Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

• This invention relates to novel heterocycles which are useful as antagonists of the ⁇ v ⁇ 3 and related integrin receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, 5 alone or in combination with other therapeutic agents, for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions.
• Angiogenesis or neovascularization is critical for normal physiological processes such as embryonic 5 development and wound repair (Folkman and Shing, J.
• angiogenesis occurs pathologically, for example, in ocular neovascularization (leading to diabetic 0 retinopathy, neovascular glaucoma, retinal vein occlusion and blindness) , in rheumatoid arthitis and in solid tumors (Folkman and Shing, J. Biol. Chem., 1992, 267 :10931-10934; Blood and Zetter, Biochim. Biophys. Acta., 1990, 1032:118-128) .
• Tumor dissemination, or metastasis involves several distinct and complementary components, including the penetration and transversion of tumor cells through basement membranes and the establishment of self- sustaining tumor foci in diverse organ systems.
• angiogenesis is critical to tumor survival. Without neovascularization, tumor cells lack the nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934) .
• Inhibition of angiogenesis in animal models of cancer has been shown to result in tumor growth suppression and prevention of metastatic growth (Herblin et al., Exp. Opin. Ther. Patents. 1994, 1-14).
• angiogenic inhibitors have been directed toward blocking initial cytokine-dependent induction of new vessel growth, e.g. antibodies to endothelial cell growth factors.
• these approaches are problematic because tumor and inflammatory cells can secrete multiple activators of angiogenesis (Brooks et al., Cell, 1994, 7_9. :1157 " 1164 ) • Therefore, a more general approach that would allow inhibition of angiogenesis due to a variety of stimuli would be of benefit.
• Integrin ⁇ v ⁇ 3 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks et al., Science, 1994, 264;569-57l; Enenstein and Kramer, J. Invest. Dermatol., 1994, 103;381-386). Integrin ⁇ v ⁇ 3 is the most promiscuous member of the integrin family, allowing endothelial cells to interact with a wide variety of extracellular matrix components (Hynes, Cell, 1992, ⁇ 9_:ll-25) . These adhesive interactions are considered to be critical for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues.
• integrin ⁇ v ⁇ 3 promotes adhesive events important for angiogenesis
• this receptor also transmits signals from the extracellular environment to the intracellular compartment (Leavesley et al., J. Cell Biol., 1993, 121:163-170, 1993).
• the interaction between the ⁇ v ⁇ 3 integrin and extracellular matrix components promotes a calcium signal required for cell motility.
• the basement membrane zones of blood vessels express several adhesive proteins, including but not "limited to von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is ⁇ v / ⁇ 3 , the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin) , vitronectin, thrombospondin, and osteopontin. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell, smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology.
• ⁇ v ⁇ 3 integrin antagonists induced apoptosis of the proliferating angiogenic vascular cells, leaving pre-existing quiescent blood vessels unaffected.
• ⁇ v ⁇ 3 integrin antagonists have been shown to inhibit angiogenesis. Based on this property, therapeutic utility of such agents is expected in human diseases such as cancer, rheumatoid arthritis and ocular vasculopathies (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934) .
• integrins a gene superfamily
• Integrin subfamilies contain a common ⁇ -subunit combined with different ⁇ -subunits to form adhesion receptors with unique specificity.
• the genes for eight distinct ⁇ - subunits have been cloned and sequenced to date.
• ⁇ _ prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther- Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti- ⁇ _ antibodies provide evidence that ⁇ _/ ⁇ may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp.
• Anti- ⁇ 4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).
• the ⁇ v / ⁇ 3 heterodimer is a member of the ⁇ 3 integrin subfamily and has been described on platelets, endothelial cells, melanoma, smooth muscle cells, and osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al. , J. Cell. Biol. 1989, 109:1817- 1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759).
• the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombosponden in a manner mediated by the RGD sequence.
• a key event in bone resorption is the adhesion of osteoclasts to the matrix of bone.
• Studies with monoclonal antibodies have implicated the ⁇ v / ⁇ 3 receptor in this process and suggest that _ selective ⁇ v / ⁇ 3 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al. , J. Bone Miner. Res. , 1992, 7:335-343) .
• European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula:
• the present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes.
• the compounds of the present invention are useful for the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions in a mammal.
• One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the ⁇ v / ⁇ 3 or vitronectin receptor.
• the compounds of the present invention inhibit the binding of vironectin to ⁇ v / ⁇ 3 and inhibit cell adhesion.
• the present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders.
• the present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, thrombosis, inflammatory bowel disease and other autoimmune diseases.
• diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic
• kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including, but not limited to, angiogenic disorders.
• the present invention provides novel nonpeptide compounds of Formula I (described below) which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes.
• the compounds of the present invention are useful for the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions in a mammal.
• One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the ⁇ v / ⁇ 3 or vitronectin receptor.
• the compounds of the present invention inhibit the binding of vitronectin to ⁇ v / ⁇ 3 and inhibit cell adhesion.
• the present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders.
