CN86105972A - 新的苯甲酰胺类 - Google Patents
新的苯甲酰胺类 Download PDFInfo
- Publication number
- CN86105972A CN86105972A CN86105972.7A CN86105972A CN86105972A CN 86105972 A CN86105972 A CN 86105972A CN 86105972 A CN86105972 A CN 86105972A CN 86105972 A CN86105972 A CN 86105972A
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- CN
- China
- Prior art keywords
- compound
- methyl
- amino
- group
- general formula
- 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.)
- Granted
Links
- 150000003936 benzamides Chemical class 0.000 title abstract description 7
- 229940054066 benzamide antipsychotics Drugs 0.000 title abstract description 6
- -1 aromatic cyclic ether Chemical class 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 150000002923 oximes Chemical class 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 5
- 230000009467 reduction Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 67
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 20
- 150000004292 cyclic ethers Chemical class 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000004593 Epoxy Substances 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000002430 hydrocarbons Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- FITOXKLLCGQZEV-UHFFFAOYSA-N 4-amino-2-butoxy-5-chlorobenzamide Chemical compound CCCCOC1=CC(N)=C(Cl)C=C1C(N)=O FITOXKLLCGQZEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 4
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- ITNXJLXLFAFOHO-UHFFFAOYSA-N n-piperidin-1-ylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NN1CCCCC1 ITNXJLXLFAFOHO-UHFFFAOYSA-N 0.000 claims 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims 1
- 125000000101 thioether group Chemical group 0.000 claims 1
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 150000004294 cyclic thioethers Chemical group 0.000 abstract 1
- 208000010643 digestive system disease Diseases 0.000 abstract 1
- 208000018685 gastrointestinal system disease Diseases 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229940080693 reglan Drugs 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 239000003205 fragrance Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 241000219161 Theobroma Species 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 230000002973 anti-dopamine Effects 0.000 description 4
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 4
- 229960004046 apomorphine Drugs 0.000 description 4
- ZAYITQDIKSBHDD-UHFFFAOYSA-N benzene methane Chemical class C.C1=CC=CC=C1.C1=CC=CC=C1 ZAYITQDIKSBHDD-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 235000011194 food seasoning agent Nutrition 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000008673 vomiting Effects 0.000 description 4
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000004278 EU approved seasoning Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000004006 stereotypic behavior Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 102000015554 Dopamine receptor Human genes 0.000 description 2
