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  • 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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  • 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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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
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  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to pharmaceutical agents (compounds) which are useful as ⁇ v ⁇ 3 integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by ⁇ v ⁇ 3 by inhibiting or antagonizing ⁇ v ⁇ 3 0 integrins.
• Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion 5 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.
• the integrin identified as ⁇ ⁇ 3 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy 5 including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Additionally, it has been found that such agents would be 2
• RGD Arg-Gly-Asp
• the adhesion receptor integrin ⁇ v ⁇ 3 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 ⁇ ⁇ 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.
• ⁇ ⁇ 3 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571 ). It has been reported that the cell surface receptor ⁇ 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 ⁇ ⁇ 3 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity.
• it would be beneficial to provide antagonists of osteoclast ⁇ ⁇ 3 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
• ⁇ ⁇ 3 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). 4 Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
• X 1 is selected from the group consisting of CH, CH 2 , N, NH, O and S;
• A is Y'
• 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; aryl; hydroxy; alkoxy; cyano; nitro; amino; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid
• 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, 6 thioalkyl. alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl;
• 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 5-9 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl, alkoxy and hydroxy;
• R 2 taken together with R 7 forms a 5 membered heteroaromatic ring fused with a 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; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, ary
• 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, alkyl, alkenyl, alkynyl, benzyl, and phenethyl; 8 or
• A is — N ' ⁇ NR'
• Y ,2 is selected from the group consisting of alkyl; cycloalkyi; bicycloalkyl; aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -S-R 9 and - O-R 9 wherein R 9 is selected from the group consisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R 9 taken together with R 7 forms a
• R 5 and R 7 are as defined above;
• R 7 forms a 4-12 membered mononitrogen or dinitrogen containing ring optionally substituted with alkyl, aryl, keto or hydroxy;
• R 5 is defined as above
• R 2 and R 7 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl;
• R 8 are both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl;
• Z 1 is one or more substituent selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; halogen; haloalkyl; haloalkoxy; nitro; amino; alkylamino; acylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; t haloacetamide; acetamide; acyl; aryl; fused aryl; cycloalkyi; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above; 10
• V is selected from the group consisting of -N-(R 6 )- wherein R 6 is selected from the group consisting of H; lower alkyl; cycloalkyi; aralkyl; aryl; and monocyclic heterocycles; or R 6 taken together with Y, forms a 4-12 membered mononitrogen containing ring;
• Y, Y 3 , Z and Z 3 are independently selected from the group consisting of hydrogen; alkyl; aryl; and cycloalkyi; or Y and Z taken together form a cycloalkyi; or Y 3 and Z 3 taken together form a cycloalkyi; n is an integer 1 , 2, or 3;
• t is an integer 0, 1 , or 2;
• p is an integer 0, 1 , 2, or 3;
• R is X-R 3 wherein X is selected from the group consisting of O, S and NR 4 , wherein R 3 and R 4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids; polyalkylethers; alkylamido; alkyl N,N- dialkylamido; pivaloyloxymethyl; and in the case of the free acid, all pharmaceutically acceptable salts thereof;
• R 1 is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; carboxyl derivatives; haloalkyl; cycloalkyi; monocyclic heterocycles; monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido;
• alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, 11 arylthio.
• alkylcarbonyl haloalkylcarbonyl, and arylcarbonyl
• aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy; amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles; and
• R 7 and R 8 are as defined above and provided that taken together with the nitrogen, R 7 and R 8 comprise an amino acid
• R 11 is selected from the group consisting of H, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl or haloalkynyl or R 11 taken together with Y forms a
• Such compounds and compositions are useful in selectively inhibiting or antagonizing the ⁇ v ⁇ 3 integrin and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the ⁇ ⁇ 3 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. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials.
• the present invention relates to a class of compounds represented by the Formula I, described above.
