CN1345307A - 作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 - Google Patents
作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 Download PDFInfo
- Publication number
- CN1345307A CN1345307A CN00805623A CN00805623A CN1345307A CN 1345307 A CN1345307 A CN 1345307A CN 00805623 A CN00805623 A CN 00805623A CN 00805623 A CN00805623 A CN 00805623A CN 1345307 A CN1345307 A CN 1345307A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- alkyl
- group
- hydrogen
- Prior art date
- 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.)
- Pending
Links
- VFTQJCVZNTYOKM-UHFFFAOYSA-N n-(4-amino-2-phenylbutyl)naphthalene-1-carboxamide Chemical class C=1C=CC2=CC=CC=C2C=1C(=O)NCC(CCN)C1=CC=CC=C1 VFTQJCVZNTYOKM-UHFFFAOYSA-N 0.000 title description 2
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 6
- -1 methoxyl group Chemical group 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 210000002784 stomach Anatomy 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 3
- 206010047700 Vomiting Diseases 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 230000008673 vomiting Effects 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 206010030113 Oedema Diseases 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 claims description 2
- 208000028017 Psychotic disease Diseases 0.000 claims description 2
- 208000024780 Urticaria Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 230000036407 pain Effects 0.000 claims description 2
- 230000008855 peristalsis Effects 0.000 claims description 2
- FUTGSLRCERHDMB-UHFFFAOYSA-N propan-2-yl hypofluorite Chemical compound CC(C)OF FUTGSLRCERHDMB-UHFFFAOYSA-N 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
- 230000000994 depressogenic effect Effects 0.000 claims 1
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 abstract description 15
- 102100024304 Protachykinin-1 Human genes 0.000 abstract description 15
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 abstract description 15
- 102000003141 Tachykinin Human genes 0.000 abstract description 8
- 108060008037 tachykinin Proteins 0.000 abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 abstract 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 238000001819 mass spectrum Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000370 acceptor Substances 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000011097 chromatography purification Methods 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 101800000399 Neurokinin A Proteins 0.000 description 7
- 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 description 7
- 102400000097 Neurokinin A Human genes 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005576 amination reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 102000046798 Neurokinin B Human genes 0.000 description 3
- NHXYSAFTNPANFK-HDMCBQFHSA-N Neurokinin B 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](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O)C1=CC=CC=C1 NHXYSAFTNPANFK-HDMCBQFHSA-N 0.000 description 3
- 101800002813 Neurokinin-B Proteins 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 210000001170 unmyelinated nerve fiber Anatomy 0.000 description 3
- 238000007738 vacuum evaporation Methods 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- SBGVNBGHCCLMRR-UHFFFAOYSA-N 3-bromonaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC(Br)=CC2=C1 SBGVNBGHCCLMRR-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 2
- 208000036566 Erythroleukaemia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101100454393 Homo sapiens LCOR gene Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 102100038260 Ligand-dependent corepressor Human genes 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 2