- 108050004812 Dopamine receptor Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- YAZGADZUKMSMOV-UHFFFAOYSA-N n-piperidin-4-ylidenehydroxylamine Chemical compound ON=C1CCNCC1 YAZGADZUKMSMOV-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
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- 235000017550 sodium carbonate Nutrition 0.000 description 2
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- 239000000600 sorbitol Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 description 1
- YLKLDLKLEXDSJY-UHFFFAOYSA-N 4-amino-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(N)C([N+]([O-])=O)=C1 YLKLDLKLEXDSJY-UHFFFAOYSA-N 0.000 description 1
- BVPWJMCABCPUQY-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)NC1CCN(CC=2C=CC=CC=2)CC1 BVPWJMCABCPUQY-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- GHKOFFNLGXMVNJ-UHFFFAOYSA-N Didodecyl thiobispropanoate Chemical compound CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC GHKOFFNLGXMVNJ-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
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Abstract
通式(I)的取代苯甲酰胺及其医药上可接受的盐,可用于治疗胃肠失调。本发明还描述了包括式(IIIa)的新胺的各种合成法(IIIa本身由相应的肟还原而得)。下面式(I)中的R、R1、R2、R3、X和Y与其在说明书中的定义相同,这里着重指出Y代表一个非芳香环醚或非芳香环硫醚基。
Description
本发明涉及N-杂环取代的苯甲酰胺类,它们的制备方法,含有这些化合物的配方及其在医疗上的应用。
取代的苯甲酰胺类已显示具有许多药理性质,多数是关于它们对抗多巴胺的中枢及外周作用和/或促进向胃肠道平滑肌中的蕈毒碱样受体释放乙酰胆碱的能力。这些性质使它们能成功地临床用作止吐剂及治疗广泛围的由身体,心理因素及医原性起因所致的胃肠道失调。
然而,在用苯甲酰胺类药物如胃复安及克力搏哌(clebop-ride)治疗时,对某些病人在纹状体及垂体中的多巴胺受体的阻断常伴随发生锥体囊外的症状及血内促性腺激素过多的有关副反应,这限制了它们的广泛应用。
我们发现向N-4-哌啶基系列的苯甲酰胺的环氮原子上引入各种环醚或环硫醚后所得到的化合物,在保持所需的胃活动活性的同时,会显着地降低抗多巴胺的活性。
因此,本发明提供了通式Ⅰ的化合物及其药学上可接受的盐
其中
R代表烷氧基,链烯氧基或炔氧基,基团中含有多至7个碳原子,R1是氢或NR4R5,或NR6COR7基,其中R4。R5及R6可以相同也可不同,各为氢或烷基,R7为烷基或三氟甲基,
R2是氢,卤原子或硝基,或氨磺酰基,
R3代表氢,或甲基或甲氧基,
x代表含1~4个碳原子的碳氢链,其中之一也可被氧原子所取代
y代表一个非芳香的环醚基或一个非芳香的环硫醚基。
本发明化合物中提到的关于R1-R7基团的烷基或烷氧基通常为“较低级”的烷基或烷氧基,它们含有多至6个碳原子,特别是多至4个碳原子,碳氢链为支链或直链。
在本发明的化合物中,y代表一个非芳香的环醚基或非芳香的环硫醚基。这意味着y不含有芳香环系统,但含有至少一个环系统,该环系统具有至少两个环碳原子及一个或多个环氧或环硫原子。环系统可以是一个含至少三个环原子的单核环或一个螺环或一个稠合的或非稠合的双核或多核环系统。这样的螺环或其他双或多核环系统将含有至少六个环原子。含有5~8个环原子的单核环是特别重要的,环原子中至少一个是氧或硫,其余的环原子通常为碳。这些环醚或环硫醚系统亦可含有多于一个的环氧原子和/或环硫原子,当存在多于一个的环氧和/或环硫原子时,它们在环中处于非相邻位置。环醚或环硫醚系统可以含有双键,但该双键应不形成芳香环系统的一部分。环醚或环硫醚系统除含有环醚或环硫醚外,还可含有另一个环系统,这另一个环系统可以是包含另一环醚或环硫醚的非芳香的碳环系统,或非芳香杂环系统,这另一个环系统与第一个环醚或环硫醚可以从稠合的形式或以一个直接的键或通过一个两价的连结基如亚甲基或C2-C6的聚亚甲基相连。
当环醚或环硫醚系统含有另一个环系统时,环醚或环硫醚最好是直接与通式Ⅰ中的X基团键合。
环醚或环硫醚系统可以被烷基,烷氧基或烷氧烷基取代基所取代。当这种取代基存在时,烷基或在烷氧基或烷氧烷基中的烷基残基最好含有1~6个碳原子,这里可具体提及甲基,甲氧基或甲氧甲基的取代。
在本发明化合物中作为y基团的典型的环醚或环硫醚如下所示:
本发明化合物中的x基团为含有1~4个原子的直链或支链的碳氢链。这一链最好是亚甲基或聚亚甲基链,但当聚亚甲基链存在时,其中一个亚甲基可被醚氧取代。当X基团为支链时,X基可为甲基亚丙基或乙基亚乙基等。虽然在正常情况下X将是饱和的,但亦可能在基团的一个位置上存在碳-碳不饱和键,如烯烃双键。
在分子中的苯甲酰胺残基部分在2-位上将有一个醚基。这就是R基。在正常情况下R将含有多至7个碳原子,最好R是一个直链的或支链的烷氧基。当R为一烷氧基时,最好该基团含有多至6个碳原子,因为已发现该基团能明显地影响该化合物的抗多巴胺的活性。因此,R可以是烷氧基,如,甲氧基,乙氧基,正-丙氧基,正-丁氧基,正-戊氧基或正-己氧基。
R基也可代表不饱和醚基,如链烯氧基或炔氧基,在这种情况下,可能是直链或支链的不饱和基最好含有2~6个碳原子,如烯丙氧基或炔丙氧基。
R基可能是苯甲酰胺残基上唯一的取代基。然而,最好苯甲酰胺残基是双取代的,通常三取代的更好。在这种情况下,R2基可代表卤素,如溴或氟但最好是氯,或可代表硝基。另一种情况,R2可代表氨磺酰基,并也可为N-取代的,或可被含有多至6个碳原子的一到两个烷基所取代,如N-乙基或N,N-二乙氨基磺酰基。
