WO1994014750A1 - Novel salicylic acid derivatives, their salts, pharmaceutical compositions containing them and process for preparing same - Google Patents
Novel salicylic acid derivatives, their salts, pharmaceutical compositions containing them and process for preparing same Download PDFInfo
- Publication number
- WO1994014750A1 WO1994014750A1 PCT/HU1993/000077 HU9300077W WO9414750A1 WO 1994014750 A1 WO1994014750 A1 WO 1994014750A1 HU 9300077 W HU9300077 W HU 9300077W WO 9414750 A1 WO9414750 A1 WO 9414750A1
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- Prior art keywords
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- formula
- stands
- compound
- means hydrogen
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- 150000003839 salts Chemical class 0.000 title claims abstract description 24
- 150000003872 salicylic acid derivatives Chemical class 0.000 title claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims abstract description 31
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims abstract description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 229960001380 cimetidine Drugs 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 210000002784 stomach Anatomy 0.000 claims abstract description 12
- 239000003485 histamine H2 receptor antagonist Substances 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- 230000035876 healing Effects 0.000 claims abstract description 5
- 210000001198 duodenum Anatomy 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- -1 methyl 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- butenoate Famotidine salt Chemical class 0.000 claims description 18
- 239000004480 active ingredient Substances 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 150000001350 alkyl halides Chemical class 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 150000008050 dialkyl sulfates Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- NZRDKNBIPVLNHA-UHFFFAOYSA-N 5-Acetylsalicylic acid Chemical compound CC(=O)C1=CC=C(O)C(C(O)=O)=C1 NZRDKNBIPVLNHA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 230000003213 activating effect Effects 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 230000001131 transforming effect Effects 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims 2
- 230000000996 additive effect Effects 0.000 claims 2
- 230000000875 corresponding effect Effects 0.000 claims 2
- 238000007911 parenteral administration Methods 0.000 claims 2
- 101150056637 Hrh2 gene Proteins 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 229960001596 famotidine Drugs 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
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- 241000590002 Helicobacter pylori Species 0.000 abstract description 6
- 229940037467 helicobacter pylori Drugs 0.000 abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 235000013350 formula milk Nutrition 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- VFSNCGRKNXKSPK-ONEGZZNKSA-N 5-[(e)-3-carboxyprop-2-enoyl]-2-hydroxybenzoic acid Chemical compound OC(=O)\C=C\C(=O)C1=CC=C(O)C(C(O)=O)=C1 VFSNCGRKNXKSPK-ONEGZZNKSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 208000025865 Ulcer Diseases 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 231100000397 ulcer Toxicity 0.000 description 9
- MFGNGNIHTGVOCH-SNAWJCMRSA-N 2-hydroxy-5-[(e)-4-methoxy-4-oxobut-2-enoyl]benzoic acid Chemical compound COC(=O)\C=C\C(=O)C1=CC=C(O)C(C(O)=O)=C1 MFGNGNIHTGVOCH-SNAWJCMRSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 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 4
- 238000006317 isomerization reaction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 210000001187 pylorus Anatomy 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- 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 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical class ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000000762 glandular Effects 0.000 description 3
- 235000003642 hunger Nutrition 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229960004838 phosphoric acid Drugs 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000037351 starvation Effects 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- NNBNJDITTBURMA-AATRIKPKSA-N 5-[(e)-4-[(2-ethoxy-2-oxoethyl)amino]-4-oxobut-2-enoyl]-2-hydroxybenzoic acid Chemical compound CCOC(=O)CNC(=O)\C=C\C(=O)C1=CC=C(O)C(C(O)=O)=C1 NNBNJDITTBURMA-AATRIKPKSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 0 CN(CC1)CCN1C(*)=O Chemical compound CN(CC1)CCN1C(*)=O 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 210000003815 abdominal wall Anatomy 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 231100000319 bleeding Toxicity 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- XWPKFYYTTOOWBP-AATRIKPKSA-N methyl 2-hydroxy-5-[(e)-4-methoxy-4-oxobut-2-enoyl]benzoate Chemical compound COC(=O)\C=C\C(=O)C1=CC=C(O)C(C(=O)OC)=C1 XWPKFYYTTOOWBP-AATRIKPKSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- GIUTUZDGHNZVIA-UHFFFAOYSA-N 2-(ethylamino)acetic acid;hydrochloride Chemical compound Cl.CCNCC(O)=O GIUTUZDGHNZVIA-UHFFFAOYSA-N 0.000 description 1
- MFGNGNIHTGVOCH-PLNGDYQASA-N 2-hydroxy-5-[(z)-4-methoxy-4-oxobut-2-enoyl]benzoic acid Chemical compound COC(=O)\C=C/C(=O)C1=CC=C(O)C(C(O)=O)=C1 MFGNGNIHTGVOCH-PLNGDYQASA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940045971 anti bac Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- QFFVPLLCYGOFPU-UHFFFAOYSA-N barium chromate Chemical compound [Ba+2].[O-][Cr]([O-])(=O)=O QFFVPLLCYGOFPU-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
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- 230000001684 chronic effect Effects 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- OONJNILIBCMSNC-UHFFFAOYSA-N famotidine hydrochloride Chemical compound [H+].[Cl-].NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 OONJNILIBCMSNC-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
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- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
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- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
-
- 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
- C07D295/16—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 acylated on ring nitrogen atoms
- C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
Definitions
- the invention relates to a novel, therapeutically active salicylic acid derivative of the formula
- R means hydrogen or a C ⁇ _4alkyl group
- R 1 stands for hydroxy group; a C ⁇ _ 4 alkoxy group; or a group of the formula
- R 2 means hydrogen or benzyl group
- R 3 stands for a C ] __4alkyl group; or a group of the formula
- R 4 means a C 1 _ 4 alkyl group, as well as ' a salt thereof formed with a H2 receptor antagonist, preferably with Cimetidine or Famotidine; and a pharmaceutical compositions containing said compound.
- the invention relates to a process for the preparation of said compounds and compositions. More particularly, the invention relates to a gastric acid secretion inhibitory and gastrocyto ⁇ protective pharmaceutical composition containing as active ingredient - a compound of the formula (I) , wherein R and R 1 are as defined above; or - a compound of the formula
- R 1 is as defined above; or - a compound of the formula
- R 1 is as defined above.
- the compounds of formulae (II) and (III) are salts formed from the salicylic acid derivatives of the for ⁇ mula (I) with Cimetidine and Famotidine, respectively.
- Alkyl substituents in themselves or as structural moieties of other groups in the formulae are straight or branched chain, saturated hydrocarbyl groups containing a number of carbon atoms within the range defined above, such as e.g. the methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl or tert.-butyl groups.
