MXPA06011047A - Compounds and methods for treating dyslipidemia - Google Patents
Compounds and methods for treating dyslipidemiaInfo
- Publication number
- MXPA06011047A MXPA06011047A MXPA/A/2006/011047A MXPA06011047A MXPA06011047A MX PA06011047 A MXPA06011047 A MX PA06011047A MX PA06011047 A MXPA06011047 A MX PA06011047A MX PA06011047 A MXPA06011047 A MX PA06011047A
- Authority
- MX
- Mexico
- Prior art keywords
- trifluoromethyl
- ethyl
- amino
- dihydro
- benzyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 246
- 206010058108 Dyslipidaemia Diseases 0.000 title claims abstract description 9
- 206010061227 Lipid metabolism disease Diseases 0.000 title claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- -1 OC 2 -C 6 alkoalkyl Chemical group 0.000 claims description 392
- SKRDXYBATCVEMS-UHFFFAOYSA-N Isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 claims description 150
- 239000000203 mixture Substances 0.000 claims description 109
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 79
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 68
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 53
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 49
- 125000001188 haloalkyl group Chemical group 0.000 claims description 45
- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
- 239000011780 sodium chloride Substances 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 33
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 229940107161 Cholesterol Drugs 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 230000000694 effects Effects 0.000 claims description 26
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 26
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 25
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 24
- 239000012453 solvate Substances 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 235000012000 cholesterol Nutrition 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 19
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 18
- 210000002381 Plasma Anatomy 0.000 claims description 18
- FSIAYZKBDOJEGD-UHFFFAOYSA-N N1(CC=CC2=NC=CC=C12)C(=O)O Chemical compound N1(CC=CC2=NC=CC=C12)C(=O)O FSIAYZKBDOJEGD-UHFFFAOYSA-N 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 15
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 15
- 201000001320 atherosclerosis Diseases 0.000 claims description 15
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 150000003973 alkyl amines Chemical class 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 238000008214 LDL Cholesterol Methods 0.000 claims description 11
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 11
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- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- COSGGOLUPXUUCN-ZBFHGGJFSA-N (2R,4S)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylic acid Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(O)=O)CC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 COSGGOLUPXUUCN-ZBFHGGJFSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 239000000969 carrier Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- VZIHTQKMHLOIII-UHFFFAOYSA-N 3,5-dihydro-2H-furan Chemical group [CH]1CCOC1 VZIHTQKMHLOIII-UHFFFAOYSA-N 0.000 claims description 6
- 125000005024 alkenyl aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000001575 pathological Effects 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 5
- 125000005025 alkynylaryl group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000005842 heteroatoms Chemical group 0.000 claims description 5
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
- TWBYWOBDOCUKOW-UHFFFAOYSA-N Isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 4
- 230000033228 biological regulation Effects 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- BHHDWIGDJNNNOP-UHFFFAOYSA-N C(C)C1N(C2=CC=C(N=C2CC1)C(F)(F)F)C(=O)O Chemical compound C(C)C1N(C2=CC=C(N=C2CC1)C(F)(F)F)C(=O)O BHHDWIGDJNNNOP-UHFFFAOYSA-N 0.000 claims description 3
- 229910014585 C2-Ce Inorganic materials 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- VRESBNUEIKZECD-UHFFFAOYSA-N 2-methyltetrazole Chemical compound CN1N=CN=N1 VRESBNUEIKZECD-UHFFFAOYSA-N 0.000 claims description 2
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 230000001105 regulatory Effects 0.000 claims description 2
- 102100019883 CETP Human genes 0.000 claims 3
- 101700077539 CETP Proteins 0.000 claims 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 2
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims 2
- 150000004702 methyl esters Chemical class 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- HRBYTTGPZNPCOO-UHFFFAOYSA-N 1,2-oxazole;1H-pyrazole Chemical compound C=1C=NNC=1.C=1C=NOC=1 HRBYTTGPZNPCOO-UHFFFAOYSA-N 0.000 claims 1
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 claims 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N Glycol stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims 1
- 101710019691 Olfr1 Proteins 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 125000005741 alkyl alkenyl group Chemical group 0.000 claims 1
- 125000004948 alkyl aryl alkyl group Chemical group 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 125000005418 aryl aryl group Chemical group 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 1
- 125000006492 halo alkyl aryl group Chemical group 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 229
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- 238000002360 preparation method Methods 0.000 description 77
- 238000006243 chemical reaction Methods 0.000 description 74
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- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 69
- 238000000034 method Methods 0.000 description 59
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- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
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- 238000004090 dissolution Methods 0.000 description 1
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- KPXWNJGVBKCXKB-UHFFFAOYSA-N ethyl 7-methyl-4-oxo-1H-1,8-naphthyridine-3-carboxylate Chemical compound CC1=CC=C2C(=O)C(C(=O)OCC)=CNC2=N1 KPXWNJGVBKCXKB-UHFFFAOYSA-N 0.000 description 1
- WVXUVVDDUHEOBM-UHFFFAOYSA-N ethyl 7-oxo-4H-thieno[3,2-b]pyridine-6-carboxylate Chemical compound CCOC(=O)C1=CN=C2C=CSC2=C1O WVXUVVDDUHEOBM-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- KJRFTNVYOAGTHK-UHFFFAOYSA-N methyl 3-hydroxy-2,2-dimethylpropanoate Chemical compound COC(=O)C(C)(C)CO KJRFTNVYOAGTHK-UHFFFAOYSA-N 0.000 description 1
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- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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- 230000000207 pro-atherogenic Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (NE)-N-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
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- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 235000012239 silicon dioxide Nutrition 0.000 description 1
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- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
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- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl N-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- BBUQUBATODVRRV-UHFFFAOYSA-N triacetyloxyboron(1-) Chemical compound CC(=O)O[B-](OC(C)=O)OC(C)=O BBUQUBATODVRRV-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
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Abstract
The present invention discloses compounds of formula (I) wherein A, n, q, K, W, X, Y, Z, R1, R2, R3, R4, R5, and R6 are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and its sequelae.
Description
COMPOUNDS AND METHODS FOR THE TREATMENT OF DISLIPIDEMIA
FIELD OF THE INVENTION The present invention relates to the field of organic medicinal chemistry, pharmacology and medicine.
In addition, the present invention relates to a group of compounds that demonstrate utility to treat pathological conditions generated by dyslipide ia.
BACKGROUND OF THE INVENTION "Coronary heart disease" (CHD) is one of the leading causes of morbidity and mortality worldwide. Despite attempts to modify risk factors such as obesity, smoking, lack of exercise, as well as the treatment of dyslipidemia with dietary changes or drug therapy, CHD remains the most common cause of death in the United States. . More than 50% of all CHD deaths are due to fundamental atherosclerotic coronary heart disease. Dyslipidemia is a determinant risk factor for CHD. Low plasma levels of high density lipoprotein (HDL) cholesterol with either normal or elevated levels of low density lipoprotein (LDL) cholesterol is a significant risk factor for the development of atherosclerosis and coronary artery disease in humans . Indeed, various studies on the lipoprotein profile in CHD patients showed that approximately 50% of patients with CHD have cholesterol levels that are considered to be in the normal range (<200 g / dl). In addition, these studies have found low HDL cholesterol in approximately 40% of CHD nor-cholelemic patients, compared with the general population reported in the National Health and Nutrition Examination Survey (National Survey of Health and Nutrition) . Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods of increasing HDL cholesterol in plasma would be therapeutically beneficial, for the treatment of cardiovascular diseases, including, but not limited to, atherosclerosis, CHD, stroke and vascular disease. peripheral. Cholesterol ester transfer protein (CETP) is a 74 KD glycoprotein that facilitates the exchange of cholesterol esters in HDL by triglycerides in triglyceride-rich lipoproteins (AR Tall et al., (1999) 1999 George Lyman Duss Memorial Lecture: Lipid transfer proteins, HDL metabolism and atherogenesis, Arterio, Thromb, Vasc. Biol. 20: 1185-1188. The net result of CETP activity is a decrease in HDL cholesterol and an increase in LDL cholesterol. This effect on the profile of lipoprotein is believed to be proatherogenic, especially in subjects whose lipid profiles constitute an increasing risk for CHD. Niacin can significantly increase HDL, but it has serious tolerance sequelae that reduce performance. The fibrates currently marketed and inhibitors of HMG
CoA reductase raise HDL cholesterol only modestly
(~ 10-12%). As a result, there is a significant unmet medical need for a well-tolerated agent that can significantly elevate plasma HDL levels, thereby reversing or diminishing the progression of atherosclerosis. CETP is expressed in multiple tissues and is secreted in the plasma, where it is associated with HDL (XC Jiang et al., (1991) Mammalian adipose tissue and muscle are sources of lipid transfer protein mRNA J. Biol. Chem .
266: 4631-4639). Humans and monkeys, which express CETP, have relatively low HDL cholesterol, while mice and rats do not express CETP and carry almost all of their cholesterol in HDL. Moreover, the transgenic expression of CETP in mice results in significantly reduced levels of HDL cholesterol and severe atherosclerosis, compared with control mice (KR Marotti et al., (1993) Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer Protein Nature: 364, 73-75). The expression of human CETP in hypertensive salt-sensitive Dahl rats led to spontaneous combined hyperlipidemia, coronary heart disease and decreased survival (VLM Herrera et al., (1999) Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt -sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein, Nature Medicine: 5, 1383-1389). Antibodies either injected directly into the plasma or generated through the injection of vaccines, can effectively inhibit CETP activity in hamsters and rabbits resulting in high HDL cholesterol (C. W. Rittershaus, (1999)). Antibiotics induced by vaccines inhibit the activity of CETP in vivo and reduce aortic lesions in a model of atherosclerosis in rabbits. In addition, the neutralization of CETP antibodies in rabbits has been shown to be anti-atherogenic. { Arterio Thromb. Vasc, Biol. 20, 2106-2112; G.F. Evans et. al., (1994) Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholesterolemic hamsters: effects on HDL subspecies, quantity, and apolipoprotein distribution. J. Lipid Research. 35, 1634-1645). However, antibody and / or vaccine therapy is currently not a viable option for the treatment of large populations of patients in need of treatment for dyslipidemia and manifestations of associated or resultant disease states.
The cholesterol ester transfer protein (CETP) catalyzes the exchange of neutral lipid between HDL and lipoprotein particles containing apoB. As a result of this change, HDL cholesterol is reduced and LDL particles are further enriched with cholesterol, resulting in an elevation of LDL cholesterol and formation of small dense LDL particles, which are believed to be more atherogenic. Inhibition of CETP (small molecule, antibody, antisense oligo, etc.), effectively raises HDL cholesterol and also reduces LDL cholesterol in animal models, as well as in humans (Whitlock, M. et al., J. of Clin Invest., 1989, Vol. 84, 129-137, Hirochi, 0. et al., Nature, 2000, Vol. 406, 203-207, Grooth, G. et al., Circulation, 2002; 105: 2159- 2165, Clark, R. et al., Arterioscler Thromb Vasc Biol. 2004; 24: 1-9, Brousseau M. et al., New Engl. J. Med., 2004, Vol. 350: 1505-1515). In addition, inhibition of CETP leads to the formation of less dense LDL particles a benefit in the addition of the LDL cholesterol decrease (Brousseau M. et al., New Engl. J. Med., 2004, Vol. 350: 1505- 1515). Thus, the administration of CETP inhibitors to humans in need of it, could significantly raise the level of HDL cholesterol and reduce LDL cholesterol levels and increase the LDL particle size, all of which are believed to benefit exposed patients. at atherosclerotic risk.
There have also been several reports of small molecule CETP inhibitors. Barrret et al. (J.Am. Chem. Soc, 188, 7863, (1996)) and Kuo et al. (J. Am. Chem. Soc, 117, 10629, (1995)), describe inhibitors of CETP containing cyclopropane. Pietzonka et al. (Biorg, Med. Chem. Lett., 6, 1951 (1996)) describe phosphonate-containing analogues as CETP inhibitors. Coval and collaborators. (Bioorg, Med. Chem. Lett., 5, 605, (1995)), describe sesquiterpine related to Wiedendiol-A and -B as inhibitors of CETP. Japanese Patent Application Number No. 10287662-A discloses natural polyhydroxy, non-amino-containing, polycyclic compounds possessing CETP inhibiting properties. Lee and collaborators. (J. Antibiotics, 49, 693-96 (1996)), describe inhibitors of CETP derived from insect fungi. Busch and collaborators. (Lipids, 25, 216-220 (1990)), describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zillversmit (J. Lipid Res., 35, 836-47 (1982)), describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl ercurithiosalicylate, inhibit CETP. Connolly and collaborators. (Biochem. Biophys, Res.Comia. 223, 42-47 (1996)), describe other cysteine modification reagents as CETP inhibitors. Xia and co-workers describe 1, 3, 5-triazines as inhibitors of CETP (Bioorg, Med. Chem. Lett., 6, 919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole thiol as a CETP inhibitor, Oomura et al. Describe hexacyclic and tetracyclic phenols. non-peptidic as inhibitors of CETP, in Japanese Patent Application No. 10287662. US Pat. No. 6,586,448 Bl, describes 1, 2, 3, 4-tetrahydroquinolines 4-carboxamino-2-substituted of formula I
I and prodrugs thereof, as well as pharmaceutically acceptable salts of such compounds and said prodrugs; where R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein. Similarly, PCT patent applications WO 03/063868A1, WO 0017164, No.0017165, and WO 0017166, describe in various forms, formulations, methods of preparation and use of tetrahydroquinoline compounds, generally related to those of US Patent 6,586,448 Bl from which it derives or is a divisional application thereof.
European Patent Application No. 818448 by Schmidt et al. Describes tetrahydroquinoline derivatives as inhibitors of cholesteryl ester transfer protein. European Patent Application No. 818197 to Schmek et al.describes pyridines with fused heterocycles as inhibitors of cholesteryl ester transfer protein. Brandes et al., In German Patent Application No. 19627430, discloses fused bicyclic pyridine derivatives as inhibitors of the cholesteryl ester transfer protein. In U.S. Patent No. 6,207,671 to Schmidt et al., They describe substituted pyridine compounds as inhibitors of CETP. In the patent application WO 0 098 392 99, and in the patent application WO 03028727 by Muller-gliemann et al., And Erfinder / Anmelder respectively, quinoline derivatives are described as inhibitors of the cholesteryl ester transfer protein. Notwithstanding the above descriptions, there remains a great need for effective compounds useful as CETP inhibitors to treat conditions caused by, associated with or exacerbated by dyslipidemia.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of formula I
where n is 0, 1, 2, or 3; q is 0, 1, or 2; W, X, Y and Z are each independently CH, C, N, S or O, with appropriate single or double bonds and / or hydrogen atoms to complete valence requirements; Ring A is a ring of five or six elements, where one of W, X, Y and Z may be absent; as long as ring A is not phenyl; K is a bond, C = O, or S (0) p; p is 0, 1 or 2; R1 when n is 0, and k is C = 0 or S (0) p, is selected from the group consisting of alkyl -OC1-C6 alkyl, -O-aryl, -OC2-Ce alkenyl, -OC? -C6 haloalkyl, -OC? -C6 alkylheterocyclic, -OC3-C8 cycloalkyl, -OC? -C6 alkylcycloalkyl, -NR7R8, -OC? -C6 alkylaryl, OC1-C6alkylC02R1111, -OC2-C6alkyl alcohol, -0C? -C6 alkylNR7R8, -OC2- C6 alkylocyano, CONR ^ R12, NR1: LS02R12, NR1: LCOR12, C2-C3 alkylNRuR12, C? -C3 alkylCOR11, C0-C6 alkylCOOR11 and wherein each cycloalkyl, aryl and heterocyclic group is optionally substituted with 1 to 3 independently selected groups of oxo, hydroxy, halo, Ci-Cß alkyl, C2-C al alkenyl, C2-Cd alkynyl, Ci-Cß alkoxy, Ci-Ce haloalkyl, C 1 -C 6 alkylalcohol, OC 2 -C 6 alkyl alcohol, halo C 1 -C 6 alkoxy, CONR ^ R12, NR11S02R12 NR1: LCOR12, C0-C3 alkylNRlxR12, C1-C3 alkylCOR11, C0-C6 alkylCOOR11, alkylocyano Co-Ce, -OC2-C6alkylocyano, C? -C6 alkylcycloalkyl, phenyl, -OCi-Cg alkylcycloalkyl, -OC? -C6 alkylaryl, -OC? -C6 alkylheter occyclic, and Ci-Cβ alkylaryl; R1 when n is 1 or 2 or 3, and K is a bond, is selected from the group consisting of hydroxy, Ci-Cg alkyl, C2-C6 alkenyl, Ci-Ce haloalkyl, C?-C6 heterocyclic alkyl, C3-C8 cycloalkyl , Ci-Cg alkylcycloalkyl; Ci-Cd alkylaryl, aryl, heterocyclyl, Ci-Cβalkyl, Ci-CβalkylNR7R8, wherein each cycloalkyl, aryl and heterocyclic is optionally substituted with 1 or 2 groups independently selected from the groups consisting of oxo, hydroxy, halo, alkyl Ci-Ce, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cß alkoxy, C? -C6 haloalkyl, C1-C6 alkylalcohol, OC2-C5 alkyl alcohol, haloalkoxy C? -C6, CONR1: LR12, NR1: LS02R12, NR COR12, C0-C3 alkylNR1: LR12, C? -C3 alkylCOR11, C0-C6 alkylCOOR11, C0-C6alkylocyano, -OC2-C6alkylocyano, C? -C6alkylalkyl, phenyl, -OC? -C6 alkylcycloalkyl, -OC? C6 alkylaryl, -OC? -C6 alkylheterocyclic, and C? -C6 alkylaryl; R2 is each independently selected from the group consisting of hydrogen, halo, C6-C6 alkyl, C2-Cd alkenyl, C2-C6 alkynyl, Ci-Cß haloalkyl, OCi-Cß alkyl, C?-C6 alkylaryl, aryl, C 0- C6 alkylNR7R8, heteroaryl, heterocyclyl, C3-C8 cycloalkyl, Ci-Cß alkylcycloalkyl and C?-C6 alkylheterocyclyl; wherein each cycloalkyl, aryl, or heterocyclic is optionally substituted with 1 to 3 groups independently selected from oxo, hydroxy, halo, Ci-Cß alkyl, C 2 -C β alkenyl, C 2 -C 6 alkynyl, C-α-C alcohol, alkoxy Ci-Cβ, C?-C6 haloalkyl, C?-C6 haloalkoxy, CONR ^R12, NRnS02R12, NR1: LCOR12, C0-C3 alkylNR1 ^ 12, C1-C3 alkylCOR11, C0-C6 alkylCOOR11, cyano, and phenyl; R3 is each independently selected from hydrogen, Ci-Ce alkyl, aryl, C2-C6 alkenyl, C2-C6 alkynyl, C6-6 alkylaryl, Ci-C3 heterocyclic alkyl, C3-C8 cycloalkyl, or C6-C6 alkylcycloalkyl; R4 is a group represented by the formula -NR9R10; R5 is selected from the group consisting of hydrogen, halogen, hydroxy, Ci-Cß alkyl, C2-C al alkenyl, C2-C6 alkynyl, C?-C6 alkoxy, Ci-C halo haloalkyl, C3-C8 cycloalkyl, C?-C6 alkylcycloalkyl , Ci-Cβ alkylaryl, Ci-Cβheterocyclic alkyl, aryl, Ci-Cß alkylaryl, heteroaryl, aryloxy, -OC2-C6 alkenyl, -OC? -C6 haloalkyl, -NR7R8, and -OC? ~ C6 alkylaryl; and wherein when q is 1, 2 or 3, two adjacent R5 groups can be combined to form an optionally substituted 5 or 6-membered carbocyclic or heterocyclic ring fused to ring A; R6 is independently selected from the group consisting of hydrogen, C? -C6 alkyl, C2-C6 alkenyl, hydroxy, Ci-Cg alkyl, C2-Ce alkenyl, Ci-Ce alkoxy, aryloxy, -OC2-C6 alkenyl, -OC? -C6 haloalkyl, C? -C6 alkylNR7R8, C3-C8 cycloalkyl, and C? -C6 alkylcycloalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, Ci-Cß alkylcycloalkyl, C3-C8 cycloalkyl, C?-C6heterocyclic alkyl, C?-C6 haloalkyl, NRa ?R12, hydroxy, oxo, COOH, C (0) OC ? -C4 alkyl, C? -C6 alkyl, C2-C6 alkenyl, C2-C? Alkynyl, Ci-Ce alkoxy, C? -C6 alkylalcohol, C? -C6 alkylamine, C? -C6 alkylaryl, C2-C6 alkenylaryl, alkylarylaryl C2-C6, C 1 -C 6 alkyl-C-C6 alkylaryl, C6-C6-NR2-alkylaryl C6-C6 alkyl, C6-C6-alkyanoic acid, C6-C6-C6R7R8-alkyl, C6-C6-R7R8-alkyl, alkyl C? -C6NR11COR12, and aryl, wherein each cycloalkyl or aryl group is optionally substituted with halo, hydroxy, oxo, amino, COOH, C (0) 0C? -C4 alkyl, Ci-C? Haloalkyl, Ci-Ce alkyl, alkenyl C2-C6, C2-C6 alkynyl, Ci-Ce alkoxy, C6-C6alkyl, and Ci-Cd alkylamine;
or R7 and R8 combine to form a nitrogen-containing heterocyclic ring, which may have 0,
1, or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur, and may be optionally substituted with oxo, or Ci-Cß alkyl; R9 is the group C C-C6 alkyl, C2-Cd alkenyl, C3-C8 cycloalkyl, C?-C6 alkylcycloalkyl, aryl, heterocyclic, Cx-Cß, C72R7, C alquilo-Cß alkyl, C alquilo-Cß alkyl, C C-C3 alkyl, ) pNR7R8, or C0-C3S (O) pR7 alkyl wherein R7 is as defined above, and wherein each alkyl, cycloalkyl, aryl, and heterocyclic is optionally substituted with one to two groups independently selected from halo, hydroxy, oxo, COOH, C (0) OC? -C alkyl, C? -C6 haloalkyl, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C? -C6 alkoxy, C? -C6 alkyl alkoxy, C? Alkylamine? C6, C? -C6 alkylaryl, C2-C6 alkenylaryl, C2-C6 alkynylaryl, C? -C6 -heterocyclic alkyl, -NR7R8, C3-C8 cycloalkyl, C? -C6 alkylcycloalkyl, C? -C6 alkyl -0-C? -C6 alkylaryl, C? -C6-NR2-alkylaryl C? -C6 alkyl, C? -C6 alkylcyano, C? -C6C0NR7R8 alkyl, C? -C6NR7R8 alkyl, C? -C6NR2COR11 alkyl, and aryl, wherein each cycloalkyl or aryl group is optionally substituted with halo, hydroxy, oxo, amin or, COOH, C (0) 0C? -C4 alkyl, C? -C6 haloalkyl, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C? -C6 alkoxy, Ci-C? alkylalcohol, and alkylamine C ? -C6;
R10 is selected from the group consisting of aryl, Ci-Cß alkylaryl, C2-C6 alkenylaryl, C2-C6 alkynylaryl, Ci-Cßhaloalkylaryl, Ci-Cßheterocyclic / C2-Ce alkenylheterocyclic, Ci-Cd alkylcycloalkyl, C3-C8 cycloalkyl, C? -C6-0-Alkylaryl C? -C6 alkyl, and wherein each cycloalkyl, aryl, or heterocyclic group is optionally substituted with 1-3 groups independently selected from the group consisting of hydroxy, oxo, SCi-Ce alkyl, Ci-Ce alkyl, Ci-Cß alkenyl, Ci-Cß alkynyl, C?-C6 haloalkyl, halogen, C?-C6 alkoxy, aryloxy, alkenyloxy Ci-Cßr haloalkoxyalkyl Ci-Cßr alkyl Co-CeNR1 ^12, -OC ?- C6 alkylaryl, nitro, cyano, -0C? -C6 haloalkyl, haloalkylC? -C6 alcohol, and C1-Ce alkylalcohol; R11 and R12 are independently selected from the group consisting of hydrogen, Ci-Cß alkyl, Ci-Cß alkenyl, C3-C8 cycloalkyl, heterocyclic, aryl, and Ci-Cß alkylaryl, wherein each aryl group is optionally substituted with 1-3 groups independently selected from halogen, Ci-Cβheterocyclic alkyl, and Ci-Ce haloalkyl, or R11 and R12 combine to form a nitrogen-containing heterocyclic ring, which may have 0, 1 or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and it is optionally substituted with oxo, or C? -C6 alkyl; or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.