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000021841 acute erythroid leukemia Diseases 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000007885 bronchoconstriction Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000024732 dysthymic disease Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- SWTFBLUIBHXOAH-UHFFFAOYSA-N n-butylhydroxylamine Chemical compound CCCCNO SWTFBLUIBHXOAH-UHFFFAOYSA-N 0.000 description 2
- RMHJJUOPOWPRBP-UHFFFAOYSA-N naphthalene-1-carboxamide Chemical class C1=CC=C2C(C(=O)N)=CC=CC2=C1 RMHJJUOPOWPRBP-UHFFFAOYSA-N 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- WYWNEDARFVJQSG-UHFFFAOYSA-N 2-methylserotonin Chemical compound C1=C(O)C=C2C(CCN)=C(C)NC2=C1 WYWNEDARFVJQSG-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- ZQRJVPHFWVEIPS-UHFFFAOYSA-N 3-hydroxy-4-iodonaphthalene-2-carboxylic acid Chemical compound C1=CC=C2C(I)=C(O)C(C(=O)O)=CC2=C1 ZQRJVPHFWVEIPS-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 108010036928 Thiorphan Proteins 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002466 tachykinin receptor agonist Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 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
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 230000009466 transformation Effects 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
-
- 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
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- 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
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
Abstract
本发明涉及通式(I)的化合物:R1R2N-CH2CH2-CHAr1-CH2-NR3-CO-R4(I),其中:R1是氢、C1-6烷基、C2-6烯基、芳基、C1-6烷酰基、C1-6烷氧基羰基或芳基羰基;任何上述基团被任选取代;R2是氢或C1-6烷基;或R1或R2相连构成任选取代的吗啉代环;Ar1是被卤素一-或二-取代的苯基;R3是氢或C1-6烷基;R4是任选取代的萘-1-基;或及其可药用盐。这些化合物拮抗内源性神经肽速激肽的药理学作用,特别是神经激肽1(NK1)受体。
Description
背景
哺乳动物的神经激肽包含一类发现存在于外周和中枢神经系统中的肽类神经递质。三种主要的神经激肽是P物质(SP)、神经激肽A(NKA)和神经激肽B(NKB)。至少NKA还存在N-末端伸展形式。对于这三种主要神经激肽已知至少存在三种受体类型。基于它们对神经激肽激动剂SP、NKA和NKB的相对选择性,这些受体分别被分为神经激肽1(NK1)、神经激肽2(NK2)和神经激肽3(NK3)受体。在外周中,SP和NKA定位在C-传入感觉神经元中,这些神经元的特征在于是非有髓神经末梢,称作C-纤维,通过这些神经元的选择性去极化或C-纤维的选择性刺激释放出SP和NKA。C-纤维位于气道上皮,并且已知速激肽会诱导深度效应,其显然与在哮喘中观察到的多种症状平行。速激肽的释放或引入在哺乳动物气道中产生的效应包括:支气管收缩、微血管渗透性增高、血管舒张、粘液分泌增加和肥大细胞的激活。所以,速激肽参与哮喘中观察到的病生理学和气道超反应性;而阻断已释放速激肽的作用可以有效治疗哮喘及有关症状。
发明概述
本发明涉及被氨基丁基基团N-取代的萘羧酰胺类化合物、含有这些化合物的药物组合物、它们的应用及其制备方法。这些化合物可以拮抗内源性神经肽速激肽(称作神经激肽),特别是在神经激肽1(NK1)受体的药理学作用。这些化合物适用于任何需要这种拮抗作用的时候。因此,此类化合物在那些P物质参与其中的疾病的治疗中具有价值,例如哮喘、焦虑、抑郁、呕吐和有关病症的治疗。
本发明的N-取代萘羧酰胺类化合物表现出高度的NK1受体拮抗活性。发明详述
按照本发明提供式(I)的化合物:
R1R2N-CH2CH2-CHAr1-CH2-NR3-CO-R4 (I)其中:R1是氢、C1-6烷基、C2-6烯基、芳基、C1-6烷酰基、C1-6烷氧基羰基或芳基羰基;任何上述基团被任选取代;R2是氢或C1-6烷基;或R1或R2相连构成任选取代的吗啉代环;Ar1是被卤素一-或二-取代的苯基;R3是氢或C1-6烷基;R4是任选取代的萘-1-基;及其可药用盐。
当R1是任选取代的C2-6烷基(例如乙基或丙基)、C2-6烯基(例如丙烯基)、C1-6烷氧基羰基(例如甲氧基羰基或乙氧基羰基)和C1-6烷酰基(例如乙酰基或丙酰基)时,适合的取代基包括:卤素,例如氯、溴或氟;硝基;氰基;羟基;C1-6烷氧基,例如甲氧基或乙氧基;氨基;C1-6烷基氨基,例如甲基氨基或乙基氨基;二-C1-6烷基氨基,例如二甲基氨基;三氟甲基;羧基;氨基甲酰基(NH2CO-);C1-6烷基氨基甲酰基,例如甲基氨基甲酰基或乙基氨基甲酰基;二-C1-6烷基氨基甲酰基,例如二甲基-氨基甲酰基;C1-6烷酰基,例如乙酰基;巯基;C1-6烷硫基,例如甲硫基或乙硫基;C1-6烷基亚磺酰基,例如甲基亚磺酰基或乙基亚磺酰基;C1-6烷基磺酰基,例如甲基磺酰基或乙基磺酰基;氨磺酰基;C1-6烷氧基羰基,例如甲氧基羰基或乙氧基羰基;C3-8环烷基,例如环丙基、环戊基或环己基;环丁基、芳基;或杂芳基。
当R1是取代甲基时,适宜的取代基是:C3-8环烷基,例如环丙基、环丁基、环戊基或环己基;芳基;或杂芳基。
当R1是取代芳基或芳基羰基时(或当R1和R2与其所连的氮原子一起构成吗啉代环时),适宜的取代基包括如上所述(也就是R1是其他基团时)的取代基,以及C1-6烷基,例如甲基或乙基;C2-6烯基,例如烯丙基或乙烯基;或C2-6炔基,例如乙炔基。
术语“芳基”和“芳基羰基”中的“芳基”是指苯基和萘基。
优选的R1是氢、被苯基任选取代的C1-6烷基、C2-6烯基、苯基或苯甲酰基。
特别是R1是氢、甲基、乙基、正丙基、异丙基、丙烯-2-基、苯基或苯甲酰基。
优选R2是氢或甲基。
在特别优选的方面R1是甲基或乙基和R2是氢或甲基,例如R1R2N-是甲基氨基。
在另一优选方面R1和R2与其所连的氮原子一起构成吗啉代环。
适宜的Ar1是被氯二取代的苯基,例如Ar1是3,4-二氯苯基。
R3是氢或C1-6烷基,例如甲基、乙基或正丙基。优选R3是甲基。
