WO2002018340A1 - Antagonistes de l'integrine $g(a)v$g(b)3 gem-substitues - Google Patents

Antagonistes de l'integrine $g(a)v$g(b)3 gem-substitues Download PDF

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WO2002018340A1
WO2002018340A1 PCT/US2001/026963 US0126963W WO0218340A1 WO 2002018340 A1 WO2002018340 A1 WO 2002018340A1 US 0126963 W US0126963 W US 0126963W WO 0218340 A1 WO0218340 A1 WO 0218340A1
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phenyl
solution
alkyl
product
group
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PCT/US2001/026963
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Ish Kumar Khanna
Yi Yu
Hwang Fun-Lu
Nizal S. Chandrakumar
Renee M. Huff
Mark A. Russell
Mark L. Boys
Lori A. Schretzman
Barbara B. Chen
Bipinchandra N. Desai
Srinivasan Raj Nagarajan
Alan F. Gasiecki
Thomas D. Penning
Thomas Rogers
John Adam Wendt
Albert Khilevich
Yaping Wang
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Pharmacia Corporation
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Priority to KR10-2003-7003099A priority Critical patent/KR20030027106A/ko
Priority to NZ524159A priority patent/NZ524159A/en
Priority to IL15449601A priority patent/IL154496A0/xx
Priority to MXPA03001759A priority patent/MXPA03001759A/es
Priority to PL01365729A priority patent/PL365729A1/xx
Priority to CA002419699A priority patent/CA2419699A1/fr
Priority to AU2001288515A priority patent/AU2001288515A1/en
Priority to EP01968257A priority patent/EP1313705A1/fr
Application filed by Pharmacia Corporation filed Critical Pharmacia Corporation
Priority to BR0113671-2A priority patent/BR0113671A/pt
Priority to JP2002523458A priority patent/JP2004510708A/ja
Priority to EA200300226A priority patent/EA200300226A1/ru
Publication of WO2002018340A1 publication Critical patent/WO2002018340A1/fr
Priority to US10/348,273 priority patent/US20040043994A1/en
Priority to NO20030925A priority patent/NO20030925L/no

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D213/73—Unsubstituted amino or imino radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • 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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical agents which are ⁇ vp 3 and/or ⁇ v ⁇ integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by ⁇ v ⁇ 3 and/or ⁇ v ⁇ s integrins.
  • Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked and ⁇ polypeptide subunits. Currently eleven different subunits have been identified and six different ⁇ subunits have been identified. The various subunits can combine with various ⁇ subunits to form distinct integrins.
  • v ⁇ 3 also known as the vitronectin receptor
  • v ⁇ 3 has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis (Ross, et al., J. Biol, Chem., 1987, 262, 7703), Paget's disease, humoral hypercalcemia of malignancy (Carron et al., Cancer Res. 1998, 58, 1930), osteopenia (Lark et al., J Bone Miner Res. 2001 ,16, 319), endometriosis (Healy et al., Hum. Reproductive Update, 1998, 4, 736), angiogenesis, including tumor angiogenesis (Cheresh,
  • the compounds of the present invention are ⁇ v ⁇ 3 antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively antagonize ⁇ 3 would be beneficial for treating such conditions.
  • the integrin ⁇ v ⁇ s plays a role in neovascularization. Antagonists of the ⁇ v ⁇ s integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy. M.C.
  • Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor. Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the ⁇ v ⁇ integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol.
  • the adhesion receptor integrin ⁇ v ⁇ was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization.
  • Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells.
  • Antagonists of ⁇ v ⁇ 3 inhibit this process by selectively promoting apoptosis of cells in neovasculature.
  • the growth of new blood vessels, or angiogenesis also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol.
  • ⁇ v ⁇ 3 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
  • ⁇ v ⁇ 3 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of ⁇ v ⁇ 3 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413].
  • Antagonism of ⁇ v ⁇ 3 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity.
  • antagonists of osteoclast v ⁇ which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
  • ⁇ v ⁇ integrin The role of the ⁇ v ⁇ integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vase. Surg. Vol. 19(1) (1994) 125-34).
  • the compounds of this invention are 1) ⁇ v ⁇ integrin antagonists; or 2) ⁇ v ⁇ s integrin antagonists; or 3) mixed or dual v ⁇ s/ocv ⁇ s antagonists.
  • the present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds.
  • the present invention further provides for methods for treating or preventing conditions mediated by the ⁇ v ⁇ and/or ⁇ v ⁇ s receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention.
  • Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
  • the present invention relates to a class of compounds represented by the Formula I.
  • n is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring, optionally saturated or unsaturated, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, alkylsulfone, sulfonamide, alkylsulfoxide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and -(CH 2 )n COR wherein n is 0-2 and R is hydroxy, alkoxy, alkyl or amino;
  • a 1 is a 5-9 membered monocyclic or 7-12 membered bicyclic heterocycle of the formula
  • R k selected from the group consisting of hydroxy, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, thioalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and -COR wherein R is hydroxy, alkoxy, alkyl or amino;
  • a 1 i is
  • Y 1 is selected from the group consisting of N-R 2 , O, and S;
  • R 2 is selected from the group consisting of H; alkyl; cycloalkyl; aryl; hydroxy; alkoxy; cyano; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymeth oxycarbonyl ;
  • R 2 taken together with R 7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, • carboxyl or carboxyl ester, and fused phenyl; or R 2 taken together with R 7 forms a 4-12 membered heterocycle containing one or more heteroatom selected from O, N and S optionally unsaturated;
  • R 2 taken together with R 7 forms a 5 membered heteroaromatic ring fused with an aryl or heteroaryl ring;
  • R 7 (when not taken together with R 2 ) and R 8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl, aryloxy, aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl;
  • NR 7 and R 8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
  • R 5 is selected from the group consisting of H, hydroxy, alkoxy, cycloalkyl, and alkyl;
  • a 1 is — N ⁇ NR 7
  • Y 2 is selected from the group consisting of alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;
  • Zi is selected from the group consisting of CH 2 , O, CH 2 0, NR k , CO, S, SO, CH(OH) and S0 2 , wherein R k is selected from H or lower alkyl;
  • Z 2 is a 1 -5 carbon linker optionally containing one or more heteroatom selected from the group consisting of O, S and N; alternatively Z - Z 2 may further contain a carboxamide, sulfone, sulfonamide, alkenyl, alkynyl, or acyl group;
  • carbon and nitrogen atoms of Z-i - Z 2 are optionally substituted by alkyl, cycloalkyl, alkoxy, thioalkyl, alkylsulfone, aryl, arylsulfone, alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalkyl or acylamino;
  • n is an integer 1 or 2;
  • R c is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino, sulfonyl, sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and -(CH 2 ) n COR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;
  • X is selected from the group consisting of -CHR e -, -NR -, -0-, -S-, -S0 2 -, and -CO- wherein R e is H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl or aryl; wherein when R e is hydroxy, the hydroxy group can optionally form a lactone with the carboxylic acid function of the chain; wherein R is selected from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, arakylheteroaryl, and haloalkyl; Y is selected from the group consisting of (CH 2 ) P , -CR 9 -, -NR 9 , CO and SO 2 , wherein R g is selected from the group consisting of H, alkyl,
  • the group X-Y can contain a moiety selected from the group consisting of acyl, alkyl, sulfonyl, amino, ether, thioether, carboxamido, sulfonamido, aminosulfonyl and olefins;
  • Y 3 and Y 4 are independently selected from the group consisting of alkyl, haloalkyl, hydroxy, alkoxy, cyano, halogen, aralkyl, hetero- aralkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, alkyisulfone, alkene or alkyne; wherein the alkyl group optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
  • Y 4 when Y 3 is an aryl or a heteroaryl, Y 4 may be an aryl, heteroaryl, alkene, alkyne, alkoxy, hydroxy, cyano, alkoxyalkyl or an alkyisulfone;
  • Y 5 is C
  • Y 3 , Y 4 and Y 5 may form a sulfone (S0 2 ) group;
  • Y 3 taken together with Y 4 forms a 3-8 membered monocyclic or a 7- 11 membered bicyclic ring, optionally containing one or more double bonds, optionally containing one or more heteroatom or functional group selected from O, NR g , S, CO or S0 2 , optionally substituted with one or more substituent selected from the group consisting of alkyl, heteroalkyl, hydroxy, halogen, haloalkyl, alkoxy, alkyne, cyano, alkyisulfone, sulfonamide, aryl, heteroaryl, arakylaryl, heteroarakyl- arylcarboalkoxy and carboxyalkyl;
  • R b is X 2 - R h wherein X 2 is selected from the group consisting of O, S and NR J wherein R h and R J are independently selected from the group consisting of H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl,
  • compositions comprising compounds of the Formula I.