- novel salicylic acid derivatives of the formula (I) as well as their Cimetidine salts of the formula (II) and Famotidine salts of the formula (III) respectively possess valuable pharmacological activities; namely, they show gastric acid secretion inhibitory, gastrocyto ⁇ protective effects and antibacterial effect against the bacterial strain Helicobacter pylori. Thus, they are useful for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duo ⁇ denum.
- the invention relates also to a method for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum in a mammal, including man by administering one or more therapeutically effective dose(s) of a novel salicylic acid derivative of the formula (I) according to the invention or a salt thereof formed with a H2 antagonist, preferably with Cimetidine or Famotidine, to said mammal.
- a novel salicylic acid derivative of the formula (I) according to the invention or a salt thereof formed with a H2 antagonist, preferably with Cimetidine or Famotidine
- Cimetidine and Famotidine respectively formed with aspartic acid and glutamic acid as well as the double salts thereof formed with ascorbic acid are disclosed. These salts are sup ⁇ posed to neutralize the toxic side effects of the drugs.
- Cimetidine B A number of simple salts (e.g. acetate, sulfate, hydrochloride, fumarate, aleate and the like) of Cimetidine " are described in the European patent spe ⁇ cification No. 255,376 since the polymorph Cimetidine B can be prepared by treating these salts with ammonia.
- Famotidine salts e.g. Famotidine hydrochloride
- the Cimetidine salts of the formula (II) and Famo ⁇ tidine salts of formula (III) are new compounds possess ⁇ ing significant gastrocytoprotective and antibacterial effects in addition to their expected gastric acid secretion inhibitory activity. Thus, they are useful not only for the treatment but also for the prevention of the disease.
- the gastric acid secretion inhibitory effect of the compounds tested was expressed in relation to the acid content measured in the gastric juice of untreated control animals.
- the gastrocytoprotective effect was expressed by the percentage of the average total length of longitud- inal bleedings in relation to the average total length measured in the control group treated with acidic alcohol alone.
- the number of the point-like ulcers appearing in the stomach was evaluated by the so-called ulcer index scoring from 0 to 5 in such a way that the values of control animals untreated with the active compound were taken as score 5 whereas the value of stomach showing the lowest number of ulcers was taken as score O.
- the abdominal wall of the female rat starved previously for 24 hours was opened under etheral ana- esthesia. Near the pylorus 25 ⁇ l of 20% acetic acid solution were injected to the glandular part of the stomach, into the subserosal layer. Subsequently, the abdominal wall was closed and the animal received food and drink ad libitum. The treatment was started on the 5th day following surgery and was continued with one daily dose for 10 days. On the 15th day following surgery the rats were killed and their stomach was re ⁇ moved. The ulcer was evaluated by measuring the diame ⁇ ters and calculating the areas of necrotic regions. The healing effect of the compound tested was calculated by using the following formula: ulcerous area(control. - ulcerous areafcompound tested ⁇ x 100 ulcerous area(control)
- Table I illustrates that the compounds of the for ⁇ mula (I) according to the invention in themselves are effective anti-ulcer and gastrocytoprotective substances possessing an additional favourable antibacterial effect, too.
- Cimetidine salts of compounds of the formula (I) possess an excellent gastrocytoprotective action while maintaining the favourable ulcer-inhibiting effect of Cimetidine.
- Famotidine Pharmacological activities of: Famotidine; active compounds of Examples 1, 3 and 7 of the invention; and Famotidine salts of Examples 11 and 13
- ED 50 oral dose (mg/kg) causing 50% inhibition
- Table II illustrates that: on the one hand, the com ⁇ pounds of the formula (I) of the invention in themselves are effective anti-ulcer and gastrocytoprotective sub ⁇ stances; and on the other hand, the Famotidine salts of the compounds being inactive in themselves in the above tests, retain the favourable ulcer-inhibiting effect of Famotidine and exert an excellent gastrocyto ⁇ protective action.
- the active compounds of formula (I) can be trans ⁇ formed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharmaceuticals for parenteral or enteral administration.
- Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vegetable oils such as peanut oil, olive oil and the like.
- the active agent can be formulated to usual pharmaceutical compositions, par ⁇ ticularly solid compositions, e.g. rounded or edged tablet, dragee or capsule such as gelatine capsule, pill, suppository and the like.
- the amount of the solid active agent in one unit of the pharmaceutical composi ⁇ tion may be varied in a broad range, preferably it is between about 25 mg and 1 g.
- these compositions may also contain other commonly used pharmaceutical auxiliaries, e.g. stabilizers, preserva ⁇ tives, wetting agents, emulsifying agents and the like.
- the compositions can be prepared in a known manner, e.g. by sieving, mixing, granulating and compressing the in ⁇ gredients in the case of solid compositions.
- the com ⁇ positions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization.
- the dose level to be used can be varied within broad limits depending on the body weight and the indi ⁇ vidual response of the patient or animal being treated, severity of the condition to be influenced as well as the frequency and the particular route of administra ⁇ tion.
- the amount of the suitable dose can easily be determined by a physician skilled in the art.
- novel salicylic acid derivatives of the formula (I) are prepared by: a) reacting 5-acetyl-2-hydroxybenzoic acid of the formula
- R 4 is as defined above, in the presence of an activating agent, to obtain compounds of the formula (I) , wherein R means hydrogen and R 1 stands for a group of the formula (A) or formula (B) , wherein R 2 , R 3 and R 4 are as defined above and, if desired, converting a compound of the formula (I) , wherein R means hydrogen and R 1 is as defined above, obtained by using any of the processes a) , b) or d) , with a H2 receptor antagonist to a salt thereof.
- the preparation of salicylic acid derivatives of the formula (I) will hereinafter be discussed in more detail.
- the 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- butenoic acid of the formula (la) falling within the scope of the salicylic acid derivatives of the formula (I) of the invention has an own biological activity and simultaneously represents the starting substance for the preparation of a compound of the formula (I) , wherein the meaning of R or R 1 is different from hydrogen.
- the compound of the formula (la) can be prepared by the condensation reaction of 5-acetyl-2-hydroxybenzoic acid of the formula (lb) with glyoxylic acid mono- hydrate.
- This condensation reaction is preferably car- ried out in an inert organic solvent under mild heating in the presence of an acid catalyst. No catalyst is needed when acetic acid is used as solvent.
- This con ⁇ densation may be carried out by heating the components in concentrated phosphoric acid, preferably in a phos- phoric acid of 85% by weight. In this latter case the reaction carried out at 80 °C for 8 hours results in 65% yield of the compound of the formula (la) .
- the starting substance of formula (lb), i.e. 5- acetyl-2-hydroxybenzoic acid can be prepared according to the literature [J. Indian Chem. Soc. 2 ⁇ _, pages 235 to 238 (1949)]. Glyoxylic acid monohydrate is commercially available.