• the present invention comprises compounds of the Formula I:
• R 1 is selected from:
• a 1 and B 1 are independently -CH 2 - or -N(R 10 )-;
• J, K, L and M are independently selected from -C(R 2 )- or " -N-, provided that at least one of J, K, L and M is -C(R 2 )-;
• R 2 and R 3 when substituents on adjacent atoms, can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 R 7 ;
• R 2a is absent or R 12 ;
• U is selected from:
• V is selected from: - (CH 2 ) n -,
• W is selected from:
• X is selected from: a single bond (i.e., X is absent) -(C(R 4 ) 2 ) q - [C(R 4 ) (R ⁇ )] s -C(R 4 ) (R 9 )-
• Y is selected from:
• Z is selected from -CH(R 9 )-, or -N(R 16 )-;
• R 4 is selected from H, C_-C__ alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
• two R 4 groups on adjacent carbon atoms may join to form a bond, thereby to form a carbon-carbon double or triple bond between the adjacent carbon atoms;
• R 5 is selected from H, C_-Cg alkyl, C 2 -C 6 alkenyl, C 2 ' C ⁇ alkynyl, C 3 -C 7 cycloalkyl, C -C_ bicycloalkyl, hydroxy, C_-Cg alkoxy, Ci-C alkylthio, Cx-Cg alkylsulfinyl, C_-Cg alkylsulfonyl, nitro, C_-Cg alkylcarbonyl, C 6 -C_ 0 aryl, -N(R 11 -)R 12 , halo, CF 3 CN, Ci-Cg alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; R 6 is selected from:
• Cg to C_o aryl optionally substituted with 1-3 groups selected from halogen, C_-Cg alkoxy, C_-Cg alkyl, CF 3 , S(0)mMe, or -NMe 2 ;
• C to C_ ⁇ arylalkyl said aryl being optionally substituted with 1-3 groups selected from halogen, C_-Cg alkoxy, C_-Cg alkyl, CF 3 , S(0) p Me, or -NMe 2 , methylenedioxy when R 6 is a substituent on aryl, or a 5-10 membered heterocyclic ring containing 1-3 N, 0, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
• R 7 is selected from:
• Ci-Cio alkyl substituted with 0-3 R 6 , C 2 -C ⁇ o alkenyl, substituted with 0-3 R 6 , C 2 -C ⁇ o alkynyl, substituted with 0-3 R 6 ,
• R 9 is selected from H, hydroxy, C_-C_ 0 alkoxy, nitro,
• R 10 is selected from H, C_-Cg alkyl, C3-Cg alkenyl,
• R 11 is selected from hydrogen, hydroxy, C_ to Cg alkyl, C3-Cg alkenyl, C3 to C u cycloalkyl, C 4 to Cn cycloalkylmethyl, C_-Cg alkoxy, benzyloxy, Cg to C__ aryl, heteroaryl, heteroarylalkyl, C 7 to Cn arylalkyl, adamantylmethyl, or C_-C__ alkyl substituted with 0-2 R 4 ;
• R 10 and R 11 when both are substituents on the same nitrogen atom can be taken " together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-l-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C_-C 6 alkyl, Cg-C_o aryl, heteroaryl, C 7 -Cn arylalkyl, C_-C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C_-Cg alkoxycarbonyl, C -Cn arylalkoxycarbonyl
• R 12 is selected from: H, C_-C_o alkyl, triphenylmethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyoxy (SEM) , C_-C_o alkoxycarbonyl, Ci-Cio alkylcarbonyl, C_-C__ alkylsulfonyl, aryl(C_-C 10 alkyl) sulfonyl, arylsulfonyl, aryl(C 2 -C ⁇ o alkenyl) sulfonyl, heteroarylsulfonyl, aryl, C -Cg alkenyl, C 3 -C 11 cycloalkyl, C 4 -Cn cycloalkylalkyl, C -C ⁇ arylalkyl, C -Cn arylcarbonyl, C 4 -Cn cycloalkoxycarbonyl, C 7 -Cn bicycloalkoxy
• R 15 is selected from:
• R 6 , -C0 2 R 10 , -C( 0)N(R 10 )R ll ; Ci-Cio alkoxycarbonyl substituted with 0-2 R 6 ; c ⁇ -C_o alkyl, substituted with 0-3 R 6 ; C 2 -C ⁇ o alkenyl, substituted with 0-3 R 6 ; C ⁇ -C o alkoxy, substituted with 0-3 R 6 ; aryl, substituted with 0-3 R 6 ; or 5-10 membered heterocyclic ring containing 1-3 N,
• heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
• R 17 is selected from: H, C ⁇ -C ⁇ 0 alkyl, C 2 -Cg alkenyl, C 3 - C 11 cycloalkyl, C 4 -C_s cycloalkylalkyl, aryl, aryl (Ci-C_ 0 alkyl) - ;
• j_ s selected from: C_-C 8 alkyl substituted with 0-2 R 19 ,
• R 18b is selected from R 18a or H
• R 19 is selected from H, halogen, CF 3 , C0 2 H, CN, N0 2/
• R 20 is selected from hydroxy, C_ to C_ 0 alkyloxy, C 3 to Cn cycloalkyloxy, Cg to C__ aryloxy, C 7 to Cn
• R 21 is selected from: C ⁇ -C_ alkyl, C 2 -Cg alkenyl, C 3 -C 11 cycloalkyl, C 4 -Cn cycloalkylmethyl, C -Cio aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 5 ;
• R 22 is selected from:
• Preferred compounds of the present invention are compounds of Formula I:
• R 1 is selected from:
• A is selected from -CH 2 -, or -N(R 12 )
• a 1 and B are independently -CH 2 - or -N(R 10 )
• D is -N(R 12 ) -, or -s-
• J is either -C(R 2 )- or -N-
• K, L and M are independently selected from -C(R 2 )- or -C(R 3 )-;
• R 2 and R 3 when substituents on adjacent atoms can be taken together when substituents on adjacent atoms, with the carbon atoms to which they are attached, to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic with the carbon atoms to which they are attached, aromatic or nonaromatic ring system, said
• carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from C -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or N0 2 ;