• R ,3 2 is H, alkyl, alkoxyalkyl, aminoalkyi, dialkylamino alkyl, wherein the alkyl group is optionally substituted by one or more substituent selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl- or alkyl-sulfonyl, carboxyl, and carboxyl derivatives and the other variables are as described in Formula I.
• the invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formulas l-VI.
• the invention also relates to a method of selectively inhibiting or antagonizing the ⁇ ⁇ 3 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 l-VI 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. 16 As used herein the terms “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.
• cycloalkyi 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 cycloalkyi 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
• hydroxy and "hydroxyl” as used herein are synonymous hOH . _, , _. .. ._
• radical refers to a 5-10 membered monocyclic or bicyclic heterocyclic ring, optionally containing unsaturation, containing 1 to 3 hetero atoms selected from the group consisting of O, N and S; wherein X 1 is CH, N, O or S.
• Representative examples of the radical include pyridones, pyridines, pyrimidines, imidazoles, oxazoles, isoxazoles, thiazoles, pyridazines, thiophenes, furans, pyrazoles and bicyclic heterocyclics such as benzimidazole, imidazopyridine, benzofuran and the like. 17
• 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.
• 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
• 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, aralkyl or aryl as defined above.
• Y 6 and Y 7 are independently selected 18 from the group consisting of O, N or S and R 23 is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above.
• amino is represented by a radical of the formula -NH 2 .
• alkylsulfonyl or “alkylsulfone” refers to a O
• alkylthio refers to a radical of the formula -SR 24 wherein R 24 is alkyl as defined above.
• sulfonic acid refers to a o radical of the formula — s —OR wherein R 25 is alkyl as defined above.
• sulfonamide refers to a radical of the
• 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.
• the terms “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. 19
• fused monocyclic heterocycle refers to a monocyclic heterocycle as defined above with a benzene fused thereto.
• fused monocyclic heterocycles examples include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
• m is 1 or 2 and R 19 is H, alkyl, aryl, or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
• R 19 is H, alkyl, aryl, 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
• [ or ⁇ N H H and "5-membered heteroaromatic ring fused with a phenyl” refers to such a “5-membered heteroaromatic ring” with a phenyl fused thereto.
• 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 6 is alkyl, alkenyl, alkynyl, aryl or aralkyl and 20 optionally substituted thereon as defined above.
• R 6 is alkyl, alkenyl, alkynyl, aryl or aralkyl and 20 optionally substituted thereon as defined above.
• R 6 is alkyl, alkenyl, alkynyl, aryl or aralkyl and 20 optionally substituted thereon as defined above.
• R 6 is alkyl, alkenyl, alkynyl, aryl or aralkyl and 20 optionally substituted thereon as defined above.
• acetyl benzoyl and the like.
• thio refers to a radical of the formula — SH .
• sulfonyl refers to a radical of the formula O 10
• R 27 is alkyl, aryl or aralkyl as defined above.
• haloalkylthio refers to a radical of the formula -S-R 2 wherein R 8 is haloalkyl as defined above.
• aryloxy refers to a radical of the formula
• acylamino refers to a radical of the o formula I wherein R is alkyl, aralkyl or aryl as defined
• alkylamino refers to a radical of the formula -NHR 32 wherein R 32 is alkyl 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 groups as defined above.
• trifluoromethyl refers to a radical of the
• alkylaminosulfonyl refers to a radical of
• alkylsulfonylamino refers to a radical of
• R 36 O the formula R 36 — s — NH — wherein R 36 is alkyl 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 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 22 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. Encompassed within this definition are rings such as thiazoline and the like.
• arylsulfonyl or “arylsulfone” refers to a O
• alkylsulfoxide or arylsulfoxide refer to
• R 38 O radicals of the formula R 38 — s — wherein R 38 is, respectively, alkyl or aryl as defined above.
• phosphinic acid derivatives refers to a
• R 41 is H, alkyl, aryl or aralkyl as defined above.