R4是任选取代的萘-1-基。对于萘-1-基可有可无的适当取代基包括:羟基;氰基;硝基;三氟甲氧基;三氟甲基;C1-6烷基磺酰基,例如甲基磺酰基;卤素,例如氯、溴、氟或碘;C1-6烷氧基,例如甲氧基、乙氧基或丙氧基;亚甲基二氧基(-OCH2O-)、C1-6烷基,例如甲基或乙基;C2-6烯基,例如乙烯基、丙-1-烯基或丙-2-烯基;C2-6炔基,例如乙炔基;羧基,C1-6烷氧基-羰基,例如甲氧基羰基;氨基甲酰基;C1-6烷基氨基甲酰基,例如甲基氨基甲酰基或乙基氨基甲酰基;二-C1-6烷基氨基甲酰基,例如二-甲基氨基甲酰基;C1-6烷酰基,例如乙酰基或丙酰基;C1-6烷酰基氨基,例如乙酰基氨基或丙酰基氨基;氨基磺酰基;和C1-6烷基,例如被上述任意取代基取代的甲基。
优选的萘-1-基是未取代或被至多三个取代基取代。萘-1-基所优选的取代基包括:氰基;硝基;C1-6烷基磺酰基,例如甲基磺酰基;卤素,例如氯、溴、氟或碘;C1-6烷氧基,例如甲氧基、乙氧基、正丙氧基或异丙氧基;亚甲基二氧基(-OCH2O-);C1-6烷基,例如甲基或乙基;C2-6烯基,例如丙-2-烯基;C2-6炔基,例如乙炔基;羧基,氨基甲酰基;C1-6烷基-氨基甲酰基,例如甲基氨基甲酰基;二-C1-6烷基氨基甲酰基,例如二-甲基氨基甲酰基;C1-6烷酰基,例如乙酰基;C1-6烷酰基氨基,例如乙酰基氨基;氨基磺酰基;和氰基C1-6烷基,例如氰基甲基。
对于萘-1-基更优选的取代基是氰基、甲氧基、乙氧基、异丙氧基、氟、溴、氯、碘、硝基、氰基甲基、羧基、氨基甲酰基、乙炔基、甲基、乙基、二甲基氨基甲酰基、甲基磺酰基、氨基磺酰基、丙-2-烯基、乙酰基和乙酰基氨基。
特别是萘-1-基可以被至多两个取代基取代,该取代基选自氰基、甲氧基、乙基、氟和硝基。对于萘-1-基特别优选的取代模式是3-氰基。进一步特别优选的取代模式为3-氰基、2-甲氧基。另一特别优选的取代模式是2,3-二甲氧基。再一特别优选的取代模式是3-氰基、2-乙基。
本发明的化合物在-CHAr1-具有手性中心,并且可以在任选的取代基中具有手性中心。本发明包括所有拮抗NK1受体的异构体、非对映异构体及其混合物。
-CHAr1-处的优选构型如下式(Ia)所示:
所以,本发明优选类型的化合物为式(Ia)的化合物,其中R1是氢、甲基或乙基;R2是氢或甲基;R3是甲基;Ar1是3,4-二氯苯基;和R4是被至多两个取代基任选取代的萘-1-基,该取代基选自氰基、甲氧基、乙基、氟和硝基。
本发明的特定化合物是实施例中的那些化合物。
式(I)的化合物的可药用盐包括那些与提供生理可接受阴离子的无机或有机酸形成的盐,所述酸为例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、氨基磺酸、对甲苯磺酸、乙酸、柠檬酸、乳酸、酒石酸、丙二酸、富马酸、乙磺酸、苯磺酸、环己基氨基磺酸、水杨酸和奎尼酸。
为了利用式(I)的化合物或其可药用盐治疗性治疗(包括预防性治疗)哺乳动物,包括人体,一般按照标准制药实践配制为药物组合物。
因此,本发明的另一方面提供一种药物组合物,该组合物包含式(I)的化合物或其可药用盐和可药用载体。
本发明的药物组合物可以以标准方式针对需要治疗的疾病症状给药,例如经口服、局部、胃肠非、经颊、经鼻、阴道或直肠给药或通过吸入或吹入给药。出于这些目的,可以利用所属领域已知的方式将本发明的化合物配制为例如片剂、胶囊、水或油溶液、混悬液、乳液、霜剂、软膏、凝胶、鼻用喷雾剂、栓剂、微粉化粉末或气溶胶或吸入用雾化剂的形式,和用于非胃肠使用的(包括静脉内、肌内或输注)灭菌水或油溶液或混悬液或灭菌乳液。
除了本发明的化合物以外,本发明的药物组合物也可以含有,或联合给予(同时或顺序),一种或多种具有治疗本文所述一种或多种疾病症状的药剂。
本发明的药物组合物一般对人体给药,例如使其接受0.01至25mg/kg体重(优选0.1至5mg/kg体重)的日剂量。该日剂量可以根据需要分次给药,按照所属领域已知的原则,所给化合物的精确用量和给药的途径取决于被治疗患者的体重、年龄和性别,并且取决于被治疗的病症。
通常,单位剂型含有约1mg至500mg的本发明化合物。例如,口服给药的片剂或胶囊一般可以含有最高达250mg(和通常为5至100mg)的式(I)的化合物或其可药用盐。在另一实施例中,为了通过吸入给药,式(I)的化合物或其可药用盐可以以5至100mg的日剂量每天一次或分成两次至四次给药。在另一实施例中,为了通过静脉内或肌内注射或输注给药,可以采用含有至多10%w/w(和一般为5%w/w)的式(I)化合物或其可药用盐的灭菌溶液或混悬液。
所以,在另一方面,本发明提供应用于人体或动物机体的治疗性治疗方法中的式(I)的化合物或其可药用盐。
在另一方面,本发明提供一种病症的治疗方法,该病症受益于对NK1受体的拮抗作用,该方法包含给温血动物施用有效量的式(I)化合物或其可药用盐。本发明还提供式(I)的化合物或其可药用盐在制备用于可从NK1受体的拮抗作用获益的病症的药物中的应用。
通过在此描述和例举的方法或其类似方法以及利用化学领域的已知方法可以制备式(I)的化合物及其可药用盐。如果无法购得,可以通过化学领域中合成已知化合物的相似或类似方法所采用的技术来制备这些方法中的起始原料。
在另一方面,本发明提供一种制备式(I)的化合物或其可药用盐的方法,该方法包含:
a)使式(III)的化合物:
OHC-CH2-CHAr1-CH2-NR3-COR4 (III)其中Ar1、R3和R4如上定义,与式R1R2NH的化合物反应;或
b)使式(IV)的化合物:
R1R2N-CH2-CH2-CHAr1-CH2-NHR3 (IV)其中R1、R2、R3和Ar1定义如上,与式L-CO-R4的化合物反应,其中L是离去基团;其中如果必要,任何官能团均加以保护,和
i)除去任何保护基;
ii)任选转化式(I)的化合物成为另一种式(I)的化合物;
iii)任选形成可药用盐。
保护基一般可以选自任何文献中记载的或化学专业人员已知的、适合保护指定基团的保护基,并且可以利用常规方法引入和脱除;参见,例如Protecting Groups in Organic Chemistry;TheodoraW.Greene。对保护基的脱除方法进行选择,从而脱去保护基,同时最低限度地干扰分子内的其他基团。
还应理解,式(I)化合物中某些不同的任选取代基可以在上述方法之前或之后立刻通过标准的芳族取代反应引入或通过常规的官能团修饰产生。这些方法的反应物和反应条件为化学领域公知。
从相应的酸按照常规方式可以制得可药用盐。非可药用盐可以用作中间体并且其本身也是本发明的另一方面。
所属领域熟知如何制备旋光体(例如,通过拆分外消旋体或从旋光起始原料开始合成)和如何利用该领域中已知和下文所述的标准试验测定NK1拮抗特性。
式(III)化合物和R1R2NH在还原胺化的条件下反应。该反应通常在非极限的温度下进行,例如0-100℃,更适宜在室温下进行,于基本惰性的溶剂如二氯甲烷或甲醇中反应。典型的还原剂包括硼氢化物,如氰基硼氢化钠。式R1R2NH的化合物是已知化合物或可以以常规方式制备。式(III)的化合物可以从相应的醇制得,其本身可以通过相应取代羟丁基胺的N-酰化制成。
式(IV)和LCOR4的化合物在常规酰化条件下反应,其中LCOR4是酸或活化的酸衍生物,例如酰氯。式(IV)的化合物可以通过式(V)的化合物:
OHC-CH2-CHAr1-CH2NHR3 (V)其中Ar1和R3如上定义,与R1R2NH在还原胺化条件下反应制备,如果必要同时保护官能团。例如,当希望制备R3是氢的式(IV)化合物时,式(V)的化合物的-NHR3官能可以保护为苯二甲酰亚氨基,一般通过例如肼解可以脱除该基团。式(V)的化合物是已知化合物,或可以以常规方式制备,例如从相应的取代羟丁基胺。
式(I)的化合物可以转化为其他的式(I)化合物,例如其中R1为氢的式(I)化合物可以以常规方式酰化生成其中R1是芳基羰基或烷酰基羰基的相应化合物。
下面的生物试验方法、数据和实施例举例和进一步说明本发明。
通过标准试验和临床研究可以证实本发明化合物或其可药用盐(此后总称为“化合物”)的实用性,包括下列文献中公开的那些标准试验和临床研究。SP受体结合试验(试验A)