- diesters of the compound of formula (la) are diesters of the compound of formula (la) .
- diesters may similarly be prepared as the monoesters, except that the triethylamine base is used in the twofold of the stoichiometric amount and the alkylating component is taken in an excess of at least the twofold of the stoichiometric amount.
- the suitable alkyl halides preferably an alkyl iodide or the corres ⁇ ponding dialkyl sulfate may be used in this case, too.
- the compound of formula (la) is transformed to a mixed anhydride with a chloroformate ester, preferably ethyl chloroformate in an inert organic solvent, prefer ⁇ ably anhydrous methylene chloride, in the presence of a stoichiometric amount of a base, preferably triethyl ⁇ amine, then a compound of formula (Ic) or (Id) , respectively is reacted with this mixed anhydride.
- the mixed anhydride as well as the acylation are preferably carried out at a temperature of about -15 °C in such a way that during the progress of the acylating reaction the temperature of the reaction mixture is slowly raised to room temperature.
- the compounds of the formula (I) described above have (E) configuration; however, if desired, products of (Z) configuration can also be obtained by isomeriza- tion.
- the isomerization can be achieved by subjecting the compounds of the formula (I) having (E) configuration to a photocatalytic isomerization.
- This isomerization is preferably performed by irradiating a compound of the formula (I) having (E) configuration with a high- pressure mercury vapour lamp at a wave-length of 366 nm at room temperature in an inert organic solvent, prefer ⁇ ably acetone.
- the product of (Z) configuration can alternatively be prepared by isomerizing the starting compound of the formula (la) and then preparing the compound of the for- mula (I) from the resulting (Z) isomer.
- the salts of the formulae (II) or (III) , respective ⁇ ly are formed from a starting compound of the formula (I) , wherein R and R 1 are as defined above, with
- Cimetidine or Famotidine base respectively.
- the salts are formed by reacting stochiometric amounts of both components in an inert organic solvent at room temperature for a few hours. Methanol or ethanol are preferable solvents for this purpose.
- Cimetidine base may be prepared e.g. according to the British patent specification No. 2,103,206.
- Famotidine base is disclosed in the Belgian patent specification No. 905,409.
- novel pharmaceutical compositions according to the invention can be prepared by admixing as active ingredient a compound of the formula (I) , wherein R and
- R 1 are as defined above; or a compound of the formula
- Particularly preferred active agents among the compounds according to the invention are the following substances : 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) -butenoic acid , methyl 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoate ,
- Example 1 The invention is illustrated in detail by the following non-limiting Examples .
- Example 1 The invention is illustrated in detail by the following non-limiting Examples .
- Example 5 Preparation of ethyl N-[4-(3-carboxy-4-hydroxy- phenyl)-4-oxo-(2E)-butenoyl]glycinate
- a suspension of 9.44 g (0.04 mol) of 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry methylene chloride 11.2 ml (0.08 mol) of triethylamine are added.
- the solution is cooled to -15 °C, 4 ml (0.04 mol) of ethyl chloroformate are dropwise added and the reaction mixture is maintained at the same temperature for 30 minutes.
- Tablets weighing 150 or 300 mg, respectively each are compressed from the powder mixture with the composition defined under a) or under b) , respectively in the usual manner by wet granulation and compression.
- Each tablet contains 5 or 50 mg, respectively of active ingredient.
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Abstract
There is provided a novel salicylic acid derivative of formula (I), wherein R means hydrogen or a C1-4alkyl group; R1 stands for hydroxy; a C¿1-4?alkoxy group; or a group of formula (A), wherein R?2¿ means hydrogen or benzyl group; and R3 stands for a C¿1-4?alkyl group; or a group of formula (B), wherein R?4¿ means a C¿1-4?alkyl group, as well as a salt thereof formed with a H2 receptor antagonist, preferably with Cimetidine or Famotidine; and a pharmaceutical composition containing said compound. A process for the preparation of the above compounds and compositions is also described. The compounds of formula (I) and their salts with Famotidine or Cimetidine possess significant gastric acid secretion inhibitory and gastrocytoprotective effects and exert also an antibacterial effect against Helicobacter pylori. Thus, they are useful for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum in a mammal including man.
Description
NOVEL SALICYLIC ACID DERIVATIVES, THEIR SALTS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME
The invention relates to a novel, therapeutically active salicylic acid derivative of the formula
wherein
R means hydrogen or a Cι_4alkyl group; R1 stands for hydroxy group; a Cι_4alkoxy group; or a group of the formula
wherein R2 means hydrogen or benzyl group; and R3 stands for a C]__4alkyl group; or a group of the formula
wherein
R4 means a C1_4alkyl group, as well as' a salt thereof formed with a H2 receptor antagonist, preferably with Cimetidine or Famotidine; and a pharmaceutical compositions containing said compound.
Furthermore, the invention relates to a process for the preparation of said compounds and compositions. More particularly, the invention relates to a gastric acid secretion inhibitory and gastrocyto¬ protective pharmaceutical composition containing as active ingredient - a compound of the formula (I) , wherein R and R1 are as defined above; or - a compound of the formula
(II)
wherein R1 is as defined above; or - a compound of the formula
( III)
wherein R1 is as defined above.
The compounds of formulae (II) and (III) are salts formed from the salicylic acid derivatives of the for¬ mula (I) with Cimetidine and Famotidine, respectively.
Alkyl substituents in themselves or as structural moieties of other groups in the formulae are straight or branched chain, saturated hydrocarbyl groups containing a number of carbon atoms within the range defined above, such as e.g. the methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl or tert.-butyl groups.
The novel salicylic acid derivatives of the formula (I) as well as their Cimetidine salts of the formula (II) and Famotidine salts of the formula (III) , respectively possess valuable pharmacological activities; namely, they show gastric acid secretion inhibitory, gastrocyto¬ protective effects and antibacterial effect against the bacterial strain Helicobacter pylori. Thus, they are useful for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duo¬ denum.
Accordingly, the invention relates also to a method for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum in a mammal, including man by administering one or more therapeutically effective dose(s) of a novel salicylic
acid derivative of the formula (I) according to the invention or a salt thereof formed with a H2 antagonist, preferably with Cimetidine or Famotidine, to said mammal. Cimetidine of the formula
(chemically 2-cyano-l-methyl-3- [2- [ [ (5-methylimidazol-4- yl)methyl]tio]ethyl]guanidine) and Famotidine of the formula
("la) 
(chemically 3-[[[2-[ (aminoiminomethyl)amino]thiazol- yl]methyl]thio]-N-(aminosulfonyl)propaneimide amide) are known H2 receptor-antagonistic gastric acid secretion inhibitory drugs. sed in the therapy, however, their gastrocytoprotective effect is weak. Therefore, they are useful only for the treatment of gastric ulcer and gastritis but cannot prevent these diseases. A number of Cimetidine salts have been described in
the literature but no more effective derivative than the base itself has been found. In the European patent spe¬ cification No. 277,900 the salts of Cimetidine and Famotidine, respectively formed with aspartic acid and glutamic acid as well as the double salts thereof formed with ascorbic acid are disclosed. These salts are sup¬ posed to neutralize the toxic side effects of the drugs.