• arylthio refers to a radical of the formula h i -SR 42 wherein R is aryl as defined above.
• alkylcarbonyl refers to a radical of the O
• R 50 formula R ⁇ C wherein R 50 is alkyl as defined above.
• arylcarbonyl refers to a radical of the O
• alkoxycarbonyl refers to a radical of the O p 5 0 2 ⁇ p " 52 formula ⁇ wherein R is alkoxy as defined above.
• aryloxycarbonyl refers to a radical of the
• haloalkylcarbonyl refers to a radical of the O
• haloalkoxycarbonyl refers to a radical of O p 5 3 3 J pi p " 53 the formula w ° wherein R is haloalkyl as defined above.
• alkylthiocarbonyl refers to a radical of the O
• arylthiocarbonyl refers to a radical of the O
• arylamino refers to a radical of the formula R 51 -NH- wherein R 51 is aryl as defined above.
• polyalkylether refers to commonly used glycols such as triethyleneglycol, tetraethylene glycol, polyethylene glycol and the like.
• alkylamido refers to a radical of the O
• N,N-dialkylamido refers to a radical of the
• R 55 is acyl 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 25 response of a tissue, system or animal that is being sought by a researcher or clinician.
• CDMT 2-chloro-4,6-dimethoxytriazine
• CHNCI analysis carbon/hydrogen/nitrogen/chlorine elemental analysis
• CHNS analysis carbon/hydrogen/nitrogen/sulfur elemental analysis
• DIBAL diisobutylaluminum hydride
• DIEA diisopropylethylamine
• DMAP 4-(N.,N-dimethylamino)pyridine
• DMF N.,N-dimethylformamide
• GIHA meta-guanidinohippuric acid
• GIHA HCI meta-guanidinohippuric acid hydrochloride
• HMPA hexamethylphosphoramide
• HOBT 1 -hydroxy benzotriazole hydrate
• HPLC high performance liquid chromatography
• K 2 CO 3 potassium carbonate
• KMnO 4 potassium permanganate
• KSCN potassium thiocyanate
• LiOH lithium hydroxide
• MCPBA m-chloroperoxybenzoic acid or m-chloroperbenzoic acid
• MEMCI methoxyethoxy methyl chloride
• NaCNBH 3 sodium cyanoborohydride
• NaH - sodium hydride NaHCO 3 sodium bicarbonate
• NaOMe sodium methoxide
• Na 2 PO 4 sodium phosphate
• NMM N-methylmorpholine
• NMP 1-methyl-2-pyrrolidinone
• Ph phenyl
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• TMEDA tetramethylethylenediamine 27
• TMS t ⁇ methylsilyl
• a bond drawn across a bond of 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
• examples of pharmacologically acceptable salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succmate, tartrate salts and the like All of the pharmacologically acceptable salts may be prepared by conventional means (See Berge et al , J Pharm Sci . 66(1 ). 1-19 (1977) for additional examples of pharmaceutically acceptable salts )
• 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, infusion techniques or intrapentonally
• 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 treatment 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 28 Accordingly the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the ⁇ ⁇ 3 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in Formulas l-VI, where
• 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 survivabi ty 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 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 1000 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
• the active ingredient administered by injection is formulated as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
• a suitable daily dose would typically be about 0.01 to 10 mg/kg body weight injected per day in multiple doses depending on the factors listed above.
• 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 30 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.
• conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
• the general synthetic sequences for preparing the compounds useful in the present invention are outlined in Schemes 1-15. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate.
• the following Schemes and Examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those with skill in the art will readily understand that known variations of the conditions and processes described in the Schemes and Examples can be used to synthesize the compounds of the present invention. Unless otherwise indicated all starting materials and equipment employed were commercially available.
