DE4218159C2 - 4,4,4-trifluoroacetoacetic acid amides, process for their preparation and pharmaceuticals - Google Patents
4,4,4-trifluoroacetoacetic acid amides, process for their preparation and pharmaceuticalsInfo
- Publication number
- DE4218159C2 DE4218159C2 DE19924218159 DE4218159A DE4218159C2 DE 4218159 C2 DE4218159 C2 DE 4218159C2 DE 19924218159 DE19924218159 DE 19924218159 DE 4218159 A DE4218159 A DE 4218159A DE 4218159 C2 DE4218159 C2 DE 4218159C2
- Authority
- DE
- Germany
- Prior art keywords
- radical
- radicals
- group
- general formula
- residues
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- XVNRPZOWBZNEFL-UHFFFAOYSA-N 4,4,4-trifluoro-3-oxobutanamide Chemical class NC(=O)CC(=O)C(F)(F)F XVNRPZOWBZNEFL-UHFFFAOYSA-N 0.000 title description 2
- -1 4-methyloxyphenyl group Chemical group 0.000 claims description 125
- 150000001875 compounds Chemical class 0.000 claims description 34
- 150000003254 radicals Chemical class 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 2
- UJLNJPMMZFHLCI-UHFFFAOYSA-N 4,4,4-trifluoro-N-methyl-3-oxo-N-phenylbutanamide Chemical compound CN(C(CC(=O)C(F)(F)F)=O)C1=CC=CC=C1 UJLNJPMMZFHLCI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- GEAXLHPORCRESC-UHFFFAOYSA-N chlorocyclohexatriene Chemical compound ClC1=CC=C=C[CH]1 GEAXLHPORCRESC-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
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- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 2
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000006149 azo coupling reaction Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000020226 cashew nut Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- LKMUBWWZTSZGGV-UHFFFAOYSA-N methyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound COC(=O)CC(=O)C(F)(F)F LKMUBWWZTSZGGV-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000010466 nut oil Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 208000006934 radiodermatitis Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- 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
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Die Erfindung betrifft Verbindungen der allgemeinen Formel I,The invention relates to compounds of the general formula I
worin
R¹ einen Phenylrest, einen 4-Methylphenylrest, einen
4-Methyloxyphenylrest, einen 2,4-Dimethyloxyphenylrest, ei
nen 2,5-Dimethyloxyphenylrest einen 2-Fluorphenylrest
einen 4-Fluorphenylrest, einen 4-Chlorphenylrest, einen
2,4-Dichlorphenylrest, einen 2,6-Dichlorphenylrest, einen
3-Trifluormethylphenylrest, einen 4-N,N-Dimethylaminophe
nylrest oder einen 4-N,N-Diethylaminophenylrest bedeutet,
oder
worin
R¹ einen 2-Imidazolylrest, einen 2-Thiazolylrest, einen
5-Methyl-2-thiazolylrest, einen 5-Trifluoromethyl-1,3,4-
thiadiazol-2-ylrest, einen 5-Methyl-3-isoxazolylrest, ei
nen 2-Benzimidazolylrest, einen 2-Benzothiazolylrest, ei
nen 6-Methyloxy-2-benzothiazolylrest, einen 5-Chlor-2-
benzoxazolylrest, einen 2-Pyridylrest, einen 5-Chlor-2-
pyridylrest einen 2-Pyrimidylrest einen 3-Chinolinylrest
oder einen 1-Isochinolinylrest bedeutet und
worin
R² ein Wasserstoffatom oder einen C₁- bis C₆-Niedrig
alkylrest bedeutet,
R³ und R⁴ unabhängig voneinander ein Wasserstoffatom,
einen Rest der allgemeinen Formel II, einen C₁- bis C₆-
Niedrigalkylrest oder C₁- bis C₆-Niedrigalkylrest, ver
bunden mit einem Rest der allgemeinen Formel II, be