R1基最好是一个氨基,或一个N-烷氨基或N,N-二烷氨基,其中每个烷基含1~6个碳原子或一个酰氨残基,其中酰基是含有1~6个碳原子的链烷酰基,特别是乙酰基或三氟乙酰基。
本发明也提供了结构Ⅰ化合物,与生物学上及药学上可接受的无机酸或有机酸形成的盐,这些盐的例子是硫酸盐,氢卤酸盐,磷酸盐,D1~C6烷基磺酸盐,芳基磺酸盐,含1~20个碳原子的脂肪酸盐或芳香酸盐,但并不限于这些,这些酸可含一个或几个双键或其他官能团,如羟基,烷氧基,氨基或酮基。通式Ⅰ化合物的药学上可接受的季胺盐也包括在本发明的范围内,其中哌啶环上的叔氮原子,例如与C1~C6的烷基卤化物或硫酸酯反应而季胺化。
根据本发明的特点,本发明化合物按以下方法制备,该方法包括通式Ⅱ的苯甲酸的活性衍生物与通式Ⅲ的哌啶衍生物反应。
式Ⅱ中R,R1,R2规定如上,
式Ⅲ中R3,x,y已如上述。所述苯甲酸的活性衍生物可以是酰卤(最好是酰氯),烷基酯(最好是甲酯),酸酐或混合酸酐。
反应最好在惰性的有机溶剂中进行,如苯、甲苯,氯仿,四氢呋喃,N,N-二甲基甲酰胺或二噁烷,温度在-5℃和120℃之间。
通式Ⅱ的苯甲酸的酰卤可用酸与二氯亚砜或磷卤化物在惰性有机溶剂,如苯,甲苯或卤代碳氢化合物存在下反应而制得。通式Ⅱ的苯甲酸的混合酸酐可用酸与烷基甲酰氯等在有机含氮碱,如三乙胺的存在下,在惰性有机溶剂,如四氢呋喃,N,N-二甲基甲酰胺或二氯甲烷中,温度在-20℃和+25℃之间反应而制得。在上述方法中可作为原料的通式Ⅱ的酯及酸酐可从苯甲酸用已知方法制备。
在其R1代表氨基的通式Ⅰ的那些化合物的制备中,有时建议采用其氨基用酰基保护的相应的化合物作为原料,酰基保护基最好是乙酰基,氯乙酰基,三氟乙酰基或邻苯二甲酰基。反应后,对N-酰化的中间体产物进行碱水解,得到相应的通式Ⅰ的化合物,其中R1代表一个氨基。N-酰化化合物的碱水解最好在温度在20°到90℃之间用氢氧化钠或氢氧化钾在水-醇溶液中进行。当本发明的化合物的R2已如上所规定,但为硝基以外的基团时,它也可从通式Ⅳ的N-未取代的化合物制备:
其中R′ 2与上述R2所规定的但不是硝基,R,R1及R3如上面所规定的。
化合物Ⅳ可用相应的N-苄基化合物在溶剂如C1~C6的醇中,在贵金属催化剂,如吸附在惰性支持剂如碳或硫酸钡上的钯或铂的存在下,在氢氯中,常压或加压下,室温到100℃之间进行催化氢解而制得。化合物Ⅳ也可在有机溶剂,如乙醇或异丙醇中,在溶剂沸点温度下,用氢氧化钠或氢氧化钾对式Ⅴ的乙氧基羰基化合物水解而制得。
其中R,R1R′ 2及R3如上面所规定。然后化合物Ⅳ可与结构Ⅵ的适当的卤化物或磺酸酯反应:
其中w为卤原子或甲基磺酸酯,对甲苯磺酸酯或苯磺酸酯基,x及y如上面所规定的,该反应在碱如碳酸钠或碳酸钾、或碳酸氢钠或碳酸氢钾的存在下,在有机溶剂如甲苯,二噁烷或甲基异丁基酮中,在温度40℃~140℃之间进行。
通式Ⅰ的本发明的化合物也可用包括在合成的最后一步形成环醚或环硫醚的方法制备。更明确地,通式Ⅰ的化合物可以从通式Ⅶ相应的羟基或硫基衍生物制备。
其中A及B可以相同或不同,各为一个氧或硫原子,m为0,1,2,3,或4,R9为氢或C1-C6的烷基,R,R1,R2,R3及x均如上面所规定的,化合物Ⅶ可用脱水剂,双羟化合物或醛在溶剂如苯或甲苯存在下,在提高温度如溶剂沸点的条件下环化。
根据本发明的另一特点,通式Ⅰ的化合物也可用通式Ⅱ的苯甲酸在适当的脱水剂的存在下与通式Ⅲ的哌啶衍生物直接反应而制备。这种脱水剂包括四氯化硅,单、双或三烷基氯化硅,四氯化钛,N,N-二环己基碳二亚胺,羰基双-咪唑,二氯亚砜,在二甲基亚砜中的三氧化硫,对-甲苯磺酰氯,丙酮缩二甲醇或多聚脱水剂。反应可在惰性有机溶剂,如二氯甲烷,丙酮,吡啶,乙酸乙酯或二噁烷中,在温度20°~110℃之间进行。
通式Ⅰ的本发明化合物也可从通式Ⅷ的羟基衍生物与通式Ⅸ的卤代衍生物反应而制备。
其中R1,R2,R3,x及y为上面所规定,
其中Z为氯,溴,碘,R如上面所规定的。反应可在有机溶剂如甲基异丁基酮,甲苯,二噁烷中,在温度40°到140℃之间并在有机碱或无机碱如碳酸钾或碳酸钠存在下进行。
R3为氢的通式Ⅲ的中间体胺本身就是新化合物并形成本发明的另一方面。其R3为氢的通式Ⅲ的那些化合物的制法是在二乙醚或四氢呋喃中,在温度为5°~65℃之间,用氢化锂铝对通式Ⅹ相应的肟还原而制备
其中x,及y如上所规定。肟X可由通式Ⅺ的4-哌啶酮肟与通式Ⅵ的卤代物或磺酸酯衍生物在酸结合剂如碱金属的碳酸盐或碳酸氢盐的存在下,在有机溶剂如甲苯,二噁烷或甲基异丁基酮中在温度为40~140℃之间进行反应而制备。
肟X也可由通式Ⅻ相应的酮与羟胺用已知的方法反应制备。
用作制备本发明的化合物的中间体Ⅱ也为已知化合物,并在GB1,507,462,GB1,088,531及GB1,019,781中有描述。
一系列N-杂环取代的苯甲酰胺衍生物的药理筛选已充分证明在缺乏多巴胺拮抗剂作用时,它具有强烈的胃运动活性。
该类化合物对于胃肠运动效应最佳化的药理筛选用以下实验进行:
1.大鼠胃排空,经口服(0.1~1毫克/公斤)及腹膜内给化合物(1~10毫克/公斤)(见Jacoby,H.I.and Brodie,D.A.,Gastroenterol.52,676~684,1967)。
胃排空指数计算如下:
以0.1,0.3及1毫克/公斤的剂量口服试验化合物后,给每只大鼠40个玻璃小珠(直径约1毫米),按公式计算出结果:
R= (nX- nC)/(40 - nC) × 100
其中:nc=被对照动物排空的珠数
nx=被给药动物排空的珠数
及:R=最大反应的百分数
SEI=胃排空指数
SEI= (R(0.1)+R(0.3)+R(1))/3
对中枢和外围D2(DA2)-多巴胺受体不合适效应的药理筛选用以下实验进行:
2.大鼠由阿朴吗啡(Apomorphine)诱导的刻板行为,腹膜内给试验化合物。(见Janssen,P.A.J.,Niemegeers,C.J.E.及Jageneau,A.H.Arzneim,Forsch.10,1003~1005,1960)。
3.阿朴吗啡诱导的狗呕吐,静脉给试验化合物,最大剂量1毫克/公斤静注。(见Prala,J.J.,High,J.P.,Hasses,G.L.,Burke,J.C.及Craveni,B.N.,J.Pharmac.Exp.Therap.,127,55~65,1959)。
在上述试验2中,腹膜内给药试验至30毫克/公斤及上述试验3中,静脉内给药试验至1毫克/公斤时,结构与活性关系表示,通式Ⅰ的物质可保留克力搏哌的强的胃排空性质,但有所降低,在一些试验中甚至没有抗多巴胺的活性。
例如,通式Ⅰ的样品化合物在上述1,2,3试验中的试验结果与胃复安(metoclopramide)及克力搏哌相比较的结果,列于表Ⅰ。为了对比的目的,有芳香杂环的本发明化合物的类似物也按上述1,2,3试验法试验,其结果与胃复安及克力搏哌所给结果比较,列于表Ⅱ。
表Ⅰ.
