RU2515895C2 - Производные спиро(5.5)ундекана - Google Patents
Производные спиро(5.5)ундекана Download PDFInfo
- Publication number
- RU2515895C2 RU2515895C2 RU2010143446/04A RU2010143446A RU2515895C2 RU 2515895 C2 RU2515895 C2 RU 2515895C2 RU 2010143446/04 A RU2010143446/04 A RU 2010143446/04A RU 2010143446 A RU2010143446 A RU 2010143446A RU 2515895 C2 RU2515895 C2 RU 2515895C2
- Authority
- RU
- Russia
- Prior art keywords
- cyclohexane
- carbazole
- tetrahydrospiro
- phenyl
- aliphatic
- Prior art date
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- NECLQTPQJZSWOE-UHFFFAOYSA-N spiro[5.5]undecane Chemical class C1CCCCC21CCCCC2 NECLQTPQJZSWOE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- -1 monosubstituted -phenyl Chemical group 0.000 claims abstract description 40
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 125000001424 substituent group Chemical group 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 17
- 230000036407 pain Effects 0.000 claims abstract description 14
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 47
- 125000001246 bromo group Chemical group Br* 0.000 claims description 36
- 229940005483 opioid analgesics Drugs 0.000 claims description 11
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 6
- ZWSWDQBQPBWPSH-UHFFFAOYSA-N 1'-benzyl-n,n-dimethylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCC2)CCC1(N(C)C)CC1=CC=CC=C1 ZWSWDQBQPBWPSH-UHFFFAOYSA-N 0.000 claims description 5
- 208000004880 Polyuria Diseases 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 230000035619 diuresis Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HMQKGJUWZHOQND-UHFFFAOYSA-N n,n-dimethyl-1'-thiophen-2-ylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCC2)CCC1(N(C)C)C1=CC=CS1 HMQKGJUWZHOQND-UHFFFAOYSA-N 0.000 claims description 5
- PQFYWECBSCAADP-UHFFFAOYSA-N 1'-butyl-n,n-dimethylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC(CCCC)(N(C)C)CCC11C(NC=2C3=CC=CC=2)=C3CCC1 PQFYWECBSCAADP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
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- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 206010012335 Dependence Diseases 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000003444 anaesthetic effect Effects 0.000 claims description 3
- CKXYQFTYCZAZNM-UHFFFAOYSA-N n,n,4,4-tetramethyl-1'-phenylspiro[3,9-dihydro-2h-carbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)C(C)(C)CC2)CCC1(N(C)C)C1=CC=CC=C1 CKXYQFTYCZAZNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- JHKZMRRZLZULNB-ILPVEIHGSA-N (3s)-n,n,3-trimethyl-1'-phenylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C([C@H](C1)C)C(C2=CC=CC=C2N2)=C2C1(CC1)CCC1(N(C)C)C1=CC=CC=C1 JHKZMRRZLZULNB-ILPVEIHGSA-N 0.000 claims description 2
- RBXHJSPYKKEICU-UHFFFAOYSA-N 1'-(3-fluorophenyl)-n,n-dimethyl-3-phenylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)C1)CC1C1=CC=CC=C1 RBXHJSPYKKEICU-UHFFFAOYSA-N 0.000 claims description 2
- RDAXQKOSJRUMOO-UHFFFAOYSA-N 2-(benzenesulfonyl)-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC(N(C)C)(C=2C=CC=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)CC1)C1S(=O)(=O)C1=CC=CC=C1 RDAXQKOSJRUMOO-UHFFFAOYSA-N 0.000 claims description 2
