RU2337911C2 - Производные гуанидина и их применение в качестве антагонистов рецептора нейропептида ff - Google Patents

Info

Publication number

RU2337911C2

RU2337911C2 RU2005132308/04A RU2005132308A RU2337911C2 RU 2337911 C2 RU2337911 C2 RU 2337911C2 RU 2005132308/04 A RU2005132308/04 A RU 2005132308/04A RU 2005132308 A RU2005132308 A RU 2005132308A RU 2337911 C2 RU2337911 C2 RU 2337911C2

Authority

RU

Russia

Prior art keywords

guanidine

tetrahydrobenzothiazol

formate

methyl

group

Prior art date

2003-03-20

Links

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• 102000011015 Neuropeptide FF receptor Human genes 0.000 title claims abstract description 13
• 108010061550 Neuropeptide FF receptor Proteins 0.000 title claims abstract description 13
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title description 29
• 239000002464 receptor antagonist Substances 0.000 title description 3
• 229940044551 receptor antagonist Drugs 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 119
• 150000003839 salts Chemical class 0.000 claims abstract description 26
• 208000002193 Pain Diseases 0.000 claims abstract description 13
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
• 230000036407 pain Effects 0.000 claims abstract description 11
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
• 239000001257 hydrogen Substances 0.000 claims abstract description 10
• 239000003814 drug Substances 0.000 claims abstract description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 8
• 238000011282 treatment Methods 0.000 claims abstract description 7
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 6
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
• 229940079593 drug Drugs 0.000 claims abstract description 5
• 230000006386 memory function Effects 0.000 claims abstract description 5
• 230000036772 blood pressure Effects 0.000 claims abstract description 4
• 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
• UMWKPIKCOCKMIH-UHFFFAOYSA-N 5,6,7,8-tetrahydro-4h-cyclohepta[d][1,3]thiazole Chemical compound C1CCCCC2=C1SC=N2 UMWKPIKCOCKMIH-UHFFFAOYSA-N 0.000 claims abstract description 3
• QCCKBDNIBZPFCH-UHFFFAOYSA-N 5,6-dihydro-4h-cyclopenta[d][1,3]thiazole Chemical group N1=CSC2=C1CCC2 QCCKBDNIBZPFCH-UHFFFAOYSA-N 0.000 claims abstract description 3
• 208000004454 Hyperalgesia Diseases 0.000 claims abstract description 3
• 208000035154 Hyperesthesia Diseases 0.000 claims abstract description 3
• 206010057852 Nicotine dependence Diseases 0.000 claims abstract description 3
• 208000025569 Tobacco Use disease Diseases 0.000 claims abstract description 3
• RMFVVPBBEDMZQI-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1,3-benzothiazole Chemical compound C1CCCC2=C1N=CS2 RMFVVPBBEDMZQI-UHFFFAOYSA-N 0.000 claims abstract 2
• 230000008030 elimination Effects 0.000 claims abstract 2
• 238000003379 elimination reaction Methods 0.000 claims abstract 2
• 230000000506 psychotropic effect Effects 0.000 claims abstract 2
• 208000011580 syndromic disease Diseases 0.000 claims abstract 2
• BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 53
• 239000002253 acid Substances 0.000 claims description 24
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 9
• 150000007514 bases Chemical class 0.000 claims description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 6
