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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
  • C07D213/72—Nitrogen atoms
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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  • 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
  • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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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
  • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D471/00—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
  • 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
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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
  • C07D471/10—Spiro-condensed systems

Definitions

• the present invention relates to alkanoic acid derivatives, their synthesis, and their use as ⁇ v integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors ocv ⁇ 3, ⁇ v ⁇ 5, and ⁇ v integrin receptors associated with other ⁇ -subunits, and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
• Integrin receptors are heterodimeric transmembrane receptors through which cells attach and communicate with extracellular matrices and other cells. (See S.B. Rodan and G.A. Rodan, "Integrin Function In Osteoclasts," Journal of Endocrinology, 154: S47- S56 (1997), which is incorporated by reference herein in its entirety).
• the compounds herein are useful for inhibiting bone reso ⁇ tion.
• Bone resorption is mediated by the action of cells known as osteoclasts.
• Osteoclasts are large multinucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates.
• Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual reso ⁇ tion of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state.
• osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone.
• the adhesion of osteoclasts to bone surfaces is an important initial step in bone reso ⁇ tion.
• the osteoclasts migrate across bone matrix and do not take part in reso ⁇ tion until they again attach to bone. Integrins are involved in osteoclast attachment, activation and migration.
• integrin receptor known as ⁇ v ⁇ 3, which is thought to interact in bone with matrix proteins that contain the RGD sequence.
• Antibodies to ⁇ v ⁇ 3 block bone reso ⁇ tion in vitro indicating that this integrin plays a key role in the reso ⁇ tive process.
• ⁇ v ⁇ 3 ligands can be used effectively to inhibit osteoclast mediated bone reso ⁇ tion in vivo in mammals.
• osteoporosis hypercalcemia of malignancy
• osteopenia due to bone metastases
• periodontal disease hype ⁇ arathyroidism
• periarticular erosions in rheumatoid arthritis Paget's disease
• immobilization-induced osteopenia and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone reso ⁇ tion, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average.
• the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones.
• the potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
• In the United States there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis.
• ⁇ v ⁇ 3 ligands have been found to be useful in treating and/or inhibiting restenosis (i.e. recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (i.e. formation of new blood vessels), and inhibiting viral disease.
• restenosis i.e. recurrence of stenosis after corrective surgery on the heart valve
• atherosclerosis i.e. recurrence of stenosis after corrective surgery on the heart valve
• diabetic retinopathy diabetic retinopathy
• macular degeneration macular degeneration
• angiogenesis i.e. formation of new blood vessels
• ⁇ v ⁇ 3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al., Cell, 79: 1157-1164 (1994), which is inco ⁇ orated by reference herein in its entirety).
• ⁇ v ⁇ 3 antagonists which inhibit angiogenesis may represent a novel therapeutic approach to the treatment of arthritic disease, such as rheumatoid arthritis (see CM. Storgard, et al., "Decreased angiogenesis and arthritic disease in rabbits treated with an ⁇ v ⁇ 3 antagonist," J. Clin. Invest., 103: 47-54 (1999), which is inco ⁇ orated by reference herein in its entirety).
• compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, ⁇ v ⁇ 5.
• a monoclonal antibody for ⁇ v ⁇ 5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M.C.
• compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of ⁇ v integrin receptors associated with other ⁇ subunits, suh as ⁇ v ⁇ 6 and ⁇ v ⁇ 8 (See, for example, Melpo Christofidou-Solomidou, et al., "Expression and Function of Endothelial Cell ⁇ v Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice Chimeras," American Journal of Pathology, 151: 975-83 (1997) and Xiao-Zhu Huang, et al., "Inactivation of the Integrin ⁇ 6 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin," Journal of Cell Biology, 133: 921-28 (1996), which are inco ⁇ orated by reference herein in their entirety).
• certain compounds of this invention antagonize both the ⁇ v ⁇ 3 and ⁇ v ⁇ 5 receptors.
• These compounds referred to as “dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonists,” are useful for inhibiting bone reso ⁇ tion, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
• Peptidyl as well as peptidomimetic antagonists of the ⁇ v ⁇ 3 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to W.J. Hoekstra and B.L. Poulter, Curr. Med. Chem.
• the ⁇ v ⁇ 3 integrin receptor recognizes the Arg-Gly-Asp (RGD) tripeptide sequence in its cognate matrix and cell surface glycoproteins (see J. Samanen, et al., "Vascular Indications for Integrin ⁇ v Antagonists," Curr. Pharmaceut. Design 3: 545-584 (1997)).
• RGD Arg-Gly-Asp
• a benzazepine nucleus has been employed among others by Genentech and SmithKline Beecham as a conformationally constrained Gly-Asp mimetic to elaborate nonpeptide ⁇ v ⁇ 3 integrin receptor antagonists substituted at the N-terminus with heterocyclic arginine mimetics (see R.M.
• Keenan et al. "Discovery of Potent Nonpeptide Vitronectin Receptor ( ⁇ v ⁇ 3) Antagonists," J. Med. Chem. 40: 2289-2292 (1997); R.M. Keenan et al., "Benzimidazole Derivatives As Arginine Mimetics in 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor ( ⁇ v ⁇ 3) Antagonists," Bioorg. Med. Chem. Lett. 8: 3165-3170 (1998); and R.M.