- RXHJKRXNICCUQP-UHFFFAOYSA-N 4'-(dimethylamino)-n-methoxy-n-methyl-4'-phenylspiro[2,3,4,9-tetrahydrocarbazole-1,1'-cyclohexane]-2-carboxamide Chemical compound CON(C)C(=O)C1CCC(C2=CC=CC=C2N2)=C2C1(CC1)CCC1(N(C)C)C1=CC=CC=C1 RXHJKRXNICCUQP-UHFFFAOYSA-N 0.000 claims description 2
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- YXDXKFCUECMCNW-UHFFFAOYSA-N [4'-(dimethylamino)-4'-phenylspiro[2,3,4,9-tetrahydrocarbazole-1,1'-cyclohexane]-2-yl]methanol Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCC2CO)CCC1(N(C)C)C1=CC=CC=C1 YXDXKFCUECMCNW-UHFFFAOYSA-N 0.000 claims description 2
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- MOXMAPCGWRNWAA-UHFFFAOYSA-N n,n,3,3-tetramethyl-1'-phenylspiro[4,9-dihydro-2h-carbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CC(C)(C)C2)CCC1(N(C)C)C1=CC=CC=C1 MOXMAPCGWRNWAA-UHFFFAOYSA-N 0.000 claims description 2
- WYLWVLYVNOVMBU-UHFFFAOYSA-N n,n-dimethyl-1',3-diphenylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC(N(C)C)(C=2C=CC=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)C1)CC1C1=CC=CC=C1 WYLWVLYVNOVMBU-UHFFFAOYSA-N 0.000 claims description 2
- IAQIOQVRAXQROI-UHFFFAOYSA-N n,n-dimethyl-1'-phenyl-2-piperidin-1-ylsulfonylspiro[2,3,4,9-tetrahydrocarbazole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC(N(C)C)(C=2C=CC=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)CC1)C1S(=O)(=O)N1CCCCC1 IAQIOQVRAXQROI-UHFFFAOYSA-N 0.000 claims description 2
- GVBGFSRACMUVRH-UHFFFAOYSA-N n-[4'-(dimethylamino)-4'-(3-fluorophenyl)spiro[2,3,4,9-tetrahydrocarbazole-1,1'-cyclohexane]-3-yl]-2-phenylacetamide Chemical compound C1CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)C1)CC1NC(=O)CC1=CC=CC=C1 GVBGFSRACMUVRH-UHFFFAOYSA-N 0.000 claims description 2
- DKIBPLUWPVADNW-UHFFFAOYSA-N n-[4'-(dimethylamino)-4'-(3-fluorophenyl)spiro[2,3,4,9-tetrahydrocarbazole-1,1'-cyclohexane]-3-yl]-2-phenylcyclopropane-1-carboxamide Chemical compound C1CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)C1)CC1NC(=O)C1CC1C1=CC=CC=C1 DKIBPLUWPVADNW-UHFFFAOYSA-N 0.000 claims description 2
- DMBLBMRJZZCVDC-UHFFFAOYSA-N n-[4'-(dimethylamino)-4'-(3-fluorophenyl)spiro[2,3,4,9-tetrahydrocarbazole-1,1'-cyclohexane]-3-yl]-3-phenylpropanamide Chemical compound C1CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)C1)CC1NC(=O)CCC1=CC=CC=C1 DMBLBMRJZZCVDC-UHFFFAOYSA-N 0.000 claims description 2
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- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical compound NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 claims description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
- 125000003118 aryl group Chemical group 0.000 description 56
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 34
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- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940126589 solid medicine Drugs 0.000 description 1
- 238000006265 spirocyclization reaction Methods 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003459 sulfonic acid esters Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 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