• Schemes 1 -3 are illustrative of methodology useful for preparing the guanidinopyridine/cycloguanidino pyridine carboxylic acid portions of the present invention which are used for coupling to the gly- ⁇ -amino acid portion. This can be accomplished using other appropriate guanidating reagents known to those skilled in the art. The methodologies of Schemes 1 -3 can be modified using conventional techniques and methods to prepare alternate compounds useful for coupling to the gly- ⁇ -amino acid portion.
• Scheme 4 is illustrative of methodology used for preparing the guanidinothiazole carboxylic acid portion of the present invention which is used for coupling to the gly- ⁇ -amino acid portion.
• the methodology of Scheme 4 can be modified using conventional techniques known to those skilled in the art to prepare this and alternate compounds useful for coupling to the gly- ⁇ -amino acid portion.
• 3-chloro-5-bromo-2- hydroxybenzaldehyde 3- ⁇ odo-5-chlorosal ⁇ cylaldehyde was prepared by reacting 5-chlorosal ⁇ cylaldehyde with N-iodosuccinimide in DMF and subjecting the reaction mixture to conventional work-up conditions
• 3- ⁇ odo- 5-bromosal ⁇ cylaldehyde can be prepared by reacting 5- bromosalicylaldehyde in acetonit ⁇ le with potassium iodide and chloramme T
• Conventional work-up gives a material that when treated with hexanes gives the desired 3- ⁇ odo-5-chlorosal ⁇ cylaldehyde
• Couma ⁇ ns are readily prepared from salicylaldehydes using a modified Perkm reaction (e g , Vogel's Textbook of Practical Organic Chemistry, 5 th Ed , 1989, p 1040)
• the halo-substituted couma ⁇ ns were converted to 3-am ⁇ nohydrocouma ⁇ ns (see J G Rico, Tett Let , 1994, 35, 6599-6602) which were readily opened in acidic alcohol to give 3-am ⁇ no-3- (3,5-halo-2-hydroxy)phenyl propanoic acid esters
• Scheme 6 illustrates methodology useful for coupling the heterocyclic acid portion (A1-A13) to the gly- ⁇ -amino portion (C) of the present invention.
• Scheme 7 illustrates methodology for preparing the gly- ⁇ -amino acid portion of the molecule (F) in a general manner.
• Aldehydes (R'CHO) used in this methodology are either commercially available or can be prepared from commercially available reagents using methodologies for the preparation of aldehydes which are commonly known to those with ordinary skill in the art.
• Scheme 8 illustrates methodology useful for coupling the heterocyclic acid portion (A1-13) to a gly- ⁇ -amino acid portion (F) to prepare compounds of the present invention.
• Schemes 9-12 illustrate general methodology for preparing compounds of the present invention.
• Scheme 9 illustrates the general methodology for the synthesis of the heterocycle derived gly- ⁇ -amino acid coupled target compounds.
• This transformation may also be carried out chemically using SnCI 2 .
• the amino group can be elaborated to guanidino or other functional groups of Formula I using the methodologies discussed above.
• the target compounds may be synthesized by building the left hand portion of the molecule prior to coupling with the gly- ⁇ -amino acid (Scheme 10).
• the amino functionality of the heterocycle amine (1) is functionalized to the guanidine or other groups (A, Formula I) and then coupled to the gly- ⁇ -amino acid under standard coupling conditions.
• Scheme 11 shows a general synthesis of substituted pyridines and pyridone derived target compounds. Nitration of 6-hydroxynicotinic acid followed by chlorination gives 6-chloro-5-nitronicotinic acid. Coupling of the intermediate 3 with the gly- ⁇ -amino acid gives the product 4. The chloro group in versatile intermediate 4 can be readily displaced by a variety of nucleophiles to give 5. Reduction of the nitro group on 4 or 5 and further elaboration of the amino group as discussed in Scheme 9 gives the target compounds.
• Scheme 12 shows the synthesis of substituted pyridine and pyridone derived target compounds starting with 2-amino-6-hydroxypridine-4-carboxylic acid.