A number of simple salts (e.g. acetate, sulfate, hydrochloride, fumarate, aleate and the like) of Cimetidine" are described in the European patent spe¬ cification No. 255,376 since the polymorph Cimetidine B can be prepared by treating these salts with ammonia.
Up to the present no salts of Famotidine have been known in the literature which significantly influenced the pharmaceutical spectrum of effects of Famotidine. The Famotidine salts (e.g. Famotidine hydrochloride) described till now are known as the intermediates of the preparation of Famotidine (see e.g. the Spanish patent specification No. 2,012,735). The Cimetidine salts of the formula (II) and Famo¬ tidine salts of formula (III) are new compounds possess¬ ing significant gastrocytoprotective and antibacterial effects in addition to their expected gastric acid secretion inhibitory activity. Thus, they are useful not only for the treatment but also for the prevention of the disease.
The biological activity of the compounds according to our invention is illustrated by the tests described hereinafter. 1) Gastric acid secretion inhibitory effect in the pylorus ligature The method of Shay et al. [Gastroenterology 5 , pages 43 to 61 (1945)] was used.
Female Hannover- istar rats weighing 120 to 150 g each were starved for 24 hours, then pylorus ligature
was carried out in the animals. Active agents of the formula (I) were orally (p.o.) administered to the animals 30 minutes before the pylorus ligation. Four hours after the surgery, intervention the animals were killed and the acid content of the gastric juice was determined.
The gastric acid secretion inhibitory effect of the compounds tested was expressed in relation to the acid content measured in the gastric juice of untreated control animals.
2) Effect on the σastric lesion induced by acid- containinσ alcohol
The method of A. Robert [Gastroenterology 7_7, pages 761 to 767 (1979)] was followed. Female rats weighing 120 to 150 g each were used after starvation for 24 hours. A mixture containing 1 ml of concentrated hydrochloric acid and 50 ml of absolute ethanol administered in a dose of 0.5 ml/100 g of body weight was employed as necrotizing agent. The compounds of formula (I) were introduced to the stomach 30 minutes before administration of the acidic alcohol. One hour following the administration of the acidic alcohol, the animals were killed. The length of longitudinal bleedings induced by the acidic alcohol treatment on the glandular part of the stomach was measured, and the average total length per stomach cal¬ culated.
The gastrocytoprotective effect was expressed by the percentage of the average total length of longitud- inal bleedings in relation to the average total length measured in the control group treated with acidic alcohol alone.
3) Inhibition of the Indomethacin-induced σastric ulcer After starvation for 24 hours female RG- istar rats
were orally treated with the compounds to be tested and subsequently, after 30 minutes with 20 mg/kg of Indo- methacin. The evaluation was carried out in relation to the control group and the ED50 values were determined. 4) Inhibition of the gastric ulcer induced by Aspirin and stress The method of K. D. Rainsford [Agents, Actions 5 , pages 553 to 558 (1975)] was followed.
Female RG- istar rats weighing 120 to 150 g each were used "after starvation for 24 hours. The animals were treated with the compounds to be tested and sub¬ sequently, after 60 minutes they were given an oral dose of 50 mg/kg of body weight of Aspirin. The pre- treatment with Aspirin sensitized the animals and the subsequent stress (fastening, dipping in water at a temperature of 22 °C for 1 hour) induced a strong ulceration on the glandular part of stomach.
The number of the point-like ulcers appearing in the stomach was evaluated by the so-called ulcer index scoring from 0 to 5 in such a way that the values of control animals untreated with the active compound were taken as score 5 whereas the value of stomach showing the lowest number of ulcers was taken as score O.
5) Test on the acetic acid-induced chronic ulcer model
The method of Tagaki et al. [Japan Journal of Pharmacology .19., pages 418 to 426 (1969) ] was used.
The abdominal wall of the female rat starved previously for 24 hours was opened under etheral ana- esthesia. Near the pylorus 25 μl of 20% acetic acid solution were injected to the glandular part of the stomach, into the subserosal layer. Subsequently, the abdominal wall was closed and the animal received food and drink ad libitum. The treatment was started on the 5th day following surgery and was continued with one
daily dose for 10 days. On the 15th day following surgery the rats were killed and their stomach was re¬ moved. The ulcer was evaluated by measuring the diame¬ ters and calculating the areas of necrotic regions. The healing effect of the compound tested was calculated by using the following formula: ulcerous area(control. - ulcerous areafcompound tested^ x 100 ulcerous area(control)
6) Investigation of the activity against Helico- bacter pylori The activity of compounds of the formula (I) accord¬ ing to the invention was tested by using the agar diffusion and agar dilution methods. The experiments were carried out on Helicobacter pylori cultures isolated from five various human ulcer patients and the minimum inhibitory concentrations (MIC values) were determined.
The results obtained in the above tests are summarized in Tables I and II.
Table I Pharmacological activities of: Cimetidine; active compound of Example 3 of the invention; and Cimitidine salt of the same active compound of Example 8
Notes and abbreviations used in the Table:
ED50 oral dose (mg/kg) causing 50% inhibition * inhibition
** enhancement xx in vitro bactericidal effect measured on Helicobacter pylori
MIC minimum inhibitory concentration
Table I illustrates that the compounds of the for¬ mula (I) according to the invention in themselves are effective anti-ulcer and gastrocytoprotective substances possessing an additional favourable antibacterial effect, too. Cimetidine salts of compounds of the formula (I) possess an excellent gastrocytoprotective action while maintaining the favourable ulcer-inhibiting effect of Cimetidine.
Table II
Pharmacological activities of: Famotidine; active compounds of Examples 1, 3 and 7 of the invention; and Famotidine salts of Examples 11 and 13
Abbreviations:
ED50 : oral dose (mg/kg) causing 50% inhibition
* : inhibition
Table II illustrates that: on the one hand, the com¬ pounds of the formula (I) of the invention in themselves
are effective anti-ulcer and gastrocytoprotective sub¬ stances; and on the other hand, the Famotidine salts of the compounds being inactive in themselves in the above tests, retain the favourable ulcer-inhibiting effect of Famotidine and exert an excellent gastrocyto¬ protective action.