利用表达在小鼠红白血病(MEL)细胞中的人体NK1受体的试验可以证明本发明的化合物拮抗SP在NK1受体上的结合的能力。人体NK1受体的分离和定性如下所述:B.Hopkins等“Isolation andcharacterization of the human lung NK1 receptor cDNA”Biochem.Biophys.Res.Comm.,1991,180,1110-1117;和,采用类似于Aharony,D.等“Isolation and PharmacologicalCharacterization of a Hamster Neurokinin A ReceptorcDNA”Molecular Pharmacology,1994,45,9-19所述方法,使NK1受体表达在小鼠红白血病(MEL)细胞中。兔肺动脉:NK1体外机能试验(试验C)
本发明的化合物对激动剂Ac-[Arg6,Sar9,Met(O2)11]P物质(6-11),ASMSP在肺部组织内的作用的拮抗能力可以按照已公开的方法证实;J.Pharmacol.Exp.Ther.1993,267,1168;Buckner CK,Liberati N,Dea D,Lengel D,Stinson-Fisher C,Campbell J,Miller S,Shenvi A,Krell RD。
从耳静脉静脉内注射60mg/kg戊巴比妥钠(50mg/ml)致雄性新西兰白兔安乐死。出于抗凝目的,在静脉内注射戊巴比妥钠之前注射0.0025ml/kg的肝素(1000单位/ml)。自肋支架的顶部至胸骨打开胸腔,取出心脏、肺和部分气管。从其余的组织分离出肺动脉并且切为一半作为成对。
令节段悬浮在不锈钢镫之间,以不除去任何内皮,并且置于水夹套(37.0℃)组织浴中,该浴中含有下列组成的生理盐溶液(mM):NaCl,118.0;KCl,4.7;CaCl2,1.8;MgCl2,0.54;NaH2PO4,1.0;NaHCO3,25.0;葡萄糖,11.0;消炎痛,0.005(抑制环氧合酶);和dl-普萘洛尔,0.001(阻断β受体);连续用95%O2-5%CO2通气。利用Grass FT-O3传感器测定在Grass多种波动描记器上的反应,并且利用Mi2软件/硬件系统获得电信号(数据),随后转化为松弛的量度。
施加在各组织上的起始张力为2克,在1.0小时的平衡期中维持这种张力。以15分钟的时间间隔用生理盐溶液冲洗组织。在30和45分钟冲洗时,加入下面的处理:1×10-6M Thiorphan(阻断E.C.3.4.24.11),3×10-8M(S)-N-[2-(3,4-二氯苯基)-4-[4-(2-氧代全氢嘧啶-1-基)哌啶子基]丁基]-N-甲基苯甲酰胺(阻断NK2受体),和指定浓度的试验化合物。在1.0个小时的平衡结束时,加入1×106ML-去氧肾上腺素盐酸盐1.0小时。在该1.0小时结束后,作出ASMSP的剂量松弛曲线。各个组织作为个体处理,并且当其在2个连续剂量下无法弛豫时被视作终结。当完成方案的这个部分时,加入1×10-3M罂粟碱以达到最大松弛。
对于非竞争性拮抗剂,在指定的拮抗剂浓度下测定松弛的百分抑制率。当试验化合物引起总松弛的统计学意义(P<0.05)降低时测定百分抑制率,其利用总松弛计算为空白值的百分率。竞争性化合物的效价是通过用标准公式计算出各试验浓度下的表观解离常数(KB)来测定:
KB=[拮抗剂]/(剂量比例-1)其中剂量比例=反对数[(激动剂-log无化合物的摩尔EC50)-(-log含化合物的摩尔EC50)]。KB值可以转化为负对数并且表示为-log摩尔KB(即pKB)。为了这种评价,利用成对的肺动脉环在试验化合物不存在和存在下获取激动剂的完全浓度-反应曲线。在各曲线中其50%最大松弛时测定激动剂的效价。EC50值转化为负对数并且表示为-log摩尔EC50NK1体内机能试验(试验E)
化合物作为NK1受体拮抗剂的活性可以在下述的体内试验动物中加以证实:Buckner等“Differential Blockade by Tachykinin NK1and NK2 Receptor Antagonists of Bronchoconstriction Inducedby Direct-Acting Agonists and the Indirect-Acting MimeticsCapsaicin,Serotonin and 2-Methyl-Serotonin in theAnesthetized Guinea Pig.”I.Pharm.Exp.Ther.,1993,Vol 267(3),pp 1168-1175。
本发明代表性化合物在上述方法中的试验结果如表I所示:
表1
临床研究
实施例 | NK1pKb(试验C) |
4 | 8.3 |
6 | 8.7 |
验证本发明化合物功效的临床研究可以利用标准方法进行。
试验提供了SP的全身性拮抗作用的证据。SP参与多种疾病的病理学,所述疾病包括:类风湿关节炎、阿耳茨海默氏病、癌症、精神分裂症、水肿、变应性鼻炎、炎症、疼痛、胃肠蠕动过强、胃源性哮喘、胃食管反流、焦虑、呕吐、杭廷顿氏舞蹈病、精神病(包括抑郁)、高血压、偏头痛和荨麻疹。
所以,本发明的一个方面是式(I)的化合物或其可药用盐在治疗需要其的人体或其他哺乳动物中的SP参与其中且期望拮抗SP作用的疾病中的应用。
P物质拮抗剂在抑郁症的治疗中可能起作用。所以,本发明的另一特征是式(I)的化合物或其可药用盐在治疗需要其的人体或其他哺乳动物中的抑郁症中的应用。
因为效应的范围由SP的作用决定,所以能够阻断其作用的化合物还可以用作进一步评价其他神经递质在速激肽类物质中的生物学作用的工具。因此,本发明的另一特征提供了式I化合物或其盐在用于开发治疗SP参与其中的疾病的新治疗剂的新疾病模型或试验或其诊断试验的开发和标准化中作为药理学标准的应用。
本发明通过下列非限定实施例举例说明,它们适用和除非另外说明,其中,
(i)在室温或环境温度下操作,也就是18-25℃的温度;
(ii)用无水硫酸镁干燥有机溶液;利用旋转蒸发体系在减压下(600-4000帕斯卡;4.5-30mmHg)在至多60℃的浴温中蒸发溶剂;
(iii)未校正熔点;
(iv)终产物满足质子核磁共振(NMR)波谱;
(v)质谱(MS)利用带有气压化学电离(APCI)的自动系统中进行。通常,只报告观察到母体质量的波谱。
缩写:CO,一氧化碳;DCM,二氯甲烷;DMF,N,N-二甲基甲酰胺;DMSO,二甲基亚砜;Et2O,乙醚;EtOAc,乙酸乙酯;h,小时(s);min,分钟;NMR,核磁共振;psi,磅/平方英寸;THF,四氢呋喃。
标准酰化是指典型方法,其中将酰氯(1-1.2当量)加入胺(1-1.2当量)和三乙胺(2当量)在DCM中的搅拌溶液内。1-16h后任选浓缩该反应,溶于DCM,用饱和碳酸氢钠洗涤,随后通过层析纯化。
标准还原胺化是指典型方法,其中胺(1-1.2当量)、醛(1-1.2当量)和乙酸(2当量)的溶于在甲醇中搅拌5至60分钟,随后加入NaBH3CN(1.7当量)。1-16h后,任选浓缩该反应,溶于DCM,用饱和碳酸氢钠洗涤,随后通过层析纯化。
最终的化合物转化为柠檬酸盐。将游离碱与柠檬酸(1.0当量)在甲醇中混合,减压下浓缩并且真空下干燥(25-50℃)。
实施例1N-[(S)-2-(3,4-二氯苯基)-4-(苯基氨基)丁基]-N-甲基-2-甲氧基-3-氰基-1-萘甲酰胺
N-[(S)-2-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-2-甲氧基-3-氰基-1-萘甲酰胺与苯胺在标准还原胺化条件下反应生成标题化合物,其转化为柠檬酸盐。
1H NMR(300MHz,DMSO-d6)δ8.64-8.61(m),8.07-7.98(m),7.79-7.55(m),7.51-7.47(m),7.37-7.32(t),7.08-7.00(m),6.53-6.49(m),6.31-6.28(d),4.60-4.50(t),4.07-3.96(m),3.92(s),3.90-3.78(m),3.86(s),3.45-3.11(m),3.00-2.88(m),2.79(s),2.73(s),2.68(s),2.56-2.44(m),2.03-1.88(m);MS APCI,m/z=532(M+).N-[(S)-2-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-2-甲氧基-3-氰基-1-萘甲酰胺制备如下:
(a)3-氰基-4-碘-2-萘甲酸