• R a is absent or R 12 ;
• V is selected from: -(CH 2 ) n -, - (Ci-Cg alkylene) -Q- , substituted with 0-3 groups independently selected from R 13 ,
• Q is selected from: * -(CH 2 ) n -,
• W is selected from:
• X is selected from: a single bond (i.e., X is absent) or, -(C(R 4 ) 2 ) q - [C(R 4 ) (R 8 )] S -C(R 4 ) (R 9 )-;
• Y is selected from:
• Z is selected from -CH(R 9 )-, or -N(R 16 )-;
• R 4 is selected from H, Ci-Cio alkyl, Ci-Cio alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
• R 4 is selected from:
• Ci-Cio alkyl hydroxy, Ci-Cio alkoxy, nitro, Ci- Cio alkylcarbonyl, -N(R 11 )R 12 , cyano, halo,
• R 7 is selected from selected from H, C 1 - C 4 alkyl , hydroxy, C 1 - C 4 alkoxy, Cg - C ⁇ o aryl , C7 - C1 1 arylalkyl , (C ⁇ - C 4 alkyl) carbonyl , C0 2 R 18a , SO2R 11 , SO 2 I ⁇ R 10 R 11 , OR 10 , or N (R 11 ) R 12 ;
• R8 " is selected from:
• C 3 -C 8 cycloalkyl substituted with 0-1 R 6 , C_-Cg cycloalkenyl, substituted with 0-1 R 6 , aryl, substituted with 0-3 R 6 , or 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
• R 9 is selected from H, hydroxy, C 1 -C 10 alkoxy, nitro,
• N(R 10 )R 1:L , -N(R 16 )R 17 , OR 22 , C_-C_o alkyl substituted with 0-3 R 7 , aryl substituted with 0-3 R 7 , heteroaryl substituted with 0-3 R 7 ' C 1 -C 10 alkylcarbonyl; ryKCo- ⁇ alkyl) carbonyl, C1-C1 0 alkenyl, C 1 -C 10 alkynyl ,C 3 -C ⁇ o cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl(C ⁇ -Cg alkyl) -, heteroaryl (Ci- Cg alkyl)-, C0 2 R 18a , C( 0)R i8a , CONR i8a R 20 , S0 2 R 18a , or S0 2 R 18a R 2 °, provided that any of the above alkyl, cycloalkyl,
• Rio is selected from H, Ci-Ce alkyl, C 3 -C alkenyl,
• R 11 is selected from hydrogen, hydroxy, Ci to Cg alkyl, C 3 -Cg alkenyl, C 3 to Cn cycloalkyl, C 4 to Cn cycloalkylmethyl, Ci-Cg alkoxy, benzyloxy, Cg to Cio aryl, heteroaryl, heteroarylalkyl, C 7 to Cn arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4 ;
• R 10 and R 11 when both are substituents on the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-l-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: Ci-Cg alkyl, Cg-Cio aryl, heteroaryl, C 7 -C 11 arylalkyl, Ci-C alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, Ci-C ⁇ alkoxycarbonyl, C 7 -Cn arylalkoxycarbonyl, Ci-C
• R 12 is selected from:
• C ⁇ -Cg alkyl triphenylmethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyoxy (SEM) , (C ⁇ -Cg alkyl) carbonyl, (C ⁇ Cg alkoxy) carbonyl; (C ⁇ -C 6 alkyl)aminocarbonyl, C 3 -Cg alkenyl, C 3 -C 7 cycloalkyl, C 4 -Cn cycloalkylalkyl, aryl, heteroaryl (Ci-Cg alkyl) carbonyl, heteroarylcarbonyl, aryl C ⁇ -Cg alkyl, (Ci-C alkyl) carbonyl, or arylcarbonyl, Ci-C alkylsulfonyl, arylsulfonyl, aryl(C ⁇ -Cg alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (Ci-Cg alkyl
• R 13 is selected from: H, hydroxy, C 1 -C 10 alkoxy, nitro, N(R 10 )R 11 , -N(R 16 )R 17 , C_-C_ 0 alkyl substituted with 0-3 R 7 , aryl substituted with 0-3 R 7 , heteroaryl substituted with 0-3 R 7 , or C 1 -C 10 alkylcarbonyl;
• R 17 is selected from: H, Ci - C alkyl , C 3 - C 7 cycloalkyl ,
• Ri ⁇ a i s selected from: C ⁇ -C 8 alkyl, C 3 -Cn cycloalkyl, aryl(Ci-C alkyl) -, (Ci-Cg alkyl)aryl, heteroaryl(Ci-Cg alkylj -, (Ci-Cg alkyl)heteroaryl, biaryl(C ⁇ -Cg alkyl), heteroaryl, or aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19 ;
• R i8b is selected from R 18a or H;
• R 19 is selected from H, halogen, CF 3 , C0 2 H, CN, N0 2 ,
• JJR U R 12 C ⁇ -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3 -C 11 cycloalkyl, C -Cn cycloalkylalkyl, aryl(C ⁇ -Cg alkyl)-, Ci-C alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, -O-aryl, -S ⁇ 2 _ aryl, heteroaryl, or -S0 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C x -C 3 alkyl, or C ⁇ -C 3 alkoxy;
• R 20 is selected from hydroxy, Ci to C ⁇ 0 alkyloxy, C 3 to Cn cycloalkyloxy, C 6 to Cio aryloxy, C 7 to Cn aralkyloxy, C 3 to Cio alkylcarbonyloxyalkyloxy, C 3 to Cio alkoxycarbonyloxyalkyloxy, C 2 to C i0 alkoxycarbonylalkyloxy, C 5 to Cio cycloalkylcarbonyloxyalkyloxy, C 5 to Cio cycloalkoxycarbonyloxyalkyloxy, C 5 to Cio cycloalkoxycarbonylalkyloxy, C 7 to Cn aryloxycarbonylalkyloxy, C 8 to C i2 aryloxycarbonyloxyalkyloxy, Cs to C i2 arylcarbonyloxyalkyloxy, C 5 to C ⁇ 0 alkoxyalkylcarbonyloxyalkyloxy, C 5 to C i0 (5-alky
• R 21 is selected from: C ⁇ -C 8 alkyl, C2"C alkenyl, C 3 -C cycloalkyl, C 4 -C1 1 cycloalkylmethyl, C -Cio aryl, C 7 -C 11 arylalkyl, or C 1 -C 1 0 alkyl substituted with 0-2 R 7 ;
• n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 8-14;
• R 1 is selected from:
• R 2 and R 3 are independently selected from: H, C 1 -C alkoxy, NR X1 R 12 , halogen, N0 2 , CN, CF 3 , C ⁇ -C 6 alkyl, C 3 -Cg alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, Cg-Cio aryl substituted with 0-2 R 7 , C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, or C 7 -C 11 aryl carbonyl ;