  • Such compounds and compositions are useful in selectively inhibiting or antagonizing the ⁇ v ⁇ and/or ⁇ v ⁇ s integrins and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the ⁇ v ⁇ 3 and/or ⁇ v ⁇ s integrin.
  • the invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment.
  • pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment.
  • the present invention relates to a class of compounds represented by the Formula I, described above.
  • a 4-8 membered monocyclic or a 7-12 membered bicyclic ring optionally saturated or unsaturated, optionally substituted with one or more substituent selected from the group consisting of lower alkyl, alkynyl, alkenyl, halogen, alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino or methylsulfonamide.
  • a 1 is a 5-9 membered monocyclic or 7-12 membered bicyclic heterocycle of the formula
  • Z a is H, alkyl, alkoxy, hydroxy, amine, alkylamine, dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or haloalkyl and R 1 is H, alkyl, alkoxyalkyl, acyl, haloalkyl or alkoxycarbonyl.
  • some examples include pyridylamino, imidazolylamino, morpholinopyridine, tetrahydronaphthyridine, oxazolylamino, thiazolylamino, pyrimidinylamino, quinoline, tetrahydroquinoline, imidazopyridine, benzimidazole, pyridone or quinolone.
  • the following heteroaryls include the ring systems described above.
  • the substituents X 4 and X 5 are selected from the group consisting of H, alkyl, branched alkyl, alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano or acylamino groups.
  • the substituents X 4 and X 5 can be methyl, methoxy, amine, methylamine, trifluoromethyl, dimethyl- amine, hydroxy, chloro, bromo, fluoro and cyano.
  • X 6 may preferentially be H, alkyl, hydroxy, halogen, alkoxy and haloalkyl.
  • the pyridyl ring can be fused with a 4 - 8 membered ring, optionally saturated or unsaturated.
  • ring systems include tetrahydronaphthyridine, quinoline, tetrahydroquinoline, azaquinoline, morpholino- pyridine, imidazopyridine and the like.
  • the monocyclic ring systems such as imidazole, thiazole, oxazole, pyrazole, and the like, may contain an amino or alkylamino substituent at any position within the ring.
  • the linkage A 1 -Z 2 of Formula I includes the heterocycle derived ring systems such as: pyridine, imidazole, thiazole, oxazole, benzimidazole, imidazopyridine and the like.
  • heterocycles for A 1 -Z 2 of the present invention include
  • Y and Y are as defined above; or
  • Y 3 taken together with Y 4 forms a 3-8 membered monocyclic or a 7- 11 membered bicyclic ring, optionally containing one or more double bonds, optionally containing one or more heteroatoms or functional groups selected from O, NR g , S, CO or S0 2 , optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, halogen, haloalkyl, alkoxy, alkyne, cyano, alkyisulfone, sulfonamide, carboalkoxy and carboxyalkyl; wherein R g is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, aryl, heteroaryl, aralkyl, and carboxyalkyl.
  • the invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formulal .
  • the invention also relates to a method of selectively inhibiting or antagonizing the ⁇ v ⁇ integrin and/or the ⁇ v ⁇ s integrin and more specifically relates to a method of inhibiting bone resorption, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I to achieve such inhibition together with a pharmaceutically acceptable carrier.
  • alkyl or “lower alkyl” refer to a straight chain or branched chain hydrocarbon radicals having from about 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms.
  • alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
  • alkenyl or “lower alkenyl” refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
  • alkynyl or “lower alkynyl” refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • cycloalkyl as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms.
  • examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1 -yl, and the like.
  • aryl denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like.
  • cyano is represented by a radical of the
  • lower alkylene or “alkylene” as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms.
  • alkoxy refers to straight or branched chain oxy containing radicals of the formula -OR 20 , wherein R 20 is an alkyl group as defined above. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t- butoxy and the like.
  • arylalkyl or “aralkyl” refer to a radical of
  • aryl as defined above and R 22 is an alkylene as defined above.
  • aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.
  • nitro is represented by a radical of the
  • halo or halogen refers to bromo, chloro, fluoro or iodo.
  • haloalkyl refers to alkyl groups as defined above substituted with one or more of the same or different halo groups at one or more carbon atom.
  • haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like.
  • carboxyl or “carboxy” refers to a radical of the formula -COOH.
  • carboxyl ester refers to a radical of the formula -COOR 23 wherein R 23 is selected from the group consisting of H, alkyl, heteroalkyl, heteroaryl, heteroaralkylalkyl, aralkyl or aryl as defined above.
  • carboxyl derivative refers to a radical of the ⁇ 3
  • Y 6 and Y 7 are independently selected from the group consisting of O, N or S and R 23 is selected from the group consisting of H, alkyl, aralkyl, heteroalkyl, heteroaryl, heteroaralkylalkyl or aryl as defined above.
  • amino is represented by a radical of the formula -NH 2 .
  • alkylsulfonyl or “alkyisulfone” refers to a O
  • R 24 is alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl as defined above.
  • alkylthio refers to a radical of the formula SR 24 wherein R 24 is alkyl or heteroalkyl as defined above.
  • R 25 is alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl as defined above.
  • sulfonamide or “sulfonamido” refers to a
  • fused aryl refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings. Embraced by the term “fused aryl” is the radical naphthyl and the like.
  • monocyclic heterocycle or “monocyclic heterocyclic” refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen.
  • monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like.
  • fused monocyclic heterocycle refers to a monocyclic heterocycle as defined above with a benzene fused thereto.
  • fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
  • R 19 is H, alkyl, aryl, heteroalkyl, heteroaryl, heteroaralkyl, alkyl or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
  • 5-membered optionally substituted heteroaromatic ring includes for example a radical of the formula
  • benzimidazole Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole.
