WO2005019200A2 - Derives d'arylpiperidine utilises en tant qu'antagonistes d'integrine vla-1 et utilisations de ceux-ci - Google Patents

Derives d'arylpiperidine utilises en tant qu'antagonistes d'integrine vla-1 et utilisations de ceux-ci Download PDF

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WO2005019200A2
WO2005019200A2 PCT/US2004/026206 US2004026206W WO2005019200A2 WO 2005019200 A2 WO2005019200 A2 WO 2005019200A2 US 2004026206 W US2004026206 W US 2004026206W WO 2005019200 A2 WO2005019200 A2 WO 2005019200A2
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amino
carbonyl
phenyl
propionic acid
piperidine
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WO2005019200A3 (fr
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Steven A. Boyd
Jason Demeese
Indrani Gunawardana
Irina C. Jacobson
Yvan Lehuerou
Mark L. Lupher, Jr.
Martin Mclaughlin
Scott Miller
Allen Thomas
Eugene Thorsett
Rui Xu
Matthew Yanik
Gan Zhang
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Icos Corp
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Icos Corp
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings

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 polypeptide chains, ⁇ and ⁇ . Integrins are the major receptor for cell adhesion to the extracellular matrix and play important roles in certain cell-cell and cell-matrix adhesion events. These integrin- mediated adhesion events are critical for both normal and pathophysiological processes during cell activation, migration, proliferation, and differen- tiation (for reviews see Hynes (1992) Cell 69: 11 ; Springer (1994) Cell 76: 301 ; Hynes (2002) Cell 110: 613 ) .
  • VLA-1 (very late antigen-1) is an integrin heterodimer 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 vitro (Tulla et al. (2001) J. Biol . Chem . 51:48206).
  • ⁇ 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 (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, macrophages, and NK cells (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 (He Ler et al. (1986) J. Clin . Invest . 78:696), lesions of giant cell arteritis patients (Schaufelberger et al. (1993) Clin .
  • 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 (de
  • 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. Abs against ⁇ l have also been shown to block collagen-induced cyto- kine release, including release of TNF- ⁇ , a .key mediator in arthritis (Miyake et al. (1994) Eur. J. Immunol. 24:2000). In addition, VLA-1 also regulates matrix metalloproteinase (MMP) expression (Gardner et al . (1996) Dev. Biol.
  • MMP matrix metalloproteinase
  • VLA-1 is an upstream regulator of multiple disease promoting factors
  • VLA-1 is expressed on myofibroblasts in vi tro 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 (Cosgrove et al. (2000) Am . J. Pathol . 157:1649).
  • ⁇ l mAb blocks hepatic stellate cell adhesion to collagen and endothelin-stimulated- hepatic stellate cell- mediated contraction of collagen- lattices in vi tro, .
  • VLA-1 is the sole integrin utilized by contracting hepatic stellate cells in vivo (Racine-Sampson et al. (1997) J. Biol . Chem . 272:30911).
  • blocking anti- ⁇ l antibody has shown efficacy therapeutically in two independent models of fi- brotic kidney disease (Kagami et al. (2002) Lab .
  • 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 (Pozzi et al. (1998) J. Cell . Biol . 142:587; Senger et al. (2002) Am . J. Pathol . 160: 195) , and 2) by regulating the production of matrix metallopro- teinase 9 which in turn regulates the activity of angiostatin, a potent angiogenesis inhibitor (Pozzi et al. (2000) PNAS 97: 2202 ; Pozzi et al .
  • 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 treatment, prevention, or suppression of various path- ologies mediated by VLA-1 binding and cellular adhesion, migration, activation or differentiation.
  • the present invention provides aryl piper- idine compounds that are antagonists to the VLA-1 integrin.
  • this invention is directed to a compound of Formula I:
  • Ar is selected from the group con- sisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • A together with the nitrogen atom bound thereto, forms a 4-8 membered nitrogen containing heterocyclic group containing 1 to 2 nitrogen atoms, wherein said heterocyclic group may be optionally substituted with 1 to 3 additional substituents each independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, sub- stituted heteroaryl, heterocyclic and substituted heterocyclic, hydroxy, alkoxy, thioalkyl, 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 and alkoxy substituents, if present, may be attached to a carbon atom in said heterocyclic group, wherein the one or more thioalkyl and the one or more halo substituents, if present,
  • W is selected from the group consisting of -C(X)-NH and -NH-C (X) -, ⁇ wherein X is oxygen or sul- fur,
  • Y is selected, from the group consisting of a bond, alkylene, and substituted alkylene;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, amino, substituted amino, aminocarbonyloxy, oxycarbonyl- a ino / aminoacyl, acylamino, aminocarbonyla ino, aminosulfonylamino, aminosulfonyl, sulfonylamino, heterocyclic, substituted heterocyclic, aryl, sub- stituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, carboxyl, and carboxyl esters; or R 3 -C-R 4 forms a cycloalkyl, substituted cycloalkyl, heterocyclic, or substituted heterocyclic group; R 5 is selected from the group consisting of
  • R a is selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, heterocyclic (e.g., tetrazolyl) , and substi- tuted heterocyclic; with the proviso that when Y is a bond and W is C(0)NH, then R 3 and/or R 4 are not amino, substituted amino, hydroxy, or alkoxy; and pharmaceutically acceptable salts, prodrugs, and any and all tautomers thereof.
  • a and the nitrogen atom pendent thereto form a piperidine ring.
  • W is -C(0)-NH- or -NH-C(O)-.
  • Y is a bond or methylene
  • R 4 is hydrogen
  • R 5 is -C0 2 H.
  • R 3 is alkyl or substituted alkyl.
  • Particularly preferred Y groups include a bond, methylene, and substituted methylene.
  • R 3 groups include methyl, N-benzylimidazol-4-ylmethylene, and phenyl - acetamidomethylene.
  • Ar is selected from the group consisting of:
  • this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I as de- fined 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 mediated, 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 for inhibiting adhesion of mam- malian 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 for 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 therapeu- tically effective amount of a compound or co posi- tion of this invention.
  • said disease, disorder, or condition is selected from the group consisting of asthma, trachoma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflamma- tory- 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 di- . • sease, 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, sarcoido ' sis, 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 selec- ted from the group consisting of chronic renal fail- ure, lupus nephritis, alport syndrome, glomerulo- nephritis, and diabetic nephritis.
  • the invention is directed to a method for ameliorating cancers 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 therapeutically effective amount of a compound or composition of this invention.