The present invention also provides a method for modulating or regulating the activity of CETP, which comprises the use of a compound of formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, for the treatment , prevention or relief of diseases mediated by the CETP. The present invention provides a method for treating or preventing dyslipidemia, comprising administering a compound of formula I, salt, solvate, enantiomer, racemate, diastereomer or mixture of pharmaceutically acceptable diastereomers thereof, or prodrug thereof, to a patient in need. of the same. The present invention provides a method for treating or preventing CHD, which comprises administering a compound of formula I, salt, solvate, enantiomer, racemate, diastereomer or mixture of pharmaceutically acceptable diastereomers thereof, or prodrug thereof to a patient in need of same. The present invention provides a method for treating and / or preventing atherosclerosis, comprising the administration of a pharmaceutically acceptable compound, formula I, salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, or prodrug thereof to a patient in need of it.
The present invention provides a method for treating and / or preventing diseases related to the abnormal activity of CETP, which comprises the administration of a pharmaceutically acceptable compound of formula I, salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof. , or prodrug thereof to a patient in need thereof. The present invention provides a method for raising the ratio of plasma HDL cholesterol to plasma LDL cholesterol, in a mammal, comprising administering a therapeutically effective dose of a compound of formula I, salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers of the same pharmaceutically acceptable, or prodrug thereof to a patient in need thereof. The present invention provides a method for raising the plasma HDL cholesterol level in a mammal, which comprises administering a therapeutically effective dose of a compound of formula I, pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof. , or prodrug thereof to a patient in need thereof. The present invention provides a method for lowering the level of plasma LDL cholesterol in a mammal, which comprises administering a therapeutically effective dose of a compound of formula I, pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof. , or prodrug thereof to a patient in need thereof. The present invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, and a carrier. The present invention also provides a method of treatment and / or prevention of pathological sequelae caused by low levels of plasma HDL and / or high levels of LDL cholesterol in a mammal, comprising administering an effective dose of a compound of formula I , salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof pharmaceutically acceptable, to a patient in need thereof. The present invention also relates to the use of a compound of formula I for the manufacture of a medicament for the treatment and / or prevention of atherosclerosis in a mammal, comprising the administration of an effective dose of a compound of formula I, salt, pharmaceutically acceptable solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, or prodrug thereof to a patient in need thereof. The present invention also provides a combination therapy involving a compound of formula I and one or more other cardioprotective agents, such as, for example, statins, leptin and / or other LXR, CETP, ABC Al or lipid regulating agents. , useful for the treatment and / or prevention of atherosclerosis.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides new compounds of formula I useful in the modulation of CETP activity. The terms "modulation" or "regulation" may include, but are not limited to, ascending regulation, down regulation, inhibition, agonism, antagonism of appropriate CETP receptors to obtain the increase or decrease of HDL or LDL, together with the sequela biological result of such intervention. The phrase "diseases" or "diseases related to abnormal activity of CETP" or "diseases mediated by CETP activity", refers to disease states in which atherosclerosis and / or other cardiovascular diseases are prone due to dyslipidemia and / or to other risk factors and, therefore, are beneficially affected by the modulation, particularly down-regulation, of CETP activity. These diseases include but are not limited to hyperlipidemia and its sequelae, such as atherosclerosis, CHD, high blood pressure, CHF, stroke, hypertension, hypertriglycemia, diabetes, obesity, inflammatory diseases including but not limited to, dermatitis, arthritis and pain, as well as diseases of the central nervous system including but not limited to dementia , cognitive disorders such as, for example, Alzheimer's disease. The term "treatment" retains its conventional meaning which includes prohibiting, inhibiting, alleviating, interrupting, slowing, slowing down or reversing progress, or reducing the intensity of a related pathological symptom or resulting from the modulation of CETP activity, particularly with that related to the elevation of HDL plasma levels, or decrease in HDL cholesterol levels, or increase the HDL / LDL ratio or control atherosclerosis, hyperlipidemia and / or hypercholesterolemia. In general, someone of skill in the art will be aware that the valence should be conserved (completely) for all stable molecules. Therefore, the necessary implication that hydrogen atoms are necessary and available to complete the valence in all structures, which include Formula I, unless otherwise indicated, is imputed to someone's general knowledge of skills in the technique. General chemical terms used in the description of compounds in this document described retain their conventional meanings. For example, the term "C?-6 alkyl," or "(C?-C6) alkyl" or "C?-C6 alkyl", refers to a straight or branched aliphatic chain of 1 to 6 carbon atoms, which includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, pentyl and hexyl. Unless stated otherwise, the term "alkyl" means C? -C6 alkyl. Similarly, the term "C0-Cß alkyl" implies an alkyl group as indicated where, when the term Co applies, the alkyl group is not present, and the remaining groups are attached directly to the substrate. The present invention also contemplates that the term C? -C6 alkyl, or C2-C6 alkenyl, or similar terms also embrace the specified alkyl, alkenyl, or the like group, which may be chiral, regio, or steroisomeric. Such chiral or regio or steroisomeric groups are also object of the present invention. The term "alkylaryl" refers to an alkyl group substituted by an aryl group. For example C 1 -C 6 alkylaryl indicates that a Ci-Cß alkyl group is attached to the aryl group, and that the resulting C?-C6 alkylaryl is attached to the nucleus, via the alkyl group, a more preferred alkylaryl group includes phenylethyl (phenethyl) benzyl The term "substituted phenyl" or "optionally substituted phenyl" refers to a phenyl group having one or more substituents selected from the group consisting of C?-C6 alkyl, Ci-Cß alkoxy, hydroxy, COR7, -COOR7, alkyl Co-C6NR7R8, nitro, chloro, fluoro, bromo, iodo, haloalkyl C ± -Cβ, haloalkoxyalkyl Ci-Ce, alkylheterocyclic Co-C6. The term "optionally substituted heterocyclic or carbocyclic ring" refers to a five or six aromatic or non-aromatic, saturated or unsaturated ring having optional substituents selected from the group consisting of Ci-Ce alkyl, C 1 -C 6 alkoxy, hydroxy, COR7, -COOR7, C0-C6NR7R8 alkyl, nitro, oxo, chloro, fluoro, bromo, iodo, haloalkyl C? -C6, haloalkoxyalkyl Ci-C?, heterocyclic, and alkylheterocyclic Co-C6. The term "aryl" refers to an aromatic or heteroaromatic radical, substituted or unsubstituted. Illustrative aryl groups include, but are not limited to, naphthyl, quinolyl, tetrahydroquinolyl, indazolyl, pyrimidinyl, triazinyl, pyrazine, pyridazinyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyranyl, tetrazolyl, imidazolyl, 1,2,3-trazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazopyridine, benzimidazolyl, triazolon-yl, imidazolone, imidazolidinon-1-yl, 2-furyl, 3-furyl, 2-thienyl 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5- benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, tetrazole, imidazole, isoxazole, pyrazole, 7-indolyl and isomers of the same. As used herein, the term aryl also encompasses the benzyl group. The term "C3-C8 cycloalkyl" or similar terms refers to a saturated carbocyclic ring having from 3 to 8 carbon atoms, wherein the term "cycloalkyl" is used, a carbocyclic ring having 3 to 8 carbon atoms is involved. carbon. The term "carbocycle" as used herein, refers to a cyclic group having only carbon and an appropriate number of hydrogen atoms. The term embraces groups such as cycloalkyl, cycloalkene, cycloalkylene, naphthyl, phenyl and the like. The term "heterocycle", "heterocyclyl" or "heterocyclic", refers to a bicyclic or monocyclic, saturated, partially unsaturated or aromatic ring of 5, 6, 7, 8, 9 or 10 elements, containing 1-5 heteroatoms selected from N, S or O, wherein said heterocycle is optionally substituted on the carbon or nitrogen atom (s), unless otherwise specified. More preferred heterocyclic groups include pyridinyl, pyrolidinyl, piperidinyl, hexamethyleneimino, morpholino, thiophene, indolyl, quinolyl, isoquinolyl and tetrazolyl. As a corollary, the term "alkylheterocyclic" or
"alkylheterocycle" is meant to indicate that the alkyl group is attached to the heterocycle and the point of attachment to the molecular structure or nucleus is the alkyl group. The term
"alkyl" without a qualifier implies a Ci-Cß alkyl group. The term "haloalkoxyalkyl" as used herein, includes for example trifluoromethoxy, pentafluoroethoxy, trifluoroethoxy (OCH2CF3) and the like. The term "Prodrugs" describes derivatives of the compounds of the invention that have chemically or metabolically dexalable groups, and come to be by solvolysis or under physiological conditions, the compounds of the invention, which are pharmaceutically active, in vivo. Derivatives of the compounds of this invention have activity in both their acid and base-derived forms, but the acid-derived form often has disadvantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, Bundgard, H. , Design of Prodrugs, pp. 7-9, 21-24,
Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as esters prepared by reaction of the acidic precursor compound with a suitable alcohol, or amides prepared by reaction of the acidic precursor compound with a suitable amine. Simple aliphatic esters (eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from acidic groups pending the compounds of the invention are preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonyl ethoxy. In some cases it is desirable to prepare prodrugs of the double ester type such as alkyl esters (acyloxy) or esters of ((alkoxycarbonyl) oxy) alkyl. As used herein, the term "protecting group" refers to a group useful for masking reactive sites in one molecule to improve the reactivity of another group or allow reaction at another site, or desired sites with what then the protective group can be removed. Protecting groups are usually used to protect or mask groups, including but not limited to -OH, -NH and -COOH. Suitable protecting groups are known to one of skill in the art and are described in Protecting groups in Organic Synthesis, 3rd edition, Greene, T.
W .; Wuts, P.G.M. Eds., John Wiley & Sons, New York, 1999. As used herein, the term "solvate" is a form of the compound of the invention wherein a crystal or crystals, of a compound of the invention, have been formed in a stoichiometric amount or non-stoichiometric of the compound of formula I and a solvent. Typical solvation solvents include, for example, water, methanol, ethanol, acetone and dimethylformamide. In these cases where a compound of the invention possesses acidic or basic functional groups, various salts can be formed, which are more water soluble and / or more physiologically suitable than the parent compound. Pharmaceutically representative salts include, but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. The salts are conveniently prepared from the free acid, treating the acid in solution with a base or by exposure of the acid to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, organic or inorganic acid or base addition salts of compounds of the present invention. The base addition salts include, for example, ammonium, quaternary ammonium and amine cations, nitrogenous base derivatives of sufficient basicity to form salts with the compounds of this invention (see for example, SM Berge, et al., "Pharmaceutical Salts. , "J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group (s) of the compound of the invention can be reacted with the appropriate organic or inorganic acids., to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate, clavulanate, citrate, chloride, edetate, edisilate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylaminosanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate, hydroiodine, isothionate, lactate, lactobionate, laureate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate. Preferred salts for purposes of the invention include, hydrochloride salt, hydrobromide salt, bisulfate salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, bitartrate salt, acetate and citrate. A compound of the invention as illustrated by formula I, can originate as any of its positional isomers, stereochemical isomers or regio-isomers, all of which are objects of the invention. Certain compounds of the invention may possess one or more chiral centers, and thus, may exist in optically active forms. Likewise, when the compounds contain an alkylene or alkenylene group, there is a possibility of cis and trans isomeric forms of the compounds. The R and S isomers and mixtures thereof, which include racemic mixtures, as well as mixtures of enantiomers or cis and trans isomers, are contemplated by this invention. Additional asymmetric carbon atoms may be present in a substituent group such as an alkyl group. All isomers, as well as mixtures thereof, are proposed to be included in the invention. If a particular isomer is desired, it can be prepared by methods well known in the art, using stereo-specific reactions with initiator materials containing asymmetric centers and are already resolved. Alternately desired stereoisomers can be prepared by methods that lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture can be reacted with a single enantiomer of some other compound, i.e., a chiral resolving agent. This changes the racemic form in a mixture of stereoisomers and diastereomers, because they have different melting points, different boiling points and different solubilities, and can be separated by conventional means, such as crystallization.
Preferred Modes of the Invention N, p, and q are preferred. Preferably n is 0, or 1. More preferably, n is 0. Preferably p is 1, or 2. Preferably q is 0, 1 or 2. More preferably q is 1 or 2 Preferred Ring A A preferred ring A is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, 1,2,5-triazine, thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, and 1 , 2, 3-triazole. More preferred is a ring A selected from the group consisting of pyridine, pyrazine, thiophene, pyrazole, isoxazole, oxazole, and thiazole. More preferred ring A is pyridine. Preferred R1 A preferred R1 group when n is 0, and k is C = 0, is selected from the group consisting of -OCi-Cβ alkyl, -OC3-C8 cycloalkyl, -OC? ~ C6 alkylcycloalkyl, -OCp-Ce alkylcycloalkylNR7R8, - OC0-C6 alkylaryl, -OCx-Ce haloalkyl, -OCi-Cealkylocyano, -OC? -C6alkylC02R1: l, OC? -C6alkylhydroxy, -0C3-C8 cycloalkylC02Rxl, -OC? -C6 alkylNR7R8 and -OCi-Ce alkylheterocyclic. A most preferred group for when R1 when n is 0, and k is C = 0, is selected from -OC? -C6 alkylaryl, OC? -C6 alkyl, -OC0-C6 alkylaryl, -OC1-C3 alkylcycloalkyl, -OC0-C3 Heterocyclic alkyl, -OC? -C6alkylocyano, OC? -C6alkylC02R1: L, -OC? -C6alkylhydroxy, -OC? -C6 alkylNR7R8 and -OC0-C6 alkylcycloalkylNR7R8 A preferred group R1 when n is l, 2 or 3 and K is a bond , is selected from the group consisting of cycloalkyl, aryl, heterocyclic, wherein each cycloalkyl, aryl or heterocycle, is optionally substituted with 1 or 2 groups selected from C1-C3 alkyl alcohol, C1-C3 alkylamine, COOH, CONH2, and C ( 0) OC? -C3 alkyl. Preferred R 2 Preferred R 2 groups are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, hydroxy, Ci-Cß haloalkyl, halo, C 1 -C 6 alkyl halide, Ci-C 1 alkylcycloaryl, C 3 -C 6 cycloalkyl, C 1 alkylaryl Cß, -OC? -C6 alkyl, -OC? -C6 haloalkyl, -OC1-C5 alkylcycloalkyl, Co-Cg alkylNR7R8, -OCi-Cg alkylaryl, alkylheterocyclic Ci-C? And -OCi-Cd alkylheterocyclic. More preferred is a group R2 selected from hydroxy, Ci-Cd alkyl, halo, C3-C8 cycloalkyl, C6-C6 alkylaryl and C6-C6 alkoxyalkyl. More preferred is a group R2 represented by hydrogen, C3-C8 cycloalkyl, or C? -C6 alkyl.