• R 2 and R 3 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 R 7 ;
• V is selected from: -(CH 2 ) n -,
• Q is selected from: - ( CH ) n 0 ( CH2 ) m-,
• W is selected from:
• X is - ( CH 2 ) q - CH (R 8 ) - CH (R 9 ) - ;
• Y is - COR 20 ;
• R 6 is selected from:
• Cio aryl optionally substituted with 0-3 groups selected from halogen, Ci-C alkoxy, Ci-Cg alkyl, CF 3/ S(0)m e, or -NMe 2 ; a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl, or morpholinyl;
• R 7 is selected from:
• R8 is selected from:
• R 9 is selected from: H or -N(R 16 )R 17 ;
• R i o is selected from H or Ci-Cio alkyl, or C 7 -C ⁇ 0 arylalkyl;
• R 11 is selected from hydrogen, hydroxy, Ci to Cs alkyl, C 3 -Cg alkenyl, C 3 to Cn cycloalkyl, C 4 to Cn cycloalkylmethyl, Ci-Cg alkoxy, benzyloxy, Cg to Cio aryl, heteroaryl, heteroarylalkyl, C 7 to Cn arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4 ;
• R 10 and R 11 when both are substituents on the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-1etrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1- yrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; said heterocycle being optionally substituted with 1-3 groups selected from: Ci-C alkyl, Cg-C ⁇ 0 aryl, heteroaryl, C 7 -C 11 arylalkyl, C ⁇ C alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, Ci-C alkoxycarbonyl, C 7 -C n arylalkoxycarbonyl, Ci-Cg
• R 12 is selected from: H, Ci-Cg alkyl, triphenylmethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxyrrtethyoxy (SEM) , C ⁇ -C 4 alkoxycarbonyl, Ci-Cg alkylcarbonyl, Ci-C alkylsulfonyl, aryl (Ci-C alkyl) sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryl groups are substituted with 0-3 substituents selected from the group consisting of: C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, halo, CF 3 , and N0 2 ;
• R 13 is selected from: H, hydroxy, C ⁇ -C ⁇ 0 alkoxy,
• Ci-Cio alkyl substituted with 0-3 R 7 aryl substituted with 0-3 R 7 , heteroaryl substituted with 0-3 R 7 , or Ci-Cio alkylcarbonyl;
• R 17 is selected from H or C 1 -C 4 alkyl
• Ri ⁇ a is selected from: Ci-Cg alkyl, C 3 -Cn cycloalkyl, aryl(C ⁇ -C 6 alkyl)-, (Ci-Cg alkyl) aryl, heteroaryl (Ci-Cg alkyl) - , (C ⁇ -C 6 alkyl)heteroaryl, biaryKCi-Cg alkyl) , heteroaryl, or aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-2 R 19 ;
• R 19 is selected from H, halogen, CF 3 , C0 H, CN, N0 2 ,
• NR 1J -R 12 C ⁇ -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 11 cycloalkyl, C -Cn cycloalkylalkyl, aryl(C ⁇ -Cg alkyl)-, Ci-Cg alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, -o-aryl, -S ⁇ 2-aryl, heteroaryl, or -S0 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF3, C 1 -C3 alkyl, or C ⁇ -C 3 alkoxy;
• R 20 is selected from: hydroxy
• Ci Cio alkoxy; methylcarbonyloxymethoxy- ; ethylcarbonyloxymethoxy- ; t-butylcarbonyloxymethoxy- ; cyclohexylcarbonyloxymethoxy- ;
• R2I is selected from Ci-C ⁇ alkyl, C 2 "Cg alkenyl, C 3 -C 11 cycloalkyl, C 4 -Cn cycloalkylmethyl, Cg-Cio aryl, C 7 -C 11 arylalkyl, or C ⁇ -C ⁇ 0 alkyl substituted with 0-2 R 4 ;
• n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 8-14;
• R 1 -U taken together are selected from:
• R 2 and R 3 are independently selected from: H, C1-C 4 alkoxy, halogen, Ci-Cg alkyl, or C 3 -C 6 alkenyl;
• V is selected from:
• Q is selected from: - ⁇ CH 2 ) n- ,
• R 7 is selected from:
• R 8 is selected from:
• R 9 is selected from: H or -NHR 16 ;
• R 10 is selected from H or C 1 -C 10 alkyl
• R 11 is selected from hydrogen, hydroxy, C x to C 8 alkyl, C 3 -C 6 alkenyl, C 3 to Cn cycloalkyl, C 4 to Cn cycloalkylmethyl, Ci-Cg alkoxy, benzyloxy, Cg to Cio aryl, heteroaryl, heteroarylalkyl, C 7 to Cn arylalkyl, or adamantylmethyl;
• R 13 is selected from: H, hydroxy, C 1 -C 10 alkoxy,
• R i8 a i s selected from: C ⁇ -C 8 alkyl, C 3 -C 11 cycloalkyl, aryl (Ci-Cg alkyl) -, (Ci-Cg alkyl) aryl,
• R 19 is selected from: H, Br, F, CI, CF 3 , CN, NO 2/ NHR 11 , C 1 -C 4 alkyl, aryl, aryl(C ⁇ -C 4 alkyl)-, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, or -O-aryl, wherein said aryl groups are optionally substituted with 0-3 substituents selected from a group consisting of halogen, CF 3 , C ⁇ -C 3 alkyl, or C 1 -C 3 alkoxy;
• R 20 is selected from: hydroxy; Ci to Cio alkoxy; methylcarbonyloxymethoxy- ; ethylcarbonyloxymethoxy- ; t-butylcarbonyloxymethoxy- • ; eyelohexylcarbonyloxymet oxy- ; 1- (methylcarbonyloxy) ethoxy- ;
• n, and q are chosen such that the number of atoms connecting R 1 and COR 20 is in the range of 8-14;
• Specifically preferred compounds of .the above invention are compounds of Formula I, including enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof selected from the group consisting of:
• the compounds of Formula I above are useful as inhibitors of cell-matrix and cell-cell adhesion processes.
