EA017939B1 - Производные 1,2-дизамещенного 4-бензиламинопирролидина в качестве ингибиторов белка-переносчика холестерилового эфира, используемые для лечения заболеваний, таких как гиперлипидемия или артериосклероз - Google Patents

Info

Publication number

EA017939B1

EA017939B1 EA201000884A EA201000884A EA017939B1 EA 017939 B1 EA017939 B1 EA 017939B1 EA 201000884 A EA201000884 A EA 201000884A EA 201000884 A EA201000884 A EA 201000884A EA 017939 B1 EA017939 B1 EA 017939B1

Authority

EA

Eurasian Patent Office

Prior art keywords

amino

trifluoromethylbenzyl

bis

pyrimidin

methyl

Prior art date

2007-12-03

Links

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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 47
• 201000010099 disease Diseases 0.000 title claims abstract description 27
• -1 1,2-disubstituted 4-benzylaminopyrrolidine Chemical class 0.000 title claims description 315
• 208000031226 Hyperlipidaemia Diseases 0.000 title claims description 8
• 206010003210 Arteriosclerosis Diseases 0.000 title description 5
• 208000011775 arteriosclerosis disease Diseases 0.000 title description 5
• 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 166
• 208000035475 disorder Diseases 0.000 claims abstract description 20
• 230000005764 inhibitory process Effects 0.000 claims abstract description 13
• 230000001404 mediated effect Effects 0.000 claims abstract description 7
• 239000000203 mixture Substances 0.000 claims description 233
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 100
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 88
• 150000003839 salts Chemical class 0.000 claims description 88
• 238000000034 method Methods 0.000 claims description 69
• 229920006395 saturated elastomer Polymers 0.000 claims description 60
• AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims description 58
• 125000000217 alkyl group Chemical group 0.000 claims description 56
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 49
• 125000003118 aryl group Chemical group 0.000 claims description 44
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 125000003545 alkoxy group Chemical group 0.000 claims description 29
• 229910052736 halogen Inorganic materials 0.000 claims description 29
• 239000002253 acid Substances 0.000 claims description 25
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol 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 24
• 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 23
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
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• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000005843 halogen group Chemical group 0.000 claims description 18
• 150000002367 halogens Chemical class 0.000 claims description 15
• 238000002360 preparation method Methods 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 14
• 230000003287 optical effect Effects 0.000 claims description 14
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• 239000001257 hydrogen Substances 0.000 claims description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
• 208000018262 Peripheral vascular disease Diseases 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
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• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
• 125000004149 thio group Chemical group *S* 0.000 claims description 10
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
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• ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 8
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 8
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 8
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• 125000003282 alkyl amino group Chemical group 0.000 claims description 7
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• UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims description 6
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• 206010045261 Type IIa hyperlipidaemia Diseases 0.000 claims description 6
• 238000002399 angioplasty Methods 0.000 claims description 6
• 125000004122 cyclic group Chemical group 0.000 claims description 6
• 125000004494 ethyl ester group Chemical group 0.000 claims description 6
• 208000006575 hypertriglyceridemia Diseases 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 235000020824 obesity Nutrition 0.000 claims description 6
• ZMQUKUZJULWUSZ-UHFFFAOYSA-N 4-(4-carboxycyclohexyl)oxycyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1OC1CCC(C(O)=O)CC1 ZMQUKUZJULWUSZ-UHFFFAOYSA-N 0.000 claims description 5