- 229910052723 transition metal Inorganic materials 0.000 description 1
- FWSPXZXVNVQHIF-UHFFFAOYSA-N triethyl(ethynyl)silane Chemical group CC[Si](CC)(CC)C#C FWSPXZXVNVQHIF-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08005804 | 2008-03-27 | ||
| EP08005804.3 | 2008-03-27 | ||
| PCT/EP2009/002180 WO2009118169A1 (de) | 2008-03-27 | 2009-03-25 | Spiro(5.5)undecan derivate |
Publications (2)
| Publication Number | Publication Date |
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| RU2010143446A RU2010143446A (ru) | 2012-05-10 |
| RU2515895C2 true RU2515895C2 (ru) | 2014-05-20 |
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| US (1) | US8288430B2 (enExample) |
| EP (1) | EP2257526B1 (enExample) |
| JP (1) | JP5542119B2 (enExample) |
| CN (1) | CN102083790B (enExample) |
| AT (1) | ATE537143T1 (enExample) |
| AU (1) | AU2009228643B2 (enExample) |
| CA (1) | CA2719736C (enExample) |
| CY (1) | CY1112322T1 (enExample) |
| DK (1) | DK2257526T3 (enExample) |
| ES (1) | ES2375543T3 (enExample) |
| HR (1) | HRP20120017T1 (enExample) |
| IL (1) | IL208279A (enExample) |
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| PT (1) | PT2257526E (enExample) |
| RU (1) | RU2515895C2 (enExample) |
| SI (1) | SI2257526T1 (enExample) |
| WO (1) | WO2009118169A1 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009118163A1 (de) | 2008-03-27 | 2009-10-01 | Grünenthal GmbH | (hetero-)aryl-cyclohexan-derivate |
| PL2271613T3 (pl) | 2008-03-27 | 2014-09-30 | Gruenenthal Gmbh | Hydroksymetylocykloheksyloaminy |
| AR071067A1 (es) | 2008-03-27 | 2010-05-26 | Gruenenthal Chemie | Ciclohexildiaminas sustituidas |
| PT2260042E (pt) | 2008-03-27 | 2011-12-06 | Gruenenthal Gmbh | Derivados de ciclo-hexano espirocíclicos substituídos |
| CA2719736C (en) | 2008-03-27 | 2016-02-09 | Gruenenthal Gmbh | Spiro(5.5)undecane derivatives |
| EP2502907B1 (de) | 2008-03-27 | 2018-08-29 | Grünenthal GmbH | Substituierte 4-Aminocyclohexan-Derivate |
| SI2649044T1 (en) * | 2010-12-08 | 2018-01-31 | Gruenenthal Gmbh | A process for the synthesis of substituted aminocyclohexanone derivatives |
| TW201607923A (zh) | 2014-07-15 | 2016-03-01 | 歌林達有限公司 | 被取代之氮螺環（４．５）癸烷衍生物 |
| ES2686326T3 (es) | 2014-07-15 | 2018-10-17 | Grünenthal GmbH | Derivados de azaspiro(4,5)decano sustituidos |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1482915A1 (ru) * | 1985-04-22 | 1989-05-30 | Американ Хоум Продактс Корпорейшн (Фирма) | Производные 2,3,4,9-тетрагидро-1Н-карбазол-1-уксусной кислоты, про вл ющие болеутол ющее и противовоспалительное действие и метиловый эфир 2,3,4,9-тетрагидро-1Н-карбазол-1-уксусной кислоты как промежуточный продукт дл синтеза производных 2,3,4,9-тетрагидро-1Н-карбазол-1-уксусной кислоты, про вл ющих болеутол ющее и противовоспалительное действие |
| RU2006126787A (ru) * | 2003-12-23 | 2008-01-27 | Грюненталь ГмбХ (DE) | Спироциклические производные циклогексана со сродством к orli-рецептору |
Family Cites Families (56)
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| US759311A (en) * | 1903-11-19 | 1904-05-10 | Press Publishing Company | News-stand. |