• the present invention includes novel compounds of Formula I and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host in need of such treatment a therapeutically effective amount of such compound of Formula I.
• the compounds of Formula I above are useful as inhibitors of ⁇ v ⁇ 3 .
• the compounds of the present invention inhibit the binding of vitronectin to ⁇ v ⁇ 3 and inhibit cell adhesion.
• the present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
• the compounds of Formula I of the present invention are useful for the treatment (including prevention) of angiogenic disorders.
• angiogenic disorders includes conditions involving abnormal neovascularization, such as tumor metastasis and ocular neovascularization, including, for example, diabetic retinopathy, neovascular glaucoma, age-related macular degeneration, and retinal vein occlusion, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
• the compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, thromboembolic disorders, restenosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, inflammatory bowel disease and other autoimmune diseases.
• the compounds of Formula I of the present invention may also be useful for wound healing.
• thromboembolic disorders includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
• the compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
• the compounds of the present invention can also be administered in combination with one or more additional therapeutic agents selected from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.
• anti-coagulant or coagulation inhibitory agents such as heparin or warfarin
• anti-platelet or platelet inhibitory agents such as aspirin, piroxicam, or ticlopidine
• thrombin inhibitors such as boropeptides, hirudin or argatroban
• thrombolytic or fibrinolytic agents such as plasminogen activators, anistreplase, urokinase,
• the compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect.
• the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component.
• a lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent.
• Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
• terapéuticaally effective amount it is meant an amount of a compound of Formula I that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
• administered in combination or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
• each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
• anti-coagulant agents denotes agents that inhibit blood coagulation.
• agents include warfarin (available as COUMADINTM) and heparin.
• anti-platelet agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
• agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
• NSAIDS non-steroidal anti-inflammatory drugs
• aspirin acetylsalicyclic acid or ASA
• Piroxicam is commercially available from Pfizer Inc.
• Suitable anti- platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use.
• Still other suitable platelet inhibitory agents include thromboxane- 2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
• thrombin inhibitors or anti-thrombin agents, as used herein, denotes inhibitors of the serine protease thrombin.
• thrombin-mediated processes such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted.
• thrombin-mediated platelet activation that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin
• fibrin formation include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
• Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
• Boroarginine derivatives and boropeptides include
• N-acetyl and peptide derivatives of boronic acid such as C-terminal ⁇ -aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof.
• hirudin includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
• Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference.
• boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
• thrombolytics or fibrinolytic agents
• fibrinolytics or fibrinolytics agents that lyse blood clots (thrombi) .
• agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof.
• Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, California.
• anistreplase refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No.
• urokinase is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
• Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
• the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of vitronectin or fibrinogen to ⁇ v ⁇ 3 .
• Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving ⁇ v ⁇ 3 .
• the compounds of the present invention may also be used in diagnostic assays involving ⁇ v ⁇ 3 -
• any variable for example but not limited to, R 2 , R 4 , R 6 , R 7 , R 8 , R 12 ,and R 14 , n, etc.
• its definition on each occurrence is independent of its definition at every other occurrence.
• said group may optionally be substituted with up to two R 4 and R 4 at each occurrence is selected independently from the defined list of possible R 4 .
• each of the two R 5a substituents on N is independently selected from the defined list of possible R 5a .
• each of the two R 7 substituents on C is independently selected from the defined list of possible R 7 .
• the substituent is piperazinyl, piperidinyl, or tetrazolyl
• said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
• stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• substituted means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• 2 hydrogens on the atom are replaced.
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "Ci-Cio” denotes alkyl having 1 to 10 carbon atoms) ;
• alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge;
• cycloalkyl is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamant
• alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
• alkylene alkenylene, phenylene, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I.
• alkylene alkenylene
• phenylene alkenylene
• phenylene arylene
• alkenylene alkenylene
• phenylene arylene
• Halo or "halogen” as used herein refers to fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like. .
• aryl or “aromatic residue” is intended to mean phenyl or naphthyl; the term
• arylalkyl represents an aryl group attached through an alkyl bridge.
• carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7 - to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
• carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
• heterocycle or “heterocyclic” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from l to 4 heteroatoms independently selected from the group consisting of N, 0 and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
• the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
• Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl) , pyri idinyl, furanyl (furyl) , thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, te
• heteroaryl refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl) , pyrimidinyl, furanyl (furyl) , thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl!