• Patents assigned to SmithKline Beecham that disclose such benzazepine, as well as related benzodiazepine and benzocycloheptene, ⁇ v ⁇ 3 integrin receptor antagonists include WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO 98/15278, WO 99/05107, WO 99/06049, WO 99/15170, and WO 99/15178, and to Genentech include WO 97/34865.
• dibenzocycloheptene, as well as dibenzoxazepine, nucleus has also been employed as a Gly-Asp mimetic to afford ⁇ v ⁇ 3 antagonists (see WO 97/01540, WO 98/30542, WO 99/11626, and WO 99/15508 all assigned to SmithKline Beecham).
• the present invention relates to novel alkanoic acid derivatives represented by structural formula (I), or a pharmaceutically acceptable salt thereof, which are useful as ⁇ v integrin receptor antagonists.
• the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
• the present invention also relates to methods for making the pharmaceutical compositions of the present invention.
• the present invention also relates to methods for eliciting an ⁇ v integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
• the present invention also relates to methods for inhibiting bone reso ⁇ tion, restenosis, atherosclerosis, inflammatory arthritis, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth by administering the compounds and pharmaceutical compositions of the present invention.
• the present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention.
• the present invention relates to alkanoic acid derivatives useful as ⁇ v integrin receptor antagonists.
• Representative compounds of the present invention are described by the following structural formula (I):
• X is selected from the group consisting of
• Y-Z is -CH2CH2- or -CONR3-;
• A is O or NRl;
• m is O or l;
• Rl is hydrogen or C1 -3 alkyl; each non-aromatic ring carbon atom is unsubstituted or independently substituted with one or two R2 substituents and each aromatic ring carbon atom is unsubstituted or independently substituted with one R2 substituent selected from the group consisting of
• R3 is hydrogen or Ci-4 alkyl
• R4 is aryl wherein the aryl group is selected from the group consisting of (1) phenyl,
• aryl is as defined above and the substituents are independently hydrogen, hydroxy, hydroxy-Ci-6 alkyl, halogen, Ci-8 alkyl, C3-8 cycloalkyl, aryl, aryl C1.3 alkyl, amino, amino Ci -6 alkyl, C1.3 acylamino, C1 -.3 acylamino-Ci -6 alkyl, Ci-6 alkylamino, di(Ci-6)alkylamino, Ci -6 alkylamino-Ci-6 alkyl, di(Ci-6)alkylamino-Ci-6 alkyl, C1-4 alkoxy, Ci-4 alkylthio, Ci -4 alkylsulfinyl, C1.4 alkylsulfonyl, Ci-4 alkoxy-Ci -6 alkyl, hydroxycarbonyl, hydroxycarbonyl-Ci-6 alkyl, C1 -5 alkoxycarbonyl
• R5 is hydrogen or C1.3 alkyl.
• X is selected from the group consisting of
• Y is -CH2CH2-.
• R4 is mono- or di- substituted phenyl, pyridinyl, quinolyl, pyrimidinyl, pyrazinyl, quinoxalinyl, or dihydrobenzofuryl ;
• substituents are independently hydrogen, hydroxy, hydroxy-Ci -6 alkyl, halogen, Ci -8 alkyl, C3-8 cycloalkyl, aryl, aryl C1 -3 alkyl, amino, amino-C ⁇ _6 alkyl, Ci-3 acylamino, Ci-3 acylamino-Ci -6 alkyl, C ⁇ _6 alkylamino, di(Ci -6)alkylamino, Ci-6 alkylamino Ci-6 alkyl, di(Ci -6)alkylamino-Ci -6 alkyl, C1.4 alkoxy, Ci-4 alkylthio, Ci -4 alkylsulfinyl, Ci-4 alkylsulfonyl, C ⁇ _4 alkoxy-Ci-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-Ci-6 alkyl, Ci _5 alkoxycarbonyl, C1 -.3 alkoxycarbonyl Ci-6 alkyl, Ci
• R is mono- or di-substituted pyridinyl, quinolyl, pyrimidinyl, pyrazinyl, quinoxalinyl, or dihydrobenzofuryl ;
• substituents are independently hydrogen, halogen, phenyl, Ci -4 alkyl, C3-6 cycloalkyl, C1 -3 alkoxy, amino, Ci -3 alkylamino, di(C ⁇ _3) alkylamino, hydroxy, cyano, trifluoromethyl, 1,1,1 -trifluoroethyl, trifluoromethoxy, or trifluoroethoxy.
• R2 is selected from the group consisting of hydrogen, amino, Ci-4 alkylamino,
• Ci-6 alkyl 1-2 aminocarbonyl, Ci -4 alkoxycarbonyl, trifluoromethyl, and trifluoromethoxy.
• R2 is selected from the group consisting of hydrogen, amino,
• Illustrative but nonlimiting examples of compounds of the present invention that are useful as ⁇ v integrin receptor antagonists are the following:
• salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.”
• Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
• Salts of basic compounds encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
• Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
• suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmo ⁇ holine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
• basic ion-exchange resins such as arginine, betaine, caffeine,
• the compounds of the present invention can have chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers, with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
• tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention.