| GB1055203A (en) | 1964-09-16 | 1967-01-18 | Ici Ltd | -ß-carboline derivatives, a process for their manufacture, and compositions containing them |
| US4065573A (en) * | 1976-06-03 | 1977-12-27 | The Upjohn Company | 4-Amino-4-phenylcyclohexanone ketal compositions and process of use |
| US4115589A (en) * | 1977-05-17 | 1978-09-19 | The Upjohn Company | Compounds, compositions and method of use |
| US4366172A (en) * | 1977-09-29 | 1982-12-28 | The Upjohn Company | 4-Amino-cyclohexanols, their pharmaceutical compositions and methods of use |
| US4291039A (en) * | 1980-08-08 | 1981-09-22 | Miles Laboratories, Inc. | Tetrahydro β-carbolines having anti-hypertensive activity |
| DE3309596A1 (de) * | 1982-08-05 | 1984-04-05 | Basf Ag, 6700 Ludwigshafen | 2-substituierte 1-(3'-aminoalkyl)-1,2,3,4-tetrahydro-ss-carboline, ihre herstellung und verwendung als arzneimittel |
| US5328905A (en) * | 1987-07-20 | 1994-07-12 | Duphar International Research B.V. | 8,9-anellated-1,2,3,4-tetrahydro-β-carboline derivatives |
| EP0620222A3 (en) * | 1993-04-14 | 1995-04-12 | Lilly Co Eli | Tetrahydro-beta-carbolines. |
| US5631265A (en) * | 1994-03-11 | 1997-05-20 | Eli Lilly And Company | 8-substituted tetrahydro-beta-carbolines |
| US5869691A (en) * | 1995-05-19 | 1999-02-09 | Eli Lilly And Company | Aminoalkyl-indoles |
| GB0012240D0 (en) | 2000-05-19 | 2000-07-12 | Merck Sharp & Dohme | Therapeutic agents |
| DE10123163A1 (de) | 2001-05-09 | 2003-01-16 | Gruenenthal Gmbh | Substituierte Cyclohexan-1,4-diaminderivate |
| DE10135636A1 (de) | 2001-07-17 | 2003-02-06 | Gruenenthal Gmbh | Substituierte 4-Aminocyclohexanole |
| IL159317A0 (en) | 2001-07-18 | 2004-06-01 | Dipiemme Dies And Plastic Mach | A corrugated/undulated sheet having protuberances in the grooves defined by the corrugations, process and apparatus |
| DE10213051B4 (de) | 2002-03-23 | 2013-03-07 | Grünenthal GmbH | Substituierte 4-Aminocyclohexanole |
| TWI329111B (en) * | 2002-05-24 | 2010-08-21 | X Ceptor Therapeutics Inc | Azepinoindole and pyridoindole derivatives as pharmaceutical agents |
| US7595311B2 (en) * | 2002-05-24 | 2009-09-29 | Exelixis, Inc. | Azepinoindole derivatives as pharmaceutical agents |
| DE10252667A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE10252665A1 (de) | 2002-11-11 | 2004-06-03 | Grünenthal GmbH | 4-Aminomethyl-1-aryl-cyclohexylamin-Derivate |
| DE10252650A1 (de) | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Cyclohexyl-Harnstoff-Derivate |
| DE10252666A1 (de) | 2002-11-11 | 2004-08-05 | Grünenthal GmbH | N-Piperidyl-cyclohexan-Derivate |
| ES2279195T3 (es) | 2002-11-12 | 2007-08-16 | Grunenthal Gmbh | Derivados de 4-alquil/4-alquenil/4-alquenilmetil/-1-arilciclohexilamina. |
| WO2004043902A1 (de) | 2002-11-12 | 2004-05-27 | Grünenthal GmbH | 4-hydroxymethyl-1-aryl-cyclohexylamin-derivative |
| WO2004113336A1 (en) * | 2003-06-16 | 2004-12-29 | Chroma Therapeutics Limited | Carboline and betacarboline derivatives for use as hdac enzyme inhibitors |
| DE10360793A1 (de) | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE102004023508A1 (de) | 2004-05-10 | 2005-12-08 | Grünenthal GmbH | Säurederivate substituierter Cyclohexyl-1,4-diamine |