化合物(实例 经口服大鼠的 抗多巴胺活性: 抗多巴胺活性:
2后面的表) 胃排空指数 阿朴吗啉诱导 狗呕吐筛选
大鼠刻板行为 ID50(微克/
ID50(毫克 公斤)静注.
内给药.
胃复安 24.7 5.4 76.7
克力搏哌 50.0 0.3 9.6
化合物57 51.0 >30.0 >1000.0
化合物66 53.7 >30.0 >1000.0
化合物109 61.3 >30.0 >1000.0
化合物98 60.1 >30.0 >1000.0
化合物95 49.0 >30.0 >1000.0
化合物91 54.9 >30.0 >1000.0
化合物108 51.0 >30.0 >1000.0
化合物116 56.2 >30.0 >1000.0
化合物39 45.8 >30.0 >1000.0
表2.芳香化合物
化合物 经口服大鼠的 抗多巴胺活性: 抗多巴胺活性:
胃排空指数 阿朴吗啡诱发大 狗呕吐筛选
鼠刻板行为 ID50(微克/
ID50(毫克/ 公斤)静注
公斤)腹腔内给
药
胃复安 24.7 5.4 76.7
克力搏哌 50.0 0.3 9.6
化合物A 40.3 3-10 10-30
化合物B 17.7 10-30 30-100
化合物C 25.0 10-30 30-100
化合物D 19.3 3-10 10-30
克力搏哌是N(1-苄基哌啶-4-基)-2-甲氧基-4-氨基-5-氯代苯甲酰胺。
胃复安是N〔2-(二乙胺基)乙基-〕-2-甲氧基-4-氨基-5-氯代苯甲酰胺。
化合物A:N-〔1-(2-噻吩甲基)哌啶-4-基〕-2-甲氧基-4-氨基-5-氯代苯甲酰胺。
化合物B:N-〔1-(2-噻吩甲基)哌啶-4-基〕-2-甲氧基4-氨基-5-硝基苯甲酰胺。
化合物C:N-〔1-(2-吡啶甲基)哌啶-4基〕-2-甲氧基4-氨基-5-氯代苯甲酰胺。
化合物D:N-〔1-(2-呋喃甲基)哌啶-4-基〕-2-甲氧基-5-氯代苯甲酰胺。
因此,新化合物对已有的治疗某些胃肠能动性失调的药物是一个重要的进步,它在于在这些化合物的治疗剂量水平上,可避免与多巴胺受体阻断有关的不希望有的付反应(如锥体囊外的付反应,增加催乳激素的分泌等)。
本发明也提供了药物组合物,它包括至少一种通式Ⅰ的化合物或其药学上可接受的盐作为活性成份,并与药学上可接受的载体或稀释剂组合。这些组合物最好制成便于口服,局部给药,经皮肤给药或非肠道给药的形式。
药学上可接受的载体或稀释剂用以与活性化合物或几个活性化合物或这些化合物的盐混合,以形成本发明的组合物,本身都是已知的,所用的赋形剂尤其取决于准备服用该组合物的方法。本发明组合物的给药方法最好是口服,在这种情况下,口服组合物可采用片剂,胶囊,锭剂或泡腾颗粒剂的形式,或液态制剂,如合剂,配剂,糖浆或悬浮液,所有这些制剂均含有一个或多个本发明的化合物,这些制剂均可按工艺上熟知的方法制备。
在制备组合物过程中,可用的稀释剂包括那些与活性成份适合的液态或固体稀释剂,如果需要,还可与着色剂或调味剂合用。片剂或胶囊可方便地含有1~20毫克的活性成份或它们相当量的酸加成盐。
口服用的液体组合物可用溶液或悬浮液形式。溶液可以是活性化合物的可溶性盐或其它衍生物的水溶液与,例如,蔗糖一起形成糖浆。悬浮液可含有与水混合的本发明不溶的活性化合物或其药学上可接受的盐,和悬浮剂或调味剂。
注射剂组合物可从可溶性盐制备,可以亦可不冷冻干燥,可以溶于水中或溶于其他适合于注射用的液体中。
本发明的另一方面提供了一个治疗各种胃肠道失调,包括哺乳类动物(包括人)的呕吐的方法,它是将有效量的通式Ⅰ的化合物或其盐,用上面描述的适当的组合物及途径给药。正常的有效剂量为每天1~100毫克活性成份。
本发明的再一个方面,该化合物可与抗酸及抗溃疡的活性物(不包括抗胆碱药)混合作口服或在适宜情况下非肠道服用。
以下参考实例及实例阐明本发明化合物的制备。
参考实例
哌啶-4-酮肟(46克;0.40摩尔),2-四氢呋喃甲基磺酸甲酯(79.3克;0.44摩尔)及无水碳酸钾(56.5克;0.40摩尔)在甲基异丁基酮(625毫升)中的混合物,迴流搅拌48小时。冷却后,反应混合物用盐水洗,干燥(Na2SO4),在真空中除去溶剂,残留物从二异丙醚中重结晶,得1-(2-四氢呋喃甲基)-哌啶-4-酮肟(42.5克),熔点104-106℃
将1-(2-四氢呋喃甲基)哌啶-4-酮肟(42.5克;0.22摩尔)在无水四氢呋喃(700毫升)中的溶液滴加至氢化铝锂(24.4克;0.64摩尔)在无水四氢呋喃(300毫升)的悬浮液中。反应混合物在室温搅拌过夜,然后依次加入水(24.5毫升),4N氢氧化钠水溶液(24.5毫升)及水(73.5毫升),过滤,滤液干燥(Na2SO4),在真空中蒸干。将所得到的油(28克)蒸馏,得(1-(2-四氢呋喃甲基)-4-氨基哌啶,沸点94-98℃/0.2毫米汞柱。
用适宜的肟作原料,用相似的方法可制备下表列举的化合物。
实例1
将三乙胺(5.6毫升;0.04摩尔)及氯甲酸乙酯(3.84毫升;0.04摩尔)依次加至搅拌着的2-乙氧基-4-氨基-5-氯代苯甲酸(8.6克;0.04摩尔)在无水四氢呋喃(300毫升)的悬浮液中,温度保持在-5°及-10℃之间。在此温度搅拌0.5小时后,加入1-(2-四氢呋喃甲基)-4-氨基哌啶(8.0克;0.04摩尔)在无水四氢呋喃(50毫升)中的溶液,温度保持在-5°到-10℃一小时,然后放置过夜使至室温。混合物的溶剂在真空中除去,残留物倒入水中,用氯仿萃取,有机层用水洗。将氯仿溶液干燥(Na2SO4),在真空中除去溶剂,得到的油用化学计量的富马酸在沸腾的无水乙醇中处理,得N-〔1-(2-四氢呋喃甲基)哌啶-4-基〕-2-乙氧基-4-氨基-5-氯代苯甲酰胺富马酸盐(10.6克),熔点199°-201℃(分解)。
实例2