Preferred groups R3 Preferably R3 is hydrogen. Preferred R4 groups A preferred R4 is R4 represented by the group -NR? 9rR > 10, which is also represented by a group selected from the group consisting of
wherein R7 is as defined above. Also preferred is -NR9R10 (R4) wherein the R9 group is selected from the group consisting of C02R7, CONR7R8, S (0) 2NR7R8, or S (0) R7, wherein R7 is as defined above. More preferably, R4 is NR9R10, wherein R1Q is a mono- or di-substituted haloalkylbenzyl, and R9 is an optionally substituted heterocycle selected from the group consisting of:
R R R «- R - R - Jjt R" R *
? -H N-o N-S l-f .- R 4:? R- «-W < - &
wherein R is independently H, OH, NR7R8 or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally substituted with OH, halo, cyano, CONR7R8, C02R1: L, or NR7R8. Preferred R5 groups R5 is preferably selected from a group consisting of hydrogen, halogen, hydroxy, C?-C6 haloalkyl, C?-C6 alkyl, Ci-Cß alkenyl, C?-C6heterocyclic alkyl, C?-C6 alkylaryl, aryl, Ci-Cβ alkoxy, aryloxy, -OC2-C6 alkenyl, -OC? -C6 haloalkyl, -NR7R8, -CH2NR7R8, -NH2, -CN, -COOH, and N02; More preferably, R5 is in each case, independently selected from the group consisting of hydrogen, halogen, C? -C6 alkyl, C? -C6 haloalkyl? -NRR8 and C6-C6 alkoxy. Preferred R6 R6 is preferably selected from a group consisting of hydrogen, C2-C6 haloalkyl, Ci-Ce alkyl, and Ci-Cβ alkenyl. Preferred R7 and R8 R7 and R8 are independently selected from the group consisting of hydrogen, C? -C6 alkyl, C2-C6 alkenyl, C? -C6 alkylaryl and C1-C6 alkylheterocyclic, wherein each aryl group is optionally substituted with 1-3 groups independently selected from Ci-Ce alkyl, halo, and Ci-Cβ haloalkyl. Preferred R11 and R12 R11 and R12 are independently selected from the group consisting of hydrogen, Ci-Cd alkyl, C2-C6 alkenyl, Ci-Ce alkylaryl and Che-Cg alkylheterocyclic, wherein each aryl group is optionally substituted with 1- 3 groups independently selected from C 1 -C 6 alkyl, halo and C 1 -C 6 haloalkyl. A more preferred compound of the invention is a compound selected from the group consisting of: 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-7-methyl-3 isopropyl ester , 4-dihydro-2fT- [1, 8] naphthyridine-1-carboxylic acid, cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-isopropyl ester methoxy-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2i? -tetrazole-5-) isopropyl ester il) -amino] -2-ethyl-6-methoxy-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, cis-4- [(3,5-bis-trifluoromethyl) isopropyl ester -benzyl) - (2-methyl-2i? -tetrazol-5-yl) -amino] -2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic ester 7- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -5-ethyl-6,7-dihydro-5H-thieno [3,2- b] pyridine-4-carboxylic acid isopropyl ester isopropyl (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-be ncil) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [acetyl-] isopropyl ester (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-bromo-3,4-dihydro-2H- [1,5] aftiridine-1-carboxylic acid, isopropyl ester (+/- ) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-dimethylamino-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid , isopropyl ester of (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3, 4-dihydro-2H- [ 1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) - isopropyl ester amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (2S, 4) -4- [(3,5-bis-) isopropyl ester trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, isopropyl esterof (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4 -dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-ter) isopropyl ester -jutoxycarbonylamino-ethyl) -2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid, isopropyl ester (+/-) -cis-4- [[2- (2-amino-ethyl) -2H-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H- [1, 5] aftiridine-1-carboxylic acid, (2S, R) -cis-4- [[2- (2-amino-ethyl) -2i) isopropyl ester ? -tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridin-l- carboxylic acid, (2R, S) -cis-4- [[2- (2-amino-ethyl) -2i? -tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) - isopropyl ester amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2 # - [1,5] naftiri din-1-carboxylic acid isopropyl ester (+/-) - cis and trans-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazole- 5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2f? - [1,5] naphthyridine-1-carboxylic acid ester (2R, 4S) -4- [( 3, 5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2-f-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] aftiridine-1-carboxylic acid, (2S, 4R) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2-yl- isopropyl ester tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2ff- [1,5] naphthyridine-1-carboxylic acid, (+/-) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2H-] isopropyl ester tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2-yf- [1, 5] naphthyridine-1-carboxylic acid, trifluoroacetate of the isopropyl ester of (22? 4 S) - 4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-22β-tetrazol-5-yl] -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [ 1, 5] naphthyridine-1-carboxylic acid, isopropyl ester trifluoroacetate
(2S, 42?) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-22T-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4 -dihydro-22? - [1,5] aftiridine-1-carboxylic acid (+/-) -cis-4- [[2- (2-amino-ethyl) ~ 22T-tetrazol-5-yl) isopropyl ester ] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-22α- [1,5] naphthyridine-1-carboxylic acid isopropyl ester ( +/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -22? -tetrazol-5-yl) -amino] -2-ethyl- 6-methyl-3, 4-dihydro-22? - [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-6-amino-4- [(3,5-bis-) isopropyl ester trifluoromethyl-benzyl) - [2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-7-methyl-3, -dihydro-2H- [1, 5] aftiridine-1-carboxylic acid, isopropyl ester of the (+/-) - trans-6-amino-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2-fluoro-tetrazol-5-yl) -amino] -2-ethyl- acid 7-methyl-3, 4-dihydro-22? - [1, 5] naphthyridine-1-carboxylic acid, isopropyl ester of (+/-) -cis-4- acid [(3, 5-bis-trifluoromethyl-benzyl) - (2-methyl-22? -tetrazol-5-yl) -amino] -2-ethyl-6-methoxy-7-methyl-3,4-dihydro-22 ? - [1, 5] naphthyridine-1-carboxylic acid ethyl ester (22? 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole-5-) il) -amino] -2- ethyl-ß-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, 2-dimethylamino-ethyl ester of (22? 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5 ] naphthyridine-l-carboxylic acid, tetrahydropyran-4-yl ester of (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole-5-) il) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, l-methyl-piperidin-4-yl ester of (22? 4S) acid ) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid ester tetrahydrofuran-3-yl
(22 ?, 3 '2 ?, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, tetrahydrofuran-3-yl ester of (22? 3 'S, 4S) -4- [(3, 5- bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid , 2-morpholin-4-yl-ethyl ester of (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino ester ] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid 2- (4-methyl-piperazin-1-yl) -ethyl ester of (22? , 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H- [1,5] naphthyridine-1-carboxylic acid, 2-methoxycarbonyl-2-methyl-propyl ester of (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2- methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridi n-1-carboxylic acid 2-carboxy-2-methyl-propyl ester
(22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4 -dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, 2-cyano-ethyl ester of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl- 2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic ester 2- (2H-tetrazol-5-yl) ) -ethyl acid (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, 2 (2-benzyloxyethyl) acid ester (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic ester 2-hydroxy- Ethyl (22 ?, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl- 3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester of the acid (+/-) -cis-4- [(3, 5-bis-trifluoromethylbenzyl) - (5-methyl-1,2-pyrazol-3-yl) amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid , (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (3-methyl-isoxazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3-isopropyl ester , 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (5-methyl-) isopropyl ester [1,2,4] oxadiazol-3-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid isopropyl ester (+ / -) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2,5-dimethyl-2H-pyrazole-3-carbonyl) -amino] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid, (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzyl) -1- (cyclopentylmethyl-2-ethyl-6-methoxy-2) , 3, -tetrahydro- [1, 5] naphthyridin-4-yl) -acetamide, isopropyl ester of (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino acid ] -6-methoxy-2-methyl-3, - dihydro- 22? - [1, 5] naphthyridine-1-carboxylic acid, (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6-methoxy-isopropyl ester 2-methyl-3, 4-dihydro-22? - [1, 5] naphthyridine-1-carboxylic acid, (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) isopropyl ester) - (3-Fluoro-5-trifluoromethyl-benzoyl) -amino] -6-methoxy-2-methyl-3,4-dihydro-22í- [1,5] naphthyridine-1-carboxylic acid, (+/-) -cis -N- (3, 5-bis-trifluoromethyl-benzyl) -N- (1-cyclopentyl-6-methoxy-2-methyl-1,2,4,4-tetrahydro- [1,5] naphthyridin-4-yl ) -acetamide, isopropyl ester of (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3, -dihydro-2H acid - [1, 5] naphthyridine-1-carboxylic acid, (+/-) -cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-isopropyl ester trifluoromethyl-3, 4-dihydro-22? - [1, 5] naphthyridine-1-carboxylic acid, (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - isopropyl ester ( 2methyl-2 2'-tetrazol-5-yl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-22? - [1,5] aftiridine-1-carboxylic acid, isopropyl ester of 4- [(3, 5-bis-trifluoromethyl-benzyl) - (5,6,7,8-tetrahydro-quinolin-3-yl) -amino] -2,3-dimethyl-3, 4, 6, 7, 8, 9-hexahydro- 22? -benzo [b] [1, 5] naphthyridine-1-carboxylic acid methyl ester (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H) -tetrazol-5-yl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- [1, 5] aftiridine-1-carboxylic acid ethyl ester (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-ethyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- [1,5 ] naphthyridine-1-carboxylic acid methyl ester (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] - 2, 6-dimethyl-3,4-dihydro-2H- [1,5] aftiridine-1-carboxylic acid ethyl ester (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2,6-dimethyl-3,4-dihydro-2H - [1, 5] naphthyridine-1-carboxylic acid (22? 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) isopropyl ester ) -amino] -2,6-dimethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (22? 45) -4- [(3-cyano-5) isopropyl ester -trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester of (22? 45) -4- [(3,5-dichloro-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3 acid , 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, (22? 4S) -4 - [(3-chloro-5-trifluoromethyl-benzyl) - (2-methyl-2H) isopropyl ester -tetrazol-5-yl) -amino] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid isopropyl ester (22? 45) -2 -ethyl-4 ~ [(3-fluoro-5-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, isopropyl ester (22? 45) -4- [(3,5-dimethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (22? 45) -4- [(3,5-difluoro-benzyl) - (2-methyl-2H-tetrazole) isopropyl ester -5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid methyl ester (22? 45) -4- [ [2- (2-amino-ethyl) -2H-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H - [1, 5] naphthyridine-l-carboxylic acid methyl ester (22? 4S) -4-. { (3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl] -amino} -2-ethyl-ß-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid ethyl ester (22? 45) -4- [[2- (2-amino- ethyl) -2H-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3, -dihydro-2H- [1,5] naphthyridin-1 - carboxylic acid ethyl ester (22? 4S) ~ 4-. { (3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl] -amino} -2-ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (22? 45) -4- [[2- (2- Amino- ethyl) -2H-tetrazol-5-yl] - (3-cyano-5-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridin- 1-carboxylic acid (22? 45) -4- isopropyl ester. { (3-cyano-5-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl] -amino} -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, or a pharmaceutically acceptable salt, solvate, enantiomer or diastereomer or mixture thereof. The emitted positional isomers and geometric isomers associated with the asymmetric carbon atoms of compounds of formula I are also contemplated as being within the scope of the present invention, as useful for the treatment of diseases related to the modulation of CETP.
Synthesis of Compounds of the Invention The compounds of the present invention can be synthesized as exemplified in the following reaction schemes. Intermediates of the aryl ester of the formula I can be prepared chemically, for example, by following the synthetic routes established in the reaction schemes below. However, the following discussion is not intended to be limiting to the scope of the present invention in any way. Reagents and initiator materials are commercially available to one of ordinary skill in the art. Other necessary reagents as well as initiator materials can be made by methods that are selected from standard techniques of organic and heterocyclic chemistry, techniques that are analogous to the synthesis of known, structurally similar intermediates or initiator materials and the methods described in the preparations and examples below, which include any new procedure. Such known methods include, but are not limited to, the esterification of carboxylic acid, hydrolysis of a nitrile to a carboxylic acid and subsequent esterification. Additionally, one of ordinary skill in the art will appreciate that many of the necessary starting materials or reagents can be easily obtained from commercial suppliers or common synthesis groups. The R, R1, R2, R3, R4, R5, R6, W, X, Y, Z, etc., used in this section for illustrative purposes of various methods for synthesizing compounds of the invention, are not necessarily synonymous in scope or meaning with similar groups used in the generic structure for compounds of formula I, assuming that W, X, Y, Z are not all the same carbons. However, groups in similar positions are co-extensive in scope and meaning, compared to groups occupying similar positions, as defined for the generic structure of compounds of formula I.
Reaction Scheme 1
Synthetic Reaction Scheme 1, shows the preparation of compounds of formula I, wherein n is 0. For example, heteroarylamino substituted 1-esters, which are either commercially available or prepared as disclosed in the literature or in the Reaction Scheme up to Id, can be protected with tosyl chloride, isopropyl chloroformate or other suitable protecting group to provide 2. The compound 2 can instead be alkylated with appropriately substituted or unsubstituted 3-bromoethyl esters 11, thus providing 3. The condensation- Dieckmann cyclization of intermediate 3, provides N-protected naphthyridine 4, which is subjected to acid hydrolysis and decarboxylation to provide ketone derivatives 5. Removal of the protecting group, if necessary, with acid (eg, PPA (acid polyphosphoric)), TMSI (trimethylsilyliodide), or HCl, provides intermediary 6. Alternatively, using the same conditions for If you choose 7 or 8, you can proceed directly to 8 without check out. N-acylation of 6 by treatment with an appropriately substituted aryl chloroformate or alkyl in the presence of an organic base such as pyridine, provides carbamates of structure 7. Alternatively, treatment of 6 with an appropriate acid chloride or ester activated, such as those generated in situ, from the reaction of an appropriately substituted aryl carboxylic acid or alkyl, provide compounds of formula 7. The generation of urea derivatives from 6, is accomplished by treatment with a carbamoyl chloride in the presence of a base such as pyridine and DMPA (dimethylaminopyridine) or an alternative base, such as NaH in DMF. Alternatively, treatment with phosgene, or carbodiimide reagent (CDI) such as cyclohexylcarbodiimide or analog thereof, followed by addition of an appropriately di-substituted amine, will provide ureas of structure 7. The formation of sulfonamide derivatives of 6, may be carried out by reaction with appropriately substituted sulfonyl chlorides in the presence of a base. The conversion of ketone 7 to 10 can be performed through direct reductive amination with an appropriately substituted alkylamine or arylamine, to provide compound 9. Alternatively, compound 9 can be prepared through the formation of amine derivative 8 by reduction of an intermediate oxime, followed by alkylation with an appropriately substituted benzyl halide, mesylate or tosylate, or by reductive alkylation with the appropriate aldehyde or ketone in the presence of a reducing agent such as NaCNBH3. Compound 9 is converted to 10 (a compound of the invention), by acylation with an appropriately substituted symmetrical acid anhydride or acid halides, to provide amides. The reaction of compound 9 with chloroformates, provides the corresponding carbamates, the reaction of 9 with isocyanates, carbamoyl chlorides or appropriately substituted sulfonyl chlorides, provides the corresponding urea or sulfonamides, respectively. Intermediates useful for the practice of the invention can be prepared following the procedures of the Reaction Schemes up to and described below and / or minor variations thereof, known to one of skill in the art.
Reaction scheme
1
In the Reaction Scheme, nucleophilic aromatic substitution occurs by methods known in the art, (Wells, K.M. et al., Tetrahedron Letters, 1996, 37 (36), 6439-6442). The appropriately substituted amine 14, such as benzylamine, is dissolved in a suitable solvent, such as DMF or DMSO. A base is added, such as cesium or carbonate. Also added is the appropriately substituted heterobenzoate or heterobenzonitrile 13 (R6 = CN or C02R3), such as methyl fluoronicotinate ester. The reaction proceeds at 0 ° C at elevated temperatures (up to about 150 ° C), anywhere from 10 minutes to several days depending on the stability of the initiator materials. The product of structure 15 (R6 = CN) or 1 (R6 = C02R3) can then be isolated by a standard aqueous lift, followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.
Reaction Scheme Ib
1 Re = C02R3
In Reaction Scheme Ib, the coupling of N-heteroaryl occurs through methods known in the art, (Hartwig, J. F. et al., Angew, Chem., Int. Ed. Engl. 1998, 37, 2046-2067). The appropriately substituted amine 14 is dissolved in a suitable solvent, such as DMF. A base, such as cesium carbonate or sodium tert-oxide, the appropriately substituted heterobenzoate or heterobenzoate, is added 16 (R6 = CN or C02R3), and a suitable catalyst complex, such as palladium acetate and diphenylphosphino ferrocene ligand. The reaction proceeds at 0 ° C at elevated temperatures (up to 150 ° C) anywhere from 10 minutes to several days depending on the stability of the initiator materials. The product of structure 15 (R6 = CN), or 1 (R6 = C02R3), can then be isolated through a standard aqueous lift, followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.
Reaction scheme
17
In the Reaction Scheme, the carbonization occurs through methods known in the art (Heck, Palladium Reagents in Organic Synthesis, Academic Press: New York, 1985, pp. 348-358). Appropriately substituted heteroaryl bromide 17 is dissolved in a suitable solvent, such as DMF, followed by the addition of a base, such as cesium carbonate or sodium tert-butoxide. A suitable catalyst complex, such as palladium acetate and diphenylphosnino ferrocene, is added, an appropriate alcohol (R3-OH). The reaction mixture is then saturated with carbon monoxide. The reaction proceeds at 0 ° C at elevated temperatures
(up to approximately 150 ° C), anywhere from 10 minutes to several days, depending on the stability of the initiating materials. The reaction can also be carried out under pressure using methods known to one of skill in the art. The product of structure 1 can then be isolated by a standard aqueous lift, optionally followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.
Reaction Scheme Id
In the Reaction Scheme Id, aromatic carboxylation occurs through methods known in the art, (Boger, DL et al., Journal of Organic Chemistry, 1994, 59 (17), 4943-4949, Volpin et al. , Organomet, Reactions, 1975, 5, 313-386). The appropriately substituted heteroaryl bromide 17 is dissolved in a suitable solvent, such as diethyl ether or tetrahydrofuran. An alkyl lithium is added, such as n-butyl lithium or tert-butyl lithium or magnesium conversions. The resulting anion is quenched with a suitable source of carbon dioxide, such as dry ice or dimethyl carbonate. The reaction proceeds at -78 ° C at room temperature anywhere, from 5 minutes to several hours, depending on the stability of the initiator materials. The product of structure 1 can then be isolated by standard aqueous lifting, followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.
Reaction scheme
The ketone intermediate 19 can be prepared by following the procedure of the Reaction Scheme. (See also Booker-Milburn, K.I., et al., J ^ Chem. Soc., Perkin Trans. 1, 3261-3273 (1997)). N- (p-tolylsulfonyl) -3-aminopropanoic acids can be made by alkylation of the appropriate heterocyclic amine, via a procedure similar to that shown in Reaction Scheme 1 and then, saponification of the resulting ester to provide compound 18. compound 18 can then be subjected to intermolecular acylation to form 4-keto quinolin-4-one 19, using a variety of methods known in the art. The compounds of formula I can be prepared according to Reaction Scheme 2 below.
Reaction Scheme 2
dlC
As shown in Reaction Scheme 2, intermediaries of the general structure 19 (prepared in the
Reaction Scheme le), are converted to 23 (a compound of the invention), using conditions similar to those described in Reaction Scheme 1. The compounds of formula I can be prepared according to Reaction Scheme 3 below.
Reaction Scheme 3
tosyl tosyl 20 27
R1tfclH2. TijCO-i-Pr), NaBHt
29 22
As shown in Reaction Scheme 3, intermediates of the general structure 1, such as, for example, 2-aminopyridine 3-methylcarboxylate, are converted to 30 (a compound of the invention), using conditions similar to those described in Reaction Scheme 1. The compounds of the invention, such as 8, can be prepared according to Reaction Scheme 4.
Reaction Scheme 4
As shown in reaction scheme 4, heteroarylamine 1 such as, for example, 2-methoxy-5-aminopyridine, can be converted to 31 by reaction of the appropriate aldehyde or ketone, followed by treatment with an N-acylated enamine in the presence of an acid. Reductive amination or alkylation provides 32, a compound of the invention, which can be further functionalized at the nitrogen N-4 by hydrolysis of amide to give 33, which is instead alkylated via reductive amination to provide 34. it can be acylated or sulfonated using standard procedures by one of skill in the art, to provide 35. Alternatively, the amide 32 can be directly alkylated using an alkyl halide, appropriate alkyl tosylate or the like, in the presence of a base to provide 35. Alternatively, the compounds of the present invention can also be prepared according to Reaction Scheme 5 or known variations thereof.
Reaction Scheme 5
The compound 31 is acylated to provide the compound 32, which in turn is selectively hydrolyzed to provide the amine 22. The compound 32 can be alkylated using an appropriate alkyl halide, alkyl tosylate, or the like, in the presence of a base, to provide 30. Alternatively, 22 can be alkylated using reductive amination conditions to provide 29, which in turn, can be acylated or sulfonated to provide 30. Certain compounds of formula I can be prepared as shown in the Scheme of Reaction 6.
As shown in Reaction Scheme 6, amine 29 can be treated with for example, cyanogen bromide or N-cyanoimidazole in the presence or absence of a base, to form the N-cyano derivative 36. Imidazole synthesis 37, tetrazole 38, triazole 39 and oxadiazole 40, is illustrated in the Reaction Scheme. The tetrazole 89 can be alkylated using the appropriate alcohol, under Mitsunobu conditions or, with the appropriate alkyl iodide, mesylate, or the like, in the presence of a base to provide 41. Triazole 39 can be alkylated using an appropriate alkyl iodide. , mesylate or the like, in the presence of a base to provide 42.
Reaction Scheme 7
As shown in Reaction Scheme 7, compound 29 can be transformed to compound 43 by reaction with diketene or an a-haloketone, further, treatment with hydroxylamine hydrochloride can provide isoxazole 44. Alternatively, 43 can react with hydrazine at a solvent such as ethanol, to provide pyrazole 45, which may be alkylated or acylated to provide compound 46. Alternatively, compound 43 may be converted to oxazole 47 by treatment with sodium azide and methanesulfonic acid.
Reaction Scheme 8
As shown in Reaction Scheme 8, secondary amine 29 can be transformed to acyl chloride 48, by treatment with triphosgene. Compound 48 can be converted to oxadiazole 49 by reaction with an appropriate amidoxime. Alternatively, 48 can be reacted with hydrazine to provide compound 50. Compound 50 after treatment with an appropriate acyl chloride in the presence of ammonia, provides the triazole 39 or in the presence of an acid such as sulfuric acid and water , provides oxadiazole 51. Compound 48 can be treated with ammonia to provide the ureido derivative 52 which can be transformed into oxazole 53 by reaction with an a-haloketone in the presence of a base. Alternatively, compound 52 can be converted to the corresponding thioamide with the Lawesson reagent and which then, reacting with an α-haloketone can provide the thiazole 54.
Reaction Scheme 9
SG
As shown in Reaction Scheme 9, compound 41 can be hydrolyzed to the corresponding amine 55, and can be further acylated using standard procedures by one of skill in the art to provide 41. Alternatively, 55 can be treated with triphosgene or trichloromethylchloroformate to provide 56. Compound 56 can provide compound 41, by reaction with the appropriate alcohols.
Reaction Scheme 10
As shown in Reaction Scheme 10, tetrazole 38 can be alkylated with the appropriate protected aminoalcohol under Mitsunobu conditions or with the appropriate protected aminoalkyl, iodide or mesylate bromide, or the like, in the presence of a base to provide a Protected aminoalkyltetrazole 57. Removal of Pl using methods well known in the art can provide compound 58. Alternatively, tetrazole 38 can be alkylated with the appropriate alkylcyan bromide or with the appropriate acrylonitrile under Michael reaction conditions. The cyano derivative 59 can then be reduced to the corresponding amine 58. The tetrazole 38 can be alkylated using the appropriate alcohol under Mitsunobu conditions, or with the appropriate alkyl halide or the like, in the presence of a base to provide 60. Removal of Pl (protecting group), using methods well known in the art, can provide compound 61. Alternatively, hydroxyalkyltetrazole 61 can be obtained by alkylation of 38 with the corresponding halide in the presence of a base.
Reaction Scheme 11
R1C0CI or (R1C0) 20
64 63
As shown in Reaction Scheme 11, heteroaryl amine 1 can be converted to 62 by reaction with the appropriate aldehyde in the presence of an acid. The compound 62 can be acylated using standard procedures by one of skill in the art to provide 63. The heteroaryl derivative 63 can be alkylated using an appropriate or tosylated halide or the like, in the presence of a base to provide 64.
TEST The following test protocols and result (s) thereof, which demonstrate the utility and effectiveness of the compounds and / or methods of the present invention are given for purposes of illustration and do not mean limitation in any way.
In vitro assay of Cetp inhibitor: Spa assay A scintillation proximity test (SPA) in vitro, has been used to test the ability of compounds of the present invention to inhibit the transfer of radiolabeled cholesterol esters between HDL and LDL. This assay monitors the inhibition of the transfer of [3 H] cholesterol esters from HDL (Amersham) to biotinylated LDL (Amersham) by a CETP source. CETP produced by AV-12 cells that have been created to express human CETP has been used to mediate the transfer. After a 30 minute incubation in which the radiolabelled cholesterol is transferred to a buffer based on HEPES-NaCl, the reaction is stopped and the biotinylated LDL is bound to streptavidin / scintillant-coated SPA beads (Amersham). Then the radioactive signal is measured by a Packard 96-well scintillation topcounter with the option of fully open windows, a decrease in the radioactive signal, represents the ability of the compounds of the invention to inhibit the activity of CETP. Alternatively, additional sources of CETP can be used in this assay, to mediate the transfer of the radiolabeled cholesterol ester in this assay. Endogenous CETP from human plasma, CETP from mice engineered to express human CETP, and endogenous CETP from hamsters, can be used as a source of CETP in this assay. Alternatively, other sources can be used as the buffer. In addition to the HEPES-NaCl buffer that has been used in this assay, human plasma, mouse plasma or a Tris buffer that can be high in albumin, can be used as the buffer in which the transfer of radiolabelled cholesterol esters can occur , from HDL to LDL. Alternatively, other sources of radioactivity can be used to track the activity of CETP in this assay. In yet another alternative, the LDL-radiolabel can be used in this test. The tested compounds of the present invention have shown inhibition of CETP activity below about 100 micromolar when subjected to subsequent SPA testing procedures.
Activity Test Cetp in vivo Syrian Golden hamsters, which express the endogenous CETP, are used to assess the activity of the compounds in vivo. The test compounds are administered once orally in selected oil-based or aqueous vehicles, for one week. On several occasions after the dosage which varies from 4 h to 8 h, blood is obtained. The activity of CETP is determined by a method similar to that described for the in vitro assay of CETP activity, except that the plasma of treated animals is used as the source of CETP in the assay. A strain of transgenic mice expressing human CETP (Taconic, Germantown, NY), is used to test the compounds of this invention. The test compounds are administered orally in selected water-based or oily vehicles, for up to one week. On several occasions after dosing, which varies from 4h to 48h, blood can be obtained. The CETP activity is determined by a method similar to that described by the in vitro CETP activity assay, except that the plasma of treated animals is used as the CETP source in the assay. Alternatively, a strain of transgenic mice expressing both human CETP and human apolipoprotein A-1 CETP (Taconic, Germantown, NY) is used to test the compounds of the present invention. The test compounds are administered once orally in selected oil-based or aqueous vehicles, for up to one week. On several occasions after dosing that vary from 4 h to 48 h, blood is obtained. The CETP activity is determined by a method similar to that described for the in vitro assay of CETP activity, except that the plasma of the treated animals is used as the source of CETP in the assay.