  • said cancer is a tumor or a neoplasm selected from the group consisting of carcinomas, adenocarcinomas, and sarcomas .
  • said can- cer 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, uro- logical 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 effusion, mesothelioma, Wilms's tumors, gall bladder cancer, trophoblastic neoplasms, hemangioperi
  • said cancer is a cell proliferative disorder, 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 inven- tion may be administered to the mammal by any suitable route, such as orally, intravenously, par- enterally, 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 aryl piperidine derivatives.
  • alkyl refers to mono- valent alkyl groups having from 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms, even ' more preferably 1 to 4 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, ⁇ n-
  • 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,
  • Hydroa ⁇ kyl refers to an alkyl group having from 1 to 3 hydroxy substituents provided that there is no more than one hydroxy group per
  • Haldroxy refers to the group -OH.
  • Alkylene refers to divalent alkylene groups having from 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term is ex-
  • substituted alkylene refers to an alkylene group as defined above substituted with from 1 to 3 substituents as described for substituted alkyl.
  • Alkoxy refers to the group “alkyl-0-" 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
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C (0) -, alkenyl-C (0) -, substituted alkenyl-C (0) -, cycloalkyl-C (O) -, substi- tuted cycloalkyl-C (0) -, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C (0) -, substituted hetero- ⁇ aryl-C(O), heterocyclic-C (0) -, and substituted het- erocyclic-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 hetero- aryl-C(0)0-, heterocyclic-C (0) 0-, and substituted heterocyclic-C (0) 0- .
  • Alkenyl refers to monovalent alkenyl groups having from 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms, and having at least 1 site, and preferably from 1-2 sites, of alkenyl unsaturation.
  • 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, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, thiol, thioalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxycarbonylamino, provided that the hydroxy or the
  • Amino refers to the group -NH 2 .
  • substituted amino refers to the group -NRR where each R is independently 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 provided that both R groups are not hydrogen.
  • Aminoacyl refers to.the groups -NRC(O)- alkyl, -NRC (0) substituted alkyl, -NRC (0) alkenyl, -NRC (0) substituted alkenyl, -NRC (0) cycloalkyl,
  • -NRC (0) substituted cycloalkyl -NRC (0) aryl, --NRC- (0) substituted aryl, -NRC (0) 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) 0-substituted alkyl, -NRC(0)- O-cycloalkyl, -NRC.(O) 0-substituted cycloalkyl, - -NRC- (O)O-aryl, -NRC (0) 0-substituted- aryl, -NRC (0) O-het- eroaryl, -NRC (0) O-substituted heteroaryl, -NRC (0)0- heterocyclic, and -NRC (0) 0-substituted- heterocyclic, where R is hydrogen or alkyl.
  • aminosulfonyl refers to the group ⁇ S0 2 Q where Q is amino- or substituted amino, as defined . herein.
  • Aminosulfonylamino refers to the group QS0 2 Q where each Q is independently amino or substituted amino, as defined herein.
  • Oxycarbonylamino refers to the group -0C(0)Q where Q is amino or substituted amino, as defined herein.
  • Aminocarbonylamino refers to the group -QC(0)Q where each Q is independently amino or substituted amino, as defined herein.
  • 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., 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) - one-7yl, 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 hydroxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, amino, substituted amino, aminoacyl, amino- carbonyloxy, aminocarbonyiamino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl esters, cyano, thiol, thioalkyl, substituted thioalkyl, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • Aryloxy refers to the group aryl-O- which includes, by way -of example, phenoxy, naph- thoxy, and the like.
  • Substituted aryloxy refers to substituted aryl-O- groups.
  • Carboxyl refers to the group -COOH, and salts thereof.
  • 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, carboxyl-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.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo, and preferably is fluoro, chloro, or bromo.
  • 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, nitro- gen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indoli- zinyl or benzothienyl) provided that the point of attachment is to a heteroaryl group atom and further provided that the heteroaryl group contains five ring atoms.
  • Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, and furyl.
  • 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.
  • Heterocycle or “heterocyclic” refers to a onovalent 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 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 pro- vided that the point of attachment is to a heterocyclic ring atom.
  • Substituted heterocyclic refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group of substit- uents defined for substituted cycloalkyl.
  • 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, piperi- dine, piperazine, indoline, phthalimide, 1,2,3,4- tetrahydroisoquino
  • Thioalkyl refers to the group -S-alkyl.
  • Substituted thioalkyl refers to the group -S-substituted alkyl.
  • Sulfonylamino refers. to the group QS0 2 where Q is amino or substituted amino, as defined herein.
  • Tautomers refers to chemical compounds that exist as a mixture of two interconvertible iso- -10- mers in equilibrium.
  • “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 15 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- 20 mide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • Prodrugs are compounds which convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound of the invention.
  • the effective- 25 ness of an orally administered drug is dependent upon the drug's efficient- transport across the muco- sal epithelium and its stability in entero-hepatic circulation.
  • Drugs that are effective after par- enteral administration but less effective orally, or 30 whose plasma half-life is considered too short, may be chemically modified into a prodrug form.
  • a pro- drug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive 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 prodrugs according to the invention, including:
  • Ester or amide derivatives which may • ' be cleaved by, for example, esterases or lipases.
  • ester-' is derived from the. carboxylic acid moiety of- the drug molecule by known means.
  • the amide may be derived from the carboxylic acid moiety or the a ine moiety of the drug molecule by known means.
  • ⁇ (2) Peptides that may be recognized by specific or nonspecific proteinases.
  • 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.
  • substituted as used with, for example, “substituted alkyl” does not include polymers derived therefrom but are limited to a maximum of 3 substituents groups, e.g., alkyl-Ar-Ar-Ar.
  • 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 pre- ferred 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.
  • 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, (1991) 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.
  • stereoisomers and enriched mixtures are included within the scope of this invention, unless otherwise indicated.
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art.
  • 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.
  • This reaction is run at a temperature of about 25°C to about 90 °C for a time sufficient for the reaction to go to completion, typically about 1 to about 12 hours.
  • the product can be recovered using standard techniques such as filtration, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • the reaction also can be performed in the reverse direction by switching the halide and transition metal of the aryl groups.
  • Scheme 2 for illustrative purposes only, describes how a halopyridine such as compound 105, can be synthesized by treating a pyridine biaryl compound useful in the preparation of compounds of formula I, for example compound 104, with an oxidizing agent (e.g., m-CPBA, hydrogen peroxide, etc.), in a suitable solvent (e.g., DCM, DCE, CC1 4 ) .