In tests showing the gastric acid secretion inhib¬ itory and gastrocytoprotective effect, the activity of the compounds of the formula (I) according to the inven- tion significantly exceed the activity of the reference drugs and, in addition, they possess a strong antibac¬ terial activity against Helicobacter pylori cultures.
In addition to the expected gastric acid secretion inhibitory effect, the novel Cimitidine and Famotidine salts of the formulae (II) and (III), respectively possess a significant gastrocytoprotective effect, too and therefore, they can be used not only for the treat¬ ment but also the prevention of the disease.
These two effects appear not only as a simple sum of the effects of both components forming the salt; but a significant synergism can also be observed.
For adult human patients the daily therapeutic dose of the active compounds of the invention may be varied between 25 and 500 mg. The active compounds of formula (I) can be trans¬ formed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharmaceuticals for parenteral or enteral administration. Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vegetable oils such as peanut oil, olive oil and the like. The active agent can be formulated to usual pharmaceutical compositions, par¬ ticularly solid compositions, e.g. rounded or edged tablet, dragee or capsule such as gelatine capsule,
pill, suppository and the like. The amount of the solid active agent in one unit of the pharmaceutical composi¬ tion (tablet, capsule, one unit of formulated solution and the like) may be varied in a broad range, preferably it is between about 25 mg and 1 g. Optionally these compositions may also contain other commonly used pharmaceutical auxiliaries, e.g. stabilizers, preserva¬ tives, wetting agents, emulsifying agents and the like. The compositions can be prepared in a known manner, e.g. by sieving, mixing, granulating and compressing the in¬ gredients in the case of solid compositions. The com¬ positions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization. The dose level to be used can be varied within broad limits depending on the body weight and the indi¬ vidual response of the patient or animal being treated, severity of the condition to be influenced as well as the frequency and the particular route of administra¬ tion. The amount of the suitable dose can easily be determined by a physician skilled in the art.
According to the invention the novel salicylic acid derivatives of the formula (I) are prepared by: a) reacting 5-acetyl-2-hydroxybenzoic acid of the formula
with glyoxylic acid monohydrate in the presence of an acid catalyst, to obtain a compound of the formula (I) , wherein R means hydrogen and R1 stands for a
hydroxy group; or b) reacting the compound of the formula
with the stoichiometric amount of an alkyl halide or dialkyl sulfate containing an alkyl moiety corres-. ponding to the meaning of R1, to obtain a compound of the formula (I) , wherein R means hydrogen and R1 stands for a C^-4alkoxy group; or c) reacting the compound of the formula (la) with at least twofold of the stoichiometric amount of an alkyl halide a dialkyl sulfate containing an alkyl moiety (moieties) corresponding to the meaning of R and/or R1, respectively to obtain compounds of the formula (I) , wherein R means a Cι_4alkyl group and R1 stands for a C- -4alkoxy group; or d) reacting the compound of the formula (la) with an amino acid ester of the formula
(IC)
wherein R4 is as defined above, in the presence of an activating agent, to obtain compounds of the formula (I) , wherein R means hydrogen and R1 stands for a group of the formula (A) or formula (B) , wherein R2, R3 and R4 are as defined above and, if desired, converting a compound of the formula (I) , wherein R means hydrogen and R1 is as defined above, obtained by using any of the processes a) , b) or d) , with a H2 receptor antagonist to a salt thereof. The preparation of salicylic acid derivatives of the formula (I) will hereinafter be discussed in more detail.
The 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- butenoic acid of the formula (la) falling within the scope of the salicylic acid derivatives of the formula (I) of the invention has an own biological activity and simultaneously represents the starting substance for the preparation of a compound of the formula (I) , wherein the meaning of R or R1 is different from hydrogen.
The compound of the formula (la) can be prepared by the condensation reaction of 5-acetyl-2-hydroxybenzoic acid of the formula (lb) with glyoxylic acid mono- hydrate. This condensation reaction is preferably car- ried out in an inert organic solvent under mild heating
in the presence of an acid catalyst. No catalyst is needed when acetic acid is used as solvent. This con¬ densation may be carried out by heating the components in concentrated phosphoric acid, preferably in a phos- phoric acid of 85% by weight. In this latter case the reaction carried out at 80 °C for 8 hours results in 65% yield of the compound of the formula (la) .
The starting substance of formula (lb), i.e. 5- acetyl-2-hydroxybenzoic acid can be prepared according to the literature [J. Indian Chem. Soc. 2 β_, pages 235 to 238 (1949)]. Glyoxylic acid monohydrate is commercially available.
Compounds of the formula (I) , wherein R means hydrogen and R1 stands for a
group [i.e. the monoesters of the compound of formula (la)], can be obtained by the esterification of the compound of formula (la) . It has been found that the esterifica¬ tion can be carried out with the corresponding alkyl halides or dialkyl sulfates most suitably in a dipolar aprotic solvent, preferably dimethylformamide, in the presence of a stoichiometric amount of a base, preferably triethylamine under mild heating, preferably at a temperature range of 50 °C to 80 °C.
Compounds of the formula (I) , wherein R and R1 mean the same Cι_4alkyl group, are diesters of the compound of formula (la) . These diesters may similarly be prepared as the monoesters, except that the triethylamine base is used in the twofold of the stoichiometric amount and the alkylating component is taken in an excess of at least the twofold of the stoichiometric amount. For esterification, the suitable alkyl halides, preferably an alkyl iodide or the corres¬ ponding dialkyl sulfate may be used in this case, too. Compounds of the formula (I) , wherein R means hydrogen and R1 stands for a group of the formula (A) or
(B) , wherein R2, R3 and R4 are as defined above, can be prepared by acylating an amino acid ester of the formula (Ic) , wherein R2 and R3 are as defined above, or a piperazine derivative of the formula (Id) , wherein R4 is as defined above, with the compound of formula (la) in the presence of an activating agent.
According to a preferred embodiment of the acyla- tion, the compound of formula (la) is transformed to a mixed anhydride with a chloroformate ester, preferably ethyl chloroformate in an inert organic solvent, prefer¬ ably anhydrous methylene chloride, in the presence of a stoichiometric amount of a base, preferably triethyl¬ amine, then a compound of formula (Ic) or (Id) , respectively is reacted with this mixed anhydride. The mixed anhydride as well as the acylation are preferably carried out at a temperature of about -15 °C in such a way that during the progress of the acylating reaction the temperature of the reaction mixture is slowly raised to room temperature. The compounds of the formula (I) described above have (E) configuration; however, if desired, products of (Z) configuration can also be obtained by isomeriza- tion.
The isomerization can be achieved by subjecting the compounds of the formula (I) having (E) configuration to a photocatalytic isomerization. This isomerization is preferably performed by irradiating a compound of the formula (I) having (E) configuration with a high- pressure mercury vapour lamp at a wave-length of 366 nm at room temperature in an inert organic solvent, prefer¬ ably acetone.