In Vitro Assay of Plasma Lipids The in vivo activity of the compounds of this invention can be determined by comparing the level of elevation of HDL cholesterol relative to the control by a given amount of compound in animal species containing CETP. A strain of transgenic mice has been used that also express human CETP and human apolipoprotein A-l
(Taconic, Germantown, NY), to test the compounds of the present invention. The test compounds are administered once orally in selected oil-based or aqueous vehicles. On several occasions after dosing, which vary from 4h to 24h, blood is obtained. The blood is left to coagulate and serum is obtained by centrifugation. HDL cholesterol levels in serum are determined by HDL-C plus reagents (Roche / Hitachi, Indianapolis, IN), with a clinical chemistry analyzer (Roche / Hitachi, Indianapolis, IN). Additional serum lipids can be analyzed by enzymatic methods. Lipids in fractions of VLDL, LDL and HDL, are analyzed by enzymatic methods after precipitation or chromatography by size exclusion, an example of the elevation of HDL cholesterol levels to 8 hr is summarized in table 1.
Table 1. Elevation of HDL cholesterol levels at 8hr
The efficacy of these compounds of the invention in vivo can also be determined using Syrian Golden Hamster. The compounds can be tested in hamsters made hypercholesterolemic fed a diet of high cholesterol and high fat, at least two weeks, or in non-hypercholesteroid hamsters, fed normal food for 2 weeks. The test compounds can be administered orally in selected oil-based or aqueous vehicles, for up to 1 week. Serum can be obtained and lipids can be analyzed by enzymatic methods. Lipids in the VLDL, LDL and HDL fractions are analyzed by enzymatic methods after chromatography by size exclusion or precipitation. Alternatively, a strain of transgenic mice expressing human CETP (Taconic, Germantown, NY) has been used to test the efficacy of the compounds of this invention. HCETP mice can be made cholelemic by feeding them a high-fat diet, such as TD 88051, as described by Nishina et al., (J Lipid Res., 31, 859-869 (1990)) for at least two weeks before the start of the study. The test compounds can be administered orally in oil-based or water-based vehicles selected for up to 1 week. Whey can be obtained and the lipids can be analyzed by enzymatic methods. Lipids in the VLDL, LDL, and HDL fractions are analyzed by enzymatic methods after chromatography by size exclusion or precipitation.
Method of treatment As used herein, the term "effective amount" means an amount of compound of the present invention, ie, formula I, which is capable of alleviating the symptoms of various pathological conditions described herein. The specific dose of a compound administered in accordance with this invention will, of course, be determined by the particular circumstances that define the case, including, for example, the compound administered, the route of administration, the patient's state of life, and the pathological condition under treatment, a typical daily dose will contain a non-toxic dose level from about 0.01 mg to about 100 mg / per day of a compound of the present invention. The preferred daily dose will generally be from about 1 mg to about 250 mg per day. The compounds of this invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are preferably formulated prior to administration, the selection of which will be decided by the attending physician. Thus, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate, prodrug, enantiomer or prodrug thereof, and a carrier, diluent. or pharmaceutically acceptable excipients. The total active ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable", it is understood that the carrier, diluent, excipients and salt must be compatible with the other ingredients of the formulation, and not be deleterious to the recipient thereof. Pharmaceutical formulations of the present invention can be prepared by methods known in the art, using well-known and readily available ingredients. For example, the compounds of formula I can be formulated with common excipients, diluents or carriers, and formed into tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol and silicic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives; alginates, gelatin and polyvinyl pyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents to delay dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate, adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylglycols.
The compounds can also be formulated as elixirs or solutions for convenient oral administrations or as appropriate solutions for parenteral administrations, for example, by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to be formulated as controlled release dosage forms, or the like. The formulations can be constituted so that they release the active ingredient only, or preferably, in a physiologically particular location, possibly over a period of time. The coatings, envelopes and protective matrices can be made, for example, from polymeric substances or waxes. The compounds of formula I, generally, can be administered in a convenient formulation, determined by the attending physician. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.
Formulations In the formulations that follow, "Ingredient
Active "means a compound of Formula I, a salt, solvate, racemate, diastereomer enantiomer or mixture of diastereomers, or prodrugs thereof, or a combination of a compound of formula I and another effective agent useful for the practice of the invention.
Formulation 1: Gelatin Capsules Solid gelatin capsules are prepared using the following:
Ingredient Quantity (mg / capsule)
Active ingredient 0.1 - 1000 Starch, NF 0 - 650 Flueble starch powder 0 - 650 Silicone fluid 350 - 15 centistokes
The above formulation can be changed in accordance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients:
Formulation 2: Tablets
Ingredient Quantity (mg / tablet) Active ingredient 2.5-1000 Microcrystalline cellulose 200-650 Silicon dioxide, smoked 10-650 Stearic acid 5-15
The components are mixed and compressed to form tablets.
Alternatively, each tablet containing 2.5-1000 mg of active ingredient, is made as follows:
Formulation 3: Tablets
Ingredient Quantity (mg / tablet)
Active ingredient 25-100 Starch 45 Icrystalline cellulose 35 Polyvinylpyrrolidone (as 10% 4 solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1
The active ingredient, starch and cellulose, are passed through a U.S. No. 45 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders which are then passed through a sieve ü.S. No. 14. The granules thus produced are dried at 50 ° -60 ° C and passed through a U.S. No. 18 mesh. Sodium carboxymethyl starch, magnesium stearate and talcum are previously passed through a U.S. No. 60 mesh, and then added to the granules, which after mixing, are compressed in a tabletting machine, to provide tablets.
The suspensions that each contain 0.1-1000 mg of medication per 5 ml of dose, are made as follows:
Formulation 4: Suspensions
Ingredient Quantity (mg / 5 ml)
Active ingredient 0.1-1000 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor c.v. Colorant c.v. Purified water for 5 mL
The medicament is passed through a U.S. sieve. 45 mesh and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid, flavoring and coloring solution is diluted with some of the water and added with agitation. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients:
Formulation 5: Aerosol
Ingredient Quantity (% by weight)
Active ingredient 0.25 Ethanol 25.75 Propellant 22 70.00 (chlorodifluoromethane)
The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C, and transferred to a filling device. The required amount is then fed to a stainless steel vessel and diluted with the remaining propellant. The valve units are then adjusted to the container.
Formulation 6: Intravenous Solution
Ingredient Quantity Active ingredient 50 mg Isotonic saline 1,000 mL
The solution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per minute.
EXAMPLES The following examples are illustrative of the compounds made or compounds that could be made by one of skill in the art, following the teachings described herein and known to one of skill in the art and requiring minimal experimentation. The examples described should not in any way limit the scope of the claims.
Example 1 7- (Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -5-ethyl-6,7-dihydro-5H-thieno [3,2- b] pyridin-4-isopropyl acid isopropyl ester carboxylic
Step 1. Preparation of 3-amino-thiophene-2-carboxylic acid
5N NaOH (50 mL) was added to a solution of methyl 3-aminothiophen-2-carboxylate (7.86, 50.0 mole) in methanol (259 mL). The reaction mixture was heated at 60 ° C overnight. The pH was adjusted to approximately 6 to 7, adding 1N of HCl. It was extracted with ethyl acetate (5 x 200 mL). The organic layers were combined, dried over Na2SO4. They were filtered and concentrated to provide 3-amino-thiophene-2-carboxylic acid (5.84 g, 82%), as a white powder, which was used immediately for the next step. MS (ES +): 144 (M + H); (ES-): 142 (M-H).
Step 2. Preparation of 2- (thiophene-3-ylaminomethylene) -malonic acid diethyl ester
Diethyl ethoxymethylenemalonate (8.99 ml, 44.9 mmol) was added to a solution of 3-amino-thiophene-2-carboxylic acid (5.84 g, 40.8 mmol) in toluene (100 ml). The mixture was heated under reflux overnight. The solvent was evaporated in vacuo. Purified using column chromatography on silica gel (levigating gradient, 0-20% ethyl acetate in hexane), to give 2- (thiophene-3-ylaminomethylene) -malonic acid diethyl ester (7.86 g, 86%) as a white crystalline solid. MS (ES +): 270 (M + H).
Step 3. Preparation of 7-hydroxy-thieno [3,2-b] pyridine-6-carboxylic acid ethyl ester
2- (Thiophene-3-ylaminomethylene) -malonic acid diethyl ester (7.66 g, 2.84 mmol) was added to refluxing phenyl ether (100 ml) over a period of 5 minutes under nitrogen. After the addition is complete, the reaction is maintained under reflux for 30 minutes. The reaction mixture is cooled to room temperature, and then poured into ethyl acetate (1000 ml). The brown precipitate is collected by filtration to obtain the ethyl ester of 7-hydroxy-thieno [3,2-, b] pyridine-6-carboxylic acid (4.82 g, 76%). EM
(ES +): 224 (M + H); (ES-): 222 (M-H).
Step 4. Preparation of 4-isopropyl ester of 7-oxo-7H-thieno [3, 2-b] pyridin-4,6-dicarboxylic acid ethyl ester
Pyridine (1.20 ml, 1.48 mmol) was added to a suspension of 7-hydroxy-thieno [3,2-b] pyridine-6-carboxylic acid ethyl ester (1.10 g, 4.93 mmol) in dichloromethane (50 ml), and then isopropyl chloroformate (l.ON in toluene, 14.8 ml) was added. The reaction mixture was stirred at room temperature overnight. The mixture was washed with 1N HCl (50 ml), followed by brine (3 x 50 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. Purified using silica gel column chromatography (levigating gradient, 0-60% ethyl acetate in hexane), to give 7-oxo-7H-thieno 6-isopropyl ester of 6-ethyl ester [3, 2 -b] pyridine-4,6-dicarboxylic acid (1.37 g, 90%) as a white crystalline solid. MS (ES +): 310 (M + H).
Step 5. Preparation of 4-isopropyl ester of 6-ethyl-7-oxo-6,7-dihydro-5H-thieno [3,2-b] pyridin-4,6-dicarboxylic acid 6-ethyl ester
4-isopropyl ester of 7-oxo-7H-thieno [3,2-b] pyridin-4,6-dicarboxylic acid 6-ethyl ester (0.512 g, 1.66 mmol) and copper (I) iodide (0.695) were mixed. g, 3.65 mmol) in THF (35 ml). The mixture was cooled to -78 ° C. Ethyl magnesium bromide (3.0 M in diethyl ether, 3.30 ml) was injected and the reaction was maintained at -78 ° C for more than one hour. It was tempered until -20 ° C during the night in a freezer. The reaction mixture was poured into a saturated solution of ammonium chloride (200 ml). It was extracted with ethyl acetate (3 x 200 mL). All organic layers were combined, dried over Na 2 SO 4, filtered and concentrated to give 4-isopropyl ester of 6-ethyl-7-oxo-6,7-dihydro-5H-thieno 6-ethyl ester [3, 2- b] pyridine-4,6-dicarboxylic acid (0.520 g, 93% as a crude oil, MS (ES +): 340 (M + H).
Step 6. Preparation of 5-ethyl-7-oxo-6,7-dihydro-5H-thieno [3,2-b] pyridine-4-carboxylic acid isopropyl ester
Lithium chloride (0.162 g, 3.83 mmol) in one portion was added to a mixture of ester 4-isopropyl ester
6-Ethyl-7-oxo-6,7-dihydro-5H-thieno [3,2- b] pyridin-4,6-dicarboxylic acid ethyl ester (0.520 g, 1.53 mmol) in dimethylsulfoxide (15 ml) and water (2 drops). The mixture was heated at 160 ° C for 4 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 ml) and brine (50 ml). The organic layer was separated and washed with brine (3 x 50 mL). The organic portion was dried over sodium sulfate, filtered and concentrated. Purified using silica gel column chromatography (levigating gradient, 0-15% ethyl acetate in hexane), to give 5-ethyl-7-oxo-6,7-dihydro-5H-thieno isopropyl ester [ 3, 2-b] pyridine-4-carboxylic acid (0.236 g, 58% by two steps) as an oil. MS (ES +): 268 (M + H).
Step 7. Preparation of 7- (3,5-bis-trifluoromethyl-benzylamino) -5-ethyl-β, 7- dihydro-5H-thieno [3,2-b] pyridine-4-carboxylic acid isoproneyl ester
Titanium (IV) isopropoxide (0.372 ml, 1.26 mmol) was injected into a mixture of 5-ethyl-7-oxo-β, 7-dihydro-5H-thieno [3,2- b] pyridine- isopropyl ester. 4-carboxylic acid (0.225 g, 0.842 mmol), 3,5-bis (trifluoromethyl) benzylamine (0.211 g, 0.842 mmol), and then stirred at room temperature for 4 hours. A solution of sodium cyanoborohydride (0.212 g, 3.37 mmol) in methanol (8 ml) was injected into the reaction mixture and stirring was continued at room temperature overnight. Another portion of sodium cyanoborohydride solution (0.212 g, 3.37 mmol) in methanol (8 mL) was added and stirring was continued for 4 hours. Sodium borohydride (0.159 g, 4.21 mmol) was added and the reaction was heated at 60 ° C overnight. The mixture was treated with 0.1 N sodium hydroxide (25 ml) for 10 minutes, and then filtered through a pad of Celite®. The filtered residue was washed uniformly with ethyl acetate. The organic layer was separated, washed with brine (3 x 50 mL), dried over Na 2 SO 4, filtered and concentrated to give the 7- (3,5-bis-trifluoromethyl-benzylamino) -5-ethyl- isopropyl ester. Crude 6,7-dihydro-5H-thieno [3,2- b] pyridine-4-carboxylic acid (0.315 g), which was made without further purification. MS (ES +): 495 (M + H).
Step 8. Preparation of 7- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -5-ethyl-6,7-dihydro-5H-thieno [3,2-b] pyridin isopropyl ester -4-carboxylic
Acetic anhydride (0.250 ml, 2.65 mmol) was injected dropwise into a solution of 7- (3,5-bis-trifluoromethyl-benzylamino) -5-ethyl-β, 7-dihydro-5H-thieno isopropyl ester [7]. 3, 2-b] crude pyridine-4-carboxylic acid (0.120 g, 0.243 mmol) and pyridine (0.250 mL, 3.10 mmol) in dichloromethane (1 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The solvents were evaporated and the resulting residue was purified using silica gel column chromatography (levigating gradient, 0-35% ethyl acetate in hexane), to give the title compound (0.0290 g, 2%). MS (ES +): 559 (M + Na); (ES-): 535 (M-H).
Example 2 4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-7-methyl-3,4-dihydro-2H- [1,8] naphthyridin-1 isopropyl ester -carboxylic
Step 1. Preparation of 2- [(6-methyl-pyridin-2-ylamino) -methylene] -malonic acid diethyl ester
Diethyl ethoxymethylenemalonate (10.0 ml, 55.0 mmol) was added to a solution of 6-methyl-pyridin-2-ylamine (5.41 g, 50.0 mmol) in toluene (100 ml). The mixture was heated under reflux overnight. The solvent was evaporated in vacuo to give 2- [((6-methyl-pyridin-2-ylamino) -methylene] -malonic acid diethyl ester (14.8 g) as a white solid MS (ES +): 279 (M + H).
Step 2. Preparation of 7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester
2- [((6-Methyl-pyridin-2-ylamino) -methylene] -malonic acid diethyl ester (14.8 g) was added to the phenyl ether subjected to reflux (100 ml) for a period of 5 minutes under nitrogen. After the addition is complete, the reaction is maintained under reflux for 3 hours, cooled to room temperature, and then the reaction mixture is poured into hexane / ethyl acetate 1: 1 (2000 ml). by filtration to obtain 7-methyl-4-oxo-l, 4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester (8.35 g, 72% by two steps). MS (ES +): 233 ( M + H); (ES-): 231 (MH).
Step 3. Preparation of 1-isopropyl ester of 7-methyl-4-oxo-4H- [1,8] naphthyridin-1,3-dicarboxylic acid 3-ethyl ester
Pyridine (2.43 ml, 30.0 mmol) is added to a suspension of 7-methyl-4-oxo-l, 4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester (2.32 g, 10.0 mmol). in dichloromethane (100 ml), and then isopropyl chloroformate (l.ON in toluene, 30.0 ml) is added. The reaction mixture is stirred at room temperature overnight. Wash with brine (3 x 100 ml). The organic layer is separated, dried over Na 2 SO 4, filtered and concentrated. Purify using column chromatography on silica gel (levigant gradient, 0-60% ethyl acetate in hexane), to give 1-isopropyl ester of the 3-ethyl ester of 7-methyl-4-oxo-4H- [ 1,8] naphthyridin-l, 3-dicarboxylic acid
(1.31 g, 41%). MS (ES +): 319 (M + H).
Step 4. Preparation of 1-isopropyl ester of 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H- [1,8] naphthyridin-1,3-dicarboxylic acid 3-ethyl ester
1-isopropyl ester of 7-methyl-4-oxo-4H- [1,8] aftiridin-1,3-dicarboxylic acid 3-ethyl ester was mixed
(1.21 g, 3.80 mmol) and copper iodide (I) (1.59 g, 8.36 mmol) in THF (75 mL). The mixture was cooled to -78 ° C. Ethyl magnesium bromide (3.0 M in diethyl ether, 7.60 ml) was injected and stirred for 2 hours. It was warmed to -20 ° C and the reaction was maintained at that temperature for 3 hours. The reaction mixture was poured into saturated ammonium chloride solution (100 ml). It was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purified using silica gel column chromatography (levigant gradient, 0-60% ethyl acetate in hexane) to provide 1-isopropyl ester of 2-ethyl-7-methyl-4-oxo-3-ethyl ester. 3,4-dihydro-2H- [1,8] naphthyridin-1,3-dicarboxylic acid (0.715 g, 54%). MS (ES +): 349 (M + H).
Step 5. Preparation of 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H- [1,8] naphthyridine-l-carboxylic acid isopropyl ester
Lithium chloride (0.216 g, 5.10 mmol) was added in one portion, to a mixture of ester 1-isopropyl ester
3-Ethyl 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H- [1,8] naphthyridin-1,3-dicarboxylic acid (0.710 g, 2.04 mmol) in dimethylsulfoxide (20 mL) and water (4 drops). The mixture was heated to 160 ° C for 3 hours. It was cooled down to room temperature, partitioned between ethyl acetate (100 ml) and brine (100 ml). The organic layer was separated, washed with brine (3 x 100 mL). Dried over sodium sulfate, filtered and concentrated. Purified using silica gel column (levigant gradient, 0-20% ethyl acetate in hexane), to provide 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H- isopropyl ester [1,8] naphthyridine-1-carboxylic acid (0.457 g, 81) as a pale yellow solid. EM
(ES +); 277 (M + H).
Step 6. Preparation of 4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-7-methyl-3, 4-dihydro-2H- [1,8] naphthyridine-1-carboxylic acid isopropyl ester
Titanium (IV) isopropoxide (0.0870 ml, 0.299 mmol) was injected into a mixture of 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H- [1, 8] naphthyridine isopropyl ester. α-carboxylic acid (0.055 g, 0.199 mmol), and 3,5-bis (trifluoromethyl) benzylamine (0.0500 g, 0.199 mmol), and then stirred at room temperature for 6 hours. Methanol (2 mL) was added, followed by NaBH 4 (0.0380 g, 0.995 mmol) and stirred at room temperature overnight. The mixture was treated with 1N sodium hydroxide (2 mL) and ethyl acetate (5 mL), and then filtered through a pad of Celite®. The filtered residue was washed uniformly with ethyl acetate (30 ml). The organic layer was separated, washed with brine (3 x 50 mL), dried over sodium sulfate, filtered and concentrated to provide the 4- (3,5-bis-trifluoromethyl-benzylamino) isopropyl ester. crude ethyl-7-methyl-3, 4-dihydro-2H- [1,8] naphthyridine-1-carboxylic acid (0.0900 g), which was made without further purification. MS (ES +): 504 (M + H).
Step 7. Preparation of 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2- ethyl-7-methyl-3, 4-dihydro-2H- [1,8] isopropyl ester naphthyridine-1-carboxylic acid
Acetic anhydride (0.250 ml, 2.65 mmol) was injected dropwise into a solution of 4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-7-methyl-3,4-dihydro-2H isopropyl ester. - [1, 8] crude naphthyridine-l-carboxylic acid (0.090 g,
0. 199 mmol), and pyridine (0.250 mL, 3.10 mmol) in dichloromethane (1 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The solvents were evaporated and purified using silica gel column chromatography (levigant gradient, 0-40% ethyl acetate in hexane), to provide the title compound (0.0650 g, 66%). MS (ES +): 546 (M + H).
Example 3 (+/-) -cis-4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methoxy-3,4-dihydro-2H- isopropyl ester [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) -cis- (2-ethyl-6-methoxy-1,2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide
6-methoxy-pyridin-3-ylamine (1.05 g, 8.05 mmol) was dissolved in anhydrous dichloromethane (35 ml), sodium sulfate (1.14 g) was added and the reaction mixture was cooled to -20 ° C. Propionaldehyde (0.659 g, 8.85 mmol) was added and the mixture was stirred from -20 to 0 ° C for 1.5 hours. Sodium sulfate was filtered and N-vinyl acetamide (0.706 g, 8.85 mmol) was added to the filtrate at -20 ° C, followed by boron trifluoride diethyl etherate (0.088 mL, 0.805 mmol). The reaction mixture was stirred from -20 to -10 ° C for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica cartridge, levigating with hexanes / ethyl acetate to give the title compound (1.25 g, 63%). MS (ES +): 250 (M + H).
Step 2. Preparation of (+/-) - cis-4-acetylamino-2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid isopropyl ester
Isopropyl chloroformate (3.10 ml,
2. 82 mmol, 1.0 M in toluene) by dripping into a solution of
(+/-) -cis-N- (2-ethyl-6-methoxy-l, 2,3, 4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide (702 mg, 3,102 mmol) and pyridine (0.677 mL, 8.46 mmol) in dichloromethane (15 mL) at 0 ° C, under a nitrogen atmosphere and stirred at room temperature for 10 minutes. 1M HCl was added and the layers separated. The aqueous layer was extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to provide the title compound (895 mg, 95%). MS (ES +): 336 (M + H).
Step 3. Preparation of (+/-) - cis-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid isopropyl ester
A solution of (+/-) - cis-4-acetylamino-2-ethyl-6-methoxy-3, -dihydro-2H- [1,5] naphthyridin-1- isopropyl ester was heated at 80 ° C. carboxylic acid (100 mg, 0.298 mmol) in 5 H HCl (1 mL) for 4 hours. The reaction mixture was cooled to room temperature, the crude was poured into a saturated sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to provide the title compound (85 mg, 98%). MS (ES +): 277 (M-NH2).