• 239000003792 electrolyte Substances 0.000 claims description 4
• 235000013305 food Nutrition 0.000 claims description 4
• NDKWSGBHKXFNCC-UHFFFAOYSA-N 2-(4-butan-2-yl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound CCC(C)C1CCCC2=C1N=C(NC(N)=N)S2 NDKWSGBHKXFNCC-UHFFFAOYSA-N 0.000 claims description 3
• QSOMFWDDWOFLBS-UHFFFAOYSA-N 2-(4-ethyl-4-methyl-6,7-dihydro-5h-1,3-benzothiazol-2-yl)guanidine Chemical compound CCC1(C)CCCC2=C1N=C(NC(N)=N)S2 QSOMFWDDWOFLBS-UHFFFAOYSA-N 0.000 claims description 3
• LYLYGOUPJRCBLS-UHFFFAOYSA-N 2-(4-methyl-4-propyl-6,7-dihydro-5h-1,3-benzothiazol-2-yl)guanidine Chemical compound CCCC1(C)CCCC2=C1N=C(NC(N)=N)S2 LYLYGOUPJRCBLS-UHFFFAOYSA-N 0.000 claims description 3
• ALIMGROCSLBETQ-UHFFFAOYSA-N 2-(4-tert-butyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound CC(C)(C)C1CCCC2=C1N=C(NC(N)=N)S2 ALIMGROCSLBETQ-UHFFFAOYSA-N 0.000 claims description 3
• WLACEDJDTIXJHA-UHFFFAOYSA-N 2-(5,5,7-trimethyl-6,7-dihydro-4h-1,3-benzothiazol-2-yl)guanidine Chemical compound CC1CC(C)(C)CC2=C1SC(NC(N)=N)=N2 WLACEDJDTIXJHA-UHFFFAOYSA-N 0.000 claims description 3
• KLFUHWVGNPXLLK-UHFFFAOYSA-N 2-(5,5-dimethyl-6,7-dihydro-4h-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(C)(C)CCC2=C1N=C(NC(N)=N)S2 KLFUHWVGNPXLLK-UHFFFAOYSA-N 0.000 claims description 3
• JVACMLRJYVWKJM-UHFFFAOYSA-N 2-(5,5-dimethyl-6-phenyl-6,7-dihydro-4h-1,3-benzothiazol-2-yl)guanidine Chemical compound CC1(C)CC=2N=C(NC(N)=N)SC=2CC1C1=CC=CC=C1 JVACMLRJYVWKJM-UHFFFAOYSA-N 0.000 claims description 3
• LNXDWHDZNHLNAB-UHFFFAOYSA-N 2-(5-butyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(CCCC)CCC2=C1N=C(NC(N)=N)S2 LNXDWHDZNHLNAB-UHFFFAOYSA-N 0.000 claims description 3
• GMABAPWOAXNDDE-UHFFFAOYSA-N 2-(5-butyl-5,6,7,8-tetrahydro-4h-cyclohepta[d][1,3]thiazol-2-yl)guanidine Chemical compound C1C(CCCC)CCCC2=C1N=C(NC(N)=N)S2 GMABAPWOAXNDDE-UHFFFAOYSA-N 0.000 claims description 3
• ZYPREDXHNDNTCV-UHFFFAOYSA-N 2-(5-ethyl-5-methyl-6,7-dihydro-4h-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(CC)(C)CCC2=C1N=C(NC(N)=N)S2 ZYPREDXHNDNTCV-UHFFFAOYSA-N 0.000 claims description 3
• RDQBDBMPQLZPSN-UHFFFAOYSA-N 2-(5-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(C)CCC2=C1N=C(NC(N)=N)S2 RDQBDBMPQLZPSN-UHFFFAOYSA-N 0.000 claims description 3
• AKOBTVQNQFUIFL-UHFFFAOYSA-N 2-(6,6-dimethyl-5,7-dihydro-4h-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(C)(C)CCC2=C1SC(NC(N)=N)=N2 AKOBTVQNQFUIFL-UHFFFAOYSA-N 0.000 claims description 3
• WPRMMSUIODPDQQ-UHFFFAOYSA-N 2-(6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C=2SC(NC(=N)N)=NC=2CCC1C1=CC=CC=C1 WPRMMSUIODPDQQ-UHFFFAOYSA-N 0.000 claims description 3
• QDOXNVJQBUENNN-UHFFFAOYSA-N 2-(6-propan-2-yl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(C(C)C)CCC2=C1SC(NC(N)=N)=N2 QDOXNVJQBUENNN-UHFFFAOYSA-N 0.000 claims description 3
• GGSJEFBOSRYGBZ-UHFFFAOYSA-N 2-(6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(CCC)CCC2=C1SC(NC(N)=N)=N2 GGSJEFBOSRYGBZ-UHFFFAOYSA-N 0.000 claims description 3
• RFZXGFBVQUEHCE-UHFFFAOYSA-N 2-(6-tert-butyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(C(C)(C)C)CCC2=C1SC(NC(N)=N)=N2 RFZXGFBVQUEHCE-UHFFFAOYSA-N 0.000 claims description 3
• KUORHFIBNWNBCM-UHFFFAOYSA-N 2-[4-methyl-4-(2-methylpropyl)-6,7-dihydro-5h-1,3-benzothiazol-2-yl]guanidine Chemical compound CC(C)CC1(C)CCCC2=C1N=C(NC(N)=N)S2 KUORHFIBNWNBCM-UHFFFAOYSA-N 0.000 claims description 3