  • an oxidizing agent e.g., m-CPBA, hydrogen peroxide, etc.
  • a suitable solvent e.g., DCM, DCE, CC1 4
  • the N-oxide intermediate is then reacted with a phosphorus oxyhalide (e.g., P0C13, POBr 3 ) to furnish the halopyridine.
  • the halopyridine of this reaction may be optionally substituted with substituents suitable for use in the subsequent reactions.
  • Step 1 of the reaction shown in Scheme 2 is run at a temperature of about -10 °C to about 30°C for a time sufficient for the reaction to fo to completion, typically about 1 to about 18 hours.
  • Step 2 of the reaction shown in Scheme 2 is run at a temperature of about 25 °C to about 90 °C for a time sufficient for the reaction to go to completion, typically about 1 to about 18 hours.
  • the product can be recovered using standard techniques such as filtration, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • R 3 ' is either a carboxylic acid with a suitable protecting group (OCOPg, where Pg may be alkyl, or more specifically, t-butyl) or an amine with a suitable protecting group (NHPg*, where Pg* may be boc, cbz, or frnoc) , n is 0 to 4, and the halopyridine may be optionally substituted with substituents suitable for use in the subsequent reaction.
  • OCOPg a carboxylic acid with a suitable protecting group
  • Pg may be alkyl, or more specifically, t-butyl
  • NHSg* a suitable protecting group
  • n is 0 to 4
  • the halopyridine may be optionally substituted with substituents suitable for use in the subsequent reaction.
  • Scheme 3 illustrates a method for converting a halopyridine, such as compound 105, [e.g., 2- (4-methoxyphenyl)pyri- dine] , to a 2-aminopyridine, compound 106, through a melt reaction using various amines (e.g., ethyl or methyl isonipecotate or 4- ( t-butyloxycarbonyl- amino) piperidine or methyl azetidine-3-carboxylate) .
  • This reaction is typically run neat, preferably using an excess of amine, at a suitable temperature, from about 25°C to about 90°C in an inert atmosphere in a closed tube.
  • the reaction is run for a time sufficient for the reaction to go to completion, typically about 1 to 50 hours.
  • the product can be recovered using standard techniques such as filtra- tion, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • the reaction is run for a time suffi- cient for the reaction to go to completion, typically about' 1 to about 20 hours.
  • the product can be recovered using standard techniques such as filtra- tion, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification. 5
  • the nitro group of compound 108 may be reduced to form the aniline, (compound not shown) , using a, suitable reducing conditions (e.g., zinc in acetic acid or FeS0 4 (H 2 0) 7 in THF) followed by formation of a diazo salt (NaN0 2 , sulfuric acid, or
  • the resulting diazonium salt - may be reduced . (H 3 P ⁇ 4 or HMPA in ethanol or sodium stannite, see Ruchardt et al. (1977) Chem . Ber. 210:2494) to the hydrido product compound 109. This reaction is run at a temperature of about 0° to about 90 °C for a
  • the product can be recovered using standard .techniques such, as filtration, chromatography, distillation, extraction, and the like. Alternatively, the product may
  • Biaryl halides such as compound 111, (2, 3-methyl-3 ' -iodo-biphenyl, etc.) can also be synthesized from biaryl nitro compounds, such as
  • compound 107a (e.g., 2, 3-dichloro-3 ' -nitro-biphen- yl, and the like) . Reduction of the nitro group of compound 107a leads to an aniline derivative, compound 110. This intermediate can then be converted to an aryl halide, such as compound 111, by first
  • halopyridines such as compound 105
  • aryl halides such as compound 111, (e.g., 3 bromobiphenyl, 2, 3-dichloro-3 ' - iodo-biphenyl, 2-chloro-4- (m-tolyl) -pyridine)
  • aryl halides such as compound 111, can be converted to various substituted aminoaryls, such compounds 106, 109> 109a, (and, as illustrated in Scheme 5 below, compound 112) by a palladium mediated coupling (WO 00/39081; Old et al.
  • Ar 2 , R 3' , n, X, and Y' are defined herein above.
  • the coupling can be performed as described in Schemes 3 and 4 to give compound 112.
  • Compound 112 may be halogenated by using techniques described herein and/or by methods well known in the art, to give compound 112a, where Y' is a boronic acid, boronic ester, or an organo stannane.
  • compound 112a can be coupled to Ar 2 -Y' when Y' is a boronic acid, boronic ester, or an organo stannane via copper mediated Chan-Lam coupling (see Lam et al. (2002) Tetrahedron Lett . 43:3091; Chan et al .
  • a second palladium coupling (as indicated in Scheme 1) can provide compound 113 from compound 112a.
  • compound 112 may be transmetallated to give compound 114, (Miyaura et al . (1995) J. Org. Chem . 60: 1508- 7510) , which can then be coupled as in Scheme 1 to other aromatic halides to give compound 113.
  • the above reactions are run under conditions described herein or using techniques well known in the art.
  • Substituted benzothiophenes were synthesized according to Scheme 6.
  • One method entails the alkylation of bromoacetic acid compound 116 with substituted thiophenols compound 115 (3-methyl thio- henol, 2,3-dichloro thiophenol, etc.) in aqueous solvent and in the presence of a base (NaOH, Cs 2 C0 3 , and the like) to afford compound 117.
  • Bromination e.g., using iron filings and
  • ketone compound 119 by treatment with a Lewis acid such as A1C1 3 or polyphos- phoric acid.
  • a Lewis acid such as A1C1 3 or polyphos- phoric acid.
  • the reaction is generally carried out at -78°C to 25°C.
  • Reduction of the ketone is afforded by a reducing agent (NaBH 4 , LiAlH , or DIBAL-H, or the like) , in a solvent such as ethanol, at a tempera- ture of about -10 °C to about 10 °C for a period of time sufficient for completion of the reaction.
  • a reducing agent NaBH 4 , LiAlH , or DIBAL-H, or the like
  • a solvent such as ethanol
  • the intermediate alcohol is eliminated to benzothiophene compound 120 using techniques well known in the art.
  • the product can be recovered using standard tech- niques such as filtration, chromatography, distilla- tion, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • the bromide can be converted to the corresponding iodide compound 121 (Buchwald et al. (2002) J. Am . Chem . Soc. 224:14844-14845) .
  • the product can be recovered using standard techniques such as filtra- tion, chromatography, distillation, extraction, and • the like. Alternatively, the product may be used in the next step without further ' isolation and/or purification.