  • the term "bicycloalkyl” refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated.
  • acyl refers to a radical of the formula
  • R 26 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterc- alkyl, heterocycloalkyl, or aralkyl and optionally substituted thereon as defined above.
  • R 26 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterc- alkyl, heterocycloalkyl, or aralkyl and optionally substituted thereon as defined above.
  • R 26 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterc- alkyl, heterocycloalkyl, or aralkyl and optionally substituted thereon as defined above.
  • acetyl benzoyl and the like.
  • thio refers to a radical of the formula
  • sulfonyl refers to a radical of the formula
  • R is alkyl, aryl, heteroalkyl, heteroaryl, heteroaralkylalkyl or aralkyl as defined above.
  • haloalkylthio refers to a radical of the formula -S-R 28 wherein R 28 is haloalkyl as defined above.
  • aryloxy refers to a radical of the formula 5 wherein R 29 is aryl or heteroaryl as defined above.
  • acylamino refers to a radical of the formula
  • R 30 is alkyl, heteroalkyl, heteroaryl, hetero- aralkylalkyl, aralkyl or aryl as defined above.
  • alkylamino refers to a radical of the formula -NHR 32 wherein R 32 is alkyl or heteroalkyl as defined above.
  • dialkylamino refers to a radical of the formula -NR 33 R 34 wherein R 33 and R 34 are the same or different alkyl or cycloalkyl groups as defined above.
  • trifluoromethyl refers to a radical of the
  • trifluoroalkoxy refers to a radical of the
  • alkylaminosulfonyl or “aminosulfonyl”
  • alkylsulfonylamino or ""alkylsulfonamide
  • R refers to a radical of the formula20 wherein R is alkyl, heteroalkyl, heterocycloalkyl, or cycloalkyl as defined above.
  • trifluoromethylthio refers to a radical of the
  • trifluoromethylsulfonyl refers to a radical
  • 4-12 membered mono-nitrogen containing monocyclic or bicyclic ring refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a mono or bicyclic ring of 4-9 atoms wherein one atom is nitrogen.
  • Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.
  • the term "4-12 membered mono-nitrogen containing monosulfur or monooxygen containing heterocyclic ring” refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur.
  • arylsulfonyl or “arylsulfone” refers to a
  • alkylsulfoxide or arylsulfoxide refer to
  • R 38 is, respectively, alkyl, heteroalkyl, heteroaryl or aryl as defined above.
  • arylthio refers to a radical of the formula
  • R 42 is aryl as defined above.
  • R 43 is a monocyclic heterocycle radical as defined above.
  • alkylcarbonyl refers to a radical of the O
  • R 50 formula R ⁇ C 31 wherein R 50 is alkyl, heteroaryl, heterocycloaryl or cycloalkyl as defined above.
  • arylcarbonyl refers to a radical of the O
  • aryloxycarbonyl refers to a radical of the O
  • haloalkoxycarbonyl refers to a radical of O
  • alkylthiocarbonyl refers to a radical of the O ⁇ ⁇ en formula ° ° 37wherein R is alkyl or cycloalkyl as defined above.
  • arylthiocarbonyl refers to a radical of the
  • acyloxymethoxycarbonyl refers to a radical
  • arylamino refers to a radical of the formula R 51 -NH- wherein R 51 is aryl as defined above.
  • acyloxy refers to a radical of the formula R 55 -0- wherein R 55 is acyl as defined above.
  • alkenylalkyl refers to a radical of the formula R 50 — R 57 — wherein R 50 is an alkenyl as defined above and R 57 is alkylene as defined above.
  • alkenylene refers to a linear hydrocarbon radical of 1 to about 8 carbon atoms containing at least one double bond.
  • alkoxyalkyl refers to a radical of the formula R 56 ⁇ R 57 ⁇ wherein R 56 is alkoxy as defined above and R 57 is alkylene as defined above.
  • alkynylalkyl refers to a radical of the formula R 59 — R 60 — wherein R 59 is alkynyl as defined as above and R 60 is alkylene as defined as above.
  • alkynylene refers to divalent alkynyl radicals of 1 to about 6 carbon atoms.
  • aminoalkyl refers to a radical of the formula H 2 N-R 61 wherein R 61 is alkylene as defined above.
  • benzoyl refers to the aryl radical C 6 H 5 -CO-.
  • carboxylate or “carboxamido” refer to a radical of the formula -CO-NH 2 .
  • Carboxyalkyl refers to a radical HOOC--R 62 — wherein R 62 is alkylene as defined as above.
  • carboxylic acid refers to the radical -COOH .
  • ether refers to a radical of the formula
  • R O wherein R 63 is selected from the group consisting of alkyl, aryl and heteroaryl.
  • haloalkylsulfonyl refers to a radical of the O
  • heteroaryl refers to an aryl radical contain at least one heteroatom.
  • hydroxyalkyl refers to a radical of the formula HO— R _. wherein R 65 is alkylene as defined above.
  • keto refers to a carbonyl group joined to 2 carbon atoms.
  • lactone refers to an anhydro cyclic ester produced by intramolecular condensation of a hydroxy acid with the elimination of water.
  • olefin refers to an unsaturated hydrocarbon radical of the type C n H 2 n.
  • R is alkyl or cycloalkyl as defined above.
  • thioalkyl refers to a radical of the formula
  • R -S wherein R 78 is alkyl, aryl or heteroaryl.
  • trifluoroalkyl refers to an alkyl radical as defined above substituted with three halo radicals as defined above.
  • composition means a product which results from the mixing or combining of more than one element or ingredient.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
  • terapéuticaally effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • a tissue, system or animal that is being sought by a researcher or clinician.
  • CH 3 CN acetonitrile
  • CH3I iodomethane
  • CHN analysis carbon/hydrogen/nitrogen elemental analysis
  • CHNCI analysis carbon/hydrogen/nitrogen/chlorine elemental analysis
  • CHNS analysis carbon/hydrogen/nitrogen/sulfur elemental analysis
  • DIAD diisopropylazodicarboxylate
  • DMA N.N-dimethylacetamide
  • DMAC N ( N-dimethylacetamide
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • hplc high performance liquid chromatography
  • HPLC high performance liquid chromatography
  • IPA isopropyl alcohol
  • i-Pr iso propyl
  • i-Prop iso propyl
  • KOH potassium hydroxide
  • KSCN potassium thiocyanate
  • NaOH sodium hydroxide
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • a bond drawn across a bond of a ring can be to any available atom on the ring, a ring can be to any available atom on the ring.
  • pharmaceutically acceptable salt refers to a salt prepared by contacting a compound of Formula I with an acid whose anion is generally considered suitable for human consumption.
  • pharmacologically acceptable salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, propionate, lactate, maleate, malate, succinate, tartrate salts and the like.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; or alkaline earth metal salts. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Pharm. Sci..
  • the present invention includes within its scope prodrugs of compounds of Formula I.
  • These prodrugs are typically derivatives of the compounds of Formula I which are convertible to the active compounds on in-vivo exposure. These compounds may be derivatives of carboxylic acid (such as ester, amide, orthoester, urea and the like). Similarly derivatives of amine, hydroxy or other functional groups may be used as handles for pro- drug formation.
