HRP970509A2 - Pyrrolidinyl and pyrrolinylethylamine compounds as kappa agonists - Google Patents
Pyrrolidinyl and pyrrolinylethylamine compounds as kappa agonistsInfo
- Publication number
- HRP970509A2 HRP970509A2 HRPCT/IB96/00957A HRP970509A HRP970509A2 HR P970509 A2 HRP970509 A2 HR P970509A2 HR P970509 A HRP970509 A HR P970509A HR P970509 A2 HRP970509 A2 HR P970509A2
- Authority
- HR
- Croatia
- Prior art keywords
- methylamino
- phenylethyl
- hydroxypyrrolidin
- propylbenzamide
- methoxymethoxypyrrolidin
- Prior art date
Links
- 239000000556 agonist Substances 0.000 title claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 title description 4
- ABOAZLNMRQLBNH-UHFFFAOYSA-N 2-(2,3-dihydropyrrol-1-yl)ethanamine Chemical class NCCN1CCC=C1 ABOAZLNMRQLBNH-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims description 179
- 150000001875 compounds Chemical class 0.000 claims description 124
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 103
- 239000000203 mixture Substances 0.000 claims description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 76
- -1 hydroxy, amino Chemical group 0.000 claims description 70
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 34
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 18
- 239000012442 inert solvent Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 239000000730 antalgic agent Substances 0.000 claims description 9
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 230000000202 analgesic effect Effects 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 102000048260 kappa Opioid Receptors Human genes 0.000 claims description 7
- 108020001588 κ-opioid receptors Proteins 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 125000005543 phthalimide group Chemical group 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 230000003444 anaesthetic effect Effects 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 239000004090 neuroprotective agent Substances 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- FVPPPNWXMSRIOO-AVVPKOCDSA-N 2-[3-[[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-methylamino]pyrrolidin-1-yl]benzamide Chemical compound C([C@@H](N(C)C1CN(CC1)C=1C(=CC=CC=1)C(N)=O)C=1C=CC=CC=1)N1CC[C@H](O)C1 FVPPPNWXMSRIOO-AVVPKOCDSA-N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 239000003193 general anesthetic agent Substances 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 230000035939 shock Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 356
- 238000005160 1H NMR spectroscopy Methods 0.000 description 185
- 238000002360 preparation method Methods 0.000 description 146
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 143
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 96
- 239000007787 solid Substances 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- 150000001412 amines Chemical class 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 48
- 150000003840 hydrochlorides Chemical class 0.000 description 46
- 239000002904 solvent Substances 0.000 description 45
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 42
- 239000003921 oil Substances 0.000 description 42
- 235000019198 oils Nutrition 0.000 description 42
- 239000012267 brine Substances 0.000 description 41
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
- 238000003756 stirring Methods 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000007832 Na2SO4 Substances 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 28
- 235000011152 sodium sulphate Nutrition 0.000 description 28