  • a process for preparing substituted heteroaryl derivatives is illustrated in Scheme 7, following a Hantzsch type synthesis (Beugelmans et al. (1996) J. Org. Chem . 61 : 118 ) , wherein Ar 1 , R 3 ', and n are defined herein above, and Q* is sulfur or oxygen.
  • the starting aryl ketone compound 122 is chlorinated by reaction with oxalyl chloride in toluene yielding compound 123. This reaction is run at a temperature of about 0°C to about 90 °C for a time sufficient for the reaction to go to completion, typically about 1 to 24 hours.
  • the product can be recovered using standard techniques such as filtration, chromatography, distillation, extrac- tion, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • Ureas such as compound 124
  • an aprotic solvent e.g., DCM, toluene
  • the product can be recovered using standard techniques such as fil- tration, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • the product can be recovered using standard techniques such as filtration, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • Scheme 8 illustrates the synthesis of sub- stituted arylethers, aryl. thioethers and amino derivatives, such as compound 128, wherein X is as defined herein, Ar i.s aryl,. substituted aryl, het- roaryl, or substituted ' heteroaryl, R 2* is alkyl, substituted alkyl, aryl, substituted aryl, ..hetercryl,- and substituted heteroaryl, and Y* is NH, 0 or S.
  • amino acid derivatives such as compound 131 are coupled to the carboxylic acids, com- pound 130, in an inert solvent (DCM, THF, DMF or the like) using any of a wide variety of well known coupling agents.
  • Suitable coupling agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3- ethylcarbodimide hydrochloride (EDC) , dicyclohexyl- carbodiimide (DCC) , N, N' -carbonyldiimidazole (CDl), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) , and diethylcyanophos- phonate (DECP) .
  • well known coupling promoters for example 1-hydroxybenzotriazole
  • the acid may be coupled utilizing solid support resins such as 1% cross linked polystyrene tetrafluoro phenol (PS-TFP) , polystyrene dicyclohexyl carbodiimide (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-dimethylamino pyridine, triethyl amine, etc.) and solvent (DMF, methylene chloride.)
  • PS-TFP cross linked polystyrene tetrafluoro phenol
  • PS- DCC polystyrene dicyclohexyl carbodiimide
  • PS-HOBT polystyrene 1-hydroxybenzotriazole
  • the coupled amide compound 132 is then subjected to basic hydrolysis conditions listed above to afford the final acid compound 133.
  • the product can be recovered using standard techniques such as filtration, chromatography, distillation, extraction, and the like. Alternatively, the product may be used in the next step without further isolation and/or purification.
  • Scheme 10 depicts the preparation of- re- versed amide analogs, wherein Ar, R 3 , R 4 , n, Pg and Pg* are as defined herein- above.
  • the protecting group Pg* on the protected amine, compound 134, (also compound 112 or compound 113 from Scheme 5 wherein R 3 ' is an amine protected with a- suitable protecting group such as Boc, Cbz, Fmoc, trifluoro- ⁇ acetamide, or the like) , is removed using conditions suitable for the protecting group, to afford the amine compound 135.
  • Amine compound 135 is then coupled using conditions listed above to an acid, compound 136, to provide for the amide compound 137.
  • the ester of the resulting amide compound 137 is then hydrolyzed using conditions listed above to yield the acid, compound 138.
  • 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, chro- matography, 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 tri- chloride, 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 tetrachloride, at temperature in the range of about 0°C to about 80°C ,- for about 1 to about 48 hours.
  • a catalyst such .as DMF, may also be used in .this reaction.
  • compound 300 can be re- covered by conventional methods including neutrali- zation, extraction, precipitation, chromatography, filtration, and the like or used in the next step of the reaction without purification and/or isolation.
  • This compound is reacted with at least an equimolar equivalent of a heteroaryl or heterocyclic halide, i.e., Het-X (compound 500) to provide for compound 600.
  • a heteroaryl or heterocyclic halide i.e., Het-X (compound 500)
  • Het-X compound 500
  • - Transition-metal catalysts may be used to facilitate this transformation, for example using copper (I) (e.g., copper (I) iodide, copper (I) - bromide dimethylsulfide complex) or palladium complexes .
  • 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 con- tainer.
  • 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, manni- tol, starches, gum acacia, calcium phosphate, algi- nates, tragacanth, gelatin, calcium silicate, micro- crystalline cellulose, polyvinylpyrrolidone, cellu- lose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubri- eating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as ethyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubri- eating 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 ethyl- 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.
  • 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 par- enterally 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 pre- formulation composition containing a homogeneous mixture of a compound of the present invention.
  • preformulation compositions When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient 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 preformu- lation is then subdivided -into unit dosage forms of the type described, above -containing from, for example, 0.1 to .about -500 mg of the active ingredient of the present invention. - .
  • the tablets or pills of the present inven- ' ⁇ •. tion . may be • coated or otherwise .compounded to pro-- vide a dosage form affording the advantage of prolonged action.
  • the-.tablet or pill can comprise an inner dosage and an outer dosage com- ponent, 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 mate- • . rials 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 incorporated 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 pharmaceu- tically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra .
  • the 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 compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the following formulation examples illustrate representative pharmaceutical compositions of the present invention.
  • Hard gelatin capsules containing the fol- lowing 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 pre- pared containing the following components:
  • 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 polyvinylpyrroli- done 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, pre- viously 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 capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the satur- ated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 mL dose are made as follows:
  • the active ingredient, sucrose and xanthan 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.
  • 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:
  • Another preferred formulation employed in 5 the methods of the " present invention employs txans- ⁇ dermal delivery devices ("patches") .
  • Such trans- dermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery, of pharmaceutical agents is well known in the art. See ' , e.g., U.S. Patent 5,023,252, herein incorporated by reference.. Such patches may be constructed for continuous, pulsatile, . or on demand ' delivery, of
  • 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 trans- portation 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.
  • Other suitable formulations for use in the present invention can be found in Remington ' s Pharmaceutical Sciences, (1985), Seventeenth Edition, Mack Publishing Company, Philadelphia, PA.
  • 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 techniques 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 and/or compositions of this invention can be employed to bind VLA-1 in biolog- ical samples, for instance in mammalian patients suspected 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.
  • compounds of this invention and/or pharmaceutical compositions thereof inhibit, in vivo, adhesion of mammalian cells to the extracellular matrix mediate ⁇ , 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 is regulated, at least in part, by VLA-1 expression or activity.
  • diseases, condi- tions, or disorders include, but are not limited to, inflammatory diseases, fibrotic diseases, and cancer.