• the starting material 1 used in the scheme may be prepared by reacting commercially available 2-chloro-6-methoxy-pyridine-4-carboxylic acid with ammonium hydroxide under high pressure conditions. Elaboration of the amino group followed by coupling to the gly- ⁇ -amino acid as discussed in Scheme 10 gives the target compounds.
• Scheme 13 shows the synthesis of isomeric pyridines and pyridones starting with 6-amino-4-methoxy-picolinic acid.
• the starting material 1 used in the Scheme 13 may be prepared as described in the literature (J. Am. Chem. Soc, 78, 4130, 1956). Functionalization of the amino group in 1 followed by coupling reaction and hydrolysis (as in Scheme 10) gives the target compounds.
• the isomeric pyridine and pyridone derived compounds may be prepared using the methodology shown in Scheme 14.
• the key intermediate 4 may be prepared by starting with 6-chloro-picolinic acid. Oxidation followed by nitration gives the 4-nitropyridine derivative (3). Deoxygenation of the N- oxide, reduction of the nitro group and nucleophilic displacement of chloro group gives the intermediate 4.
• the methodology discussed in Scheme 10 may be applied to achieve the synthesis of target compounds.
• Scheme 10 The methodology shown in Scheme 10 can also be used for the synthesis of pyrimidine derived target compounds (Scheme 15).
• the isomeric pyrimidine derivatives 1 and 2 may be synthesized by following the literature preparations (J. Org. Chem., 26, 2755, 1961 ).
• Step 2 To the product from Step 1 above (5.3g, 0.021 mole) and triethylamine
• Step i To 2-methylthio-2-imidazoline hydroiodide (20 g, 0.082 mole) (Aldrich), and triethylamine (8.28 g, 0.082 mole) in CH 2 CI 2 (100 mL) was added BOC anhydride (17.9 g, 0.082 mole) at ice bath temperature. The reaction was stirred overnight at room temperature. The CH 2 CI 2 was washed with H 2 O (2x), dried over MgSO 4 and removed under vacuum to yield N-BOC-2-methylthio-2- imidazoline as a viscous oil turned waxy white solid (15.93 g).
• the temperature was maintained below 0°C overnight.
• the reaction mixture was concentrated to about one-half its original volume and partitioned between EtOAc (3L) and water (2L).
• the organic layer was washed with aqueous HCI (3 x 1L, 0.5 N HCI).
• the pH of the combined water layers was adjusted to about 7 by addition of 10% aqueous NaOH and extracted with methylene chloride (3 x 2L).
• the combined organic layers were dried (MgSO 4 ), filtered, and HCI (210 mL of 4M in dioxane) added with stirring. Upon completion of precipitation the solid was removed by filtration.
• the filtrate was concentrated to a small volume and methyl t-butyl ether added.
• N-t-Boc-glycine N-hydroxysuccinimide ester (Sigma, 15.0 g, 0.055 mol), dry DMF (Aldrich Sure Seal, 200 mL) and the product from Step 2 (21.67 g, 0.055 mol) under an inert atmosphere (Ar).
• the reaction mixture was cooled to approximately 0°C (salt-ice bath) and N-methyl morpholine (5.58 g, 0.056 mole) and a catalytic amount of DMAP added. The reaction was allowed to proceed overnight.
• the reaction mixture was concentrated to a slush, and partitioned between EtOAc (0.4 L) and aqueous base (2x 0.2 L, aqueous saturated NaHCO 3 ).
• the organic layer was washed consecutively with aqueous citric acid (2x 0.2 L, 10% w/v), with aqueous sodium bicarbonate (2x 0.2 L), brine and dried (Na 2 SO 4 ). Volatiles were removed under vacuum at 55°C to give an oil (22.5 g, 92% yield) that solidified on standing.
• Step 3 The product obtained in Step 3 was deprotected to give the amine hydrochloride salt using the following procedure.