搅拌NaOH(2.12g)在甲醇(100ml)中的混合物直至溶液均匀。加入碘化钠(3.98g)和3-羟基-2-萘甲酸(5.00g)并搅拌30分钟。使所得混悬液冷却至0℃,滴加5.25%(w/v)次氯酸钠的水溶液,连续搅拌1小时。加入饱和硫代硫酸钠(25ml),5分钟后加入6N HCl酸化该溶液至pH2,导致黄色沉淀的形成,将其过滤并用水(50ml)洗涤。把沉淀转移到圆底烧瓶内,溶于甲醇(70ml)和甲苯(100ml)中,浓缩,再溶于甲醇(70ml),浓缩、再溶于甲醇(70ml)和甲苯(100ml)中,浓缩得到产物,为黄色固体(6.26g):MS m/z 313(M-1)。1HNMR(DMSO-d6):δ12.41(宽,1H),8.63(s,1H),8.05-7.97(m,2H),7.70(m,1H),7.42(m,1H)。
(b)3-甲氧基-4-碘-2-萘甲酸甲酯
3-羟基-4-碘-2-萘甲酸(8.0g)、硫酸二甲酯(8.03g)、粉状碳酸钾(8.80g)和干燥丙酮(150mL)的溶液在回流下加热18小时。将溶液冷却至室温,加入三乙胺(15mL),连续搅拌30min。经硅藻土垫过滤该溶液,用干燥丙酮(50mL)洗涤。浓缩滤液得到黄色油,用EtOAc稀释,依次用1N HCl(100mL)、饱和碳酸氢钠水溶液(100mL)和盐水(100mL)洗涤。干燥有机相(硫酸钠),过滤,浓缩,通过层析纯化(含0-10%EtOAc的己烷),得到产物,为黄色油(5.53g)。1H NMR(DMSO-d6)δ8.47(s,1H),8.09(m,2H),7.74(m,1H),7.61(m,1H),3.94(s,3H),3.87(s,3H)。
(c)1-碘-2-甲氧基-3-氰基萘
基于Wood,JL;Khatri,NA;Weinreb,SM;Tetrahedron Lett;51,4907(1979)的方法,将3-甲氧基-4-碘-2-萘甲酸甲酯(5.0g)悬浮在二甲苯(100mL),冷却至0℃,加入二甲基氨化铝溶液(约37mmol),该溶液在回流下加热2.5h。随后冷却该溶液至0℃,通过加入1N HCl酸化至pH2,用EtOAc提取(3×100mL)。合并的EtOAc提取液用饱和碳酸氢钠水溶液(150mL)和盐水(150mL)洗涤,干燥(硫酸钠),过滤,浓缩,通过层析纯化(1∶1 EtOAc∶DCM,随后含10-20%EtOAc的DCM)得到产物,为白色固体(3.29g)。1H NMR(DMSO-d6):δ8.69(s,1H),8.24-8.04(m,2H),7.91-7.81(m,1H),7.76-7.65(m,1H),3.99(s,3H);MS m/z 311(M+H)。
(d)2-甲氧基-3-氰基-1-苯甲酸甲酯
向1-碘-2-甲氧基-3-氰基萘(0.250g)、Pd(OAc)2(0.018g)、三乙胺(0.081g)和甲醇(20mL)的混悬液中吹入一氧化碳25分钟,随后在70℃一氧化碳(1atm)下搅拌18h。将冷却的溶液过滤,用甲醇(20mL)和DCM(20mL)洗涤,浓缩,预吸附在硅胶(1g)上,通过层析纯化(含0-10%EtOAc的己烷)得到产物,为白色固体(0.113g)。1HNMR(DMSO-d6):δ8.78(s,1H),8.12-8.09(m,1H),7.84-7.78(m,2H),7.70-7.63(m,1H),4.02-4.01(m,6H);IR(cm-1):2228,1724,1296,1236,1208,1017。
(e)2-甲氧基-3-氰基-1-萘甲酸
2-甲氧基-3-氰基-1-苯甲酸甲酯(0.113g)、LiOH·H2O(0.0196g)、THF(3mL)、水(1mL)和甲醇(1mL)的溶液在室温下搅拌过夜。该溶液用饱和碳酸氢钠稀释,用Et2O提取。通过加入1N HCl酸化水层至pH2,用Et2O提取。有机层用水(30mL)和盐水(40mL)洗涤,干燥(硫酸钠),过滤,浓缩,得到白色固体。1H NMR(DMSO-d6):δ14.06(宽,1H),8.08-8.02(m,1H),7.83-7.76(m,2H),7.69-7.63(m,1H),4.02(s,3H);MS m/z:226(M-1)。
(f)2-甲氧基-3-氰基-1-萘甲酰氯
通过与草酰氯在含有催化量的DMF的DCM中反应使羧酸转化为相应的酰氯。浓缩后,干燥反应混合物,无需纯化即可利用该酰氯。(g)N-[2-(S)-(3,4-二氯苯基)-4-羟丁基]-N-甲基-3-氰基-2-甲氧基-1-萘甲酰胺
N-[(S)-2-(3,4-二氯苯基)-4-羟丁基]-N-甲基胺(Miller,SC;WO 9512577)在DCM中的溶于与10%碳酸氢钠水溶液混合。冷却该混合物至0℃,在30分钟内滴加存在于DCM中的3-氰基-2-甲氧基-1-萘甲酰氯溶液。室温下搅拌过夜后,浓缩有机相,通过柱层析纯化得到N-[2-(S)-(3,4-二氯苯基)-4-羟丁基]-N-甲基-3-氰基-2-甲氧基-1-萘甲酰胺。1H NMR(300 MHz,DMSO-d6)δ9.70-9.64(m),8.67-8.57(m),8.07-7.97(m),7.80(s),7.72-7.55(m),7.52-7.48(m),7.40-7.33(m),7.12-7.10(d),7.04-7.02(d),6.87-6.83(m),6.37-6.29(d),4.53-4.44(t),4.11-4.00(m),3.94(s),3.92(s),3.91-3.73(m),3.71(s),3.45-3.38(m),3.33(s),3.14(s),2.97-2.95(d),2.63(s),2.60(s);MS APCI,m/z=455(M+)。该化合物定性为阻转异构体(atropoisomer)的混合物。
(h)N-[2-(S)-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-3-氰基-2-甲氧基-1-萘甲酰胺
得自(g)的醇利用草酰氯和DMSO在标准Swern条件下氧化得到醛。1H NMR(300 MHz,DMSO-d6)δ9.70-9.64(m),8.67-8.57(m),8.07-7.97(m),7.80(s),7.72-7.55(m),7.52-7.48(m),7.40-7.33(m),7.12-7.10(d),7.04-7.02(d),6.87-6.83(m),6.37-6.29(d),4.53-4.44(t),4.11-4.00(m),3.94(s),3.92(s),3.91-3.73(m),3.71(s),3.45-3.38(m),3.33(s),3.14(s),2.97-2.95(d),2.63(s),2.60(s);
MS APCI,m/z=455(M+)。该化合物定性为阻转异构体的混合物。
实施例2-6
对于实施例2、3、4和6,使N-[(S)-2-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-2-甲氧基-3-氰基-1-萘甲酰胺与适当的胺在标准还原胺化条件下反应。实施例5按照类似方式制备,除了N-[(S)-2-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-2-甲氧基-3-氰基-1-萘甲酰胺被N-[(S)-2-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-3-氰基-1-萘甲酰胺代替。所有化合物转化为相应的柠檬酸盐。
实施例2 1H NMR(300MHz,DMSO-d6)δ8.65-8.63(m),8.12-7.98(m),7.77-7.55(m),7.51-7.46(t),7.39-7.34(t),7.07-7.02(m),6.89-6.80(m),6.32-6.29(d),5.87-5.76(m),5.39-5.21(m),4.55-4.47(t),3.94(s),3.93-3.77(m),3.70(s),3.64-3.17(m),3.11-2.74(m),2.67-2.47(m),2.38-2.14(m),2.00(bs),1.35-1.07(m);MS APCI,m/z=510(M+).实施例3 1H NMR(300MHz,DMSO-d6)δ8.65-8.63(m),8.08-7.97(m),7.71-7.69(m),7.67-7.49(m),7.40-7.37(m),7.31-7.22(m),7.03-7.00(d),6.89-6.85(d),6.77-6.74(d), 6.31-6.29(d),4.53-4.46(t),4.01-3.96(m),3.94(s),3.92(s),3.88-3.76(m),3.68(s),3.47-3.16(m),3.10(s),3.01(s),2.70-2.45(m),2.34(bs),2.06-1.96(m);MS APCI,m/z=560(M+).