  • diseases, conditions, and disorders which are expected to be trea able by the compounds and/or compositions 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, enceph- alitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myo- cardial 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 5 vasculature (including idiopathic
  • 10.- 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,
  • Dermatomyositis can be associated with fibrosing or
  • hypertrophic aspects including fibrosing alveolitis and pulmonary fibrosis.
  • Treatment using the compounds or compositions of .the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy
  • Amelioration includes reducing the rate of progression of a disease.
  • fibrotic diseases that have as a manifestation fibrotic vascular intimal hypertrophy. These diseases include vascu-
  • fibrotic diseases include diseases that have as a ' manifestation fibrotic hypertrophy of skin -and/or muscle tissue. These diseases include scleroderma, eosinophilic fasci- itis, 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 cerebroscler- osis,' annular sclerosis, diffuse sclerosis, and lobar sclerosis.
  • Treatment using the compounds or . ' compositions' 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 sarcoidosis, fibrosing alveolitis, the fibrotic or hypertrophic element of cystic fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and emphysema.
  • Treatment using the compounds 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.
  • Such 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.
  • BPH benign prostatic hypertrophy
  • Treatment using the compounds 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.
  • fibrotic diseases further include diseases that have as a manifestation fibrotic hypertrophy or fibrosis of the kidney, such as chronic renal failure, lupus nephritis, alport syndrome, glomerulonephritis, and diabetic nephritis.
  • Treatment using the compound or compositions of the present invention is expected to treat, prevent, reduce, or ameliorate such diseases, or hypertrophy, fibrotic hypertrophy, or fibrosis of the kidney.
  • Cancers which are expected to be treatable by the compounds or compositions of the present invention typically occur in mammals. 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.
  • 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 “malignant” 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 "de- differentiation”) 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 the compounds or compositions 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 infiltrate (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 5 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,
  • non-Hodgkin' s lymphoma 15- lymphoma, non-Hodgkin' s lymphoma,- cancer of the adrenal cortex, ACTH-producing tumors, nonsmail cell cancers, breast cancer '(including small cell carcinoma and ductal carcinoma) , gastrointestinal cancers (including stomach cancer, colon cancer, colo-
  • rectal cancer polyps associated with colorectal ; neoplasia, pancreatic cancer and liver cancer),, urological cancers (including bladder cancer, especially primary superficial bladder tumors, invasive transitional cell carcinoma of the bladder,
  • malignancies of the female genital tract including ovarian carcinoma, primary peritoneal epithelial neoplasms, cervical carcinoma, uterine endometrial cancers, vaginal cancer, cancer of the
  • vulva, uterine cancer, and solid tumors in the ovarian follicle malignancies of the male genital tract (including testicular cancer and penile cancer) , kidney cancer (including renal cell carcinoma) , brain cancer (including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas and metastatic tumor cell invasion in central nervous system) , bone cancers (including oste- omas and osteosarcomas) , skin cancers (including malignant melanoma, tumor progression of human skin keratinocytes and squamous cell cancer) , thyroid cancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms's tumors, gall bladder cancer, trophoblastic neoplasms, hemangiopericytoma, and Kaposi's sarcoma.
  • Cancers and other cell proliferative disorders treatable by the compounds or compositions of the present invention also include angiogenesis-mediated diseases, benign tumors (e.g., hemangiomas) , 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 and/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 recombinant fusion protein having acidic and basic leucine-zipper tails so that binding to extracellular matrix -may be de- . tected in an immunoassay.
  • the labeling systems can be in a vari- • ety 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, 14 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.
  • the choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements', and available instrumentation.
  • 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, bioavailabil- ity) ,- 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 sig- ⁇ nal .
  • the compounds and compositions of the subject invention may be modified in a variety of ways for a variety of end purposes while still retaining 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 cofac- tors, 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 cofac- tors enzyme inhibitors
  • chemiluminescent compounds chemiluminescent compounds
  • bioluminescent compounds bioluminescent compounds
  • the compounds and compositions of. this invention can 15 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/Extraeellular matrix interactions. 20 - For in vivo diagnostic - imaging to identi-
  • radioisotopes • are typically used in accordance with well-known techniques.
  • the radioisotopes may be bound to the compound either directly or indirectly using inter- 25 mediate functional groups.
  • chelating ⁇ agents such as diethylenetriaminepentacetic acid (DTPA) , ethylenediaminetetraacetic acid (EDTA) , and similar molecules have been used to bind compounds to metallic ion radioisotopes.
  • DTPA diethylenetriaminepentacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • the complexes can also- be labeled with a paramagnetic isotope for purposes of in vivo diag- nosis, as in magnetic resonance imaging (MRI) pr 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
  • the amount administered to the patient will vary depending- upon what is.-.being administered, the purpose of the administration, such as prophyl- - axis or therapy, the state of the patient, the manner of administration, and the like. In thera-
  • 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
  • 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 and 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 administration.
  • 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.
  • the therapeutic dosage of the compounds and/or 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 con- dition 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 typ- ically 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/or composi- tions of the subject invention will be administered • in a therapeutically effective amount by any Of the v..
  • Toxici-ty 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 the ED 5 0 (the dose therapeutically effective in.50% •- • of the population) .- .
  • the dose ratio between toxic - and therapeutic . effects is the therapeutic index and ' . it can be expressed as the ratio LD 5 o/ED 50 .
  • Compounds that exhibit large therapeutic indices are preferred.
  • 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 circulating concentrations, that include the ED 5 0 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • 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 IC50 (the concentration of the test compound which achieves a half-maximal inhibition of activity) as determined in cell culture.
  • IC50 the concentration of the test compound which achieves a half-maximal inhibition of activity
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • Method A Varian HPLC System: Pumps: arian ProStar Solvent Delivery System, Model 210; Detector: Varian ProStar UV-VIS Detector, Model
  • Method B Varian HPLC System: (Pumps: Varian -ProStar Solvent Delivery System, Model 210; Detector: Rainin Dynamax Absorbance Detector, Model UV-DII; Autosampler: ' Varian ProStar Autosampler, Model ' 430).
  • Analytical column YMC ODS-AQ, 4.6 x 50 mm, S3 ⁇ , Waters Corporation. ' Detection: 220nm and 254nm.
  • Solvent A H 2 0, 0.01% HFBA, .1.0% IPA. .
  • Solvent B Acetonitrile, 0.01%HFBA, 1.0% IPA.