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- ZHUMSHOAHIDXSN-LEWJYISDSA-N 4-[[(1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoic acid Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=CC=CC=1)N(C)C1=CC=C(C(O)=O)C=C1 ZHUMSHOAHIDXSN-LEWJYISDSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- WQEDXHXAKOGILB-UONOGXRCSA-N (1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethanol Chemical compound C1[C@@H](OCOC)CCN1C[C@@H](O)C1=CC=CC=C1 WQEDXHXAKOGILB-UONOGXRCSA-N 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 239000002632 kappa opiate receptor agonist Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 239000005711 Benzoic acid Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 235000010233 benzoic acid Nutrition 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- AWMVMTVKBNGEAK-QMMMGPOBSA-N (R)-styrene oxide Chemical compound C1O[C@@H]1C1=CC=CC=C1 AWMVMTVKBNGEAK-QMMMGPOBSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229940035676 analgesics Drugs 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- LLAMGYUWYUMHCH-UHFFFAOYSA-N methyl 4-(methylamino)benzoate Chemical compound CNC1=CC=C(C(=O)OC)C=C1 LLAMGYUWYUMHCH-UHFFFAOYSA-N 0.000 description 6
- 229940044601 receptor agonist Drugs 0.000 description 6
- 239000000018 receptor agonist Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- XXZDIDFBKZKGQB-NWDGAFQWSA-N (1s)-2-[(3s)-3-fluoropyrrolidin-1-yl]-1-phenylethanol Chemical compound C([C@@H](O)C=1C=CC=CC=1)N1CC[C@H](F)C1 XXZDIDFBKZKGQB-NWDGAFQWSA-N 0.000 description 5
- CNONYXFNOHXTLC-KBPBESRZSA-N (2r)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-2-phenylethanol Chemical compound C1[C@@H](OCOC)CCN1[C@@H](CO)C1=CC=CC=C1 CNONYXFNOHXTLC-KBPBESRZSA-N 0.000 description 5
- JVWZVGMSJISZQR-PYNWJHIZSA-N (2r)-2-[(3s)-3-(oxan-2-yloxy)pyrrolidin-1-yl]-2-phenylethanol Chemical compound O([C@H]1CCN(C1)[C@@H](CO)C=1C=CC=CC=1)C1CCCCO1 JVWZVGMSJISZQR-PYNWJHIZSA-N 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000003377 acid catalyst Substances 0.000 description 5
- 150000001350 alkyl halides Chemical class 0.000 description 5
- 230000009435 amidation Effects 0.000 description 5
- 238000007112 amidation reaction Methods 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 5
- BRAAQHGNTNZTFR-NWDGAFQWSA-N (1s)-2-[(3s)-3-chloropyrrolidin-1-yl]-1-phenylethanol Chemical compound C([C@@H](O)C=1C=CC=CC=1)N1CC[C@H](Cl)C1 BRAAQHGNTNZTFR-NWDGAFQWSA-N 0.000 description 4
- AFTQVONOXWGZPJ-UHFFFAOYSA-N 1-benzyl-3-chloropyrrolidine Chemical compound C1C(Cl)CCN1CC1=CC=CC=C1 AFTQVONOXWGZPJ-UHFFFAOYSA-N 0.000 description 4
- YQMXOIAIYXXXEE-UHFFFAOYSA-N 1-benzylpyrrolidin-3-ol Chemical class C1C(O)CCN1CC1=CC=CC=C1 YQMXOIAIYXXXEE-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- WMLUGDYHEFJEMS-PKOBYXMFSA-N 4-[[(1s)-2-[(3s)-3-fluoropyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoic acid Chemical compound C([C@@H](N(C)C=1C=CC(=CC=1)C(O)=O)C=1C=CC=CC=1)N1CC[C@H](F)C1 WMLUGDYHEFJEMS-PKOBYXMFSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- ZVIDMSBTYRSMAR-UHFFFAOYSA-N N-Methyl-4-aminobenzoate Chemical compound CNC1=CC=C(C(O)=O)C=C1 ZVIDMSBTYRSMAR-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- XXZDIDFBKZKGQB-RYUDHWBXSA-N (1r)-2-[(3s)-3-fluoropyrrolidin-1-yl]-1-phenylethanol Chemical compound C([C@H](O)C=1C=CC=CC=1)N1CC[C@H](F)C1 XXZDIDFBKZKGQB-RYUDHWBXSA-N 0.000 description 3
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- 150000003936 benzamides Chemical class 0.000 description 1
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- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- JGHYBJVUQGTEEB-UHFFFAOYSA-M dimethylalumanylium;chloride Chemical compound C[Al](C)Cl JGHYBJVUQGTEEB-UHFFFAOYSA-M 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
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- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
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- 229940050410 gluconate Drugs 0.000 description 1
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- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
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- 159000000003 magnesium salts Chemical class 0.000 description 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000005667 methoxymethylation reaction Methods 0.000 description 1