• Compounds of the present invention may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof.
• the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by the use of an optically active acid as a resolving agent, or by HPLC using a chiral stationary phase.
• any enantiomer of a compound of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
• polymo ⁇ hs and hydrates of the compounds of the instant invention are also included within the scope of the invention.
• the present invention includes within its scope prodrugs of the compounds of this invention.
• prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
• the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is inco ⁇ orated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
• terapéuticaally effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
• ⁇ v integrin receptor antagonist refers to a compound which binds to and antagonizes either the ⁇ v ⁇ 3 receptor or the ⁇ v ⁇ 5 receptor, or a compound which binds to and antagonizes a combination of these receptors (for example, a dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 receptor antagonist).
• bone reso ⁇ tion refers to the process by which osteoclasts degrade bone.
• alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1- propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
• alkenyl shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
• alkynyl shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
• cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
• cycloheteroalkyl shall mean a 3- to 8- membered fully saturated heterocyclic ring containing one or two heteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, mo ⁇ holinyl, piperazinyl.
• alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., C ⁇ _5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
• aryl refers to a monocyclic or bicyclic system comprising at least one aromatic ring, wherein the monocylic or bicyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherein the monocylic orbicylic system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Ci -8 alkyl, C3-8 cycloalkyl, aryl, aryl C1 -.3 alkyl, amino, amino Ci -6 alkyl, C1.3 acylamino, C1.3 acylamino Ci -6 alkyl, Ci- alkylamino, C1 -6 alkylamino Ci-6 alkyl, di(Ci-6) alkylamino, di(Ci -6) alkylamino-Ci-6 alkyl, Ci-4 alkoxy, Ci -4 alkylthio, Ci-4 alkylsulfinyl, Ci-4 alkyl
• aryl examples include, but are not limited to, phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(l,3)dioxolanyl, benzo(l,4)dioxanyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C1 _8 alkyl, C3-8 cycloalkyl, aryl, aryl C ⁇ _3 alkyl, amino, amino C1 -6 alkyl, Ci -3 acylamino, Ci-3 acylamino Ci-6
• the aryl group is unsubstituted, mono-, di-, or tri- substituted with one to three of the above-named substituents; more preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents.
• alkyl or aryl or either of their prefix roots appears in a name of a substituent (e.g., aryl C ⁇ -8 alkyl), it shall be inte ⁇ reted as including those limitations given above for "alkyl” and “aryl.”
• Designated numbers of carbon atoms e.g., Ci -8) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
• arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
• arylalkyl examples include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenyl ethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
• alkylaryl examples include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
• two R2 substituents when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group.
• halogen shall include iodine, bromine, chlorine, and fluorine.
• oxy means an oxygen (O) atom.
• thio means a sulfur (S) atom.
• substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
• Ci .5 alkylcarbonylamino Ci -6 alkyl substituent is equivalent to
• Illustrating the invention is the method wherein the ⁇ v integrin receptor antagonizing effect is an ⁇ v ⁇ 3 antagonizing effect. More particularly, the ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of: bone reso ⁇ tion, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, or metastatic tumor growth. In one embodiment of the method, the ⁇ v ⁇ 3 antagonizing effect is the inhibition of bone reso ⁇ tion. Another example of the invention is the method wherein the ⁇ v integrin receptor antagonizing effect is an ⁇ v ⁇ 5 antagonizing effect.
• the ⁇ v ⁇ 5 antagonizing effect is selected from inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, cancer, or metastatic tumor growth.
• the method wherein the ⁇ v integrin receptor antagonizing effect is a dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonizing effect.
• the dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonizing effect is selected from inhibition of: bone reso ⁇ tion, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, or metastatic tumor growth.
• a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier.
• Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
• Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
• the condition is selected from bone reso ⁇ tion, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, tumor growth, and metastasis. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.
• the invention is a method of eliciting an ⁇ v integrin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
• the ⁇ v integrin antagonizing effect is an ⁇ v ⁇ 3 antagonizing effect; more specifically, the ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of bone reso ⁇ tion, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammatory arthritis, or inhibition of cancer or metastatic tumor growth.
• the ⁇ v ⁇ 3 antagonizing effect is inhibition of bone reso ⁇ tion.
• the ⁇ v integrin antagonizing effect is an ⁇ v ⁇ 5 antagonizing effect or a dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonizing effect.
• Examples of ⁇ v ⁇ 5 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, or metastatic tumor growth.
• Additional examples of the invention are methods of inhibiting bone reso ⁇ tion and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions decribed above.
• Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hype ⁇ arathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
• More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone reso ⁇ tion, metastatic tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammatory arthritis, and/or angiogenesis.
• compositions further comprising an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) a cytotoxic/antiproliferative agent, e) a matrix metalloproteinase inhibitor, f) an inhibitor of epidermal-derived, fibroblast-derived, or platelet- derived growth factors, g) an inhibitor of VEGF, h) an antibody to a growth factor or to a growth factor receptor, i) an inhibitor of Flk-1/KDR, Fit- 1 , Tck/Tie-2, or Tie-1, j) a cathepsin K inhibitor, k) a growth hormone secretagogue, 1) an inhibitor of osteoclast proton ATPase, m) an inhibitor of urokinase plasminogen activator (u-PA), n) a tumor-specific antibody
• an active ingredient selected from the
• the active ingredient is selected from the group consisting of: a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) an inhibitor of osteoclast proton ATPase, e) an inhibitor of HMG-CoA reductase, and f) a cathepsin K inhibitor; and mixtures thereof.
