic group, and wherein the one or more hydroxy, alkoxy, and halo substituents, if present, may not be attached to a carbon atom which is adjacent to a nitrogen atom in said heterocyclic group, R 1 is aryl, substituted ary
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, and fluoro- alkyl, wherein the fluoroalkyl group comprises from 1-4 carbon atoms and is substituted with 2-7 fluoro atoms,
  • R 4 is selected from the group consisting of hydrogen, alkyl, halo, alkoxy, hydroxy, alkylsul- fanyl, amino, substituted amino, aminocarbonyl, cyano, and CONR a 2 ,
  • R 8 is not cyano or -COCOOR
  • R 6 or R 7 is aryl, substituted aryl, heteroaryl, substituted hetero- aryl, heterocyclic, or substituted heterocyclic, then R' is -CR b R b COOR a ;
  • R 1 is not a phenyl group comprising an arylsulfanyl substituent, a substituted arylsulfanyl substituent, a hetero- arylsulfanyl substituent, or a substituted hetero- arylsulfanyl substituent,
  • R 1 is not a phenyl group comprising an arylsulfanyl substituent, a substituted arylsulfanyl substituent, a heteroarylsulfanyl substituent, or a substituted heteroarylsulfanyl substituent,
  • R 2 , R 3 , and R 4 are hydrogen; one of R 6 and R 7 is hydrogen; R 8 is COOH, COOCH 3 , or COOCH 2 CH3,- and A together with N form a piperidine ring substituted at the 4 position with the -C(0)NH- C(R 6 ) (R 7 ) (R 8 ) moiety, then R 1 is not an unsubstituted phenyl ring; and G.
  • a together with N form a 4-6 membered heterocyclic ring.
  • a together with N form a piperidine, pyrrolidine, or an azetidine ring.
  • a together with N form a piperidine ring.
  • R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In another preferred embodiment, R 1 is substituted aryl .
  • R 1 groups examples include:
  • R 3 is selected from the group consisting of hydrogen and alkyl. In a particularly preferred embodiment, R 3 is selected from the group consisting of hydrogen and CH 3 .
  • R 4 is selected from the group consisting of hydrogen, halo, and hydroxy. Particularly preferred R 4 groups include hydrogen, F, and hydroxy.
  • R 6 is hydrogen.
  • R 7 is selected from the group consisting of alkyl, alkenyl, and substituted alkyl. In another preferred embodiment, R 7 is heteroaryl.
  • R 7 groups include: methyl; ethyl; propyl; butyl; tert-butyl,
  • R 7 is quinolin-3-yl, 4-methoxy-phenylaminocarbonylmethyl; 3-methoxy-phenylaminocarbonylmethy; 2-methoxy- phenylminocarbonylmethyl; N-pyrrolidin-3-aminocar- onylethyl; N-Boc-pyrrolidin-3-aminocarbonylmethy; 3- phenyloxybenzyl; 4-phenyloxybenzyl; 3-hydroxyphenyl; 4-hydroxyphenyl; 3-bromophenyl; 4-bromophenyl; 3- aminophenyl; 4-aminophenyl; 3-dimethylaminocarbonyl- xyphenyl; 4-dimethylaminocarbonyloxyphenyl; 4- benzyloxybenzyl; 3-benzyloxybenzyl; 4-pyridyl; 2- pyridyl; 3-pyridyl; 4-methoxy-3-pyridyl; 4-
  • R 8 is COOH or CH 2 COOH.
  • the -NHCR 6 R 7 COOH or ester functionality of the compounds of Formula I is derived from an (L) -amino acid.
  • compounds of Formula I exhibit a biological activity of at least fifty percent inhibition against VLA-1 when tested at a concentration of 50 ⁇ M.
  • compounds of Formula I exhibit a biological activity of at least fifty percent inhibition against VLA-1 when tested at a concentration of 40 ⁇ M.
  • compounds of Formula I exhibit a biological activity of at least fifty percent inhibition against VLA-1 when tested at a concentration of 20 ⁇ M.
  • this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as defined herein.
  • this invention is directed to a method for assaying a biological sample from a mammalian patient suspected of having a disease, condition, or disorder medi- ated, at least in part, by VLA-1, which method comprises obtaining a biological sample from said patient and assaying said sample for the presence of VLA-1.
  • this invention is directed to a method of inhibiting adhesion of mammalian cells to the extracellular matrix mediated, at least in part, by VLA-1, which method comprises contacting said cells with a compound or pharmaceutical composition of this invention.
  • this invention is directed to a method of treating a disease, condition, or disorder whose progression is regulated, at least in part, by VLA-1 expression or activity in a mammalian patient in need thereof comprising administering to said patient a thera- Commissionically effective amount of a compound or composition of this invention.
  • said disease, disorder, or condition is selected from the group consisting of asthma, trachoma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, tumor migration, and/or tumor growth, proliferation of fibroblasts in cancer, solid tumors, meningitis, encephalitis, stroke, cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, acute leukocyte-mediated lung injury, and fibrotic diseases.
  • said disease, disorder, or condition is a fibrotic disease.
  • said fibrotic disease is selected from the group consisting of systemic sclerosis, mixed connective tissue disease, fibrodysplasia, fibrocystic disease, sarcoidosis, and myositis.
  • said fibrotic disease has a manifestation of fibrotic vascular intimal hypertrophy, and is selected from the group consisting of vasculitis, polyarteritis nodosa, and temporal arteritis.
  • said fibrotic disease has a manifestation of fibrotic hypertrophy of skin and/or muscle tissue, and is selected from the group consisting of scleroderma, eosinophilic fasciitis, discoid lesions associated with lupus or discoid lupus, and surgical adhesions.
  • said fibrotic disease has a manifestation of fibrotic hypertrophy of nerve tissue, and is selected from the group consisting of cerebrosclerosis, annular sclerosis, diffuse sclerosis, and lobar sclerosis.
  • said fibrotic disease has a manifestation of fibrotic hypertrophy or fibrosis of lung tissue, and is selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, the fibrotic element of pneumoconiosis, pulmonary sarcoidosis, fibrosing alveolitis, the fibrotic or hypertrophic element of cystic fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and emphysema.
  • said fibrotic disease has a manifestation of fibrotic hypertrophy or fibrosis of prostate, liver, the pleura, or pancreas, and is selected from the group consisting of benign prostatic hypertrophy (BPH) , nonalcoholic steato hepatitis, and fibrosis of the liver.
  • BPH benign prostatic hypertrophy
  • nonalcoholic steato hepatitis fibrosis of the liver.
  • said fibrotic disease has a manifestation of fibrotic hypertrophy or fibrosis of the kidney, and is selected from the group consisting of chronic renal failure, lupus nephritis, alports syndrome, glomerulonephritis, and diabetic nephritis.
  • said disease, disorder, or condition is cancer.
  • said cancer is a tumor or a neoplasm, selected from the group consisting of carcinomas, adenocarcinomas, and sarcomas .
  • said cancer is selected from the group consisting of growth of solid tumors/malignancies, myxoid and round cell carcinoma, locally advanced tumors, human soft tissue carcinoma, cancer metastases, squamous cell carcinoma, esophageal squamous cell carcinoma, oral carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin' s lymphoma, cancer of the adrenal cortex, ACTH-producing tumors, nonsmall cell cancers, breast cancer, gastrointestinal cancers, urological cancers, malignancies of the female genital tract, malignancies of the male genital tract, kidney cancer, brain cancer, bone cancers, skin cancers, thyroid cancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural
  • said cancer is a cell proliferative disorders, and is selected from the group consisting of angiogenesis- mediated diseases, benign tumors, acoustic neuromas, neurofibromas, pyogenic granulomas, biliary tract cancer, choriocarcinoma, esophageal cancer, gastric cancer, intraepithelial neoplasms, lung cancer, and neuroblastomas .
  • a compound or composition of this invention may be administered to the mammal by any suitable route, such as orally, intravenously, parenterally, transdermally, topically, rectally, or intranasally.
  • Mammals include, for example, humans and other primates, pet or companion animals, such as dogs and cats, laboratory animals, such as rats, mice and rabbits, and farm animals, such as horses, pigs, sheep, and cattle.
  • the present invention is directed to novel acrylamide derivatives.
  • alkyl refers to monovalent alkyl groups having from 1 to 10 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, and the like.
  • Substituted alkyl refers to an alkyl group having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, thiol, alkylsulfanyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxycarbonylamino.
  • Alkylene refers to divalent alkylene groups having from 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene, n-heptyl- ene, 1, 3-octylene, and the like.
  • Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec- butoxy, n-pentoxy, n-hexoxy, 1, 2-dimethylbutoxy, and the like.
  • Substituted alkoxy refers to the group “substituted alkyl-O-.”
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C (0) -, substituted alkenyl-C (0) -, cycloalkyl-C (0) -, substituted cycloalkyl-C (0) -, aryl-C(O)-, substi- tuted aryl-C(O)-, heteroaryl-C (0) -, substituted heteroaryl-C (0) , heterocyclic-C (0) -, and substituted heterocyclic-C (0) - .
  • Acylamino refers to the group -C(0)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and where each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring.
  • Acyloxy refers to the groups alkyl- C(0)0-, substituted alkyl-C (0) 0-, alkenyl-C (0) 0-, substituted alkenyl-C (0) 0-, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C (0) 0-, substituted cycloalkyl-C (0) 0-, heteroaryl-C (0)0-, substituted heteroaryl-C (0) 0-, heterocyclic-C (0)0-, and substituted heterocyclic-C (0)0-.