  • administering a compound for treatment of various conditions would include compounds specifically disclosed or the compounds which may not be specifically disclosed but would be converted to the specifically disclosed compound of Formula 1 on in-vivo administration.
  • the methods described in literature e.g., Design of pro-drugs, H.
  • the compounds of the present invention may be chiral or achiral.
  • compounds of the present invention may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, transmuscular infusion techniques or intraperitonally.
  • the compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the tre atment intended.
  • Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the ⁇ v ⁇ and/or ⁇ v ⁇ ⁇ Cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in the above formulas, wherein one or more compound is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and if desired other active ingredients. More specifically, the present invention provides a method for inhibition of the ⁇ v ⁇ 3 and/or ⁇ v ⁇ s cell surface receptors.
  • the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget's disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating retinopathy including macular degeneration and diabetic retinopathy, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
  • the compounds of Formula I can be used in the treatment of patients suffering from the above pathological conditions.
  • selection of the most appropriate compound of the invention is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models.
  • Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound of the Formula I which is therapeutically effective in controlling the condition or in prolonging the survivability of the patient beyond that expected in the absence of such treatment.
  • the term "inhibition" of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent.
  • the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these compounds are useful in prevention or treatment of any disease state or condition wherein the ⁇ v ⁇ 3 and/or ⁇ v ⁇ s integrin plays a role.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 1.0 mg/kg/day.
  • compositions are preferably provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient.
  • the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regiment.
  • the compounds in a therapeutically effective amount are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
  • the present invention provides treatment or prevention of a neoplasia disease in a mammal by combining one or more ⁇ v ⁇ 3 integrin antagonists of the present invention with one or more chemotherapeutic agents.
  • chemotherapeutic agents that may be used in combination with the ⁇ v ⁇ 3 antagonist compounds include but are not limited to 5-fluorouacil, cyclophosphamide, cisplatin, taxol, and doxorubicin are preferred.
  • chemotherapeutics useful in combination and within the scope of the present invention include but are not limited to buserelin, topoisomerase inhibitors such as topotecan and irinotecan, mitoxantrone, BCNU, CPT-11 , chlorotranisene, chromic phosphate, gemcitabine, dexamethasone, estradiol, estradiol valerate, estrogens conjugated and esterified, estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea, carboplatin, melphalan, methotrexate, mitomycin and prednisone.
  • buserelin topoisomerase inhibitors
  • topoisomerase inhibitors such as topotecan and irinotecan
  • mitoxantrone BCNU, CPT-11
  • chlorotranisene chromic phosphate
  • gemcitabine gemcitabine
  • dexamethasone estradiol, estradi
  • the methods and combinations using one provide treatment or prevention of a neoplasia disease in a mammal using one or more ⁇ v ⁇ 3 integrin antagonists described above with one or more chemotherapeutic agents described above.
  • the method comprises treating a mammal with a therapeutically effective amount of an ⁇ v ⁇ 3 integrin antagonist in combination with a chemotherapeutic agent.
  • chemotherapeutic agents there are five major classes of chemotherapeutic agents currently in use for the treatment of cancer: natural products and their derivatives; anthracyclins; alkylating agents; antimetabolites; and hormonal agents. Chemotherapeutic agents are often referred to as antineoplastic agents. The alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases.
  • Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cislatin, and various nitrosoureas.
  • a disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa and fetal tissue.
  • Antimetaloties are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids.
  • 5-fluorouacil A well-known nucleoside derivative with strong anticancer activity is 5-fluorouacil.
  • 5-fluorouacil has been used clinically in the treatment of malignant tumors, including, for example, carcinomas, sarcomas, skin cancer, cancer of the digestive organs, and breast cancer.
  • 5-fluoroucil causes serious adverse reactions such as nausea, alopecia, stomatites, leukocytic thrombocytopenia, anorexia, pigmentation and edema.
  • Cytosine arabinoside also referred to as Cytarabin, araC, and
  • Cytosar is a nucleoside analog of deoxycytidine that was first synthesized in 1950 and introduced into clinical medicine in 1963. It is currently an important drug in the treatment of acute myeloid leukemia. It is also active against acute lymphocytic leukemia, and to a lesser extent, is useful in chronic myelocytic leukemia and non-Hodgkin's lymphoma.
  • Table 1 provides illustrative examples of median dosages for selected cancer agents that may be used in combination with a v ⁇ 3 integrin antagonist agent. It should be noted that the specific dose regimen for the chemotherapeutic agents below will depend upon dosing considerations based upon a variety of factors including the type of neoplasia; the state of the neoplasm, the age, weight, sex and medical condition of the patient; the route of administration, the renal and hepatic function of the patient; and the particular combination employed.
  • compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
  • the compounds of formula A- ⁇ 7 are generally prepared by reacting an intermediate of formula A ⁇ 6 with a compound of the formula A 15 .
  • Z 3 and Z 4 are both OH, the ether formation to product A 17 may be accomplished by using Mitsunobu reaction.
  • This reaction may preferentially be carried out using triarylphosphine (such as triphenylphoshine) and azodicarboxylate (such as diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propyl azodicarboxylate) in solvents such as DMF, methylene chloride, THF and the like.
  • triarylphosphine such as triphenylphoshine
  • azodicarboxylate such as diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propyl azodicarboxylate
  • solvents such as DMF, methylene chloride, THF and the like.
  • the compounds of formula A17 may be prepared by starting with compounds of general formula A ⁇ 8 .
  • Z 5 in A 1 8 is NH 2
  • cyclic or acyclic guanidino containing compounds of formula A- ⁇ 7 may be synthesized by adopting the methodologies discussed in e. g. U. S. Patent 5,852, 210 or U. S. Patent 5,773,646.
  • heteroaromatic system such as 2-fluoropyridine or 2-chloropyridine N- oxide
  • This reaction may preferentially be carried out by refluxing the intermediate A ⁇ 8 and 2-halopyridine N-oxide (such as 2-chloropyridine N-oxide) in solvents such as tert-butyl alcohol, tert-amyl alcohol in the presence of a base (such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate).
  • 2-halopyridine N-oxide such as 2-chloropyridine N-oxide
  • solvents such as tert-butyl alcohol, tert-amyl alcohol
  • a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate
  • R H or alkyl
  • Compounds of the formula A 4 containing a methyl substituent may be prepared by starting with substituted propiophenone A-i.
  • Generation of enolate with a base such as HMDS, LDA, NaH, KH
  • an electrophile such as ethyl bromoacetate
  • Base hydrolysis of the ester using e.g; 1 N NaOH
  • repetition of the enolate chemistry using excess of a base (such as HMDS, LDA, NaH, KH) followed by reaction with electrophile (such as alkyl iodide, or benzyl halide) gives the intermediate A 3 .
  • esterification of the resulting acid with an alcohol in the presence of drops of acid gives the desired ester intermediate A 3 .
  • Deoxygenation of carbonyl group gives the intermediate A 4 .
  • This transformation may be carried out using catalytic hydrogenation conditions in the presence of an acid (such as phosphoric acid). Palladium on carbon and hydrogen under 5-60 psi can be used to achieve this reduction .
  • the intermediates A 3 and A 4 are processed to the target compounds of Formula I by synthetic transformations outlined in Scheme 1.
