MXPA99011017A - QUINOLINE AND QUINOXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/OR p56lck - Google Patents
QUINOLINE AND QUINOXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/OR p56lckInfo
- Publication number
- MXPA99011017A MXPA99011017A MXPA/A/1999/011017A MX9911017A MXPA99011017A MX PA99011017 A MXPA99011017 A MX PA99011017A MX 9911017 A MX9911017 A MX 9911017A MX PA99011017 A MXPA99011017 A MX PA99011017A
- Authority
- MX
- Mexico
- Prior art keywords
- optionally substituted
- compound according
- further characterized
- dimethoxy
- amine
- Prior art date
Links
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 title claims abstract description 11
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 title claims abstract description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title description 12
- 150000003252 quinoxalines Chemical class 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 267
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 26
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 230000001413 cellular Effects 0.000 claims abstract description 9
- 230000035755 proliferation Effects 0.000 claims abstract description 9
- 230000004663 cell proliferation Effects 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 methylcyclopentyl Chemical group 0.000 claims description 156
- 239000000203 mixture Substances 0.000 claims description 82
- 239000011780 sodium chloride Substances 0.000 claims description 65
- 125000003545 alkoxy group Chemical group 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- 230000002401 inhibitory effect Effects 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 150000001412 amines Chemical class 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 229910052736 halogen Chemical group 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 229940002612 prodrugs Drugs 0.000 claims description 16
- 150000001204 N-oxides Chemical class 0.000 claims description 15
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 13
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 200000000008 restenosis Diseases 0.000 claims description 12
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 11
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 11
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 238000002399 angioplasty Methods 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 7
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 201000001320 atherosclerosis Diseases 0.000 claims description 6
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 5
- 210000003734 Kidney Anatomy 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 230000004761 fibrosis Effects 0.000 claims description 5
- 230000003463 hyperproliferative Effects 0.000 claims description 5
- FTXKUBNATJTYSH-UHFFFAOYSA-N methyl 4-[(6,7-dimethoxyquinoxalin-2-yl)amino]cyclohexane-1-carboxylate Chemical compound C1CC(C(=O)OC)CCC1NC1=CN=C(C=C(OC)C(OC)=C2)C2=N1 FTXKUBNATJTYSH-UHFFFAOYSA-N 0.000 claims description 5
- 150000004702 methyl esters Chemical class 0.000 claims description 5
- 150000002829 nitrogen Chemical group 0.000 claims description 5
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 5
- 201000004681 psoriasis Diseases 0.000 claims description 5
- CSLYLUOENYVUID-UHFFFAOYSA-N 2-cyclopentyloxy-6,7-dimethoxyquinoxaline Chemical compound N1=C2C=C(OC)C(OC)=CC2=NC=C1OC1CCCC1 CSLYLUOENYVUID-UHFFFAOYSA-N 0.000 claims description 4
- PVNGNXVCAKDIGS-UHFFFAOYSA-N 6,7-dimethoxy-2-(oxan-4-yloxy)quinoxaline Chemical compound N1=C2C=C(OC)C(OC)=CC2=NC=C1OC1CCOCC1 PVNGNXVCAKDIGS-UHFFFAOYSA-N 0.000 claims description 4
- 208000005017 Glioblastoma Diseases 0.000 claims description 4
- 210000004185 Liver Anatomy 0.000 claims description 4
- 210000004072 Lung Anatomy 0.000 claims description 4
- FVMOLSMWWNSWLX-UHFFFAOYSA-N N-(3-bicyclo[2.2.1]heptanyl)-6,7-dimethylquinoxalin-2-amine Chemical compound N1=C2C=C(C)C(C)=CC2=NC=C1NC1C(C2)CCC2C1 FVMOLSMWWNSWLX-UHFFFAOYSA-N 0.000 claims description 4
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 4
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims description 4
- 230000003176 fibrotic Effects 0.000 claims description 4
- JYDYHSHPBDZRPU-RNFRBKRXSA-N (1R,3R)-3-methylcyclohexan-1-amine Chemical compound C[C@@H]1CCC[C@@H](N)C1 JYDYHSHPBDZRPU-RNFRBKRXSA-N 0.000 claims description 3
- VJIOUBTXSNPMNO-UHFFFAOYSA-N 2,7-dicyclohexyloxy-6-methoxyquinoxaline Chemical compound N1=C2C=C(OC3CCCCC3)C(OC)=CC2=NC=C1OC1CCCCC1 VJIOUBTXSNPMNO-UHFFFAOYSA-N 0.000 claims description 3
- GRBVFGKKVXWZII-UHFFFAOYSA-N 2-(cyclopentylmethoxy)-6,7-dimethoxyquinoxaline Chemical compound N1=C2C=C(OC)C(OC)=CC2=NC=C1OCC1CCCC1 GRBVFGKKVXWZII-UHFFFAOYSA-N 0.000 claims description 3
- ZHAMQTUXCPUZFN-UHFFFAOYSA-N 2-cyclopentylsulfanyl-6,7-dimethoxyquinoxaline Chemical compound N1=C2C=C(OC)C(OC)=CC2=NC=C1SC1CCCC1 ZHAMQTUXCPUZFN-UHFFFAOYSA-N 0.000 claims description 3
- LZKQFCCBVWQXPE-UHFFFAOYSA-N 3-(6,7-dimethoxyquinolin-2-yl)cyclohexan-1-amine Chemical compound N1=C2C=C(OC)C(OC)=CC2=CC=C1C1CCCC(N)C1 LZKQFCCBVWQXPE-UHFFFAOYSA-N 0.000 claims description 3
- ZECSITHIZNOWKL-UHFFFAOYSA-N 3-cyclohexyloxy-6,7-dimethoxyquinoline Chemical compound C=1N=C2C=C(OC)C(OC)=CC2=CC=1OC1CCCCC1 ZECSITHIZNOWKL-UHFFFAOYSA-N 0.000 claims description 3
- URBJHKSWBUTEPR-TZMCWYRMSA-N 6,7-dimethoxy-N-[(1R,3R)-3-methylcyclohexyl]quinolin-3-amine Chemical compound C=1N=C2C=C(OC)C(OC)=CC2=CC=1N[C@@H]1CCC[C@@H](C)C1 URBJHKSWBUTEPR-TZMCWYRMSA-N 0.000 claims description 3
- URBJHKSWBUTEPR-OCCSQVGLSA-N 6,7-dimethoxy-N-[(1S,3R)-3-methylcyclohexyl]quinolin-3-amine Chemical compound C=1N=C2C=C(OC)C(OC)=CC2=CC=1N[C@H]1CCC[C@@H](C)C1 URBJHKSWBUTEPR-OCCSQVGLSA-N 0.000 claims description 3
- 206010003246 Arthritis Diseases 0.000 claims description 3
- 208000003432 Bone Disease Diseases 0.000 claims description 3
- 208000007766 Kaposi Sarcoma Diseases 0.000 claims description 3
- 206010024324 Leukaemias Diseases 0.000 claims description 3
- HFYHDNNINOTPHW-UHFFFAOYSA-N N-cyclohexyl-6,8-dimethylquinoxalin-2-amine Chemical compound C1=NC2=CC(C)=CC(C)=C2N=C1NC1CCCCC1 HFYHDNNINOTPHW-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 230000024245 cell differentiation Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 200000000018 inflammatory disease Diseases 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 3
- PDYLXMCEYVFXEF-UHFFFAOYSA-N 2-(3-bicyclo[2.2.2]octanyloxy)-6,7-dimethoxyquinoxaline Chemical compound C1C(CC2)CCC2C1OC1=CN=C2C=C(OC)C(OC)=CC2=N1 PDYLXMCEYVFXEF-UHFFFAOYSA-N 0.000 claims description 2
- BCNNPNXBUFWMLE-UHFFFAOYSA-N 4-(6,7-dimethoxyquinoxalin-2-yl)-3-azabicyclo[2.2.2]octan-2-one Chemical compound C1CC(C(=O)N2)CCC12C1=CN=C2C=C(OC)C(OC)=CC2=N1 BCNNPNXBUFWMLE-UHFFFAOYSA-N 0.000 claims description 2
- OMHPHFWGEQHURJ-UHFFFAOYSA-N 6,7-dimethoxy-2-(4-methoxycyclohexyl)oxyquinoxaline Chemical compound C1CC(OC)CCC1OC1=CN=C(C=C(OC)C(OC)=C2)C2=N1 OMHPHFWGEQHURJ-UHFFFAOYSA-N 0.000 claims description 2
- BXIVNNOVMZKTJO-UHFFFAOYSA-N 6,7-dimethoxy-N-(3-methylcyclopentyl)quinolin-3-amine Chemical compound C=1N=C2C=C(OC)C(OC)=CC2=CC=1NC1CCC(C)C1 BXIVNNOVMZKTJO-UHFFFAOYSA-N 0.000 claims description 2
- 208000006673 Asthma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 210000004351 Coronary Vessels Anatomy 0.000 claims description 2
- 210000001105 Femoral Artery Anatomy 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025650 Malignant melanoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
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- 201000005202 lung cancer Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- YSVWGWBSXUMUGW-UHFFFAOYSA-N methyl 4-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound COC(=O)C1CCC(NC(=O)N(CCCl)N=O)CC1 YSVWGWBSXUMUGW-UHFFFAOYSA-N 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 206010018651 Graft versus host disease Diseases 0.000 claims 1
- 208000009329 Graft vs Host Disease Diseases 0.000 claims 1
- 206010022114 Injury Diseases 0.000 claims 1
- RHZYQTPCJHEBKB-UHFFFAOYSA-N N-cyclohexyl-6-methoxy-7-morpholin-4-ylquinoxalin-2-amine Chemical compound N1=C2C=C(N3CCOCC3)C(OC)=CC2=NC=C1NC1CCCCC1 RHZYQTPCJHEBKB-UHFFFAOYSA-N 0.000 claims 1
- 230000003143 atherosclerotic Effects 0.000 claims 1
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- 210000004509 vascular smooth muscle cell Anatomy 0.000 claims 1
- 150000003248 quinolines Chemical class 0.000 abstract description 4
- 210000002744 Extracellular Matrix Anatomy 0.000 abstract description 3
- 230000004069 differentiation Effects 0.000 abstract description 3
- 230000020411 cell activation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 136
- 235000019439 ethyl acetate Nutrition 0.000 description 59
- 239000000243 solution Substances 0.000 description 59
- 210000004027 cells Anatomy 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000047 product Substances 0.000 description 40
- 239000008079 hexane Substances 0.000 description 35
- 229910001868 water Inorganic materials 0.000 description 35
- 239000007787 solid Substances 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- 239000002253 acid Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 238000007792 addition Methods 0.000 description 22
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 21
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- 238000004458 analytical method Methods 0.000 description 21
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 239000003112 inhibitor Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N Diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 14
- 108091007929 PDGF receptors Proteins 0.000 description 14
- 125000004432 carbon atoms Chemical group C* 0.000 description 14
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- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 13
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Abstract
This invention is directed to quinoline/quinoxaline compounds which inhibit platelet-derived growth factor or p56lck tyrosine kinase activity, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for treating a patient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release and/or T cell activation and proliferation.
Description
QUINOLINE AND QUINOXALINE COMPOUNDS THAT INHIBIT GROWTH FACTOR DERIVED FROM PLATELETS AND / OR p56 / c TIROSINE KINASES
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION This invention is directed to the inhibition of cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) and / or activation and proliferation of T cells using quinoline / quinoxallin compounds that are useful tyrosine kinase inhibitors (TKI). Cell signaling is mediated through a system of interactions that include contact between cells or contact between cell and matrix or contact between extracellular receptor and substrate. The extracellular signal is commonly communicated to other parts of the cell by means of a tyrosine kinase-mediated phosphorylation event that affects the substrate proteins downstream of the membrane of the cell bound to the signaling complex. A specific set of receptor enzymes such as the insulin receptor, the epidermal growth factor receptor (EGF-R) or the platelet-derived growth factor receptor (PDGF-R) are examples of tyrosine kinase enzymes that are involved in cell signaling. The autophosphorylation of the enzyme is required for efficient enzyme-mediated phosphorylation of substrate proteins containing tyrosine residues. It is known that these substrates are responsible for a variety of cellular events that include cell proliferation, cell matrix production, cell migration and apoptosis to name a few. It is understood that a large number of disease states are caused either by the uncontrolled reproduction of cells or by matrix overproduction or programmed poorly regulated cell death (apoptosis). These disease states include a variety of cell types and include disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and restenosis subsequent to angioplasty of the coronary, femoral or kidney arteries, or fibroproliferative diseases such as arthritis, fibrosis of the lung, kidney and liver. In addition, dysregulated cell proliferative conditions continue after coronary bypass surgery. It is believed that the inhibition of tyrosine kinase activity has utility in the control of uncontrolled cell reproduction or in overproduction of matrix or poorly regulated programmed cell death (apoptosis). It is also known that certain tyrosine kinase inhibitors can interact with more than one type of tyrosine kinase enzyme. Several tyrosine kinase enzymes are critical for the normal functioning of the body. For example, it would not be desirable to inhibit the action of insulin in most normal circumstances. Therefore, compounds that inhibit the activity of PDGF-R tyrosine kinase at concentrations lower than the effective concentrations for inhibiting insulin receptor kinase could provide valuable agents for the selective treatment of diseases characterized by cell proliferation and / or production of cell matrix and / or movement of cells (chemotaxis) such as restenosis. This invention relates to the modulation and / or inhibition of cell signaling, cell proliferation, extracellular matrix production, chemotaxis, the control of abnormal cell growth and the inflammatory response of cells. More specifically, this invention relates to the use of substituted quinoxaline compounds that exhibit selective inhibition of differentiation, proliferation or mediating release by effectively inhibiting tyrosine kinase activity and / or Lck tyrosine kinase activity of the platelet-derived growth factor receptor. (PDGF-R).
2. BACKGROUND OF THE INVENTION A number of literature reports describe tyrosine kinase inhibitors that are selective for tyrosine kinase receptor enzymes such as EGF-R or PDGF-R or non-receptor cytosolic tyrosine kinase enzymes such as v-abl, p56lck or c-src. Recent articles by Spada and Myers (Exp. Opin. Ther.Patents 1995, 5 (8), 805) and Baridges (Exp. Opin. Ther.Patents 1995, 5 (12), 1245) summarize the literature for tyrosine kinase inhibitors and selective EGF-R inhibitors respectively. In addition, Law and Lydon have condensed the anticancer potential of tyrosine kinase inhibitors (Emerging Drugs: The Prospect For Improved Medicines 1996,
241-260). Known inhibitors of PDGF-R tyrosine kinase activity
They include the quinoline-based inhibitors reported by Maguire et al. (J. Med. Chem. 994, 37, 2129) and by Dolle et al (J. Med. ChemA994, 37, 2627).
A class of phenylamino-pyrimidine-based inhibitors was recently reported by Traxler et al in EP 564409 and by Zimmerman, J. and Traxler,
P. et al. (Biorg. & Med. Chem. Lett. 1996, 6 (11), 1221-1226) and by
Buchdunger, E. et al. (Proc. Nat. Acad. Sci. 1995, 92, 2558). Despite progress in the field, there are no agents of these classes of compounds that have been approved for use in humans to treat proliferative diseases. The correlation between the multifactorial disease of restenosis with PDGF and PDGF-R is well documented throughout the scientific literature. However, recent developments in the understanding of fibrotic diseases of the lung (Anoniades, H. N. et al J. Clin. Invest.
1990, 86, 1055), kidney and liver (Peterson, T.C. Hepatology, 1993, 17, 486) have also implicated PDGF and PDGF-R as playing an important role.
For example, glomerulonephritis is a major cause of renal failure and PDGF has been identified as a potent mitogen for mesangial cells in vitro, as demonstrated by Shultz et al. (Am. J. Physiol.