deuten,
wobeiwherein
R¹ is phenyl, 4-methylphenyl, 4-methyloxyphenyl, 2,4-dimethyloxyphenyl, 2,5-dimethyloxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, one 2,6-dichlorophenyl radical, a 3-trifluoromethylphenyl radical, a 4-N, N-dimethylaminophenyl radical or a 4-N, N-diethylaminophenyl radical, or
wherein
R¹ is a 2-imidazolyl group, a 2-thiazolyl group, a 5-methyl-2-thiazolyl group, a 5-trifluoromethyl-1,3,4-thiadiazol-2-yl group, a 5-methyl-3-isoxazolyl group, a 2- Benzimidazolyl, 2-benzothiazolyl, 6-methyloxy-2-benzothiazolyl, 5-chloro-2-benzoxazolyl, 2-pyridyl, 5-chloro-2-pyridyl, 2-pyrimidyl, 3-quinolinyl, or 1 -Isoquinolinyl radical means and
wherein
R² represents a hydrogen atom or a C₁ to C₆ lower alkyl radical,
R³ and R⁴ independently of one another are a hydrogen atom, a radical of the general formula II, a C₁- to C₆- lower alkyl radical or C₁- to C₆-lower alkyl radical, related to a radical of the general formula II, be,
in which
Ra für einen Rest mit einer der folgenden Bedeutungen
steht:
C₁- bis C₆-Niedrigalkylreste, Hydroxylreste, C₁- bis C₆-
Niedrigalkyloxyreste, Mercaptoreste, C₁- bis C₆-Niedrig
alkylthioreste, Halogenatome, Nitrogruppen, Trifluor
methylreste, Cyanoreste, Sulfonsäurereste, Carbonsäure
gruppen, C₁- bis C₆-Niedrigalkyloxycarbonylreste oder un
substituierte, einfach oder zweifach mit C₁- bis C₆-Nie
drigalkylresten substituierte Aminoreste, und
wobei
n gleich 0, 1, 2 oder 3 ist, und
worin
X ein Sauerstoffatom bedeutet,
sowie deren Salze mit physiologisch verträglichen Säuren
und Basen,
ausgenommen
N-Methyl-N-phenyl-4,4,4-trifluoracetessigsäureamid,
und mit der Maßgabe, daß wenn R², R³ und R⁴ gleichzeitig
ein Wasserstoffatom bedeuten, in diesem Falle R¹ von
einem Phenylrest, einem 4-Methyloxyphenylrest, einem 4-
Methylphenylrest, einem 4-Chlorphenylrest oder einem 2,4-
Dichlorphenylrest verschieden ist.Ra stands for a residue with one of the following meanings:
C₁ to C₆ lower alkyl radicals, hydroxyl radicals, C₁ to C₆ lower alkyloxy radicals, mercapto radicals, C₁ to C₆ lower alkylthio radicals, halogen atoms, nitro groups, trifluoromethyl radicals, cyano radicals, sulfonic acid radicals, carboxylic acid groups, C₁ to C₆ lower alkyloxy substituted carbonyl radicals, amino radicals substituted once or twice with C₁- to C₆-never drigalkyl radicals, and
in which
n is 0, 1, 2 or 3, and
wherein
X represents an oxygen atom,
as well as their salts with physiologically compatible acids and bases,
except
N-methyl-N-phenyl-4,4,4-trifluoroacetoacetic acid amide,
and with the proviso that when R², R³ and R⁴ simultaneously represent a hydrogen atom, in this case R¹ is different from a phenyl radical, a 4-methyloxyphenyl radical, a 4-methylphenyl radical, a 4-chlorophenyl radical or a 2,4-dichlorophenyl radical.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können für den Fall, daß R³ oder R⁴ ein Wasserstoffatom bedeuten, im Sinne einer Keto-Enol-Tautomerie beziehungs weise im Sinne einer Imino-Enamin-Tautomerie einzeln oder im Gemisch vorliegen. Sie können in reiner Form oder als Hydrat-Addukt vorliegen.The compounds of the general formula according to the invention I can in the event that R³ or R⁴ is a hydrogen atom mean in the sense of a keto-enol tautomerism individually or in the sense of an imino-enamine tautomerism are present in the mixture. They can be in pure form or as Hydrate adduct are present.