N-(哌啶-4-基)-2-甲氧基-4-氨基-5-氯代苯甲酰胺(2.8克;0.010摩尔),2-(2-氯乙基)-1,3-二噁烷(1.65克;0.011摩尔)及无水碳酸钾(1.4克;0.010摩尔)在甲基异丁基酮(125毫升)中的混合物在搅拌下回流煮沸96小时。将反应混合物冷却,用水洗,干燥(Na2SO4)及在真空中除去溶剂,所得到的油状残留物用化学计量的富马酸在沸腾的无水乙醇中处理。冷却后得N-〔1-(2-(1,3-二噁烷基)-乙基〕-哌啶-4-基〕-2-甲氧基-4-氨基-5-氯代苯甲酰胺富马酸盐(2.1克),熔点223-225℃(分解)。
包括在下表中的通式Ⅰ的化合物是按实例1或2所公开的方法制备的。
实例3
N-〔1-〔2-(1,3-二氧戊环基)甲基〕哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯甲酰胺(2克;0.005摩尔)及碘甲烷(1.25毫升;0.02摩尔)在氯仿(60毫升)中的溶液室温搅拌过夜。四级沉凝的固体过滤,用丙酮及乙醚洗涤,得1.8克的N-〔1-〔2-1,3二氧戊环基)甲基〕哌啶-4-基〕-2-丁氧基-4-氨基-5氯代苯甲酰胺碘甲烷,熔点215-217℃。
用相似方法制备以下化合物:
N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-己氧基-4-氨基-5-氯代苯甲酰胺碘甲烷,熔点188-190℃。
以下实例说明根据本发明的药学组合物及其制备步骤。
实例4
从以下配方制备出每片含1毫克的N-〔1-〔2-(1,3-二氧戊环基)甲基〕哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯甲酰胺的片剂50.000片。
N-〔1-〔2-(1,3-二氧戊环基)甲基〕哌啶-4-基〕-2-丁氧基-4-
氨基-5-氯代苯甲酰胺 50克
微晶纤维素 950克
喷雾干燥的乳糖 4950克
羧甲基淀粉 200克
富马酸十八烷酯钠盐 50克
胶状的二氧化硅 50克
操作步骤
所有的粉末都通过筛孔为0.6毫米的筛,然后在适宜的混合器中混合20分钟,用6毫米的圆盘及平的斜面冲头压成125毫克的片剂。片剂的崩解时间为60秒。
实例5
2,000并(125毫升体积)每并含25毫克的N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯酰甲胺按下法制备:
N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯甲酰胺 50克
山梨糖醇 120000克
山梨酸 250克
柠檬酸 250克
蒸馏水足量 250升
调味剂 250升
操作步骤 适量
将N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4〕-2-丁氧基-4-氨基-5-氯代苯甲酰胺及山梨酸溶于150升水中,然后加入山梨糖醇,柠檬酸及调味剂,搅拌重溶。混合物用250升的水稀释,用适当的灌注机灌注到125毫升的并中。
实例6
每支含0.5毫克的N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯甲酸胺的针剂10,000支从以下配方制备:
N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-
氨基-5-氯代苯甲酰胺 5克
氯化钠 250克
乳酸 5克
1N氢氧化钠水溶液 适量至pH=4
注射级水足量 50升
操作步骤
将N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯苯甲酰胺,乳酸及氯化钠溶于40升的水中。所得溶液用氢氧化钠溶液中和至pH=4,稀释至50升,然后通过一滤菌过滤器,在无菌条件下按已知方法灌注入5毫升的玻璃安瓿中。
实例7
每个含1毫克的N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯甲酰胺的栓剂5,000个按下法制备:
N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯代苯甲酰胺 5克
可可油 9995克
操作步骤
将可可油熔化,将活性化合物悬浮其中。然后将混合物注入适宜的栓剂模中以制成2.0克的栓剂。
实例8
每个含1毫克N-〔1-〔2-(1,3二氧戊烷基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基氯化苯甲酰胺的胶囊
100,000个的制备如下:
N-〔1-〔2-(1,3-二氧戊烷基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基氯代苯甲酰胺 100克
乳糖 10500克
玉米淀粉 9000克
胶体二氧化硅 200克
硬脂酸镁 200克
操作步骤
所有的粉末预先通过筛孔为0.6毫米的筛,混和20分钟,用灌注机分装入100,000个大小适宜的胶囊中。
实例9
每个含10毫克的N-〔1-〔2-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-丁氧基-4-氨基-5-氯苯甲酰胺的栓剂8,000个的制备如下:
N-〔1-〔2-(1,3-二氧戊环基)甲基〕哌啶-4-基〕-2-丁氧基-4-氨基-5-氯苯甲酰胺 80克
可可油 15920克
操作步骤
将可可油熔化及将活性化合物悬浮其中。混合物注入适当的栓剂模中以制成2.0克的栓剂。
Claims (19)
1、制备N-哌啶基苯甲酰胺的方法,其特征在于通式I的化合物或其药学上可接受的盐按下列方法制备:
其中:
R代表一个烷氧基,链烯氧基或炔氧基,在基团中含多至7个碳原子,R1是氢或一个NR4R5,或NR6COR7基,其中R4,R5及R6可以是相同的也可以不同,各为氢或一个烷基及R7为一烷基或三氟甲基,
R2是氢,卤素,或硝基,或氨磺酰基,