• 102000004877 Insulin Human genes 0.000 claims description 3
• 108090001061 Insulin Proteins 0.000 claims description 3
• 206010046543 Urinary incontinence Diseases 0.000 claims description 3
• 230000009102 absorption Effects 0.000 claims description 3
• 238000010521 absorption reaction Methods 0.000 claims description 3
• 230000037149 energy metabolism Effects 0.000 claims description 3
• 229940125396 insulin Drugs 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• WUUADCHFBLXQKF-UHFFFAOYSA-N 2-(4,4-dimethyl-6,7-dihydro-5h-1,3-benzothiazol-2-yl)guanidine Chemical compound CC1(C)CCCC2=C1N=C(NC(N)=N)S2 WUUADCHFBLXQKF-UHFFFAOYSA-N 0.000 claims description 2
• OYBQOMBJSHYEAL-UHFFFAOYSA-N 2-(4-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound CC1CCCC2=C1N=C(NC(N)=N)S2 OYBQOMBJSHYEAL-UHFFFAOYSA-N 0.000 claims description 2
• BYPPQYJAMBPADG-UHFFFAOYSA-N 2-(4-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1CCC=2SC(NC(=N)N)=NC=2C1C1=CC=CC=C1 BYPPQYJAMBPADG-UHFFFAOYSA-N 0.000 claims description 2
• QXOFHSUKWFCEBI-UHFFFAOYSA-N 2-(5,5,7,7-tetramethyl-4,6-dihydro-1,3-benzothiazol-2-yl)guanidine Chemical compound CC1(C)CC(C)(C)CC2=C1SC(NC(N)=N)=N2 QXOFHSUKWFCEBI-UHFFFAOYSA-N 0.000 claims description 2
• UFTXCRWHCXBQKN-UHFFFAOYSA-N 2-(5,6,7,8-tetrahydro-4h-cyclohepta[d][1,3]thiazol-2-yl)guanidine Chemical compound C1CCCCC2=C1N=C(NC(=N)N)S2 UFTXCRWHCXBQKN-UHFFFAOYSA-N 0.000 claims description 2
• ICDGFGKAIBXUJJ-UHFFFAOYSA-N 2-(5-methyl-5-phenyl-6,7-dihydro-4h-1,3-benzothiazol-2-yl)guanidine Chemical compound C1CC=2SC(NC(N)=N)=NC=2CC1(C)C1=CC=CC=C1 ICDGFGKAIBXUJJ-UHFFFAOYSA-N 0.000 claims description 2
• AOCYGZXXCPMOJM-UHFFFAOYSA-N 2-(5-phenyl-5,6,7,8-tetrahydro-4h-cyclohepta[d][1,3]thiazol-2-yl)guanidine Chemical compound C1CCC=2SC(NC(=N)N)=NC=2CC1C1=CC=CC=C1 AOCYGZXXCPMOJM-UHFFFAOYSA-N 0.000 claims description 2
• GUWOIUDVUADBQM-UHFFFAOYSA-N 2-(6-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound C1C(C)CCC2=C1SC(NC(N)=N)=N2 GUWOIUDVUADBQM-UHFFFAOYSA-N 0.000 claims description 2
• WVIAKQLSKCZTNT-UHFFFAOYSA-N 2-(7-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)guanidine Chemical compound CC1CCCC2=C1SC(NC(N)=N)=N2 WVIAKQLSKCZTNT-UHFFFAOYSA-N 0.000 claims description 2
• DNVHHWOTOLMWSB-UHFFFAOYSA-N 2-[6-(2-methylbutan-2-yl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]guanidine Chemical compound C1C(C(C)(C)CC)CCC2=C1SC(NC(N)=N)=N2 DNVHHWOTOLMWSB-UHFFFAOYSA-N 0.000 claims description 2
• 230000003042 antagnostic effect Effects 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
• 230000001105 regulatory effect Effects 0.000 claims 1
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• 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
• XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
• 238000013518 transcription Methods 0.000 description 1
• 230000035897 transcription Effects 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
• IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• 239000005051 trimethylchlorosilane Substances 0.000 description 1
• YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
• 125000005289 uranyl group Chemical group 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 239000008096 xylene Substances 0.000 description 1