实施例4 1H NMR(300MHz,DMSO-d6,373K)δ8.6-8.7(m),7.9-8.1(m),7.3-7.8(m),6.8-7.1(m),6.3(d),4.5(t),3.0-4.0(m),2.6-2.7(m),1.8-2.4(m);MS APCI,m/z=526(M+);分析理论值C28H29Cl2N3O3,1.0柠檬酸,1.0水,C55.44,H5.34,N5.70,实测值C55.57,H5.12,N5.65.实施例5
吗啉是所述的胺,除了用N-[2-(S)-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-3-氰基-1-萘甲酰胺代替N-[2-(S)-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-3-氰基-2-甲氧基-1-萘甲酰胺。1H NMR(300 MHz,DMSO-d6,373K)δ8.4(s),8.0(d),7.2-7.7(m),3.8(s),3.5(m),3.2(s),2.6-2.8(m),2.2-2.4(m),1.6-2.0(m);MS APCI,m/z=496(M+);分析计算值C27H27C12N3O2,1.0柠檬酸,1.0水,C56.10,H5.28,N5.95,实测值C56.40,H5.07,N5.95。
实施例6 1H NMR(300MHz,DMSO-d6)δ8.64(d),8.04(m),7.79-7.56(m),7.49(d),7.40-7.32(m),7.08(m),6.84(m),6.32(d),4.50(t),3.95(m),3.89-3.75(m),3.7 1(s),3.49(m),3.32(m),3.14(m),3.07(s),2.95(m),2.64(s),2.58(s),2.54(s),2.50(s),2.45(m),2.38(m),2.18(m),2.08-1.98(m);MS APCI,m/z=484(M+).
对于实施例5,中间体N-[2-(S)-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-3-氰基-1-萘甲酰胺制备如下:
(i)3-氰基-1-萘甲酰氯
利用Rule,HG和Thompson,SB;J.Chem.Soc.1764-1767(1937)的方法,溴化1,8-萘甲酸酐并且转化为3-溴-1-萘甲酸。按照下面的方法酯化为3-溴-1-萘甲酸甲酯。将3-溴-1萘甲酸(103.0g,410mmol)溶于DCM(1250mL),将溶液冷却至0℃。一次性加入草酰氯(67.5g,532mmol),随后加入催化量的DMF(1.5mL),令所得溶液升至室温,搅拌4小时。真空蒸发该混合物,残余物再从甲苯浓缩。所得酰氯溶于甲醇(1250mL),环境温度下搅拌18h。真空蒸发混合物,残余物通过层析纯化(洗脱剂:DCM∶己烷1∶3)得到3-溴-1-萘甲酸甲酯,为白色固体(106.9g,98%)。1H-NMR(CDCl3)δ4.01(s,3H,CO2CH3);7.50-7.69(m,2H,芳族);7.78-7.87(d,1H,芳族);8.18(s,1H,芳族);8.25(s,1H,芳族);8.80-8.94(d,1H,芳族)。采用Dewar,JS and Grisdale,PJ;J.Amer.Chem.Soc.,84,3541-3546(1962)的方法,3-溴-1-萘甲酸甲酯转化3-氰基-1-萘甲酸甲酯,皂化(LiOH)得到3-氰基-1-萘甲酸。把3-氰基-1-萘甲酸(15.9g,80.6mmol)悬浮在DCM(450mL)中。向一次性搅拌的混合物中加入草酰氯(12.8g,100mmol),随后加入催化量(5滴)的DMF。室温下搅拌该混合物5小时得到澄清溶液。真空浓缩该混合物,残余物自甲苯浓缩2次,得到酰氯粗品,为浅黄色固体(17.4g,定量)。1H-NMR(300MHz,d6丙酮)δ7.86-7.91(t,1H,芳族);7.98-8.04(t,1H,芳族);8.28-8.32(d,1H,芳族);8.66-8.72(d,1H,芳族);8.80(s,1H,芳族);8.93(s,1H,芳族)。
(ii)N-[(S)-2-(3,4-二氯苯基)-4-羟丁基]-N-甲基-3-氰基-1-萘甲酰胺
(S)-2-(3,4-二氯苯基)-4-羟基丁基胺(20.8g,83.8mmol)溶于DCM(700mL)中。向搅拌的溶液中加入10%碳酸氢钠水溶液(300mL),将混合物冷却至0℃。在30分钟内滴加3-氰基-1-萘甲酰氯(17.4g,80.6mmol)在DCM(300mL)中的溶液。随后令所述混合物温热至环境温度,搅拌20h。分离各层,用DCM(300mL)洗涤水相。合并的有机层干燥(Na2SO4),过滤,真空蒸发,得到白色泡沫。通过层析纯化(硅胶:含0-25%乙腈的DCM)得到预期产物,为白色泡沫(27.0g,78%)。1H-NMR(DMSO-d6)δ1.46-1.60(m,1H,CH);1.77-1.91(m,3H,CH);4.38-4.41(t,1H,CH);4.54-4.57(t,2H,CH);6.43(宽,1H,OH);6.84-7.26(m,2H,芳族);7.44-7.54(m,3H,芳族);7.57-7.80(m,7H,芳族);8.04-8.33(m,2H,芳族);8.61(s,1H,芳族)。
(iii)N-[(S)-2-(3,4-二氯苯基)-4-氧代丁基]-N-甲基-3-氰基-1-萘甲酰胺
把溶于DCM(350mL)中的草酰氯(15.9g,125.4mmol)溶液冷却至-78℃。在10分钟内滴加DMSO(19.6g,251mmol),同时反应混合物的温度维持在-70℃下。将混合物在-78℃搅拌30分钟。N-[(S)-2-(3,4-二氯苯基)-4-羟丁基]-N-甲基-3-氰基-1-萘甲酰胺(26.8g,62.7mmol)的溶液溶于DCM(350mL)中并且在30分钟内滴加,同时混合物的温度维持在-70℃以下。混合物在-78℃下搅拌1小时,随后温热至-50℃并且再搅拌30分钟。将该混合物冷却至-78℃,在10分钟内滴加溶于DCM(70mL)中的三乙胺(25.4g,251mmol)溶液。令该混合物逐渐升至环境温度并且搅拌20小时。该混合物用0.5N盐酸(2×250mL)、水(250mL)和饱和碳酸氢钠(250mL)洗涤。将有机层干燥(Na2SO4),过滤,真空浓缩。残余物通过层析纯化(硅胶;含0-20%Et2O的DCM),得到预期产物,为浅黄色泡沫(26.0g,97%)。MS:425(M+H)。1H-NMR(DMSO-d6)δ2.63(bs,3H,NCH3);2.99-3.93(m,5H,CH);6.91-7.15(m,1H,芳族);7.33-7.81(m,6H,芳族);8.62(s,1H,芳族);9.45和9.73(单峰,1H全部,CHO)。
实施例7
在2-巯基苯甲酸的存在下,按照Lemaire-Andoire et al.,Tetr.Lett.1995,36,1267的方法用Pd(dba)2(即:双(二亚苄基丙酮)钯)脱去实施例2的产物中的烯丙基,得到相应的甲基胺。 1H NMR(300MHz,DMSO-d6)δ8.66-8.64(m),8.08-7.96(m),7.80-7.56(m),7.51-7.47(m),7.40-7.35(m),7.07-7.05(m),6.85-6.79(m),6.35-6.32(d),4.54-4.45(t),3.95(s),3.92(s),3.90-3.70(m),3.72(s),3.50-3.10(m),2.86-2.50(m),2.44-1.69(m);MS APCI,m/z=470(M+).