  • the compounds of Formula I, wherein A is substituted pyridyl may be prepared by adopting the general synthetic Scheme 3.
  • reaction of substituted 2-halopyridine ⁇ /-oxide such as A ⁇ g a -Ai 9d
  • e. g. 3-aminopropanol gives the intermediates A 2 o a -A 2 o d -
  • This reaction may preferentially be carried out by refluxing the intermediate 2-halopyridine N- oxide (such as 2-chloropyridine N-oxide) in solvents such as tert-butyl alcohol, tert-amyl alcohol in the presence of base (such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate).
  • N-Deoxygenation of the resulting intermediates followed by hydrolysis of the ester gives the target compounds (A 2 - ⁇ a -A2id)- Reduction of the N-oxide bond may be accomplished using e. g., transfer hydrogenation (cyclohexene/Pd on carbon) or ammonium formate and Pd on carbon or iron powder and acetic acid.
  • the nitro group in 21 may be hydrogenated using Pd on carbon or Pt on carbon as catalysts. This transformation may be carried out using solvents such as methanol, ethanol or THF.
  • the hydrolysis of the ester group may be carried out using aqueous base (such as sodium hydroxide, lithium hydroxide or potassium hydroxide) in solvents such as methanol, ethanol and THF.
  • aqueous base such as sodium hydroxide, lithium hydroxide or potassium hydroxide
  • the above compound was prepared from the product prepared in STEP 2 (450mg) using the same procedure as described in STEP 4, EXAMPLE 1.
  • the crude product was purified on a silica gel column eluting with 97% CH 2 CI 2 -2.5% CH 3 OH-0.5% NH 4 OH to afford a viscous oil (314 mg).
  • the 1 H NMR was consistent with the proposed structure.
  • the above compound was prepared from the product of STEP 3 (305 mg) using the procedure described in STEP 5, EXAMPLE 1.
  • the crude product was purified on a silica gel column eluting with 98% CH 2 CI 2 -1.5% CH 3 OH- 0.5% NH 4 OH to afford a viscous colorless oil (160 mg).
  • the 1 H NMR was consistent with the proposed structure.
  • the reaction mixture was quenched with concentrated hydrochloric acid (50 mL). The mixture was extracted with ether and water. The organic phase was dried and concentrated. An ether solution of the residue was treated with excess diazomethane in ether 0 °C. The resulting solution was concentrated in vacuo and the residue was purified by chromatography over silica gel using 10% ethyl acetate in hexane as eluant to provide the above compound as a colorless thick liquid.
  • tert-butyl 6-methylpyridin-2-ylcarbamate A solution of di-tert-butyl dicarbonate (32 g, Aldrich), 2-amino-6-picoline (15 g, Aldrich) and ether (20 mL) was allowed to stand at ambient temperature for 4 days. The volatiles were removed. The residue was purified by chromatography to give the above product as a white solid.
  • the diol (4.38 g; 42.9mmoles) from the previous step was dissolved in pyridine (42.9 mL). To this solution was added, in a dropwise fashion, thionyl chloride (6.2 mL). After the addition the solution was stirred at 25°C for 1 hour and the reaction mixture was filtered through a coarse fritted funnel. The precipitate was washed with fresh pyridine and the filtrates were concentrated to dryness. The resulting residue was diluted with anhydrous ether (450 mL) which caused a solid precipitate to form. The solution was decanted away from the solid and then washed with 6N aqueous HCI solution and a saturated solution of sodium bicarbonate.
  • the starting cyclic sulfite (4.9625 g; 37.5 mmoles) produced in STEP 2 was dissolved in dry DMF (37mL). To this solution was added sodium cyanide (2.01 g; 41.2 mmoles) and sodium iodide (1.12 g; 7.5 mmoles). The solution was heated to 70°C. After four days, the reaction mixture was diluted with toluene (59 mL) and then water (0.89 mL) was added slowly. The resulting yellow precipitate was filtered and washed with fresh toluene.
  • the aldehyde from STEP 4 was dissolved in anhydrous ether (50 mL). To this solution was added 30.8 mL of a 0.5 M solution of 4-methoxyphenyl- magnesium bromide in tetrahydrofuran in a dropwise fashion over 1 hour at -30°C. After 1hour, the reaction mixture was poured into a cold sulfuric acid solution (prepared by pouring 30 mL of concentrated sulfuric acid onto 250 g of crushed ice then adding 250mL of water). The aqueous solution was extracted with ether. The ether extracts were washed with a saturated solution of sodium bicarbonate followed by brine and the organic extracts were dried (MgS0 4 ).
  • the hydroxynitrile (3.0 g; 13.8 mmole) prepared in STEP 5 was suspended in 10 ml of a 1.68 M aqueous potassium hydroxide solution.
  • the reaction was heated overnight to 80 °C. The temperature was raised to 100 °C. The traces of organic solvent left in the product from the previous step prevented the reaction to reach the required temperature so it was removed under reduced pressure.
  • the resulting solution was heated overnight to 80 °C and by tic , the following day, the reaction went to completion.
  • the reaction was worked up by extracting it with ether.
  • the aqueous layer was acidified to pH 6 then extracted with ethyl acetate then methylene chloride.
  • the tic was taken on the extracted aqueous layer and it was noted that UV activity was present.
  • the carboxylic acid (706 mg; 3.26 mmoles) obtained from the previous step was dissolved in anhydrous methylene chloride (3.5mL) and cooled to 0 °C. To this solution was added a 1 M solution of boron tribromide in methylene chloride (7.35 mL) all at once. The solution turned a red-brown color. After 30-40 minutes at 0 °C, water (9 mL) was added along with additional methylene chloride until the layers cleanly separated. The aqueous layer was extracted once with methylene chloride and several times with ethyl acetate.
  • the crude acid (586 mg; 2.90 mmoles) isolated from the previous step was dissolved in absolute ethanol (5 mL) and 4N HCI in dioxane (5 mL) at 25°C. After stirring for 12 hours, the reaction mixture was evaporated to dryness under reduced pressure. The crude oil was redissolved in ethylacetate and washed with a saturated solution of aqueous sodium bicarbonate then washed with brine. The organic extracts were dried (MgS0 4 ), filtered and evaporated under reduced pressure to give a brown oil (609 mg). The oil was dissolved in anhydrous ether, which caused the brown color to precipitate out of solution. The precipitate was filtered away which resulted in a yellow oil (550 mg; 82% yield), which was taken to the next step without further purification. The 1 H NMR spectrum was consistent with the structure of the desired product.
  • the reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (Si0 2 ; 100% ethyl acetate then 92 CH 2 CI 2 /8IPA 0.5% acetic acid) to give a yellow oil (239 mg; 50% yield).
  • This material was converted to the free base by dissolving the yellow oil in absolute ethanol (1ml) and then adding concentrated ammonium hydroxide (0.33 mL). This was followed by concentrating down the solution under reduced pressure then subjecting the resulting residue to high vacuum for 1 hour to give a pink oil (203 mg).
  • the 1 H NMR spectrum was consistent with the structure of the desired product.
  • the compound (5g; 16 mmol) isolated from STEP 1 was dissolved in MeOH (50mL). THF (10mL) was added to help solubilize the compound, which was followed by the addition of 20% palladium hydroxide on carbon (1g).