Für die im Zusammenhang mit der vorliegenden Beschreibung genannten verschiedenen Substituenten bzw. Reste in den Formeln I bis IV gelten folgende Erläuterungen:For those in connection with the present description mentioned various substituents or residues in the The following explanations apply to formulas I to IV:
Beispiele für C₁- bis C₆-Niedrigalkylreste sind unver zweigte und verzweigte Kohlenwasserstoffreste mit bis zu sechs Kohlenstoffatomen wie Methylreste, Ethylreste, n- Propylreste, iso-Propylreste, n-Butylreste, iso-Butyl reste, 1-Methylpropylreste, tert.-Butylreste, n-Pentyl reste, 1-Methylbutylreste, 2-Methylbutylreste, 3-Methyl butylreste, 1,1-Dimethylpropylreste, 2,2-Dimethylpropyl reste, 1,2-Dimethylpropylreste, 1-Ethylpropylreste, n- Hexylreste, 1-Methylpentylreste, 2-Methylpentylreste, 3- Methylpentylreste, 4-Methylpentylreste, 1,1-Dimethyl butylreste, 2,2-Dimethylbutylreste, 3,3-Dimethylbutyl reste, 1,2-Dimethylbutylreste, 2,3-Dimethylbutylreste, 1,3-Dimethylbutylreste, 1-Ethylbutylreste, 2-Ethylbutyl reste, 1,1,2-Trimethylpropylreste, 1,2,2-Trimethylpropyl reste, 1-Ethyl-2-methylpropylreste oder 1-Ethyl-1-methyl propylreste.Examples of C₁ to C₆ lower alkyl radicals are not branched and branched hydrocarbon residues with up to six carbon atoms such as methyl radicals, ethyl radicals, n- Propyl residues, iso-propyl residues, n-butyl residues, iso-butyl residues, 1-methylpropyl residues, tert-butyl residues, n-pentyl residues, 1-methylbutyl residues, 2-methylbutyl residues, 3-methyl butyl residues, 1,1-dimethylpropyl residues, 2,2-dimethylpropyl residues, 1,2-dimethylpropyl residues, 1-ethylpropyl residues, n- Hexyl residues, 1-methylpentyl residues, 2-methylpentyl residues, 3- Methylpentyl residues, 4-methylpentyl residues, 1,1-dimethyl butyl residues, 2,2-dimethylbutyl residues, 3,3-dimethylbutyl residues, 1,2-dimethylbutyl residues, 2,3-dimethylbutyl residues, 1,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl residues, 1,1,2-trimethylpropyl residues, 1,2,2-trimethylpropyl residues, 1-ethyl-2-methylpropyl residues or 1-ethyl-1-methyl propyl residues.
Dabei sind Methylreste, Ethylreste, n-Propylreste, iso- Propylreste, n-Butylreste oder iso-Butylreste bevorzugt.Here are methyl residues, ethyl residues, n-propyl residues, iso- Propyl residues, n-butyl residues or iso-butyl residues are preferred.
Soweit in der vorliegenden Anmeldung der Ausdruck "Nie drigalkyl" allein oder in Kombination mit anderen funk tionellen Gruppen (z B. Niedrigalkyloxy-, Niedrigalkyloxy carbonyl-, Niedrigalkylthiogruppen) erscheint, besitzt dieser Ausdruck die vorstehend angegebenen Definitionen.As far as the expression "Never drigalkyl "alone or in combination with other funk tional groups (e.g. lower alkyloxy, lower alkyloxy carbonyl, lower alkylthio groups) appears this expression has the definitions given above.
Beispiele für C₁- bis C₆-Niedrigalkylreste, verbunden mit einem Rest der allgemeinen Formel II, sind die vorstehend definierten C₁- bis C₆-Niedrigalkylreste, verknüpft mit einem Rest der allgemeinen Formel II, der wie vorstehend definiert ist. Bevorzugt sind Benzylreste, Phenylethyl reste, 4-Fluorbenzylreste, 2-(4′-Fluorphenyl)ethylreste, 4-Chlorbenzylreste, 2-(4′-Chlorphenyl)ethylreste, 2-Hy droxybenzylreste, 2-(2′-Hydroxyphenyl)ethylreste, 3-Hy droxybenzylreste, 2-(3′-Hydroxyphenyl)ethylreste, 4-Hy droxybenzylreste, 2-(4′-Hydroxyphenyl)ethylreste, 2-Methyl oxybenzylreste, 2-(2′-Methyloxyphenyl)ethylreste, 4-Methyl oxybenzylreste, 2-(4′-Methyloxyphenyl)ethylreste, 2,5-Di methyloxybenzylreste, 