• N-t-Boc-glycine N-hydroxysuccinimide ester (Sigma, 2.72 g, 0.010 mol)
• dry THF Aldrich Sure Seal, 50 mL
• the product of Step 3 (3.10 g, 0.01 mole, vacuum desiccated overnight over P 2 O 5 ) under an inert atmosphere (Ar).
• the reaction mixture was cooled to approximately 0°C (salt- ice bath) and triethylamine (1.01 g, 0.010 mole) was added. The reaction was allowed to proceed overnight.
• the reaction mixture was concentrated to a semi-solid and worked up in a fashion similar to Example A, Step 3. Volatiles were removed from the organic layer under vacuum at 55°C to give an oil (4.0 g, 83% yield) that solidified on standing.
• Step 4 The product obtained in Step 4 was deprotected to give the hydrochloride salt using the following procedure. To the product obtained in Step 4 (4.0 g, 0.0084 mole) in a flame-dried round bottom flask (0.1 L) with stir bar was added dry dioxane (20 mL). To this was added HCI (4N in dioxane, 20 mL) and the reaction allowed to proceed until gas evolution ceased and the reaction was complete (about 1 hour). Volatiles were removed under vacuum and the residue triturated with diethyl ether (50 mL). Solids were collected by filtration, washed with ether and dried to give a light brown solid (2.7 g, 78% yield).
• N-lodosuccinimide 144.0 g, 0.641 mole was added to a solution of
• Lithium hexamethyldisilazane (21.62 mL, 1M, 21.62 mmol) was added to a solution of 6-chloro-8-iodocoumarin (6.63 g, 21.62 mmol) in tetrahydrofuran (100 mL) at -78°C. The reaction mixture was stirred at this temperature for 30 minutes, then at 0°C for 1 hour.
• Acetic acid 1.3 g,
• the mixture was cooled to 50°C before charging tert-butyl bromoacetate (488 g, 369 mL, 2.5 mol) via 50 mL syringe and syringe pump (delivery set to 4.1 mL/min) over 1.5 hours. Reaction temperature of 50° +/- 5°C was maintained throughout the addition. The reaction mixture was allowed to stir at 50°C for one hour after the addition was complete. Subsequently, the mixture was allowed to cool to 25°C and the precipitated product allowed to settle. The THF mother liquor is decanted into a 2-L round bottom flask using a coarse fritted filter stick and partial vacuum transfer (20 mm Hg). This removed about 65% of the THF from the mixture.
• 1-Methyl-2-pyrrolidinone 74 (NMP, 800 mL) was added and agitation resumed for 5 minutes.
• the reaction mixture can be filtered to remove any remaining zinc. Analysis indicated a titer of desired Reformatski reagent of 1.57 M with a molar yield of 94%.
• the solid reagent can be isolated by filtration from the original reaction mixture. The cake was washed with THF until a white solid was obtained and dried under N 2 to obtain the desired product as a mono THF solvate that may be stored at -20°C (desicated) for extended periods. Typical recoveries are 85-90%.
• Potassium carbonate (powder, oven dried at 100°C under vacuum, 8.82 g, 60 mmoles) was added to a solution of 3,5-dichlorosalicylaldehyde (11.46 g, 60 moles) in DMF (40 mL) at room temperature to give a bright yellow slurry.
• MEMCI (neat, 7.64 g, 61 mmoles) was then added while maintaining the bath temperature at 20°C. The mixture was stirred at 22°C for 6 hours and MEMCI (0.3 g, 2.4 mmoles) was added. The mixture was stirred for another 0.5 hour and the reaction mixture poured into cold water (200 mL) to precipitate the product.
• the Boc-protected glycine amide prepared in Step 4 (27.0 g, 0.062 mole) was dried overnight over P 2 O 5 and NaOH pellets.
• the solid was dissolved in dioxane (40 mL) and the solution cooled to 0°C.
• An equivalent volume of 4N HCI/dioxane (0.062 mole) was added and the reaction was run for 2 hours. At this point the conversion was 80% as determined by rphplc.