• Nonlimiting examples of such bisphosphonates include alendronate, etidronate, pamidronate, risedronate, ibandronate, and pharmaceutically acceptable salts and esters thereof.
• a particularly preferred bisphosphonate is alendronate, especially alendronate monosodium trihydrate.
• Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.
• Nonlimiting examples of cytotoxic/antiproliferative agents are taxol, vincristine, vinblastine, and doxorubicin.
• Cathepsin K formerly known as cathepsin O2
• cathepsin O2 is a cysteine protease and is described in PCT International Application Publication No. WO 96/13523, published May 9, 1996; U.S. Patent No. 5,501,969, issued March 3, 1996; and U.S. Patent No. 5,736,357, issued April 7, 1998, all of which are inco ⁇ orated by reference herein in their entirety.
• Cysteine proteases specifically cathepsins, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthritis, and bone remodeling. At acidic pH's, cathepsins can degrade type-I collagen.
• Cathepsin protease inhibitors can inhibit osteoclastic bone reso ⁇ tion by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone reso ⁇ tion diseases, such as osteoporosis.
• statins Members of the class of HMG-CoA reductase inhibitors, known as the "statins,” have been found to trigger the growth of new bone, replacing bone mass lost as a result of osteoporosis (see The Wall Street Journal, Friday, December 3, 1999, page Bl). Therefore, the statins hold promise for the treatment of bone reso ⁇ tion.
• statins are lovastatin, simvastatin, atorvastatin, and pravastatin.
• PPAR ⁇ peroxisome proliferator-activated receptor- ⁇
• PPAR ⁇ peroxisome proliferator-activated receptor- ⁇
• ZD's thiazolidinediones
• PPAR ⁇ activators include troglitazone, pioglitazone, rosiglitazone, and BRL 49653.
• the present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis.
• the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, a cathepsin K inhibitor, an HMG-CoA reductase inhibitor, a PPAR ⁇ activator, or an inhibitor of the osteoclast proton ATPase.
• Additional illustrations of the invention are methods of treating cancer or metastatic tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound described above and one or more agents known to be cytotoxic/antiproliferative.
• the compounds of the present invention can be administered in combination with radiation therapy for treating cancer and metastatic tumor growth.
• the integrin ⁇ v ⁇ 3 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases include conditions which can benefit from a reduction in bone reso ⁇ tion.
• a reduction in bone reso ⁇ tion should improve the balance between reso ⁇ tion and formation, reduce bone loss or result in bone augmentation.
• a reduction in bone reso ⁇ tion can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions.
• osteoporosis including estrogen deficiency, immobilization, glucocorticoid-induced and senile
• osteodystrophy Paget's disease
• myositis ossificans Bechterew's disease
• malignant hypercalcemia metastatic bone disease
• metastatic bone disease periodontal disease
• cholelithiasis nephrolithiasis
• urolithiasis urolithiasis
• urinary calculus hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany.
• Increased bone reso ⁇ tion can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment.
• the present invention would be useful in increasing bone mass in patients with growth hormone deficiency.
• preferred combinations are simultaneous or alternating treatments of an ⁇ v ⁇ 3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably alendronate monosodium trihydrate.
• the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
• the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term "administering" is to be inte ⁇ reted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating integrin-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosis.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an ⁇ v ⁇ 3 antagonist.
• the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
• An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
• 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 5.0 mg/kg/day.
• the 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 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 intermittent throughout the dosage regimen.
• the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
• suitable pharmaceutical diluents, excipients or carriers collectively referred to herein as 'carrier' materials
• the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
• Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
• Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
• BOP Benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate.
• CBZ(Cbz) Carbobenzyloxy or benzyloxycarbonyl.
• CDl Carbonyldiimidazole.
• DIAD Diisopropyl azodicarboxylate.
• DIBAL-H Diisobutylaluminum hydride.
• DIPEA Diisopropylethylamine.
• DPFN 3,5-Dimethyl-l-pyrazolylformamidine nitrate.
• DPPF 1 , 1 ' -Bis(diphenylphosphino)-ferrocene.
• HOAc Acetic acid
• HOBT 1 -Hydroxybenzotriazole.
• LDA Lithium diisopropylamide.
• NEt 3 Triethylamine.
• NMM N-methylmo ⁇ holine.
• PCA-HC1 Pyrazole carboxamidine hydrochloride.
• PCTLC Preparative centrifugal thin-layer chromatography.
• Pd(PPh3)2Cl2 Dichlorobis(triphenylphosphine)palladium (U)
• Pd/C Palladium on activated carbon catalyst.
• TMEDA N,N,N',N'-Tetramethylethylenediamine.
• novel compounds of the present invention can be prepared according to the procedures of the following reaction Schemes and Examples, or modifications thereof, using readily available starting materials, reagents, and, where appropriate, conventional synthetic procedures. In these procedures, it is also possible to make use of variants which are themselves known to those of ordinary skill in the organic synthetic arts, but are not mentioned in greater detail.