Step 4. Preparation of isopropyl ester of (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2- ethyl-6-methoxy-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
Sodium triacetoxyborohydride (0.091 mg, 0.409 mmol) was added to a mixture of 3,5-bis (trifluoromethyl) benzaldehyde (0.045 ml, 0.273 mmol), acetic acid (0.018 ml, 0.303 mmol) and isopropyl ester of the acid (+ / -) -cis-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid (0.08 mg, 0.273 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. A saturated solution of ammonium chloride was added, the layers were separated and the aqueous layer was extracted with dichloromethane. The dried organic layers were combined over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (125 mg, 88%). MS (ES +): 520 (M + H).
Step 5. Preparation of (+/-) - cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methoxy-3,4-dihydro isopropyl ester -2H- [1, 5] naphthyridine-1-carboxylic acid
Acetic anhydride (0.023 ml, 1.205 ml) was added to a solution of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-methoxy-isopropyl ester. 3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (125 mg, 0.241 mmol) and pyridine (0.097 mL, 1.205 mmol) in dichloromethane (2 mL), and stirred at room temperature for 14 hours . The solvent was removed under reduced pressure and the residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (105 mg, 78%). XH NMR (CDC13, 300 MHz): d 0.66-0.72 (m, 3H), 1.20-1.29
(, 7H), 1.33-1.69 (m, 3H), 2.01-2.21 (m, 3H), 2.26-2.33 (m,
1H), 3.82, 3.86 (s, 3H), 4.22-4.28 (m, 1H), 4.81-5.01 (m,
2H), 6.59, 6.65 (d, J = 8.7 Hz, 1H), 7.61-7.73 (m, 4H). AND
(ES +): 562 (M + H).
Example 4 (+/-) -cis-4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- isopropyl ester [1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedures described in Example 3, Steps 1-5, by replacing 6-methoxy-pyridin-3-ylamine with 6-trifluoromethyl-pyridin-3-ylamine in Example 3, Step 1. MS (ES +): 600 (M + H).
Example 5 (+/-) -cis-4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-bromo-3,4-dihydro-2H- isopropyl ester [1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially by following the procedures described in Example 3, Steps 1-5, replacing 6-methoxy-pyridin-3-ylamine with 6-bromo-pyridin-3-ylamine in Example 3, Step 1. MS (ES +): 610, 612 (M + H).
Example 6 (+/-) -cis-4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-dimethylamino-3, 4-dihydro-2H- isopropyl ester [1,5] naphthyridine-1-carboxylic
40% N, N-dimethylamine in water (0.5 ml) was added to a solution of (+/-) - cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino acid isopropyl ester. ] -2- ethyl-6-bromo-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (60 mg, 0.098 mmol) in dimethylsulfoxide (0.2 ml) and the mixture was heated to 100 ° C in a sealed tube for 15 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel cartridge, levigating with hexanes / ethyl acetate to give the title compound (32 mg, 57%). MS (ES +): 575 (M + H).
Example 7 (+/-) -cis-4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- isopropyl ester [1, 5] naphthyridine-1-carboxylic acid
1, -bis (diphenylphosphino) (II) chloride, complex with dichloromethane (9 mg, 0.012 mmol) was added to a suspension of (+/-) - cis-4- [acetyl- (3, 5) isopropyl ester) bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-bromo-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (50 mg, 0.08 mmol), methyl boronic acid (15 mg). mg, 0.24 mmol) and cesium fluoride (40 mg, 0.28 mmol) in dry dioxane (1.5 ml) and the mixture was heated at 80 ° C in a sealed tube for 15 hours. The mixture was cooled to room temperature, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the solvent was filtered and stirred under reduced pressure. The residue was chromatographed on a silica gel cartridge, levigating with hexanes / ethyl acetate to give the title compound (37 mg, 84%). MS (ES +): 546 (M + H).
Example 8 (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2-yl-tetrazol-5-yl) -amino] -2- ethyl-6 isopropyl ester -methoxy-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) -ciano-amino] -2-ethyl-6-methoxy-3,4-dihydro isopropyl ester -2i? - [1, 5] naphthyridine-1-carboxylic acid
Diisopropylethylamine (0.146 ml, 0.962 mmol) followed by cyanogen bromide (63 mg, 0.577 mmol) was added to a solution of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamine) isopropyl ester. ) -2-ethyl-6-methoxy-3, 4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid (200 mg, 0.385 mmol) in dry tetrahydrofuran (5 ml) and the mixture was stirred at room temperature environment for 15 hours. Water was added, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sulfate, the solvent was filtered and stirred under reduced pressure. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (104 mg, 50%). MS (ES +); 545 (M + H).
Step 2. Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl) -amino] -2-ethyl-6 isopropyl ester -methoxy-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
A mixture of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) -ciano-amino] -2-ethyl-6-methoxy-3 isopropyl ester was heated to 120 ° C. , 4-dihydro-2iT- [1, 5] naphthyridine-1-carboxylic acid (100 mg, 0.184 mmol), sodium azide (17 mg, 0.258 mmol) and triethylamine hydrochloride (35 mg, 0.258 mmol) in dry dry toluene a nitrogen atmosphere for 8 hours. Then, more sodium azide (6 mg) and triethylamine hydrochloride (13 mg) were added and the mixture was heated for 4 hours. It was cooled to room temperature, diluted with ethyl acetate and washed with 1N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (61 mg, 50%). MS (ES +): 588 (M + H).
Step 3: Preparation of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2 isopropyl ester -ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
Triphenylphosphine (27 mg, 0.104 mmol), methanol (17 mg, 0.52 mmol) and diisopropylazodicarboxylate were added.
(0.018 mL, 0.104 mmol) was added to a solution of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl) -amino) isopropyl ester. -2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid in dry dichloromethane (1 ml) and the mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel, levigating with ethyl acetate / hexanes to give the title compound (41 mg, 66%). MS (ES +): 602 (M + H).
Example 9 (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2- ethyl-6 isopropyl ester -trifluoromethyl-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedures described in Example 8 (Steps 1-3) by replacing (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) isopropyl ester. ethyl-6-methoxy-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid ester with (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzylamino) isopropyl ester) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2-r7- [1,5] naphthyridine-l-carboxylic acid (from Example 4) in Example 8, Step 1. MS (ES +): 640 (M + H).
Example 10 (2S, 4R) -4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl isopropyl ester -3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) - isopropyl ester amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] aftiridine-1-carboxylic acid (Example 9) in a Chiralpak AD (4.6 x 150 mm), flow ratio 0.6 ml / min, solvents: 10% propan-2-ol in heptane with N, N-dimethylethylamine, Rf = 5.2 min, wavelength: 270 nm. EE = 100%. MS (ES +): 640 (M + H).
EXAMPLE 11 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl (isopropyl) isopropyl ester -3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) - isopropyl ester amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (Example 9) in a Chiralpak AD (4.6 x 150 mm), flow ratio 0.6 ml / min, solvents: 10% propan-2-ol in heptane with -V, N-dimethylethylamine, Rf = 6.1 min, wavelength: 270 nm. EE = 100%. MS (ES +): 640 (M + H).
Example 12 (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-tert-butoxycarbonylamino-ethyl) -2J [beta] -tetrazole-5-yl isopropyl ester ) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedures described in Example 8, Step 3, replacing methanol with (2-amino-ethyl) carbamic acid tert-butyl ester and (+/-) - cis-4 isopropyl ester - [(3,5-bis-trifluoromethyl-benzyl) - (2β-tetrazol-5-yl) -amino] -2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] Naphthyridine-1-carboxylic acid ester with (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [i] isopropyl ester , 5] naphthyridine-l-carboxylic acid. MS (ES +): 767 (M-H).
Example 13 (+/-) -cis-4- [[2- (2-Amino-ethyl) -2u-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino acid isopropyl ester ] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1, 5] naphthyridine-l-carboxylic acid
Trifluoroacetic acid (1 ml) was added to a solution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-tert-jutoxycarbonylamino-ethyl) isopropyl ester. ) -2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid (61 mg, 0.079 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel, levigating with ethyl acetate, to give the title compound (24 mg, 45%). MS (ES +): 669 (M + H).
EXAMPLE 14 (2S, 4R) -cis-4- [[2- (2-Amino-ethyl) -2-t-tetrazol-5-yl] - (3, 5-bis-trifluoromethyl-benzyl) -amino isopropyl ester ] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2 - [1,5] naphthyridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) - cis-4- [[2- (2-amino-ethyl) -2i] -tetrazol-5-yl] - (3, 5) isopropyl ester. bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridine-l-carboxylic acid (Example 13) in a Chiralpak AD (4.6 x 150 mm), flow ratio 0.6 ml / min, solvents: absolute ethanol in 10% heptane with dimethylethylamine, Rf = 5.2 min, wavelength: 270 nm. EE > 97%. MS (ES +): 669 (M + H).
Example 15 (2R, 45) -cis-4- [[2- (2-Amino-ethyl) -2H-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino isopropyl ester ] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1, 5] aftiridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) -cis-4- [[2- (2-amino-ethyl) -2 # -tetrazol-5-yl] - (3, 5) isopropyl ester. -bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2 # - [1,5] naphthyridine-l-carboxylic acid (Example 13) in a Chiralpak AD (4.6 x 150 mm), flow ratio 0.6 ml / min, solvents: absolute ethanol in 10% heptane with dimethylethylamine, Rf = 6.1 min, wavelength: 270 nm. EE > 97%. MS (ES +): 669 (M + H).
Example 16 (+/-) - cis and trans-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2-fluoro-5-yl) isopropyl ester amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2J? - [1,5] naphthyridine-1-carboxylic acid
2-Bromoethanol (0.093 mL, 1.25 mmol) was added to a solution of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzyl- (2H-tetrazol-5-yl) isopropyl ester) amino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2ff- [1,5] naphthyridine-1-carboxylic acid (653 mg, 1045 mmol) and cesium carbonate (749 mg, 2.30 mmol) in Dry dimethylformamide under a nitrogen atmosphere and the mixture was stirred at 50 ° C for 24 hours. It was cooled to room temperature, water was added, and it was extracted with ethyl acetate. The organic solvent was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography, levigating with ethyl acetate / hexanes to provide a mixture of two compounds. It was separated by normal phase CLAR by levigating with standard hexane / ethanol gradient to provide (+/-) - trans-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy) isopropyl ester ethyl) -2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid (48 mg, 7%). aH NMR (CDC13, 300
MHz): d 0.95 (t, J = 7.7 Hz, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.35 (d, J = 6.3 Hz, 3H), 1.55-1.69 (m, 2H), 2.31 -2.47 (m, 3H), 3.98-4.00 (m, 2H), 4.49-4.73 (m, 5H), 5.09 (septuplet, J = 7.5 Hz, 1H), 5.41 (dd, J = 11.9, 7.5 Hz, 1H ), 7.49 (d, J = 8.7 Hz, 1H), 7.75 (s, 1H), 7.81 (s, 2H), 8.39 (d, J = 8.6 Hz, 1H). MS (ES +): 670 (M + H). and (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl) -amino] isopropyl ester -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid (132 mg, 19%). XH NMR (CDC13, 300 MHz): d 0.84 (t, J = 7.4 Hz, 3H), 1.30 (d, J = 6.3 Hz, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.51-1.68 ( m, 1H), 1.76-2.03 (m, 2H), 2.21 (t, J = 6.5 Hz, 1H), 2.57-2.65 (m, 1H), 4.01-4.06 (m, 2H), 4.39-4.61 (m, 4H), 4.98-5.13 (m, 2H), 5.39 (dd, J = 12.7, 4.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.90 (s, 2H) ), 7.99 (d, J = 8.5 Hz, 1H). MS (ES +): 670) (M + H).
Example 17 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl) -amino] - isopropyl ester 2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H- isopropyl ester tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (Example 16) in a Chiralpak AD
(4.6 x 250 mm), flow ratio 1 ml / min, solvents: propan-2-ol in 15% hexane, 0.2% dimethylethylamine, Rf =
6. 1 min, wavelength: 215.26 nm. EE > 97%. MS (ES +): 670
(M + H).
EXAMPLE 18 (2S, 4R) -4- [(3,5-Bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2l-tetrazol-5-yl) -amino] - isopropyl ester 2-ethyl-6-trifluoromethyl-3,4-dihydro-2iT- [1, 5] aftiridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H- isopropyl ester tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2fT- [1,5] naphthyridine-l-carboxylic acid (Example 16) in a Chiralpak AD
(4.6 x 250mm), flow ratio 1 ml / min, solvents: propan-2-ol in 15% hexane, 0.2% dimethylethylamine, Rf = 9.3 min, wavelength: 215.26 nm. EE > 97%. MS (ES +): 670
(M + H).
Example 19 (+/-) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2i-tetrazol-5-yl] -amino] -2-ethyl-6 isopropyl ester -trifluoromethyl-3, 4-dihydro-2? - [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl-amino) -2-ethyl-6-isopropyl ester bromo-3, 4-dihydro-2íT- [1, 5] naftiridin-l-carboxylic acid
The title compound was prepared essentially following the procedures described in Example 8
(Stages 1-2), replacing isopropyl acid ester
(+/-) -cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic ester isopropyl (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-bromo-3,4-dihydro-2i? - [1,5] naphthyridin-1 carboxylic acid in Example 8, Step 1. MS (ES +): 638, 640 (M + H).
Preparation 2: Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl-amino) -2-ethyl-6-isopropyl ester methyl-3, 4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedure described in Example 7, replacing (+/-) - cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2 isopropyl ester. -ethyl-6-bromo-3,4-dihydro-2- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [(3,5-bis-trifluoromethyl) isopropyl ester) benzyl) - (2H-tetrazol-5-yl-amino) -2-ethyl-6-bromo-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid. MS (ES +): 573 (M + H).
Step 3: Preparation of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2H-tetrazol-5-yl] -amino] -2 isopropyl ester -ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedure described in Example 8, Step 3, replacing (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-) isopropyl ester. tetrazol-5-yl) -amino] -2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4 isopropyl ester - [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl-amino) -2-ethyl-6-methyl-3,4-dihydro-2.ff- [1,5] naphthyridine -1-carboxylic acid. ""? NMR (CDC13, 300 MHz): d 0.79 (t, J = 7.3 Hz, 3H), 1.27 (d, J = 6.2 Hz, 3H), 1.32 (d, J = 6.2 Hz, 3H), 1.41-1.56 (m , 1H), 1.71-1.82 (m, 1H), 1.87-1.99 (m, 1H), 2.36-2.44 (m, 4 H), 4.15 (s, 3 H), 4.23-4.39 (m, 1H), 4.65 (d, J = 16.5 Hz, 1H), 4.97 (d, J = 16.5 Hz, 1H), 4.99-5.09 (m, 1 H), 5.27 (dd, J = 12.7, 3.6 Hz, 1H), 7.12 (d , J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.93 (s, 2H). MS (ES +): 586 (M + H).
EXAMPLE 20 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2-yl-tetrazol-5-yl] -amino] -2-ethyl- isopropyl isopropyl ester 6-trifluoromethyl-3,4-dihydro-2ii- [1, 5] naphthyridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2-fluoro-tetrazol-5-yl] isopropyl ester) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2-yl- [1,5] -naphthyridine-1-carboxylic acid (Example 19, Step 3) in a Chiralpak AD (4.6 x 250 mm), ratio flow rate 1 ml / min, solvents: 0.05% hexane-trifluoroacetic acid / ethanol. 5% ethanol in isocratic form, Rf = 4.7 min, wavelength: 215.26 nm. EE > 97%. MS (ES +): 586 (M + H).
EXAMPLE 21 (2S, 4i?) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2i? -tetrazol-5-yl] -amino] -2- isopropyl acetate ester trifluoroacetate ethyl-6-trifluoromethyl-3,4-dihydro-2ii- [1,5] naphthyridine-1-carboxylic acid
The title compound was obtained by chiral resolution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2H-tetrazol-5-yl] isopropyl ester) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] -naphthyridine-1-carboxylic acid (Example 19, Step 3) in a Chiralpak AD (4.6 x 250 mm), flow ratio 1 ml / min, solvents: 0.05% hexane-trifluoroacetic acid / ethanol. 5% Ethanol isocratic form, Rf = 5.3 min, wavelength: 215.26 nm. EE > 97%. MS (ES +): 586 (M + H).
Example 22 (+/-) -cis-4- [[2- (2-Amino-ethyl) 2-t-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] isopropyl ester -2- ethyl-6-methyl-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid
Step 1. Preparation of isopropyl ester of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-tert-butoxycarbonylamino-ethyl) -2i] -tetrazole- 5-yl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedures described in Example 12, replacing (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2i? -tetrazole-) isopropyl ester. 5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid ester with isopropyl (+/-) -cis-4- [ (3, 5-bis-trifluoromethyl-benzyl) - (2-HT-tetrazol-5-yl-amino) -2-ethyl-6-methyl-3,4-dihydro-2i? - [1,5] naphthyridin-l- carboxylic MS (ES +): 715 (M + H).
Step 2. Preparation of (+/-) -cis-4- [[2- (2-amino-ethyl) -2 # -tetrazol-5-yl] - (3,5-bis-trifluoromethyl) isopropyl ester benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedures described in Example 13, replacing (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2- (2- (2- ter-J-butoxycarbonylamino-ethyl) -2i? -tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridine-l-carboxylic ester with isopropyl ester of the acid (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-tert-butoxycarbonylamino-ethyl) -2i? -tetrazol-5-yl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid. MS (ES +): 615 (M + H).
Example 23 (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -227-tetrazol-5-yl) amino] isopropyl ester -2-Ethyl-6-methyl-3,4-dihydro-2-yl- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedures described in Example 16, by replacing (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-tetrazole-) isopropyl ester. 5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid with (+/-) -cis-4- isopropyl ester [(3,5-bis-trifluoromethyl-benzyl) - (2-phenyl-tetrazol-5-yl-amino) -2-ethyl-6-methyl-3, 4-dihydro-2-yl "- [1,5] naphthyridin-1 carboxyl, MS (ES +): 616 (M + H).
Example 24 (+/-) - Cis-6-amino-4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2E-tetrazol-5-yl] -amino] - isopropyl ester 2- ethyl-7-methyl-3,4-dihydro-2-fi- [1,5] naphthyridine-1-carboxylic acid
Step 1. Preparation of benzyl- (3-methyl-5-nitro-pyridin-2-yl) -amine
A mixture of 2-chloro-3-methyl-5-nitropyridine (3.0 g, 17.39 mmol), benzylamine (2.85 mL, 26.08 mmol), palladium (II) acetate (195 mg, 0.869 mmol) was heated at 100 ° C. , 2,2'-bis (diphenylphosphino) -l, 1-binaphthyl (BINAP) (812 mg, 1.30 mmol) and sodium tert -butoxide (2.58 g, 26.08 mmol) in dry toluene (15 ml) under one atmosphere of nitrogen for 15 hours. It was cooled to room temperature, water was added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel, levigating with hexanes / ethyl acetate, to give the title compound (2.12 g, 50%). MS (ES-): 242 (M-H).
Stage 2 . Preparation of benzyl-3-methyl-pyridin-2, 5-diamine
A mixture of benzyl- (3-methyl-5-nitro-pyridin-2-yl) -amine (2.1 g, 8.63 mmol), ammonium formate (2.17 g, 34.52 mmol) and palladium on carbon was heated at 90 ° C. 10% (0.2 g) in ethanol (30 ml) for 3 hours. It leaked through
Celite® and the solvent was evaporated in vacuo. The residue was purified using an SCX cartridge to provide the title compound (652 mg, 35%). MS (ES +): 214 (M + H).
Step 3. Preparation of (+/-) -cis- (6-benzylamino-2-ethyl-7-methyl-1, 2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide
The title compound was prepared, essentially following the procedures described in Example 3, Step 1, replacing 6-methoxy-pyridin-3-yl-amine with benzyl-3-methyl-pyridine-2,5-diamine. MS (ES +): 339 (M + H).
Step 4. Preparation of (+/-) - cis-4-acetylamino-6-benzylamino-2-ethyl-7-methyl-3, 4-dihydro-2ii- [1,5] naphthyridin-1 isopropyl ester carboxylic
The title compound was prepared, essentially following the procedures described in Example 3, Step 2, by replacing (+/-) -cis- (2-ethyl-6-methoxy-1,2,3,4-tetrahydro- [1] , 5] naphthyridin-4-yl) acetamide with (+/-) - cis- (6-benzylamino-2-ethyl-7-methyl-1,2,3,4-tetrahydro- [1,5] naphthyridin-4) -yl) acetamide. MS (ES +): 425 (M + H).
Step 5. Preparation of (+/-) - cis-4-Amino-6-benzylamino-2-ethyl-7-methyl-3, 4-dihydro-2i? - [1,5] naphthyridinyl isopropyl ester -carboxylic
The title compound was prepared, essentially by following the procedures described in Example 3, Step 3, by replacing (+/-) - cis-4-acetylamino-2-ethyl-6-methoxy-3, 4-isopropyl ester. dihydro-2i? - [1, 5] naphthyridine-1-carboxylic acid (+/-) -cis-4-acetylamino-6-benzylamino-2-ethyl-7-methyl-3, 4-dihydro- isopropyl ester 2E- [1, 5] naphthyridine-1-carboxylic acid. MS (ES +): 383 (M + H).
Step 6. Preparation of (+/-) -cis-6-benzylamino-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-7-methyl-3,4-dihydro-2i isopropyl ester ? - [1, 5] naphthyridine-l-carboxylic acid
The title compound was prepared, essentially following the procedure described in Example 3, Step 4, replacing (+/-) - cis-4-amino-2-ethyl-6-methoxy-3,4-dihydro isopropyl ester. -2i? - [1, 5] -naphyridine-1-carboxylic acid ester with (+/-) -cis-4-amino-6-benzylamino-2-ethyl-7-methyl-3,4-dihydro- isopropyl ester 2iT- [1, 5] naphthyridine-1-carboxylic acid. MS (ES +): 609 (M + H).