• the reaction mixture was allowed to warm to room temperature over 4 hours.
• the reaction mixture was concentrated at 40°C to a foam which was triturated with ether (200 mL).
• the white solid that formed was 79 filtered and dried over P 2 O 5 to yield the desired glycine beta-amino acid ethyl ester compound as the HCI salt (20.4%, 88.5% isolated yield.
• Potassium carbonate (powder, oven dried at 100°C under vacuum, 22.1 g, 0.16 moles) was added to a solution of 3-chloro-5- bromosalicylaldehyde (35 g, 0.15 moles) in DMF (175 ml) at room temperature to give a bright yellow slurry.
• MEMCI (neat, 25.0 g, 0.2 moles) was then added while maintaining the bath temperature at 20°C. The mixture was then stirred at 22°C for 6 hours and was poured into Dl water (1200 mL) to precipitate the product.
• Step 1 The product obtained in Step 1 (32.35 g, 0.1 mol) was charged in a 500 ml 3N round bottom flask fitted with a mechanical stirrer, followed by the addition of THF (160 ml) and (S)-phenylglycinol (13.71 g, 0.1 mol). After 30 minutes at 22°C, MgSO 4 (20 g) was added. The mixture was stirred for 1 hour at 22°C and filtered on a coarse fritted filter. The filtrate was concentrated under reduced pressure to afford a pale yellow oil (48.0 g) containing the imine. No further purification was performed and the crude product was used directly in the coupling reaction. Microanalytical: calculated for C 19 H 21 BrCINO 4 :
• Example G The above compound was prepared according to the procedures outlined in Example G, Step 4 and Step 5 where an equivalent quantity of the intermediate prepared in Step 5 as the free base was substituted for Example G, Step 4.
• Example G The above compound was prepared using the procedure of Example G, Step 4 and substituting the compound prepared in Step 3 to produce the BOC protected intermediate.
• the resulting BOC protected intermediate was converted to the desired compound using the procedure of Example G, Step 5.
• N-t-BOC-glycine N-hydroxysuccinimide ester (225 g, 0.826 moles) (Sigma) in several portions at 5-10°C.
• the reaction mixture was stirred overnight at room temperature.
• the resulting precipitate was filtered and washed with THF.
• the solvent from the filtrate was removed under vacuum.
• the residue was taken up in ethyl acetate (2.3 liters).
• the ethyl acetate layer was washed with saturated sodium bicarbonate (2 x 900 ml) and H 2 O (3 x 900 ml), dried over MgSO 4 and removed under vacuum.
• Step 2 To the product of Step 1 (5.0 g, 0.023 mole) slurried in H 2 O (100 mL) and ethanol (40 mL) was added NaOH (0.93 g, 0.023 mole). The solution was stirred overnight at room temperature. Additional ethanol (20 mL) and NaOH (0.93 g) were added to the reaction mixture and the solution was stirred at room temperature for 1 more hour. The pH was lowered to 7 with 1 N HCI and the resultant precipitate was filtered, washed with H 2 O and ether, then dried to yield the product (4.1 g) as the zwitterion.
• This compound (M) was prepared by a procedure similar to the procedure for preparing 2-aminopyridine-6-carbethoxypyridine hydrochloride of Example L starting from 2-acetylamino-4-methyl-pyridine. 1 H-NMR and MS were consistent with the structure.
• Example E (0.83 g, 0.002 mole), triethylamine (0.2 g, 0.002 mole), and DMAP (24 mg) in anhydrous DMA (5 mL) was added EDCI (0.38 g, 0.002 mole) at ice bath temperature. The reaction was stirred at room temperature for 2 days. The ester product was isolated by reverse phase preparatory HPLC. To the ester in H 2 O (3 mL) and CH 3 CN (3 mL) was added LiOH (0.51 g, 0.012 mole). This was stirred at room temperature for 1 hour. The pH was lowered to 2 with TFA and the product was isolated by reverse phase preparatory HPLC to yield (after lyophilization) the desired product as a white solid (350 mg). MS and 1 H-NMR were consistent with the desired structure.