R3代表氢或一个甲基或甲氧基,
x代表碳氢链,含1-4个碳原子,其中一个可随意地被一个氧原子取代,
y代表非芳香环醚或一个非芳香环醚或一个非芳香环硫醚基:
a)将通式Ⅱ的化合物
或其活性的羧酸衍生物与通式Ⅲ的胺反应
其中R,R1,R2,R3,x及y如上所规定。
或(b)对R2为氢,卤素或氨磺酰基的化合物,将通式为Ⅳ的化合物与通式为Ⅳ的化合物
其中R′ 2为氢,卤素或氨磺酰基,R,R1,R3如上所规定,
其中w为卤素或磺酸酯基,x,y如上规定。
或(c)环合通式Ⅶ的化合物
其中R,R1,R2,R3及x如上所规定,A及B可以相同或不同,各为氧或硫,m为0,1,2,3或4及R9为氢或C1-C4烷基。或(d)用醚化剂醚化通式Ⅷ的2-羟基化合物,将2-OH转化为2-OR,并且如果需要用药学上可接受的酸将游离碱转化成盐。
其中R,R1,R2,R3,x及y如上所规定。
2、按权利要求1的方法,其特征在于y为环状醚基。
3、权利要求1或2的方法,其特征在于y为单核环系统该系统含5-8个环原子,其中1个或2个为环氧及/或环硫原子,其余的为碳原子的。
4、按前面任一权利要求的方法,其特征在于y在环的非相邻位置上包含多于一个的环氧或环硫原子。
5、按照前面任一权利要求的方法,其特征在于y包含一个直接或间接与另一个非芳香环系统稠合或连接的环醚或环硫醚。
6、按权利要求5的方法,其特征在于另一个环系统为一环醚或环硫醚。
7、按照权利要求5或6的方法,其特征在于环醚或环硫醚与x基团直接连接。
8、按照前面任一权利要求的方法,其特征在于y是一个1,3-二氧戊环-2-基,1,3-二氧戊环-4-基,4,4,5,5-四甲基-1,3-二氧戊环-2-基,1,3-二噁烷-2-基,1,3-二氧环庚烷基或四氢呋喃-2-基环,或是一个包括它们之中之一的基团。
9、按照前面任一权利要求的方法,其特征在于x为CH2-或-CH2-CH2-CH2-。
10、按照前面任一权利要求的方法,其特征在于R为C2-C4烷氧基。
11、按权利要求10的方法,其中特征在于R为甲氧基,n-丙氧基或正-丁氧基。
12、按照前面任一权利要求的方法,其特征在于R1为NH2。
13、按照前面任何一个权利要求的方法,其特征在于R2为Cl。
14、按照权利要求1的方法,其特征在于制备N-〔1-〔2-(1,3-二氧戊环基)甲基〕哌啶-4-基〕-2-丁氧基-4-氨基-5-氯苯甲酰胺。
15、按照权利要求1的方法,其特征在于制备N-〔1-〔4-(1,3-二氧戊环基)甲基〕-哌啶-4-基〕-2-甲氧基-4-氨基-5-氯代苯甲酰胺,N-〔1-〔2-(1,3-二氧环庚烷基)甲基〕-哌啶-4-基〕2-正丁氧基-4-氨基-5-氯苯甲酰胺,N-〔1-〔3-(2-四氢呋喃基)丙基〕-哌啶-4-基〕-2-正丙氧基-4-氨基5-氯代苯甲酸胺,N-〔1-〔2-(1,3-二噁烷基)甲基〕哌啶-4-基〕-2-正丙氧基-4-氨基-5-氯代苯甲酰胺,N-〔1-〔2-(4,4,5,5-四甲基-1,3-二噁戊烷基)甲基〕-哌啶-4-基〕2-正丁氧基-4-氨基-5-氯代苯甲酰胺或N-〔1-〔2-(1,3-二噁烷基)甲基〕-哌啶-4-基〕-2-正丁氧基-4-氨基-5-氯代苯甲酰胺。
16、一种包含活性成份与药学上可接受的载体或稀释剂的药学组合物,其特征在于活性成份为如在权利要求1-15中任一项中所规定的通式Ⅰ的化合物或其盐。
17、配制由一种活性成分与一种药学上可接受的载体或稀释剂的药物组合物的方法,其特征在于活性成分为如权利要求1-15中任一项新规定的通式Ⅰ的化合物或盐。
18、制备一种胺的方法,其特征在于通式Ⅲa的化合物是由还原通式x的肟制备的,
其中,x及y为如在权利要求1-9,14或15中任一项新规定的。
19、按照权利要求18的方法,其特征在于制备4-氨基-1-〔2-(1,3-二氧戊环基)甲基〕哌啶。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8519707 | 1985-08-06 | ||
GB858519707A GB8519707D0 (en) | 1985-08-06 | 1985-08-06 | Chemical compounds |
GB8519707(P.3149) | 1985-08-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN86105972A true CN86105972A (zh) | 1987-04-01 |
CN1022830C CN1022830C (zh) | 1993-11-24 |
Family
ID=10583372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86105972A Expired - Fee Related CN1022830C (zh) | 1985-08-06 | 1986-08-06 | N-哌啶基苯甲酰胺衍生物的制备方法 |
Country Status (28)
Country | Link |
---|---|
US (1) | US4772618A (zh) |
EP (1) | EP0213775B1 (zh) |
JP (1) | JPH0662614B2 (zh) |
KR (1) | KR920001763B1 (zh) |
CN (1) | CN1022830C (zh) |
AR (2) | AR243521A1 (zh) |
AT (1) | ATE49206T1 (zh) |
AU (1) | AU596110B2 (zh) |
CA (1) | CA1300154C (zh) |
DD (1) | DD287502A5 (zh) |
DE (1) | DE3667975D1 (zh) |
DK (1) | DK370586A (zh) |