Step 7. Preparation of (+/-) - cis-6-benzylamino-4- [(3,5-bis-trifluoromethyl-benzyl) -ciano-amino] -2-ethyl-7-methyl-3-isopropyl ester , 4-dihydro-2íf- [1, 5] naftiridin-l-carboxylic acid
The title compound was prepared, essentially by following the procedure described in Example 8, Step 1, by replacing (+/-) - cis-4- [(3,5-bis-trif luoromethyl-benzyl) -amino isopropyl ester. ] -2-ethyl-6-methoxy-3,4-dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid ester (+/-) - cis-6-benzylamino-4- (3, 5-bis-trif luoromethyl-benzylamino) -2-ethyl-7-methyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid. MS (ES +): 634 (M + H).
Step 8. Preparation of (+/-) - cis and trans-6-Benzylamino-4- [(3,5-bis-trif-loromethyl-benzyl) - (2-methyl-2i-tetrazol-5) isopropyl ester -yl) -amino] -2-ethyl-7-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
A mixture of (+/-) - cis-6-benzylamino-4- [(3,5-bis-trifluoromethyl-benzyl) -ciano-amino] -2-ethyl-7 isopropyl ester was heated at 110 ° C. -methyl-3, 4-dihydro-2i? - [1,5] naphthyridine-l-carboxylic acid (110 mg, 0.174 mmol), sodium azide (16 mg, 0.244 mmol) and triethyl amine hydrochloride (33 mg, 0.244) mmol) in dry toluene under a nitrogen atmosphere for 15 hours. Then more sodium azide was added
(10 mg) and triethyl amine chloride (25 mg) and the mixture was heated for 20 hours. It was cooled to room temperature, diluted with ethyl acetate and washed with 1N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate. The residue was dissolved in dry dichloromethane (1 mL), added triphenylphosphine (38 mg, 0.146 mmol), methanol (22 mg, 0.66 mmol) followed by diisopropylazodiarboxylate (0.046 mL, 0.104 mmol) and the mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel, levigating with ethyl acetate / hexanes to give (+/-) - trans-4- [(3,5-bis-trifluoromethyl) isopropyl ester -benzyl) -2-methyl-2ff-tetrazol-5-yl) -amino] -2-ethyl-6-benzylamino-7-methyl-3,4-dihydro-2i? - [1, 5] naphthyridin-l- carboxylic acid [15 mg, 16%, MS (ES +): 691 (M + H)] and isopropyl ester of (+/-) -cis-4- [(3,5-bistrifluoromethyl-benzyl) -2- methyl-2fT-tetrazol-5-yl) -amino] -2- ethyl-6-benzylamino-7-methyl-3, 4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid [20 mg, 22 %, MS (ES +): 691 (M + H)].
Step 9. Preparation of (+/-) -cis-6-amino-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2i-tetrazol-5-yl) isopropyl ester) -amino] -2-ethyl-7-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid.
A mixture of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2.ff-tetrazol-5-yl) - isopropyl ester is stirred at room temperature. amino] -2-ethyl-6-benzylamino-7-methyl-3, -dihydro-2f- [1, 5] naphthyridine-1-carboxylic acid (20 mg, 0.029 mmol) and 10% palladium on carbon (2 mg) in methanol (1 ml) under a hydrogen atmosphere for 20 hours. Filtered through Celite®, the solvent was evaporated in vacuo, and the residue was purified using a silica gel cartridge, levigating with hexanes / ethyl acetate 1: 1 to give the title compound (8 mg, 44% ). - "" H NMR (CDC13, 300 MHz): d 0.79 (t, J = 7.3 Hz, 3H), 1.26 (d, J = 6.2 Hz, 3H), 1.30 (d, J = 6.2 Hz, 3H), 1.41 -1.50 (, 1H), 1.61-1.72 (m, 2H), 2.09 (s, 3H), 2.42-2.51 (m, 1H), 4.13 (s, 3 H), 4.32-4.39 (m, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.95-5.04 (m, 2 H), 5.28 (dd, J = 12.1, 4.4 Hz, 1H), 7.41 (s, 1H), 7.74 (s, 1H), 7.91 (s, 2H). MS (ES +): 601 (M + H).
Example 25 (+/-) Trans-6-amino-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2-fluoro-tetrazol-5-yl) -amino] - isopropyl ester 2- ethyl-7-methyl-3,4-dihydro-2iJ- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedure described in Example 24, Step 9, replacing isopropyl ester (+/-) - cis 4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl- 2l-tetrazol-5-yl) -amino] -2-ethyl-6-benzylamino-7-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid with isopropyl ester (+ / -) -trans 4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2i'-tetrazol-5-yl) -amino] -2-ethyl-6-benzylamino-7-methyl-3, 4 -dihydro-2i? - [1, 5] naphthyridine-l-carboxylic acid. XH NMR (CDC13, 300 MHz): d 0.90 (t, J = 7.3 Hz, 3H), 1.28 (d, J = 6.2 Hz, 3H), 1.31 (d, J = 6.2 Hz, 3H), 1.51-1.60 ( m, 2H), 2.05 (s, 3H), 2.07-2.16 (m, 1H), 2.27-2.34 (m, 1 H), 4.14 (s, 3 H), 4.31-4.57 (m, 3 H), 5.03 (septuplet, J = 6.2 Hz, 1H), 5.40 (dd, J = 10.6, 7.7 Hz, 1H), 7.60 (bs, 1H), 7.67 (s, 1H), 7.82 (s, 2H). MS (ES +): 601 (M + H).
Example 26 (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2i-tetrazol-5-yl) -amino] -2- ethyl isopropyl ester -6-methoxy-7-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
Step 1. Preparation of 2-methoxy-3-methyl-5-nitro-pyridine
% sodium methoxide in methanol (3.26 ml, 17.4 mmol) was added to a solution of 2-chloro-3-methyl-5-nitro-pyridine (1.0 g, 5.8 mmol) in methanol (5 ml) and the mixture it was heated at 100 ° C under a nitrogen atmosphere for 6 hours. The solvent was removed under reduced pressure, the residue was suspended in water, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to provide the title compound (859 mg, 88%). %). - "NMR (CDC13, 300 MHz): d 2.26 (s, 3H), 4.07 (s, 3H), 8.17 (d, J = 2.8 Hz, 1H), 8.92 (d, J = 2.4 Hz, 1H).
Step 2. Preparation of 2-methoxy-3-methyl-pyridine-3-ylamino
The title compound was prepared, essentially following the procedure described in Example 24, Step
2, replacing benzyl- (3-methyl-5-nitro-pyridin-2-yl) -amine with 2-methoxy-3-methyl-5-nitro-pyridine, heating the mixture for 1 hour. MS (ES +): 139 (M + H).
Step 3. Preparation of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-methoxy-7-methyl-3,4-dihydro-2H isopropyl ester - [1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedures described in Example 3, Steps 1-4, by replacing 6-methoxy-pyridin-3-ylamino with 2-methoxy-3-methyl-pyridin-3-ylamine in Example 3 , Step 1. MS (ES +): 534 (M + H).
Step 4. Preparation of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2 isopropyl ester -ethyl-6-methoxy-7-methyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
The title compound was prepared, essentially following the procedures described in Example 8, Steps 1-3, by replacing (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2 isopropyl ester. -ethyl-6-methoxy-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid ester (+/-) -cis-4- (3,5-bis-trifluoromethyl) isopropyl ester benzylamino) -2-ethyl-6-methoxy-7-methyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid in Example 8, Step 1. MS (ES +): 616 (M + H).
Example 27 (2R, S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-ethyl ester trifluoromethyl-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (2R, 4S) - (3,5-bis-trifluoromethyl-benzyl) - (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro- [1,5] naphthyridin-4) -yl) - (2-methyl-2H-tetrazol-5-yl) -amine
98% sulfuric acid (7 ml) was added to a solution of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole-5) isopropyl ester. -yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (Example 11) (3.30 g, 5.60 mmol) in trifluoroacetic acid (88 ml) ). The mixture was stirred at room temperature overnight. The residue was concentrated and dissolved in dichloromethane. It was washed with saturated NaHCO 3 and brine. The organic layers were dried over Na 2 SO, filtered, and concentrated to give the title compound (2.88 g, 100%). MS (ES +): 554 (M + H).
Step 2. Preparation of (2R, S) -4- [(3, 5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6 chloride -trifluoromethyl-3, 4-dihydro-2H- [1, 5] naphthyridin-1-carbonyl
Trichloromethyl chloroformate (0.36 ml, 3.02 mmol) was added to a solution of (2R, S) - (3,5-bis-trifluoromethyl-benzyl) - (2-ethyl-6-trifluoromethyl-1,3,3,4). -tetrahydro- [1, 5] naphthyridin-4-yl) - (2-methyl-2H-tetrazol-5-yl) -amine (1.67 g, 3.02 mmol) and triethylamine (0.84 mL, 6.04 mmol) in toluene
(19 mi) The mixture was stirred at room temperature under nitrogen for 3 hours, then more triethylamine was added.
(0.50 mL, 3.6 mmol) and trichloromethyl chloroformate (0.21 mL, 1.8 mmol). The mixture was stirred overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (levigation with hexane / ethyl acetate) to give the title compound (1.83 g, 99%). MS (ES +): 616 (M + H).
Step 3. Preparation of ethyl ester of acid
(22? 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4 -dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
Triethylamine (25 μl) and 4-dimethylaminopyridine (10 mg, 80 μmol) were added to a solution of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-) chloride. 2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] aftiridin-1-carbonyl (100 mg, 0.16 mmol) and ethanol (28 μl ) in dichloromethane (0.9 ml). The mixture was stirred at room temperature for 8 hours. The solvent was evaporated and the crude material was purified by chromatography on silica gel (levigation with hexane / ethyl acetate) to give the title compound (51 mg, 51%) MS (ES +): 626 (M + H).
Example 28 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] 2-dimethylaminoethyl ester] -2- ethyl-6- trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with 2-dimethylaminoethanol in Example 27, Step 3. MS (ES +): 669 (M + H).
EXAMPLE 29 Tetrahydropyran-4-yl ester of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] - 2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with tetrahydro-pyran-4-ol in Example 27, Step 3. MS (ES +): 682 (M + H).
EXAMPLE 30 L-Methyl-piperidin-4-yl ester of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino acid ] -2- Ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with l-methyl-piperidin-4-ol in Example 27, Step 3. MS (ES +): 695 (M + H) .
EXAMPLE 31 Tetrahydrofuran-3-yl ester of (2R, 3 'R, S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] - 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] aftiridin-1-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with 3R-tetrahydro-furan-3-ol in Example 27, Step 3. MS (ES +): 668 (M + H) .
Example 32 Tetrahydrofuran-3-yl ester of (2R, 3 'S, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] - 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with 3S-tetrahydro-furan-3-ol in Example 27, Step 3. MS (ES +): 668 (M + H) .
EXAMPLE 33 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino acid 2-morpholin-4-yl-ethyl ester ] -2- Ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedure as described in Example 27 by replacing ethanol with 2-morpholin-4-yl-ethanol in Example 27, Step 3. MS (ES +): 711 (M + H).
EXAMPLE 34 (2R, 4S) 4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole-5-methyl) 2- (4-methyl-piperazin-1-yl) -ethyl ester. - il) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
The title compound was prepared, essentially following the procedure as described in Example 27 by replacing ethanol with 2- (4-methyl-piperazin-1-yl) -ethanol in Example 27, Step 3. MS (ES +): 724 (M + H).
Example 35 2-Methoxycarbonyl-2-methyl-propyl ester of (2R, S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino) ] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with 3-hydroxy-2,2-dimethyl-propionic acid methyl ester in Example 27, Step 3. MS (ES +): 712 (M + H).
EXAMPLE 36 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino acid 2-carboxy-2-methyl-propyl ester ] -2-ethyl-6- trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
2.5 M LiOH (1.9 ml, 4.8 mmol) was added to a solution of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) 2-methoxycarbonyl-2-methyl-propyl ester ( 2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid (74 mg, 0.10 mmol) in THF (1.9 mi). The mixture was stirred at room temperature for 72 hours. It was acidified with 1M HCl. The aqueous phase was extracted with dichloromethane. The organic layers were dried over Na 2 SO, filtered and concentrated. The residue was purified using silica gel chromatography (levigating with hexane / ethyl acetate) to give the title compound (14 mg, 20%). MS (ES +): 698 (M + H).
EXAMPLE 37 (2R, 4S) -4- [(3,5-bistrifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] 2-cyano-ethyl ester 2-cyano-ethyl] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially by following the procedure as described in Example 27, replacing ethanol with 3-hydroxy-propionitrile in Example 27, Step 3. MS (ES +): 651 (M + H):
EXAMPLE 38 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole-5- (2- (2H-tetrazol-5-yl) -ethyl ester) il) -amino] - 2-ethyl-6-trifluoromethyl-3, -dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
Sodium azide (16 mg, 0.24 mmol) and triethylamine hydrochloride (33 mg, 0.24 mmol) were added to a solution of (2R, 4S) -4- [(3,5-bis) 2-cyano-ethyl ester. -trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid ( 77 mg, 0.12 mmol) in toluene (2.4 ml). The mixture was stirred at 80 ° C for 1.5 hours and at 100 ° C overnight. Additional sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) were added and the mixture was stirred for 8 hours at 100 ° C. Additional sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) were added and the mixture was stirred for 6 hours at 100 ° C. It was cooled to room temperature. 1M HCl was added and the aqueous phase was extracted with dichloromethane. The organic layers were washed with water and brine, then dried over Na 2 SO, filtered and concentrated. The crude material was purified by chromatography on silica gel (levigating with dichloromethane / methanol) to give the title compound (55 mg, 66%). MS (ES +): 694 (M + H).
Example 39 (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] 2-benzyloxyethyl ester 2 - ethyl-6-trifluoromethyl-3, -dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared essentially following the procedure as described in Example 27, replacing ethanol with 2-benzyloxy-ethanol in Example 27, Step 3. MS (ES +): 732 (M + H).
EXAMPLE 40 (2R, AS) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] 2-hydroxy-ethyl ester 2-hydroxy-ethyl] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
A mixture of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] 2-benzyloxyethyl ester was stirred. -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (69 mg, 94 μmol) and
% Pd / C (7 mg) in MeOH (1 mL) under a hydrogen atmosphere for 1 hour. The mixture was filtered on a pad of Celite®. The solids were washed with dichloromethane. The filtrate was concentrated and purified by chromatography on silica gel (levigation with hexane / ethyl acetate) to give the title compound (45 mg, 75%). MS (ES +): 642 (M + H).
Example 41 (+/-) - cis-4- [(3,5-trifluoromethylbenzyl) - (5-methyl-1-pyrazol-3-yl) amino] -2-ethyl-6-trifluoromethyl-3 isopropyl ester , 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (3-oxo-butyryl) -amino] -2-ethyl-6-trifluoromethyl isopropyl ester -3,4-dihydro-2H- [1, 5] naftiridin-l-carboxylic acid
A solution of diketene (0.539 mL, 6.99 mmol) in dry THF (3.7 mL) was added to a solution of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) - isopropyl ester. 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid (from Example 4) (1.95 g, 3.49 mmol) and dimethylaminopyridine (55 mg, 0.45 mmol) in dry THF
(12.5 ml) at 0 ° C under nitrogen atmosphere. The mixture was stirred at 0 ° C for 5 minutes and 4 hours at room temperature. The solvents were then removed under reduced pressure and the residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (1.97 g, 85%): MS (ES +): 642 (M + H) .
Step 2. Preparation of (+/-) - cis-4- [(3,5-bistrifluoromethylbenzyl) - (5-methyl-li? -pyrazol-3-yl) amino] -2-ethyl-6 isopropyl ester -trifluoromethyl-3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
Cold absolute EtOH (ice bath) (1.7 ml) was slowly added to a stirred mixture at 0 ° C quenched with (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) isopropyl ester. ) - (3-oxo-butyryl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (221 mg, 0.34 mmol) and phosphorous pentoxide ( 880 mg, 6.2 mmol). Hydrazine hydrate (0.105 ml) was added, 3.4 mmol) while kept cooled to 0 ° C. The tube was sealed and the reaction mixture was heated at 100 ° C overnight. The mixture was cooled and the solvents were removed under reduced pressure. The residue was partitioned between water and dichloromethane. The layers were separated and the organic phase was dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, levigating with hexanes / ethyl acetate, to give the title compound (82 mg, 38%). MS (ES +): 638 (M + H).
Example 42 (+/-) -cis-4- [(3,5-bistrifluoromethylbenzyl) - (3-methyl-isoxazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl- isopropyl ester 3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid
To a solution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (3-oxo-butyryl) -amino] -2-ethyl-6-trifluoromethyl- isopropyl ester 3,4-dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid (225 mg, 0.35 mmol) in MeOH (1.7 mL) at 0 ° C, hydroxylamine hydrochloride (37 mg, 0.53 mmol) and acetate were added. of sodium (1.4 mg, 0.017 mmol). The reaction mixture was stirred at reflux overnight. The mixture was cooled and the solvents were removed under reduced pressure. The residue was diluted with ethyl acetate and brine. The layers were separated, and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (12 mg, 5%). MS (ES +): 639 (M + H).
Example 43 (+/-) -cis-4- [(3,5-bistrifluoromethyl-benzyl) - (5-methyl- [1,2,4] oxadiazol-3-yl) -amino] -iso isopropyl ester -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) - cis-4- [N- (3,5-bis-trifluoromethyl-benzyl) -hydroxyguanidino] -2-ethyl-6-trifluoromethyl-3,4-dihydro isopropyl ester -2H- [1, 5] naphthyridine-1-carboxylic acid
To a solution of 4- [(3,5-bis-trifluoromethyl-benzyl) -ciano-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine isopropyl ester -1-carboxylic acid (from Example 9) (250 mg, 0.429 mmol) in EtOH (2.6 mL), hydroxylamine hydrochloride (75 mg, 1.07 mmol) and triethylamine (0.150 mL, 1.07 mmol) were added at room temperature. The reaction mixture was stirred at 80 ° C overnight. The mixture was cooled and the solvents were removed under reduced pressure. The residue was diluted with ethyl acetate and brine was added. The layers were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (84 mg, 32%). MS (ES +): 616 (M + H).
Step 2. Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (5-methyl- [1,2,4] oxadiazol-3-yl) isopropyl ester -amino] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
To isopropyl ester of (+/-) - cis-4- [N- (3,5-bis-trifluoromethyl-benzyl) -hydroxyguanidino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [ 1, 5] naphthyridine-1-carboxylic acid (80 mg, 0.13 mmol), acetic anhydride (0.5 ml) was added. The tube was sealed and the reaction mixture was heated at 80 ° C overnight. The mixture was cooled and the solvents were removed under reduced pressure. 2N NaOH (2 mL) and ether were added to the crude material. The layers were separated, and the aqueous phase was extracted with ether. The combined organic phase was dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (32 mg,%). MS (ES +): 640 (M + H).
Example 44 (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2,5-dimethyl-2H-pyrazole-3-carbonyl) -amino] isopropyl ester] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid
A solution of 1,3-dimethyl-lH-pyrazole-5-carbonyl chloride (50 mg, 0.31 mmol) in dry dichloromethane (0.5 ml) was added to a solution of 4- (3,5-bis) isopropyl ester. -trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid
(159 mg, 0.28 mmol) in dry dichloromethane (2 ml) and pyridine
(0.045 mL, 0.56 mmol) at 0 ° C. The mixture was stirred at room temperature for 3 hours. A solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (57 mg, 0.36 mmol) in dry dichloromethane (0.5 ml) was added and the mixture was stirred overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel, levigating with hexanes / ethyl acetate, to give the title compound (106 mg, 56%). MS (ES +): 680 (M + H)
Example 45 (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzyl) -1- (cyclopentylmethyl-2-ethyl-6-methoxy-1,2,3-tetrahydro- [1,5 ] naphthyridin-4-yl) -acetamide
Step 1. Preparation of (+/-) - cis-l- (cyclopentylmethyl-2-ethyl-6-methoxy-l, 2,3,4-tetrahydro- [1,5] naphthyridin-4-yl) -acetamide
Triacetoxyborohydride (591 mg, 2.64 mmol) was added to a mixture of (+/-) -cis- (2-ethyl-6-methoxy-1,2,3,4-tetrahydro- [1,5] naphthyridin-4- il) acetamide (Example 3, Step 1) (300 mg, 1.20 mmol), cyclopentanecarboxaldehyde (145 mg, 1.44 mmol) and acetic acid (0.086 mL, 1.44 mmol) in dichloroethane (7 mL) under a nitrogen atmosphere and the mixture it was stirred for 5 hours at room temperature. A saturated solution of ammonium chloride was added, the layers were separated over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified using flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (281 mg, 71%). MS (ES +): 332 (M + 1).
Step 2. Preparation of (+/-) - cis-l-cyclopentylmethyl-2-ethyl-6-methoxy-l, 2,3,4-tetrahydro- [1,5] naphthyridin-4-ylamine
The title compound was prepared, essentially by following the procedure described in Example 3, Step 3, by replacing (+/-) - cis-4-acetylamino-2-ethyl-6-methoxy-3-dihydro-isopropyl ester. 2i? - [1, 5] naphthyridine-1-carboxylic acid with (+/-) -cis-1- (cyclopentylmethyl-2-ethyl-6-methoxy-1,2,3-tetrahydro- [1,5] naphthyridine -4-yl) -acetamide. MS (ES +): 273 (M-NH2).
Stage 3 Preparation of (+/-) -cis-4- (3,5-bis-trif-loromethyl-benzyl) -1- (cyclopentylmethyl-2-ethyl-6-methoxy-1, 2, 3, 4-tetrahydro- [1 , 5] aftiridin-4-yl) -amine
The title compound was prepared essentially following the procedure described in Example 3, Step 4, replacing (+/-) - cis-4-amino-2-ethyl-6-methoxy-3,4-dihydro-isopropyl ester. 2H- [1,5] naphthyridine-1-carboxylic acid with (+/-) -cis-l-cyclopentylmethyl-2-ethyl-6-methoxy-l, 2,3,4-tetrahydro- [1,5] naphthyridin- 4-ilamine. MS (ES +): 273 (M-NHAr).
Step 4. Preparation of (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzyl) -1- (cyclopentylmethyl-2-ethyl-6-methoxy-1,2,3,4-tetrahydro- [1,5] naphthyridin-4-yl) -acetamide
The title compound was prepared, essentially following the procedure described in Example 3, Step 5, by replacing (+/-) - cis-4- (3, 5-bis-trifluoromethyl-benzylamine) -isopropyl ester. ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid with (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzyl) -1- ( Cyclopentylmethyl-2-ethyl-6-methoxy-1,2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) -amine. MS (ES +): 558 (M + H).