• the titled compound was prepared according to the methodology of
• Example 1 substituting an equivalent amount of the product of Example D for the product of Example E to yield the desired product as a white solid (210 mg).
• Example C To the product of Example C (19.5 g, 0.045 mole) and N- methylmorpholine (9.1 g, 0.09 mole) in anhydrous DMA (85 mL) in a flame dried flask under N 2 was added isobutylchloroformate (6.2 g, 0.045 mole) slowly at ice bath temperature. The solution was stirred at ice bath temperature for 15 minutes. The product of Example D (15 g, 0.04 mole) was then added at ice bath temperature followed by slow addition of N- methylmorpholine (4.1 g, 0.04 mole). The reaction mixture was stirred overnight at room temperature.
• Example 9 To the product of Step 3 of Example 9 (0.6 g, 0.0019 mole) in anhydrous DMA (4 mL) was added isobutylchloroformate (0.27 g, 0.002 mole) at ice bath temperature followed by N-methylmorpholine (0.4 g, 0.0038 mole). The solution was stirred for 15 minutes at ice bath temperature.
• the product of Example H (0.71 g, 0.0017 mole) was added at ice bath temperature followed by N-methylmorpholine (0.17 g, 0.0017 100 mole). The reaction was stirred overnight at room temperature. HPLC analysis indicated product plus significant amount of starting material.
• Example K To the product of Example K (0.5 g, 0.0022 mole) and N- methylmorpholine (0.23 g, 0.0022 mole) in anhydrous DMF (8 mL) was added isobutylchloroformate (0.31 g, 0.0022 mole) at ice bath temperature. After stirring for 5 minutes at ice bath temperature, the product of Example J (0.73 g, 0.0022 mole) and N-methylmorpholine (0.45 g, 0.0045 mole) in anhydrous DMF (8 mL) were added at ice bath temperature in one portion. The reaction mixture was stirred overnight at room temperature. The ester was isolated by reverse phase preparatory HPLC (530 mg).
• This compound (O) was prepared using a procedure similar to that of Example N. MS analysis [m/z 565 (M+H)] confirmed the formation of the desired tris-BOC product O.
• Step 2 A stirred suspension of 3-amino-pyridine-6-carboxylic acid (25 g) in ethanol (300 mL) at 0°C was saturated with gaseous hydrogen chloride. The mixture was allowed to warm to 23°C and heated to reflux for 2 hours. A clear solution was obtained. After cooling to 23°C, the mixture was concentrated in vacuo, neutralized with aqueous NaHCO 3 and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO , and concentrated in vacuo to give ethyl 3-amino-pyridine-6- carboxylate as a pale yellow solid.
• Step 3 The product of Step 3 (0.308 g) was suspended in DMF (10 mL) and 4-methylmorpholine (0.2 mL) was added to the suspension. The mixture was stirred at 23°C for 1 hour. After cooling the reaction mixture to 0°C, IBCF (0.129 mL) was added. After ! hour, a solution of the product of Example R (0.416 g) and 4-methylmorpholine (0.11 mL) in DMF (3 mL) was added. The mixture was allowed to warm to 23°C over 2 hours. Then the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to provide 5. Micro-analytical data, NMR and MS were consistent with the desired structure.
• Step 1
• Step B was prepared using the product of Step 1 (2.2 g) and following the coupling conditions as described in Step 4 of Example 12. The reaction was concentrated and the residue partitioned between ethyl acetate and water. The organic extract was washed with saturated sodium chloride solution, dried (Na 2 SO 4 ) and concentrated. The residue was recrystallized from ethyl acetate to afford a tan solid (3.5 g). 1 H-NMR was consistent with the proposed structure.

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