1988, 255, F674) and by Floege, et al (Clin. Exp. Imnun., 1991, 86, 334). It has been reported by Thornton, S.C. et al (Clin. Exp. Imnun., 1991, 86, 79) that FNT-alpha and PDGF (obtained from human patients with rheumatoid arthritis) are the main cytokines involved in the proliferation of synovial cells. In addition, specific types of tumor cells have been identified (see Silver, BJ, Biofactors, 1992, 3, 217) such as glioblastoma and Kaposi's sarcoma, which overexpress either the protein or the PDGF receptor thereby leading to uncontrolled growth of cancer cells by an autocrine or paracrine mechanism. Therefore, it is anticipated that a PDGF tyrosine kinase inhibitor would be useful to treat a variety of disease conditions in apparently unrelated humans that could be characterized by the involvement of PDGF and / or PDGF-R in its etiology. The role of several non-receptor tyrosine kinases such as p56fc? (hereinafter "Lck") in conditions related to inflammation involving the activation and proliferation of T cells has been reviewed by Hanke, et al (Inflamm Res 1995, 44, 357) and by Bolen and Brugge (Ann Re. Immunol., 1997, 15, 371). These inflammatory conditions include allergy, autoimmune diseases, rheumatoid arthritis and rejection of transplants. Another recent review concludes several classes of tyrosine kinase inhibitors, including compounds that have Lck inhibitory activity (Groundwater, et al Progress in Medicinal Chemistry, 1996, 3, 233). Inhibitors of Lck tyrosine kinase activity include several natural products that are generally nonselective tyrosine kinase inhibitors such as staurosporine, genistein, certain flavones and erbstatin. Damnacantol was recently reported as a low nM Lck inhibitor (Faltynek, et al Biochemintry, 1995, 34, 12404). Examples of synthetic Lck inhibitors include: a series of dihydroxy-isoquinoline inhibitors reported to have low micromolar activity at submicromolar activity (Burke, et al J. Med. Cem. 1993, 36, 425) and a quinoline derivative which was found it was much less active with an IC50 of Lck of 610 micromolar. Researchers have also described a series of 4-substituted quinazolines that inhibit Lck on the low micromolar and submicromolar scale (Myers et al, WO 95/15758 and Myers, et al Bioorg, Med.Chem.Lett.R. 1997, 7, 417) . Researchers at Pfizer (Hanke, et al J. Biol. Chem. 1996, 271, 695) have described two specific pyrazolopyrimidine inhibitors known as PP1 and PP2, which have low nanomolar potency against Lck and Fyn (another Src family of kinase) . No inhibitory activity of Lck has been reported that refers to quinoline or quinoxaline-based compounds. Therefore, it is anticipated that an inhibitor of quinoline or quinoxaline quinoline-based tyrosine kinase activity would be useful for treating a variety of apparently unrelated human disease conditions that could be characterized by the involvement of Lck tyrosine kinase signaling. in its etiology.
BRIEF DESCRIPTION OF THE INVENTION
This invention is directed to a compound of formula I:
where: X is or L2Z2; Li is (CR3aR3b) r O (CRsgRsbJm-Zs-ÍCRs'aRs't n; L2 is (CR3aR3b) p- 4- (CR3'aR3'b) qo etenllo; Z1 is CH or N; Z2 is optionally substituted cycloalkyl, substituted cycloalkenyl opclonalmente, heterocyclyl optionally substituted or heterocyclenyl optionally substituted; Z3 is O, NR4, S, SO or SO2; Z4 is O, NR4, S, SO, SO2 or a bond; m is 0 or 1; n is 2 or 3 , and n + m = 2 or 3, p and q are independently 0, 1, 2, 3 or 4, and p + q = 0, 1, 2, 3 or 4 when Z * \ is a bond, and p + q = 0, 1 , 2 or 3 when £ 4 is not a bond, r is 2, 3 or 4;
Ia and Rib are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, alkoxy optionally substituted cycloalkoxy, optionally substituted heterocyclyloxy optionally substituted, heterociclilcarbonlloxi optionally substituted aryloxy optionally substituted heteroaryloxy optionally substituted, cyano, R5R6N- or aciloR5N-, or one of R1a and Rib is hydrogen or halogen and the other is alkyl optionally substituted, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, alkoxy optionally substituted cycloalkenyl, optionally substituted heterocyclyloxy optionally substituted, heterocyclylcarbonyloxy optionally substituted aryloxy optionally substituted, optionally substituted heteroaryloxy, cyano, RsRßN- or aciIR5N-. R? C is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, cycloalkyloxy optionally substituted heterocyclyloxy optionally substituted, heterocyclylcarbonyloxy optionally substituted aryloxy optionally substituted heteroaryloxy optionally substituted, halogen, cyano, RSRTN- O acylR5N-; 3a-R3, 3'a and are independently hydrogen or alkyl; R is hydrogen, alkyl or acyl; and R5 and R are independently hydrogen or alkyl, or R5 and RQ taken together with the nitrogen to which R5 and RQ are attached form azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or salt pharmaceutically acceptable thereof. Another aspect of the invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula I and a pharmaceutically acceptable carrier. The invention is also directed to intermediates useful for preparing compounds of the formula I, to methods for the preparation of the intermediates and compounds of the formula I, and to the use of a compound of the formula I to treat a patient suffering from, or is subject to, disorders / conditions involving cell differentiation, cell proliferation, production of extracellular matrix or mediator releaser and / or activation and proliferation of T cells.
DETAILED DESCRIPTION OF THE INVENTION
As used above and throughout the description of the invention, it should be understood that the following terms have the following meanings, unless otherwise indicated:
Definitions "Patient" includes both humans and other mammals. "Effective amount" means an amount of compound of the present invention effective to inhibit PDGF-R tyrosine kinase activity of and / or Lck tyrosine kinase activity, thereby producing the desired therapeutic effect. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched chain and having about 1 to about 10 carbon atoms. The alkyl which is preferred is the "lower alkyl" having about 1 to about 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halogen, carboxy, hydroxy or R5RßN-. Examples of alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl. "Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched and having from about 2 to about 10 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 6 carbon atoms in the chain; and most preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group can be replaced by carbalkoxy. Exemplary alkenyl groups include ethenyl, n-butenyl, / -butenyl, 3-methylbut-2-enyl, A? -pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl. "Ethanol" means a group -CH = CH-. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. The cycloalkyl group as a portion of the variables R? A, Rib or
R-ic is optionally substituted by one or more, preferably one to three, most preferably one to two, of the following "alkyl substituents": alkyl, hydroxy, acyloxy, alkoxy, halogen, R5R6N-, acylR5N-, carboxy or » R5R6NCO-, or a divalent oxygen (-O) on two adjacent carbon atoms to form an epoxide, the substituents which are most preferred are alkyl, hydroxy, aclloxy, alkoxy, bivalent oxygen and R5ReNCO-. The cycloalkyl group as a portion of the Z2 variables is optionally substituted by one or more, preferably one to three, most preferably one to two, of the following "cycloalkyl substituents": alkyl, alkoxy, halogen, R5R6N-, acylRsN-, carboxy or Rs-RECO-, or a divalent oxygen (-O) on two adjacent carbon atoms to form an epoxide, the most preferred substituents are alkyl, hydroxy, acyloxy, alkoxy, bivalent oxygen and RsRβNCO-. Further, when the cycloalkyl group is substituted with at least two hydroxy substituents, then at least two of the hydroxy substituents can be ketalized or acetalized with an aldehyde or ketone of one to six carbon atoms to form the corresponding ketal or acetal. The ketalization of a gem diol results in the formation of a spirofused ring system. A preferred spirocycloalkyl ring is 1,4-dioxaspiro [4.5] dec-8-yl. Preferred substituted and unsubstituted monocyclic cycloalkyl rings include cyclopentyl, hydroxycyclopentyl, fluorocyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxymethylcyclohexyl and cycloheptyl. More hydroxycyclohexyl and hydroxycyclopentyl are preferred. Exemplary cycloalkyl multicyclic rings include 1-decalin, adamant- (1- or 2-) yl, [2.2.1] bicoloheptanyl (norbornyl, hydroxy [2.2.1] bicycloheptanyl (hydroxynorbornyl), [2.2.2] bicyclooctanyl and hydroxy [2.2.2] bicyclooctanyl, more hydroxy [2.2.1] bicycloheptane (hydroxynorbornyl) and hydroxy [2.2.2] bicyclooctanyl are preferred. "Cycloalkenyl" means a monocyclic or non-aromatic multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms The cycloalkenyl group as a portion of the variables R-? a, R-? D or R? c, is optionally substituted by one or more, preferably one to three, most preferably one to two cycloalkyl substituents as described above The cycloalkenyl group as a portion of the Z2 variables, is optionally substituted by one or more, preferably one to three, most preferably one to two cycloalkyl substituents as described above The substituted or unsubstituted monocyclic cycloalkenyl rings that are preferred include cyclopentenyl, cyclohexenyl and cycloheptenyl; more cyclopentenyl and cyclohexenyl are preferred. Preferred multicyclic cycloalkenyl rings include [2.2.1] bicycloheptenyl (norbornenyl) and [2.2.2] bicyclooctenyl. "Aryl" means an aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl includes phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, wherein "aryl group substituent" includes hydrogen, hydroxy, halogen, alkyl, alkoxy, carboxy, alkoxycarbonyl or Y1Y2NCO-, wherein Y1 and Y2 are independently hydrogen or alkyl. Preferred aryl group substituents include hydrogen, halogen and alkoxy. "Heteroaryl" means an aromatic monocyclic or multicyclic hydrocarbon ring system of 5 to about 10 members in which one or more of the carbon atoms in the ring system is or are non-carbon elements, eg nitrogen, oxygen or sulfur. The designation of the prefix aza, oxa or thia as a prefix before heteroaryl defines that at least one nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The "heteroaryl" can also be substituted by one or more of the "aryl group substituents" mentioned above. Exemplary heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, pyrrolyl, imidazo [2,1-b] thiazolyl, benzofurazinyl indolyl, azaindoyl, benzimidazolyl, benzothienyl, quinolyl, imidazolyl and substituted izoquinolinyl. "Heterocyclyl" means a monocyclic or multicyclic ring system of about 4 to about 10 members in which one or more of the atoms in the ring system is an element that is not a carbon, chosen from nitrogen, oxygen or sulfur. The heterocyclyl group as a portion of the variables R a, R-t D or R c, is optionally substituted by one or more, preferably one to three, most preferably one to two cycloalkyl substituents as described above. The heterocyclyl group as a portion of the variables Z2) is optionally substituted by one or more, preferably one to three, most preferably one to two cycloalkyl substituents as described above. The designation of the prefix aza, oxa or thia as a prefix before heteroaryl defines that at least one nitrogen, oxygen or sulfur atom is present respectively as a ring atom. Monocyclic heterocyclyl groups include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Exemplary heterocyclic moieties include quinuclidinyl, pentamethylene sulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl, 7-oxabicyclo [2.2.1] heptanyl or 4-piperidinopiperidine. "Heterocyclycarbonyloxy" means a heterocyclyl-C (O) O- group in which the heterocyclyl is as defined herein. An exemplary heterocycliccarbonyloxy group is [1, 4 '] - biperidinyl-1'-carbonyloxy and (4-piperidinopiperid-1-ylcarbonyloxy). "Heterocyclenyl" means a monocyclic or multicyclic ring system that is partially unsaturated and in which one or more of the atoms in the ring system is an element that is not a carbon chosen from nitrogen, oxygen or sulfur. The heterocyclenyl group as a portion of the variables R-ta, R-? D or R? C, is optionally substituted by one or more, preferably one to three, most preferably one to two cycloalkyl substituents as described above. The heterocyclenyl group as a portion of the Z2 variables is optionally substituted by one or more, preferably one to three, most preferably one to two cycloalkyl substituents as described above. The designation of the prefix aza, oxa or thia as a prefix before heteroaryl defines that at least one nitrogen, oxygen or sulfur atom is present respectively as a ring atom. Representative monocyclic azaheterocyclenyl groups include 1, 2,3,4-tetrahydrohydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1, 2,3,6-tetrahydropyridyl, 1, 4,5,6-tetrahydropyrimidyl, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl and the like. Exemplary oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl and fluorodihydrofuranyl. A multicyclic oxaheterocyclenyl group is 7-oxabicyclo [2.2.1] heptenyl. Exemplary monocyclic thiaheterocyclenyl groups include dihydrothiophenyl and dihydrothiopyranyl.
"Acyl" means a group H-CO- or alkyl-CO- in which the alkyl group is as described above. The preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and caproyl. "Aroyl" means an aryl-CO- group in which the alkyl group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl. "Acoxy" means an alkyl-O- group in which the alkyl group is as previously described. The preferred alkoxy is "lower alkoxy" having about 1 to about 6 carbon atoms. The alkoxy may be optionally substituted by one or more of amino, alkoxy, carboxy, alkoxycarbonyl, carboxiaryl, carbamoyl or heterocyclyl. Exemplary alkoxy groups include methoxy, ethoxy, p-propoxy, / -propoxy, p-butoxy, heptoxy, 2- (morpholin-4-yl) ethoxy, 2- (ethoxy) ethoxy, 2- (4 -methylpiperazin-1-yl) ethoxy, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, carboxymethoxy and methoxycarbonylmethoxy. "Cycloalkyloxy" means a cycloalkyl-O- group in which the cycloalkyl group is as previously described. Exemplary cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, hydrocyclopentyloxy and hydroxycyclohexyloxy. "Heterocyclyloxy" means a heterocyclyl-O- group in which the heterocyclyl group is as previously defined. Exemplary heterocyclyloxy groups include qunuclidyloxy, pentamethylethyloxy sulfide, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy or 7-oxabicyclo [2.2.1] heptanyloxy, hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo [2.2.1] heptanyloxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously defined. "Heteroaryloxy" means a heteroaryl-O- group in which the heteroaryl group is as previously described. "Acyloxy" means an acyl-O- group in which the acyl group is as previously described. "Carboxy" means a group HO (O) C- (carboxylic acid). "5R6N-" means a substituted or unsubstituted amino group, wherein R5 and Re are as described above. Exemplary groups include amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino. "R5R6NCO-" means a substituted or unsubstituted carbamoyl group, wherein R5 and R6 are as previously described. Exemplary groups are carbamoyl (H2NCO-), N-methylcarbamoyl (MeNHCO-) and N, N-dimethylaminocarbamoyl (Me2NCO-). "Acyl R5N-" means an acylamino group in which R5 and acyl are as defined herein. "Halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred, and more fluorine or chlorine is preferred. "Prodrug" means a form of the compound of the formula I suitable for administration to a patient without undue toxicity, irritation, allergic response and the like, and effective for its desired dose, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to produce the parent compound of the above formula, for example by hydrolysis in the blood. A careful description is provided in T. Higuchi and V. stella. Pro-druqs as Novel Delivery Systems. Vol. 14 of A.C.S. Symposium Series, and in Edward B. Roche, ed. Bioreversible Carriers in Drug Desiqn. American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent binding, including hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystalline structure of the crystalline solid. "Solvate" covers solvates of both phase in solution and isolates. Representative solvates include ethanolates, methanolates and the like. "Hydrate" is a solvate in which the solvent molecule is or are H2O.
Preferred Modes One aspect of the compound that is preferred in the invention is a compound of the formula I wherein Li is (CR3aR3b) m-Z3- (CR3'aR3'b) n; L is (CR3aR3b) p- 4- (CR3'aR3'b) q;
Z2 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocyclyl; Z4 is O and NR4; M is O; N is 2 or 3; p + q = O or 1: R-ia and Rib are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heteroxykyloxy or RSRTN, O one of R and R and R is hydrogen or halogen and the other is alkyl optionally substituted, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heteroxykyloxy or R5R6N-; R-ic is hydrogen, optionally substituted alkyl or optionally substituted alkoxy; R3a, R3b > R3-a and R3'b are independently hydrogen or lower alkyl; R is hydrogen and s and Re taken together with the nitrogen atom to which R5 and e are attached form azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein:
X is L2Z2; Z2 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl; Z3 is O and NR4; p is 0; q is 0 or 1; Ria and Rib are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy, or one of R-? A and R ^ is hydrogen or halogen; R-ic is hydrogen; R3'a and R3'b are independently hydrogen and * is hydrogen, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Li is lower alkyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Zi is CH. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Zi is N.
Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z2 is optionally substituted cycloalkyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z 2 is alkyl-substituted monocyclic cycloalkyl; very preferred methylcyclopentyl or methylcyclohexyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z 2 is multicyclic cycloalkyl; highly preferred [2.2.1] bicycloheptanyl (norbornyl) and [2.2.2] bicyclooctanyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z2 is optionally substituted cycloalkenyl; very preferred cyclopentenyl and cyclohexenyl. Preferred multicyclic cycloalkenyl rings include [2.2.1] bicycloheptanyl (norbornyl) and [2.2.2] bicyclooctanyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z 2 is cyclopentenyl or cyclohexenyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z 2 is multicyclic cycloalkenyl; highly preferred [2.2.1] bicycloheptanyl (norbornyl) and [2.2.2] bicyclooctanyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein p and q are 0. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein p + q = 1.