• Step B 5-(2,4-diaminopyrimid-6-yl)pentanoic acid (2-3)
• Step C 3(S)- ⁇ f5-(2,4-diaminopyrimidin-6-yl)pentanovn-(N-methyl)amino ⁇ -3-
• Step A 3(S)-i r5-(3-aminoisoquinolin-l-yl)pentanoyll-(N-methyl)amino
• Step B 3(S)- 5-(3-amino-5,6,7,8-tetrahydroisoquinolin-l-yl)pentanoyll-(N- methyl)amino ⁇ -3-(6- methoxypyridin-3-yl)-propanoic acid (3-6)
• Step A [2-(2,6-Diiodo-pyridin-3-yloxy)-ethyn-carbamic acid tert-butyl ester
• Step B 2-(2,6-Diiodo-pyridin-3-yloxy)-ethylamine (4-3).
• Step C 6-Iodo-3,4-dihvdro-2H-pyridor3,2-bi ⁇ ,41oxazine (4-4).
• Step D 5-(3,4-Dihvdro-2H-pyridor3,2-bir 41oxazin-6-yl)-pent-4-ynoic acid butyl ester (4-5).
• Step E 5-(3,4-Dihydro-2H-pyridor3,2-b1[l,41oxazin-6-yl)-pentanoic acid butyl ester (4-6).
• Step F 5-(3,4-Dihvdro-2H-pyridor3,2-bin,41oxazin-6-yl)-pentanoic acid (4-
• Step G 3-(5-3,4-Dihvdro-2H-pyridor3,2-b1IT,41oxazin-6-yl-pentanoylamino)-
• Step H 3-(5-3,4-Dihvdro-2H-pyridor3,2-bllT,41oxazin-6-yl-pentanoylamino)-
• Step A 6-Iodo-3-nitro-pyridin-2-ylamine (5-2).
• Step C 6-Iodo-pyridor2,3-blpyrazine(5-4).
• Step D 5-Pyridor2,3-blpyrazin-6-yl-pent-4-ynoic acid butyl ester (5-5).
• Step E 5-(1.2.3,4-Tetrahvdro-pyridor2,3-blpyrazin-6-yl)-pentanoic acid butyl ester (5-6).
• Step F 5-(l,2,3,4-Tetrahvdro-pyridor2,3-b1pyrazin-6-yl)-pentanoic acid (5-7).
• Step G 3-(Ouinolin-3-yl)-3-(5-l,2,3,4-tetrahvdro-pyridor2,3-b1 ⁇ yrazin-6-yl- pentanoylaminoVpropionic acid ethyl ester (5-8).
• Step H 3-(Ouinolin-3-yl)-3-(5-l,2,3,4-tetrahvdro-pyridor2,3-blpyrazin-6-yl- pentanoylaminoVpropionic acid (5-9).
• a solution of 5_ (0.141 g, 0.305 mmol) and 1.0 N NaOH solution
• Step C 5-r6-(4-Methoxy-benzylamino)-pyridin-2-yll-pent-4-vnoic acid butyl ester (6-5)
• Step D 5-r6-(4-Methoxy-benzylarnino)-pyridin-2-yl1-pentanoic acid butyl ester
• Step E ⁇ 6- r6-(4-Methoxy-benzylamino)-pyridin-2-yll -2-oxo-hexyl I - phosphonic acid dimethyl ester (6-7)
• a solution of dimethyl methylphosphonate (2.48 g, 20 mmol) in anhydrous THF (30 mL) was cooled to -78° and treated dropwise with 2.5 M n-BuLi (8.0 mL). After stirring at -78° for 45 min, a solution of ester 6 ⁇ 6 (1.85 g, 5.0 mmol) in THF (10 mL) was added dropwise and the resulting solution stirred for 30 min at -78°, quenched with sat.
• Step F 7-r6-(4-Methoxy-benzylamino)-pyridin-2-yll-l-pyrimidin-4-yl-hept-l- en-3-one (6-8)
• pyrimidine-5-carbaldehyde (0.480 g, 4.44 mmol) in 15 mL DMF
• K2CO3 0.22 g, 6.67 mmol
• the mixture was stirred at ambient temperature for 15 hr, and concentrated to a paste. The residue was diluted with water, extracted with ethyl acetate, and dried over sodium sulfate.