2,4-Dimethyloxybenzylreste, 4-Methyl benzylreste, 2-(4′-Methylphenyl)ethylreste, 4-Nitrobenzyl reste, 2-(4′-Nitrophenyl)ethylreste, 4-(N,N-Dimethylamino) benzylreste, 2-(4′-N,N-Dimethylaminophenyl)ethylreste, 2- Trifluormethylbenzylreste, 3-Trifluormethylbenzylreste, 4-Trifluormethylbenzylreste, 4-Methyloxycarbonylbenzyl reste, 4-Methylmercaptobenzylreste oder 2-Methyloxy-5-me thylbenzylreste.Examples of C₁ to C₆ lower alkyl radicals associated with a radical of the general formula II, are the above defined C₁ to C₆ lower alkyl radicals linked with a radical of the general formula II which is as above is defined. Benzyl radicals, phenylethyl are preferred residues, 4-fluorobenzyl residues, 2- (4′-fluorophenyl) ethyl residues, 4-chlorobenzyl, 2- (4'-chlorophenyl) ethyl, 2-Hy droxybenzyl residues, 2- (2'-hydroxyphenyl) ethyl residues, 3-Hy droxybenzyl residues, 2- (3'-hydroxyphenyl) ethyl residues, 4-Hy droxybenzyl residues, 2- (4'-hydroxyphenyl) ethyl residues, 2-methyl oxybenzyl residues, 2- (2'-methyloxyphenyl) ethyl residues, 4-methyl oxybenzyl residues, 2- (4'-methyloxyphenyl) ethyl residues, 2,5-di methyloxybenzyl residues, 2,4-dimethyloxybenzyl residues, 4-methyl benzyl radicals, 2- (4'-methylphenyl) ethyl radicals, 4-nitrobenzyl residues, 2- (4′-nitrophenyl) ethyl residues, 4- (N, N-dimethylamino) benzyl residues, 2- (4′-N, N-dimethylaminophenyl) ethyl residues, 2- Trifluoromethylbenzyl residues, 3-trifluoromethylbenzyl residues, 4-trifluoromethylbenzyl, 4-methyloxycarbonylbenzyl residues, 4-methylmercaptobenzyl residues or 2-methyloxy-5-me thylbenzyl residues.
Besonders bevorzugt sind der Benzylrest, der Phenylethyl rest, der 4-Chlorbenzylrest und der 4-Methyloxybenzyl rest.The benzyl radical, phenylethyl, is particularly preferred rest, the 4-chlorobenzyl and the 4-methyloxybenzyl rest.
Beispiele für Halogenatome sind Fluor-, Chlor-, Brom- oder Iodatome.Examples of halogen atoms are fluorine, chlorine, bromine or Iodine atoms.
Die genannten Reste Ra können gleich oder verschieden sein. Sie können in jeder möglichen Position der sie tragenden Ringstruktur gebunden sein.The radicals Ra mentioned can be the same or different. You can wear them in any position Be ring structure bound.
Bevorzugte Beispiele für Reste der allgemeinen Formel II
sind der Phenylrest und solche Reste der allgemeinen
Formel II, worin Ra für einen oder zwei Reste mit einer
der folgenden Bedeutungen steht:
Methylreste, Ethylreste, n-Propylreste, iso-Propylreste,
tert.-Butylreste, Hydroxylreste, Methyloxyreste, Ethyloxy
reste, n-Propyloxyreste, iso-Propyloxyreste, tert.-Butyl
oxyreste, Fluoratome, Chloratome, Trifluormethylreste,
Carbonsäuregruppen, Methyloxycarbonylreste, Ethyloxycar
bonylreste, n-Propyloxycarbonylreste, iso-Propyloxycar
bonylreste, tert.-Butyloxycarbonylreste, unsubstituierte,
einfach oder zweifach mit Methylresten oder Ethylresten
substituierte Aminogruppen.Preferred examples of radicals of the general formula II are the phenyl radical and those radicals of the general formula II in which Ra represents one or two radicals with one of the following meanings:
Methyl radicals, ethyl radicals, n-propyl, iso-propyl, tert-butyl radicals, hydroxyl radicals, Methyloxyreste, ethyloxy radicals, n-Propyloxyreste, iso-Propyloxyreste, tert-butyl oxy groups, fluorine atoms, chlorine atoms, trifluoromethyl, carboxylic acid groups, Methyloxycarbonylreste, Ethyloxycar bonylreste , n-Propyloxycarbonylreste, iso-Propyloxycar bonylreste, tert-Butyloxycarbonylreste, unsubstituted, mono- or disubstituted with methyl or ethyl radicals.