实施例8
Claims (11)
1.式(I)的化合物:
R1R2N-CH2CH2-CHAr1-CH2-NR3-CO-R4 (I)其中:
R1是氢、C1-6烷基、C2-6烯基、芳基、C1-6烷酰基、C1-6烷氧基羰基或芳基羰基;任何上述基团被任选取代;
R2是氢或C1-6烷基;或R1或R2相连构成任选取代的吗啉代环;
Ar1是被卤素一-或二-取代的苯基;
R3是氢或C1-6烷基;
R4是任选取代的萘-1-基;或及其可药用盐。
2.按照权利要求1的化合物,其中R1是氢、C2-6烯基、苯基、苯甲酰基或被苯基任选取代的C1-6烷基。
3.按照权利要求1的化合物,其中R1是氢、甲基、乙基、正丙基、异丙基、丙烯-2-基、苯基或苯甲酰基。
4.按照权利要求1的化合物,其中R2是氢或甲基。
5.按照权利要求1的化合物,其中
R1是甲基或乙基;和
R2是氢或甲基;或R1和R2与其相连的氮原子一起形成吗啉代环。
6.按照权利要求1、2、3、4或5任一项的化合物,其中R4是萘基,其未取代或被至多3个取代基取代,所述取代基选自:氰基;硝基;C1-6烷基磺酰基;卤素;C1-6烷氧基;亚甲基二氧基(-OCH2O-);C1-6烷基;C2-6烯基;C2-6炔基;C1-6烷基-氨基甲酰基;二-C1-6烷基氨基甲酰基;C1-6烷酰基;C1-6烷酰基氨基;氨基磺酰基;和氰基C1-6烷基。
7.按照权利要求6的化合物,其中R4是萘基,其未取代或被至多三个取代基取代,所述取代基选自氰基、甲氧基、乙氧基、异丙氧基、氟、溴、氯、碘、硝基、氰基甲基、羧基、氨基甲酰基、乙炔基、甲基、乙基、二甲基氨基甲酰基、甲基磺酰基、氨基磺酰基、丙-2-烯基、乙酰基和乙酰基氨基。
8.按照权利要求6的化合物,其中R4是萘基,其未取代或被至多两个取代基取代,所述取代基选自氰基、甲氧基、乙基、氟和硝基。
9.按照权利要求8的化合物,其中R4是3-氰基萘-1-基、3-氰基-2-甲氧基萘-1-基、2,3-二甲氧基萘-1-基或3-氰基-2-乙基萘-1-基。
10.一种药物组合物,其中包含
权利要求1-9任一项的化合物;和
可药用载体或稀释剂。
11.一种治疗疾病的方法,所述疾病选自:类风湿性关节炎、阿耳茨海默氏病、癌症、精神分裂症、水肿、变应性鼻炎、炎症、疼痛、胃肠蠕动过强、胃源性哮喘、胃食管反流、焦虑、呕吐、杭廷顿氏舞蹈病、包括抑郁的精神病、高血压、偏头痛和荨麻疹,该方法包含给温血动物施用治疗有效量的权利要求1至9任一项的化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9907571.5A GB9907571D0 (en) | 1999-04-06 | 1999-04-06 | Compounds |
GB9907571.5 | 1999-04-06 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004100053467A Division CN1534017A (zh) | 1999-04-06 | 2000-04-03 | 作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1345307A true CN1345307A (zh) | 2002-04-17 |
Family
ID=10850835
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004100053467A Pending CN1534017A (zh) | 1999-04-06 | 2000-04-03 | 作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 |
CN00805623A Pending CN1345307A (zh) | 1999-04-06 | 2000-04-03 | 作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004100053467A Pending CN1534017A (zh) | 1999-04-06 | 2000-04-03 | 作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 |
Country Status (25)
Country | Link |
---|---|
US (3) | US6476077B1 (zh) |
EP (1) | EP1169302B1 (zh) |
JP (1) | JP2002541137A (zh) |
KR (1) | KR20010102580A (zh) |
CN (2) | CN1534017A (zh) |
AT (1) | ATE277893T1 (zh) |
AU (1) | AU3569200A (zh) |
BG (1) | BG106074A (zh) |
BR (1) | BR0009582A (zh) |
CA (1) | CA2368240A1 (zh) |
CZ (1) | CZ20013574A3 (zh) |
DE (1) | DE60014343T2 (zh) |
EE (1) | EE200100520A (zh) |
GB (1) | GB9907571D0 (zh) |
HK (1) | HK1044145A1 (zh) |
HU (1) | HUP0200707A3 (zh) |
IL (1) | IL145645A0 (zh) |
IS (1) | IS6087A (zh) |
NO (1) | NO20014855L (zh) |
PL (1) | PL350568A1 (zh) |
SK (1) | SK13012001A3 (zh) |
TR (1) | TR200102875T2 (zh) |
UA (1) | UA67839C2 (zh) |
WO (1) | WO2000059873A1 (zh) |
ZA (1) | ZA200108176B (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9907571D0 (en) * | 1999-04-06 | 1999-05-26 | Zeneca Ltd | Compounds |
GB0019008D0 (en) * | 2000-08-04 | 2000-09-27 | Astrazeneca Ab | Therapeutic compounds |
SE0201938D0 (sv) * | 2002-06-20 | 2002-06-20 | Astrazeneca Ab | New process |
KR20050072786A (ko) * | 2002-11-05 | 2005-07-12 | 아스트라제네카 아베 | 잠금 덮개를 갖는 안전 용기 및 덮개를 잠그는 방법 |
US20060058352A1 (en) * | 2002-12-20 | 2006-03-16 | Peter Bernstein | Piperidine amine compounds and their use |
US20080045610A1 (en) * | 2004-09-23 | 2008-02-21 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
CA2580694A1 (en) * | 2004-09-23 | 2006-03-30 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
ES2672099T3 (es) | 2011-07-04 | 2018-06-12 | Irbm - Science Park S.P.A. | Antagonistas del receptor NK-1 para el tratamiento de la neovascularización corneal |
MX2017012720A (es) | 2015-05-18 | 2018-02-09 | Nerre Therapeutics Ltd | Antagonistas duales de receptores de neurocinina-1 (nk-1) / neurocinina-3 (nk-3) para el tratamiento de enfermedades dependientes de hormonas sexuales. |
US20210015834A1 (en) | 2018-02-26 | 2021-01-21 | Ospedale San Raffaele S.R.L. | Nk-1 antagonists for use in the treatment of ocular pain |
MA51999B1 (fr) | 2018-03-14 | 2024-02-29 | Kandy Therapeutics Ltd | Nouvelle formulation pharmaceutique comprenant deux antagonistes recepteurs de nk-1/nk-3. |
RU2697414C1 (ru) | 2018-05-11 | 2019-08-14 | Общество с ограниченной ответственностью "АЙ БИ ДИ Терапевтикс" | Новый антагонист тахикининовых рецепторов и его применение |
US20230134843A1 (en) | 2020-03-11 | 2023-05-04 | Ospedale San Raffaele S.R.L. | Treatment of stem cell deficiency |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE903957A1 (en) * | 1989-11-06 | 1991-05-08 | Sanofi Sa | Aromatic amine compounds, their method of preparation and¹pharmaceutical compositions in which they are present |
CA2163995A1 (en) * | 1993-06-07 | 1994-12-22 | Malcolm Maccoss | Spiro-substituted azacycles as neurokinin antagonists |
DK0777659T3 (da) * | 1994-08-15 | 2001-09-03 | Merck Sharp & Dohme | Morpholinderivater og deres anvendelse som terapeutiske midler |
AU5522498A (en) | 1996-12-13 | 1998-07-03 | Merck & Co., Inc. | Substituted aryl piperazines as modulators of chemokine receptor activity |
GB9907571D0 (en) * | 1999-04-06 | 1999-05-26 | Zeneca Ltd | Compounds |