  • 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, 4.6 x 50 mm, S3 ⁇ , Waters Corporation. Detection: 220nm and 254nm.
  • 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 E Agilent Technologies 1100.HPLC ,' ⁇ ' System (Pump: QuatPump Model G1311A; Detector:. DAD, Model G1315B; Column Compartment: Model
  • TSP HPLC System (Pump: TSP Spec- ' traSYSTEM® P4000; Detector: TSP SpectraSYSTEM® . .. - UV2000, 220nm and 254 ; Autosampler: TSP Spectra- SYSTEM® AS3000 Degasser: ⁇ TSP SpectraSYSTEM® Model SCMIOOO Solvent Degasser) .
  • Detection -220nm and 254nm.
  • Analytical column YMC ODS-AQ, 4.6 x 50 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, 220nm and 254 m; Autosampler: TSP Spectra- SYSTEM® AS3000; Degasser: TSP SpectraSYSTEM® Model SCM1000 Solvent Degasser) . Detection: 220nm and 254nm. Analytical column: YMC ODS-AQ 4.6 x 50 mm S3 ⁇ , Waters Corporation. Solvent C: 10 mM Ammonium Acetate in H ? 0. Solvent D: 10 mM Ammonium Acetate in Acetonitrile, 1.0% IPA. Flow Rate: 2.0 mL/min.
  • TSP HPLC System (Pump: TSP SpectraSYSTEM® P4000; Detector: TSP SpectraSYSTEM® UV2000, 220nm and 254 m; Autosampler: TSP SpectraSYSTEM® AS3000; Degasser: TSP SpectraSYSTEM® Model SCM1000 Solvent Degasser) . Detection: 220nm and 254nm. Analytical column: Zorbax Extend C18 Rapid Resolution®, 50 x 4.6 mm, 3.5 ⁇ , 80A, Agilent Tech- nologies. 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 Spec- 5 traSYSTEM® P2000; Detector: TSP SpectraSYSTEM® . UV2000, 220nm and 254 m; Autosampler: TSP SpectraSYSTEM® AS3000; Degasser: TSP SpectraSYSTEM® Model SCM1000 Solvent Degasser) . Detection: - 220nm and 254nm. Analytical column: Zorbax Extend C18 Rapid-0 Resolution®, .50 x 4.6 mm, 3.5 ⁇ , 80A, Agilent Technologies.
  • Solvent B 0.02 min 95% Solvent A, 5% Solvent B; 4.10 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. Purity based on 220 nm wavelength channel.
  • Example 1A (1.76 g, 80.1%) as a white solid.
  • Example IB (1.60 g, 99%) as a white solid.
  • IC 1.00 g, 3.87 mmol
  • ethyl isonipecotate 6.08 g, 38.68 mmol
  • the tube was placed under nitrogen, sealed and heated with stirring to 145°C for 24 h.
  • the mixture was cooled to ambient temperature.
  • the mixture was purified by flash chromatography on silica gel eluting with 10% 7N methanolic ammonia/- DCM to provide the title compound (0.890g, 3.87 mmol, 61%).
  • Example 2 was prepared, according to the same reaction protocol as. described for, Example 1 substituting. L-I ⁇ -benzyl histidine methyl ester di- hydrochloride for L-alanine, methyl ester HCl. The procedure provided the title . compound (0.036 mmol,. 8%) as a white solid.
  • Example 3 was prepared according to the same reaction protocol as described for Example 1 substituting 2-tributylstannanyl-pyridine for 4-tri- butylstannanyl-pyridine. The procedure resulted in the. title compound (0.0 ' 80 g, 0.190 mmol, 41%) as a ' white solid-.
  • Example 4 was prepared according to the same reaction protocol as described for Example 1 substituting 4A for 1A. The procedure resulted in the title compound (0.020 g, 0.046 mmol, 26%) as a white solid.
  • Example 5B (as a 3;2 mixture of regioiso- mers) was prepared according to the same reaction protocol as described for Example 1 substituting 5A for IB. The procedure resulted in the title compound
  • Example 6 was prepared according . to the same reaction protocol as described for Example 1 substituting 3-tributylstannanyl-pyridine for 4-tri- butylstannanylpyridine . The procedure 'resulted in the title compound (0.103-g, 0.246 mmol, 61%) as a white powder.
  • Example 7C was prepared according to the , . same reaction protocol as described for Example 1 substituting 7B for ID. The procedure resulted in
  • Example 8 was prepared according to the same reaction protocol as described for Example 7 substituting L- ⁇ -benzyl histidine methyl ester di- hydrochloride for L-alanine methyl ester HCl. The procedure resulted in the title compound (0.058 g, 0.286 mmol, 32.1%) as a white solid.
  • Example " 9 was prepared' according to the same reaction protocol as • described for 'Example 7 substituting L-2-amino-3-benzoylamino-propionic acid methyl ester HCl for L-aianine methyl ester HCl. - The procedure resulted in the title compound (0.062 ' g, 0.285 mmol, 41%) as a white solid.
  • Example 10 was prepared according to the same reaction protocol as described for Example 1 substituting 7A for IE. The procedure resulted in the title compound (0.019 g, 0.351 mmol, 15.2%) as a white solid.
  • Example 11 was prepared according to the same reaction protocol as described for Example 10 substituting L-2-amino-3-benzoylamino-propionic acid methyl ester HCl for L-alanine methyl ester HCl. The procedure resulted in the title compound as a white solid (0.110 g, 0.350 mmol, 66.0%).
  • Example 12 was prepared according to the same reaction protocol as described for Example 10 substituting L-I ⁇ -benzyl histidine methyl ester di- hydrochloride for L-alanine methyl ester HCl. The procedure resulted in the title compound (0.101 g, 0.351- mmol, 57.0%) as a white solid.
  • Example 14 was prepared according to'the • " same reaction protocol as described for Example 13 substituting L-Z ⁇ -benzyl histidine methyl ' ester ' di- hydrochloride for L-alanine methyl ester HCl. The procedure resulted in the title compound (0.030 g, 0.48 mmol, 14.0%) as a white solid.
  • LCMS (ESI-Method G) m/z 432.0 (M-2H) " , Rt 2.02 min (220 : nm, 100.0 area! .
  • Example 15B was prepared according to the same reaction protocol as described for Example 7B substituting 15A for 7A. The procedure resulted in the title compound (0.160 g, 42.0! as an off-white solid.
  • Example 15C was prepared according to the same reaction protocol as described for Example 1 substituting 15E for IE and 15G for L-alanine methyl ester to provide the title compound (0.145 g, 95! as an off-white solid.