  • Alkenyl refers to onovalent alkenyl groups having from 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms, and having at least 1 and preferably from 1-2 sites of alkenyl unsatur- ation.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminocarbonylamino, ammocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, thiol, alkylsulfanyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxycarbonylamino, provided that the hydroxy or the thio group is not pendent to an unsaturated carbon atom.
  • Amino refers to the group -NH 2 .
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylsul- fonyl, arylalkylsulfonyl, alkylsulfonyl, substituted aryl, cycloalkyl, substituted cycloalkyl, hetero- aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and where each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring provided that both R's are not hydrogen.
  • Aminoacyl refers to the groups -NRC (0) alkyl, -NRC (0) substituted alkyl, -NRC (0) alkenyl, -NRC (0) substituted alkenyl, -NRC(O)- cycloalkyl, -NRC (0) substituted cycloalkyl, -NRC(O)- aryl, -NRC (0) substituted aryl, -NRC (O) heteroaryl, -NRC (0) substituted heteroaryl, -NRC (0) heterocyclic, and -NRC (0) substituted heterocyclic, where R is hydrogen or alkyl.
  • Aminocarbonyloxy refers to the groups -NRC(0)0-alkyl, -NRC (0) O-substituted alkyl, -NRC(0)- O-cycloalkyl, -NRC (0) O-substituted cycloalkyl, -NRC(0)0-alkenyl, -NRC (0) O-substituted alkenyl, -NRC(0)0-aryl, -NRC (0) O-substituted aryl, -NRC (0)0- heteroaryl, -NRC (0) O-substituted heteroaryl, -NRC(0)0-heterocyclic, and -NRC (0) O-substituted heterocyclic, where R is hydrogen or alkyl.
  • Oxycarbonylamino refers to the groups
  • Aminocarbonylamino or “aminoacylamino” refers to the groups -QC(0)Q where each Q is independently amino or substituted amino.
  • Aryl or “Ar” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 5-bromo-benzo [1, 3] dioxole-6yl, benzo [b] thiophen-5-yl, 7, 8-dichloro-thiochroman-4- one-6-yl, and the like) provided that the point of attachment is on an aromatic carbocyclic group atom.
  • Preferred aryls include phenyl and naphthyl.
  • “Substituted aryl” refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, amino, substituted amino, aminoacyl, ammocarbonyloxy, oxycarbonylamino, aminocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substi- tuted heterocyclyloxy, carboxyl, carboxyl esters, carboxylamido, cyano, thiol, alkylsulfanyl, sub- stituted alkylsulfanyl,
  • Substituted aryloxy refers to substituted aryl-O- groups.
  • Carboxyl refers to the group -COOH.
  • Carboxyl esters refer to the group -COOR where R is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • Cycloalkyl refers to monovalent cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like.
  • Cycloalkoxy refers to the group -0- cycloalkyl .
  • Substituted cycloalkoxy refers to the group -O-substituted cycloalkyl.
  • Cycloalkenyl refers to monovalent cyclic alkenyl groups of from 3 to 8 carbon atoms having a single cyclic ring.
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring, and further provided that the heteroaryl group contains at least 5 ring atoms.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) provided that the point of attachment is on the heteroaryl group.
  • Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, furyl, thiophenyl, and imidazole.
  • Heteroarylsulfanyl refers to the group -S-heteroaryl.
  • Substituted heteroaryl refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group of substituents defined for substituted aryl.
  • Substituted heteroarylsulfanyl refers to the group -S-substituted heteroaryl.
  • Heteroaryloxy refers to the group -0- heteroaryl and “substituted heteroaryloxy” refers to the group -O-substituted heteroaryl.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated or unsaturated, but not aromatic, group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur, or oxygen within the ring, and wherein, in fused ring systems, one or more the rings can be aryl or heteroaryl, provided that the heterocyclic ring has at least 4. atoms and further provided that the point of attachment is to a heterocyclic ring atom.
  • Preferred heterocycles include piperidinyl, pyrrolidinyl, and azetidinyl.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydro- indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinox- aline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4- tetrahydroisoquinoline,
  • Heterocyclicalkyl refers to the group -alkylene-heterocyclic .
  • Heterocyclyloxy refers to the group -O-heterocyclic and “substituted heterocyclyloxy” refers to the group -O-substituted heterocyclic.
  • Hydrox refers to the group -OH.
  • Niro refers to the group -N0 2
  • Alkylsulfanyl refers to the group -S-alkyl.
  • Substituted alkylsulfanyl refers to the group -S-substituted alkyl.
  • Arylsulfanyl refers to the group -S-aryl.
  • Substituted arylsulfanyl refers to the group -S-substituted aryl.
  • Cycloalkylsulfanyl refers to the group -S-cycloalkyl.
  • Heteroarylsulfanyl refers to the group -S-heteroaryl .
  • Substituted heteroarylsulfanyl refers to the group -S-substituted heteroaryl.
  • Heterocyclicsulfanyl refers to the group -S-heterocyclic .
  • Substituted heterocyclicsulfanyl refers to the group -S-substituted heterocyclic.
  • Arylalkylsulfanyl refers to the group -S-alkylene-aryl .
  • Arylalkylsulfonyl refers to the group -S (0) 2 -alkylene-aryl .
  • Alkylsulfmyl refers to the group -S(0)- alkyl.
  • Substituted alkylsulfamyl refers to the group -S (0) -substituted alkyl.
  • Alkylsulfonyl refers to the group -S(0) - alkyl.
  • Substituted alkylsulfonyl refers to the group -S (0) 2 -substituted alkyl.
  • Arylsulfonyl refers to the group -S(0) 2 -aryl.
  • Thiol refers to the group -SH.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkyl- ammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobro- mide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • Prodrugs are compounds which convert (e.g., hydrolyze, metabolize) in vivo to a compound of the invention.
  • the effectiveness of an orally administered drug is dependent upon the drug's efficient transport of the drug across the mucosal epithelium and its stability in entero- hepatic circulation.
  • Drugs that are effective after parenteral administration but less effective orally, or whose plasma half-life is considered too short, may be chemically modified into a prodrug form.
  • the prodrug should have a pharmacokinetic profile that is different from that of the parent, enabling easier absorption across the mucosal epithelium, better salt, formulation and/or solubility, and/or improved systemic stability (for an increase in plasma half-life, for example) .
  • Many chemical modifications may be suitable for the creation of the prodrugs according to the invention, including:
  • Ester or amide derivatives which may be cleaved by, for example, esterases or lipases.
  • ester derivatives the ester is derived from the carboxylic acid moiety of the drug molecule by known means.
  • amide derivatives the amide may be derived from the carboxylic acid moiety or the amine moiety of the .drug molecule by known means.
  • a peptide may be coupled to the drug molecule via amide bond formation with the amine or carboxylic acid moiety of the drug molecule by known means.
  • Bio activity refers to an inhibition concentration when tested in at least one of the assays outlined in Example A or B.
  • substituted as used with, for example, “substituted alkyl” does not include polymers derived therefrom but are limited to a maximum of 4 substituents groups, e.g., Ar-Ar-Ar-Ar.
  • tautomer refers to an isomer in which migration of a hydrogen atom results in two or more structures.
  • ⁇ -amino acid residue refers to a moiety of the formula -NH(R 6 ) (R 7 )C00H.
  • ⁇ -amino acid methyl ester residue refers to a moiety of the formula -NH(R 6 ) (R 7 )COOCH 3 .
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Greene and Wuts (1999) Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, and references cited therein.
  • the compounds of this invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. Compounds in the present invention may be better understood by the following synthetic Schemes that illustrate methods for the synthesis of compounds of the invention.
  • R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 are as defined above;xis halo; "alk” is alkyl; n is 0-4; q is 1-4; "PG,” “Pg,” P x , and P 2 are suitable protecting groups; Ar 2 and Ar 3 are aryl, substituted aryl, heteroaryl, or substituted heteroaryl groups; W is oxygen or sulfur; "Het” is heteroaryl or substituted heteroaryl; R 10 , R x , R y , R", R 2 ', and R 3 ', are groups selected to be compatible with subsequent reactions; R 15 is substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl; R 4 ' is isopropyl or
  • Halo-substituted aromatic, cycloalkyl, and heterocyclic derivatives 1 may be prepared according to several methods, as shown in Scheme 1.
  • R 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • Direct halogenation of an aromatic compound 2 can be accomplished by the use of Br 2 or Cl in the presence of iodine, a metal, or a Lewis acid (e.g., iron, ferric chloride) in a solvent (such as acetic acid or dichloromethane) .
  • anilines 3 can be converted to halides through a Sandmeyer reaction with diazonium intermediates (formed with NaN0 2 , sulfuric acid, or HN0 2 ) to furnish aryl iodides and aryl bromides using Nal or CuBr 2 (J. Chem . Soc. Perkin Trans . L (1987) 645) .
  • aryl, cycloalkyl, or heterocyclic triflates 4 may be converted to iodides by reacting with sodium iodide in the presence of DMSO and molecular sieves.
  • Scheme 2 illustrates the preparation of halo-substituted aryl, heterocyclic, or cycloalkyl sulfides, sulfoxides, and sulfones.