  • the reaction mixture was charged into 250mL hydrogenation bottle and shaken in a Parr hydrogenation apparatus at 25°C for 1 hour.
  • the catalyst was removed by filtration and washed with methanol (2 x 20mL). The washes and filtrate were combined and concentrated under reduced pressure to give the desired product (3.01 g; 75% yield).
  • the reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (Si0 2 ; 100% ethyl acetate then 92 CH 2 CI 2 /8IPA 0.5% acetic acid) to give a yellow oil (239 mg; 50%).
  • This material was converted to the free base by dissolving the yellow oil in absolute ethanol (1ml) and then adding concentrated ammonium hydroxide (0.33 mL).
  • the mixture was concentrated under reduced pressure and the resulting residue was subjected to high vacuum for 1 hour to give the desired compound (189mg; 44% yield).
  • the 1 H NMR spectrum was consistent with the structure of the desired product.
  • the desired pyridine-N-oxide (189 mg; 0.465 mmoles) isolated from STEP 3 was dissolved in isopropanol (4.4 mL). To this solution was added 10% palladium on carbon (46mg) followed by cyclohexene (0.44 mL). After 2 hours, the TLC showed no reaction. Equivalent quantities of catalyst and cyclohexene were added. Some THF was added to enhance solubility of the starting material. The following day tic indicated both product and starting material were present. The catalyst and cyclohexene (quantities used are stated above) were added. By 6 hours, the reaction was complete. The reaction mixture was filtered through celite and the filtrates were concentrated under reduced pressure.
  • the reaction was stirred at -10 °C for 1 hour, and then gradually warmed to 30-35 °C. After 1 hour, the reaction mixture was quenched with a saturated NH 4 CI solution (120 ml). The solvents were partially removed under reduced pressure. A 5% aqueous NaOH solution was added to adjust the pH to 12. The mixture was washed with ether (3x150 ml). The aqueous layer was acidified with concentrated HCI, and thoroughly extracted with CH 2 CI (3x150 ml). The combined CH CI 2 layers were dried with Na 2 S0 4 , and concentrated to give the crude product mixture (12.1 g). The 1 H-NMR spectrum was consistent with the proposed structure.
  • a lithium bis(trimethylsilyl)amide solution (40.3 ml, 40.3 mmoles, 1 M in THF) was added to the reaction over 15 minutes at -78 °C.
  • the reaction was warmed to -20 °C and then cooled to -78 °C.
  • a solution of s-butyl lithium (62 ml, 80.6 mmoles, 1.3M in cyclohexane) was added at -60°C over 20 minutes.
  • the reaction was warmed to -20°C.
  • a solution of n-butyl lithium (16.1 ml, 40.3 mmoles, 2.5M in hexane) was added.
  • the reaction was allowed to warm to room temperature, and stirred for 1 hour.
  • Triphenyl phosphine (0.51 g, 1.97 mmoles) was added to a solution of the product from STEP 4 (0.35 g, 1.41 mmoles) in THF (20 ml) at 0°C.
  • Diethyl azodicarboxylate (0.31ml, 1.97 mmoles) was added to above solution at 0°C under Argon. The resulting solution was stirred at 0°C for 20 minutes.
  • 2-(3-hydroxypropylamino)pyridine N-oxide (0.26 g, 1.55 mmoles) was added to the reaction at 0°C over 15 minutes. The reaction was allowed to warm to 25°C and stirred for 18 hours.
  • a boron tribromide solution (2.97 ml, 1 M in CH 2 CI 2 ) was added dropwise to a solution of product from STEP 3 (0.62 g) in CH 2 CI 2 (8 ml) at 0°C. The cold bath was removed. After 20 minutes, ethanol (8 ml) was added to the reaction. The resulting mixture was stirred at room temperature for 30 minutes. The solvents were removed from the reaction under reduced pressure. The residue was diluted with ethyl acetate (100 ml), and washed with a saturated aqueous NaHC0 3 solution (50 ml). The aqueous layer was extracted with ethyl acetate (2x20 ml).
  • Triphenyl phosphine (0.393 g, 1.5 mmoles) was added to a solution of the product from STEP 4 (0.28 g, 1.07 mmoles) in THF (15 ml) at 0°C.
  • Diethyl azodicarboxylate (0.24 ml, 1.5 mmoles) was added to above solution at 0°C under argon. The resulting solution was stirred at 0°C for 20 minutes.
  • 2-(3- hydroxypropylamino)pyridine N-oxide (0.197 g, 1.17 mmoles) was added to the reaction over 15 minutes. The reaction was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed from the reaction mixture under reduced pressure to give an oily residue.
  • the reaction mixture was diluted with water (15.0 mL) and extracted with EtOAc (3 x 10 mL) to remove the thiol containing bye-products.
  • the aqueous phase was acidified with citric acid and extracted with EtOAc (3 x 15 mL).
  • the combined organic extracts were washed with water, dried (anhydrous Na2S04), and concentrated to dryness to give the title compound as a white solid (0.18 g, 56%).
  • the acid from STEP 3 (0.5 g) was suspended in absolute EtOH (3.0 mL), added 4N HCl/dioxane (2.0 mL) and stirred overnight at room temperature, and heated to reflux for 1 h. The solution was concentrated to dryness and the residue was dissolved in EtOAC (15 mL), washed with water, dried and concentrated to dryness. The resulting syrup (0.4 g) was dissolved in EtOH (10 mL), added acetic acid (0.1 mL), Pd/C (10%, 0.25 g), and stirred in an atmosphere of hydrogen gas at 50 psi at room temperature . After 16 h, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure.
  • reaction mixture was cooled, diluted with water (1.0 mL), acidified with trifluoroacetic acid and purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 70 mL/min.
  • Example 13 The product of STEP 1 , Example 13 (0.987 g, 3.0 mmol) was dissolved in methylene chloride (10 ml) and was cooled to 0 C and 1 M boron tribromide in methylene chloride (6.0 ml) was added. The mixture was stirred at 0 C for 30 minutes under nitrogen atmosphere. The reaction mixture was quenched with ethanol (2.0 ml) and was warmed to room temperature and was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate and was washed with a saturated solution of sodium bicarbonate and water, dried over Na 2 S0 . The solid was filtered and.
  • the product of STEP 4 (150mg ) was dissolved in a mixture of 1.5 ml methanol and 1.5 ml of THF and 1.5 ml of 1 N NaOH solution was added. The reaction mixture was stirred at ambient temperature for 5 hours. The volatile solvents were removed under vacuo and remaining aqueous solution was acidified with 1.5 ml of 1 N HCI and was concentrated in vacuo to give a crude product. The crude product was purified on HPLC using acetonitrile Water gradient 10-50% in 30 min to yield 89 mg of the title compound as TFA salt.
  • the cude product was purified by flash chromatography on silica gel (EtOAc/Hexane/NH 4 OH : 80/19.5/0.5) to give 181 mg of desired compound as oily gum. . NMR spectrum was consistent for the proposed structure.
  • N-methyl morpholine-N-oxide (1.036 g, 2.94 mmol) and powdered 4 angstrom molecular sieves (2.945 g) were added to a solution of the product of STEP 3 (2.08 g, 5.89 mmol) in 82 ml of dichloromethane.