  • Bromoacetic acid tert-butyl ester (67.7 g, 347 mmol) was added dropwise over 20 min and the mixture was stirred for 30 min at -78 ⁇ C .
  • the mixture was warmed to 0°C by placing the flask in a water-ice bath for 20 min.
  • the mixture was quenched by pouring into 1 L separatory funnel containing 200 mL of sat. aq NH 4 C1.
  • the mixture was diluted with EtOAc (300 mL) , the phases were separated and the organic phase was washed sequentially with 1 N HCl (2X100 mL) , sat.
  • Example 15F (29.0 g, 83.5 mmol) and THF/water (300 mL, 4:,1 mixture). The mixture was cooled to 0°C in an ice bath and 30! v H 2 0 2 (17.0 g, 501 mmol, in water) was added over 10
  • Example 16 was prepared as in Example IG substituting 15C for IE. The procedure provided the title compounds as an off-white solid.
  • 1 H NMR (DMSO- d 6 r 400 MHz) ⁇ 12.09 (s, IH) , 8.36 (d, J 2 .
  • Example 17D (0.350 g, 0.925 mmol) was processed as in Example IE to provide the title compound (0.292 g, 90.1!) as a cream color powder.
  • Example 17E (0.150 g, 0.428 mmol) was processed as in Example IF to provide the title compound (0.1600 g, 85.8! as a cream color powder.
  • Example 17F (0.230 g, 0.368 mmol) was processed as in Example IG to provide the title compound (0.104 g, 67.2%) as a cream color powder.
  • Example 18 was prepared as in Example 17
  • Example 19D (O.lOOg, 0.280 mmol) was pro-5 Stepd as in Example IF to provide the title compound (0.100 g, 81.0%) as a light yellow colored powder.
  • Example 19E . (0-.230 g, 0..368 mmol) for Example ID. 'The title compound (0.104 g, 67.2%) was obtained as a pale yellow powder.
  • Example . 19D (0.120 g, 0.336 mmol) was processed as in Example 19 ⁇ • substituting ⁇ L-i ⁇ J 1 -benzyl histidine methyl ester dihydrochloride for L-alanine methyl ester, to provide the title compound (0.100 g,- 50.9%) as a light yellow colored powder..- X H NMR
  • Example 21A A solution of Example 21A (298 mg, 1.205 mmol) in THF:MeOH (1:1, 6 mL) was treated with a solution of LiOH'H 2 0 (76 mg, 1.807 mmol) in water (2 mL) at ambient temperature for 18 h. The solvents were removed under reduced pressure. The residue dissolved in water (5 mL) and washed with EtOAc (2X5 mL) to remove organic impurities. Then the aqueous layer was made acidic with 10% aq HCl. The product formed was soluble in aqueous acidic medium and water was removed by evaporating with CH 3 CN to provide the lithium salt of the title compound (159 mg, 50%).
  • LCMS APCI+; Method D) m/z 220, (M+H) + .
  • Example 21B A solution of Example 21B (159 mg, 0.607 mmol), HOBt.H 2 0 (139 mg, 0.9098 mmol) , L-N x -benzyl histidine methyl ester dihydrochloride (242 mg, 0.728 mmol), and triethylamine (0.296 mL, 2.123 mmol), in dry DMF (3'mL) was treated with EDC (174 mg, 0.9098 mmol) at ambient temperature under N 2 atmosphere for 18 h. The reaction mixture was diluted' with EtOAc (10 mL) , washed with water (2x5 mL) , dried (MgS0 4 ) , filtered, and evaporated to dry- ' ness.
  • Example 22A (190 mg, 0.727 mmol) was hydrolyzed with LiOH * H 2 0 (37 mg, 0.872 mmol) as described in Example 2IB to provide the title compound (210 mg, 87! as an off-white color powder.
  • LCMS (APCI+; Method D) m/z 234, (M+H) + .
  • Example 22B 150 mg, 0.643 mmol. as described in Example 21C.
  • LCMS m/z 476, (M+H) + .
  • Example 23A (340 mg, 1.235 mmol) was hydrolyzed with LiOH.H 2 0 (78 mg, 1.852 mmol) as described in Example 21B to provide the title compound (300 mg, 84! as a white powder.
  • LCMS APCI+; Method D) m/z 248, (M+H) + .
  • Example 23D (88 mg, 39%) was obtained as a white powder.
  • Example 24A (270 mg, 0.896 mmol) was hydrolyzed with LiOH.H 2 0 (57 mg, 1.344 mmol) as described in Example 21B to provide the title compound (165 mg, 58! as a white powder.
  • X R NMR 400 MHz, DMSO-de) ⁇ 7.48-7.39 ( , 3H) , 7.18 (s, IH) , 3.73-3.65 (m, 2H), 3.06-2.94 (m, 2H) , 2.46 (m, IH) , 1.97-1.93 (m, 2H) , 1.77-1.71 (m, 2H) .
  • LCMS (APCI ; Method D) m/z 274, (M+H) + .
  • Example 24D 3-(l-Benzyl ⁇ lH-imidazol-4-yl)-2- ⁇ [1-O- trifluoromethyl-phenyl) -piperidine-4-carbonyl] - ' ⁇ ⁇ amino ⁇ -propionic acid
  • Example 24C 150 mg, 0.292 mmol
  • Example 21D The title compound (73 mg, 50%) was obtained as a white powder.
  • Example 2.5A (259 mg, 0.937 mmol) was- hydrolyzed with LiOH'H 2 0 (59 g, 1.406 mmol) as described in Example 21B to provide the title compound (151 mg, 55! as a white powder.
  • LCMS (APCI+; Method D) m/z 249, (M+H) + .
  • Example 25C 120 mg, 0.245 mmol
  • the title compound 50 mg, 43! was obtained as a white powder.
  • Example 26A (331 mg, 1.017 mmol) was - treated with LiOH*H 2 0 (64 mg, 1.526 mmol) as described in Example 2IB to provide the title compound (180 mg, 59! as a white powder.
  • LCMS (APCI+; Method D) m/z 316, (M+H) + .
  • Example 26C The title compound was prepared from Example 26C (130 mg, 0.234 mmol) as. described in Example 21D.
  • Example 26D (70 mg, 55!) was obtained as a white powder.
  • X H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.03 (d, J-8.19 Hz, IH), 7.68 (s, IH) , 7.34-7.31 (m, 2H) ,
  • Example 27A (280 mg, 0.877 mmol) was treated with LiOH'H 2 0 (55 mg, 1.315 mmol) as described in Example 21B to, provide the title compound (177.mg, 61! as a -white powder.