  • Substituted thiol analogs 6 can be constructed from halo- substituted alcohols 5 according to known methods (Newman et al. (1966) J. Org. Chem . 32:3980).
  • Alkylation of 6 with substituted alkyl and arylalkyl halides or sulfonates can be accomplished in the presence of base (NaH or LiHMDS and the like) .
  • base NaH or LiHMDS and the like
  • a Mitsunobu procedure can be utilized (Mitsunobu (1967) Bull . Chem . Soc. Jpn . 40 : 2380 ; Camp (1989) J. Org. Chem . 54 : 3045 and 3049) to furnish 7.
  • Subsequent oxidation of sulfides 7 to sulfoxides 8 can be accomplished utilizing an oxidizing agent (sodium periodate or 30% H 2 0 or sodium chlorite) in a solvent (e.g., DCM, toluene).
  • the sulfoxides 8 can be converted to sulfones 9 by further use of an oxidant (e.g., KMn04 or Oxone) .
  • a base e.g., NaH or LiHMDS
  • solvent e.g., DMF, DMA
  • the resulting carboxylic acid 10 may be coupled with amines to give amides 11 by one of several procedures including, but not limited to, the following coupling reagents: 1- (3-dimethyl- aminopropyl) -3 ethylcarbodimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC) , . or N,N' -carbonyl- diimidazole (CDI) , benzotriazol-1-yloxy-tris-
  • EDC 1- (3-dimethyl- aminopropyl) -3 ethylcarbodimide hydrochloride
  • the acid 10 may be activated in the presence of 1-hydroxybenzotriazole (HOBt) or N-hydroxy- succinimide.
  • the acid 10 may be coupled utilizing solid support resins, such as 1% crosslinked polystyrene tetrafluorophenol (PS-TFP) , polystyrene dicyclohexylcarbodiimide (PS-DCC) , or polystyrene 1-hydroxybenzotriazole (PS-HOBt) , by the use of one of the listed coupling reagents in the presence of a base (4-dimethylaminopyridine, triethylamine, etc.) and solvent (DMF, methylene chloride) .
  • PS-TFP polystyrene dicyclohexylcarbodiimide
  • PS-HOBt polystyrene 1-hydroxybenzotriazole
  • Substituted 5-bromo benzothiophenes are prepared by the methods illustrated in Scheme 4.
  • a suitable phenylsulfanyl acetic acid 12 (where the phenyl group is optionally substituted with 1 to 3 groups which are compatible with the subsequent reactions) is selectively brominated with bromine in a solvent (for example dichloromethane, glacial acetic acid, or the like) in the presence of iron or iodine as catalysts.
  • the reaction is typically performed at room temperature for 1 to 96 hours.
  • the resulting bromo acid 13 is then converted to an acid halide intermediate by treatment with an inorganic acid halide (for example, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorus tribromide, oxalyl chloride, or the like) in an inert solvent (for example dichloromethane or the like) , at a temperature in the range of 0°C to 110°C for about 1 to 48 hours.
  • an appropriate solvent typically dichloromethane, and subjected to Friedel-Crafts cyclizations by treatment with Lewis acids such as A1C1 3 or polyphosphoric acid.
  • the reaction is generally carried out at -78°C to 25°C.
  • the resulting ketone 14 is not stable and is promptly reduced to an alcohol intermediate by a hydride reducing reagent (for example, NaBH 4 or the like) .
  • the alcohol may be used directly in the next step, or first purified by chromatography or recrystalli- zation as appropriate.
  • the dehydration of the alcohol is accomplished by treatment with an acid (for example, boron trifluoride etherate) in an appropriate solvent (for example, glacial acetic acid, or the like) at a temperature ranging from ambient temperature to the reflux temperature of the solvent.
  • an acid for example, boron trifluoride etherate
  • an appropriate solvent for example, glacial acetic acid, or the like
  • substituted 6-bromo- thiochroman-4-ones 18 can be produced using the analogous procedures described for Scheme 4 above.
  • the 3-phenylsulfanyl-propionic acids of formula 16 (where the phenyl group is optionally substituted with 1 to 3 groups which are compatible with the subsequent reactions) required for the preparation of 18 may be prepared by alkylation of thiophenols with 3-halo-propionic acids in the presence of an appropriate base (for example NaH, K 2 C0 3 , NaOH, or the like) .
  • Phenyl sulfide 16 is then converted to 6-bromothiochroman-4-ones 18 in 3 steps by the procedures described for Scheme .
  • Cinnamic acid intermediates 20 may be prepared by a Heck-type, palladium-mediated coupling (e.g., using tetrakis (o-tolyl phosphine) palladium (0), Pd 2 (dba) 3 , Pd(OAc) 2 , or the like) of halo-sub- stituted aromatic derivatives 1 with an appropriate olefinic substrate 19 (e.g., methyl acrylate ethyl crotonate, or the like; Buchwald (1999) Chem . Eur. J. 5:3107-3112).
  • the intermediate ester (R X ⁇ H) may require a separate hydrolysis to the acid 20, or this hydrolysis may occur under the reaction conditions.
  • R 3 may also optionally be lower fluoroalkyl.
  • Substituted aldehydes 22 may also be prepared from the corresponding carboxylic acids 21 by utilizing a reducing agent (e.g., borane-THF, LiAlH 4 -ether) to reduce the acid to the alcohol (not shown) .
  • a reducing agent e.g., borane-THF, LiAlH 4 -ether
  • the resulting alcohol can then undergo partial oxidation (for example, using pyridinium chlorochromate, Swern, or Moffat oxi- dation protocol) to the desired aldehyde 22.
  • aldehyde 22 may be reacted with a Wittig, Homer-Emmons, or Wadsworth-Emmons reagent (e.g., 2- (diethoxyphosphoryl) -propionic acid ethyl ester, or the like) in a solvent (CH 2 C1 2 , CH 2 C1CH 2 C1, or like) and a base (NaOH, NaOEt, NaH, or the like) to furnish the desired ester.
  • the ester may undergo hydrolysis to the acid 23 with the use of a base (LiOH, NaOH, or the like) in a solvent (THF-water, CH 2 C1 2 -Water) .
  • the resulting aromatic iodides may be reacted with substituted amines via palladium or copper-mediated coupling (Buchwald et al. (2000) Org. Chem . 65 : 1144 ; Hartwig et al. (1998) Angew. Chem. , Int . Ed. Eng. 37:2046) to furnish 27.
  • Scheme 9 illustrates the preparation of various substituted benzoxazole, benzthiazole, and benzimidazole amino acid esters 29 (where the phenyl group is optionally substituted with 1 to 3 groups which are compatible with the subsequent reactions) , from a suitably protected aspartic acid alkyl esters of formula 28 according to the procedure described in the literature (Nester et al. (1984) J Med. Chem . 27:320-325). Similar amino acid esters with fused heteroaromatic ring systems can be prepared from aspartic acid as described in- the literature by Svete et al. (Svete et al . (1994). J Heterocyclic Chem . 32:1259). These procedures may be employed to prepare either enantiomer of the desired compounds.
  • Scheme 10 describes the synthesis of novel ⁇ -aryl alanine methyl esters 32.
  • Many protected ⁇ - aryl alanines 31 are commercially available, where the protecting group Pg is, for example, Boc, Cbz, or Fmoc groups .
  • Other compounds can be prepared by conventional synthetic procedures.
  • Amino acid methyl esters 32 may be prepared from amino acids 30 under Fisher esterification conditions (for example acetyl chloride in methanol, thionyl chloride in methanol, or the like) .
  • compounds of formula 30 can be treated with trimethylsilyldiazo- methane in appropriate solvents, preferably a mixture of methanol and toluene, to afford methyl esters 31.
  • Intermediates 31 may be transformed to amines 32 by removal of the protecting group Pg using conventional procedures.
  • the addition and removal of numerous protecting groups is discussed by Greene and Wuts in Protective Groups in Organic Synthesis ((1999) Second Edition, Wiley, New York).
  • the Boc protecting group may be removed by treating with a strong acid such as trifluoro- acetic acid (TFA) or hydrochloric acid in the presence of an inert solvent such as dichloromethane or methanol.
  • TFA trifluoro- acetic acid
  • Cbz groups can be carried out by catalytic hydrogenation with hydrogen in the presence of a palladium catalyst or by transfer hydrogenation.
  • Fmoc groups can be removed with a low boiling point amine (for example piperidine or the like) in a solvent such as DMF.
  • Scheme 11 presents a synthesis of a particular class of 2, 3-diamino-propionic acid derivatives bearing an N-Me group.
  • 2-Amino-3- methylamino-propionic acid methyl esters 33 where Pg is a suitable protecting group, and R 10 is a substituent that is compatible with the subsequent reactions, can be prepared from the corresponding N ⁇ - protected 2, 3-diaminopropionic acids using the Diels-Alder methodology developed by Greico (Greico et al. (1987) J Org. Chem . 52:5746-5749; Webber et al. (1998) J. Med. Chem . 42:2786-2805).
  • Scheme 12 describes a synthesis of an amino acid methyl ester 40 containing a 2-oxo-l- indole ring.
  • Compound 36 can be prepared in a known manner by the reaction of 1, 3-dihydroindol-2-one and 2, 2-dimethyl-4- (toluene-4-sulfonyloxymethyl)— oxazolidine-3-carboxylic acid tert-butyl ester (Array Biopharma) in the presence of a base (for example, NaH, KOt-Bu, or the like) .
