AU678023B2 - Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists - Google Patents

Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists Download PDF

Info

Publication number: AU678023B2
Authority: AU; Australia
Prior art keywords: phenyl; compound; ethyl; pyrrolidin; mmol
Prior art date: 1993-05-06
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.): Ceased

Application number

AU69426/94A

Other languages

English (en)

Other versions

AU6942694A (en

Inventor

Timothy P. Burkholder

Elizabeth M Kudlacz

Tieu-Binh Le

George D Maynard

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Aventis Inc

Original Assignee

Merrell Dow Pharmaceuticals Inc

Priority date (The priority date 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 date listed.)

1993-05-06

Filing date

1994-04-22

Publication date

1997-05-15

1994-04-22 Application filed by Merrell Dow Pharmaceuticals Inc filed Critical Merrell Dow Pharmaceuticals Inc

1994-12-12 Publication of AU6942694A publication Critical patent/AU6942694A/en

1997-05-15 Application granted granted Critical

1997-05-15 Publication of AU678023B2 publication Critical patent/AU678023B2/en

2001-02-15 Assigned to MERRELL PHARMACEUTICALS INC. reassignment MERRELL PHARMACEUTICALS INC. Request to Amend Deed and Register Assignors: MERRELL DOW PHARMACEUTICALS INC.

2006-03-09 Assigned to AVENTIS INC. reassignment AVENTIS INC. Alteration of Name(s) in Register under S187 Assignors: MERRELL PHARMACEUTICALS INC.