Another aspect of the compound that is preferred in the present invention is a compound of the formula I wherein Z4 is O. Another aspect of the compound that is preferred in the present invention is a compound of the formula I wherein Z4 is O, ypyq are 0. Another aspect of compound that is preferred in the present invention is a compound of formula I wherein Z4 is O, and p + q = 1. Another aspect of compound that is preferred in the present invention is a compound of the formula I wherein Z4 is NR4. Another aspect of the compound that is preferred in the present invention is a compound of the formula I wherein Z4 is NR4, and p and q are 0. Another aspect of the compound that is preferred in the present invention is a compound of the formula I wherein Z4 is NR4, and m + n = 1. Another aspect of compound that is preferred in the invention is a compound of the formula I wherein Z4 is S. Another aspect of compound that is preferred in the invention is a compound of the formula I wherein Z4 is S, and p and p are 0. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z * \ is S and p + q = 1. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R and R1 are independently hydroxy-substituted lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy, or one of R a and R e is hydrogen or halogen
Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R a and R y are independently heterocyclylcarbonyloxy or optionally substituted alkoxy; most preferably the lower alkoxy is methoxy or ethoxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R a and R are lower alkyl; most preferably the lower alkyl is methyl or ethyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein one of R a and R 2 is lower alkoxy, and the other of R a and R 4 is halogen; most preferably the lower alkoxy is methoxy or ethoxy, and the halogen is chloro or bromo. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein one of R a and R b is lower alkyl, and the other of R a and Rib is lower alkoxy; most preferably the lower alkoxy is methoxy or ethoxy, and the lower alkyl is methyl or ethyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein one of R a and R 4 is lower alkoxy, and the other of R a and R 4 is cycloalkyloxy; most preferably the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein one of R1a and R? B is hydrogen, and the other of R? A and R ^ is lower alkoxy, cycloalkyloxy or heterocyclyloxy; most preferably, lower alkoxy is methoxy or ethoxy, and cycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and heterocyclyloxy is furanyloxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R c is hydrogen, lower alkyl or lower alkoxy; most preferably the lower alkoxy is methoxy or ethoxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Z2 is hydroxycycloalkyl (hydroxy or substituted alkyl), most preferably it is hydroxycycloalkyl (lower alkyl). Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R a and R are lower alkoxy wherein the lower alkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. Another aspect of the compound which is preferred in the invention is a compound of the formula I wherein one of R a and R b is unsubstituted lower alkoxy, and the other of R a and R b is lower alkoxy substituted by alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein one of R a and R is [1,4 '] - bipiperadin-1' -carbonyloxy, 2- (ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy, 2- (4-methylpiperazinyl-1-yl) ethoxy, carboxymethoxy, methoxycarbonylmethoxy, aminocarbonylmethoxy, N-methylaminocarbonylmethoxy or N, N-dimethylaminocarbonylmethoxy. The preferred compounds according to the invention are selected from the following species: 3-cyclohexyloxy-6,7-dimethoxy-quinoline; 2-cyclohexylamino-6,7-dimethoxyquinoline; exo-bicyclo [2.2.1] hept-2-yl- (6-chloro-7-methoxyquinolalin-2-yl) amine; exo-bicyclo [2.2.1] hept-2-yl- (7-chloro-6-methoxy-quinoxalin-2-yl) amine; bicyclo [2.2.1] hept-2-yl- (6,7-dimethyl-quinoxalin-2-yl) -amine; 2-cycloheptylamino-6,7-dimethoxyquinolaline; 2-cyclopentylamino-6,7-dimethoxyquinolaline; 2-cyclohexylamino-6-methoxyquinolaline; 3-aminocyclohexyl-6,7-dimethoxyquinoline; (6,7-dimethoxy-quinolin-3-yl) -cis- (3- (R) -methyl-cyclohexyl) amine; 2-cyclohexylamino-6-methoxy-7-bromo-quinoxaline hydrochloride; (6,7-dimethoxyquinolin-3-yl) -cis / trans- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxyquinol-3-yl) -trans- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxyquinolin-3-yl) -cis- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxyquinolin-3-yl) - (3-methyl-cyclopentyl) -amine; cyclohex-3-enyl- (6,7-dimethoxyquinolalin-2-yl) -amina; 2,7-bis-cyclohexyloxy-6-methoxy-quinoxaline; cyclohexyl- (6,7-dimethoxy-quinotoxan-2-ylmethyl) -amine; (6,7-dimethoxyquinolin-3-yl) -isobutyl amine; cyclohexyl- (6-methoxy-7-morpholin-4-yl-quinoxalin-2-yl) -amina; (±) -bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) amine; exo-bicyclo [2.2.1] hept-5-en-2-yl- (6,7-dimethoxyquinolaln-2-yl) -amine;
cyclohexyl- (6,8-dimethyl-quinoxalin-2-yl) -amine; endo-bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine; (6,7-dimethoxyquinolaln-2-yl) - (4-methoxy-cyclohexyl) -amine; Exo-bicyclo [2.2.1] hept-2-yl- (6-methoxyquinolalin-2-yl) -amine; exo-2- (bicyclo [2.2.2] hept-2-yloxy) -6,7-dimethoxyquinoline: (bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline; endo-2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline; exo-2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline; bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline; 2-cyclohexyloxy-6,7-dimethoxyquinoaline; 2-cyclopentylthio-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline; 2-Cyclopentylmethyloxy-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-tetrahydropyran-4-oxy-quinoxaline; exo, exo-6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptan-2-yloxy) -quinoxaline; cis / trans-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanecarboxylic acid; 6,7-dimethoxy-2- (4-methoxy-cyclohexyloxy) -quinoxaline; (1 R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxy-quinol-2-yl) -amine; (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolaln-2-yl) -amine;
(6,7-dimethoxy-quinoxalin-2-yl) -2-aza-bicyclo [2.2.2] octane-3-one; cis / trans-4- (6,7-dimethoxy-quinoxalyn-2-ylamino) -cyclohexanecarboxylic acid methyl ester; cis / trans-4- (6,7-dimethoxy-quinoxalyn-2-ylamino) -cyclohexanecarboxylic acid; cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; methyl ester of trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; (6,7-dimethoxy-quinoxalin-2-yl) -cis / trans- (3- (R) -methylcyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) -trans- (3- (R) -methylcyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) -cis- (3- (R) -methylcyclohexyl) amine; or methyl cis / trans-4- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexancarboxylate, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically salt acceptable of them. The most preferred compounds are the following: 2-cyclohexyloxy-6,7-dimethoxyquinitol; exo-bicyclo [2.2.1] hept-2-yl- (6-chloro-7-methoxyquinolalin-2-yl) amine; exo-bicyclo [2.2.1] hept-2-yl- (7-chloro-6-methoxy-quinoxalin-2-yl) amine; bicyclo [2.2.1] hept-2-yl- (6,7-dimethyl-quinoxalin-2-yl) -amine; 2-cycloheptylamino-6,7-dimethoxyquinolaline;
2-cyclopentylamino-6,7-d-methoxyquinoline; 3-aminociclohexil-6,7-d¡methoxyquinoline; (6,7-dimethoxy-quinolin-3-yl) -cis- (3- (R) -methyl-cyclohexyl) amine; (6,7-dimethoxyquinolin-3-yl) -c 's / trans- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxyquinolin-3-yl) -trans- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxyquinolin-3-yl) -cis- (3- (R) -methyl-cyclohexyl) -amine; cyclohex-3-enyl- (6,7-dimethoxyquinolalin-2-yl) -amine; 2,7-bis-cyclohexyloxy-6-methoxy-quinoxaline; (6,7-dimethoxyquinolin-3-yl) -isobutyl amine; (+) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinol-2-yl) amine; exo-bicyclo [2.2.1] hept-5-en-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine; endo-bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine; exo-bicyclo [2.2.1] hept-2-yl- (6-methoxyquinol-2-yl) -amine; exo-2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxyquinol: 2- (bicyclo [2.2.2] oct-2 -loxy) -6,7-dimethoxy -quinoxaline; endo-2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaIine; exo-2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline; 2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline; 2-cyclohexyloxy-6,7-dimethoxyquinolaline; 2-cyclopentylthio-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline; 2-cyclopentylmethyloxy-6,7-dimethoxy-quinoxaline;
6,7-dimethoxy-2-tetrahydropyran-4-oxy-quinoxaline; exo, exo-6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptan-2-yloxy) -quinoxaline; 6,7-dimethoxy-2- (4-methoxy-cyclohexylloxy) -quinoxaline; (1 R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinol-2-yl) -amine; (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinol-2-yl) -amine; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; methyl ester of trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; (6,7-dimethoxy-quinoxalin-2-yl) -cis / trans- (3- (R) -methylcyclohexyl) amine; (6,7-dimethoxy-quinoxalyn-2-yl) -trans- (3- (R) -methyl-cyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) -cis- (3- (R) -methyl-cyclohexyl) amine; and methyl cis / trans-4- (6,7-dimethoxy-quinxoalin-2-yloxy) -cyclohexancarboxylate, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
It should be understood that this invention covers all suitable combinations of the particular and preferred groupings mentioned herein. The compounds of this invention can be prepared using procedures known in the literature starting from known compounds or easily prepared intermediates. Following are exemplary general procedures. In addition, the compounds of the formula I are prepared according to the following schemes l-Vlll, wherein the variables are as described above, except those variables that one skilled in the art would appreciate were incongruent with the described method.
SCHEME I
SCHEME II
SCHEME
SCHEME IV
SCHEME V
SCHEME VI
wherein at least one of R a, R e and R e is lower alkoxy and X '"is Where at least one of R a,
L "OP" or L2Z2 where P 'is a Rb and Rie are defined herein, and where suitable protective group for X is LiOP', the protecting group P 'is to protect a hydroxyl portion in then removed to provide the presence and a base and of a corresponding alkylating OH portion agent
In Schemes VI, VII and VIII, R represents a precursor group to RIA, R1 and R1C as defined herein, such that the reaction of RBr, ROH, or RCOCI with the aromatic hydroxy group under the conditions described in schemes VI, VII and VIII result in the formation of R | a,
Rlb and R? .c Representative RBr moieties include bromoacetic acid and methyl and ethyl bromoacetate. Representative ROH moieties include 2-ethoxyethanol, 2- (4-mofolinyl) ethanol and 3- (4-methylpyrazinyl) propanol. A representative RCOCI portion is [1,4'-b] pperidin-1'-ylcarbonyl chloride.
SCHEME Vil
wherein X '"is L1OP" or L2Z2, wherein P "is a suitable group described for in Schemes I, II, III or IX protecting a hydroxyl portion under the reaction conditions described in Schemes I, II, III and IX
SCHEME VIII
as described where X '"is L ^ P'" or in Schemes I, II, III or IX L2Z2 where P "and P" are suitable groups to protect a hydroxyl portion under the reaction conditions in the schemes
SCHEME IX
Catalyst of Ni Xa is Cl, Br or I X '"is (L ^ P' or L2Z2), Where X '" is where P' is a LiOP 'after the group suitable for OP' portion can protect a portion become in the hydroxy in the presence OH portion of a corresponding Gringard reagent using a
adequate deprotection
SCHEME X
SEO, sNaBH. Wittig
1) Zj amine to form mine 1) base 2) NaBH4 2) Zg-electrophile
I. GENERAL PROCEDURES
1. - Duplication of 2-chloro substituted quinoxaline and amines or anilines A mixture of 2-chloro-6,7-dimethoxyquinolaline (1 eq.) And an amine (about 1 to about 5 eq.) Was heated to about 160 to about 180 ° C for about 3 hours or overnight. The dark brown residue was dissolved in methanol / methylene chloride (0% -10%) and subjected to chromatography on silica gel eluted with hexane / ethyl acetate or methanol / methylene chloride (0% -100%) to give the desired product. The desired product can also be purified by recrystallization from methanol, methylene chloride or methanol / water.
2. - Duplication of 2-chloro substituted quinoxaline and alcohols or phenols A suspension of an alcohol or mercaptan (1 eq.) And sodium hydride (about 1 to about 3 eq.) In anhydrous DMF / THF (0% -50%) it was refluxed for 1 hour before adding 2-chloro-6,7-dimetixoquinoxaline (1 eq.). The resulting mixture was refluxed for 1 hour at about 4 hours. The suspension was neutralized to a pH of 5-8 and separated between methylene chloride and brine. After concentration, the methylene chloride residue was chromatographed on silica gel eluted with hexane / ethyl acetate or methanol / methylene chloride (0% -100%) to give the desired product.
3. - Reaction by reductive amination with amino-quinolines and aldehydes or ketones An appropriately substituted 3-aminoquinoline (1 eq.) Was stirred with 1 eq. of aldehyde or appropriate ketone in methanol (or other suitable solvent mixture) until the CCD indicated that mine formation was complete. Excess NaCNBH4 or NaBH4, or other suitable reducing agent was added and the mixture was stirred until the CCD showed intermediate consumption. The mixture was concentrated and the residue was chromatographed on silica gel with hexane / ethyl acetate (0-100%) or chloroform / methanol (0-20%) to give the desired product.
4. - Coupling reaction of 3-amino substituted quinolines and bromophenyl compounds An appropriately substituted 3-aminoquinoline (1 eq.) Was stirred with -1.4 eq. of a strong base such as sodium f-butoxide, 1 eq. of the suitable bromophenyl compound, and catalytic amounts of 2,2'-bis (diphenylphosphino) -1-1 '-b-naphthyl (S-BINAP) and bis (dibenzyl-ketone) -Paladium (Pd (dba) 2) they were mixed in an inert organic solvent such as toluene under an inert atmosphere such as argon and heated to about 80 ° C overnight. The mixture was cooled, diluted with a solvent such as ether, filtered, concentrated and chromatographed with 50% EtOAc / hexane to give the desired product.
. - Formation of ether from 3-hydroxy substituted quinolines by Mitsunobu conditions A THF solution of a suitably substituted hydroxyquininoaline (from 0 to about 25 ° C) was treated with 1 eq. of each desired alcohol, triphenylphosphine and finally diethylazodicarboxylate (DEAD) or an appropriate equivalent. The progress of the reaction is monitored through CCD and after concluding the reaction (from 1 to about 24 hours) the mixture was concentrated and the residue was chromatographed on silica gel to give the desired product.
6. - Desalkylation of a quinoline or quinoxaline substituted with lower alkoxy, and subsequent alkylation A quinoline or quinoxaline substituted with suitable lower alkoxy (1 eq.) In DMF was treated with excess sodium enantiolate (usually about 2 or more equivalents) and the The reaction mixture was stirred with heating for 1 to about 24 hours. The mixture was separated between water and ethyl acetate. Extraction treatment followed by chromatography, if necessary, provides the corresponding suitable product of quinoline or hydroxy substituted quinoxaline.
The quinoline or hydroxy substituted quinoxaline product can be alkylated using the conditions for the Mitsunobu reaction as described above. Alternatively, simple alkylation using methods well known in the art with a reactive alkyl or benzyl halide using NaH or other appropriate base in a suitable solvent provides the desired alkylated product.
7. Oxidation of a nitrogen in a quinoline or quinoxaline for the corresponding N-oxide A portion of imine (= N-) in a quinoline or quinoxaline compound of formula (I), can be converted to the corresponding compound wherein the imine portion is oxidized to an N-oxide, preferably by reaction with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at room temperature elevated The compounds of the present invention are useful in the free base or acid form or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention. If the compound of the present invention is substituted with a basic portion, acid addition salts are formed and are simply a more convenient use form; and in practice, the use of the salt form is inherently equivalent to the use of the free base form. The acids that can be used to prepare the acid addition salts preferably include those which produce, when combined with free bases, pharmaceutically acceptable salts, that is, salts whose anions are not toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free base are not vitiated by side effects attributable to anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, by itself, is used only as an intermediate product such as, for example, , when the salt is formed only for purposes of purification, and identification, or when it is used as an intermediate to prepare pharmaceutically acceptable salt by ion exchange processes. The pharmaceutically acceptable salts within the scope of the invention are those that come from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalogenides, for example hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, cetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene bis-β-hydroxynaphthoates, gentisatos, mesylates, isethionates and di-p-toluoyltartrates methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfamate and quinate, respectively. According to a further feature of the invention, the acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous solution or aqueous alcohol or other suitable solvents containing the appropriate acid and by isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt is separated directly or can be obtained by concentration of the solution. The compounds of the invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, the compounds of origin of the invention can be regenerated from their acid addition salts by treatment with an alkali, for example aqueous sodium bicarbonate solution or aqueous ammonia solution. When the compound of the invention is substituted with an acid portion, the basic addition salts can be formed and are simply a more convenient form of use; and in practice, the use of the form of 4
salt is inherently equivalent to the use of the free acid form. The bases which can be used to prepare the basic addition salts preferably include those which, when combined with a free acid, produce pharmaceutically acceptable salts, that is, salts whose cations are not toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free acid are not vitiated by the side effects attributable to the cations. Within the scope of the invention, the pharmaceutically acceptable salts, including for example alkali salts or alkaline earth metal salts, are those which are derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydroxide aluminum, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonic, triethylammonic, ethylenediamine, n-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, and the like. The metal salts of the compounds of the present invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or any mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Said reactions are normally carried out at room temperature, however, if desired, they can be carried out with heating. The amine salts of compounds of the present invention can be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. The amino acid salts can be prepared in a similar manner. The compounds of this invention can be regenerated from the basic addition salts by the application or adaptation of known methods. For example, the compounds of origin of the invention can be regenerated from their basic addition salts by treatment with an acid, for example, hydrochloric acid. In addition to being able to be used by themselves as active compounds, the salts of the compounds of the invention are useful for purification purposes of the compounds, for example by taking advantage of differences in solubility between the salts and the compounds of origin, side products and / or starting materials by techniques known to those skilled in the art. The compounds of the present invention may comprise asymmetric centers. These asymmetric centers may be independently in the R or S configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometric isomerism. Geometric isomers include the cis and trans forms of compounds of the invention, ie, compounds having alkenyl substituent portions in the ring systems. In addition, the bicyclic ring systems include endo and exo isomers. The present invention comprises the individual geometric isomers, stereoisomers, enantiomers and mixtures thereof. Said isomers can be separated from their mixtures, by application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are prepared separately from the appropriate isomers of their intermediates, for example, by applying or adapting methods described in the present. The starting materials and intermediates are prepared by applying or adapting known methods, for example methods that are described in the reference examples or their obvious chemical equivalents, or by methods described in accordance with the present invention. The present invention is also exemplified but not limited by the following illustrative examples that describe in the preparation of the compounds according to the invention. In addition, the following examples are representative of the procedures used to synthesize the compounds of this invention.