• Step G 7-r6-(4-Methoxy-benzylamino)-pyridin-2-yll-l-pyrimidin-4-yl-hept-l- en-3-ol (6-9)
• Step H ( ⁇ ) 9-[6-(4-Methoxy-benzylamino)-pyridin-2-yll-3-pyrimidin-5-yl- non-4-enoic acid ethyl ester (6-10)
• Step I ( ⁇ )- 9-
• Step J ( ⁇ )- 9- ⁇ 6-[(4-Methoxy-benzyl)-methyl-aminol-pyridin-2-yl ⁇ -3- pyrimidin-5-yl-nonanoic acid ethyl ester (6-12)
• Step K 3(S or R)- 9-(6-Methylamino-pyridin-2-yl)-3-pyrimidin-5-yl-nonanoic acid ethyl ester (6- 13a)
• Step L 3(S or RV 9-(6-Methylamino-pyridin-2-yl)-3-(pyrimidin-5-yl)- nonanoic acid (6- 14a)
• Step A 4-Chloro-2,6-dipivaloylaminopyrimidine (7-2)
• Step B 5-(2,4-Dipivaloylaminopyrimidin-6-yl)pentanoic acid ethyl ester (7-3)
• Step C 7-(2,4-Dipivaloylaminopyrimidin-6-yl)-l-(quinolin-3-yl)-3-oxo-hept- 1-ene (7-5)
• Step D 9-(2,4-Dipivaloylaminopyrimidin-6-yl)-3-(quinolin-3-yl)-4-noneneoic acid ethyl ester (7-7)
• Step E 9-(2,4-Dipivaloylaminopyrimidin-6-yl)-3-(quinolin-3-yl)-nonanoic acid ethyl ester (7-8)
• the alkene 7 7 (1.02 g, 1.74 mmol) was dissolved in EtOH (50 mL) and degassed with argon. Palladium on carbon (10%; 100 mg) was added and the mixture stirred under an atmosphere of hydrogen gas (balloon) for 3 hours. The mixture was filtered through celite and the solvent removed to give the title compound 7 ⁇ 3 . which was used as such in the next step.
• Example 8-15 was prepared as shown in Scheme 8 following procedures (Scheme 9) disclosed in US Patent No. 6,048,861 (April 11, 2000) for the preparation of 3(S)-(2-methyl- ⁇ yrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[l,8]- naphthyridin-2-yl)-nonanoic acid (9-4) and related structures.
• Resolution of the enantiomeric pair can be carried out by chiral HPLC chromatography at either the allylic alcohol intermediate stage (9-2) to give the resolved (R)- and (S)-alcohols or at the reduced ester stage (9-3) to give the resolved (R)- and (S)-esters, which can then be hydrolyzed to afford the enantiomerically pure final products.
• Step A 5-(5-Bromo-pyridin-2-yl)-pentanoic acid ethyl ester (8-2)
• Step B 2-But-3-enyl-isoindole- 1 ,3-dione (8-5) To a stirred solution of 4-bromo-l-butene (8-3, 20 g, 148 mmol) in
• Step C 5- ⁇ 5-r4-(l,3-Dioxo-l,3-dihvdro-isoindol-2-yl)-butvn- ⁇ yridin-2-yll- pentanoic acid ethyl ester (8-6)
• a stirred solution of (4.23 g, 21 mmol) in degassed THF (20 mL) at 0°C was added dropwise a solution of 9-BBN (50.4 mL of 0.5 M in THF, 25.2 mmol) and the mixture stirred for 18 hours at ambient temperature.
• Step D 5-F5-(4-Amino-butyl)-pyridin-2-vH-pentanoic acid methylamide (8-7)
• 8 ⁇ 6 45 g, 110 mmol
• a saturated solution of methylamine in methanol 300 mL
• Step E 5-(6,7,8,9-Tetrahydro-5H-pyrido
• Step F 5-(6,7,8,9-Tetrahvdro-5H-pyrido[2,3-blazepin-2-yl)-pentanoic acid ethyl ester (8-9)
• a mixture of _& (3 g, 11.5 mmol) and 6 M HCl (100 mL) in a sealed tube was heated at 70°C for 12 hours. The mixture was cooled and concentrated to an oil. The residue was azeotroped from ethanol (50 mL) twice, then dissolved in 4 M
• Step G l-(2-Methyl-pyrimidin-5-yl)-7-(6,7,8,9-tetrahvdro-5H-pyridor2,3- bl azepin-2-yl)-hept- 1 -en-3 (R)-ol (8-12)
• 8-9 was converted into 8-11 in a similar fashion as 4 was converted into 1 ⁇ 5.
• methanol 20 mL
• NaBFL 0.166 g, 4.4 mmol
• Step H 3(R)-(2-Methyl-pyrimidin-5-yl)-9-(6,7,8,9-tetrahvdro-5H-pyridor2.3- b1azepin-2-yl)-non-4-enoic acid ethyl ester (8-13)
• Step J 3(S)-(2-Methyl-pyrimidin-5-yl)-9-(6,7,8,9-tetrahvdro-5H-pyridor2,3- b1azepin-2-yl)-nonanoic acid (8-15)
• 11-7 and 15-2 were converted into 15-3 utilizing the procedure for the conversion of 11-7 to 11-12.
• Step A 7-r6-(4-Methoxy-benzylamino)-pyridin-2-yl1-l-(2-methy1-pyrimidin-5- yl)-hept-l-en-3-one (16-1)
• Step B 7-[6-(4-Methoxy-benzylamino)-pyridin-2-yl1-l-(2-methyl-pyrimidin-5- yl)-hept-l-en-3-ol (16-4)
• Step C ( ⁇ )9-[6-(4-Methoxy-benzylamino)-pyridin-2-yl]-3-(2-methyl- pyrimidin-5-yl)-non-4-enoic acid ethyl ester (16-7)
• Step D 3(R)- and 3(S)- 9-r6-(4-Methoxy-benzylamino)-pyridin-2-yll-3-(2- methyl-pyrimidin-5-yl)-nonanoic acid ethyl ester (16-10)
• a solution of the 16-7 (2.3 g, 4.70 mmol) in 150 mL absolute EtOH was treated with 10% Pd-C (0.23 g, 10% by wt) at room temperature under an argon atmosphere.