  • Tetrapropylammonium perruthenate (103.6 mg, 0.29 mmol) was added at 0 °C, and the reaction was allowed to warm to room room temperature. After 1.5 h, the reaction was filtered through a short column of silica gel (2") and washed with CH 2 CI /MeOH (9/1).
  • Lithium bis(trimethylsilyl) amide solution (4.6 ml, 4.6 mmol, 1.0M in THF) was added to a mixture of methoxymethyltriphenyl phosphonium chloride (1.58 g, 4.6 mmol) in 9 ml of THF dropwise at 0°C. After 15 min, it was added to a solution of the product of STEP 4 (1.95 g, 7.08 mmol) in 6 mL of THF at 0°C. The reaction was stirred for 1 h and quenched with H 2 0. The product was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane.
  • Silver nitrate (0.648 g, 3.82 mmol) was dissolved in 1 ml H 2 0 and added to a solution of the product of step 5 (0.698 g, 1.91 mmol) in 9 ml ethanol.
  • a solution resulting from dissolving of NaOH (0.301 g, 7.6 mmol) in 1.73 ml of H 2 0 was added dropwise, then the reaction was stirred at room temperature for 2 h.
  • the reaction was diluted with 7 ml H 2 0 and then the ethanol was evaporated and then the resulting solution extracted with ethyl acetate.
  • the organic extracts were washed with brine, dried with MgS0 4 , and concentrated to afford 0.371 gr of an oil.
  • the oil was dissolved in 10 mL of 4N HCI in dioxane and 10 ml of absolute ethanol overnight at 25°C.
  • the reaction was evaporated to dryness then taken up in ethyl acetate and extracted with a saturated solution of aqueous sodium bicarbonate.
  • the organic extracts were washed with brine, dried (MgS0 4 ), filtered and evaporated to give the desired compound.
  • the 1 H NMR spectrum of the product was consistent with the proposed structure.
  • the product from STEP 6 (0.131 g) was dissolved in 25 ml of EtOH, followed by addition of 50 mg of 20% Pd(OH) 2 /C.
  • the reaction mixture was purged with nitrogen (5x), hydrogen (5x) and hydrogenated at 40 psi and room temperature for 2 h.
  • the catalyst was removed by filtration and was washed with 2x20 ml of EtOH. Washes and filtrate were combined and evaporated to dryness to give the desired product.
  • the 1 H NMR spectrum of the product was consistent with the proposed structure.
  • the product from STEP 9 was dissolved in 5 ml methanol and 5 ml 1 N aqueous sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, acidified with trifluoroacetic acid (0.35 ml), and concentrated. The residue was purified by reversed phase HPLC using water-acetonitrile gradient 10-50% in 30 min to yield 107 mg.
  • Trifluoroacetic acid (12.5 ml) was added to a solution of the product from STEP 3 (0.48 g, 1.4 mmol) in 12.5 ml dichloromethane at 0 °C. The reaction was allowed to warm to room temperature. After 2 h, the reaction was concentrated, and dried in vacuo. The residue was dissolved in 20 ml dichloromethane, then triethylamine (1.82 g, 18.0 mmol) and dimethylaminopyridine (30 mg) were added. Acetic anhydride (1.13 ml, 12.0 mmol) was added to the above mixture at 0°C. The reaction mixture was allowed to warm to room temperature.
  • N-methyl morpholine-N-oxide (0.19 g, 1.62 mmol) and powdered 4 angstrom molecular sieves (0.5 g) were added to a solution of the product from STEP 4 (0.3 g, 1.08 mmol) in 15 ml dichloromethane.
  • Tetrapropyl- ammonium perruthenate (19 mg, 0.054 mmol) was added at 0 °C, and the reaction was allowed to warm to room room temperature. After 1.5 h, the reaction was filtered through a short column of silica gel (2") and washed with CH 2 CI 2 /MeOH (9/1).
  • lithium bis(trimethylsilyl)amide solution (10.6 ml, 10.6 mmol, 1.0M in THF) was added dropwise to a solution of methoxy methyltriphenyl phosphonium chloride (3.64 g, 10.6 mmol) in 15 ml -THF at 0°C. After 15 min, this solution was added to a solution of the product of STEP 5 (1.95 g, 7.08 mmol) in 15 ml THF at 0°C. The reaction was stirred for 1 h and quenched with H 2 0. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with H 0, brine, dried with Na.
  • Silver nitrate (1.87 g, 11.0 mmol) was dissolved in 3 ml H 2 0. It was added to a solution of the product from STEP 6 (1.6 g, 5.5 mmol) in 25 ml ethanol. A solution prepared from dissolving NaOH (0.88 g, 22.0 mmol) in 4.0 ml H 2 0 was added dropwise to the silver nitrate solution. The reaction was stirred at 25°C for 2 h. The reaction was diluted with 15 ml H 2 0. The ethanol was removed and the resulting residue was extracted with ethyl acetate (2x60 ml).
  • Diethyl azodicarboxylate (267 mg, 1.53 mmol) was added to a solution of the product from STEP 8 (348 mg, 1.09 mmol) and triphenylphosphine (437 mg, 1.66 mmol) in 3.9 ml THF at 0°C and stirred for 15 min.
  • 2-(3-Hydroxy- propylamino)pyridine N-oxide (418 mg, 2.48 mmol) was added. The reaction was warmed to 40 °C. After 15 min, the reaction was cooled to room temperature and stirred for 18 h.
  • the reaction was stirred at room temperature for 30 min, and quenched with saturated NaHC0 3 solution.
  • the product was extracted with ethyl acetate.
  • Lithium bis(trimethylsilyl) amide solution (55 ml, 55 mmol, 1 M in THF) was added to a mixture methoxy methyl triphenyl phosphonium chloride (18.9 g, 55 mmol) in 65 ml THF dropwise at 0 °C and stirred for 15 min and it was added to a mixture of the product of STEP 3 (7.3 g, 34.7 mmol ) in 35 ml THF dropwise at 0 °C. After 5 min, the reaction was quenched with H 2 0. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate.
  • a solution of Silver Nitrate (5.76 g, 33.9 mmol) in 20 ml H 2 0 was added to a solution of the product of STEP 4 (3.8 g, 16.9 mmol) in 80 ml ethanol.
  • a solution of Sodium hydroxide (2.71 g, 67.7 mmol) in 10 ml H 2 0 was added dropwise at room temperature. After 2 h, the reaction was filtered through a pad of Celite ® . The residue was diluted with H 2 0 and extracted with ether (3 x 30 ml). The aqueous layer was acidified with concentrated HCI and extracted with chloroform. The organic layer was dried with MgS ⁇ 4 and concentrated.
  • a solution of the product of STEP 1 (7.5 g, 42.1 mmol) was dissolved in 50 ml THF and a solution of lithium bis(trimethylsilyl) amide (45 ml, 45 mmol, 1.0 M in THF) was added dropwise at -70 °C.
  • the reaction was stirred at - 70 °C for 1 h and a solution of 4-methoxybenzyl chloride (7.8 g, 50 mmol) in 25 ml THF was added.
  • the reaction was allowed to warm to room temperature and quenched with 5%Na S0 3 solution (200 ml).
  • the product was extracted with ethyl acetate (3x100 ml).