• 239000005541 ACE inhibitor Substances 0.000 claims description 5
• 206010021024 Hypolipidaemia Diseases 0.000 claims description 5
• 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 5
• 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 5
• 206010063837 Reperfusion injury Diseases 0.000 claims description 5
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 5
• 208000029498 hypoalphalipoproteinemia Diseases 0.000 claims description 5
• 208000037803 restenosis Diseases 0.000 claims description 5
• SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 claims description 4
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 4
• 108050000824 Angiotensin II receptor Proteins 0.000 claims description 4
• 102000008873 Angiotensin II receptor Human genes 0.000 claims description 4
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
• 239000005557 antagonist Substances 0.000 claims description 4
• LIVQKHTVWSQZOY-UHFFFAOYSA-N cyclohexylmethanone Chemical compound O=[C+]C1CCCCC1 LIVQKHTVWSQZOY-UHFFFAOYSA-N 0.000 claims description 4
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 4
• HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 claims description 4
• 150000004702 methyl esters Chemical class 0.000 claims description 4
• HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 claims description 4
• 239000002461 renin inhibitor Substances 0.000 claims description 4
• 229940086526 renin-inhibitors Drugs 0.000 claims description 4
• XEEQGYMUWCZPDN-WFASDCNBSA-N (s)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-[(2s)-piperidin-2-yl]methanol Chemical compound C([C@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-WFASDCNBSA-N 0.000 claims description 3
• JBCFJMYPJJWIRG-UHFFFAOYSA-N 1,3-oxazole-4-carboxylic acid Chemical compound OC(=O)C1=COC=N1 JBCFJMYPJJWIRG-UHFFFAOYSA-N 0.000 claims description 3
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• 239000002308 endothelin receptor antagonist Substances 0.000 claims description 3
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• 230000002401 inhibitory effect Effects 0.000 claims description 3
• GSENCEDSCQYPIL-UHFFFAOYSA-N morpholin-4-ylmethanone Chemical compound O=[C]N1CCOCC1 GSENCEDSCQYPIL-UHFFFAOYSA-N 0.000 claims description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
• 125000004434 sulfur atom Chemical group 0.000 claims description 3
• 229940124597 therapeutic agent Drugs 0.000 claims description 3
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• YQLLSNOADZSAFD-UHFFFAOYSA-N 3-methyl-3-[(3-methyloxetan-3-yl)methoxymethyl]oxetane Chemical compound C1OCC1(C)COCC1(C)COC1 YQLLSNOADZSAFD-UHFFFAOYSA-N 0.000 claims description 2
• QEBQEVMZUWUIKD-UHFFFAOYSA-N 4-(3-carboxy-3-methylbutoxy)-2,2-dimethylbutanoic acid Chemical compound OC(=O)C(C)(C)CCOCCC(C)(C)C(O)=O QEBQEVMZUWUIKD-UHFFFAOYSA-N 0.000 claims description 2
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• BOTWMDGPXSGOBU-UHFFFAOYSA-N 5-(1-methylpyrazol-4-yl)pyrimidin-2-amine Chemical compound C1=NN(C)C=C1C1=CN=C(N)N=C1 BOTWMDGPXSGOBU-UHFFFAOYSA-N 0.000 claims description 2
• PRYPWFPMFBAZOQ-UHFFFAOYSA-N CCOC(=O)C(C)(C)OC(C)(C)C(=O)OCC Chemical compound CCOC(=O)C(C)(C)OC(C)(C)C(=O)OCC PRYPWFPMFBAZOQ-UHFFFAOYSA-N 0.000 claims description 2
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• KGPPDNUWZNWPSI-UHFFFAOYSA-N flurotyl Chemical compound FC(F)(F)COCC(F)(F)F KGPPDNUWZNWPSI-UHFFFAOYSA-N 0.000 claims description 2
• GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 claims description 2
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
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• BLDLTMVNCFWBLW-UHFFFAOYSA-N pyrrolidin-1-ylmethanone Chemical compound O=[C]N1CCCC1 BLDLTMVNCFWBLW-UHFFFAOYSA-N 0.000 claims description 2
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• 125000006626 methoxycarbonylamino group Chemical group 0.000 claims 1
• NSVJERHOCLBPOS-UHFFFAOYSA-N methyl 4-(4-methoxycarbonylcyclohexyl)oxycyclohexane-1-carboxylate Chemical compound C(=O)(OC)C1CCC(CC1)OC1CCC(CC1)C(=O)OC NSVJERHOCLBPOS-UHFFFAOYSA-N 0.000 claims 1
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• PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
• 229940117972 triolein Drugs 0.000 description 1
• YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 238000005303 weighing Methods 0.000 description 1
• 238000009736 wetting Methods 0.000 description 1
• 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
• 229910052727 yttrium Inorganic materials 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1
• 150000003953 γ-lactams Chemical class 0.000 description 1