EG (1) | EG18154A (zh) |
ES (2) | ES2000706A6 (zh) |
FI (1) | FI89168C (zh) |
GB (1) | GB8519707D0 (zh) |
GR (1) | GR862060B (zh) |
HU (1) | HU201060B (zh) |
IE (1) | IE58751B1 (zh) |
IL (1) | IL79469A0 (zh) |
MX (1) | MX3375A (zh) |
MY (1) | MY101352A (zh) |
NO (1) | NO168706C (zh) |
NZ (1) | NZ217078A (zh) |
PH (1) | PH25019A (zh) |
PL (1) | PL150228B1 (zh) |
PT (2) | PT83146B (zh) |
ZA (1) | ZA865537B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1052228C (zh) * | 1996-01-17 | 2000-05-10 | 中国科学院大连化学物理研究所 | N-甲酰基哌啶及其同系物的制备方法 |
CN103080089A (zh) * | 2010-09-01 | 2013-05-01 | 詹森药业有限公司 | 5-ht2b受体拮抗剂 |
CN110950843A (zh) * | 2019-11-28 | 2020-04-03 | 广东东阳光药业有限公司 | 取代的苯酰胺衍生物及其用途 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2640139A1 (fr) * | 1988-12-14 | 1990-06-15 | Delagrange Laboratoires | Application de benzamides substitues comme gastromoteurs |
US5374637A (en) * | 1989-03-22 | 1994-12-20 | Janssen Pharmaceutica N.V. | N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives |
GB9005014D0 (en) * | 1990-03-06 | 1990-05-02 | Janssen Pharmaceutica Nv | N.(4.piperidinyl)(dihydrobenzofuran or dihydro.2h.benzopyran)carboxamide derivatives |
JP2999669B2 (ja) * | 1993-08-24 | 2000-01-17 | 株式会社三和化学研究所 | ベンゾ[b]フランカルボキサミド誘導体、その製法及び用途 |
JPH0820586A (ja) * | 1994-07-05 | 1996-01-23 | Sanwa Kagaku Kenkyusho Co Ltd | 1−アザビシクロ[3.3.0]オクタン誘導体、その塩及び製法並びに用途 |
JPH0873463A (ja) | 1994-07-05 | 1996-03-19 | Sanwa Kagaku Kenkyusho Co Ltd | ベンゾピランカルボキサミド誘導体、その塩及び製法並びに用途 |
CN1091104C (zh) * | 1998-04-02 | 2002-09-18 | 中国科学院大连化学物理研究所 | 一种n-甲酰基哌啶的制备方法 |
CN1649766A (zh) | 2002-06-11 | 2005-08-03 | 安芸电器株式会社 | 自行车的前照灯以及前照灯电路 |
WO2005068461A1 (en) * | 2004-01-07 | 2005-07-28 | Aryx Therapeutics | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
GB0525661D0 (en) * | 2005-12-16 | 2006-01-25 | Glaxo Group Ltd | Novel compounds |
Family Cites Families (5)
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GB1019781A (zh) | 1963-03-05 | |||
US3342826A (en) | 1964-01-13 | 1967-09-19 | Ile De France | Heterocyclic aminoalkyl benzamides |
GB1507462A (en) * | 1974-03-21 | 1978-04-12 | Gallardo Antonio Sa | N-heterocyclic substituted benzamides methods for their preparation and compositions containing them |
GB1574418A (en) * | 1976-11-16 | 1980-09-03 | Anphar Sa | Piperidine derivatives |
CA1183847A (en) * | 1981-10-01 | 1985-03-12 | Georges Van Daele | N-(3-hydroxy-4-piperidinyl)benzamide derivatives |
-
1985
- 1985-08-06 GB GB858519707A patent/GB8519707D0/en active Pending
-
1986