The product of (Z) configuration can alternatively be prepared by isomerizing the starting compound of the formula (la) and then preparing the compound of the for- mula (I) from the resulting (Z) isomer.
The salts of the formulae (II) or (III) , respective¬ ly are formed from a starting compound of the formula (I) , wherein R and R1 are as defined above, with
Cimetidine or Famotidine base, respectively. The salts are formed by reacting stochiometric amounts of both components in an inert organic solvent at room temperature for a few hours. Methanol or ethanol are preferable solvents for this purpose.
Cimetidine base may be prepared e.g. according to the British patent specification No. 2,103,206.
The preparation of Famotidine base is disclosed in the Belgian patent specification No. 905,409.
The novel pharmaceutical compositions according to the invention can be prepared by admixing as active ingredient a compound of the formula (I) , wherein R and
R1 are as defined above; or a compound of the formula
(II) , wherein R1 is as defined above; or a compound of the formula (III) , wherein R1 is as defined above, with a non-toxic, inert, solid or liquid carrier and/or auxiliary commonly used in pharmaceuticals for parenteral or enteral administration and transforming the mixture to a pharmaceutical composition.
The following compounds according to the invention can be considered as active ingredients: 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid, methyl 4-(3-methoxycarbonyl-4-hydroxyphenyl)-4-oxo-(2E)- butenoate, methyl 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoate, ethyl N- [4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoyl ] glycinate , methyl N- [ 4- (3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoyl]-L-phenylalaninate, l-[4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]-4- (ethoxycarbonyl)piperazine,
Cimetidine salt or Famotidine salt of methyl 4- ( 3- carboxy-4-hydroxyphenyl) -4-oxo- ( 2E) -butenoate and Cimitidine salt or Famotidine salt of l- [ 4- ( 3-carboxy- 4-hydroxyphenyl) -4-oxo- (2E) -butenoyl] -4- (ethoxycar- bonyl) piperazine .
Particularly preferred active agents among the compounds according to the invention are the following substances : 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) -butenoic acid , methyl 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoate ,
Cimetidine salt of methyl 4- (3-carboxy-4-hydroxyphenyl) - 4-oxo- ( 2E) -butenoate, Famotidine salt of methyl 4- (3-carboxy-4-hydroxyphenyl) - 4 -oxo- ( 2E) -butenoate and
Famotidine salt of l- [ 4- ( 3-carboxy-4-hydroxyphenyl) -4- oxo- (2E) -butenoyl ] -4- (ethoxycarbonyl) piperazin .
The invention is illustrated in detail by the following non-limiting Examples . Example 1
Preparation of 4-(3-carboxy-4-hydroxyphenyl)-4-oxo- (2E)-butenoic acid
To a suspension containing 62.5 g (0.35 mol) of 5- acetyl-2-hydroxybenzoic acid in 625 ml of 85% phosphoric acid, 62.5 g (0.68 mol) of glyoxylic acid monohydrate are added. The reaction mixture is maintained at 80 °C for 8 hours, then cooled down to room temperature and poured into the mixture of 200 g of ice and 1200 ml of water. After stirring for 30 minutes the precipitate is filtered and washed with water. The product is dissolved in 300 ml of methanol and water is added until the crystallization begins. Subsequently, the solution is cooled to 10 °C and the precipitate is filtered to obtain 53 g (65%) of the title compound in the form of yellow crystals, Rf = 0.35 (ethyl acetate/acetic acid
9:1) .
Example 2
Preparation of methyl 4-(3-methoxycarbonyl-4- hydroxyphenyl)-4-oxo-(2E)-butenoate A solution containing 2.36 g (0.01 mol) of 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 30 ml of dry dimethylformamide is heated to 80 °C and 2.8 ml (0.02 mol) of triethylamine and 1.2 ml (0.02 mol) of methyl iodide are added. After 2 hours the same amounts of triethylamine and methyl iodide are again added. After heating at 80 °C for additional 2 hours, the reaction mixture is cooled to room temperature and evaporated. The residue is dissolved in 100 ml of ethyl acetate and twice washed with 50 ml of water each and twice with 520 ml of 10% sodium bicarbonate solution each. After clarification with charcoal, the organic phase is evaporated and the residue is recrystallized from 25 ml of ethyl acetate to give 1.8 g (70%) of the yellow crystalline title compound, m.p. : 128-130 °C. Example 3
Preparation of methyl 4-(3-carboxy-4-hydroxyphenyl)- 4-oxo-(2E)-butenoate
After dissolving 23.6 g (0.1 mol) of 4-(3-carboxy-4- hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry dimethylformamide, 12.0 ml (0,2 mol) of methyl iodide are added and the solution is heated at 70 °C, then 14 ml (0.1 mol) of triethylamine are dropwise added thereto. The reaction mixture is heated at a temperature of 70 °C for additional 2 hours, then the solvent is evaporated. To the residue 150 ml of water and 30 ml of 10% hydrochloric acid solution are added and the mixture is extracted 3 times with 100 ml of ethyl acetate each. After clarifying with charcoal, the organic phase is evaporated until crystals begin to pre- cipitate. On cooling, the title product precipitates in
crystalline form to give 12.0 g (53%) of the lemon- yellow crystalline title compound, m.p. : 168-170 °C. Example 4
Preparation of methyl 4-(3-carboxy-4-hydroxyphenyl)- 4-oxo-(2Z)-butenoate
A solution containing 3.5 g (14 mmol) of methyl 4- (3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate in 400 ml of acetone is irradiated by UV light of 366 nm wave-length for 4 hours. Then, the mixture is evaporated to dryness, the residue is suspended in 50 ml of diethyl ether, stirred for 30 minutes and filtered to give 2.3 g (65%) of the white crystalline title product, m.p.: 129-131 °C. Example 5 Preparation of ethyl N-[4-(3-carboxy-4-hydroxy- phenyl)-4-oxo-(2E)-butenoyl]glycinate To a suspension of 9.44 g (0.04 mol) of 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry methylene chloride 11.2 ml (0.08 mol) of triethylamine are added. The solution is cooled to -15 °C, 4 ml (0.04 mol) of ethyl chloroformate are dropwise added and the reaction mixture is maintained at the same temperature for 30 minutes. Subsequently, 5.6 g (0.04 mol) of ethyl glycinate hydrochloride and 5.6 ml (0.04 mol) of triethylamine are added and the reaction mixture is left at -15 °C for 30 minutes, at 0 °C for 1 hour and finally at 25 °C for 3 hours. The organic solution is twice extracted with 50 ml of water each, then 50 ml of 10% hydrochloric acid solution, clarified with charcoal and evaporated. After recrystallization of the residue from methanol, 8.25 g (64%) of the title compound are obtained, m.p.: 210-212 °C.