| DE102004023507A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Substituierte Cyclohexylessigsäure-Derivate |
| DE102004023635A1 (de) | 2004-05-10 | 2006-04-13 | Grünenthal GmbH | Heteroarylsubstituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004023632A1 (de) | 2004-05-10 | 2005-12-08 | Grünenthal GmbH | Substituierte Cyclohexylcarbonsäure-Derivate |
| DE102004023522A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Substituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004023501A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Oxosubstituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004023506A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Kettenverlängerte substituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004039382A1 (de) | 2004-08-13 | 2006-02-23 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| EP1824821A2 (en) * | 2004-11-23 | 2007-08-29 | PTC Therapeutics, Inc. | Carbazole, carboline and indole derivatives useful in the inhibition of vegf production |
| DE102005016460A1 (de) | 2005-04-11 | 2006-10-19 | Grünenthal GmbH | Spriocyclische Cyclohexanderivate zur Behandlung von Substanzabhängigkeit |
| EP1747779A1 (en) * | 2005-07-28 | 2007-01-31 | Laboratorios Del Dr. Esteve, S.A. | Tetrahydro-b-carbolin-sulfonamide derivatives as 5-HT6 ligands |
| WO2007062175A2 (en) * | 2005-11-21 | 2007-05-31 | Amgen Inc. | Spiro-substituted tricyclic heterocycles cxcr3 antagonists |
| DE102005061428A1 (de) | 2005-12-22 | 2007-08-16 | Grünenthal GmbH | Substituierte Cyclohexylmethyl-Derivate |
| DE102005061429A1 (de) | 2005-12-22 | 2007-06-28 | Grünenthal GmbH | Substituierte Oxazol-Derivate |
| DE102005061430A1 (de) | 2005-12-22 | 2007-07-05 | Grünenthal GmbH | Substituierte Imidazolin-Derivate |
| DE102005061427A1 (de) | 2005-12-22 | 2007-06-28 | Grünenthal GmbH | Substituierte Oxadiazol-Derivate |
| DE102006019597A1 (de) * | 2006-04-27 | 2007-10-31 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| CN101479563A (zh) | 2006-04-28 | 2009-07-08 | 麦克罗尼克激光系统公司 | 用于记录图像以及表面研究的方法和装置 |
| DE102006033114A1 (de) | 2006-07-18 | 2008-01-24 | Grünenthal GmbH | Spirocyclische Azaindol-Derivate |
| DE102006033109A1 (de) | 2006-07-18 | 2008-01-31 | Grünenthal GmbH | Substituierte Heteroaryl-Derivate |
| DE102006046745A1 (de) * | 2006-09-29 | 2008-04-03 | Grünenthal GmbH | Gemischte ORL1/µ-Agonisten zur Behandlung von Schmerz |
| DE102007009319A1 (de) | 2007-02-22 | 2008-08-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE102007009235A1 (de) * | 2007-02-22 | 2008-09-18 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| FR2921217B1 (fr) | 2007-09-14 | 2016-11-25 | Eads Secure Networks | Systeme de radiocommunications large bande, station recptrice complementaire, et procede d'optimisation d'une liaison de donnees dans un systeme de radiocommunications. |
| WO2009118163A1 (de) | 2008-03-27 | 2009-10-01 | Grünenthal GmbH | (hetero-)aryl-cyclohexan-derivate |
| CA2719736C (en) | 2008-03-27 | 2016-02-09 | Gruenenthal Gmbh | Spiro(5.5)undecane derivatives |