  • a solution of Silver Nitrate (1.73 g, 10.2 mmol) in 5 ml H 2 0 was added to a solution of the product of STEP 5 (1.37 g, 5.1 mmol) in 40 ml ethanol.
  • a solution of Sodium hydroxide (0.816 m g, 20.4 mmol) in 5 ml H 2 0 was added dropwise at room temperature. After 2 h, the reaction was filtered through a short column of Celite ® . The residue was diluted with H 2 0, acidified with 1 N HCI, and concentrated to give 0.7 g yellow solid. This yellow solid was dissolved in 15 ml ethanol and 15 ml 4N HCI in dioxane. The reaction was stirred at room temperature for 18 h.
  • Lithium bis(trimethylsilyl) amide solution (20 ml, 20 mmol, 1 M in THF) was added to a mixture methoxy methyl triphenyl phosphonium chloride (6.9 g, 20 mmol) in 25 ml THF dropwise at 0 °C and stirred for 15 min and it was added to a mixture of the product of STEP 3 (2.6 g, 7.1 mmol ) in 15 ml THF dropwise at 0 °C. After 5 min, the reaction was quenched with H 2 0. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with H 0, brine, dried with Na.
  • a solution of Silver Nitrate (0.722 g, 4.25 mmol) in 2.0 ml H 2 0 was added to a solution of the product of STEP 4 (0.775 g, 2.04 mmol) in 20 ml ethanol.
  • a solution of sodium hydroxide (2.71 g, 67.7 mmol) in 3.0 ml H 2 0 was added dropwise at room temperature. After 6 h, the reaction was filtered through a short column of Celite ® and washed with H 2 0. The filtrate was extracted with ether (3 x 30 ml). The aqueous layer was acidified with concentrated HCI and extracted with chloroform. The organic layer was dried with MgS0 , concentrated and dried in vacuo.
  • the organic layer was separated and the aqueous portion was extracted well with ethyl ether and the combined organic extract was washed with water, brine and dried over MgS0 4 .
  • the crude product was purified on a silica gel column, eluting with 10% ethyl acetate/hexane to afford light yellow oil (6.3 g).
  • the 1 H NMR was consistent with the proposed structure.

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Abstract

Cette invention se rapporte à une classe de composés représentés par la formule (I) ou à un sel de ces composés acceptable sur le plan pharmaceutique, à des compositions pharmaceutiques comprenant ces composés représentés par la formule (I) et à des procédés servant à produire sélectivement un effet inhibiteur ou antagoniste contre l'intégrine αvβ3 et/ou l'intégrine αvβ5.
PCT/US2001/026963 2000-08-30 2001-08-29 Antagonistes de l'integrine $g(a)v$g(b)3 gem-substitues WO2002018340A1 (fr)

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AU2001288515A AU2001288515A1 (en) 2000-08-30 2001-08-29 Gem-substituted alpha v beta 3 integrin antagonists
IL15449601A IL154496A0 (en) 2000-08-30 2001-08-29 GEM-SUBSTITUTED alpha v beta3 INTEGRIN ANTAGONISTS
MXPA03001759A MXPA03001759A (es) 2000-08-30 2001-08-29 Antagonistas de alfa v beta 3 integrina gem-substituidos.
PL01365729A PL365729A1 (en) 2000-08-30 2001-08-29 Gem-substituted alpha v beta 3 integrin antagonists
CA002419699A CA2419699A1 (fr) 2000-08-30 2001-08-29 Antagonistes de l'integrine $g(a)v$g(b)3 gem-substitues
KR10-2003-7003099A KR20030027106A (ko) 2000-08-30 2001-08-29 젬-치환 알파 ｖ 베타 3 인테그린 길항제
EP01968257A EP1313705A1 (fr) 2000-08-30 2001-08-29 Antagonistes gem-substitues d'integrines alpha v beta 3
NZ524159A NZ524159A (en) 2000-08-30 2001-08-29 Gem-substituted alpha v beta 3 integrin antagonists
BR0113671-2A BR0113671A (pt) 2000-08-30 2001-08-29 Antagonistas de integrina alfa v beta 3 gem-substituìda
JP2002523458A JP2004510708A (ja) 2000-08-30 2001-08-29 ＧＥＭ置換αｖβ３インテグリンアンタゴニスト
EA200300226A EA200300226A1 (ru) 2000-08-30 2001-08-29 ГЕМ-ЗАМЕЩЕННЫЕ АНТАГОНИСТЫ ИНТЕГРИНА αvβ3
US10/348,273 US20040043994A1 (en) 2000-08-30 2003-01-21 Gem-substituted alpha v beta 3 antagonists
NO20030925A NO20030925L (no) 2000-08-30 2003-02-27 Gem-substituerte <alfa>v<beta>3-integrinantagonister

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2006043930A1 (fr) * 2004-10-14 2006-04-27 Pharmacia Corporation Antagonistes l'integrine biphenyle
EP1653970A2 (fr) * 2003-08-13 2006-05-10 Chiron Corporation Inhibiteurs de gsk-3 et utilisations
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
CN115087444A (zh) * 2019-10-16 2022-09-20 莫菲克医疗股份有限公司 抑制人整联蛋白α4β7

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CN101880270B (zh) * 2009-05-07 2012-10-03 上海华升生物科技有限公司 一种制备1,1-环丙烷二甲醇环亚硫酸酯的方法

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EP0478363A2 (fr) * 1990-09-27 1992-04-01 Merck & Co. Inc. Nouveaux sulfonamides comme antagonistes des récepteurs fibrinogéniques
WO1997024124A1 (fr) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine
WO1999005107A1 (fr) * 1997-07-25 1999-02-04 Smithkline Beecham Corporation Antagonistes du recepteur de vitronectine
WO1999015170A1 (fr) * 1997-09-24 1999-04-01 Smithkline Beecham Corporation Antagoniste du recepteur de vitronectine
US5919792A (en) * 1996-10-30 1999-07-06 Merck & Co., Inc. Integrin antagonists

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0478363A2 (fr) * 1990-09-27 1992-04-01 Merck & Co. Inc. Nouveaux sulfonamides comme antagonistes des récepteurs fibrinogéniques
WO1997024124A1 (fr) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine
US5919792A (en) * 1996-10-30 1999-07-06 Merck & Co., Inc. Integrin antagonists
WO1999005107A1 (fr) * 1997-07-25 1999-02-04 Smithkline Beecham Corporation Antagonistes du recepteur de vitronectine
WO1999015170A1 (fr) * 1997-09-24 1999-04-01 Smithkline Beecham Corporation Antagoniste du recepteur de vitronectine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1653970A2 (fr) * 2003-08-13 2006-05-10 Chiron Corporation Inhibiteurs de gsk-3 et utilisations
JP2007502300A (ja) * 2003-08-13 2007-02-08 カイロン　コーポレイション Ｇｓｋ−３インヒビターおよびその使用
EP1653970A4 (fr) * 2003-08-13 2008-10-15 Novartis Vaccines & Diagnostic Inhibiteurs de gsk-3 et utilisations
WO2006043930A1 (fr) * 2004-10-14 2006-04-27 Pharmacia Corporation Antagonistes l'integrine biphenyle
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
CN115087444A (zh) * 2019-10-16 2022-09-20 莫菲克医疗股份有限公司 抑制人整联蛋白α4β7

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