  • LCMS (APCI+; Method D) m/z 292, (M+H) + , (92 area %) . ⁇
  • Example 27C The title , compound was prepared from Example 27C (218 mg, 409 mmol) as described in Example 21D.
  • Example 27D (173 mg, 82%) was obtained as a white powder.
  • Example 28A (380 mg, 1.029 mmol) was hydrolyzed with LiOH"H 2 0 (86 mg, 2.058 mmol) as described in Example 21B to provide the title compound (347 mg, 98.82! as a white powder.
  • X H NMR 400 MHz, DMSO-de) ⁇ 12.31 (s, IH) , 7.46 (s, 2H) , 7.27 (s, IH) , 3.89-3.85 (m, 2H) , 2.98-2.91 (m, 2H) , 2.47-2.44 (m, IH) , 1.94-1.89 (m, 2H) , 1.66-1.56 (m, 2H) .
  • LCMS (APCI+; Method D) m/z 342, (M+H) + .
  • Example 28C 160 mg, 0.275 mmol
  • Example 28D 117 mg, 75%) was obtained as a white powder.
  • Example 29A was used for- the preparation of Example 29B directly.
  • Example' 29A (280 mg, 0.938 mmol) was treated with LiOH'H 2 0 (59 mg, 1.408 mmol) as described in Example 21B to provide the title compound ' (164 mg, 56%) as a yellow color solid.
  • Example 29C 50 mg, 0.098 mmol
  • Example 21D The crude product obtained was purified by C- 18 Reverse phase HPLC using a gradient of 5-95! CH 3 CN/H 2 0 containing 1% TFA to provide the title compound (62 mg, 92! as a bright yellow powder.
  • Example 30A (318 mg, 1.052 mmol) was treated with LiOH.H 2 0 (88 mg, 2.105 mmol) as described in Example 21B to provide the title compound (276 mg, 96%) as a white powder.
  • Example 30C The title compound was prepared from Example 30C (130 mg, 0.2522 mmol) as described in, Example 21D.
  • Example.30D (93 mg, 73.54!). was obtained as a white powder.
  • Example 31A 120 mg, 0.397 mmol was hy- drolyzed with LiOH.H 2 0 (20 mg, 0.477 mmol) as described in Example 2IB to provide the title compound (100 mg, 96! as a white powder.
  • ⁇ H NMR 400 MHz, DMSO-de) ⁇ 12.30 (br s, IH) , 7.30-7.28 (m, 2H) , 7.14- 7.12 ( , IH), 3.24-3.19 (m, 2H) , 2.74-2.68 (m, 2H) , 2.44-2.56 (m, IH) , 1.95-1.91 (m, 2H) , 1.77-1.68 (m, 2H) .
  • LCMS (APCI+; Method D) m/z 274, 276, (M+H) + .
  • Example 31C The title compound was prepared from Example 31C (130 mg, 0.2522 mmol) as ' described in Example 21D.
  • Example 31D (78 mg, 62! was obtained as a white powder.
  • Example' " 32A (45 mg, 126 mmol) ' was hydrolyzed with LiOH"H 2 0 (6 mg, 0.151 mmol) as described in Example 2IB to provide the. title compound (30 mg, 72!).
  • LCMS (APCI+; Method D) m/z 330, 332, (M+H) 4 .
  • Example 32B The title compound (31, mg, 64%) was prepared from Example 32B (28 mg, 0.085 mmol) as described in Example 21C.
  • LCMS APCI+; Method D) m/z, 571, 573 (M+H) ⁇ .
  • Example 33A (260 mg, 0.704 mmol) was hydrolyzed with LiOH"H 2 0 (59 mg, 1.41 mmol.) as described in Example 21B to provide the title compound (225 mg, 95!).
  • X E NMR 400 MHz, DMSO-d 6 ) ⁇ 12.28 (s, IH) , 6.92 (d, J L.95 Hz, 2H) , 6.82-6.80 (m, IH) , 3.74-3.69 (m, 2H) , 2.87-2.82 (m, 2H) , 2.47-2.42 (m, IH) , 1.88-1.84 (m, 2H) , 1.61-1.52 (m, 2H) .
  • LCMS (APCI+; Method D) m/z 274, 276, (M+H) + .
  • Example 33B The title compound (156 mg, 83!) was prepared from Example 33B (100 mg, 0.365 mmol) as de- scribed in Example 21C.
  • Example 33D (112 mg, 69%) was obtained as a white powder.
  • Example 34A (500 mg, 1.803 mmol) was hydrolyzed with LiOH*H 2 0 (91 mg, 2.164 mmol) as described in Example 2IB to provide the title compound (438 mg, 97%) as a white powder.
  • X E NMR 400 MHz,
  • Example 34B (100 mg, 0.401 mmcl) as described in Example 21C.
  • Example 34D (45 mg, 41%) was obtained as a white powder.
  • Example 35A was prepared by the procedure_ .de.S-cribed- in Example.21A, - substituting -l-b-romo-3- methyl-benzene with l-bromo-4-tert-butyl-benzene (250 mg, 1.173 mmol). The title compound (194 mg,
  • Example 35A (190 mg, 0.657 mmol) was hydrolyzed with LiOH.H 2 0 (33 mg, 0.7878 mmol) as described in Example 21B to provide the title compound (127 mg, 74!).
  • LCMS (APCI+; Method D) m/z 262, (M+H) + .
  • Example 35C (175 mg, 0.3482 mmol) as described in Example 21D.
  • Example 35D (55 mg, 32!) was obtained as a white powder.

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Abstract

L'invention concerne des composés qui sont des antagonistes d'intégrine VLA-1. L'invention concerne également des compositions contenant lesdits composés et des procédés d'utilisation de ceux-ci dans le traitement de maladies dont la médiation est assurée, au moins en partie, par l'intégrine VLA-1.
PCT/US2004/026206 2003-08-14 2004-08-12 Derives d'arylpiperidine utilises en tant qu'antagonistes d'integrine vla-1 et utilisations de ceux-ci Ceased WO2005019200A2 (fr)

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WO2011130515A1 (fr) * 2010-04-14 2011-10-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Arylthiazolyl pipéridines et composés associés comme modulateurs de la production de protéine de neurone moteur de survie (smn)
US8557240B2 (en) 1999-06-01 2013-10-15 Biogen Idec Ma Inc. Method for the treatment of inflammatory disorders
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