Example 6
Preparation of methyl N-[4-(3-carboxγ-4- hydroxyphenyl)-4-oxo-(2E)-butenoyl]-L-phenyl- alaninate To a suspension containing 4.72 g (0.02 mol) of 4- (3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 150 ml of dry methylene chloride, 5.6 ml (0.04 mol) of triethylamine are added. After cooling down the solu¬ tion to -15 °C, 2 ml (0.02 mol) of ethyl chloroformate are dropwise added and the mixture is reacted at -15 °C for 90 minutes. Then, 4.32 g (0.02 mol) of methyl L-phenylalaninate hydrochloride and 2.8 ml (0.02 mol) of triethylamine are added and the reaction mixture is stirred at -15 °C for 30 minutes, at 0 °C for 1 hour and at room temperature for 3' hours'. The organic phase is washed twice with 30 ml of water each, 30 ml of 10% hydrochloric acid solution, then clarified with charcoal and evaporated. After suspending in diethyl ether, the residue is stirred for 1 hour and the yellow crystalline product is isolated. In this way the title product is obtained in a yield of 3.6 g (45%), m.p.: 168 °C (with decomposition); [α]D25 = +102.0° (c = 1, pyridine). Example 7 Preparation of l-[4-(3-carboxy-4-hydroxyphenyl)-4- oxo-(2E)-butenoyl]-4-(ethoxycarbonyl)piperazine
After suspending 7.08 g (0.03 mol) 4-(3-carboxy-4- hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry methylene chloride and adding 8.4 ml (0.06 mol) of triethylamine, a solution is obtained which is cooled down to -15 °C, 3 ml (0.03 mol) of ethyl chloroformate are dropwise added and the mixture is left at the same temperature for 30 minutes. Thereafter, 4.5 ml (0.03 mol) of N-(ethoxycarbonyl)piperazine are added and the reaction mixture is stirred at -15 °C for 30 minutes, at 0 °C for 1 hour and at room temperature for 3 hours.
The organic phase is twice washed with 50 ml of water each, then 50 ml of 10% hydrochloric acid solution. The organic solution is clarified with charcoal, then evap¬ orated. After suspending in diethyl ether the residue is stirred with the ether for 1 hour and then filtered to give 7.78 g (69%) of the yellow crystalline title product, m.p. : 211-213 °C. Example 8
Preparation of the Cimetidine salt of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate
. A solution of 1.88 g (7,5 mmol) of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate in 50 ml of methanol is added to a solution containing 1.89 g . (7.5 mmol) of Cimetidine base in 50 ml of methanol. The mixture is stirred at 25 °C for 1 hour, then the solvent is distilled off at 30 °C under reduced pressure to obtain 3.7 g (98%) of the yellow amorphous title com¬ pound.
Example 9 Preparation of the Cimetidine salt of ethyl N-[4- (3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]- glycinate
A suspension containing 1.61 g (5 mmol) of ethyl N- [4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]- glycinate in 50 ml of methanol is added to 1.26 g (5 mmol) of Cimetidine base dissolved in 50 ml of methanol. After stirring the solution for 1 hour, the solvent is evaporated at 30 °C under reduced pressure to give 2.8 g (98%) of the amorphous yellow title compound. Example 10
Preparation of the Cimetidine salt of l-[4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]-4- (ethoxycarbonyl) iperazine
A suspension containing 1.88 g (5 mmol) of l-[4-(3-
carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4-(ethoxy- carbonyl)piperazine in 50 ml of methanol is added to 1.26 g (5 mmol) of Cimetidine base dissolved in 50 ml of methanol. The solution is stirred for 1 hour, then evaporated at 30 °C under reduced pressure to obtain the title porduct as an amorphous yellow substance in a yield of 3.1 g (98%) .
Example 11
Preparation of the Famotidine salt of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate
A solution of 1.88 g (7.5 mmol) of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate in 50 ml of ethanol is added to a suspension of 2.53 g (7.5 mmol) of Famotidine base in 50 ml of ethanol. After stirring for 6 hours, the product is filtered and washed with 30 ml of ethanol to yield 4.3 g (98%) of the yellow title product, m.p. : 165-166 °C.
Example 12
Preparation of the Famotidine salt of ethyl N-[4- (3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]- glycinate
A suspension containing 1.6 g (5 mmol) of ethyl N- [4-(3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]- glycinate in 50 ml of methanol is added to a suspension of 1.68 g (5 mmol) of Famotidine base in 50 ml of me¬ thanol under vigorous stirring. After stirring for 6 hours, the product is filtered, washed with methanol to give 3.2 g (98%) of the white title product, m.p.: 199-200 °C. Example 13
Preparation of the Famotidine salt of l-[4-(3- carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4-
(ethoxycarbonyl) iperazine
A suspension containing 1.88 g (5 mmol) of l-[4-(3- carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4-(ethoxy-
carbonyl)piperazine in 50 ml of methanol is added to a suspension of 1.68 g (5 mmol) of Famotidine base in 50 ml of methanol. The mixture is stirred for 5 hours, then the product is filtered and washed with 30 ml of methanol to give the white title product in a yield of 3.4 g (95%), m.p.: 125-127 °C. Example 14 Preparation of tablets a) Tablets weighing 150 mg containing 5 mg of active ingredient each
Ingredients g
Active ingredient 5
Gelatine 3
Magnesium stearate 2 Talc 5
Potato starch 40
Lactose 95
b) Tablets weighing 300 mg containing 50 mg of active ingredient each
Ingredients g
Active ingredient 50
Polyvidone 6
Magnesium stearate 3 Talc 9
Potato starch 84
Lactose 140
Tablets weighing 150 or 300 mg, respectively each are compressed from the powder mixture with the composition defined under a) or under b) , respectively in the usual manner by wet granulation and compression. Each tablet contains 5 or 50 mg, respectively of active ingredient.
Claims
C l a i m s
1) A novel salicylic acid derivatives of the formula
wherein
R means hydrogen or a Cι_4alkyl group; R1 stands for hydroxy group; a Cι_4alkoxy group; or a group of the formula
_NH_
k-
wherein R2 means hydrogen or benzyl group; and R3 stands for a Cι_4alkyl group; or a group of the formula
• N-C-0R (B)
wherein
R4 means a
group, as well as a salt thereof formed with a H2 receptor antagonist. 2) A compound selected from the group consisting of 4-(3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoic acid, methyl 4-(3-carboxy-4-hydroxypheny1)-4-oxo-(2E)- butenoate, methyl 4-(3-carboxy-4-hydroxypheny1)-4-oxo-(2E)- butenoate Cimetidine salt, methyl 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- butenoate Famotidine salt and l-[4-(3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4- (ethoxycarbonyl)piperazine Famotidine salt. 3) A pharmaceutical composition, which c o m p r i s e s as active ingredient a therapeutically effective amount of one or more novel salicylic acid derivative(s) of the formula
wherein
R means hydrogen or a Cι_4alkyl group; R1 stands for hydroxy group; a
group; or a group of the formula
wherein
R2 means hydrogen or benzyl group; and R3 stands for a C1_4alkyl group; or a group of the formula
wherein
R4 means a Cι_4alkyl group, or their salt(s) formed with H2 receptor antagonist(s) in admixture with a non-toxic, inert, solid or liquid carrier and/or additive commonly used in pharmaceuti- cals for enteral or parenteral administration.