- GOXHKOANZONQCT-UHFFFAOYSA-N methyl 2-chloro-4-(methylamino)benzoate Chemical compound CNC1=CC=C(C(=O)OC)C(Cl)=C1 GOXHKOANZONQCT-UHFFFAOYSA-N 0.000 description 1
- UFBBWBUASTWQMC-RBBKRZOGSA-N methyl 2-methoxy-4-[[(1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoate Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=CC=CC=1)N(C)C1=CC=C(C(=O)OC)C(OC)=C1 UFBBWBUASTWQMC-RBBKRZOGSA-N 0.000 description 1
- HQRLEOWXQZXRCR-FCHUYYIVSA-N methyl 3-[[(1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoate Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=CC=CC=1)N(C)C1=CC=CC(C(=O)OC)=C1 HQRLEOWXQZXRCR-FCHUYYIVSA-N 0.000 description 1
- IAFKBTJFBOADGH-RBBKRZOGSA-N methyl 3-methoxy-4-[[(1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoate Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=CC=CC=1)N(C)C1=CC=C(C(=O)OC)C=C1OC IAFKBTJFBOADGH-RBBKRZOGSA-N 0.000 description 1
- SXUWFAHIDCNUIG-UHFFFAOYSA-N methyl 4-(hydroxyamino)benzoate Chemical compound COC(=O)C1=CC=C(NO)C=C1 SXUWFAHIDCNUIG-UHFFFAOYSA-N 0.000 description 1
- XSZOPWSDBRDCKZ-FCHUYYIVSA-N methyl 4-[[(1s)-1-(3-chlorophenyl)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]ethyl]-methylamino]benzoate Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=C(Cl)C=CC=1)N(C)C1=CC=C(C(=O)OC)C=C1 XSZOPWSDBRDCKZ-FCHUYYIVSA-N 0.000 description 1
- QZXPTQQMVUUWHM-LEWJYISDSA-N methyl 4-[[(1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethyl]amino]benzoate Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=CC=CC=1)NC1=CC=C(C(=O)OC)C=C1 QZXPTQQMVUUWHM-LEWJYISDSA-N 0.000 description 1
- CEIVCXRHQZRKRY-AZUAARDMSA-N methyl 4-[[(1s)-2-[(3s)-3-fluoropyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N(C)[C@@H](C=1C=CC=CC=1)CN1C[C@@H](F)CC1 CEIVCXRHQZRKRY-AZUAARDMSA-N 0.000 description 1
- IRMXQGRWUSVFNK-VQTJNVASSA-N methyl 4-[[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-methylamino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N(C)[C@@H](C=1C=CC=CC=1)CN1C[C@@H](O)CC1 IRMXQGRWUSVFNK-VQTJNVASSA-N 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- ZXMDPSJGMJCMNZ-VQTJNVASSA-N methyl 6-[[(1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-phenylethyl]-methylamino]pyridine-3-carboxylate Chemical compound C1[C@@H](OCOC)CCN1C[C@H](C=1C=CC=CC=1)N(C)C1=CC=C(C(=O)OC)C=N1 ZXMDPSJGMJCMNZ-VQTJNVASSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- AQFWNELGMODZGC-UHFFFAOYSA-N o-ethylhydroxylamine Chemical compound CCON AQFWNELGMODZGC-UHFFFAOYSA-N 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- UWBHMRBRLOJJAA-UHFFFAOYSA-N oxaluric acid Chemical compound NC(=O)NC(=O)C(O)=O UWBHMRBRLOJJAA-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical class C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010825 rotarod performance test Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- TWRVYXVQOJCHIF-UHFFFAOYSA-N tert-butyl-chloro-methylsilane Chemical compound C[SiH](Cl)C(C)(C)C TWRVYXVQOJCHIF-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000007070 tosylation reaction Methods 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
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/12—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 chain containing hetero atoms as chain links
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Biomedical Technology (AREA)
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- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
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- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
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- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
- Mechanical Coupling Of Light Guides (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
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IBPCT/IB96/00957 | 1996-09-18 |