Besonders bevorzugte Reste der allgemeinen Formel II sind der Phenylrest, der 4-Methylphenylrest, der 4-Methyloxy phenylrest, der 2,4-Dimethyloxyphenylrest, der 2,5-Dime thyloxyphenylrest, der 2-Fluorphenylrest, 4-Fluorphenyl rest, der 4-Chlorphenylrest, der 2,4-Dichlorphenylrest, der 2,6-Dichlorphenylrest, der 3-Trifluormethylphenyl rest, der 4-N,N-Dimethylaminophenylrest und der 4-N,N- Diethylaminophenylrest.Particularly preferred radicals of the general formula II are the phenyl radical, the 4-methylphenyl radical, the 4-methyloxy phenyl radical, the 2,4-dimethyloxyphenyl radical, the 2,5-dime thyloxyphenyl, the 2-fluorophenyl, 4-fluorophenyl residue, the 4-chlorophenyl residue, the 2,4-dichlorophenyl residue, the 2,6-dichlorophenyl radical, the 3-trifluoromethylphenyl residue, the 4-N, N-dimethylaminophenyl residue and the 4-N, N- Diethylaminophenylrest.
Sofern die erfindungsgemäßen Verbindungen in Salzform vorliegen, handelt es sich um die Salze physiologisch verträglicher anorganischer oder organischer Basen und Säuren.If the compounds according to the invention are in salt form are present, the salts are physiological compatible inorganic or organic bases and Acids.
Beispiele für Salze mit physiologisch verträglichen Basen sind Ammonium-, Natrium-, Kalium-, Lithium-, Magnesium- und Calciumsalze sowie Salze mit Ethanolamin, Triethanol amin, Morpholin oder Piperidin.Examples of salts with physiologically compatible bases are ammonium, sodium, potassium, lithium, magnesium and calcium salts and salts with ethanolamine, triethanol amine, morpholine or piperidine.
Beispiele für Salze mit physiologisch verträglichen Säu ren sind Citrat-, Tartrat-, Acetat-, Chlorid- und Bromid haltige Salze.Examples of salts with physiologically acceptable acid are citrate, tartrate, acetate, chloride and bromide containing salts.
Die Verbindungen der allgemeinen Formel I können in Ana logie zu Methoden, die aus dem Stand der Technik bekannt sind, hergestellt werden.The compounds of general formula I can in Ana logie to methods known from the prior art are manufactured.
So sind beispielsweise die Synthesen der ähnlichen Verbin dungen der Formel A von Swarts; Bull. Cl. Sci. Acad. R. Belg. 12, 690 (1926),For example, the syntheses of the similar verb are formulas of Swarts; Bull. Cl. Sci. Acad. R. Belg. 12, 690 (1926),
der Formel B von Joullie et al.; J. Org. Chem. 21, 1358 (1956)Formula B by Joullie et al .; J. Org. Chem. 21, 1358 (1956)
und der Formel C von Nes, Burger; J. Am. Chem. Soc. 72, 5409 (1950)and Formula C from Nes, Burger; J. Am. Chem. Soc. 72, 5409 (1950)
beschrieben.described.
Die Erfindung betrifft nun ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I. Dabei setzt man eine Verbindung der allgemeinen Formel III,The invention now relates to a method of manufacture of the compounds of the general formula I. a compound of the general formula III,
worin R³ und R⁴ die vorstehend genannten Bedeutungen ha ben und Rx einen C₁- bis C₆-Alkylrest, bevorzugt einen Methylrest oder einen Ethylrest, darstellt, mit einem Äquivalent eines Amins der allgemeinen Formel IV,wherein R³ and R⁴ have the meanings given above and R x represents a C₁ to C₆ alkyl radical, preferably a methyl radical or an ethyl radical, with one equivalent of an amine of the general formula IV,
R¹R²NH (IV)R¹R²NH (IV)
worin R¹ und R² die vorstehend genannten Bedeutungen ha ben, unter Abspaltung des entsprechenden Alkohols RxOH um und erhält erfindungsgemäße Verbindungen der allgemeinen Formel I, worin X ein Sauerstoffatom bedeutet (z. B. analog US-PS 2 857 373) gemäß dem folgenden Reaktionsschema:wherein R¹ and R² have the meanings given above, with elimination of the corresponding alcohol R x OH and receives compounds according to the invention of the general formula I in which X represents an oxygen atom (for example analogously to US Pat. No. 2,857,373) according to the following Reaction scheme:
Um Verbindungen der allgemeinen Formel I herzustellen, worin R³ eine von einem Wasserstoffatom verschiedene Be deutung hat und R⁴ ein Wasserstoffatom bedeutet, kann man Verbindungen der allgemeinen Formel I, worin R³ und R⁴ ein Wasserstoffatom bedeuten, mit Aldehyden oder Ketonen der allgemeinen Formel RyRzC=O analog Z. H. Khalil, A. S. Yanni; J. Indian Chem. Soc. LVIII, 168 und 494 (1981) un ter Wasserabspaltung kondensieren und anschließend kataly tisch hydrieren. Die Reste Ry und Rz werden so gewählt, daß bei der katalytischen Hydrierung aus dem Rest RyRzC= der Rest R³ mit den in Anspruch 1 genannten Bedeutungen gebildet wird. Dies ist in der nachstehenden Reaktions gleichung dargestellt.In order to prepare compounds of the general formula I in which R³ has a meaning other than a hydrogen atom and R⁴ is a hydrogen atom, compounds of the general formula I in which R³ and R⁴ are a hydrogen atom can be prepared with aldehydes or ketones of the general formula R y R z C = O analogous to ZH Khalil, AS Yanni; J. Indian Chem. Soc. Condense LVIII, 168 and 494 (1981) under elimination of water and then catalytically hydrogenate. The radicals R y and R z are chosen such that the catalytic hydrogenation from the radical R y R z C = the radical R³ with the meanings given in claim 1 is formed. This is shown in the reaction equation below.