  • a base for example, NaH, KOt-Bu, or the like
  • Scheme 13 describes a synthesis of an amino acid methyl ester containing an isooxindole ring.
  • N ⁇ -protected 2, 3-diamino-propionic acid methyl esters of formula 41 can be prepared from commercially available N ⁇ -protected 2, 3-diamino-propionic acid methyl esters by conventional protecting group transformations.
  • Cyclization of 41 with 2-bromo- methyl-benzoic acid methyl ester in the presence of a base (for example, diisopropyl ethyl amine, tri- ethyl amine, or the like) in an inert solvent (for example, acetonitrile) leads to compounds of formula 42.
  • Esters 42 can be converted to amino esters 43 by removal the protecting group.
  • PG as described in Scheme 10.
  • Suitable coupling agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3- ethylcarbodimide hydrochloride (EDC) , dicyclohexylcarbodiimide (DCC) , N,N'-carbonyldiimidazole (CDI) , benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) , diethylcyanophosphonate (DECP) , and the like.
  • EDC 1- (3-dimethylaminopropyl) -3- ethylcarbodimide hydrochloride
  • DCC dicyclohexylcarbodiimide
  • CDI N,N'-carbonyldiimidazole
  • BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
  • DECP dieth
  • a tertiary amine for example diisopropylethylamine, triethylamine, N- methylmorpholme, dimethylaminopyridine (DMAP) , or the like
  • DMAP dimethylaminopyridine
  • 44 can be converted into an acid halide (for example, using thionyl chloride, oxalyl chloride, or the like), under conditions well known in the art.
  • the acid halide intermediate is then reacted with 45 in an inert solvent (for example, dichloromethane, or the like) at -30°C to 40°C to afford the amides 46.
  • an inert solvent for example, dichloromethane, or the like
  • An organic base such as diisopropylethylamine, triethylamine, N-methylmorpholine, or DMAP, may be added as an acid scavenger to facilitate the coupling reaction.
  • the protected cyclic amino acids 44 employed in the above reactions are commercially available, where the protecting group Pi is, for example, Boc, Cbz, or Fmoc groups.
  • Other such protected cyclic amino acids can be prepared by known methods.
  • Many examples of amino acid derivatives 45 are commercially available or can be prepared by known methods or the methods described in the previous
  • Transformation of 46 into amines 47 can be accomplished by removal of the protecting group Pi as described in Scheme 10. Coupling of intermediates 47 to acids 20 can be effected using conventional peptide coupling techniques and regents, as described above, to give 48.
  • Scheme 15
  • Scheme 15 illustrates an alternative method for the preparation of a ido esters 48.
  • the intermediate ester 50 is then hydrolyzed to acids 51, and the resulting acids 51 are coupled with amino esters 45 according to standard amide formation protocols, providing esters 48.
  • amino ester 49 may be coupled with an acryloyl chloride 52 in the presence of an appropriate base (e.g., DIEA or the like) to provide amides 53.
  • an appropriate base e.g., DIEA or the like
  • an amino ester 45 is appended to the carboxyl according to the amide formation protocols described above.
  • the acrylamide olefin 55 is further elaborated by palladium-mediated coupling with a halosubstituted derivative, using protocols described in Scheme 6, to provide esters 48.
  • acrylamide intermediate 53 may undergo transition metal-mediated coupling with a halo- or sulfonate-substituted aromatic derivative prior to coupling with an amino ester.
  • Heck-type, palladium-mediated coupling of 53 and aryl halide provides 50.
  • Hydrolysis of the ester of 50 to acid 51 then allows for coupling with amino esters 45 to yield esters 48 as described above .
  • Scheme 18 describes the synthesis of a typcal substituted biaryl 57 via palladium coupling.
  • the coupling (Suzuki et al. (1995) Chem . Rev. 55:2457-2483; Org. React . (1997) 50:1) could be performed where 56 is an iodide or a bromide sub- tituted aryl compound that is reacted with a boronic acid, boronic ester in the presence of a base (e.g., Cs 2 C0 3 , CsF, KF) in a nonprotic solvent (e.g., di- oxane, DME, toluene etc) or protic solvent (e.g., DMF, acetone/water) , together with a palladium catalyst (e.g., Pd (PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(OAc) 2 , etc.).
  • a palladium catalyst e
  • intermediate of formula 56 can be reacted with various substituted aryl and alkyl- thiols (RS) in the presence of a base (e.g., K 2 C0 3 , Cs 2 C0 3 ) and a suitable copper catalyst (e.g., Cul, CuCl) to provide thioethers 58.
  • a base e.g., K 2 C0 3 , Cs 2 C0 3
  • a suitable copper catalyst e.g., Cul, CuCl
  • advanced intermediates of formula 59 may be reacted with various alkyl or aryl halides in the presence of a base (such as NaH, K 2 C0 3 , and the like) to provide ethers and thioether analogues 60.
  • Aryl amino analogues like 61 can be converted to substituted aryl amino derivatives 62 (wherein R" is a sub- stituent suitable for use in subsequent reactions) by acylation (with acid chlorides, activated carboxylic acids as described in Scheme 14) or reductive amination using standard reaction conditions.
  • analogues were func- tionalized in the amido acid portion of the molecule at a later stage in the synthesis.
  • One example is shown in Scheme 20, in which a tyrosine-containing analogue 63 was derivatized using an activated carboxyl moiety (e.g., N,N-dimethylcarbamoyl chloride or the like) in the presence of an appropriate base (e.g., DIEA or the like) to provide carbamates 64.
  • an activated carboxyl moiety e.g., N,N-dimethylcarbamoyl chloride or the like
  • an appropriate base e.g., DIEA or the like
  • esters 67 were prepared in which R 2 ' may be, e.g., acyl, carbamoyl, alkoxycarbonyl, or sulfonyl.
  • R 2 ' may be, e.g., acyl, carbamoyl, alkoxycarbonyl, or sulfonyl.
  • the carboxyl group of compound 100 is reduced using conventional techniques such as the use of a conventional reducing agent including, for example, lithium aluminum hydride to provide for the corre- sponding alcohol, compound 200.
  • a conventional reducing agent including, for example, lithium aluminum hydride
  • the reaction is preferably conducted in an inert diluent such as tetrahydrofuran, diethyl ether and the like at a temperature preferably from about -78 °C to about 25°C.
  • the reaction is continued until substantial completion, which typically occurs from within 0.5 to 18 hours.
  • compound 200 can be recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like, or used in the next step of the reaction without purification and/or isolation.
  • halo group e.g., chloro
  • Suitable halogenating agents include, for example, inorganic acid halides, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide, or phosphorous pentachloride, under conventional conditions.
  • this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachlor- ide, at temperature in the range of about 0°C to about 80°C for about 1 to about 48 hours.
  • a cat- alyst such as DMF, may also be used in this reaction.
  • compound 300 can be recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like, or used in the next step of the reaction without purification and/or isolation.
  • the compounds of the subject invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, parenteral, transdermal, topical, rectal, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of the subject invention above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the excipient employed is typically an excipient suitable for administration to human subjects or other mammals.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the quantity of active component, that is the compound according to the subject invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, and the desired concentration.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, usually about 5 to about 100 mg, occasionally about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compound of the subject invention above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier (s) .
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically or therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the severity of the condition being treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the compounds or pharmaceutical compositions thereof will be administered by any appropriate route, such as orally, topically, transdermally, and/or parenterally at a dosage to obtain and maintain a concentration, that is, an amount or blood level of active component in the animal undergoing treatment that will be therapeutically effective.
  • a dosage that is, an amount or blood level of active component in the animal undergoing treatment that will be therapeutically effective.
  • such therapeutically effective amount of dosage of active component i.e., an effective dosage
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • these preformulation compositions as homogeneous, it is meant that the active ingred- ient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 500 mg of an active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorpo- rated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous, or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. - Ill -
  • compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder composi- tions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50°C to 60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • the active ingredient, starch and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin cap- sules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a
  • Suspensions each containing 50 mg of medicament per 5.0 mL dose are made as follows:
  • the active ingredient, sucrose, and xan- than gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • the active ingredient, starch, and mag- nesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities.
  • a subcutaneous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows :
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • An intravenous formulation may be prepared as follows:
  • trans- dermal delivery devices Such trans- dermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the con- struction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, incorporated herein by reference.
  • patches maybe constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional tech- niques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka et al., U.S. Patent Nos. 4,235,871; 4,501,728; and 4,837,028, each of which is incorporated herein by reference.
  • the compounds or compositions of this invention can be employed to bind VLA-1 in biological samples, for instance in mammalian patients sus- pected of having a disease, condition, or disorder mediated, at least in part, by VLA-1. Accordingly, these compounds have utility in, for example, assaying such samples for VLA-1 mediated adhesion.
  • com- positions of this invention inhibit, in vivo, adhesion of mammalian cells to the extracellular matrix mediated, at least in part, by VLA-1 and, accordingly, can be used in the treatment, prevention, or amelioration of diseases, conditions, or disorders whose progression or symptoms are regulated, at least in part, by VLA-1 expression or activity.