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of the compounds of Formula I are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
• Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
• prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like.
• Examples of representative carboxyl and amino prodrugs are included under the definition of R 2 , R 3 , and Y.
• the pharmaceutically acceptable salts of the compounds of Formula I include the conventional non- toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non- toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
• the pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base such as an alkali or alkaline earth metal hydroxide e.g.
• an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
• pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remingto 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
• the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
• the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
• Compounds of Formula I wherein the central heterocycle is a 3,5-disubstituted isoxazoline ring can be conveniently prepared by dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles (for reviews of 1,3-dipolar cycloaddition chemistry, see 1,3- Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984; Kanemasa and Tsuge, Heterocycles 1990, 30, 719) .
• the requisite nitrile oxides are in turn prepared from the corresponding aldehydes via the intermediate oximes.
• Scheme I illustrates one synthetic sequence which will provide the 3, 5-isoxazolines of this invention.
• hydroxylamine is treated with NCS in DMF according to the method of Liu, et al. (J ⁇ Org. Chem. 1980, _45_, 3916) .
• the resulting hydroximinoyl chloride is then dehydrohalogenated in situ using TEA to give a nitrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazoline.
• the oxime may be oxidatively chlorinated, dehydrochlorinated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508) .
• the compounds of the present invention wherein Y is an oxyalkoxy group may be prepared by reacting a suitably protected carboxylic acid of Formula I with an e.g. an alkoxycarbonyloxyalkyl chloride in the presence of an iodide source, such as tetrabutylammonium iodide or potassium iodide, and an acid scavenger, such as triethylamine or potassium carbonate, using procedures known to those skilled in the art.
• an iodide source such as tetrabutylammonium iodide or potassium iodide
• an acid scavenger such as triethylamine or potassium carbonate
• racemic ⁇ -amino acids may be purchased commercially or, as is shown in Scheme II, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299) .
• Racemic ⁇ -substituted- ⁇ -amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous ethanol (Scheme I, Method 2) or by reductive amination of ⁇ -keto esters as is described in published PCT patent application WO9316038.
• Enantiomerically pure ⁇ -substituted- ⁇ -amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding ⁇ -amino acids as shown in Scheme II, Method 3 (see Meier, and Zeller, Angew, Chem. Int. Ed. Engl. 1975, l ⁇ , 32; Rodriguez, et al. Tetrahedron Lett. 1990, 3_1, 5153; Greenlee, J. Med. Chem. 1985, 2j5, 434 and references cited within) ; and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme II, Method 4 (see Asymmetric
• N 2 -substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981) .
• the dipolarophiles used to prepare the compounds of this invention may be prepared by numerous methods.
• the ⁇ -alkenoic ester class of dipolarophile may be purchased commercially or prepared by oxidation of the corresponding ⁇ -alkenols by the method of Corey and Schmidt (Tetrahedron Lett. 1979, 399, Scheme III) .
• the reverse isoxazolines may be prepared by reaction of an appropriate nitro ester with an appropriately substituted alkene in the presence of a suitable dehydrating agent such as phenylisocyanate or phosphorus oxychloride in the presence of an organic amine base, such as triethylamine or diisopropylethylamine.
• a suitable dehydrating agent such as phenylisocyanate or phosphorus oxychloride
• an organic amine base such as triethylamine or diisopropylethylamine.
• N-protected aminoalkenes useful in the synthesis of compounds of this invention can be prepared from the commercially available alcohols as shown in Scheme IVb, via reaction with a suitable activating agent such as p- toluenesulfonyl chloride in the presence of a base such 0 as pyridine, followed by displacement with sodium azide in a suitable solvent such as DMF.
• a suitable activating agent such as p- toluenesulfonyl chloride
• a base such 0 as pyridine
• sodium azide in a suitable solvent such as DMF.
• Reduction of the azide by the action of triphenylphosphine in the presence of water (for example see, Scriven, E. F.V. , Turnbull, K. , Chemical Rev. 1988, 88, 297-360, and the references therein ) provides an amine which is suitably protected, for example, Fmoc, Boc or phthalimide group according to literature procedures. (Protecting Groups in
• nitroesters are available from commercial sources or can be synthesized according to literature methods (Seebach, D.et al . , Chem. Ber. 1982, 115, 1705-1720; Chaser. D.W., Syn . Comm . 1982, 841-842) .
• Oxidation of theresuiting alcohol the corresponding aldehyde can be achieved by numerous methods described in the literature (for example see Comprehensive Organic Transformations by Larock, R.C., p 604, 605, 607-613. VCH publishers, New York, New York, 1989) . Reductive amination of the intermediate aldehyde (for suitable methods see, Abdel-Magid, A. F. , Maryanoff, C. A., and Carson, K.G., Tetrahedron Lett .
• the reductive amination can be carried out in a two step procedure, wherein initial formation of an i ine is carried out by treatment of the aldehyde with the desired amine in the presence of a dehydrating agent such as magnesium sulf te, sodium sulfate, or molecular sieves, in a suitable solvent such as carbon tetrachloride, methylene chloride, benzene or toluene (for example see, Modern Synthetic Reactions 2nd ed.
• a dehydrating agent such as magnesium sulf te, sodium sulfate, or molecular sieves
• the imine is then subsequently reduced with a variety of reducing agents such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane or 1,2- dichloroethane, to provide the desired amines.
• reducing agents such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
• Bases suitable for this reaction include alkaline hydrogen carbonates, alkaline carbonates, cesium carbonate, alkaline hydrides, and alkaline alcoholates such as sodium ethoxide and potassium t- butoxide.