WO2002076929A1 (en) * | 2001-03-21 | 2002-10-03 | Pharmacopeia, Inc. | Aryl and biaryl compounds having mch modulatory activity |
-
1999
- 1999-04-06 GB GBGB9907571.5A patent/GB9907571D0/en not_active Ceased
-
2000
- 2000-03-04 UA UA2001117535A patent/UA67839C2/uk unknown
- 2000-04-03 CZ CZ20013574A patent/CZ20013574A3/cs unknown
- 2000-04-03 CA CA002368240A patent/CA2368240A1/en not_active Abandoned
- 2000-04-03 BR BR0009582-6A patent/BR0009582A/pt not_active IP Right Cessation
- 2000-04-03 EE EEP200100520A patent/EE200100520A/xx unknown
- 2000-04-03 WO PCT/GB2000/001252 patent/WO2000059873A1/en not_active Application Discontinuation
- 2000-04-03 US US09/937,981 patent/US6476077B1/en not_active Expired - Fee Related
- 2000-04-03 HU HU0200707A patent/HUP0200707A3/hu unknown
- 2000-04-03 IL IL14564500A patent/IL145645A0/xx unknown
- 2000-04-03 SK SK1301-2001A patent/SK13012001A3/sk unknown
- 2000-04-03 PL PL00350568A patent/PL350568A1/xx unknown
- 2000-04-03 KR KR1020017012692A patent/KR20010102580A/ko not_active Application Discontinuation
- 2000-04-03 DE DE60014343T patent/DE60014343T2/de not_active Expired - Fee Related
- 2000-04-03 EP EP00914298A patent/EP1169302B1/en not_active Expired - Lifetime
- 2000-04-03 TR TR2001/02875T patent/TR200102875T2/xx unknown
- 2000-04-03 AT AT00914298T patent/ATE277893T1/de not_active IP Right Cessation
- 2000-04-03 CN CNA2004100053467A patent/CN1534017A/zh active Pending
- 2000-04-03 AU AU35692/00A patent/AU3569200A/en not_active Abandoned
- 2000-04-03 JP JP2000609386A patent/JP2002541137A/ja active Pending
- 2000-04-03 CN CN00805623A patent/CN1345307A/zh active Pending
-
2001
- 2001-09-26 IS IS6087A patent/IS6087A/is unknown
- 2001-10-04 ZA ZA200108176A patent/ZA200108176B/en unknown
- 2001-10-05 NO NO20014855A patent/NO20014855L/no not_active Application Discontinuation
- 2001-11-01 BG BG106074A patent/BG106074A/xx unknown
-
2002
- 2002-06-26 HK HK02104758.2A patent/HK1044145A1/zh unknown
- 2002-11-01 US US10/286,624 patent/US6586432B2/en not_active Expired - Fee Related
-
2003
- 2003-06-30 US US10/611,052 patent/US6821973B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
WO2000059873A1 (en) | 2000-10-12 |
NO20014855L (no) | 2001-12-06 |
ZA200108176B (en) | 2003-01-06 |
HK1044145A1 (zh) | 2002-10-11 |
CA2368240A1 (en) | 2000-10-12 |
US6586432B2 (en) | 2003-07-01 |
HUP0200707A2 (en) | 2002-06-29 |
KR20010102580A (ko) | 2001-11-15 |
EE200100520A (et) | 2002-12-16 |
CZ20013574A3 (cs) | 2002-05-15 |
ATE277893T1 (de) | 2004-10-15 |
SK13012001A3 (sk) | 2002-04-04 |
US6821973B2 (en) | 2004-11-23 |
DE60014343T2 (de) | 2006-03-02 |
HUP0200707A3 (en) | 2002-11-28 |
GB9907571D0 (en) | 1999-05-26 |
PL350568A1 (en) | 2002-12-16 |
US6476077B1 (en) | 2002-11-05 |
IS6087A (is) | 2001-09-26 |
UA67839C2 (uk) | 2004-07-15 |
JP2002541137A (ja) | 2002-12-03 |
US20040106610A1 (en) | 2004-06-03 |
EP1169302A1 (en) | 2002-01-09 |
TR200102875T2 (tr) | 2002-01-21 |
CN1534017A (zh) | 2004-10-06 |
IL145645A0 (en) | 2002-06-30 |
BG106074A (en) | 2002-05-31 |
BR0009582A (pt) | 2001-12-26 |
DE60014343D1 (de) | 2004-11-04 |
AU3569200A (en) | 2000-10-23 |
US20030092713A1 (en) | 2003-05-15 |
EP1169302B1 (en) | 2004-09-29 |
NO20014855D0 (no) | 2001-10-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1224598C (zh) | 萘衍生物 | |
JP4485354B2 (ja) | 新規な置換インドール類 | |
RU2062776C1 (ru) | Способ получения замещенных n-(арилоксиалкил)-гетероарилпиперидина или гетероарилпиперазина | |
CN1134411C (zh) | 双环氨基衍生物及含有此类化合物的前列腺素d2拮抗剂 | |
CN1345307A (zh) | 作为神经激肽-1受体拮抗剂的n-(2-苯基-4-氨基-丁基)-1-萘羧酰胺类化合物 | |
WO1998050346A2 (en) | Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders | |
KR20070091210A (ko) | 글리신 수송 억제제 | |
CN1129102A (zh) | 用作肿瘤坏死因子释放抑制剂的儿茶酚二醚化合物 | |
CN1322134A (zh) | 作为速激肽受体拮抗剂的萘甲酰胺 | |
US6403601B1 (en) | N-(2-phenyl-4-piperidinybutyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxamides and their use as neurokinin 1 (NK1) and/or neurokinin 2 (NK2) receptor antagonists | |
JP2009530247A (ja) | N−フェニル−2−オキソ−1,4−ジアザスピロ[4.5]デカ−3−エン−1−イルアセトアミド誘導体およびグリシン輸送体阻害剤としてのそれらの使用 | |
JP2012528120A (ja) | ミエロペルオキシダーゼ阻害3−アルキル−5−フルオロインドール誘導体 | |
EA009077B1 (ru) | Индазоламиды с аналгетической активностью | |
CN1738808A (zh) | 取代的苯并噻唑衍生物的环化方法 | |
CN1444558A (zh) | 新的n-(2-苯基-3-氨基丙基)萘甲酰胺类化合物 | |
CN1606557A (zh) | 经氘代的吡唑嘧啶酮以及包含该化合物的药物组合物 | |
CN1188405C (zh) | 新的吗啉代苯甲酰胺盐 | |
TW201206910A (en) | Substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives, preparation and therapeutic use thereof | |
CN1777597A (zh) | 具有止痛活性的吲唑 | |
CN1235880C (zh) | 喹啉酮类衍生物及其可接受的盐,其制备方法、作为制备阿立哌唑的应用及阿立哌唑的制备方法 | |
WO2008044632A1 (fr) | Dérivé de la 1-naphthyl alkylpipéridine | |
JPH06329535A (ja) | シグマ受容体拮抗薬 | |
MXPA01010032A (en) | N-(2-phenyl-4-amino-butyl)-1-naphthamides as neurokinin-1 receptor antagonists | |
CN1183765A (zh) | 对5-ht1a受体具高度亲和力的苯氧乙胺衍生物,其制备方法、作为药物的用途及含有它们的药物组合物 | |
JP2003212833A (ja) | 製造中間体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |