EP1888542A1 - Substituierte spiro-verbindungen und deren verwendung zur herstellung von arzneimitteln - Google Patents

Info

Publication number

EP1888542A1

EP1888542A1 EP06753674A EP06753674A EP1888542A1 EP 1888542 A1 EP1888542 A1 EP 1888542A1 EP 06753674 A EP06753674 A EP 06753674A EP 06753674 A EP06753674 A EP 06753674A EP 1888542 A1 EP1888542 A1 EP 1888542A1

Authority

EP

European Patent Office

Prior art keywords

phenyl

butyl

group

tert

radical

Prior art date

2005-05-19

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Withdrawn

Links

• Espacenet
• EPO GPI
• EP Register
• Global Dossier
• Discuss

• 150000003413 spiro compounds Chemical class 0.000 title claims abstract description 40
• 239000003814 drug Substances 0.000 title claims abstract description 35
• 150000001875 compounds Chemical class 0.000 claims abstract description 111
• -1 aliphatic radical Chemical class 0.000 claims description 783
• 150000003254 radicals Chemical class 0.000 claims description 174
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 128
• 125000001424 substituent group Chemical group 0.000 claims description 114
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 104
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 99
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 94
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 93
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 93
• 229920006395 saturated elastomer Polymers 0.000 claims description 93
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 92
• 229910052801 chlorine Inorganic materials 0.000 claims description 87
• 229910052731 fluorine Inorganic materials 0.000 claims description 85
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 83
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 81
• 229910052794 bromium Inorganic materials 0.000 claims description 79
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 79
• 125000004076 pyridyl group Chemical group 0.000 claims description 75
• 125000000217 alkyl group Chemical group 0.000 claims description 72
• YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 68
• 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 description 68
• 239000000203 mixture Substances 0.000 claims description 68
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 66
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 60
• 125000002950 monocyclic group Chemical group 0.000 claims description 58
• 125000005842 heteroatom Chemical group 0.000 claims description 52
• 229910052757 nitrogen Inorganic materials 0.000 claims description 51
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 47
• 208000002193 Pain Diseases 0.000 claims description 45
• CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 45
• 125000000335 thiazolyl group Chemical group 0.000 claims description 44
• 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 41
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 41
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 40
• 125000002541 furyl group Chemical group 0.000 claims description 39
• 229910052740 iodine Inorganic materials 0.000 claims description 39
• 125000004122 cyclic group Chemical group 0.000 claims description 38
• 208000011117 substance-related disease Diseases 0.000 claims description 38
• 125000001624 naphthyl group Chemical group 0.000 claims description 37
• 125000003386 piperidinyl group Chemical group 0.000 claims description 32
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 31
• YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 claims description 30
• 125000001041 indolyl group Chemical group 0.000 claims description 28
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 27
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 26
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 26
• 125000002757 morpholinyl group Chemical group 0.000 claims description 26
• 229910052760 oxygen Inorganic materials 0.000 claims description 26
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 26
• 206010013663 drug dependence Diseases 0.000 claims description 25
• 229910052717 sulfur Inorganic materials 0.000 claims description 25
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 24
• 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
• 239000001301 oxygen Substances 0.000 claims description 23
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 22
• 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 22
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 22
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 22
• 125000004193 piperazinyl group Chemical group 0.000 claims description 22
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 22
• 150000003839 salts Chemical class 0.000 claims description 22
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 21
• 239000011593 sulfur Substances 0.000 claims description 21
• 125000001544 thienyl group Chemical group 0.000 claims description 21
• 239000002585 base Substances 0.000 claims description 20
• YKNMBTZOEVIJCM-UHFFFAOYSA-N dec-2-ene Chemical compound CCCCCCCC=CC YKNMBTZOEVIJCM-UHFFFAOYSA-N 0.000 claims description 20
• 125000002883 imidazolyl group Chemical group 0.000 claims description 20
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 20
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 20
• 125000002971 oxazolyl group Chemical group 0.000 claims description 20
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 20
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 20
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 20
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
• 125000002947 alkylene group Chemical group 0.000 claims description 19
• 125000004419 alkynylene group Chemical group 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 19
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
• 239000012429 reaction media Substances 0.000 claims description 19
• 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 18
• 125000004450 alkenylene group Chemical group 0.000 claims description 18
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 17
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 16
• LMUMWTKZAGTZAZ-UHFFFAOYSA-N 4-(3-chloropyridin-2-yl)-2,6-dimethylpiperazine-1-carbaldehyde Chemical compound C1C(C)N(C=O)C(C)CN1C1=NC=CC=C1Cl LMUMWTKZAGTZAZ-UHFFFAOYSA-N 0.000 claims description 15
• 229960002504 capsaicin Drugs 0.000 claims description 15
• 235000017663 capsaicin Nutrition 0.000 claims description 15
• 238000011321 prophylaxis Methods 0.000 claims description 15
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 14
• 239000012453 solvate Substances 0.000 claims description 14
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 14
• 206010013654 Drug abuse Diseases 0.000 claims description 13
• 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 13
• 238000002156 mixing Methods 0.000 claims description 13
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 13
• 208000007848 Alcoholism Diseases 0.000 claims description 12
• 206010020853 Hypertonic bladder Diseases 0.000 claims description 12
• 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 12
• 108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 claims description 12
• 125000004429 atom Chemical group 0.000 claims description 12
• 208000020629 overactive bladder Diseases 0.000 claims description 12
• 125000005418 aryl aryl group Chemical group 0.000 claims description 11
• 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 11
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 11
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 11
• 230000005764 inhibitory process Effects 0.000 claims description 11
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 11
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
• FKEZQXJTZAMLOX-UHFFFAOYSA-N 4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carbaldehyde Chemical compound C1CN(C=O)C(C)CN1C1=NC=CC=C1Cl FKEZQXJTZAMLOX-UHFFFAOYSA-N 0.000 claims description 10
• 208000000094 Chronic Pain Diseases 0.000 claims description 10
• 108010025083 TRPV1 receptor Proteins 0.000 claims description 10
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 10
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
• 208000004296 neuralgia Diseases 0.000 claims description 10
• 208000021722 neuropathic pain Diseases 0.000 claims description 10
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 10
• 229920002554 vinyl polymer Polymers 0.000 claims description 10
• 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 9
• 125000006017 1-propenyl group Chemical group 0.000 claims description 9
• 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 9
• 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 9
• 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 9
• 125000006020 2-methyl-1-propenyl group Chemical group 0.000 claims description 9
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 9
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 9
• 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 9
• 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 claims description 9
• 206010046543 Urinary incontinence Diseases 0.000 claims description 9
• 208000005298 acute pain Diseases 0.000 claims description 9
• 230000000694 effects Effects 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
• 239000003153 chemical reaction reagent Substances 0.000 claims description 8
• 238000011161 development Methods 0.000 claims description 8
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• NJJHDEAXOFVGBE-UHFFFAOYSA-N n-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=C(CN)C=C1F NJJHDEAXOFVGBE-UHFFFAOYSA-N 0.000 claims description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
• 208000009935 visceral pain Diseases 0.000 claims description 8
• FGSKYUOFKOOOAY-UHFFFAOYSA-N 2-ethylidene-N-[[4-(methanesulfonamido)phenyl]methyl]nonanamide Chemical compound CS(=O)(=O)NC1=CC=C(CNC(=O)C(=CC)CCCCCCC)C=C1 FGSKYUOFKOOOAY-UHFFFAOYSA-N 0.000 claims description 7
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 7
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• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 7
• OUEKLNJUMVZULZ-UHFFFAOYSA-N 2-[4-(2-aminoethoxy)-3-methoxyphenyl]-n-[3-(3,4-dimethylphenyl)propyl]acetamide;hydron;chloride Chemical compound Cl.C1=C(OCCN)C(OC)=CC(CC(=O)NCCCC=2C=C(C)C(C)=CC=2)=C1 OUEKLNJUMVZULZ-UHFFFAOYSA-N 0.000 claims description 6
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• IYMKEGIJVNYNHI-UHFFFAOYSA-N n-[[3-fluoro-4-(methanesulfonamido)phenyl]methyl]-8-(2-methylbutan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)CC)CCC11ON=C(C(=O)NCC=2C=C(F)C(NS(C)(=O)=O)=CC=2)C1 IYMKEGIJVNYNHI-UHFFFAOYSA-N 0.000 claims description 6
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• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 6
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