• the reaction can be run in a number of different solvents including lower alkyl and branched alcohols, ethereal solvents, or halocarbons, but it proceeds most readily in polar aprotic solvents such as DMF and DMSO. Saponification of the ester using standard conditions known to one skilled in the art provides an acid intermediate which can be converted using the methods described above into compounds of Formula I.
• Heterocyclic alkenes and aldehydes useful as intermediates for the preparation of compounds of formula I in the methods depicted in Schemes I-VII can be prepared as illustrated in Scheme Villa and Vlllb.
• the carboxylic acids prepared in scheme III can be converted to an acid halide, by a variety of methods, such as treatment with oxalyl chloride or thionyl chloride either neat or in the presence of a suitable solvent such as methylene chloride or toluene, as outlined in the literature (for example, see
• the ⁇ - haloketone can be treated with N-acetylguanidine in a suitable solvent such as acetonitrile from room temperature to reflux, or N,N-dimethylformamide from room temperature to 80°C according to the method of Little, T. L., and Webber, S. E. ( J. Org. Chem. , 1994, 59, 729S-7305.) to provide a 2-amino-4-imidazole derivative.
• a suitable solvent such as acetonitrile from room temperature to reflux, or N,N-dimethylformamide from room temperature to 80°C according to the method of Little, T. L., and Webber, S. E. ( J. Org. Chem. , 1994, 59, 729S-7305.) to provide a 2-amino-4-imidazole derivative.
• the resulting amines can be converted to additional compound of formula I by treatment with a wide variety of reagents, for example, acyl halides, chloroformates, isocyanates, sulfonylchlorides, chlorosulfonamides, and sulfonylisocyanates, etc. using standard methods.
• reagents for example, acyl halides, chloroformates, isocyanates, sulfonylchlorides, chlorosulfonamides, and sulfonylisocyanates, etc. using standard methods.
• N- (4-Oxobutyl)phthalimide Oxalyl Chloride (4.01ml; 46mmol) in 90ml dichloromethane was cooled at -78°C in a dry ice-acetone bath. Dimethylsulfoxide (4.26ml; 60mmol) in 22ml dichloromethane was then added dropwise and the mixture stirred at-78°C for 30 minutes. N-(4- Hydroxybuty1)phthalimide (9.108g; 41.5 mmol) in 45ml dichloromethane was then added and the mixture stirred in the -78°C bath for 45 minutes. The mixture was then warmed in a 0°C ice bath and stirred for one hour.
• Triethylamine (23g; 230mmol) in 23ml dichloromethane was then added and the stirred for an additional 30 minutes. The mixture was worked up by washing with water. The organic layer was separated, dried (MgS0 4 ) , filtered, concentrated and the residue purified by flash chromatography; 200g silica gel column using 1:3 ethyl acetate:Hexane to provide N- (4-oxobutyl)phthalimide as a white solid ( 7.469g; 82.8% yield) .
• the mixture was treated with tert-butyl-3-butenoate (5.42g; 38.1mmol) followed by triethylamine 2.70g (26.7mmol) added dropwise over a 2 hour period.
• the mixture was stirred at room temperature for 18 hours and worked up by washing with water, drying the organic layer (MgS0 4 ) , filtering, and concentrating.
• tert-Butyl 3- (3-aminopropyl) - (5R,S) -isoxazoline-5-yl acetate tert-Butyl 3- [3- (N-phthaloyl) aminopropyl] - (5R,S) -isoxazoline-5-yl acetate (6.025g; 16.2mmol) in 200ml ethanol was treated with hydrazine and the mixture stirred at room temperature for 18 hours. A thick white precipitate that had formed was filtered off and washed with more ethanol. The mother liquor was stripped and diluted with chloroform and washed with water.
• part G (199mg; O.Smmol) , methyl 3-amino-2-phenylsulfonylaminopropionate (147mg; 0.5mmol) , and triethylamine (lOOmg; lmmol) in 3ml dimethylformamide was treated with 265mg (0.6mmol) of benzotriazol-l-yloxy-tris (dimethylamino)phosphonium hexafluorophosphate (BOP Reagent) and the mixture stirred at room temperature for 18 hours. TLC indicated no starting material; the mixture was pumped to remove most of the dimethylformamide.
• BOP Reagent benzotriazol-l-yloxy-tris (dimethylamino)phosphonium hexafluorophosphate
• the aqueous layer was neutralized with IN HCI (0.6mmol) and then stripped.
• the residue was purified on a LH20 size exclusion column using 100% methanol as eluent.
• the product obtained was lyophilyzed from 2ml IN HCI followed by 2ml distilled water.
• the desired product was obtained as an off-white solid (68mg; 76.2% yield) .
• Example 56 2-benzyloxycarbonylamino-3- [ [3- [4- [ (N-imidazolin-2- yl)amino]butyl] - (5 R,S) -isoxazolin-5-yl] carbonylamino] - propionic acid
• 5-Phthalimidopentanol A mixture of 10.317 g (100 mmol) 5-amino-l-pentanol and 14.812 g (100 mmol) phthalic anhydride in 200 mL toluene was stirred 18 h under nitrogen at reflux while employing a Dean-Stark trap for removal of water. The reaction was allowed to cool to room temperature and solvent was removed.
• C__ 5-phthalimidopentanal oxime A mixture of 20.60 g (89.08 mmol) of the product obtained from Ex. 56, Step B, 250 mL pyridine arid 12.27 g (2 equivs) of hydroxylamine hydrochloride was stirred 18 hr under nitrogen at room temperature. Solvent was removed and the residue triturated under water.
• Example 83 2 (S) -Benzyloxycarbonylamino-3- [3- (4- (N- [3,4,5,6- tetrahydropyrimidin-2-yl]amino)butyl)isoxazolin-5- (R,S) - ylcarbonyl]aminopropionic acid.