  • diseases, conditions, or disorders include, but are not limited to, inflammatory diseases, fibrotic diseases, and cancer: -
  • diseases, conditions, and disorders which are expected to be treatable by a compound or composition of the present invention include, but are not limited to, asthma, trachoma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes) , inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, migration, and/or growth (including angiogenesis) , proliferation of fibroblasts in cancer, solid tumors, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome, and fibrotic diseases, such as fibrotic diseases of the lung, kidney, liver, and vasculature (including idiopathic pulmonary fibrosis, systemic s
  • Fibrotic diseases which are expected to be treatable by the compounds and/or compositions of the present invention include systemic sclerosis, mixed connective tissue disease, fibrodysplasia, fibrocystic disease, sarcoidosis, myositis (e.g., polymyositis, primary idiopathic polymyositis, childhood polymyositis, dermatomyositis, childhood dermatomyositis, primary idiopathic dermatomyositis in adults, inclusion body myositis, polymyositis, or dermatomyositis associated with malignant tumors) .
  • myositis e.g., polymyositis, primary idiopathic polymyositis, childhood polymyositis, dermatomyositis, childhood dermatomyositis, primary idiopathic dermatomyositis in adults, inclusion body myositis, polymyo
  • Dermatomyositis can be associated with fibrosing or hypertrophic aspects, including fibrosing alveolitis and pulmonary fibrosis.
  • Treatment using the com- pounds and/or compositions of the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy, or fibrosis in such diseases.
  • Amelioration includes reducing the rate of progression of a disease.
  • fibrotic diseases are diseases that have as a manifestation fibrotic vascular intimal hypertrophy. These diseases include vasculitis (including coronary artery vasculitis), polyarteritis nodosa, and temporal arteritis.
  • Treatment using a compound or composition of the present invention is expected to treat, prevent, reduce, or ameliorate vascular intimal hypertrophy in such diseases.
  • fibrotic diseases further include diseases that have as a manifestation fibrotic hypertrophy of skin and/or muscle tissue.
  • diseases include scleroderma, eosinophilic fasciitis, discoid lesions associated with lupus or discoid lupus, or surgical adhesions.
  • Treatment using the compounds or compositions of the present invention is expected to treat, prevent, reduce, or ameliorate such indications, or hypertrophy or fibrosis of skin or muscle tissue.
  • Fibrotic diseases further include diseases that have as a manifestation fibrotic hypertrophy of nerve tissue. These diseases include cerebrosclerosis, annular sclerosis, diffuse sclerosis, and lobar sclerosis. Treatment using a compounds or composition of the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy or fibrosis of nerve tissue in such diseases.
  • fibrotic diseases further include fibrotic lung diseases that have as a manifestation fibrotic hypertrophy or fibrosis of lung tissue.
  • diseases include pulmonary, fibrosis (or interstitial lung disease or interstitial pulmonary fibrosis) , idiopathic pulmonary fibrosis, the fibrotic element of pneumoconiosis (which is associated with exposure to environmental hazards such as smoking, asbestos, cotton lint, stone dust, mine dust and other particles) , pulmonary sarcoido- sis, fibrosing alveolitis, the fibrotic or hyper- trophic element of cystic fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and emphysema.
  • Treatment using a compound or composition of the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy or fibrosis in such diseases.
  • fibrotic diseases further include diseases that have as a manifestation fibrotic hypertrophy or fibrosis of prostate, liver, the pleura (e.g., pleurisy, pleural fibrosis), or pancreas.
  • diseases include benign prostatic hypertrophy (BPH) , nonalcoholic steato hepatitis, and fibrosis of the liver.
  • Treatment using a compound or composition of the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy or fibrosis in such diseases.
  • fibrotic diseases further include diseases that have as a manifestation fibrotic hypertrophy or fibrosis of the kidney, such as chronic renal failure, lupus nephritis, alports syndrome, glomerulonephritis, and diabetic neph- ritis.
  • Treatment using a compound or composition of the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy, or fibrosis of the kidney.
  • Tumors or neoplasms include growths of tissue cells in which the multiplication of the cells is uncontrolled and progressive. Some such growths are benign, but others are termed "malig- nant" and can lead to death of the organism.
  • Malignant neoplasms or “cancers” are distinguished from benign growths in that, in addition to exhibiting aggressive cellular proliferation, they can invade surrounding tissues and metastasize. Moreover, malignant neoplasms are characterized in that they show a greater loss of differentiation (greater "dedifferentiation") and organization relative to one another and to surrounding tissues. This property is called "anaplasia.”
  • Tumors or neoplasms which are expected to be treatable by a compound or composition of the present invention include, but are not limited to, solid tumors, i.e., carcinomas, adenocarcinomas, and sarcomas.
  • Carcinomas include those malignant neoplasms derived from epithelial cells which infil- trate (invade) the surrounding tissues and give rise to metastases.
  • Adenocarcinomas are carcinomas derived from granular tissue, or from tissues which form recognizable glandular structures.
  • Another broad category of cancers includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogenous substance like embryonic connective tissue.
  • VLA-1 may be associated with adult and pediatric oncology in various forms of cancer, for example, growth of solid tumors/malignancies, myxoid and round cell carcinoma, locally advanced tumors, human soft tissue carcinoma (including Ewing's sarcoma) , cancer metastases (including lymphatic metastases) , squamous cell carcinoma (particularly of the head and neck) , esophageal squamous cell carcinoma, oral carcinoma, cutaneous T cell lym- phoma, Hodgkin's lymphoma, non-Hodgkin' s lymphoma, cancer of the adrenal cortex, ACTH-producing tumors, nonsmall cell cancers, breast cancer (including small cell carcinoma and ductal carcinoma) , gastro- intestinal cancers (including stomach cancer, colon cancer, colorectal cancer, polyps associated with colorectal neoplasia, pancreatic cancer and liver cancer) , urological cancers (including bladder cancer, especially primary superficial bladder • tumors, invasive transitional cell
  • Cancers and other cell proliferative disorders treatable by the compounds and/or compositions of the present invention also include angiogenesis- mediated diseases, benign tumors (e.g., hemangio- mas) , acoustic neuromas, neurofibromas, pyogenic granulomas, biliary tract cancer, choriocarcinoma, esophageal cancer, gastric cancer, intraepithelial neoplasms, lung cancer, and neuroblastomas.
  • the biological activity of the compounds identified above may be assayed in a variety of systems.
  • extracellular matrix such as collagen IV
  • extracellular matrix such as collagen IV
  • adhesion of cells expressing VLA-1 can be measured in the presence or absence of compound.
  • large numbers of compounds can be screened.
  • Cells suitable for this assay include smooth muscle cells, microvascular endothelial cells, fibroblasts, osteoblasts, chondrocytes, and activated cells of the immune system including effector T cells, macrophages, and NK cells.
  • a number of transfected cell lines can also be used, including, for example, CHO, K562, and the like.
  • the compounds and compositions of the invention can also be tested for the ability to inhibit binding between VLA-1 and extracellular matrix such as collagen IV, or between VLA-1 and a labeled compound known to bind VLA-1, such as a compound or composition of this invention or antibodies to VLA-1.
  • the extracellular matrix can be soluble or immobilized on a solid surface.
  • VLA-1 may also be expressed as a recombi- nant fusion protein having acidic and basic leucine- zipper tails so that binding to extracellular matrix may be detected in an immunoassay.
  • the labeling systems can be in a variety of forms.
  • The- label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art.
  • a wide variety of labels may be used.
  • the component may be labeled by any one of several methods. The most common method of detection is the use of autoradi- ography with 3 H, 125 I, 35 S, 1 C, or 32 P-labeled compounds, and 'the like.
  • Nonradioactive labels include europium, as well as ligands which bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies which can serve as specific binding pair members for a labeled ligand.
  • Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bioavail- ability) , or the ability to be detected in diagnostic applications. Stability can be assayed in a variety of ways such as by measuring the half-life of the compounds during incubation with peptidases or human plasma or serum.
  • a wide variety of labels may be linked to the compounds, which may provide, directly or indirectly, a detectable signal.
  • the compounds and/or compositions of the subject invention may be modified in a variety of ways for a variety of end purposes while still re- taining biological activity.
  • various reactive sites may be introduced for linking to particles, solid substrates, macromolecules, and the like.
  • Labeled compounds can be used in a variety of in vivo or in vi tro applications.
  • a wide variety of labels may be employed, such as radionuclides (e.g., gamma-emitting radioisotopes such as tech- netium-99 or indium-Ill), fluorescers (e.g., fluorescein) , enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.
  • radionuclides e.g., gamma-emitting radioisotopes such as tech- netium-99 or indium-Ill
  • fluorescers e.g., fluorescein
  • enzymes enzyme substrates
  • enzyme cofactors enzyme inhibitors
  • chemiluminescent compounds chemiluminescent compounds
  • bioluminescent compounds bioluminescent compounds
  • vi tro uses include diagnostic applications, such as monitoring inflammatory responses by detecting the presence of cells expressing VLA-1.
  • the compounds and compositions of this invention can also be used for isolating or labeling such cells.
  • the compounds and compositions of the invention can be used to assay for potential inhibitors of VLA-1/Extracellular matrix interactions.
  • radioisotopes are typically used in accordance with well-known techniques.
  • the radioisotopes may be bound to the compound either directly or indirectly using intermediate functional groups.
  • chelating agents such as diethylenetriamine- pentacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA) , and similar molecules, have been used to bind compounds to metallic ion radioisotopes.