Example 46 (+/-) -cis-4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -6-methoxy-2-methyl-3, 4-dihydro-2H- isopropyl ester [1, 5] naphthyridine-l-carboxylic acid
Step 1. Preparation of (+/-) -cis-W- (6-Methoxy-2-methyl-1,2,3,4-tetrahydro- [1,5] naphthyridin-4-yl) acetamide
6-methoxy-pyridin-3-ylamine (1.24 g,
. 05 mmol) in anhydrous dichloromethane (20 ml), sodium sulfate (1.0 g) was added and the reaction mixture was cooled to -20 ° C. Acetaldehyde (0.560 ml, 10.05 mmol) was added and the mixture was stirred at -20 ° C to 0 ° C for 0.5 hour. Sodium sulfate was filtered and N-vinyl acetamide (0.851 g, 10.05 mmol) was added to the filtrate at -20 ° C followed by diethyl trifluoride boron etherate (0.126 ml, 1.0 mmol). The reaction mixture was stirred at -20 to -10 ° C for 6 hours. The solvent was removed under reduced pressure and purified using silica gel column chromatography (levigating gradient, 0.5% MeOH in methyl acetate) to give the title compound (1.09 g, 47%). MS (ES +): 236 (M + H).
Step 2. Preparation of (+/-) - cis-4-acetylamino-6-methoxy-2-methyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid isopropyl ester
Isopropyl chloroformate (8.50 ml,
8. 50 mmol) to a solution of (+/-) -cis-W- (6-methoxy-2-methyl-1,2,3, -tetrahydro- [1, 5] naphthyridin-4-yl) acetamide (0.404 g ,
1. 702 mmol), pyridine (1370 ml, 17.02 mmol) in dichloromethane (10 ml) at 0 ° C and warmed slowly to room temperature.
After 12 hours, the solvent was removed under reduced pressure. The crude material was purified using chromatography on silica gel, levigating with ethyl acetate (neat), to give the title compound (0.496 g, 91%). MS (ES +): 322 (M + H).
Step 3. Preparation of (+/-) -cis-4-amino-6-methoxy-2-methyl-3, 4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid isopropyl ester
A solution of (+/-) - cis-4-acetylamino-6-methoxy-2-methyl-3,4-dihydro-2fJ- [1,5] naphthyridin-1-isopropyl ester was heated at 80 ° C. carboxylic (405 mg,
1. 261 mmol) in 5 N HCl (3 mL) for 3 hours. The reaction mixture was cooled to room temperature, poured into a sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to provide the title compound.
(0.315 g, 89%). MS (ES +): 280 (M + H).
Step 4. Preparation of isopropyl ester of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -6-methoxy-2-methyl-3,4-dihydro-2iT- [1, 5] naphthyridine-1-carboxylic acid
Sodium triacetoxyborohydride (1160 g, 5.50 mmol) was added to a mixture of 3,5-bis (trifluoromethyl) benzaldehyde (0.217 mL, 1.32 mmol), acetic acid (0.010 mL, 1.65 mmol) and isopropyl ester of the acid (+ / -) -cis-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid (0.318 mg, 1.12 mmol) in dichloroethane (10 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. A solution of sodium bicarbonate was added, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate
(levigating gradient, 0-60% ethyl acetate in hexane), to provide the title compound (0.462 g, 83%). MS (ES +): 506 (M + H).
Step 5. Preparation of (+/-) - cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -6-methoxy-2-methyl-3, 4-dihydro isopropyl ester -2H- [1, 5] naphthyridine-1-carboxylic acid
. A suspension of isopropyl ester of the acid was cooled to 0 ° C. { +/-) -cis-4- (3,5-bis-trifluoromethyl-benzylamino) -6-methoxy-2-methyl-3, -dihydro-227- [1,5] naphthyridine-1-carboxylic acid (0.210 g, 0.415 mmol) and pyridine (0.203 mL, 2.52 mmol) in dichloromethane (3 mL) under nitrogen. 5 Acetic anhydride (0.117 ml, 1.247 mmol) was added dropwise. After the addition was complete, the cooling bath was removed and the reaction was warmed to room temperature with stirring for 12 hours. The mixture was diluted with dichloromethane (25 ml) and washed with saturated aqueous sodium bicarbonate (25 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified using silica gel chromatography, levigating with hexanes / ethyl acetate (levigant gradient, 0-30% ethyl acetate in hexane), to give the title compound (0.196 g, 88%). MS (ES +): 548 (M + H).
EXAMPLE 47 (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6-methoxy-2-methyl-3, 4-dihydro-2-yl isopropyl ester [1, 5] naphthyridine-1-carboxylic acid
Ethyl chloroformate (0.118 mL, 1240 mmol) was added followed by pyridine (0.205 mL, 2.52 mmol), to a solution of (+/-) - cis-4- (3,5-bis-trifluoromethyl) isopropyl ester. benzylamino) -6-methoxy-2-methyl-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid (0.210 g, 0.415 mmol) in dichloromethane (3 mL). After stirring at room temperature for 12 hours, the solvent was removed in vacuo. Purified using silica gel chromatography, levigating with ethyl acetate / hexane (levigating gradient, 0-30% ethyl acetate in hexane) to give the title compound (0.218 g, 92%): MS (ES +): 578 (M + H).
Example 48 (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (3-fluoro-5-trifluoromethyl-benzoyl) -amino] -6-methoxy-2-isopropyl ester methyl-3, 4-dihydro-2fl- [1, 5] naftiridin-l-carboxylic acid
The title compound was prepared, essentially following the procedure described by the synthesis of Example 47, using (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -6-methoxy-isopropyl ester. 2-methyl-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid (0.210 g, 0.415 mmol), 3-fluoro-5-trifluoromethyl-benzoyl chloride (0.095 mL, 0.631 mmol) and pyridine (0.10) my). Purified using silica gel column chromatography (levigating gradient, ethyl acetate in hexane) to give the title compound (0.246 g, 68%). MS (ES +): 696 (M + H).
Example 49 (+/-) -cis-N- (3, 5-bis-trifluoromethyl-benzyl) -N- (1-cyclopentyl-6-methoxy-2-methyl-1, 2,3,4-tetrahydro- [ 1, 5] aftiridin-4-yl) - acetamide
Step 1. Preparation of (+/-) -cis-W- (1-cyclopentyl-6-methoxy-2-methyl-1, 2,3,4-tetrahydro- [1,5] naphthyridin-4-yl) - acetamide
The title compound was prepared, essentially following the procedure described in Example 45, Step 1, using (+/-) -cis-W- (6-methoxy-2-methyl-1,2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide (0.410 g, 1745 mmol), cyclopentane carboxaldehyde (0.833 ml, 8.51 mmol) and sodium triacetoxyborohydride (1.8 g, 8.5 mmol). Purified on silica gel column chromatography (levigating gradient, 0-100% ethyl acetate in hexane) to give the title compound (0.532 g, 98%). MS (ES +): 318 (M + H).
Step 2. Preparation of (+/-) - N- (3, 5-bis-trifluoromethyl-benzyl) -N- (1-cyclopentyl-6-methoxy-2-methyl-1,2,3, -tetrahydro- [ 1, 5] naphthyridin-4-yl) -acetamide
Lithium hexamethyldisilazide (0.220 mL, 0.22 mmol, 1.0 M in toluene) was added to a solution of (+/-) -N- (1-cyclopentyl-6-methoxy-2-methyl-1, 2, 3, 4 tetrahydro- [1, 5] naphthyridin-4-yl) -acetamide (0.065 g, 0.20 mmol) in THF
(1 ml) at -78 ° C and stirred for 20 minutes. The dark solution was treated with a solution of 3,5-bistrifluoromethylbenzylbromide (0.240 mmol, 0.040 ml) in THF (1 ml). The reaction mixture was stirred vigorously at -78 ° C for 1 hour and slowly warmed to room temperature for 12 hours. The reaction mixture was diluted with EtOAc (10 mL), and washed with water and brine. The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. Purified by flash column chromatography (levigating gradient, 0-50% ethyl acetate in hexane) to give the title compound (0.026 g, 27%). MS (ES +): 544 (M + H).
EXAMPLE 50 Synthesis of (+/-) - cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-isopropyl ester 2H- [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) -cis-N- (2-methyl-6-trifluoromethyl-1, 2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide
The title compound was prepared, essentially following the procedure described in Example 46, Step
1, using 6-trifluoromethyl-pyridin-3-ylamine (1.0 g, 6.168 mmol), acetaldehyde (0.380 mL, 6.780 mmol) and N-vinyl acetamide (0.520 g, 6.12 mmol). Purified using silica gel column chromatography (levigating gradient, 0-10% MeOH in ethyl acetate) to give the title compound (0.69 g, 43%). MS (ES +): 274 (M + H).
Step 2. Preparation of (+/-) - cis-4-acetylamino-2-methyl-6-trifluoromethyl-3, 4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid isopropyl ester
The title compound was prepared, essentially following the procedure described in Example 46, Step 2, by replacing (+/-) -cis-N- (6-methoxy-2-methyl-1, 2, 3, 4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide, with (+/-) -cis-W- (2-methyl-6-trifluoromethyl-l, 2,3,4-tetrahydro- [1,5] naphthyridin- 4-yl) acetamide (0.140 g, 0.512 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purified using silica gel column chromatography (levigating gradient, 0-5% MeOH in ethyl acetate) to give the title compound (0.123 g, 68%). MS (ES +): 360 (M + H).
Step 3: Preparation of (+/-) - cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro isopropyl ester -2ií- [1,5] naftiridin-1-carboxylic acid
The title compound was prepared, essentially following the procedure described in Example 49, Step 2, replacing (+/-) -N- (1-cyclopentyl-6-methoxy-2-methyl-1,2,3-tetrahydro) - [1, 5] naphthyridin-4-yl) -acetamide with cis-4-acetylamino-2-methyl-6-trifluoromethyl-3,4-dihydro-2-yl [1, 5] naphthyridin-1 isopropyl ester carboxylic
(0.065 g, 0.018 mmol), and using 3, 5-bis-trifluoromethyl benzylbromide and lithium hexamethyldisilazide. Purified using silica gel column chromatography (levigating gradient, pure ethyl acetate) to provide the title compound (0.031 g, 30%). MS (ES +): 586 (M + H).
Example 51 (+/-) -cis-4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-yl isopropyl ester [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) -cis-W- (2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide
The title compound was prepared, essentially following the procedure described in Example 46, Step 1, using 6-trifluoromethyl-pyridin-3-ylamine (1.0 g, 6,168 mmol), cyclopropanaldehyde (0.460 mL, 6,160 mmol) and N-vinyl acetamide (0.520 g, 6.12 mmol). Purification by column on silica gel (levigating gradient, 0-5% MeOH in ethyl acetate) provided the title compound (0.62 g, 29%). MS (ES +): 300 (M + H).
Step 2: Preparation of (+/-) - cis-4-acetylamino-2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2J? - [1,5] naphthyridine-1-carboxylic acid isopropyl ester
The title compound was prepared, essentially following the procedure described in Example 46, Step 2, replacing (+/-) -cis-N- (6-methoxy-2-methyl-1,2,3,4-tetrahydro- [1, 5] naphthyridin-4-yl) acetamide, with (+/-) - cis-N- (2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro- [1,5] naphthyridin- 4-yl) acetamide (1.05 g, 3.512 mmol), and using isopropyl chloroformate, pyridine and dimethylaminopyridine.
Purified using silica gel column chromatography
(levigating gradient, 0-5% MeOH in ethyl acetate) to provide the title compound (0.416 g, 31%). MS (ES +): 386 (M + H).
Step 3. Preparation of (+/-) - cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro isopropyl ester -2.fi- [1,5] aftiridine-1-carboxylic acid
The title compound was prepared, essentially following the procedure described in Example 49, Step 2, replacing (+/-) -N- (l-cyclopentyl-6-methoxy-2-methyl-1,2,3,4- tetrahydro- [1, 5] naphthyridin-4-yl) -acetamide, with isopropyl ester of (+/-) -cis-4-acetylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2i? [1,5] naphthyridine-1-carboxylic
(0.075 g, 0.019 mmol), and using 3, 5-bis-trifluoromethyl benzyl bromide and lithium hexamethyldisilazide. Purified by silica gel column chromatography (levigating gradient, pure ethyl acetate) to give the title compound (0.042 g, 35%). MS (ES +): 612 (M + H).
Example 52 (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2J-tetrazol-5-yl) -amino] -2- cyclopropyl- isopropyl ester 6-trifluoromethyl-3, 4-dihydro-2f- [1, 5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (+/-) - cis-4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-fluoro [1, 5] naphthyridine-l-carboxylic acid isopropyl ester
A solution of (+/-) - cis-4-acetylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridin-1-isopropyl ester was heated at 80 ° C. carboxylic
(0.281 g, 0.727 mmol) in 5 N HCl (3 mL) for 3 hours. The reaction mixture was cooled to room temperature, the crude product was poured into a saturated sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to provide the title compound (0.251 g, 99%). MS (ES +): 344 (M + H).
Step 2. Preparation of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-yl [1] isopropyl ester 5] naphthyridine-1-carboxylic acid and cis-4- (3,5-bis-trifluoromethyl-benzyl) -ethyl-amino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-yl isopropyl ester 1, 5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedure described in Example 46, Step 1, replacing (+/-) - cis-4-amino-6-methoxy-2-methyl-3, 4-dih, isopropyl ester. .idro-2.ff- [1, 5] naphthyridine-1-carboxylic acid ester (+/-) - cis-4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-yl isopropyl ester [1, 5] naphthyridine-l-carboxylic acid (0.252 g, 0.732 mmol), and using bis-3,5-trifluoromethyl benzaldehyde (0.145 ml, 0.861 mmol) and sodium triacetoxyborohydride (0.8 g). Purified using silica gel column chromatography (levigating gradient, 0-50% ethyl acetate in hexane) to give the title compound (0.182 g, 45%). MS (ES +): 570 (M + H) as a better compound. A minor compound, isopropyl ester of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzyl) -ethyl-amino) -2-cyclopropyl-6-trifluoromethyl-3, 4- was also isolated dihydro-2Ji- [1, 5] naphthyridine-1-carboxylic acid (0.14 g, 23%). MS (ES +): 598 (M + H).
Step 3. Preparation of (+/-) - cis-4- (3,5-bis-trifluoromethyl-benzyl) -ciano-amino) -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-isopropyl ester 2ií- [1, 5] aftiridin-1-carboxylic acid
Cyanogen bromide (0.041 g, 0.377 mmol) was added followed by \ f, W-diisopropylethylamine (0.083 ml, 0.492 mmol) to a solution of (+/-) - cis-4- (3, 5-) isopropyl ester. bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2i? [1, 5] naphthyridine-1-carboxylic acid (0.071 g, 0.123 mmol) in THF (2 mL). After stirring at 65 ° C for 12 hours, the solvent was removed under vacuum. It was diluted with ether (20 ml), washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed on silica gel, levigating with ethyl acetate / hexane (levigating gradient, 0-50% ethyl acetate in hexane) to give the title compound (0.031 g, 43%). MS (ES +): 595 (M + H).
Step 4. Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl) -amino] -2-cyclopropyl-6-isopropyl ester -trifluoromethyl-3,4-dihydro-2-yl- [1,5] naphthyridine carboxylic acid
Isopropyl ester of cis-4- (3,5-bis-trifluoromethyl-benzyl) -ciano-amino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-yl- [1,5] naphthyridine- was added. 1-carboxylic
(0.022 g, 0.037 mmol) with sodium azide (1-5 eq) and triethylamine hydrochloride (0.015 g, 0.12 mmol) in anhydrous toluene (2 mL) and heated at 110 ° C with stirring for 20 hours. The cold mixture was diluted with water and 0.1 N HCl and extracted with EtOAc. The organic layers were combined and washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Purified using silica gel column chromatography (levigating gradient, 0-50% ethyl acetate in hexane) to give the title compound (0.021 g, 81%). MS (ES +): 638 (M + H).
Step 5. Preparation of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2-yl-tetrazol-5-yl) -amino] -2- isopropyl ester -cyclopropyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-l-carboxylic acid
To a solution of (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2H-tetrazol-5-yl) -amino] -2-cyclopropyl-6-isopropyl ester trifluoromethyl-3, 4-dihydro-2.fi- [1, 5] naphthyridine-l-carboxylic acid (0.020 g, 0.032 mmol) and methanol (0.012 mL, 0.30 mmol) in dichloromethane (1 mL) at room temperature, under atmosphere of nitrogen, triphenyl phosphine (5.2 mg, 0.032 mmol) was added in one portion followed by the addition of diethyl azodicarboxylate (DEAD) (0.010 ml, 0.032 mmol). The reaction was allowed to stir at room temperature overnight. More methanol (0.015 mL, 0.36 mmol), triphenyl phosphine (5.2 mg, 0.032 mmol) and DEAD (0.010 mL, 0.032 mmol) were added. After stirring for 6 hours, the solvents were removed under pressure. The residue was purified by flash chromatography, levigating with hexanes / ethyl acetate, to give the title compound (11.2 mg, 57%): MS (ES +): 652 (M + H).
Example 53 4- [(3,5-bis-trifluoromethyl-benzyl) - (5,6,7,8-tetrahydro-quinolin-3-yl) -amino] -2,3-dimethyl-3 isopropyl ester 4,6,7,8,9-hexahydro-2ff-benzo [b] [1,5] naphthyridine-1-carboxylic acid
Step 1. Preparation of (2-ethyl-3-methyl-1,2,3,4,6,7,8,9-octahydro-benzo [b] [1,5] naphthyridin-4-yl) - (5,6) , 7, 8-tetrahydro-quinolin-3-yl) -amine
The title compound was prepared, essentially following the procedure described in Example 46, Step 1, using 5, 6, 7, 8-tetrahydro-quinolin-3-ylamine (4.0 g, 26.84 mmol), propionaldehyde (1.936 mL, 26.84 mmol) and W-vinyl acetamide (2.28 g, 26.84 mmol). Purified using silica gel column chromatography (levigant gradient, 0-5% MeOH in ethyl acetate) to give the title compound (4.39 g, 59%). MS (ES +): 377 (M + H).
Step 2. Preparation of 2-Ethyl-3-methyl-4- (5,6,7,8-tetrahydro-quinolin-3-ylamino) -3,4,6,7,8,9-hexahydro isopropyl ester -2H-benzo [b] [1, 5] naphthyridine-l-carboxylic acid.
The title compound was prepared. Essentially following the procedure described in Example 46, Step
2, replacing (+/-) -cis-N- (6-methoxy-2-methyl-1,2,3,4-tetrahydro- [1,5] naphthyridin-4-yl) acetamide with (2-ethyl- 3-methyl-1, 2,3,4,6,7,8,9-octahydrobenzo [b] [1, 5] naphthyridin-4-yl) - (5,6,7,8-tetrahydro-quinolin-3-yl) ) -amine (0.575 g, 1.52 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purified using silica gel column chromatography (levigating gradient, pure ethyl acetate) to provide the title compound (0.218 g, 31%). MS (ES +): 463 (M + H).
Step 3. Preparation of 4- [(3,5-bis-trifluoromethyl-benzyl) - (5,6,7,8-tetrahydro-quinolin-3-yl) -amino] -2, 3-dimethyl isopropyl ester -3, 4,6,7,8, 9-hexahydro-2i ¥ -benzo [b] [1,5] naphthyridine-1-carboxylic acid
The title compound was prepared, essentially following the procedure described in Example 49, Step 2, replacing (+/-) -N- (1-cyclopentyl-6-methoxy-2-methyl-1, 2, 3, 4 tetrahydro- [1, 5] aftiridin-4-yl) -acetamide with 2-ethyl-3-methyl-4- (5, 6, 7, 8-tetrahydro-quinolin-3-ylamino) -3 isopropyl ester, 4,6,7,8,9-hexahydro-2H-benzo [b] [1,5] naphthyridine-1-carboxylic acid (0.175 g, 0.378 mmol), and using 3, 5-bis trifluoromethyl benzyl bromide and hexamethyldisilazide lithium. Purified using silica gel column chromatography (levigant gradient, 50:50 ethyl acetate in hexane) to give the title compound (0.052 g, 20%). MS (ES +): 689 (M + H).