• the title compound was prepared in an analogous manner to the compound of Example 56 by substitution of 2-methylthio-3,4,5,6-tetrahydropyrimidine hydroiodide for 2-methylthio-4,5-dihydroimidazole hydroiodide in Ex. 56, Part E. mp 101-108° C.
• Example 110 2 (S) -Benzyloxycarbonylamino-3- [3- (3- (N- [3,4,5,6- tetrahydropyrimidin-2-yl] amino)propyl) isoxazolin-5- (R,S) -ylcarbonyl]aminopropionic acid.
• A. 4-Phthalimidobutyraldehyde oxime A solution of 4- phthalimidobutyraldehyde (R. Hamilton et al., Tetrahedron Letters, 1993, 34, 2847) (17.38 g, 80 mmol) in pyridine (150 mL) was treated with hydroxylamine hydrochloride (6.67 g, 96 mmol) and stirred at room temperature for 17 h. After concentration, the residue was triturated in water, stirred for 3 h, and filtered to provide the title product as a light tan solid (14.15 g, 76%) : NMR (CDCI3) ⁇ 8.06 (b, IH) , 7.85 (m, 2H) , 7.70
• Example 284 2(S) -benzyloxycarbonylamino-3- [2- [3- (2- (N-imidazolin-2- yl) - aminoethyl) isoxazolin-5- (R,S) - yl] ethylcarbonylamino]propionic acid.
• Example 637 2 (S) -Benzyloxycarbonylamino-3- [5- (3- (N- [imidazolin-2- yl]amino)propyl) isoxazolin-3- (R,S) - ylcarbonyl]aminopropionic acid.
• Oxalyl chloride ( 7.30g, 0.0575M ) was dissolved in anhydrous methylene chloride and cooled to -60°C in a dry-ice/CHCl3 bath.
• Dimethylsulfoxide ( 9.38g, 0.12M ) was dissolved in anhydrous methylene chloride and added dropwise over 30 min. to the solution of oxalyl chloride, and allowed to stir for an additional 30 min.
• the product of Ex.667, part A. ( 10.75 g, 0.05M ) was dissolved in anhydrous methylene chloride (30 mL) and added to the reaction mixture dropwise over 45 min, and allowed to stirr for an additional 30 min.
• Example 669 2- (S) -Phenylsulfonylamino-3- [5- (R,S) - (4- (N- (pyridin-2- yl)amino)butyl) isoxazolin-3-ylcarbonyl] aminopropionic acid trifluoroacetate salt ___ Methyl-2- (S) -phenylsulfonylamino-3- [5- (R,S) - (4- (N- (pyridin-2-yl) -N- (tert -butyloxycarbonyl) - amino)butylisoxazolin-3-ylcarbonyl]aminopropionate: Methyl 3-amino-2-phenylsulfonylaminopropionate ( Hartman, G.D., Prugh, J.
• the lithium hydroxide solution was added and the reaction mixture was stirred at room temperature for 72 hrs.
• the resulting red solution was concentrated in vacuo and partioned between ethyl acetate ( lOOmL ) and water ( 50mL ) .
• a mixture of 1M Hydrochloric Acid (17ml) in Citric Acid (100ml) was added until the pH of the aqeous layer was ca. 4.
• the organic layer was separated and the aqueous layer extracted with ethyl Acetate (2 x 30ml) .
• A__ Methyl 3- [3- (tert-butyloxycarbonylamino)propyloxy] - 5-isoxazolecarboxylate Diethylazodicarboxylate (1.46g, 8.39 mmol) was added dropwise to a mixture of methyl 3- hydroxy-5-isoxazolecarboxylate (lg, 4.55 mmol), triphenylphosphine (l.46g, 8.39 mmol), and 3-tert- butyloxycarbonylamino-1-propanol (l.50g, 8.39 mmol) in anhydrous tetrahydrofuran (10 mL) at 0°C under nitrogen.
• Part B (0.5g, 1.75 mmol) , 0- (lH-benzotriazol-l-yl) -N,N,N « ,N * - tetramethyluronium tetrafluoroborate (0.70g, 1,83 mmol), and ethyl ⁇ -alanine hydrochloride (0.28g, 1.83 mmol) in anhydrous dichloromethane (30 mL) at 0°C under nitrogen. After the addition was completed the mixture was allowed to warm to room temperature and stirred for 7 h.
• A_ ; _ [2- (tert- butyloxycarbonylamino)ethyl]methanesulfonate Methanesulfonyl chloride (8.2g 71.6 mmol) in dichloromethane (45 mL) was added dropwise, over 8 min at ambient temperature to a stirring solution of 2-(t- butyloxycarbonylamino)ethan-l-ol and TEA(9.83g, 97.3 mmol) in dichloromethane (150 mL) . After 2.5 hr the reaction mixture was washed with IN HCI (2 x 50 mL) , water (2 x 50 mL) , and brine (50 mL) then dried over MgS0 4 .
• F__ 2 (S) -benzyloxycarbonylamino-3- [3- [2- (imidazolin-2-yl amino) ethyloxy] isoxazol-5-yl carbonyl amino]propionic acid: 2-methylthioimidazolinium iodide (114mg, O.Smmol), the compound of Ex. 1003, Part E (0.10g, 0.23mmol), and dimethylamino pyridine (60mg) were taken up in 1ml of pyridine then heated to reflux for 2-3 min. The reaction was cooled to between 70-80°C and stirred for 24hr.
• Example 1004 2(S) -benzyloxycarbonylamino-3- [[3- [3- [ (N-imidazolin-2- yl) amino]propyloxy] isoxazol-5-yl] carbonylamino]propionic acid

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