  • the complexes can also be labeled with a paramagnetic isotope for purposes of in vivo diagnosis, as in magnetic resonance imaging (MRI) or electron spin resonance (ESR) , both of which are well known.
  • MRI magnetic resonance imaging
  • ESR electron spin resonance
  • any conventional method for visualizing diagnostic images can be used.
  • gamma- and positron-emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI.
  • the compounds can be used to monitor the course of amelioration of an inflammatory response in an individual. By measuring the increase or decrease in cells expressing VLA-1 it is possible to determine whether a particular therapeutic regimen aimed at ameliorating the disease is effective.
  • Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington 's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed. (1985).
  • compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the progression or symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.” Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, disorder or condition, the age, weight, general condition of the patient, and the like.
  • the compounds administered to a patient are typically in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophil- ized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administra- tion.
  • the pH of the compound preparations typically will be between about 3 and 11, more preferably from about 5 to 9, and most preferably from about 7 to 8. It will be understood that use of certain of the foregoing excipients, -carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds and compositions of the present invention will vary ⁇ according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the dose will typically be in the range of about 100 ⁇ g to about 50 mg per kilogram body weight per day, preferably about 5 mg to about 20 mg per kilogram body weight per day.
  • the dose will typically be in the range of about 20 ⁇ g to about 500 ⁇ g per kilogram body weight, preferably about 100 ⁇ g to about 300 ⁇ g per kilogram body weight.
  • Alternative routes of administration contemplated include, but are not limited to, intranasal, transdermal, inhaled, subcutaneous, and intramuscular. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds and compositions of the subject invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and 5 the ED 50 (the dose therapeutically effective in 50% of the population) .
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and --——--fe-ca-n-be-ex-p- ⁇ ?e-s-sed-a-s—t-he-a -io- ⁇ nV--E-D ⁇ r- ⁇ "Gom e - s -- -- that exhibit large therapeutic indices are pre-
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range which includes the IC 50 (the concentration of the test
  • Method A Varian HPLC System (Pumps: Varian ProStar Solvent Delivery System, Model 210; Detector: Varian ProStar UV-VIS Detector, Model 345; Autosampler: Varian ProStar Autosampler, Model
  • Detector Rainin Dynamax Absorbance Detector, Model UV-DII; Autosampler: Varian ProStar Autosampler, Model 430).
  • Analytical column YMC ODS-AQ, 4.6x50 mm, S3 ⁇ , Waters Corporation. Detection: 220 nm and
  • Solvent A H 2 0, 0.01% HFBA, 1.0% IPA.
  • Solvent B Acetonitrile, 0.01% HFBA, 1.0% IPA.
  • Flow Rate 2.0 mL/min.
  • Gradient Program 0.00 min 95% Solvent A, 5% Solvent B; 0.12 min 95% Solvent A, 5% Solvent B; 4.00 min 5% Solvent A, 95% Solvent B;
  • Method C Varian HPLC System: (Pumps: Varian ProStar Solvent Delivery System, Model 210; Detector: Varian ProStar PDA, Model 330; Autosampler: Varian ProStar Autosampler, Model 430) .
  • Analytical column YMC ODS-AQ, 4.6x50mm, S3 ⁇ l, Waters Corporation. Detection: 220 nm and 254 nm.
  • Solvent A H 2 0, 0.01% HFBA, 1.0% IPA.
  • Solvent B Acetonitrile, 0.01% HFBA, 1.0% IPA.
  • Flow Rate 2.0 mL/min.
  • Method D Berger SFC (Berger Dual Pump Fluid Control Module, Model FCM1200; Berger Thermal Control Module, Model TCM-2000; Hewlett Packard 1100 Series DAD, Model G1315A; Alcott Autosampler, Model 718AL) .
  • Method E Agilent Technologies 1100 HPLC System (Pump: QuatPump Model G131 IA; Detector:
  • TSP HPLC System (Pump: TSP SpectraSYSTEM ⁇ P 000; Detector: TSP SpectraSYSTEM ® UV2000, 220 nm and 254 m; Autosampler: TSP Spectra- SYSTEM ® AS3000; Degasser: TSP SpectraSYSTEM ® Model SCM1000 Solvent Degasser) . Detection: 220 nm and 254 nm. Analytical column: YMC ODS-AQ, 4.6x50 mm, S3 ⁇ , Waters Corporation. Solvent C: H 2 0, 0.01% HFBA, 1.0% IPA. Solvent D: Acetonitrile, 0.01% HFBA, 1.0% IPA. Flow Rate: 2.0 mL/min. Gradient
  • TSP HPLC System (Pump: TSP SpectraSYSTEM ® P4000; Detector: TSP SpectraSYSTEM ® UV2000, 220 nm and 254 m; Autosampler: TSP Spectra- SYSTEM ® AS3000;. Degasser: TSP SpectraSYSTEM ® Model SCM1000 Solvent Degasser) . Detection: 220 nm and 254 nm. Analytical column: YMC ODS-AQ 4.6x50 mm S3 ⁇ , Waters Corporation. Solvent C: 10 mM Ammonium Acetate in H 2 0.
  • Solvent D 10 mM Ammonium Acetate in Acetonitrile, 1.0% IPA. Flow Rate: 2.0 mL/min. Gradient Program: 0.00 min 75% Solvent C, 25% Solvent D; 0.02 min 75% Solvent C, 25% Solvent D; 4.00 min 5% Solvent C, 95% Solvent D; 4.30 min 5% Solvent C, 95% Solvent D; 4.50 min 75% Solvent C, 25% Solvent D; 5.50 min 75% Solvent C, 25% Solvent D.
  • Method H Mass Spectrometer: Finnigan LCQTMDuo, ESI.
  • TSP HPLC System (Pump: TSP SpectraSYSTEM ® P4000; Detector: TSP SpectraSYSTEM ® UV2000, 220 nm and 254 m; Autosampler: TSP Spectra- SYSTEM ® AS3000; Degasser: TSP SpectraSYSTEM ® Model SCM1000 Solvent Degasser) . Detection: 220 nm and 254 nm. Analytical column: Zorbax Extend C18 Rapid Resolution ® , 50x4.6 mm, 3.51, 80A, Agilent Technologies. Solvent C: 10 mM Ammonium Acetate in H 2 0.
  • Solvent D 10 mM Ammonium Acetate in Acetonitrile, 1.0% IPA. Flow Rate: 2.0 mL/min. Gradient Program: 0.00 min 95% Solvent C, 5% Solvent D; 0.02 min 95% Solvent C, 5% Solvent D; 4.00 min 5% Solvent C, 95% Solvent D; 4.30 min 5% Solvent C, 95% Solvent D; 4.50 min 95% Solvent C, 5% Solvent D; 5.50 min 95% Solvent C, 5% Solvent D.
  • TSP HPLC System (Pump: TSP SpectraSYSTEM ® P2000; Detector: TSP SpectraSYSTEM ® UV2000, 220 nm and 254 m; Autosampler: TSP SpectraSYSTEM ® AS3000; Degasser: TSP SpectraSYSTEM ® Model SCM1000 Solvent Degasser) . Detection: 220 nm and 254 nm.
  • Analytical column Zorbax Extend C18 Rapid Resolution ® , 50x4.6 mm, 3.5 ⁇ , 80A, Agilent Technol- ogies.
  • Solvent A 10 mM Ammonium Acetate in H 2 0.
  • Solvent B 10 mM Ammonium Acetate in Acetonitrile, 1.0% IPA.
  • Flow Rate 2.0 mL/min.
  • Gradient Program 0.00 min 95% Solvent A, 5% Solvent B; 0.02 min 95% Solvent A, 5% Solvent B; 4.00 min 5% Solvent A, 95% Solvent B; 4.30 min 5% Solvent A, 95% Solvent B; 4.50 min 95% Solvent A, 5% Solvent B; 5.50 min 95% Solvent A, 5% Solvent B.
  • Method J Mass spectrometers: LCQTMDuo and LCQTMDeca.
  • Pump Series 1100, Quat pump model G1311A, Agilent Technologies.
  • Detector Series 1100, Column model G1216A, Agilent Technologies.
  • Autosampler Series 1100, ALS model G1313A, Agilent Technologies.
  • Degasser Series 1100, Degasser model G1322A, Agilent Technologies.
  • ELSD Sedex model 75, Sedere.
  • Analytical column YMC ODS-AQ 4.6x50mm S3 ⁇ , Waters Corporation.
  • Solvent A H 2 0, 0.01% HFBA, 1.0% IPA.
  • Solvent B Acetonitrile, 0.01% HFBA, 1.0% IPA.
  • Example IB 120 mg, 0.622 mmol
  • malonic acid 142 mg, 1.37 mmol
  • piper- idine 15 mg
  • pyridine 2 mL
  • Example ID (34.3 g, 109 mmol) was treated with 109 mL of 4 N HCl in dioxane (436 mmol) at room temperature for 3 h.
  • the precipitated solid was collected by filtration and the filter cake was washed with ether.
  • the white solid was dissolved in a mixed solution of MeOH and MeCN (1:3 solution, 200 mL) .
  • K 2 C0 3 45 g
  • the mixture was stirred at room temperature ' for 2 h and filtered through a bed of Celite.
  • the filter cake was washed with MeCN.
  • the combined filtrates were concentrated in vacuo. DCM was added to the residue.