EXAMPLE 1 3-cyclohexyloxy-6,7-dimethoxyquinoline
To a solution of THF (30 mL) at 0 ° C was added 3-hydroxy-6,7-dimethoxyquinoline (0.237 g, 1.15 mmol), cyclohexanol (0.347 g, 3.46 mmol), Ph3P (0.908 g, 3.46 mmol). . The diethylazodicarboxylate was added in portions until the solution retained a dark red color (0.663 g, 3.81 mmol). Four hours later the solution was concentrated and the residue was subjected to chromatography (50% EtOAc in hexanes). The product is recrystallized from isopropanol / hexanes as the HCl salt as a white solid (m.p. 229-232 ° C.).
EXAMPLE 2 2-Anillino-6-isopropoxy-quinoxylin hydrochloride
To NaH (0.033 g, 0.84 mmol) under argon is added 1 mL of DMF. 2-Anilino-6-quinoxalinol (0.1 g, 0.42 mmol) is added portionwise in 1.5 mL of DMF. After 30 minutes 2-bromopropane is added dropwise and the solution is heated at 50 ° C for 1.5 hours. The cooled reaction mixture is quenched with water and separated between EtOAc and H 2 O, washed with H 2 O (3x), brine, dried (MgSO 4) and concentrated. The resulting residue is chromatographed (30% EtOAc / hexanes) to provide 0.05 g of dialkylated product and 0.1 g of the title compound. An analytical sample of the HCl salt is obtained by the addition of IPA (isopropanol) / HCl to an Et 2 O / IPA solution of the free base to provide the HCl salt (mp 205-210 ° C dec). Anal, cale, for C? 7H17N3O »HCI; C, 64.65; H, 5.74; N, 13.31; Found: C, 64.51; H, 5.90; N, 13.09.
EXAMPLE 3 2-Cyclohexylamino-6,7-d8-methoxyquinoline
To 0.3 g (1.34 mmol) of 2-chloro-6,7-dimethoxyquinolaline is added about 1 mL of cyclohexylamine. The mixture is heated overnight at 105 ° C and an additional 10 hours at 135 ° C. The mixture is separated between CH 2 Cl 2 and saturated NaCHO 3. The organic layer is dried (MgSO) and concentrated. The resulting syrup was chromatographed (1: 1 EtOAc: CH2Cl2) to provide 0.265 g of the product as a light brown solid in 69% yield (mp 188-189.5). Anal, caled, for C? 6H2? N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.82; H, 7.28; N, 14.45. The following compounds are prepared using the above standard coupling protocol and the appropriate starting materials: Exo-bicyclo [2.2.1] hept-2-yl- (6-chloro-7-methoxyquinolalin-2-yl) amine (mp 171 -173 ° C). Anal.calc. for C? 6H? 8N3OCI: C, 63.26; H, 5.97;
N, 13.83. Found: C, 63.37; H, 5.91; N, 13.83.
Exo-bicyclo [2.2.1] hept-2-yl- (7-chloro-6-methoxyquinolalin-2-yl) amine (mp 146-145.5 ° C). Anal.calc. for C? 6Hi8N3OCI: C, 63.26; H, 5.97; N, 13.83. Found: C, 63.34; H, 5.93; N, 13.77.
Bicyclo [2.2.1] hept-2-yl- (6,7-dimethyl-quinoxalin-2-yl) -amine (mp 155-57 ° C). Anal. cale, for C? 7H2? N3: C, 76.37; H, 7.92; N,
. 72. Found: C, 75.58; H, 7.55; N, 15.38.
2-cycloheptylamino-6,7-dimethoxyquinoxaline (m.p. 134-136 ° C). Anal. cale, for C 17 H 23 N 3 O 2: C, 67.75; H, 7.69; N, 13.94. Found: C, 67.80; H, 7.61; N, 13.77.
2-Cyclopentylamino-6,7-d-methoxyquinoline (m.p. 149-151 ° C). Anal. cale, for C15H? 9N3O: C, 65.91; H, 7.01; N, 15.37. Found: C, 66.04; H, 6.96; N, 15.47.
2-cyclohexylamino-6-methoxyquinolaline (mp 242-248 ° C).
EXAMPLE 4 3-Aminocyclohexyl-6,7-dimethoxy-quinoline
To a solution of MeOH (3 ml) of powdered molecular sieves of 4A (0.11 g) under argon, 3-amino-6,7-dimethoxy-quinoline hydrochloride (0.17 g, 0.68 mmol) and NaOMe (0.039 g) are added. g, 0.71 mmol). The reaction mixture is stirred at room temperature for 30 minutes and cyclohexanone (0.074 mL, 0.71 mmol) is added portionwise, followed by borane pyridine (0.072 mL, 0.071 mmol). The mixture is stirred for 4.5 hours, then HCl is added in portions to 5N (1.4 mL, 6.8 mmol). The reaction mixture is stirred at 45 minutes and then made strongly basic with NaOH at 5N. The mixture is separated between EtOAC and H2O, and the aqueous layer is washed with EtOAc (2X). The combined organic layers are washed with brine (1X), dried (MgSO), chromatographed (50% EtOAc / hexanes) and recrystallized from EtOAc / hexanes to obtain 0.112 g of a light yellow solid in 57% yield (pf 164-165). Anal cale, for C? 7H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.45; H, 7.49; N, 9.80.
EXAMPLE 6 2-Cyclohexylamino-6-methoxy-7-bromo-quinoxaline hydrochloride
To 0.75 g (2.7 mmol) 7: 1 of 7-bromo-6-methoxy-quinoxalin-2-ol: 6-bromo-7-methoxy-quinoxalin-2-ol in a sealed tube is added 5 mL of cyclohexylamine. The reaction mixture is heated at 120 ° C for 2 hours. Cyclohexylamine is recited under reduced pressure and the residue is separated between EtOAc / H2O. The organic layer is washed with H2O (2X), brine (1X) and dried (MgSO). The resulting material is chromatographed (20% then 30% EtOAc / hexanes) to provide 0.81 g of main product in 88% yield. An analytical sample is obtained by converting approximately 0.13 g of the free base into its hydrochloride salt (p.f. 280 dec.). Anal. cale, for C? 5H18N3OBr «HCI: C.48.34; H, 5.14; N, 11.27. Found: C, 48.51; H, 4.98; N, 11.09.
EXAMPLE 6 (6,7-Dimethoxy-quinolin-3-yl) -cis- (3- (R) -methyl-cyclohexy-pinamine hydrochloride and (6-dimethoxy-quinolin-3-yl) -trans- (3-) hydrochloride (R) - methyl-cyclohexyl) amine
A cis / trans mixture of (6,7-dimethoxy-quinolin-3-yl) - (3- (R) -methyl-cyclohexyl) -amine prepared by reductive amination of 3-amino-6,7, -dimethoxyquinoline and 3 - (R) -methyl cyclohexanone is separated by HPLC-PR. Both samples were rechromatographed (70% EtOAc / hexanes) to obtain a pure free base. An analytical sample of each isomer is obtained by separately converting the free bases into the amorphous and, to some extent, hygroscopic hydrochloride salts. The 500 MHz 1 H NMR is consistent for the product and LC / MS and FAB confirmed M + H = 301 for each isomer.
EXAMPLE 7 Cyclohex-3-enyl- (6,7-dimethoxyquinolalin-2-yl) -amine
To a solution of trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanol (303 mg, 1 mmol) in 10 mL of THF at -78 ° C is added triphenylphosphine (524 mg, 2 mmol ) and diethyl azodicarboxylate. The mixture is stirred at -78 ° C for one hour before the addition of nitrobenzoic acid (334 mg, 2 mmol). After being stirred at -78 ° C for 1 hour, the mixture is further stirred at room temperature for an additional hour and then concentrated. The residue is chromatographed on silica gel (ether) to give 250 mg (87.7%) of cyclohex-3-enyl- (6,7-dimethoxyquinolalin-2-yl) -amine.
EXAMPLE 8 2-Anilino-6-quinoxalinol
By the method of Feutrill, G. I; Mirrington, R. N. Tet. Lett. 1970, 1327; the arylmethyl ether is converted to the phenol derivative. To 2-amino-6-methoxy-quinoxaline (0.27 g, 1.07 mmol) under argon in DMF is added the sodium salt of ethanethiol (0.19 g, 2 mmol). The reaction mixture is heated at 110 ° C overnight. The mixture is concentrated and separated between EtOAc and HO / 5% tartaric acid in such a way that the pH of the aqueous layer is about 4. The organic layer is washed with H2O (4X) and then with 2.5% NaOH ( 4X). The basic layers are combined, washed with EtOAc (2X), acidified again with 5% tartaric acid and washed with several portions of EtOAc. The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated. The resulting solid is chromatographed (50% EtOAc / hexanes). An analytical sample is obtained by triturating the product with Et 2 O to provide a yellow powder (mp 211-213 ° C). Anal. cale, for C? 4 HnN3O: C. 70.88; H, 4.67; N, 17.71; Found: C. 70.64; H, 4.85; N. 17.58.
EXAMPLE 9 Phenyl-r6- (tetrahydrofuran-3- (R) -yl-oxy) quinoxalin-2-ylamine
To a solution of THF at 0 ° C under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S) - (+) - 3-hydroxytetrahydrofuran (0.086 ml, 1.3 mmol) and triphenylphosphine ( 0.31 g, 1.2 mmol). DEAD (0.18 ml, 1.2 mmol) is added in portions. The reaction is allowed to warm to room temperature and is stirred for 1.5 hours. The mixture is concentrated and separated between EtOAc and H20. The organic layer is washed with H20, brine, dried (MgSO4) and concentrated. The resulting yellow oil is chromatographed (50% EtOAc / hexanes) and taken up in Et2O / IPA. A solution of HCl / Et 2 O is added by dripping and the resulting red-orange powder is dried under vacuum. The powder is made free base by stirring in MeOH and with basic ion exchange resin (3X H2O, 5X MeOH). The mixture is stirred at 30 minutes; it is filtered, concentrated and recrystallized from EtOAc / hexanes to provide, in two crops, the product (mp 173-175 ° C). Anal. cale, for C18H? 7N3O2: C.70.35; H, 5.57; N, 13.67; Found: C. 70.19; H, 5.60; N, 13.66.
EXAMPLE 10 2.7-Bis-cyclohexyloxy-6-methoxy-quinoxaline
To a solution of DMF (5 mL) of NaH (0.32 g, 8 mmol) under argon, cyclohexanol (0.7 mL, 6.7 mmol) is added dropwise. The mixture is stirred at room temperature for 25 minutes and then 2-chloro-6,7-dimethoxyquinolaline is added in portions. The reaction is stirred for 15 minutes at room temperature, at 90 ° C for 2 hours and at 110 ° C for 1 hour. The mixture is cooled, quenched with H2O and separated between EtOAc / H2O. The organic layer is washed with H2O and brine, dried (MgSO4) and chromatographed (10% EtOAc / hexanes) to provide a white waxy solid (mp 75-78 ° C). Anal. cale, for C2? H28N2O3: C, 70.76; H, 7.92; N, 7.86; Found: C, 70.81; H, 7.79; N, 7.70.
EXAMPLE 11 CyclohexM- (6,7-d¡methoxyquinoxalin-2-phenyl) -amine
To a 0.067 M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in 2: 1 MeOH / 1,2-dichloroethane (7.5 mL, 0.5 mmol) is added cyclohexylamine (0.1 mL, 0.9 mmol). The reaction is allowed to stir at room temperature overnight, then NaBH 4 (0.038 g, 1 mmol) is added and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc / hexanes-about 5% MeOH in 50% EtOAc / hexanes.) The oil is dissolved in EtOAc / hexanes and treated with HCl in EtOH. and the solids are triturated with isopropanol to provide a white solid after drying in vacuo at 60 ° C (mp 185-190 ° C, des) Anal, cale for C 7 H 23 N 3 O 2 HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07.
EXAMPLE 12 (6.7-Dimethoxy-quinol-3-yl) -fra? S- (3- (R) -methyl-cyclohexyl) amine and (6,7-dimethoxy-quinolin-3-yl) -c / s- (3- (R) -methyl-cyclohexyl) -amine
The reaction is carried out in a manner similar to the previous preparation, using the free base of 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and (R) - (+) - 3-methylcyclohexanone (0.23 ml. 1.9 mmol). The mixture of the obtained product is chromatographed (70% EtOAc / hexanes) and recrystallized from EtOAc / hexanes to obtain a white solid (1: 1 mixture of cis and trans isomers) (mp 153-160 ° C). Anal. cale, for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33; Found: C, 72.12; H, 7.85; N, 9.29. The following compound is prepared using the standard coupling protocol described above and using the appropriate starting material: (6,7-dimethoxy-quinolin-3-yl) - (3-methylene-cyclopentyl) amine (mp 106-109) ° C). Anal, cale for C? 7H22N2O2; C, 71.30; H, 7.74; N, 9.78. Found: C, 71.24; H, 7.56; N, 9.61.
EXAMPLE 13 3- (6,7-Dimethoxyquinolin-3-yl-amino) -2,2-dimethyl-propan-1-ol
The reaction is run in a manner similar to the preparation of Example 11. To a MeOH solution of powdered molecular sieves of 4A (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2,2-dimethyl-3-hydroxypropionaldehyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH / CHCl3) to give 0.10 g of material that is separated between CH2Cl2 / 10% NaOH. The organic layer is washed with 10% NaOH, H2O and brine, then dried (MgSO4) and recrystallized from EtOAc / hexanes to provide a light orange solid (mp 170-173.5 ° C). Anal. cale, for C? 6H22N2O3; C, 66.18; H, 7.64; N, 9.65; Found C, 66.11; H, 7.49; N, 9.33. The following compound is prepared using the standard coupling protocol described above and using the appropriate starting material: (6,7-dimethoxyquinolin-3-yl) -isobutylamine (mp 158-162 ° C). Anal, cale for C? 5H20N2O2; C, 69.20; H, 7.74; N, 10.76. Found; C, 69.09; H, 7.82; N, 11.01.
EXAMPLE 14 Cyclohexyl- (6-methoxy-7-morphonyl-4-yl-quinoxalin-2-yl) -amine
This preparation is based on an adaptation of the method described by Buchwaid et al., J. Am Chem. Soc. 1996, 118, 7215. To a toluene solution of 2-cyclohexylamino-6-methoxy-7-bromo-quinoxaline (0.1 g, 0.3 mmol) under argon is added morpholine (0.1 g, 0.3 mmol), sodium t-butoxide (0.04 g, 0.42 mmol), S - (-) - BINAP (cat., 0.001 g) and bis ( dibenzylideneacetone) -palladium (cat., 0.001 g). The reaction mixture is heated at 80 ° C overnight. The mixture is cooled, diluted with Et20, filtered, concentrated and chromatographed (50% EtOAc / hexanes). The product is recrystallized from EtOAc / hexanes to provide, in two batches, a yellow solid (mp 194-196 ° C). Analysis calculated for C? 9H26N4O2: C, 66.64; H, 7.65; N, 16.36; Found: C, 66.60; H, 7.60; N, 16.51.
EXAMPLE 15 trans-4- (7-chloro-6-methoxy-quinoxalin-2-amino) -cyclohexanol v trans-4- (6-chloro-7-methoxy-quinoxalin-2-yl-amino) -cyclohexanol
To a reaction flask under argon adapted with a trap of
Dean-Stark and a condenser, is added 6: 1 of 2,7-dichloro-6-methoxy-quinoxaline: 2,6-dichloro-7-methoxy-quinoxaline (0.30 g, 1.3 mmol) and trans-4-amino -cyclohexanol (0.35 g, 3 mmol). The reaction mixture is heated at 170 ° C for about 10 hours, and then concentrated and chromatographed twice (7% MeOH / CHCl3, then 5% MeOH / CHCl3). The product is recrystallized from EtOAc / hexanes to provide a light yellow solid (mp 144-147 ° C). Analysis calculated for C? 9H26N O2 • 0.4 H2O: C, 57.20; H, 6.02; N, 13.34; found: C, 57.21; H, 5.97; N, 13.08. The 1 H NMR analysis revealed that the product is a 2: 1 mixture of trans-4- (7-chloro-6-methoxy-quinoxalin-2-amino) -cyclohexanol: trans-4- (6-chloro-7 -metoxy-quinoxalin-2-yl-amino) -cyclohexanol.