2014-04-22 Anticipated expiration legal-status Critical

Status Ceased legal-status Critical Current

Links

102000003141 Tachykinin Human genes 0.000 title abstract description 18
108060008037 tachykinin Proteins 0.000 title abstract description 18
239000005557 antagonist Substances 0.000 title description 12
150000001875 compounds Chemical class 0.000 claims abstract description 438
238000000034 method Methods 0.000 claims abstract description 214
150000003839 salts Chemical class 0.000 claims abstract description 38
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 241
-1 1-ethyl Chemical group 0.000 claims description 159
239000000203 mixture Substances 0.000 claims description 84
125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 38
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 35
125000001424 substituent group Chemical group 0.000 claims description 32
229910052739 hydrogen Inorganic materials 0.000 claims description 23
239000001257 hydrogen Substances 0.000 claims description 23
150000001408 amides Chemical class 0.000 claims description 20
238000011282 treatment Methods 0.000 claims description 19
150000002431 hydrogen Chemical class 0.000 claims description 18
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 15
150000002367 halogens Chemical class 0.000 claims description 15
239000008194 pharmaceutical composition Substances 0.000 claims description 13
125000000217 alkyl group Chemical group 0.000 claims description 9
208000006673 asthma Diseases 0.000 claims description 9
208000002193 Pain Diseases 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims description 5
206010011224 Cough Diseases 0.000 claims description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
229910021386 carbon form Inorganic materials 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
208000027866 inflammatory disease Diseases 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 3
230000001272 neurogenic effect Effects 0.000 claims description 3
208000023504 respiratory system disease Diseases 0.000 claims description 3
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
125000003386 piperidinyl group Chemical group 0.000 claims description 2
XTDYIOOONNVFMA-UHFFFAOYSA-N dimethyl pentanedioate Chemical compound COC(=O)CCCC(=O)OC XTDYIOOONNVFMA-UHFFFAOYSA-N 0.000 claims 1
239000003814 drug Substances 0.000 claims 1
125000004193 piperazinyl group Chemical group 0.000 claims 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 24
201000010099 disease Diseases 0.000 abstract description 22
230000008485 antagonism Effects 0.000 abstract description 14
101800000399 Neurokinin A Proteins 0.000 abstract description 10
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102100024304 Protachykinin-1 Human genes 0.000 abstract description 9
101800003906 Substance P Proteins 0.000 abstract description 9
238000002360 preparation method Methods 0.000 abstract description 9
QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 abstract description 8
HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 abstract description 8
208000007920 Neurogenic Inflammation Diseases 0.000 abstract description 3
230000008569 process Effects 0.000 abstract description 3
230000000144 pharmacologic effect Effects 0.000 abstract description 2
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 506
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 372
238000003786 synthesis reaction Methods 0.000 description 315
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238000006243 chemical reaction Methods 0.000 description 304
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 289
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 191
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239000000243 solution Substances 0.000 description 122
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 121
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 106
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 105
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
239000002904 solvent Substances 0.000 description 78
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
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238000001953 recrystallisation Methods 0.000 description 48
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239000012467 final product Substances 0.000 description 45
238000001665 trituration Methods 0.000 description 43
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 42
239000002253 acid Substances 0.000 description 42
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
239000002585 base Substances 0.000 description 40
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 37
235000008504 concentrate Nutrition 0.000 description 37
239000012141 concentrate Substances 0.000 description 37
150000008064 anhydrides Chemical class 0.000 description 36
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
239000002002 slurry Substances 0.000 description 35
239000012359 Methanesulfonyl chloride Substances 0.000 description 34
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 34
LZWFVOQSFVFPJK-UHFFFAOYSA-N 4-phenylpiperidine-4-carboxamide;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)N)CCNCC1 LZWFVOQSFVFPJK-UHFFFAOYSA-N 0.000 description 32
239000000543 intermediate Substances 0.000 description 32
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 30
238000004458 analytical method Methods 0.000 description 28
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 28
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 28
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 27
239000000284 extract Substances 0.000 description 27
150000001412 amines Chemical class 0.000 description 25
229910000104 sodium hydride Inorganic materials 0.000 description 24
229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
239000008346 aqueous phase Substances 0.000 description 22
PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 22
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
235000017557 sodium bicarbonate Nutrition 0.000 description 22
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 21
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 20
125000003118 aryl group Chemical group 0.000 description 20
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229920006395 saturated elastomer Polymers 0.000 description 20
239000012312 sodium hydride Substances 0.000 description 20
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 19
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 18
150000001350 alkyl halides Chemical class 0.000 description 17
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RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
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CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
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NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 14
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229960004424 carbon dioxide Drugs 0.000 description 14
239000000706 filtrate Substances 0.000 description 14
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
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125000001309 chloro group Chemical group Cl* 0.000 description 13
MKJDUHZPLQYUCB-UHFFFAOYSA-N decan-4-one Chemical compound CCCCCCC(=O)CCC MKJDUHZPLQYUCB-UHFFFAOYSA-N 0.000 description 13
238000010511 deprotection reaction Methods 0.000 description 13
QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 13
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239000007868 Raney catalyst Substances 0.000 description 12
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KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
239000007789 gas Substances 0.000 description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
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229910000027 potassium carbonate Inorganic materials 0.000 description 11
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238000004128 high performance liquid chromatography Methods 0.000 description 10
HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 10
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NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
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CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000037452 priming Effects 0.000 description 1
102000004196 processed proteins & peptides Human genes 0.000 description 1
108090000765 processed proteins & peptides Proteins 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
PSAYJRPASWETSH-UHFFFAOYSA-N pyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CC=N1 PSAYJRPASWETSH-UHFFFAOYSA-N 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
150000003242 quaternary ammonium salts Chemical class 0.000 description 1
230000000171 quenching effect Effects 0.000 description 1
239000002287 radioligand Substances 0.000 description 1
239000012066 reaction slurry Substances 0.000 description 1
239000002464 receptor antagonist Substances 0.000 description 1
229940044551 receptor antagonist Drugs 0.000 description 1
229920005989 resin Polymers 0.000 description 1
239000011347 resin Substances 0.000 description 1
230000004044 response Effects 0.000 description 1
230000004043 responsiveness Effects 0.000 description 1
CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
229940081974 saccharin Drugs 0.000 description 1
235000019204 saccharin Nutrition 0.000 description 1
239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
201000000980 schizophrenia Diseases 0.000 description 1
239000012056 semi-solid material Substances 0.000 description 1
ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
239000004208 shellac Substances 0.000 description 1
229940113147 shellac Drugs 0.000 description 1
235000013874 shellac Nutrition 0.000 description 1
230000016160 smooth muscle contraction Effects 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
230000000707 stereoselective effect Effects 0.000 description 1
239000000126 substance Substances 0.000 description 1
150000003460 sulfonic acids Chemical class 0.000 description 1
239000001117 sulphuric acid Substances 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
QMHDCIGWEAHSLF-UHFFFAOYSA-N tert-butyl 4-carbamoyl-4-pyridin-4-ylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(C(N)=O)C1=CC=NC=C1 QMHDCIGWEAHSLF-UHFFFAOYSA-N 0.000 description 1
FQZLNQAUUMSUHT-UHFFFAOYSA-N tert-butyl n,n-bis(2-chloroethyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CCCl)CCCl FQZLNQAUUMSUHT-UHFFFAOYSA-N 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
150000003527 tetrahydropyrans Chemical group 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
LJJKNPQAGWVLDQ-SNVBAGLBSA-N thiorphan Chemical compound OC(=O)CNC(=O)[C@@H](CS)CC1=CC=CC=C1 LJJKNPQAGWVLDQ-SNVBAGLBSA-N 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
239000012049 topical pharmaceutical composition Substances 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 description 1
150000003628 tricarboxylic acids Chemical class 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
239000008243 triphasic system Substances 0.000 description 1
210000001170 unmyelinated nerve fiber Anatomy 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
235000012431 wafers Nutrition 0.000 description 1
239000008215 water for injection Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
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- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
- 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
- C07D471/10—Spiro-condensed systems