  • the mixture was filtered through Celite again.
  • Example 1A The title compound was prepared by the procedures described in Example 1A, substituting 2, 3-dichloro-4-fluoro-benzoic acid with Example 1C and substituting 0,N-dimethylhydroxylamine hydrochloride with Example IE.
  • Example IF 160 mg, 0.371 mmol
  • THF THF
  • a solution of lithium hydroxide monohydrate (19 mg, 0.45 mmol) in H0 (0.5 mL)
  • the reaction mixture was stirred at room temperature for 2 h and then concentrated. The residue was taken up into H 2 0 and the pH adjusted to 4-5 with 0.5 N HCl. The resulting solid was filtered and dried in vacuo to give the title compound (137 mg, 89%) as a white solid.
  • Example 2A (0.063 g, 0.24 mmol), 1, 2, 3-trichloro-4- iodo-benzene (0.066 g, 0.21 mmol), palladium acetate (2.5 mg, 0.011 mmol), and tri-o-tolyl phosphine (6.5 mg, 0.021 mmol).
  • the flask was evacuated and flushed with N 2 .
  • Dry DMF (3 mL) and Et 3 N (0.090 L, 0.64 mmol) were added, and the mixture was heated with stirring at 85°C for 8 h. After cooling, the reaction mixture was partitioned between EtOAc and H0. The aqueous phase was extracted twice with EtOAc.
  • Example 3B 2- ( ⁇ 1- [3- (2 , 3-Dichloro-phenyl) -acryloyl] -piperidine- 4-carbonyl ⁇ -amino) -propionic acid
  • reaction mixture was filtered and resubjected to hydrogenation with fresh catalyst (5.6 g) for further 18 h. This procedure was repeated 2 more times. When all starting material was consumed, the reaction mixture was filtered through Celite 545, washing with copious amounts of EtOAc. The filtrate collected was concentrated under reduced pressure and the oily residue obtained was dried under vacuum to provide the title compound (23.4 g, 91%) as an off-white solid.
  • Example 5A (0.250 mmol/reaction 1 mL/well) in dichloroethane was added to each vial and diluted with an additional 19 mL of dichloroethane. The reaction mixtures were shaken for 42 h, filtered, and washed two additional times with 20 mL of dichloroethane. The filtrates collected were concentrated using a GeneVac evaporator. The esters obtained were , rediluted (10 mL) in dichloroethane and treated with TFA (1 mL each) . After 1 h, the solvent was removed under reduced pressure to provide Examples 5-10 (Table 1: Acrylamide Library) .
  • Example 11A A round bottom flask charged with Example 11A (2.5 g, 8.429 mmol), Pd 2 (dba) 3 (193 mg, 0.2107 mmol), and o-(Tol) 3 P (173 mg, 0.569 mmol) was purged with nitrogen. Dry DMF (34 mL) , methyl acrylate (1.9 mL, 25.286 mmol), and triethylamine (1.90 mL, 25.286 mmol) were then added. The reaction mixture was purged with nitrogen (2x) and stirred at 100°C (oil bath) for 18 hours. The reaction mixture was allowed to cool to ambient temperature and parti- tioned with EtOAc (200 mL) and water (3X80 mL) .
  • Example 11B A solution of Example 11B (1.7 g, 6.65 mmol) in glacial acetic acid (27 mL) was treated with Zn dust (4.35 g, 66.5 mmol) at ambient temperature for 30 minutes. The reaction mixture was filtered through a celite pad, washing with EtOAc (300 mL) . The filtrate was collected and washed well with water (5x100 mL) to remove acetic acid. The organic layer was separated, dried (NaS0) , filtered, and concentrated in vacuo, to provide the title compound (1.67 g, 107%).
  • Example 11D A solution of Example 11D (500 mg, 1.486 mmol) in a mixture of THF and MeOH (1:1 ratio, 5mL) was treated with LiOH»H 2 0 (187 mg, 4.457 mmol) in water (lmL) at ambient temperature for 18 h. The solvents were removed, aqueous layer diluted with 0.5N NaOH (50mL) , and washed with EtOAc (3xl5mL) to remove organic impurities. The aqueous phase was made acidic (pH 2) with 10% HCl. The resulting orange-yellow precipitate was filtered and evaporated from CH 3 CN (3x20mL) to provide the title compound (305 mg, 64%) .
  • Example 11H Alternative method for the preparation of Example IE 2- [ (Piperidine-4-carbonyl) -amino] -propionic acid methyl ester
  • Example 11G (12.85 g, 36.89 mmol) in EtOAc (250 mL) was added to a suspension of 10% Pd on C (12.85 g 10% Pd w/w) in EtOAc (200 mL) at ambient temperature under N 2 atmosphere. Then the reaction flask was purged under H 2 (3X) and stirred under H 2 atmosphere for 18 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to produce a pale yellow color liquid. This was crystallized upon cooling to provide the title compound (4 g, 50%) as a cream color solid.
  • Example HE (304 mg, 0.943 mmol), HOBt.H 2 0 (217 mg, 1.414 mmol), 4-methyl- morpholine (0.311 mL, 2.829 mmol), and Example 11H (242 mg, 1.132 mmol) in anhydrous DMF (4 mL) was treated with EDC (271 mg, 1.414mmol) at ambient temperature under N 2 atmosphere for 18 h.
  • the re- action mixture was diluted with EtOAc (100 mL) and washed with water (3x50 mL) .
  • the organic layer was separated, dried (Na 2 S0) , filtered, and evaporated under reduced pressure.
  • Example HI 360 mg, 0.694 mmol
  • THF:MeOH (1:1 mixture, 10 mL) was treated with LiOH»H 2 0 (88 mg, 1.777 mmol) in water (2 mL) at ambient temperature for 18 h.
  • the solvents were removed, the residue obtained was redissolved in water (5 mL) and made acidic (pH 2) with 10% HCl.
  • the resulting white solid material was filtered, washed with water (3x50 mL) , and crystallized from CH 3 CN to provide the title compound (225 mg, 64%) as a white solid.
  • Examples 12 and 13 were prepared as described for Examples 5-10. See Table 2.
  • Example 14 ( ⁇ 1- [3- (2 , 3-Dichloro-biphenyl-4-yl) -acryloyl] - piperidine-4-carbonyl ⁇ -amino) -propionic acid
  • Example 4C A mixture of Example 4C (0.150 g, 0.278 mmol), phenylboronic acid (0.037 g, 0.31 mmol), and KF (0.053 g, 0.918 mmol) in a round-bottom flask was evacuated and flushed with N 2 . Dry THF (1 mL) , tri- t-butyl phosphine (0.020 mL, 10% w/w solution in hexane, 0.0067 mmol), and Pd 2 dba 3 (0.0025 g, 0.0028 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether and filtered through Celite. The filtrate was washed with brine, dried and concentrated.
  • Examples 16-25 were prepared as described for Examples 5-10. See Table 3.
  • Example IG The title compound was prepared by the procedures described in Example IG, substituting Example IF with Example 26C.
  • Example 4C 100 mg, 0.186 mmol
  • copper tri- fluoro ethanethiol 61 mg, 0.37 mmol
  • NMP 3 mL
  • the reaction was stirred at 130°C for 4 h.
  • the mixture was diluted with EtOAc and filtered through Celite.
  • the filtrate was washed with brine, dried over Na 2 S0 , filtered, and concentrated in vacuo.
  • the residue was purified by Biotage Flash 40 eluting with 1-2% MeOH/DCM to give the title compound (78 mg, 82%) as a pale yellow solid.
  • Dimethyl-thiocarbamic acid O- (4-bromo-2 , 3-dichloro- phenyl) ester To a stirred suspension of NaH (95%, 1.45 g, 57.5 mmol) in DMF (100 mL) was added dropwise a solution of 4-bromo-2, 3-dichloro-phenol (prepared from 2, 3-dichlorophenol according to WO 00/59880, 12.1 g, 50.0 mmol) in DMF (25 mL) at 0°C. After stirring at the same temperature for 30 min, a solution of dimethylthiocarbonyl chloride (7.11 g, 57.5 mmol) in DMF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight.
  • Example 30A A solution of Example 30A (0.540 g, 1.64 mmol) in diphenyl ether (10 mL) was heated at 220°C for 4 h. After cooling, the reaction mixture was passed through a short silica gel column, eluting with hexanes followed by ether to give the title compound (0.526 g, 97%) as a white solid.
  • Example 30B A mixture of Example 30B (0.526 g, 1.60 mmol) EtOH (20 mL) , and 3 N NaOH (8 mL) was heated at reflux for 3 h. The reaction mixture was cooled, acidified with 3 N HCl, and extracted with ether. The combined organic layers were washed with brine, dried, and concentrated. The residue was chromatographed on silica gel, eluting with 5% EtOAc/- hexane to give the title compound (0.350 g, 85%) as a white solid.
  • Example 4C (100 mg, 0.186 mmol), sodium 1-propane- thiolate (22 mg, 0.22 mmol), and 2, 2, 6, 6-tetrameth- yl-heptane-3, 5-dione (7 mg, 0.04 mmol).