EXAMPLE 16 trans-4- (6-7-dimethoxy-quininoal-2-yl-amino-cyclohexanol
Combine trans-4-aminocyclohexanol (0.11 g, 2 eq.) And chloro-6,7-dimethoxyquinolaline (0.1 g, 1 eq.), And heat 160-180 ° C for a period of 4 to 8 hours. The dark brown suspension is filtered and concentrated. The residue is purified on a flash column eluted with 3% methanol / methylene chloride to provide the product as a yellow powder with m.p. from 119-123 ° C. Analysis calculated for C? 6H2? N3O3: C, 62.33; H, 7.05; N, 13.63; found: C, 62.35; H, 7.09; N, 13.18. The compound could be recrystallized by the following method.
Starting with 0.2 g of yellow powder in a mixture of 2.5 ml of water and 1.25 ml of methanol, a light orange solution is obtained after refluxing. The hot solution is allowed to settle and gradually cooled. Orange-shaped needle crystals are collected by filtration, and dried under high vacuum to give a yellow solid (mp 119-120 ° C). Alternatively, the HCl salt of the title compound is prepared in the following manner: to a solution of trans-4- (6,7-dimethoxyquinoxalin-2-ylamino) -cyclohexanol in isopropanol, a solution of HCl at 0 ° C. The mixture is stirred for 15 minutes before filtration. The collected solid is dried under high vacuum to provide the hydrochloric acid salt of trans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexanol. Analysis calculated for C? 6H22CIN3O3 • 1.2 of H2O: C, 53.19; H, 6.80; N, 11.63; Cl, 9.81 found: C, 53.14; H, 6.85; N, 11.24; Cl, 10.28. Alternatively, the sulfate salt of the title compound is prepared as follows: in a typical procedure, trans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexanol is dissolved in acetone or other suitable organic solvent with heating up to 45 ° C, as necessary. To the resulting solution, aqueous H2SO (1 equivalent, 1 M solution) is added with rapid stirring. The salt formed in this manner is collected and dried to provide the sulfate with more than 80% yield.
EXAMPLE 17 (+) - bicyclo f2.2.nhept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine
Procedure A: a mixture of 2-chloro-6,7-dimethoxyquinolone (5 g, 22.3 mmol) and (+) - exo-norbonyl-2-amine (10 g, 90 mmol) is heated from 160 to 180 ° C during the night. The dark brown residue is dissolved in 200 ml of methylene chloride and washed with 1 N NaOH (50 ml). The organic layer is dried over magnesium sulfate and then filtered. The residue after concentration is chromatographed on silica gel eluted with hexane / ethyl acetate (80%) to provide the desired product as a yellow solid which can be recrystallized from methanol. Method B: a mixture of 2-chloro-6,7-dimethoxyquinolaline (9 g, 40.1 mmol) and (+) - exo-norbonyl-2-amine (5.77 g, 52 mmol), sodium t-butoxide (4.22 g) , 44 mmol), 2,2'-bis (diphenylphosphino) -1 -1 '-bubfthyl (BINAP, 120 mg) and bis (dibenzylideneacetone) -palladium Pd (dba) 2, 40 mg in 80 ml of toluene, is heated at 80 ° C for 8 hours. Another portion of BINAP (60 mg) and Pd (dba) 2 (20 mg) is added, and the mixture is heated at 100 ° C overnight. After being diluted with 200 ml of methylene chloride, the reaction mixture is washed with 1 N NaOH (100 ml). The organic layer is dried over magnesium sulfate and filtered. After concentration, the residue is chromatographed on silica gel eluted with hexane / ethyl acetate (80%) to provide the desired product as a light yellow solid (mp 188-189 ° C). Analysis calculated for C? 7H2? N3O3: C, 68.20; H, 7.07; N, 14:04; Found: C, 68.18; H, 7.03; N, 14.03. The following compounds are prepared in the same way starting with the appropriate starting material (method A).
exo-bicyclo [2.2.1] hept-5-en-2-yl- (6,7-dimethoxyquinoxalin-2-yl) -amine (mp 175-177 ° C). Analysis calculated for C? 7H? 9N3O2 • 0.4 H 2 O: C, 60.94; H, 6.56; N, 13.78; found: C, 66.98; H, 6.62; N, 12.73. cyclohexyl- (6,8-dimethyl-quinoxalin-2-yl) -amine [MS m / z: 255 (M +)]. Analysis calculated for C? 6H21N3: C, 75.26; H, 8.29; N, 16.46; Found: C, 75.08; H, 8.28; N, 15.86. endo-bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine (m.p. 79-82 ° C). (6,7-dimethoxyquinolaln-2-yl) - (4-methoxy-cyclohexyl) -amine (m.p. 58-68 ° C). Analysis calculated for C? 7H23N3O3 • 0.5 H2O: C, 62.56; H, 7.41; N, 12.87; found: C, 62.53; H, 7.22; N, 12.22. Exo-bicyclo [2.2.1] hept-2-yl- (6-methoxyquinolalin-2-yl) -amine (m.p. 98-100 ° C). Analysis calculated for C? 8H? 9N3O: C, 71.35; H, 7.11; N, 15.60; found: C, 70.38; N, 15.05.
EXAMPLE 18 exo-2- (biciclor2.2.phept-2-yloxy) -6-dimethoxyquinolaline
A mixture of exo-2-norbomeol (223 mg, 2 mmol) and NaH (60%, 100 mg, 2.5 mmol) in 10 ml of anhydrous THF is refluxed for 0.5 hour before the addition of 2-chloro- 6,7-dimethoxyquinoline (336 mg, 1.5 mmol). The resulting mixture is refluxed for 2 hours. The residue after filtration and concentration is chromatographed on silica gel (50% ether / hexane) to provide the desired product as a white solid (mp 135-137 ° C). Analysis calculated for C? 7H2oN2O3: C, 67.98; H, 6.71; N, 9.33; found: C, 67.96; H, 6.762; N, 9.19. Using the above standard coupling protocol using the appropriate starting materials, prepare the following compounds: 2- (bicyclo [2.2.2] oct-2-lloxy) -6,7-d, methoxy-quinhoxaline (mp 147-148 ° C) ). endo-2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxlquinoxaline (m.p. 10-1-1 1 ° C). exo-2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxyquinolaline (m.p. 108-110 ° C). Analysis calculated for C? 7H18N2O3: C, 68.44; H, 6.08; N, 9.39; Found: C, 68.54; H, 6.23; N, 9.27. 2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline (mp 93-95 ° C). Analysis calculated for d7H? 8N2O3: C, 68.44; H, 6.08; N, 9.39; found: C, 68.32; H, 5.98; N, 9.25. 2-cyclohexyloxy-6,7-dimethoxyquinolaline (m.p. 104-106 ° C). 2-cyclopentylthio-6,7-dimethoxyquinolaline (m.p. 123-124 ° C). Analysis calculated for C? 5 H 18 N 2 O 2 S: C, 62.04; H, 6.25; N, 9.25. found: C, 61.90; H, 6.02; N, 9.48. 6,7-dimethoxy-2-cyclopentyloxyquinoxaline (mp 87-89 ° C). Analysis calculated for C? 5 H 18 N 2 O 3: C, 65.68; H, 6.61; N, 10.21; found: C, 65.63; H, 6.52; N, 10.13.
2-Cyclopentylmethyloxy-6,7-dimethoxyquinoline (p.p. 99-102 ° C). Analysis calculated for C? 6H2oN2O3: C, 66.65; H, 6.99; N, 9.72; found: C, 66.66; H, 7.03; N, 9.70. 6,7-dimethoxy-2-tetrahydropyran-4-oxy-quinoxaline (mp 155-158 ° C). Analysis calculated for Ci5H18N2O4: C, 62.06; H, 6.25; N, 9.65; found: C, 62.26; H, 6.27; N, 9.67. exo, exo-6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptan-2-yloxy) -quinoxaline (mp 173-175 ° C).
EXAMPLE 19 Acid c / s / frans-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanecarboxylic acid
A mixture of c / s? Rans-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1 mmol) and NaH (60%, 160 mg, 4 mmol) in anhydrous THF / DMF (10 ml / 2 ml) is subjected to reflux for one hour before the addition of 2-chloro-6,7-dimethoxyquinolaline (225 mg, 1 mmol). The resulting mixture is continued to reflux for 4 hours. The reaction mixture is neutralized to pH 5, and extracted with ethyl acetate (2 × 50 ml). The combined organic solutions are dried over magnesium sulfate and filtered. The residue after concentration is chromatographed on silica gel (ethyl acetate, followed by methanol) to provide the desired product as a white solid (mp 90-93 ° C). Analysis calculated for C? 7H20N2O5 • 0.5 H 2 O: C, 59.89; H, 6.19; N, 8.22; found: C, 59.91; H, 6.62; N, 7.90.
EXAMPLE 20 6,7-dimethoxy-2- (4-methoxy-cyclohexyloxy) -quinoxalyne
A mixture of cis / trans-4- (6,7-dimethoxyquinolxin-2-yloxy) -cyclohexanol (170 mg, 0.56 mmole) and NaH (60%, 22.4 mg, 0.56 mmole) in anhydrous THF / DMF (10 ml / 2 ml), is stirred at 0 ° C for 10 minutes before the addition of methyl iodide (50 μl, 0.56 mmoles). After being stirred at room temperature for 4 hours, the reaction is quenched with water (0.5 ml), and concentrated. The aqueous layer is extracted with methylene chloride (2x20ml), and the combined organic solutions are washed with brine (5 ml). The residue after concentration is chromatographed on silica gel (30% ethyl acetate / hexane) to give 80 mg (45%) of the desired product (mp 85-90 ° C).
EXAMPLE 21 1-3-cyclohexyloxy-6,7-dimethoxyquinolutin oxide
A mixture of 2-cyclohexyloxy-6,7-dimethoxyquinolaline (110 mg, 0.38 mmol) and meta-chlorobenzoic acid (70%, 113 mg, 0.46 mmol) in 10 ml of methylene chloride is stirred at room temperature for one day. The solution after filtration is concentrated, and the residue is chromatographed on silica gel (20% ethyl acetate / hexane) to provide the desired product (mp 167-169 ° C).
Trans-4- (6,7-dimethoxy-4-oxy-quinoxalin-2-ylamino) -cyclohexanol is prepared in the same manner (mp 220-222 ° C). Analysis calculated for C? 6H2? N3? 4 * 0.2 of H20: C, 59.42; H, 6.69; N, 12.99; found: C, 59.43; H, 6.64; N, 12.95.
EXAMPLE 22 (1R, 2R, 4SM +) - bicyclo r2.2.nhept-2-yl- (6-dimethoxyquinolalin-2-yl) -amine
The (±) -bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine of Example 17 is resolved on a chiral HPLC column (Chiralpac AD, 25x2 cm, heptane a 60% / 40% ethanol with (1 S) - (+) - camphor sulfonic acid at 10 mM, 12 ml / minute), and the product of the above title is obtained as the first eluent. The collected fractions are combined and washed with 50 ml of 1 N NaOH before drying (MgSO 4). The solution after filtration is concentrated in a rotary evaporator and then dried under high vacuum. A yellow solid is obtained. [α] d 20 + 19.5 ° (c = 0.20, CH 2 Cl 2) p.f. 184-186 ° C. Analysis calculated for C? 7H2? N3O2 x 0.3 H 2 O: C, 66.90; H, 7.15; N, 13.77. Found: C, 66.86; H, 7.01; N, 13.86.
EXAMPLE 23 (1S, 2S, 4R) - (-) - bicyclo r2.2.nhept-2-yl- (6-dimethoxy-cyanoxalin-2-yl) -amine
(i) The (±) -bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine of Example 17 is resolved on a chiral HPLC column (Chiralpac AD, 25x2 cm, 60% heptane / 40% ethanol with (1S) - (+) - camphor sulfonic acid at 10 mM, 12 ml / minute) as the second eluted product. The collected fractions are combined and washed with 50 ml of 1 N NaOH before being dried over magnesium sulfate. The solution after filtration is concentrated in a rotary evaporator and then dried under high vacuum. A yellow solid is obtained. [α] d 20-19.5 ° (c = 0.22, CH 2 Cl 2) p.f. 185-187 ° C. (ii) A mixture of 2-chloro-6,7-dimethoxyquinolaline (462 mg, 2.06 mmol) and (1S, 2S, 4R) -norbomil-2-amine (300 mg, 2.7 mmol), sodium t-butoxide ( 220 mg, 2.3 mmol), BINAP (9 mg) and Pd (dba) 2 (3 mg) in 10 ml of toluene, is heated from 80 ° to 100 ° C overnight. The suspension is chromatographed on silica gel eluted with hexane / ethyl acetate (60%) to give 370 mg (60%) of the desired product as a yellow solid, which had the same retention time as the first product eluted under the column conditions of previous chiral HPLC, [a] / 0 -19 ° (c = 0.19, CH2Cl2).
EXAMPLE 24 2- (6,7-Dímethoxyquinolalin-2-yl) -2-azabicycloi2.2.21octan-3-one
Dissolve 2-azabicyclo [2.2.2] octan-3-one 228 mg, 2.3 mmol) in a mixture of THF / DMF (5 ml / 3 ml), and treat with NaH (60%, 184 mg, 4.6 mmol ). The resulting mixture is heated at 60 ° C for 0.5 hours before the addition of 2-chloro-6,7-dimethoxyquinolaline (344 mg, 1.5 moles). After being heated at 80 ° C overnight, the reaction mixture is concentrated. The chromatography residue on silica gel (50% ethyl acetate / hexane) to give 164 mg (23%) of a yellow solid (mp 158-159 ° C).
EXAMPLE 25 Cis / trans- (6-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester To a solution of 2- (6,7-dimethoxyquinol-2-yl) -2-aza-bicyclo [2.2.2] octan-3-one (100 mg, 0.32 mmol) in 10 ml of methanol, a freshly prepared solution of NaOMe / methanol (54 mg, 1 mmol) is added, and the mixture is stirred at room temperature for 0.5 hours before being concentrated. For extraction, methylene chloride is used, and then dried with magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (40% ethyl acetate) to give 85 mg (77%) of cis / trans-4- (6,7-dimethoxy-quinoxalin-2) methyl ester. -ylamino) -cyclohexanecarboxylic acid as a light yellow solid (mp 68-80 ° C).
EXAMPLE 26 cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid
When the NaOMe in the above procedure is replaced with NaOH, 2- (6,7-dimethoxy-quinoxalin-2-yl) -2-aza-bicyclo [2.2.2] octan-3-one is converted to cis / acid. trans -4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid.
EXAMPLE 27 cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester and trans-4- (6,7-dimethoxy-quinoxaHn-2-ylamino) -cyclohexanecarboxylic acid methyl ester
Cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester [MS m / z: 345 (M +)] and trans-4- (6,7-) methyl ester are separated. dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid [MS m / z: 345 (M +)] on preparative TLC from cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) acid ester ) -cyclohexanecarboxylic acid with 65% ethyl acetate / hexane as first and second eluted products, respectively.
EXAMPLE 28 trans-4-r7-methoxy-6- (2-morpholin-4-yl-ethoxy) -quinoxalin-2-ylamino-1-cyclohexanol v trans-4-r6-methoxy-7- (2-morpholin-4-yl) -ethoxy) -quinoxalin-2- laminolcyclohexanol
The title compound is prepared by coupling Mitsunobu of 6-hydroxy-7-methoxy-2-chloroquinoxaline: 7- (2-morpholin-4-ylethoxy) -6-methoxy-2-chloroquinoxaline and 2- (morpholin-4-) il) ethanol using the procedure of Example 1 and the reaction of the resulting 6- (2-morpholin-4-ylethoxy) -7-methoxy-2-chloroquinoxaline: 7- (2-moforlin-4-ylethoxy) -6-methoxy -2-chloroquinoxaline and trans-4-amino-cyclohexanol using the procedure of example 11.
EXAMPLE 29 2-r2- (trans-4-hydroxy-cyclohexylamino) -7-methoxy-quinoxalin-6-yloxyp-1-acetic acid and 2-r2- (trans-4-hydroxy-cyclohexylamino) -6-methoxy acid quinoxalin-7-ilox¡p-1 -acetic
The title compound is prepared by dealkylation of 4- (6,7-dimethoxy-quinxoalin-2-ylamino) -cyclohexanol using the sodium salt of ethanediol in DMF as described in example 8, followed by alkylation with bromoacetic acid in the presence of base as described in the general procedure 6.
EXAMPLE 30 2-r 2 - (trans-4-hydroxy-cyclohexylamino) -7-methoxy-quinoxalin-6-yloxy-N, N-dimethyl-acetaminda v 2-r 2 - (trans-4-hydroxy-cyclohexylamino) -6- methoxy-quinoxalin-7-ilox¡pN, N-dimethyl-acetamide
The title compound is prepared by aminolysis of the compound of Example 29 using dimethylamine.