Claims (20)
1. A compound of the formula I I characterized in that n is 0, 1, 2, or 3; q is 0, 1, or 2; W, X, Y and Z are each independently CH, C, N, S or O, with appropriate single or double bonds and / or hydrogen atoms to complete valence requirements; Ring A is a ring of five or six elements, where one of, X, Y and Z may be absent; as long as ring A is not phenyl; K is a bond, C = O, or S (0) p; p is 0, 1 or 2; R1 when n is 0, and k is C = 0 or S (0) p, is selected from the group consisting of alkyl -OC? -C6 alkyl, -O-aryl, -OC2-C6 alkenyl, -OC? -C6 haloalkyl , -OCi-Cβ alkylheterocyclic, -OC3-C8 cycloalkyl, -OC1-C6 alkylcycloalkyl, -NR7R8, -OC? -C6 alkylaryl, -OCi-C6alkylC02RA -OC2-C6alkyl alcohol, -OC? -C6 alkylNR7R8, -OC2-C6 alkylcyano , CONR ^ R12, NR1: LS02R12, NRnCOR12, C2-C3 alkylNR1 ^ 12, C1-C3 alkylCOR11, C0-C6 alkylCOOR11 and wherein each cycloalkyl, aryl and heterocyclic group is optionally substituted with 1 to 3 groups independently selected from oxo, hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkylalcohol, C 2 -C 6 alkylalcohol, C 1 -C 6 haloalkoxy CONR 1: LR12, NR S02R12, NRuCOR12, C0-C3 alkylNRuR12, C1-C3 alkylCOR11, C0-C6 alkylCOOR11, C0-C6alkylocyano, -OC2-C6alkylocyano, Ci-Cß alkylcycloalkyl, phenyl, -OC? -C6 alkylcycloalkyl, -OC? C6 alkylaryl, -OCi-Cβ alkylheterocyc cyclic, and C? -C3 alkylaryl; R1 when n is 1 or 2 or 3, and K is a bond, is selected from the group consisting of hydroxy, Ci-Ce alkyl, C2-C6 alkenyl, haloalkyl Ci-Cβ alkylheterocyclic Ci-Cß, cycloalkyl C3-Ce, alkylcycloalkyl Ci-Cß; alkylaryl Ci-Cd ^ aryl, heterocyclyl, C 1 -C 6 alkyl, C 6 -C 6 alkylNR 7 R 8, wherein each cycloalkyl, aryl and heterocyclic is optionally substituted with 1 or 2 groups independently selected from the groups consisting of oxo, hydroxy, halo , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, Ci-Ce haloalkyl, C 1 -C 6 alkylalcohol, OC 2 -C 6 alkoalkyl, C 1 -C 6 haloalkoxy, CONR 1: LR 12, NR1: LS02R12, NRAoR12, C0-C3 alkylNR1: LR12, C? -C3 alkylCOR11, C0-C6 alkylCOOR11, alkylC0-C6, -OC2-C6alkylocyano, alkylcycloalkyl Ci-Cß, phenyl, -OC? -C6 alkylcycloalkyl, -OCi -Ce alkylaryl, -OCi-Cd alkylheterocyclic, and alkylaryl Ci-Cβ; R2 is each independently selected from the group consisting of hydrogen, halo, Ci-Cg alkyl, C2-C6 alkenyl, C2-Cd alkynyl, haloalkyl -Cβ, OC? -C6 alkyl, C? -C6 alkylaryl, aryl, C0- C 6 NR 7 R 8 alkyl, heteroaryl, heterocyclyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylcycloalkyl and C 1 -C 6 alkylheterocyclyl; wherein each cycloalkyl, aryl, or heterocyclic is optionally substituted with 1 to 3 groups independently selected from oxo, hydroxy, halo, Ci-Cd alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C? -C6 alcohol, C? alkoxy? -C6, haloalkyl Cx-Ce, haloalkoxy C? -C6, CONR? R12, NR1: LS02R12, NR? COR12, C0-C3 alkylNR1: LR12, C1-C3 alkylCOR11, C0-C6 alkylCOOR11, cyano, and phenyl; R3 is each independently selected from hydrogen, C?-C6 alkyl, aryl, C2-C6 alkenyl, C2-C alqu alkynyl, C?-C6 alkylaryl, Ci-Ce heterocyclic alkyl, C3-C8 cycloalkyl, or C?-C6 alkylcycloalkyl; R4 is a group represented by the formula -NR9R10; R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C? -C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C? -C6 alkoxy, Ci-Ce haloalkyl, C3-Cs cycloalkyl, Ci-Cg alkylcycloalkyl , C? -C6 alkylaryl, C? -C6 -heterocyclic alkyl, aryl, C? -C6 alkylaryl, heteroaryl, aryloxy, -OC2-C6 alkenyl, -OC1-C6 haloalkyl, -NR7R8, and -OC? -C6 alkylaryl; and wherein when q is 1, 2 or 3, two adjacent R5 groups can be combined to form an optionally substituted 5 or 6-membered carbocyclic or heterocyclic ring fused to ring A; R6 is independently selected from the group consisting of hydrogen, C? -C6 alkyl, C2-C6 alkenyl, hydroxy, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, aryloxy, -OC2-C6 alkenyl, -OC? -C6 haloalkyl, C? -C6 alkylNR7R8, C3-C8 cycloalkyl, and C? -C6 alkylcycloalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, Ci-Ce alkylcycloalkyl, C3-C8 cycloalkyl, Ci-Cß heterocyclic alkyl, C?-C6 haloalkyl, NR1: LR12, hydroxy, oxo, COOH, C (0) OC? -C4 alkyl, Ci-Cβ alkyl, C2-C6 alkenyl, C2-Cd alkynyl, Ci-Ce alkoxy, CiC6 alkyl alkoxy, Ci-Ce alkylamine, Ci-Cß alkylaryl, C2-C6 alkenylaryl, C2-C6 alkynylaryl, C 1 -C 6 -0-alkylaryl Ci-Ce alkyl, C 1 -C 6 -NR 2 alkylaryl Ci-Cd alkyl, C 1 -C 6 alkylocyan, C 1 -C 6 -CONR 7 R 8 alkyl, C 1 -C 6 NR 7 R 8 alkyl, C 1 -C 6 NR 1 alkyl: 1-COR12, and aryl, wherein each cycloalkyl or aryl group is optionally substituted with halo, hydroxy, oxo, amino, COOH, C (0) 0C! -C alkyl, C? -C6 haloalkyl, Ci-C? Alkyl, alkenyl C2-C6, C2-C2 alkynyl, C6-C6 alkoxy, C1-C6alkylalcohol, and Ci-Cβ alkylamine; or R7 and R8 combine to form a nitrogen-containing heterocyclic ring, which may have 0, 1, or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur, and may be optionally substituted with oxo, or C! -C6 alkyl; R9 is the group Ci-Cß alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ci-Cβ alkylcycloalkyl, aryl, heterocyclic, Ci-Cß alkyl heterocyclic, COR7, C02R7, C0-C3 alkyl CONR7R8, C0-C3S alkyl (0) pNR7R8 , or C0-C3S (O) pR7 alkyl wherein R7 is as defined above, and wherein each alkyl, cycloalkyl, aryl, and heterocyclic is optionally substituted with one to two groups independently selected from halo, hydroxy, oxo, COOH, C (0) OC? ~ C4 alkyl, C? -C6 haloalkyl, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C? -C6 alkoxy, C1-Cg alkylalcohol, C? -C6 alkylamine, alkylaryl Ci-Cβ, C2-Cd alkenylaryl, C2-C6 alkynylaryl, C-C6-alkylheterocyclic, -NR7R8, C3-C8 cycloalkyl, C? -C6 alkylcycloalkyl, Ci-C? -0-Ci-Ce alkylaryl alkyl, C? -C6 alkyl -NR 2 -alkylaryl C 1 -C 6, C 1 -C 6 alkylocyano, C 1 -C 6 -CONR 7 R 8 alkyl, C 1 -C 6 NR 7 R 8 alkyl, C 1 -C 6 NR 2 COR 1: L alkyl, and aryl, wherein each cycloalkyl or aryl group is optionally substituted with halo, hydroxy, oxo, amino, COOH, C (0) OC? ~ C4 alkyl, C? -C6 haloalkyl, Ci-Ce alkyl, C2-Cd alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkyl alkoxy, and C? alkylamine C6; R10 is selected from the group consisting of aryl, C? -C6 alkylaryl, C2-C6 alkenylaryl, C2-Cd alkynylaryl, C? -C6 haloalkylaryl, C? -β -heterocyclic, C2-Ce-alkenylocyclic, Ci-Ce alkylcycloalkyl, C3-cycloalkyl -C8, C? -C6-0-alkylaryl C? -C6 alkyl, and wherein each cycloalkyl, aryl, or heterocyclic group is optionally substituted with 1-3 groups independently selected from the group consisting of hydroxy, oxo, - SC? -C6 alkyl, C? -C6 alkyl, C? -C6 alkenyl, Ci-C? Alkynyl, C? -C6 haloalkyl, halogen, C? -C6 alkoxy, aryloxy, C? -C3 alkenyloxy, C? -C6 haloalkoxyalkyl, alkyl C0-CeNR ^ R12, -OC? -C6 alkylaryl, nitro, cyano, -OC? -C6 haloalkyl, haloalkylC? -C6alcohol, and C? -C6alkyl alcohol; R11 and R12 are independently selected from the group consisting of hydrogen, Ci-Cß alkyl / alkenyl CI-CT, C3-C8 cycloalkyl, heterocyclic, aryl, and alkylaryl Ci-Ce, wherein each aryl group is optionally substituted with 1-3 groups independently selected from halogen, C? -C6 -heterocyclic alkyl, and C? -C6 haloalkyl, or R11 and R12 combine to form a nitrogen-containing heterocyclic ring, which may have 0, 1 or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and is optionally substituted with oxo, or C? -C6 alkyl; or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.
2. A compound according to claim 1, characterized in that n is zero, k is C = 0, and R1 is selected from a group consisting of -OC1-C6 alkyl, O-aryl, -OC2-C6 alkenyl, - OCi-Cß haloalkyl, -OC3-C8 cycloalkyl, -OCi-Cß alkylcycloalkyl, -OCi-Cß alkylaryl, -0 heterocyclic, and -OC?-C6alkylC02R1: 1-, OC2-C6alkyl alcohol, -0C ?C6 alkylNR7R8, -OC2-C6 alkylocyano -OC-C6 alkylheterocyclic, wherein each cycloalkyl, aryl and heterocyclic group is optionally substituted with 1 to 3 groups independently selected from Cr-CgCOOR 11 alkyl, C0-C6 alkyl alcohol, C0-C3NR1 alkyl: 1-R12, and C0-C6 alkylocyan.
3. A compound according to claim 1, characterized in that n is 1, k is a bond and R1 is selected from a group consisting of C2-C6 alkenyl, C2-C6 haloalkyl, C3-C8 cycloalkyl, aryl, and heterocyclic. wherein each cycloalkyl, aryl, or heterocyclic is optionally substituted with 1 or 2 groups selected from C1-C3alkyl alcohol, C? -C3 alkylamine, C0-C3COOH alkyl, C0-C3CONH2 alkyl, and C0-C3C (O) OC1- alkyl C3 alkyl
4. A compound according to claim 1, characterized in that R4 is NR9R10 and R9 is a heterocyclic group optionally substituted with one or two groups independently selected from OH, halo, amino, C (0) OC? -C4 alkyl, C 1 -C 3 haloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylamine, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkylcycloalkyl , C? -C6 alkylcyano, C1-C6 alkyl R7R8 alkyl, Cl-CdCO alkyl? 11.
5. A compound according to claim 1, characterized in that ring A is selected from the group consisting of pyridine, pyrazine, thiophene, pyrazole isoxazole, oxazole and thiazole.
6. A compound according to claim 1, characterized in that ring A is pyridine.
7. A compound according to claim 1, characterized in that ring A is thiophene.
8. A compound according to claim 1, characterized in that each R3 is hydrogen and R4 is NR9R10 and R9 is selected from the group consisting of: - ^ Y ^ RA, «A« ^ »? »-A JJ-N N-H J? -N N-o N ~ s" "-" B Y- RY¿ «- *» - .- £, wherein R is independently H, OH, NR7R8 or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally substituted with OH, halo, cyano, CONR7R8, C02R1: L, or NR7R8.
9. A compound according to claim 1, characterized in that two R5 groups combine to form a cyclopentane or cyclohexane ring fused to ring A.
10. A compound according to claim 1, characterized in that R4 is selected from the group consisting of it consists of: wherein R7 is OH, C? -C3 alkyl, -OC1-C3 alkyl, or C3-C3 haloalkyl.
11. A compound, characterized in that it is selected from the group consisting of: 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-7-methyl-3, 4 isopropyl ester -dihydro-2i? - [1, 8] naphthyridine-1-carboxylic acid, cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methoxy isopropyl ester -3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-tetrazol-5-yl) isopropyl ester) -amino] -2-ethyl-6-methoxy-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, cis-4- [(3,5-bis-trifluoromethyl-benzyl) isopropyl ester ) - (2-methyl-2ff-tetrazol-5-yl) -amino] -2- ethyl-6-methoxy-3,4-dihydro-2H- [1,5] aftiridine-1-carboxylic acid isopropyl ester 7- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -5-ethyl-6,7-dihydro-5-thieno [3,2- b] pyridine-4-carboxylic acid, isopropyl ester of the acid (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2-et il-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, (+/-) -cis-4- [acetyl- (3,5-bis-trifluoromethyl) isopropyl ester -benzyl) -amino] -2-ethyl-6-bromo-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester of (+/-) -cis-4- [acetyl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-dimethylamino-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid isopropyl ester (+ / -) -cis-4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridin-1- carboxylic acid, (+/-) -cis-4- [(3, 5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-isopropyl ester -trifluoromethyl-3, 4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, (2S, 4R) -4- [(3,5-bis-trifluoromethyl-benzyl) -2-methyl) isopropyl ester -2H-tetrazol-5-yl) -amino] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester of (2R, S) - 4 - [(3,5-bis-trifluoromethyl-benzyl) -2-methyl-2H-tetrazol-5-yl) -amino] -2- ethyl-6-trifluoromethyl-3, -dihydro-2H- [1,5] Naphthyridine-1-carboxylic acid, (+/-) - cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-tert-butoxycarbonylamino-ethyl) -2-trifluoromethyl) isopropyl ester 5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2 .Fi- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4 isopropyl ester - [[2- (2-amino-ethyl) -2i] -tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3, 4- dihydro-2.fi- [1,5] naphthyridine-1-carboxylic acid, (2S, 4R) -cis-4- [[2- (2-amino-ethyl) -2H-tetrazol-5-yl) isopropyl ester ] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2-yl- [1,5] naphthyridine-1-carboxylic acid (2R) isopropyl ester , 4S) -cis-4- [[2- (2-amino-ethyl) -2i-r-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl- 6-trifluoromethyl-3,4-dihydro-2-fi- [1, 5] naphthyridine-1-carb oxyl, (+/-) - cis and trans-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2i? -tetrazol-5-yl) isopropyl ester ) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2i? - [1,5] naphthyridine-1-carboxylic acid (2R, 45) -4- [(3, 5) isopropyl ester -bis- trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2 # -tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2.fi- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester (2S), R) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl- 3, -dihydro-2½- [1, 5] naphthyridine-1-carboxylic acid, (+/-) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-ethyl-2i?] Isopropyl ester; -tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2'i- [1, 5] naphthyridine-1-carboxylic acid, trifluoroacetate of the isopropyl ester of (2R, 4S) - 4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2-Fi- tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2. fi- [1, 5] naphthyridine-1-carboxylic acid, trifluoroacetate of (2S, 4R) -4- [(3,5-bis-trifluoromethyl-benzyl) - [2-methyl-2H-tetrazole-5] isopropyl ester -yl) -amino] -2-ethyl-6-trifluoromethyl-3, -dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester of (+/-) -cis-4- [[2 - (2-amino-ethyl) -2ff-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-227- [ 1, 5] naphthyridine-1-carboxylic acid, isopropyl ester of (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2-tetrazol-5-yl) -amino] - 2-ethyl-6-methyl-3,4-dihydro-2-fi- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-6-amino-4- [(3) isopropyl ester , 5-bis-trifluoromethyl-benzyl) - [2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-7-methyl-3,4-dihydro-2H- [1,5] naphthyridin- 1-carboxylic acid isopropyl ester (+/-) -trans-6-amino-4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2i? -tetrazol-5-yl) - amino] -2-ethyl-7-methyl-3,4-dihydro-2½- [1,5] naphthyridine-1-carboxylic acid isopropyl ester (+/-) -cis-4- [(3, 5- bis-trifluoromethyl-benzyl) - (2-methyl-2ff-tetrazol-5-yl) -amino] -2-ethyl-6-methoxy-7-methyl-3,4-dihydro-2.fi- [1, 5 ] naphthyridine-1-carboxylic acid ethyl ester (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2 -ethyl-6-trifluoromethyl-3, -dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, 2-dimethyl ester amino acid (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoroacetyl -3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, tetrahydro-pyran-4-yl ester of (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, l-methyl ester piperidin-4-yl of (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6 -trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, tetrahydro-furan-3-yl ester of (2R, 3 'R, 45) -4- [(3, 5- bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, -dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, Tetrahydrofuran-3-yl ester of (2R, 3"5, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino ] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-ca carboxylic acid (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino acid 2-morpholin-4-yl-ethyl ester ] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid 2- (4-methyl-piperazin-1-yl) -ethyl ester of (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H - [1,5] naphthyridine-1-carboxylic acid, 2-methoxycarbonyl-2-methyl-propyl ester of (2R, 4S) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl- 2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, 2-carboxy-2-methyl-propyl ester of the (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3, 4 -dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, 2-cyano-ethyl ester of (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl- 2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromet il-3, 4-dihydro-2H- [1, 5] naphthyridine-1-carboxylic acid, 2- (2H-tetrazol-5-yl) -ethyl ester of (2R) acid, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H- [1,5] naphthyridine-1-carboxylic acid (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole) 2-benzyloxyethyl ester -5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid, 2-hydroxy-ethyl ester of (2R, 45) - 4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1 , 5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [(3,5-bis-trifluoromethylbenzyl) - (5-methyl-lff-pyrazol-3-yl) amino] - isopropyl ester 2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [(3,5-bis-trifluoromethylbenzyl) isopropyl ester ) - (3-Methyl-isoxazol-5-yl) -amino] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester (+ / -) -cis-4- [(3, 5 bis-trifluoromethyl-benzyl) - (5-methyl- [1,2,4] oxadiazol-3-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5 ] naphthyridine-l-carboxylic acid (+/-) -cis-4- [(3,5-bis-trifluoromethyl-benzyl) - (2, 5-dimethyl-2H-pyrazole-3-carbonyl) isopropyl ester - amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, (+/-) -cis-4- (3,5-bis-trifluoromethyl-benzyl) -1- ( Cyclopentylmethyl-2-ethyl-6-methoxy-1,2,3,4-tetrahydro- [1,5] naphthyridin-4-yl) -acetamide, isopropyl ester of (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -6-methoxy-2-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester (+/- ) -cis-4- [(3, 5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6-methoxy-2-methyl-3, 4-dihydro-2-fi- [1,5] naphthyridin-1 -carboxylic acid (+/-) -cis-4- [(3, 5-bis-trifluoromethyl-benzyl) - (3-fluoro-5-trifluoromethyl-benzoyl) -amino] -6-methoxy-2-isopropyl ester -methyl-3, 4-dihydro-2H- [1,5] af tiridin-1-carboxylic acid, (+/-) -cis-N- (3, 5-bis-trifluoromethyl-benzyl) -N- (1-cyclopentyl-6-methoxy-2-ethyl-1, 2, 3, 4 -tetrahydro- [1,5] naphthyridin-4-yl) -acetamide, (+/-) -cis-4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino] -2 isopropyl ester -methyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (+/-) -cis-4- [acetyl- (3,5-bis-) isopropyl ester trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2-yl- [1,5] naphthyridine-1-carboxylic acid, isopropyl ester of (+/-) -cis-4- [ (3, 5-bis-trifluoromethyl-benzyl) - (2-methyl-2i? -tetrazol-5-yl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2? - [1,5] Naphthyridine-1-carboxylic acid, 4- [(3,5-bis-trifluoromethyl-benzyl) - (5,6,7,8-tetrahydro-quinolin-3-yl) -amino] -2- 3- isopropyl ester dimethyl-3,, 6,7,8, 9-hexahydro-2E-benzo [b] [1,5] naphthyridine-1-carboxylic acid, methyl ester of (2R, 4S) -4- [(3, 5- bis-trifluoromethyl-benzyl) - ( 2-methyl-2H-tetrazol-5-yl) -amino] -2- ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid ethyl ester (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2- ethyl-6-methyl-3,4-dihydro-2H - [1,5] naphthyridine-1-carboxylic acid methyl ester (2R, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2,6-dimethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (2R, 4S) -4- [(3,5-bis-trifluoromethyl) ethyl ester -benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2,6-dimethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid isopropyl ester (2i ?, 45) -4- [(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2,6-dimethyl-3,4-dihydro -2H- [1,5] naphthyridine-1-carboxylic acid, (2R, 45) -4- [(3-cyano-5-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazole-5-) isopropyl ester il) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine -1-carboxylic acid (2R, 45) -4- [(3,5-dichloro-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl-6 isopropyl ester -trifluoromethyl-3, 4-dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid (2R, 5) -4 - [(3-chloro-5-trifluoromethyl-benzyl) - (2-methyl-2H-) isopropyl ester tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (2R, 45) -2-ethyl isopropyl ester -4- [(3-fluoro-5-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -6-trifluoromethyl-3,4-dihydro-2H- [1,5] Naphthyridine-1-carboxylic acid, (2R, 45) -4- [(3,5-dimethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl) -amino] -2-ethyl- isopropyl ester 6- trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (2R, 45) -4- [(3,5-difluoro-benzyl) - (2-methyl) isopropyl ester -2H-tetrazol-5-yl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid methyl ester (2R, 45) - 4- [[2- (2-Amino-ethyl) -2H-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3, -dihydro -2H- [1, 5] naphthyridine-1-carboxylic acid, methyl ester of (2R, 45) -4- acid. { (3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl] -amino} -2-ethyl-6-methyl-3, -dihydro-2H- [1, 5] naphthyridine-l-carboxylic acid ethyl ester (2R, 45) -4- [[2- (2-amino-ethyl)] -2H-tetrazol-5-yl] - (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridin-1- carboxylic acid ethyl ester (2R, 45) -4-. { (3,5-bis-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl] -amino} -2-Ethyl-6-methyl-3,4-dihydro-2H- [1,5] naphthyridine-1-carboxylic acid (2R, 4S) -4- [[2- (2-Amino-ethyl)) isopropyl ester ) -2H-tetrazol-5-yl] - (3-cyano-5-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] naphthyridin-1 -carboxylic, isopropyl ester of (2R, S) -4- acid. { (3-cyano-5-trifluoromethyl-benzyl) - [2- (2-hydroxy-ethyl) -2H-tetrazol-5-yl] -amino} -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- [1,5] aftiridine-1-carboxylic acid, or a pharmaceutically acceptable salt, solvate, enantiomer or diastereomer or mixture thereof.
12. A method for regulating the activity of CETP, characterized in that it comprises administering a compound of formula I, a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers, to a patient in need thereof.
13. A method for treating or preventing dyslipidemia, characterized in that it comprises administering a compound of formula I, a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers, to a patient in need thereof. A method for treating or preventing atherosclerosis, characterized in that it comprises administering a compound of formula I, a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers, to a patient in need thereof. 15. A method according to claim 12, characterized in that the regulation of CETP activity results in a decrease in LDL cholesterol. 16. A method in accordance with the claim 12, characterized in that the regulation of CETP activity results in an increase in LDL cholesterol. 17. A method for increasing HDL cholesterol in plasma in a mammal, characterized in that it comprises administering a therapeutically effective dose of a compound of formula I, a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers, to a patient in need of it. 18. A method for treating and / or preventing the pathological sequelae due to high levels of plasma LDL cholesterol in a mammal, characterized in that it comprises administering an effective dose of a compound of formula I, a salt, solvate, enantiomer, racemate, diastereomer or pharmaceutically acceptable diastereomer mixture, to a patient in need thereof. 19. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1, and a carrier, diluent and / or excipient. 20. Use of a compound of formula I, for 20? manufacture of a medicament for treating and / or preventing atherosclerosis in a mammal, comprising administering an effective dose of a compound of formula I, a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers, to a patient in need thereof.
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US60/557,134 | 2004-03-26 | ||
US60/621,162 | 2004-10-22 |
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