  • NMP 3 mL
  • ' and CuCl 9 mg, 0.09 mmol
  • the reaction was stirred at 130 °C for 4 h. After cooling, the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • Example 4C 100 mg, 0.186 mmol
  • copper (I) 1- butanethiolate 57 mg, 0.37 mmol
  • 2,2,6,6- tetramethyl-heptane-3, 5-dione 7 mg, 0.04 mmol
  • NMP 3 mL
  • the reaction was stirred at 130°C for 16 h. After cooling, the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • Example 32B 2- ( ⁇ 1- [3- (4-Butylsulfanyl-2 , 3-dichloro-phenyl) - acryloyl] -piperidine-4-carbonyl ⁇ -amino) -propionic acid
  • Example 33A ( ⁇ 1- [3- (2 , 3-Dichloro-4-isopropylsulfanyl-phenyl) - acryloyl] -piperidine-4-carbonyl ⁇ -amino) -propionic acid methyl ester
  • Example 4C (100 mg, 0.186 mmol), cyclohexanethiol (43 mg, 0.37 mmol), 2, 2, 6, 6-tetramethyl-heptane-3, 5- dione (7 mg, 0.04 mmol), and Cs 2 C0 3 (121 mg, 0.371 mmol) .
  • NMP 3 mL
  • CuCl 9 mg, 0.09 mmol
  • Example 2B The title compound was prepared by the procedures described in Example 2B, substituting 1, 2, 3-trichloro-4-iodo-benzene with Example 36A.
  • LCMS APCI+;
  • Example 38 2- ( ⁇ 1- [3- (2 , 3-Dichloro-4- dimethylcarbamoylmethylsulfanyl-phenyl) -acryloyl] - piperidine-4-carbonyl ⁇ -amino) -propionic acid
  • Example 1A The title compound was prepared by the procedures described in Example 1A, substituting 2, 3-dichloro-4-fluoro-benzoic acid with Example 38A and substituting 0,N-dimethyl-hydroxylamine hydrochloride with dimethylamine.
  • Example IG The title compound was prepared by the procedures described in Example IG, substituting Example IF with Example 41A.
  • Example 26B To a stirred solution of Example 26B (0.200 g, 0.735 mmol) in DCM (8 mL) was added portionwise mCPBA (0.181 g, 0.809 mmol) at 0°C.
  • Example 26B 3-dichloro-4-methanesulfonyl-benzene
  • DCM DCM
  • mCPBA 0.412 g, 1.84 mmol
  • the reaction mixture was diluted with DCM (30 mL) , washed with sat. NaHC0 3 , brine, dried (Na 2 S0 4 ) , filtered and concentrated in vacuo .
  • the residue was flash chromatographed (silica gel, 3% EtOAc in hexanes) to give the title compound (0.196 g, 93%) as a white solid.
  • Example IG The title compound was prepared by the procedures described in Example IG, substituting Example IF with Example 46B.
  • Example 1A The title compound was prepared by the procedures described in Example 1A, substituting 2, 3-dichloro-4-fluoro-benzoic acid with Example 46C and substituting 0,N-dimethyl-hydroxylamine hydrochloride with (L) - ⁇ -aminobutyric acid tert- butyl ester hydrochloride.
  • Example 1A The title compound was prepared by the procedures described in Example 1A, substituting 2, 3-dichloro-4-fluoro-benzoic acid with Example 46C and substituting 0,N-dimethyl-hydroxylamine hydrochloride with (L) -norleucine methyl ester hydrochloride.
  • Example IG The title compound was prepared by the procedures described in Example IG, substituting Example IF with Example 48A.
  • Example 1A The title compound was prepared by the procedures described in Example 1A, substituting 2, 3-dichloro-4-fluoro-benzoic acid with Example 46C and substituting 0,N-dimethyl-hydroxylamine hydrochloride with (L) -methionine methyl ester hydrochloride.
  • Example IG The title compound was prepared by the procedures described in Example IG, substituting Example IF with Example 49A.
  • Example 1A The title compound was prepared by the procedures described in Example 1A, substituting 2, 3-dichloro-4-fluoro-benzoic acid with Example 46C and substituting 0,N-dimethyl-hydroxylamine hydrochloride with Example 50A.

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Abstract

La présente invention se rapporte à des composés qui sont des antagonistes de l'intégrine VLA-1. L'invention a également trait à des compositions contenant de tels composés, et à des procédés d'utilisation de tels composés pour traiter des maladies induites au moins en partie par l'intégrine VLA-1.
PCT/US2004/026653 2003-08-14 2004-08-12 Derives d'acrylamide servant d'antagonistes de l'integrine vla-1, et leurs utilisations WO2005016883A2 (fr)

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WO2007140249A1 (fr) * 2006-05-25 2007-12-06 Biogen Idec Ma Inc. Méthodes de traitement des accidents vasculaire cérébraux
US8557240B2 (en) 1999-06-01 2013-10-15 Biogen Idec Ma Inc. Method for the treatment of inflammatory disorders
RU2492163C9 (ru) * 2009-04-03 2013-12-27 Нэйчуруайз Байэутек & Медиклз Копэрейшн Соединения коричной кислоты (варианты), промежуточные соединения для их получения, фармацевтическая композиция на их основе, способ ингибирования гистоновой деацетилазы, способ лечения диабета, способ лечения опухоли или заболевания, связанного с пролиферацией клеток, способ усиления роста аксонов и способ лечения нейродегенеративных заболеваний и спинной мышечной атрофии
US9364535B2 (en) 2012-08-15 2016-06-14 The Regents Of The University Of California Methods and compositions for modulating lymphangiogenesis, e.g., to treat transplant rejection, in a subject
US9409895B2 (en) 2012-12-19 2016-08-09 Novartis Ag Autotaxin inhibitors
JP2016164142A (ja) * 2006-01-13 2016-09-08 ダウ アグロサイエンシィズ エルエルシー ６−（多置換アリール）−４−アミノピコリネートおよび除草剤としてのそれらの使用
US9630945B2 (en) 2012-12-19 2017-04-25 Novartis Ag Autotaxin inhibitors
US9644030B2 (en) 2001-04-13 2017-05-09 Biogen Ma Inc. Antibodies to VLA-1
WO2018135659A1 (fr) 2017-01-23 2018-07-26 日本ケミファ株式会社 Inhibiteur du canal calcique de type t dépendant de la tension
US10071989B2 (en) 2011-06-27 2018-09-11 Tasly Pharmaceutical Group Co., Ltd. Substituted cinnamamide derivative, preparation method and use thereof
US10160808B2 (en) 2012-02-16 2018-12-25 Santarus, Inc. Anti-VLA1 (CD49A) antibody pharmaceutical compositions
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US8557240B2 (en) 1999-06-01 2013-10-15 Biogen Idec Ma Inc. Method for the treatment of inflammatory disorders
US9902774B2 (en) 1999-06-01 2018-02-27 Biogen Ma Inc. Method for the treatment of inflammatory disorders
US9644030B2 (en) 2001-04-13 2017-05-09 Biogen Ma Inc. Antibodies to VLA-1
JP2016164142A (ja) * 2006-01-13 2016-09-08 ダウ アグロサイエンシィズ エルエルシー ６−（多置換アリール）−４−アミノピコリネートおよび除草剤としてのそれらの使用
US10119979B2 (en) 2006-05-25 2018-11-06 Biogen Ma Inc. Methods of treating stroke and traumatic brain injury using humanized AQC2 anti-VLA-1 antibodies
CN105381459A (zh) * 2006-05-25 2016-03-09 比奥根Ma公司 治疗中风的方法
WO2007140249A1 (fr) * 2006-05-25 2007-12-06 Biogen Idec Ma Inc. Méthodes de traitement des accidents vasculaire cérébraux
RU2492163C9 (ru) * 2009-04-03 2013-12-27 Нэйчуруайз Байэутек & Медиклз Копэрейшн Соединения коричной кислоты (варианты), промежуточные соединения для их получения, фармацевтическая композиция на их основе, способ ингибирования гистоновой деацетилазы, способ лечения диабета, способ лечения опухоли или заболевания, связанного с пролиферацией клеток, способ усиления роста аксонов и способ лечения нейродегенеративных заболеваний и спинной мышечной атрофии
US10071989B2 (en) 2011-06-27 2018-09-11 Tasly Pharmaceutical Group Co., Ltd. Substituted cinnamamide derivative, preparation method and use thereof
US10160808B2 (en) 2012-02-16 2018-12-25 Santarus, Inc. Anti-VLA1 (CD49A) antibody pharmaceutical compositions
US10316095B2 (en) 2012-02-16 2019-06-11 Santarus, Inc. Antibody formulations
US9364535B2 (en) 2012-08-15 2016-06-14 The Regents Of The University Of California Methods and compositions for modulating lymphangiogenesis, e.g., to treat transplant rejection, in a subject
US10287355B2 (en) 2012-08-15 2019-05-14 The Regents Of The University Of California Methods and compositions for modulating lymphangiogenesis, E.G., to treat transplant rejection, in a subject
US9409895B2 (en) 2012-12-19 2016-08-09 Novartis Ag Autotaxin inhibitors
US9630945B2 (en) 2012-12-19 2017-04-25 Novartis Ag Autotaxin inhibitors
WO2018135659A1 (fr) 2017-01-23 2018-07-26 日本ケミファ株式会社 Inhibiteur du canal calcique de type t dépendant de la tension
WO2022008918A1 (fr) * 2020-07-10 2022-01-13 University Of Nottingham Dérivés d'azétidine pour le traitement de maladies se rapportant aux intégrines

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