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HRP970509A2 true HRP970509A2 (en) | 1998-08-31 |
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HRPCT/IB96/00957A HRP970509A2 (en) | 1996-09-18 | 1997-09-18 | Pyrrolidinyl and pyrrolinylethylamine compounds as kappa agonists |
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US (7) | US6201007B1 (ko) |
EP (1) | EP0934264B1 (ko) |
JP (2) | JP3195368B2 (ko) |
KR (1) | KR100339666B1 (ko) |
CN (1) | CN1237962A (ko) |
AP (1) | AP1016A (ko) |
AR (1) | AR008168A1 (ko) |
AT (1) | ATE249433T1 (ko) |
AU (1) | AU719895B2 (ko) |
BG (1) | BG64194B1 (ko) |
BR (1) | BR9711506A (ko) |
CA (1) | CA2266006C (ko) |
CO (1) | CO4920224A1 (ko) |
DE (1) | DE69724805T2 (ko) |
DK (1) | DK0934264T3 (ko) |
DZ (1) | DZ2309A1 (ko) |
EA (1) | EA001341B1 (ko) |
ES (1) | ES2205248T3 (ko) |
HR (1) | HRP970509A2 (ko) |
ID (1) | ID19611A (ko) |
IL (3) | IL128959A0 (ko) |
IS (1) | IS4992A (ko) |
MA (1) | MA26441A1 (ko) |
NO (1) | NO313550B1 (ko) |
NZ (1) | NZ334439A (ko) |
OA (1) | OA10996A (ko) |
PA (1) | PA8437201A1 (ko) |
PE (1) | PE109998A1 (ko) |
PL (1) | PL332546A1 (ko) |
PT (1) | PT934264E (ko) |
SK (1) | SK32799A3 (ko) |
TN (2) | TNSN97092A1 (ko) |
TR (1) | TR199900590T2 (ko) |
TW (1) | TW432047B (ko) |
UA (1) | UA60310C2 (ko) |
WO (1) | WO1998012177A1 (ko) |
YU (1) | YU13899A (ko) |
ZA (1) | ZA978358B (ko) |
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KR20020009383A (ko) | 1998-04-01 | 2002-02-01 | 우에노 도시오 | 축합 티오펜 유도체 및 이의 유도체를 유효 성분으로 하는약제 |
EP0982297A3 (en) * | 1998-08-24 | 2001-08-01 | Pfizer Products Inc. | Process for the preparation of hydroxy-pyrrolidinyl hydroxamic acid derivatives being opioid kappa receptor agonists |
MXPA03009927A (es) * | 2001-04-30 | 2004-01-29 | Pfizer Prod Inc | Procedimiento para preparar compuestos de hidroxipirrolidinietilamina utiles como agonistas de kappa. |
WO2003072544A1 (en) * | 2002-02-28 | 2003-09-04 | Pfizer Products Inc. | Crystalline anhydrous and monohydrate benzoate salts of (2's,3s)-3-hydroxy-n-{2{n-methyl-n-4-(n-propylamino-carbonyl)phenyl]amino-2-phenyl}-ethylpyrrolidine |
AU2003269399A1 (en) * | 2002-11-01 | 2004-05-25 | Pfizer Products Inc. | Process for the preparation of pyrrolidinyl ethylamine compounds via a copper-mediated aryl amination |
MXPA06011414A (es) * | 2004-03-31 | 2007-04-20 | Johnson & Johnson | Compuestos heterociclicos sin imidazol como ligandos del receptor de h3 histamina. |
US7746514B2 (en) * | 2004-04-14 | 2010-06-29 | Hung-Yi Hsu | Scanner and exposure control method thereof |
US20070213319A1 (en) * | 2006-01-11 | 2007-09-13 | Angion Biomedica Corporation | Modulators of hepatocyte growth factor/c-Met activity |
MX2008015365A (es) * | 2006-05-30 | 2008-12-16 | Janssen Pharmaceutica Nv | Compuestos de piridil amida sustituidos como moduladores del receptor h3 de la histamina. |
CN101511807A (zh) * | 2006-06-29 | 2009-08-19 | 詹森药业有限公司 | 组胺h3受体的取代的苯甲酰胺调节剂 |
UA103468C2 (ru) | 2007-11-20 | 2013-10-25 | Янссен Фармацевтика Н.В. | Соединения циклоалкилокси- и гетероциклоалкилоксипиридина как модуляторы гистаминового рецептора н3 |
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GB8801304D0 (en) * | 1988-01-21 | 1988-02-17 | Ici Plc | Diamine compounds |
DE3935371A1 (de) | 1988-12-23 | 1990-07-05 | Merck Patent Gmbh | Stickstoffhaltige ringverbindungen |
US5232978A (en) * | 1988-12-23 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 1-(2-arylethyl)-pyrrolidines |
DE4034785A1 (de) * | 1990-11-02 | 1992-05-07 | Merck Patent Gmbh | 1-(2-arylethyl)-pyrrolidine |
WO1994018165A1 (en) * | 1993-02-12 | 1994-08-18 | Pfizer Inc. | Sulfonamide compounds as opioid k-receptor agonists |
IL117440A0 (en) * | 1995-03-31 | 1996-07-23 | Pfizer | Pyrrolidinyl hydroxamic acid compounds and their production process |
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1997
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