4) A process for the preparation of a novel sali¬ cylic acid derivatives of the formula
R means hydrogen or a ^..4alkyl group; R1 stands for hydroxy group; a C--^alkoxy group; or a group of the formula
wherein
R2 means hydrogen or benzyl group; and R3 stands for a C1_4alkyl group; or a group of the formula
wherein R4 means a C1_4alkyl group, or a salt thereof formed with a H2 receptor anta¬ gonist, which c o m p r i s e s a) reacting 5-acetyl-2-hydroxybenzoic acid of the formula
with glyoxylic acid monohydrate in the presence of an acid catalyst, to obtain a compound of the formula (I) , wherein R means hydrogen and R1 stands for hydroxy group; or b) reacting the compound of the formula
with the stoichiometric amount of an alkyl halide or dialkyl sulfate containing an alkyl moiety corres- ponding to the meaning of R1, to obtain a compound of the formula (I) , wherein R means hydrogen and R1 stands for a
group; or c) reacting the compound of the formula (la) with at least twofold of the stoichiometric amount of an alkyl halide or a dialkyl sulfate containing an alkyl moiety (moieties) corresponding to the meaning of R and/or R1, respectively to obtain a compound of the formula (I) , wherein R means a Cι_4al yl group and R1 stands for a Cι_4alkoxy group; or
d) reacting the compound of the formula (la) with an amino acid ester of the formula
wherein R2 and R3 are as defined above, or with a piperazine compound of the formula
wherein R4 is as defined above, in the presence of an activating agent, to obtain a compound of the formula (I) , wherein R means hydrogen and R1 stands for a group of the formula (A) or formula (B) , wherein R , R3 and R4 are as defined above and, if desired, converting a compound of the formula (I) , wherein R means hydrogen and R1 is as defined above, obtained by using any of the processes a) , b) and d) , with a H2 receptor antagonist to a salt. 5) The process according to claim 4, which c o m p r i s e s carrying out. the reaction in a solvent being inert under the reaction conditions.
6) The process according to process a) of claim 4, which c o m p r i s e s carrying out the reaction in the presence of phosphoric acid.
7) The process according to any of the processes b) , c) and d) of claim 4, which c o m p r i s e s carry¬ ing out the reaction in the presence of an inert organic base, preferably triethylamine. 8) The process according to process d) of claim 4, which c o m p r i s e s activating the carboxylic acid of the formula (la) with a chloroformate ester. 9) The process according to claim 4, which c o m p r i s e s forming the cimetidine or Famotidine salt, respectively of the compound obtained by any of the processes a) , b) and d) .
10) A process for the preparation of a pharmaceutical composition, which c o m p r i s e s admixing as active ingredient a therapeutically effective amount of one or more novel salicylic acid derivative(s) of the formula
wherein
R means hydrogen or a C1_4alkyl group; R1 stands for hydroxy group; a Cι_4alkoxy group; or a group of the formula
wherein
R2 means hydrogen or benzyl group; and R3 stands for a C-j^alkyl group; or a group of the formula
wherein
R4 means a Cι_4alkyl group, or their salt(s) formed with H2 receptor antagonist(s) , with one or more non-toxic, inert, solid or liquid carrier(s) and/or additive(s) commonly used in pharma- ceuticals for enteral or parenteral administration and transforming the mixture to a pharmaceutical composi¬ tion.
11) A method for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach or duodenum in a mammal including man, which c o m p r i s e s administering one or more therapeutically effective dose(s) of one or more novel salicylic acid derivative(s) of the formula
wherein
R means hydrogen or a Cι_4al yl group; R1 stands for hydroxy group; a Cι_4alkoxy group; or a group of the formula
wherein
R2 means hydrogen or benzyl group; and R3 stands for a C1_4alkyl group; or a group of the formula
(B)
wherein
R4 means a C1_4alkyl group, or their salt(s) formed with H2 receptor antagonist(s) alone or in the form of a pharmaceutical composition to said mammal.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9204142A HU211731B (en) | 1992-12-29 | 1992-12-29 | Process to prepare novel salicylic acid derivs. and pharmaceutical compns. contg. them |
| HUP9204142 | 1992-12-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994014750A1 true WO1994014750A1 (en) | 1994-07-07 |
Family
ID=10982777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1993/000077 WO1994014750A1 (en) | 1992-12-29 | 1993-12-17 | Novel salicylic acid derivatives, their salts, pharmaceutical compositions containing them and process for preparing same |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HU211731B (en) |
| WO (1) | WO1994014750A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2024118506A (en) * | 2023-02-21 | 2024-09-02 | 信越化学工業株式会社 | Onium salt, resist composition, and pattern forming method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4594443A (en) * | 1983-08-25 | 1986-06-10 | Roussel-Uclaf | Derivatives of 4-phenyl-4-oxo-buten-2-oic acid and therapeutic use thereof |
| US4879404A (en) * | 1987-09-25 | 1989-11-07 | Richter Gedeon Vegyeszeti Gyar Rt | Novel salicylates, their salts, pharmaceutical compositions containing them and process for preparing same |
-
1992
- 1992-12-29 HU HU9204142A patent/HU211731B/en not_active IP Right Cessation
-
1993
- 1993-12-17 WO PCT/HU1993/000077 patent/WO1994014750A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4594443A (en) * | 1983-08-25 | 1986-06-10 | Roussel-Uclaf | Derivatives of 4-phenyl-4-oxo-buten-2-oic acid and therapeutic use thereof |
| US4879404A (en) * | 1987-09-25 | 1989-11-07 | Richter Gedeon Vegyeszeti Gyar Rt | Novel salicylates, their salts, pharmaceutical compositions containing them and process for preparing same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2024118506A (en) * | 2023-02-21 | 2024-09-02 | 信越化学工業株式会社 | Onium salt, resist composition, and pattern forming method |
Also Published As
| Publication number | Publication date |
|---|---|
| HU211731B (en) | 1996-02-28 |
| HU9204142D0 (en) | 1993-04-28 |
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