EXAMPLE 31 (6-dimethoxy-quinoxalin-2-yl) - (3- (R) -methylcyclohexyl) amine and its cis and trans isomers
The compounds are initially prepared as a mixture of cis and trans isomers. They are prepared from the cyclohexyl amine derived from the reduction of the oxime of 3- (R) -methylcyclohexanone followed by coupling the amine with 2-chloro-6,7-dimethoxyquinolaline using standard conditions. An analytical sample of each isomer is obtained by preparative RP-HPLC. The MS and 1 H NMR 300 MHz are consistent for both structures, although the relative stereochemistry could not be definitively assigned for the carbon of the cyclohexyl that the nitrogen possesses.
EXAMPLE 32 cis / trans-4- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexanecarboxylate methyl
The title compound is prepared by esterifying the product of Example 19 using standard techniques to produce the title compound, m.p. 130-132 ° C. Analysis calculated for C? 8H22N2O5: C, 62.42: H, 6.40; N, 8.09. Found: C, 62.60; H, 6.55; N, 7.89.
EXAMPLE OF INTERMEDIARY 1 4-Bromo-5-methoxy-becene-1,2-diamine dihydrochloride
To a solution of EtOAc (50 ml) and 5-bromo-4-methoxy-2-nitro-phenylamine (2.5 g, 10 mmol) under argon, Pd at 5% / C (0.5 g) is added. The reaction mixture is hydrogenated at 3515 kg per cm2 for 1 hour. The mixture is filtered through Celite in an HCI / IPA / EtOAc solution, and the pad washed with additional EtOAc. The resulting precipitate is filtered to provide a white solid.
EXAMPLE OF INTERMEDIARY 2 7-bromo-6-methoxy-quinoxaln-2-ol v 6-bromo-7-methoxyquinol-2-ol
To a solution of MeOH (15 ml) under argon, powdered NaOH pellets (0.86 g) are added., 21 mmol) and 4-bromo-5-methoxy-benzene-1,2-diamine dihydrochloride (2.7 g, 9.3 mmol). The mixture is stirred for 10 minutes, and then a solution of 45% efio glyoxylate in toluene (2.7 g, 12 mmol) is added portionwise. The reaction mixture is refluxed for 1 hour, and then cooled. Water is added, and then the suspension is filtered. The resulting solid is washed successively with H2O, MeOH, IPA and EI2O to provide a yellow powder.
EXAMPLE OF INTERMEDIARY 3 7-bromo-2-chloro-6-methoxy-quinoxaline and 6-bromo-2-chloro-7-methoxy-quinoxaline
To a mixture of 7-bromo-6-methoxy-quinoxalin-2-ol and 6-bromo-7-methoxy-quinoxalin-2-ol (1 g, 3.9 mmol) is added POCI3 (5 mL). The reaction mixture is refluxed for 1 hour, poured into ice water, filtered and then washed with water to provide a light tan solid. The ratio of 7-bromo-2-chloro-6-methoxy-quinoxaline: 6-bromo-2-chloro-7-methoxy-quinoxaline is about 7: 1 by 1 H NMR.
EXAMPLE OF INTERMEDIARY 4 5-chloro-4-methoxy-2-nitroaniline
To a solution of N- (5-chloro-4-methoxy-2-nitrophenyl) -acetamide (2 g, 8.2 mmol) in HCl at 5N (20 ml), 1,4-dioxane (10 ml) is added, and The mixture is stirred at 60 ° C for 1.5 hours. The reaction mixture is concentrated and separated between EtOAc / NaOH at 2N. The aqueous layers are washed with EtOAc (3x), brine, dried (MgSO4), adsorbed on silica gel, and chromatographed (70% EtOAc / hexanes) to provide an orange powder.
EXAMPLE OF INTERMEDIARY 5 4-Chloro-4-methoxy-benzene-1,2-diamine dihydrochloride
To a solution of EtOAc (25 ml) and 5-chloro-4-methoxy-2-nitro-phenylamine (1.6 g, 7.9 mmol) under argon is added Pd at 5% / C (0.5 g). The reaction mixture is hydrogenated at 3515 kg / cm2 for 1 hour. The mixture is filtered under N2 through Celite in a solution of 1 N HCl / Et2O in EtOAc, and the pad washed with additional EtOAc. The resulting precipitate is filtered to provide a white solid.
EXAMPLE OF INTERMEDIARY 6 7-chloro-6-methoxy-quinoxalin-2-ol and 6-chloro-7-methoxy-quinoxalin-2-ol
To a solution of 4-chloro-5-methoxy-benzene-1,2-diamine dihydrochloride (1.8 g, 7.2 mmol) in EtOH (15 mL) under argon is added TEA (2.5 mL, 18 mmol) at 0 ° C. . The mixture is stirred for 20 minutes, and then a solution of 45% ethyl glyoxylate in toluene (2.1 g, 9.3 mmol) is added portionwise. The reaction mixture is warmed to room temperature, refluxed for 1.5 hours, and then cooled. Water is added, and then the suspension is filtered and washed successively with H2O, IPA and Et20 to provide a light yellow powder. The product is azeotropically treated several times with toluene, and dried in vacuum before use.
EXAMPLE OF INTERMEDIARY 7 2,7-dichloro-6-methoxy-quinoxaline v 2,6-dichloro-7-methoxy-quinoxaline
To a mixture of 7-chloro-6-methoxy-quinoxalin-2-ol and 6-chloro-7-methoxy-quinoxalin-2-ol (1 g, 4.7 mmol) under a CaCl2 drying tube is added POCI3 (5 g). ml). The reaction mixture is refluxed for 30 minutes, poured into cold saturated NaHCOs solution, filtered and washed with water to provide a solid. The ratio of 2,7-dichloro-6-methoxy-quinoxaline: 2,6-dichloro-7-methoxy-quinoxaline is about 6: 1 by 1 H NMR.
EXAMPLE OF INTERMEDIARY 8 (1 S.2S, 4R) -norbornyl-2 -amine
(3a): To a solution of R - (+) - endo-norborneol (2.24 g, 20 mmol) in 20 ml of THF at -78 ° C are added triphenylphosphine (6.55 g, 25 mmol), phthalimide (3.68 g, 25 mmole) and diethyl azodicarboxylate (4.4 ml, 28 mmole). The mixture is stirred at room temperature overnight, and then concentrated. The residue is chromatographed on silica gel (20% ethyl acetate / hexane) to give 4.6 g (95%) of (1 S, 2S, 4R) -2-bicyclo [2.2.1] hept-2-yl isoindole -1, 3-dione. (3b): A mixture of (1S, 2S, 4R) -2-bicyclo [2.2.1] hept-2-yl isoindol-1,3-dione (1.2 g, 5 mmol) and H2NNH2 monohydrate (300 mg, mmoles) in 10 ml of methanol, refluxed for 4 hours before being concentrated to dryness. Methylene chloride (2x100 ml) is used to extract it, and the solid is removed by filtration. Evaporation of the methylene chloride yields 300 mg (54%) of (1S, 2S, 4R) -norbomil-2-amine.
EXAMPLE OF INTERMEDIARY 9 exo-bicic! Or [2.2.nhept-5-en-2-amine
Exo-bicyclo [2.2.1] hept-5-en-2-amine is prepared using the same procedures as in the example of intermediate 12 from 5-norbornen-2-ol by the versatile intermediate exo-2-bicyclo [2.2. 1] hept-5-en-2-yl isoindol-1,3-dione.
EXAMPLE OF INTERMEDIARY 10 2-methyl-6,7-dimethoxy-quinotoxaline
The title compound is prepared using an adaptation of the published method of Tamao et al., Tetrahedron, 1982, 38, 3347-3354. To a THF solution under argon is added 2-chloro-6,7-dimethoxyquinolaline (5 g, 26 mmol) and NiCl 2 (dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0 ° C, and a 3 M solution of MeMgBr in Et 2 O (13 mL, 39 mmol) is added portionwise. The reaction mixture is allowed to warm to room temperature, stirred for 1 hour and then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred for 10 minutes, and then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture is stirred overnight. Additional NaCl and CH 2 Cl 2 and H 2 O are added, and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3 times with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated on silica gel and chromatographed (50% -80% EtOAc / hexanes) to provide an orange solid (49% yield).
EXAMPLE OF INTERMEDIARY 11 6,7-dimethoxy-2-quinoxaline carboxaldehyde
To a reaction flask under argon is added 1,4-dioxane (20 ml), 2-methyl-6,7-dimethoxyquinolaline (1.09 g, 5.3 mmol) and SeO2 (1.8 g, 16 mmol). The mixture is heated at 100 ° C for 2 hours 45 minutes, cooled and filtered through Celite. The pad is washed with portions of EtOAc and CH2Cl2. The resulting solution is concentrated, taken up in MeOH / CH 2 Cl 2, deposited on a column of silica gel, and chromatographed (30% EtOAc / CH 2 Cl 2) to provide an off-white solid (73% yield).
EXAMPLE OF INTERMEDIARY 12 2 -acetate (2exo, 5exo) -5-aminobicicof2.2.1 heptane
Exo-5-acetoxy-cyclo [2.2.1] heptan-2-one and exo-6-acetoxy-cyclo [2.2.1] heptan-2-one are obtained from the [2.2.1] hepta-2,5-diene bicyclo according to the procedure of R. Gagnon (J. Chem. Soc, Perkin trans. 1, 1505 1995) with minor modification. To a solution of exo-5-acetoxy-cyclo [2.2.1] heptan-2-one (350 mg, 2.08 mmol) in 10 ml of THF at room temperature, a solution of borane at 1 M / THF (1.2 ml, 1.2 mmoles). The mixture is stirred for 0.5 hours before being quenched at 0 ° C with methanol (3 ml) and 1 N HCl (1.5 ml). To extract it, ethyl acetate (3x 30 ml) is used, and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel to provide (2endo, 5exo) -5-acetoxy-cyclo [2.2.1] heptan-2-ol. To a solution of (2endo, 5exo) -5-acetoxyethyl [2.2.1] heptan-2-oI (350 mg, 2.06 mmol) in THF (10 ml) is added phthalimide (454 mg, 3.09 mmol), triphenylphosphine (810 mg). mg, 3.09 mmol) and diethyl azodicarboxylate (0.49 mL, 3.09 mmol) at 0 ° C. The reaction is allowed to stir overnight, and is then condensed on the rotary evaporator, and the residue is purified by column chromatography (20% ethyl acetate / hexane) to provide the desired product as a yellow solid. A mixture of the above solid (300 mg, 1 mmol) and hydrazine (0.126 mL, 2.2 mmol) in 5 mL of methanol is heated to reflux for 6 hours. After removing the methanol, dichloromethane (3x 30 ml) is used to extract the residue. The concentration of the solvent produces 2-acetate (exo, exo) -5-aminobicyclo [2.2.1] heptane (127 mg, 75%), which is used in the coupling reaction without further purification. In the same way, 2-acetate (2endo, 5exo) -5-aminobicyclo [2.2.1] heptane, 2-acetate (2endo, 6exo) -6-aminobicyclo [2.2.1] are prepared from the appropriate starting material. ] heptane and 2-acetate (2exo, 6exo) -6-aminobicyclo [2.2.1] heptane.
EXAMPLE OF INTERMEDIARY 13 2-methoxy-4,5-diaminophenol dihydrochloride
The title compound is prepared by hydrogenation of 2-methoxy-4,5-dinitrophenol according to the procedure of Ehriich et al., J. Org. Chem., 1947, 12, 522.
EXAMPLE OF INTERMEDIARY 14 7-hydroxy-6-methoxy-quinoxalin-2-ol and 6-hydroxy-7-methoxy-quinoxalin-2-ol
The title compounds are prepared from 4-methoxy-5-hydroxybenzene-1,2-diamine dihydrochloride by reaction with NaOH and ethyl glyoxalate using the procedure of the example of intermediate 2.
EXAMPLE OF INTERMEDIARY 15 7-hydroxy-6-methoxy-2-cioroquinoxaline and 6-hydroxy-7-methoxy-2-chloroquinoxaline
The title compounds are prepared from 7-hydroxy-6-methoxy-quinoxalin-2-ol and 6-hydroxy-7-methoxy-quinoxalin-2-ol by reaction with POCI3 using the procedure of the example of intermediate 3 The compounds of formula I described herein exhibit inhibition of cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) by inhibiting the activity of PDGF-R tyrosine kinase. A large number of disease states are caused by the uncontrolled reproduction of cells, or matrix overproduction or poorly regulated programmed cell death (apoptosis). These disease states involve a variety of cell types, and include disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and disorders that occur subsequent to angioplasty of the coronary, femoral or renal arteries. , or iterative fibroprol disease, such as in arthritis and fibrosis of the lung, kidney and liver. In particular, it has been reported that PDGF and PDGF-R are implicated in specific types of cancers and tumors such as brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma and malignant melanoma, as well as deregulated cell proliferative conditions following coronary bypass surgery. It is thought that the inhibition of tyrosine kinase activity has utility in the control of reproduction without cell control, overproduction of matrix or programmed cell death poorly regulated (apoptosis). This invention relates to the modulation and / or inhibition of cellular signaling, cell proliferation and / or cell matrix production and / or cell movement (chemotaxis), the control of abnormal cell growth and the cellular inflammatory response. More specifically, this invention relates to the use of substituted quinoline and quinoxaline compounds that exhibit selective inhibition of differentiation, proliferation, matrix production, chemotaxis or mediator release, effectively inhibiting the activity of PDGF-R tyrosine kinase receptor-like factor. platelet-derived growth. The initiation of autophosphorylation, that is, the phosphorylation of the growth factor receptor itself, and the phosphorylation of a number of intracellular substrates, are some of the biochemical events involved in signaling, proliferation, matrix production, chemotaxis and release of cellular mediator. By effectively inhibiting the activity of Lck tyrosine kinase, the compounds of this invention are also useful in the treatment of transplant resistance and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in graft disease against host, in hyperproliferative disorders such as tumors and psoriasis, and diseases in which cells receive pro-inflammatory signals, such as in asthma, inflammatory bowel disease and pancreatitis. In the treatment of resistance to transplantation, a compound of this invention can be used prophylactically or in response to an adverse reaction by the human subject to a transplanted organ or tissue. When used prophylactically, a compound of this invention is administered to the patient or to the tissue or organ to be transplanted, in advance of the transplant operation. Prophylactic treatment may also include the administration of the medication after the transplant operation, but before signs of adverse reaction or transplantation are observed. When administered in response to an adverse reaction, a compound of this invention is administered directly to the patient to treat resistance to transplantation after external signs of resistance have manifested. In accordance with a further feature of the invention, a method is provided for the treatment of a patient suffering from, or subject to, conditions that can be ameliorated or prevented by the administration of an inhibitor of PDGF-R tyrosine kinase activity and / or LK tyrosine kinase activity, for example, conditions as described above, which comprises administering to the patient an effective amount of the compound of formula I or a composition containing a compound of formula I, or a pharmaceutically salt acceptable of it. It should be understood that the reference to the treatment herein includes prophylactic therapy, as well as the treatment of established conditions. The present invention also includes within its scope, pharmaceutical compositions comprising a pharmaceutically acceptable amount of at least one of the compounds of formula I, in association with a pharmaceutically acceptable carrier, for example, an adjuvant, diluent, coating and excipient.