| AR071067A1 (es) | 2008-03-27 | 2010-05-26 | Gruenenthal Chemie | Ciclohexildiaminas sustituidas |
| PL2271613T3 (pl) | 2008-03-27 | 2014-09-30 | Gruenenthal Gmbh | Hydroksymetylocykloheksyloaminy |
| EP2502907B1 (de) | 2008-03-27 | 2018-08-29 | Grünenthal GmbH | Substituierte 4-Aminocyclohexan-Derivate |
| PT2260042E (pt) | 2008-03-27 | 2011-12-06 | Gruenenthal Gmbh | Derivados de ciclo-hexano espirocíclicos substituídos |
-
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- 2009-03-25 HR HR20120017T patent/HRP20120017T1/hr unknown
- 2009-03-25 MX MX2010010337A patent/MX2010010337A/es active IP Right Grant
- 2009-03-25 WO PCT/EP2009/002180 patent/WO2009118169A1/de not_active Ceased
- 2009-03-25 US US12/410,605 patent/US8288430B2/en not_active Expired - Fee Related
- 2009-03-25 CN CN200980110773.2A patent/CN102083790B/zh active Active
- 2009-03-25 DK DK09725570.7T patent/DK2257526T3/da active
- 2009-03-25 PT PT09725570T patent/PT2257526E/pt unknown
- 2009-03-25 AU AU2009228643A patent/AU2009228643B2/en not_active Ceased
- 2009-03-25 AT AT09725570T patent/ATE537143T1/de active
- 2009-03-25 EP EP09725570A patent/EP2257526B1/de not_active Not-in-force
- 2009-03-25 JP JP2011501141A patent/JP5542119B2/ja not_active Expired - Fee Related
- 2009-03-25 ES ES09725570T patent/ES2375543T3/es active Active
- 2009-03-25 RU RU2010143446/04A patent/RU2515895C2/ru not_active IP Right Cessation
- 2009-03-25 SI SI200930121T patent/SI2257526T1/sl unknown
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1482915A1 (ru) * | 1985-04-22 | 1989-05-30 | Американ Хоум Продактс Корпорейшн (Фирма) | Производные 2,3,4,9-тетрагидро-1Н-карбазол-1-уксусной кислоты, про вл ющие болеутол ющее и противовоспалительное действие и метиловый эфир 2,3,4,9-тетрагидро-1Н-карбазол-1-уксусной кислоты как промежуточный продукт дл синтеза производных 2,3,4,9-тетрагидро-1Н-карбазол-1-уксусной кислоты, про вл ющих болеутол ющее и противовоспалительное действие |
| RU2006126787A (ru) * | 2003-12-23 | 2008-01-27 | Грюненталь ГмбХ (DE) | Спироциклические производные циклогексана со сродством к orli-рецептору |
Also Published As
| Publication number | Publication date |
|---|---|
| SI2257526T1 (sl) | 2012-01-31 |
| US8288430B2 (en) | 2012-10-16 |
| DK2257526T3 (da) | 2012-02-06 |
| AU2009228643A1 (en) | 2009-10-01 |
| JP5542119B2 (ja) | 2014-07-09 |
| IL208279A0 (en) | 2010-12-30 |
| PL2257526T3 (pl) | 2012-05-31 |
| IL208279A (en) | 2015-07-30 |
| AU2009228643B2 (en) | 2013-07-11 |
| RU2010143446A (ru) | 2012-05-10 |
| HK1149763A1 (en) | 2011-10-14 |
| MX2010010337A (es) | 2010-10-07 |
| ATE537143T1 (de) | 2011-12-15 |
| WO2009118169A1 (de) | 2009-10-01 |
| EP2257526B1 (de) | 2011-12-14 |
| CN102083790A (zh) | 2011-06-01 |
| EP2257526A1 (de) | 2010-12-08 |
| HRP20120017T1 (hr) | 2012-01-31 |
| US20090247505A1 (en) | 2009-10-01 |
| JP2011515430A (ja) | 2011-05-19 |
| CN102083790B (zh) | 2014-03-05 |
| CA2719736C (en) | 2016-02-09 |
| CA2719736A1 (en) | 2009-10-01 |
| ES2375543T3 (es) | 2012-03-01 |
| PT2257526E (pt) | 2012-01-24 |
| CY1112322T1 (el) | 2015-12-09 |
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