• ammonium formate (1.78 g, 28.2 mmol) was added and the heterogeneous mixture was refluxed for 30 minutes. The reaction was >50% complete (by mass spectroscopy).
• Step E 3(R)- and 3(S)-9- ⁇ 6-[(4-Methoxy-benzyl)-methyl-amino1-pyridin-2- yl j-3-(2-methyl-pyrimidin-5-yl)-nonanoic acid ethyl ester (16-13)
• paraformaldehyde (0.10 g)
• acetic acid (0.129 mL, 2.26 mmol).
• NaCNBH 3 (0.0369 g, 0.558 mmol
• Step F 3(R)- and 3(S)-9-(6-Methylamino-pyridin-2-yl)-3-(2-methyl- pyrimidin-5-yl)-nonanoic acid (16-16)
• Step A 3(R)- and 3(S)-9-(6-rEthyl-(4-methoxy-benzyl)-aminol-pyridin-2-vU-
• Step B 3(RV and 3(S)-9-(6-Ethylamino-pyridin-2-yl)-3-(2-methyl-pyrimidin- 5-yl)-nonanoic acid (17-4)
• Step A 4-Amino-6-chloro-2-ethylaminopyrimidine (18-2)
• Step B 4-Pivaloylamino-6-chloro-2-ethylaminopyrimidine (18-4)
• Step C 5-(2-ethylamino4-pivaloylaminopyrimidin-6-yl)pentanoic acid ethyl ester (18-5) Following the procedure described for Example 7, compound 1 ⁇ 3, but using 18-4 as starting material, the title compound 18-5 was prepared as an oil.
• iH NMR 600 MHz, CDCI3: 7.77 (IH, br s), 7.33 (IH, s), 4.90 (IH, br s), 4.12 (2H, quintet), 3.39 (2H, quintet), 2.55 (2H, t), 2.32 (2H, t), 1.71 (4H, m), 1.30 (9H, s), 1.25 (2H, t), 1.20 (3H, t).
• Step D 9-(2-Ethylamino-4-pivaloylaminopyrimidin-6-yl)-l-(benzofuran-6- yl)hept-l-ene-3-ol (18-6 racemate, enantiomer A and enantiomer B)
• Step E 9-(4-Amino-2-ethylaminopyrimidin-6-yl)-3-(dihvdrobenzofuran-6- yPnonanoic acid (18-7A Enantiomer A)
• Step A 7-(2,4-Dipivaloylaminopyrimidin-6-yl)-l-(2-methylpyrimidin-5-yl)-3- hydroxy-hept-1-ene (20-1 racemate, enantiomer A and enantiomer B)
• Step B 9-(4-Amino-2-aminopyrimidin-6-yl)-3-(2-methylpyrimidin-5- vDnonanoic acid (20-2A Enantiomer A)
• Step C 9-(4-Amino-2-aminopyrimidin-6-yl)-3-(2-methylpyrimidin-5- yPnonanoic acid (20-2B Enantiomer B)
• Step B 7-(2-Ethylaminopyrimidin-6-yl)-l-(2-ethoxypyrimidin-5-yl)-3- hydroxy-hept-1-ene (21-4 racemate, enantiomer A and enantiomer B) Following the procedure described for Example 7, compound 7 ⁇ 6, but starting with 21-2 and using 2-ethoxypyrimidine-5-carbaldehyde, the title compound 21-4 was prepared as a racemate.
• Step A 7- [6-(4-Methox v-benzylamino)-pyridin-2-yl1 - 1 -quinoxalin-2-yl-hept- 1 - en-3-one (22-2)
• Step B ( ⁇ )7-r6-(4-Methoxy-benzylamino)-pyridin-2-yl1-l-quinoxalin-2-yl- hept-l-en-3-ol (22-3)
• Step C ( ⁇ )9-[6-(4-Methoxy-benzylamino)-pyridin-2-yl1-3-quinoxalin-2-yl- non-4-enoic acid ethyl ester (22-4)
• Step D ( ⁇ )9-r6-(4-Methoxy-benzylamino)-pyridin-2-yl]-3-quinoxalin-2-yl- nonanoic acid ethyl ester (22-5)
• Step D ( ⁇ )9- ⁇ 6-[(4-Methoxy-benzyl)-methyl-amino1-pyridin-2-yl ⁇ -3- quinoxalin-2-yl-nonanoic acid ethyl ester (22-6)
• Step E 3(R)- and 3(S)-9-(6-Methylamino-pyridin-2-yl)-3-quinoxalin-2-yl- nonanoic acid (22-7a and 22-7b)
• Step B (6-Bromo-pyrrolor2,3-b1pyridin-l-yl)-phenyl-methanone (23-2)
• a benzene solution (25 mL) of the N-oxide was treated simultaneously with two separate solutions (PhCOBr, 6.39 g, 34.5 mmol in benzene and TMS 2 NH 2.23 g, 13.8 mmol in benzene) via addition funnels at room temperature over a 1 h period.
• the solution was stirred overnight at room temperature.