In practice, the compounds or compositions for treatment according to the present invention can be administered in any variety of suitable forms, for example, by inhalation, topically, parenterally, rectally or orally; preferably orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, infraocular, intrasynovial, colonic, peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation by insufflation, and aerosol. The compounds of formula I can be presented in forms that allow their administration by the most suitable route, and the invention also relates to pharmaceutical compositions containing at least one compound according to the invention and which are suitable for use as a medicament in a patient. These compositions can be prepared according to customary methods using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and different non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group comprising sweeteners such as sucrose, lactose, fructose, saccharin. or Nutrasweet®, flavors such as peppermint oil, wintergreen oil or cherry or orange flavors, colorants, or stabilizers such as methyl- or propylparaben, to obtain pharmaceutically acceptable preparations. The choice of the vehicle and the content of active substance therein is generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions that will be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc, they can be used to prepare tablets, troches, pills, capsules and the like. To prepare a capsule, it is advantageous to use lactose and a liquid carrier such as high molecular weight polyethylene glycols. Various other materials may be present as coatings or otherwise to modify the physical form of the dosage unit. For example, tablets, pills or capsules can be coated with lacquer, sugar, or both. When aqueous suspensions are used, they may contain emulsifying agents or agents that facilitate the suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof can also be used. In addition, the active compound can be incorporated into sustained release preparations and formulations. For oral administration, the active compound can be administered, for example, with an inert diluent or with an edible assimilable carrier, or it can be included in gelatin capsules of hard or soft shell, or it can be compressed into tablets, or it can be incorporated directly with the food of the diet, or it can be incorporated with excipient or used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention are used in vegetable oil, for example sesame oil, peanut oil or olive oil, or aqueous organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as also sterile aqueous solutions of the pharmaceutically acceptable salts. Injectable forms must be fluid to the degree that they can be easily injected, and an adequate fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prolonged absorption of the injectable compositions can be achieved by the use of agents that delay absorption, for example, aluminum monostearate and gelatin. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
A dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Aqueous solutions, which also comprise solutions of the salts in pure distilled water, can be used for intravenous administration with the proviso that their pH is adjusted appropriately, that they are thoroughly regulated in their pH, and that they are made isotonic with a sufficient amount of glucose or sodium chloride, and which are sterilized by heating and radiation, microfiltration and / or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, fimerosal, and the like. Sterile injectable solutions are prepared by incorporating the active compound in the required condition in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization with filtration. In general, the dispersions are prepared by incorporating the different sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and the freeze dehydration technique, which produce a powder of the active ingredient plus some other desired ingredient of the previously sterile filtered solution of the same. For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention can be used. The compounds of the invention can also be incorporated in a matrix or gel base for application in a patch, which would allow the controlled release of the compound through the transdermal barrier. For administration by inhalation, the compounds of the invention can be dissolved or suspended in a vehicle suitable for use in a nebulizer or aerosol in solution or suspension, or they can be adsorbed or absorbed onto a solid carrier suitable for use in a powder inhaler. dry. Solid compositions for rectal administration include suppositories formulated according to known methods and containing at least one compound of formula I. The compositions according to this invention can also be formulated in a manner that resists rapid clearance of the vascular wall ( arterial or venous) by convection and / or diffusion, thus increasing the residence time of the viral particles at the desired site of action. A periadventive deposit comprising a compound according to the invention can be used for sustained release. Said depot useful for administering a compound according to the invention may be a copolymer matrix, such as ethylene-vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic sheath. Alternatively, a compound according to the invention can be supplied locally from a silicone polymer implanted in the adventitia.
An alternative method for minimizing entrainment of a compound according to the invention during percutaneous and transvascular delivery, comprises the use of non-diffusible drug eluting microparticles. The microparticles may be formed from a variety of synthetic polymers, such as polylacid for example, or natural substances, including proteins or polysaccharides. These microparticles allow the strategic manipulation of variables that include the total dose of drug and the kinetics of its release. The microparticles can be effectively injected into the arterial or venous wall through a porous balloon catheter or a balloon onto a stent, and be retained in the vascular wall and the periadventive tissue for at least about two weeks. Formulations and methodologies for intravascular and local site-specific delivery of therapeutic agents are described in Reissen et al. (J. Am. Coil, Cardiol.; 23: 1234-1244), the contents of which are hereby incorporated by reference in their entirety. A composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polymer of polyacrylic acid which can function as a drug-absorbing sponge. Such polymers have been described, for example, in the application WO93 / 08845, the contents of which are hereby incorporated by reference in their entirety. Some of them, such as, in particular, those obtained from ethylene and / or propylene oxide, are commercially available. During the use of the compouaccording to the invention to treat pathologies that are linked to hyperproliferative disorders, the compouaccording to the invention can be administered in different ways. For the treatment of restenosis, the compouof the invention are administered directly to the wall of the blood vessel by means of an angioplasty balloon which is coated with a hydrophilic film (for example, a hydrogel), which is saturated with the compound , by means of any other catheter containing an infusion chamber for the compound which can be precisely applied in this way to the site to be treated, and allows the compound to be released locally and efficiently in the cells of the they will be treated. Advantageously, this method of administration makes it possible for the compound to rapidly come into contact with the cells in need of treatment. The method of treatment of the invention preferably consists of introducing a compound according to the invention into the site to be treated. For example, a hydrogel containing the composition can be directly deposited on the surface of the tissue to be treated, for example during a surgical intervention. Advantageously, the hydrogel is introduced into the desired intravascular site by coating a catheter, for example a balloon catheter, and supplying it to the vascular wall, preferably during angioplasty. In a particularly advantageous form, the saturated hydrogel is introduced into the site which will be treated by means of a balloon catheter. The balloon may be accompanied by a protective sheath as the catheter is advanced toward the target vessel, to minimize drug disposal after the catheter is introduced into the bloodstream. Another embodiment of the invention provides a compound according to the invention that will be administered by means of perfusion balloons. These perfusion balloons, which make it possible to maintain a blood flow and thus decrease the risks of myocardial ischemia, during inflation of the balloon, also allow the compound to be supplied locally at normal pressure for a relatively long time, more than 20 minutes, which may be necessary for your optimal action. Alternatively, a balloon catheter with channels ("balloon angioplasty catheter with channels", Mansfield Medical, Boston Scientific Corp., Watertown, MA) can be used. The latter consists of a conventional balloon covered with a layer of 24 perforated channels which are perfused by an independent lumen through an additional infusion orifice. Several types of balloon catheters, such as double balloon, porous balloon, microporous balloon, balloon with channels, balloon on stent and hydrogel catheter, all of which can be used to practice the invention, are described in Reissen et al. (1994), whose contents are incorporated herein in their entirety as a reference.
The use of a balloon catheter for perfusion is especially advantageous, since it has the advantages of keeping the balloon inflated for a longer period by requiring the properties of facilitated slippage and specificity of the hydrogel's sifio. Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the invention and poloxamer, such as Poloxamer 407, which is a commercially available biocompatible, non-toxic polyol (BASF, Parsippany, NJ). A poloxamer impregnated with a compound according to the invention can be deposited directly on the surface of the tissue to be treated, for example, during a surgical intervention. The poloxamer has essentially the same advantages as the hydrogel, but has a lower viscosity. The use of a balloon catheter with channels, with a poloxamer impregnated with a compound according to the invention, is especially advantageous. In this case, the advantages of keeping the balloon inflated for a longer period are simultaneously obtained, while retaining the properties of facilitated slippage and specific character of the poloxamer site. The percentage of active ingredient in the compositions of the invention can be varied, being necessary that it should constitute a proportion such that a suitable dosage can be obtained. Obviously, several dosage uforms can be administered at almost the same time. The dose used can be determined by a qualified physician or medical professional, and depends on the desired therapeutic effect, the route of administration, the duration of treatment and the patient's condition. In the adult, the doses are generally from about 0.001 to about 50, preferably from about 0.001 to about 5, milligrams per kilogram of body weight per day by inhalation, from about 0.01 to about 100, preferably from 0.1 to 70, more especially from 0.5 to 10, milligrams per kilogram of body weight per day by oral administration, and from about 0.001 to about 10, preferably from 0.01 to 10, milligrams per kilogram of body weight per day by intravenous administration. In each particular case, the doses are determined in accordance with the factors that distinguish the patient to be treated, such as age, weight, general state of health and other characteristics that may influence the efficacy of the compound according to the invention. The compounds / compositions according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose, and may find adequate maintenance doses much weaker. For other patients, it may be necessary to carry out long-term treatments at a rate of 1 to 4 doses per day, in accordance with the physiological requirements of each patient in particular. In general, the active product can be administered orally 1 to 4 times a day. In fact, for other patients, it will be necessary to prescribe no more than one or two doses per day. The compounds of the present invention can also be formulated to be used in conjunction with other therapeutic agents such as agents or in relation to the application of therapeutic techniques to highlight pharmacological conditions that can be ameliorated by the application of a compound of formula I, such as in the following: The compounds of the present invention can be used in the treatment of restenosis or angioplasty using any device such as a balloon, ablation or laser techniques. The compounds of the present invention can be used in the treatment of restenosis following stent placement in the vasculature such as 1) primary treatment of vascular blockage, or 2) in the case where the anglioplasty using any device fails to find a visible artery. . The compounds of the present invention can be used orally, by parenteral administration, or the compound can be applied topically by the intervention of a specific device or as a suitably formulated coating on a stent device. The compounds of the present invention can be used in the treatment of restenosis in combination with any anticoagulant, altiplatelet, antithrombotic or profibrinolytic agent. Frequently, patients are treated concurrently before, during and after interventional procedures with agents of these classes to safely perform the intervention procedure, or to prevent detrimental effects of thrombus formation. Some examples of classes of agents that are known to be anticoagulant, antiplatelet, antithrombotic or prophylactic agents include any formulation of heparin, low molecular weight heparin, pentasaccharides, fibrinogen receptor antagonists, thrombin inhibitors, factor Xa inhibitors or inhibitors of Vlla factor The compounds of the present invention can be used in combination with any antihypertensive agent or cholesterol or lipid regulating agent, in the treatment of restenosis or atherosclerosis concurrently with the treatment of high blood pressure or atherosclerosis. Some examples of agents that are useful in the treatment of high blood pressure include compounds of the following classes: beta blockers, ACE inhibitors, calcium channel blockers and alpha receptor antagonists. Some examples of agents that are useful in the treatment of elevated cholesterol levels or regulated lipid levels, include compounds known to be inhibitors of HMGCoA reductase, compounds of the fibrate class. The compounds of the present invention can be used in the treatment of various forms of cancer, alone or in combination with compounds known to be useful in the treatment thereof.
It is understood that the present invention includes combinations of compounds of this invention with one or more of the agents of the therapeutic groups mentioned above. Compounds within the scope of the present invention exhibit remarkable pharmacological activities in accordance with tests described in the literature, whose test results are thought to correlate with pharmacological activity in humans and other mammals. The following in vitro and in vivo pharmacological test results are typical for characterizing the compounds of the present invention.
PREPARATION OF PHARMACEUTICAL COMPOSITIONS AND SECTION OF
PHARMACOLOGICAL TESTS
Compounds within the scope of this invention exhibit significant activity as tyrosine kinase inhibitors, and possess therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including psoriasis, atherosclerosis and restenosis damage. Compounds within the scope of the present invention exhibit modulation and / or inhibition of cellular signaling and / or cell proliferation and / or matrix production and / or chemotaxis and / or cellular inflammatory response, and can be used to prevent or delay the incidence or recidivism of said conditions, or otherwise to treat the condition.
To determine the efficacy of the compounds of this invention, the pharmacological tests described below are used, which are accepted in the art and recognized to correlate with the pharmacological activity in mammals. The compounds within the scope of the present invention have been subjected to these different tests, and it is thought that the results obtained correlate with the useful activity of mediating cell differentiation. It is believed that the results of these tests provide sufficient information for experts in pharmacology and chemical medicine techniques to determine the parameters for the use of the compounds studied in one or more of the therapies described herein.
1. ELISA test for autophosphorylation of PDGF-R tyrosine kinase The titer test is carried out as described by Dolle et al. (J. Med. Chem. 1994, 37, 2627), citation incorporated herein by reference, except that lysates of cells derived from human aortic smooth muscle cells (HAMSC) are used, as described below:
2. General procedure of the mitochondrial test
to. Cell culture Human aortic smooth muscle cells (4 to 9 passages) are deposited in 96-well plates in a growth support medium at 6000 cells / well, and allowed to grow for 2 to 3 days. At a confluence of about 85%, growth of the cells is stopped with serum free media (SFM).
b. Myogenesis test After serum deprivation for 24 hours, the medium is removed and replaced with test / vehicle compound in SFM (200 μl / well). The compounds are solubilized in DMSO for cell culture at a concentration of 10 mM, and further dilutions are made in SFM. After preincubation for 30 minutes with compound, the cells are stimulated with PDGF at 10 ng / ml. Determinations are made in duplicate with stimulated and unstimulated wells at the concentration of each compound. Four hours later, 1 μCi of 3H thymidine / well is added. The cultures are terminated 24 hours after the addition of the growth factor. The cells are raised with trypsin, and harvested on a filter mat using an automated cell harvester (Wallac Machi 196). The counting of the filter mat is done in a scintillation counter (Wallac Betaplate) to determine the brand incorporated into the DNA.
3. Chemotaxis test Human aortic smooth muscle cells (HASMC) are obtained in previous passages of the ATCC. The cells are grown in Clonetics SmGM 2 SingleQuots (media and cells are used in passages 4 to 10). When the cells are 80% confluent, a calcein AM fluorescent probe (5 mM, molecular probe) is added to the media, and the cells are incubated for 30 minutes. After washing with saline solution regulated in its pH with HEPES, the cells are raised with trypsin, and neutralized with pH regulator MCDB 131 (Gibco) with 0.1% BSA, 10 mM glutamine and 10% fetal bovine serum . After centrifugation, the cells are washed once more and resuspended in the same pH buffer without bovine fetal serum at 30,000 cells per 50 ml. The cells are incubated with different concentrations of a compound of formula I (final concentration of DMSO = 1%) for 30 minutes at 37 ° C. For chemotaxis studies, modified 96-well Boyden chambers (Neuroprobe, Inc.) and a polycarbonate membrane with an 8-mm pore size (Poretics, CA) are used. The membrane is coated with collagen (Sigma C3657, 0.1 mg / ml). It is placed in the lower chamber PDGF-ßß (3 ng / ml) in pH regulator with and without a compound of formula I. 30,000 cells, with and without inhibitor, are placed in the upper chamber. The cells are incubated for 4 hours. The filter membrane is removed, and the cells on the upper side of the membrane are removed. After drying, the fluorescence on the membrane is determined using Cytofluor II (Millipore) at excitation / emission wavelengths of 485/530 nm. In each experiment, an average cell migration is obtained from 6 replicates. The percent inhibition is determined from control values treated with DMSO. From the concentration-dependent inhibitions of 5 points, the IC50 value is calculated. The results are presented as an ± SEM average of 5 of said experiments.
4. Purification of EGF receptor The purification of the EGF receptor is based on the procedure of Yarden and Schlessinger. A431 cells are grown in 80 cm2 flasks to confluence (2 x 107 cells per flask). Cells are washed twice with PBS and harvested with PBS containing 11.0 mmoles of EDTA (1 hour at 37 ° C), and centrifuged at 600g for 10 minutes. The cells are solubilized in 1 ml by 2 x 10 7 pH regulator cells for cold solubilization (50 mmol of pH regulator HEPES, pH 7.6, Triton X-100 at 1%, 150 mmol of NaCl, 5 mmol of EGTA, 1 mmol of PMSF, 50 mg per ml of aprotinin, 25 mmol of benzamidine, 5 mg per ml of leupeptin and 10 mg per ml of soybean trypsin inhibitor) for 20 minutes at 4 ° C. After centrifugation at 100,000g for 30 minutes, the supernatant is loaded onto a WGA-agarose column (100 ml of resin packed by 2 x 10 7 cells) and stirred for 2 hours at 4 ° C. The unabsorbed material is removed, and the resin is washed twice with pH regulator HTN (50 mmoles of HEPES, pH 7.6, Triton X-100 at 0.1%, 150 mmoles of NaCl), twice with pH regulator HTN containing NaCl at 1 M, and twice with pH regulator HTNG (50 mmoles of HEPES, pH 7.6, Triton X-100 at 0.1%, 150 mmoles of NaCl and glycerol at 10%). The EGF receptor is eluted intermittently with pH regulator HTNG containing N-acetyl-D-glucosamine at 0.5 M (200 ml for 2 x 107 cells). The eluate is stored in aliquots at -70 ° C and diluted before use with TMTNG pH regulator (50 mmol Tris-Mes pH regulator, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, 10% glycerol).
. Inhibition of EGF-R autophosphorylation A431 cells are grown to confluence on tissue culture plates coated with human fibronectin. After washing twice with ice-cold PBS, the cells are lysed by the addition of 500 ml per pH regulator plate for lysis (50 mmoles of HEPES, pH 7.5, 150 mmoles of NaCl, 1.5 mmoles of MgCl 2, 1 mmoles of EGTA, glycerol at 10%, triton X-100 at 1%, 1 mmol of PMSF, 1 mg per ml of aprotinin, 1 mg per ml of leupeptin), and incubating for 5 minutes at 4 ° C. After stimulation of EGF (500 mg / ml, 10 minutes at 37 ° C), immunoprecipitation is carried out with anti-EGF-R (Ab 108), and the autophosphorylation reaction (aliquots of 50 ml, 3 mCi of [ g'32 PjATP) is carried out in the presence of 2 or 10 mM of the compound of the present invention, for two minutes at 4 ° C. The reaction is stopped by the addition of a pH regulator for hot electrophoresis. Analysis of SDA-PAGE (7.5%) is followed by autoradiography, and the reaction is quantified by densitometry screening of the X-ray films.
to. Cell culture Cells designated HER 14 and K721A are prepared by transfecting NIH3T3 cells (clone 2.2) (from C. Fryling, NCI, NIH), which lack endogenous EGF receptors with wild-type EGF receptor cDNA constructs or mutant EGF receptor lacking tyrosine kinase activity (in which Lys 721 at the ATP binding site is replaced by an Ala residue, respectively). All cells are cultured in DMEM with 10% calf serum (Hyclone, Logan, Utah).