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Pulmonology (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Psychiatry (AREA)
Immunology (AREA)
Hospice & Palliative Care (AREA)
Anesthesiology (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Dermatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)

AU69426/94A 1993-05-06 1994-04-22 Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists Ceased AU678023B2 (en)

Applications Claiming Priority (7)

Application Number	Priority Date	Filing Date	Title
US058606		1979-07-18
US5860693A	1993-05-06	1993-05-06
US21848394A	1994-03-28	1994-03-28
US218483		1994-03-28
US22537194A	1994-04-19	1994-04-19
US225371		1994-04-19
PCT/US1994/004498 WO1994026735A1 (en)	1993-05-06	1994-04-22	Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists

Publications (2)

Publication Number	Publication Date
AU6942694A AU6942694A (en)	1994-12-12
AU678023B2 true AU678023B2 (en)	1997-05-15

Family

ID=27369482

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
AU69426/94A Ceased AU678023B2 (en)	1993-05-06	1994-04-22	Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists

Country Status (18)

Country	Link
EP (1)	EP0696280B1 (2)
JP (1)	JP3424174B2 (2)
CN (1)	CN1081635C (2)
AT (1)	ATE158580T1 (2)
AU (1)	AU678023B2 (2)
CA (1)	CA2160462C (2)
DE (1)	DE69405862T2 (2)
DK (1)	DK0696280T3 (2)
ES (1)	ES2110761T3 (2)
FI (1)	FI113047B (2)
GR (1)	GR3025475T3 (2)
HU (1)	HU224496B1 (2)
IL (1)	IL109496A (2)
MX (1)	MX9403386A (2)
NO (1)	NO309144B1 (2)
NZ (1)	NZ267209A (2)
TW (1)	TW281675B (2)
WO (1)	WO1994026735A1 (2)

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Also Published As

Publication number	Publication date
IL109496A0 (en)	1994-08-26
AU6942694A (en)	1994-12-12
IL109496A (en)	2000-07-26
HU224496B1 (hu)	2005-10-28
ATE158580T1 (de)	1997-10-15
EP0696280B1 (en)	1997-09-24
DK0696280T3 (da)	1998-01-12
JP3424174B2 (ja)	2003-07-07
CN1081635C (zh)	2002-03-27
MX9403386A (es)	1995-01-31
WO1994026735A1 (en)	1994-11-24
NZ267209A (en)	1997-09-22
TW281675B (2)	1996-07-21
DE69405862T2 (de)	1998-01-15
CN1124961A (zh)	1996-06-19
GR3025475T3 (en)	1998-02-27
HUT74085A (en)	1996-11-28
ES2110761T3 (es)	1998-02-16
EP0696280A1 (en)	1996-02-14
FI955258A0 (fi)	1995-11-02
DE69405862D1 (de)	1997-10-30
NO309144B1 (no)	2000-12-18
HU9503153D0 (en)	1996-01-29
FI113047B (fi)	2004-02-27
CA2160462C (en)	1998-12-15
NO954400L (no)	1996-01-08
CA2160462A1 (en)	1994-11-24
FI955258L (fi)	1995-11-30
NO954400D0 (no)	1995-11-03
JPH09500361A (ja)	1997-01-14

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2001-02-15

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Owner name: MERRELL PHARMACEUTICALS INC.

Free format text: FORMER NAME WAS: MERRELL DOW PHARMACEUTICALS INC.

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