- 1986-07-21 ES ES8600431A patent/ES2000706A6/es not_active Expired
- 1986-07-21 IL IL79469A patent/IL79469A0/xx not_active IP Right Cessation
- 1986-07-21 ES ES8600430A patent/ES2000705A6/es not_active Expired
- 1986-07-24 ZA ZA865537A patent/ZA865537B/xx unknown
- 1986-07-31 US US06/890,946 patent/US4772618A/en not_active Expired - Fee Related
- 1986-07-31 AU AU60758/86A patent/AU596110B2/en not_active Ceased
- 1986-08-01 IE IE207386A patent/IE58751B1/en not_active IP Right Cessation
- 1986-08-01 CA CA000515257A patent/CA1300154C/en not_active Expired - Lifetime
- 1986-08-04 EP EP86305999A patent/EP0213775B1/en not_active Expired - Lifetime
- 1986-08-04 KR KR1019860006438A patent/KR920001763B1/ko not_active IP Right Cessation
- 1986-08-04 NZ NZ217078A patent/NZ217078A/xx unknown
- 1986-08-04 GR GR862060A patent/GR862060B/el unknown
- 1986-08-04 DE DE8686305999T patent/DE3667975D1/de not_active Expired - Lifetime
- 1986-08-04 NO NO863139A patent/NO168706C/no unknown
- 1986-08-04 DK DK370586A patent/DK370586A/da not_active Application Discontinuation
- 1986-08-04 AT AT86305999T patent/ATE49206T1/de not_active IP Right Cessation
- 1986-08-04 PL PL1986260921A patent/PL150228B1/pl unknown
- 1986-08-04 FI FI863179A patent/FI89168C/fi not_active IP Right Cessation
- 1986-08-04 DD DD86293410A patent/DD287502A5/de not_active IP Right Cessation
- 1986-08-04 EG EG488/86A patent/EG18154A/xx active
- 1986-08-04 HU HU863367A patent/HU201060B/hu not_active IP Right Cessation
- 1986-08-04 JP JP61183285A patent/JPH0662614B2/ja not_active Expired - Lifetime
- 1986-08-04 PH PH34096A patent/PH25019A/en unknown
- 1986-08-05 PT PT83146A patent/PT83146B/pt unknown
- 1986-08-05 AR AR86304802A patent/AR243521A1/es active
- 1986-08-05 PT PT83147A patent/PT83147B/pt unknown
- 1986-08-05 MX MX337586A patent/MX3375A/es unknown
- 1986-08-06 CN CN86105972A patent/CN1022830C/zh not_active Expired - Fee Related
- 1986-08-06 AR AR86304820A patent/AR242793A1/es active
-
1987
- 1987-09-01 MY MYPI87001497A patent/MY101352A/en unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1052228C (zh) * | 1996-01-17 | 2000-05-10 | 中国科学院大连化学物理研究所 | N-甲酰基哌啶及其同系物的制备方法 |
CN103080089A (zh) * | 2010-09-01 | 2013-05-01 | 詹森药业有限公司 | 5-ht2b受体拮抗剂 |
CN103080089B (zh) * | 2010-09-01 | 2015-09-23 | 詹森药业有限公司 | 5-ht2b受体拮抗剂 |
CN110950843A (zh) * | 2019-11-28 | 2020-04-03 | 广东东阳光药业有限公司 | 取代的苯酰胺衍生物及其用途 |
CN110950843B (zh) * | 2019-11-28 | 2022-12-27 | 广东东阳光药业有限公司 | 取代的苯酰胺衍生物及其用途 |
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