• the solvent was removed in vacuo and the residue was purified by PCTLC (6 mm, 0 - 25% EtOAc - hexane) providing the 1.68 g (40% yield) of 23-2.
• Step C 5-(lH-Pyrrolor2.3-b1pyridin-6-yl)-pent-4-vnoic acid butyl ester (23-5a) and 5-r6-(4-Methoxy-benzylamino)-pyridin-2-yll-pent-4-ynoic acid butyl ester (23- 5b)
• Step D 5-(2,3-Dihvdro-lH-pyrrolor2,3-b1pyridin-6-yl)-pentanoic acid butyl ester (23-6)
• This material (0.839 g, 3.06 mmol) was treated with a 4.0 M HC1- dioxane solution (5 mL) at room temperature for lh, then concentrated in vacuo. The residue was dissolved in dry EtOH (30 mL), degassed (Argon purge), treated with 10% Pd-C (0.21 mg, 25% by weight), degassed, and purged to hydrogen atmosphere (balloon - 1 atmosphere).
• Step E r6-(2,3-Dihvdro-lH-pynOlor2,3-b1pyridm-6-yl)-2-oxo-hexyll- phosphonic acid dimethyl ester (23-7)
• Step F 7-(2,3-Dihvdro-lH-pyrrolor2,3-b1pyridin-6-yl)-l-(2-methyl-pyrimidin- 5-yl)-hept-l-en-3-one (23-8)
• Step G 7-(2,3-Dihvdro-lH-pyrrolor2,3-blpyridin-6-yl)-l-(2-methyl-pyrimidin-
• Step H 9-(l-Acetyl-2,3-dihvdro-lH-pyrrolor2,3-b1pyridin-6-yl)-3-(2-methyl- pyrimidin-5-yl)-non-4-enoic acid ethyl ester (23-10)
• Step I 9-(l-Acetyl-2,3-dihvdro-lH-pyrrolor2,3-blpyridin-6-yl)-3-(2-methyl- pyrimidin-5-yl)-nonanoic acid ethyl ester (23-11)
• Step J 3(R)- and 3(S)-9-(2,3-Dihvdro-lH-pyrrolor2,3-b1pyridin-6-yl)-3-(2- methyl-pyrimidin-5-yl)-nonanoic acid (23-12a and 23-12 b)
• 23-12 was resolved on a chiral AD column (2.54 x 20 cm), 8 ml/min, 70:20:10 Hexane (0.5% diethylamine):methanol (0.2% diethylamine): 1-propanol to give enantiomers 23-12a (faster-eluting) and 23-12b (slower eluting).
• iH NMR 400 MHz, CDCI3 ⁇ 8.50 (s, 2H), 7.19 (d, IH), 6.21 (d, IH), 3.82 (m, 2H),
• Step A (7-tert-Butoxycarbonylamino-2-oxo-heptyl)-phosphonic acid dimethyl ester (24-2)
• Step B f8-(2-Methyl-pyrimidin-5-yl)-6-oxo-oct-7-enyl1-carbamic acid tert- butyl ester (24-3)
• a solution of 24-2 (3.13 g, 9.28 mmol), potassium carbonate (1.75 g, 12.6 mmol), and 2-methyl-pyrimidine-5-carbaldehyde (1.04 g, 8.51 mmol) in THF (20 mL) was warmed to 40 °C for 5 h. The mixture was diluted with water and extracted four times with ether. The combined organics were washed with brine and dried (Na 2 SO 4 ).
• Step C f6-Hvdroxy-8-(2-methyl-pyrimidin-5-yl)-oct-7-enyl1-carbamic acid tert-butyl ester (24-4)
• a solution of 24 ⁇ 3 (1.419 g, 4.255 mmol) in THF (10 mL) and methanol (5 mL) was treated with sodium borohydride (162.0 mg, 4.282 mmol) and stirred at room temperature (1 h). The reaction was quenched with acetone and the solvent removed in vacuo. Purification via silica chromatography (hexane/ethyl acetate) afforded the title compound 24-4 (1.0 g).
• Step D 10-tert-Butoxycarbonylamino-3-(2-methyl-pyrimidin-5-yl)-dec-4-enoic acid ethyl ester (24-5)
• Step E 10-tert-Butoxycarbonylamino-3-(2-methyl-pyrimidin-5-yl)-decanoic acid ethyl ester (24-6)
• Step F 10-Amino-3-(2-methyl-pyrimidin-5-yl)-decanoic acid ethyl ester (24-7)
• a solution of 24-6 (495 mg, 1.21 mmol) in ethyl acetate (3 mL) was treated with a saturated solution HCl in ethyl acetate (10 mL) at room temperature overnight.
• the solvent was removed in vacuo to afford 24-7 (390 mg).
• the crude product was used directly in the next reaction.
• Step G 3-(2-Methyl-pyrimidin-5-yl)-10-(pyrimidin-2-ylamino)-decanoic acid ethyl ester (24-8)
• StepH 3-(2-Methyl-pyrimidin-5-yl)-10-(pyrimidin-2-ylamino)-decanoic acid
• Step I 3-(2-Methyl-pyrimidin-5-yl)-10-(l,4,5,6-tetrahvdro-pyrimidin-2- ylamino)-decanoic acid (24-10)

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