6. The selectivity against PKA and PKC is determined using commercial equipment a. Colorimetric equipment for PKA Pierce test, format
Spinzyme Brief protocol: 1 U of PKA enzyme (bovine heart) / test tube. Peptide peptide substrate (labeled with dye). 45 minutes at 30 ° C. Absorbance at 570 nm.
b. Colorimetric equipment for PKA Pierce test, format
Spinzyme Brief protocol: 0.025 U of PKC enzyme (rat brain) / test tube. Peptide substrate Neurogranin (labeled with dye). 30 minutes at 30 ° C. Absorbance at 570 nm.
7. Measurements of the inhibition activity of p56 Ick tyrosine kinase The inhibition activity of p56lck tyrosine kinase is determined according to a method described in the patent of E.U.A. No. 5, 714,493, incorporated herein by reference. In the alternative, the tyrosine kinase inhibition activity is determined according to the following method. A substrate (tyrosine-containing substrate, Biot- (ß Ala) 3-Lys-Val-Glu-Lys-lle-Gly-Glu-Gly-Thr-Tyr-Glu-Val-Val-Tyr-Lys- (NH2) recognized per p56lck, 1 μM) is first phosphorylated in the presence or absence of a given concentration of the test compound, by a given amount of enzyme (the enzyme is produced by expressing the p56lck gene in a yeast construct) purified from a cloned yeast (the purification of the enzyme is carried out following classical methods) in the presence of ATP (10 μM), MgCl2 (2.5 mM), MnCl2 (2.5 mM), NaCl (25 mM), DTT (0.4 mM) in Hepes at 50 mM, pH 7.5, for 10 minutes at room temperature. The total reaction volume is 50 μl, and the reactions are carried out in a 96-well black fluoroplate. The reaction is stopped by the addition of 150 μl of stop pH buffer (100 mM Hepes, pH 7.5, KF at 400 mM, EDTA at 133 mM, 1 g / L BSA), containing a selected antithyrosine antibody labeled with the Europium cryptate (PY20-K) at 0.8 μg / ml and streptavidin labeled with allophycocyanin (XL665) at 4 μg / ml. The labeling of streptavidin and anti-tyrosine antibodies was carried out by Cis-Bio International (France). The mixture is counted using a Discovery Packard counter, which is capable of measuring the homogenous transfer of resolved fluorescence with time (excitation at 337 nm, reading at 620 nm and 665 nm). The signal ratio of 665 nm / 620 nm signal is a measure of the concentration of phosphorylated tyrosine. White is obtained by replacing the enzyme with a pH regulator. The specific signal is the difference between the ratio obtained without inhibitor and the relationship with the target. The percentage of specific signal is calculated. The IC50 is calculated with 10 concentrations of inhibitor in duplicate using Xlfit soft. The reference compound is staurosporine (Sigma), and exhibits an IC5o of 30 + 6 nM (n = 20). The results obtained by the above experimental methods show that the compounds within the scope of the present invention possess useful properties of inhibition of the PDGF receptor tyrosine kinase or inhibition properties of p56lck tyrosine kinase, and that in this way they possess therapeutic value. The above pharmacological test results can be used to determine the dosage and mode of administration for the particular therapy sought. The present invention can be described in other specific forms without departing from the spirit or the essential attributes thereof.
Claims (67)
- NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula where: X is Uo L2Z2; Li is (CR3aR3b) rH or (CR3aR3b) m-Z3- (CR3.aR3'b) nH; L2 is or ethenyl; Zi is CH or N; Z2 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl or optionally substituted heterocyclenyl; Z3 is O, NR4, S, SO or SO2; Z4 is O, NR4, S, SO, SO2 or a bond; m is 0 or 1; n is 2 or 3, and n + m = 2 or 3; p and q are independently 0, 1, 2, 3 or 4, and p + q = 0, 1, 2, 3 or 4 when Z4 is a bond, and p + q = 0, 1, 2 or 3 when Z is not a bond; r is 2, 3 or 4; R1a and R? B are optionally optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, RsR? N - or acyl R5N-, or one of R and R and R is hydrogen or halogen and the other is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, substituted heterocyclylcarbonyloxy optionally, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, RsRβN- or acyl R N-; R c is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halogen, cyano, R5R6N- or acylR5N-; R3a-R3b, 3'a and R3'b are independently hydrogen or alkyl; R 4 is hydrogen, alkyl or acyl; and R5 and R6 are independently hydrogen or alkyl, or R5 and Rβ taken together with the nitrogen to which R5 and R6 are attached form azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or salt pharmaceutically acceptable thereof.
- 2. The compound according to claim 1, further characterized in that: Li is (CR3aR3b) m-Z3- (CR3'aR3'b) n; L2 is (CR3aR3b) p-Z4- (CR3'aR3'b) q; Z2 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocyclyl; Z4 is O and NR4; m is 0; n is 2 or 3; p + q = 0 or 1: R1a and Rib are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heteroxykyloxy or RsRßN, or one of R and R and R is hydrogen or halogen and the other is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heteroxykyloxy or RsReN-; R c is hydrogen, optionally substituted alkyl or optionally substituted alkoxy; R3a, R3b > 3'a and 3b are independently hydrogen or lower alkyl; R 4 is hydrogen and R 5 and R taken together with the nitrogen atom to which R 5 and R 8 are attached form azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof.
- 3. The compound according to claim 1, further characterized in that: X is L2Z; L2 is (CR3aR3b) p-Z- (CR3'aR3b) q; Z2 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl; Z3 is O and NR; p is 0; q is 0 or 1; R1a and Rib are optionally optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy, or one of R? A and R? B is hydrogen or halogen; R1c is hydrogen; R3'a and R3'b are independently hydrogen and R4 is hydrogen, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof.
- 4. The compound according to claim 1, further characterized in that L1 is lower alkyl. 5. - The compound according to claim 1, further characterized in that Zi is CH. 6. The compound according to claim 1, further characterized in that Z1 is N. 7. The compound according to claim 1, further characterized in that Z2 is optionally substituted cycloalkyl. 8. The compound according to claim 1, further characterized in that Z2 is monocyclic cycloalkyl substituted with alkyl. 9. The compound according to claim 1, further characterized in that Z2 is methylcyclopentyl or methylcyclohexyl. 10. The compound according to claim 1, further characterized in that Z2 is multicyclic cycloalkyl. 11. The compound according to claim 1, further characterized in that Z2 is [2.2.1] bicycloheptanyl (norbornyl) or [2.2.2] bicyclooctanyl. 12. The compound according to claim 1, further characterized in that Z2 is optionally substituted cycloalkenyl. 13. The compound according to claim 1, further characterized in that Z2 is cyclopentenyl and cyclohexenyl. 14. The compound according to claim 1, further characterized in that Z2 is [2.2.1] bicycloheptenyl (norbornenyl) or [2.2.2] bicyclooctenyl. 15. The compound according to claim 1, further characterized in that p and q are 0. 16. The compound according to claim 1. further characterized in that p + q = 1. 17. The compound according to claim 1, further characterized in that Z4 is O. 18. The compound according to claim 1, further characterized in that Z4 is O, and p and p are 0. 19. The compound in accordance with claim 1, further characterized in that Z4 is O, and p + q = 1. 20. The compound according to claim 1, further characterized in that Z4 is NR4. 21. The compound according to claim 1, further characterized in that Z4 is NR, and p and q are 0. 22. The compound according to claim 1, further characterized in that Z4 is NR4, and m + n = 1. 23. The compound according to claim 1, further characterized in that Z is S. The compound according to claim 1, further characterized in that Z4 is S, and p and q are 0. 25.- The compound in accordance with claim 1, further characterized in that Z4 is S, and p + q = 1. 26. The compound according to claim 1, further characterized in that R a and R y are independently lower alkyl optionally substituted with hydroxy, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy, or one of R 1a and Rib is hydrogen or halogen. 27. The compound according to claim 1, further characterized in that R a and R y are independently heterocyclylcarbonyloxy or optionally substituted lower alkoxy. 28. The compound according to claim 1, further characterized in that the lower alkoxy is methoxy or ethoxy. 29. The compound according to claim 1, further characterized in that R a and Rib are lower alkyl. 30. The compound according to claim 1, further characterized in that the lower alkyl is methyl or ethyl. 31. The compound according to claim 1, further characterized in that one of R a and R a is lower alkoxy, and the other of Ria and Rib is halogen. 32. The compound according to claim 1, further characterized in that the lower alkoxy is methoxy or hetoxy, and the halogen is chlorine or bromine. 33. The compound according to claim 1, further characterized in that one of R? A and R ^ is lower alkyl, and the other of Ria and Rib is lower alkoxy. 34. The compound according to claim 1, further characterized in that the lower alkoxy is methoxy or ethoxy, and the lower alkyl is methyl or ethyl. 35.- The compound according to claim 1, further characterized in that one of R a and R e is lower alkoxy, and the other R a and Ib is cycloalkyloxy. 36. The compound according to claim 1, further characterized in that the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. 37. The compound according to claim 1, further characterized in that one of R? A and Rib is hydrogen, and the other of R? A and Ri is lower alkoxy, cycloalkyloxy or heterocyclyloxy. 38.- The compound according to claim 37, further characterized in that the lower alkoxy is methoxy or ethoxy. 39.- The compound according to claim 37, further characterized in that the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. The compound according to claim 37, further characterized in that the heterocyclyloxy is furanyloxy. 41. The compound according to claim 1, further characterized in that R? C is hydrogen, lower alkyl or lower alkoxy. 42. The compound according to claim 41, further characterized in that the lower alkoxy is methoxy or ethoxy. 43. The compound according to claim 1, further characterized in that R a and R y are lower alkoxy optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. The compound according to claim 1, further characterized in that one of R a and Rib is unsubstituted lower alkoxy, and the other of R a and Rib is lower alkoxy substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. 45.- The compound according to claim 1, further characterized in that one of R a and R b is methoxy, and the other of R a and R ^ is [1,4 '] -bipiperidin-1'-ylcarbonyloxy, 2- (ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy, 2- (4-methylpiperazin-1-yl) ethoxy, carboxymethoxy, methoxycarbonylmethoxy, aminocarbonyl methoxy, N-methylaminocarbonylmethoxy or N, N-dimethylaminocarbonylmethoxy. 46. A compound according to claim 1, characterized in that it is: 3-cyclohexyloxy-6,7-dimethoxy-quinoline; 2-cyclohexylammon-6,7-d-methoxyquinoline; exo-bicyclo [2.2.1] hept-2-yl- (6-chloro-7-methoxyquinolalin-2-yl) amine; exo-bicyclo [2.2.1] hept-2-yl- (7-chloro-6-methoxy-quinoxalin-2-yl) amine; Bicyclo [2.2.1] hept-2-yl- (6,7-dimethyl-quinoxalin-2-yl) -amine: 2-cycloheptylamino-6,7-dimethoxy-quinotoxaline; 2-cyclopentylamino-6,7-dimethoxyquinolaline; 2-cyclohexylammon-6-methoxyquinolaline; 3-aminocyclohexyl-6,7-dimethoxyquinoline; (6,7-dimethoxy-quinolin-3-yl) -c 's - (3- (R) -methyl-cyclohexyl) amine; 2-cyclohexylammono-6-methoxy-7-bromo-quinoxaline hydrochloride; (6,7-dimethoxyquinolin-3-yl) -c 's / trans- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxyquinolin-3-yl) -trans- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxy-quinolin-3-yl) -cis- (3- (R) -methyl-cyclohexyl) -amine; (6,7-dimethoxy-quinolin-3-yl) - (3-methyl-cyclopentyl) -amine; cyclohex-3-enyl- (6,7-dimethoxyquinolalin-2-yl) -amine; 2,7-bis-cyclohexyloxy-6-methoxy-quinoxaline; cyclohexyl- (6,7-dimethoxy-cyanoxalin-2-methylmethyl) -amine; (6,7-dimethoxyquinolin-3-yl) -isobutyl amine; cyclohexyl- (6-methoxy-7-morpholin-4-yl-quinoxalin-2-yl) -amine; (±) -bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) amine; exo-bicyclo [2.2.1] hept-5-en-2-yl- (6,7-dimethoxy-cyanoxalin-2-yl) -amine; cyclohexyl- (6,8-dimethyl-quinoxalin-2-yl) -amine; endo-bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine; (6,7-dimethoxyquinolalin-2-yl) - (4-methoxy-cyclohexyl) -amine; exo-bicyclo [2.2.1] hept-2-yl- (6-methoxyquinonoin-2-yl) -amina; exo-2- (bicyclo [2.2.2] hept-2-yloxy) -6,7-dimethoxyquinolaline: (bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline; endo-2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-d-methoxy-quinoxaline; exo-2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline; bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline; 2-cyclohexyloxy-6,7-dimethoxyquinolaline; 2-cyclopentylthio-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline; 2-cyclopentylmethyloxy-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-tetrahydropyran-4-oxy-quinoxaline; exo, exo-6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptan-2-yloxy) -quinoxaline; cis / trans-4- (6,7-dimethoxy-quinotoxal-2-yloxy) -cyclohexanecarboxylic acid; 6,7-dimethoxy-2- (4-methoxy-cyclohexyloxy) -quinoxaline; (1 R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinol-2-yl) -amine; (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine; (6,7-dimethoxy-quinoxalin-2-yl) -2-aza-bicyclo [2.2.2] octane-3-one; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylammon) -cyclohexanecarboxylic acid; cis-4- (6,7-dimethoxy-quinoxalyn-2-ylammon) -cyclohexanecarboxylic acid methyl ester; methyl ester of trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanecarboxylic acid methyl ester; (6,7-dimethoxy-quinoxalin-2-yl) -cis / trans- (3- (R) -methylcyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) -trans- (3- (R) -methylcyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) -cis- (3- (R) -methylcyclohexyl) amine; or methyl cis / trans-4- (6,7-dimethoxy-quinxoalin-2-yloxy) -cyclohexanecarboxylate, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 47. A compound according to claim 1, further characterized in that it is exo-bicyclo [2.2.1] hept-5-en-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine, or a N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 48. A compound according to claim 1, further characterized in that it is (1 R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinoline-2) -yl) -amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 49.- A compound according to claim 1, further characterized in that it is (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquininoalin-2-yl) ) -amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 50.- A compound according to claim 1, further characterized in that it is (6,7-dimethoxy-quinoxalin-2-yl) -frans- (3- (R) -methylcyclohexyl) amine, or an N-oxide thereof , hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 51. A compound according to claim 1, further characterized in that it is (6,7-dimethoxy-quinoxalin-2-yl) -cis- (3- (R) -methylcyclohexyl) amine, or an N- oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 52. A pharmaceutical composition, characterized in that it comprises the compound according to claim 1, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 53. A method for inhibiting the activity of PDGF tyrosine kinase, characterized in that it comprises contacting a compound according to claim 1, with a composition containing a PDGF tyrosine kinase. 54.- A method for inhibiting the activity of Lck tyrosine kinase, characterized in that it comprises contacting a compound according to claim 1, with a composition containing an Lck tyrosine kinase. 55. The use of the compound according to claim 1, for the manufacture of a medicament for inhibiting cell proliferation, cell differentiation, or release of cellular mediator in a patient. 56.- The use of the compound according to claim 1, for the manufacture of a medicament for treating a pathology linked to a hyperproliferative disorder in a patient 57.- The use according to claim 56, wherein said pathology is restenosis . The use of the compound according to claim 1, for the manufacture of a medicament for treating restenosis in a patient, wherein said compound is capable of inhibiting the proliferation and migration of vascular smooth muscle cells at a predetermined site. . 59. The use according to claim 56, wherein said hyperproliferative disorder exists at a site of mechanical injury of an arterial wall, produced by treatment of an atherosclerotic lesion by angioplasty. 60. The use according to claim 56, wherein the compound of claim 1 is administered by an angioplasty balloon coated with a hydrophilic film saturated therewith. 61. The use according to claim 56, wherein the compound of claim 1 is administered by a catheter comprising an infusion chamber containing a solution of the same compound. 62. The use of a compound according to claim 1, for the manufacture of a medicament for treating inflammation in a patient. 63. The use according to claim 57, wherein the compound of claim 1 is administered by a coating on a stent device, and wherein the coating comprises a compound according to claim 1. 64.- The use according to claim 57, wherein the pathology linked to a hyperproliferative disorder is a cancer susceptible to treatment by inhibition of PDGF tyrosine kinase. 65.- The use according to claim 64, wherein the cancer is brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma or malignant melanoma. 66.- The use according to claim 55, wherein the disorder is leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, arthritis, fibrosis of the lung, fibrosis of the kidney, fibrosis of the liver, atherosclerosis or Restenosis that occurs subsequent to angioplasty of the coronary, femoral or renal arteries. 67.- The use of an Lck tyrosine kinase inhibitor amount of the compound according to claim 1, for the manufacture of a medicament for the treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, asthma, Inflammatory bowel disease or pancreatitis, in a patient.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/972,614 | 1997-11-18 | ||
US08/864,455 | 1997-11-18 |
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