Verbindungen der allgemeinen Formel I, wobei X ein Sauer stoffatom bedeutet, können gemäß dem folgenden Reaktions schema auch aus Verbindungen der allgemeinen Formel I, wobei X den Rest =NR⁵ bedeutet, durch Hydrolyse, beispiels weise mit wäßriger Ameisensäure gewonnen werden. (R⁵ kann Wasserstoff oder einen Substituenten darstellen.)Compounds of general formula I, wherein X is an acid Substance atom means can according to the following reaction also from compounds of the general formula I, where X is the radical = NR⁵, by hydrolysis, for example be obtained with aqueous formic acid. (R⁵ can Represent hydrogen or a substituent.)
Die Ausgangsverbindungen der allgemeinen Formel III sind nach diversen bekannten Methoden herstellbar. The starting compounds of general formula III are can be produced by various known methods.
So erhält man durch Umsetzung von unsubstituierten oder gegebenenfalls mit R³ und R⁴ substituierten, in α-Posi tion deprotonierten Essigsäureestern mit reaktiven Tri fluoressigsäurederivaten wie beispielsweise -säurechlori den, -estern oder -anhydriden analog E. T. McBee, O. R. Pierce, H. W. Kilbourne, E. R. Wilson; J. Am. Chem. Soc. 75, 3152 (1953) oder analog E. T. McBee, C. E. Hathaway, C. W. Roberts; J. Am. Chem. Soc. 78, 4053 (1956) Verbin dungen der allgemeinen Formel III gemäß dem folgenden Reaktionsschema:So you get through implementation of unsubstituted or optionally substituted with R³ and R⁴, in α-Posi tion deprotonated acetic acid esters with reactive tri fluoroacetic acid derivatives such as acid chlori the, esters or anhydrides analogous to E. T. McBee, O. R. Pierce, H.W. Kilbourne, E.R. Wilson; J. Am. Chem. Soc. 75, 3152 (1953) or analogously to E. T. McBee, C. E. Hathaway, C.W. Roberts; J. Am. Chem. Soc. 78, 4053 (1956) Verbin of general formula III according to the following Reaction scheme:
Eine ähnliche Methode unter Verwendung von mit R³ und R⁴ substituierten Ketonen anstelle der Essigsäureester führt nach anschließender Alkoholyse ebenfalls zu entsprechend substituierten 4,4,4-Trifluoracetessigsäureestern (J. Boivin, L. El Kaim, S. Z. Zard; Tetrahedron Lett. 33, 1285 (1992)).A similar method using R³ and R⁴ substituted ketones instead of the acetic acid ester after subsequent alcoholysis too substituted 4,4,4-trifluoroacetoacetic acid esters (J. Boivin, L. El Kaim, S. Z. Zard; Tetrahedron Lett. 33, 1285 (1992)).
In Analogie zu R. E. Ireland, J. A. Marshall; J. Am. Chem. Soc. 81, 2907 (1959) können auch in 2-Position substitu ierte Malonsäuremonoester, worin R⁴ ein Wasserstoffatom bedeutet, mit reaktiven Trifluoressigsäurederivaten unter CO₂-Abspaltung zu 4,4,4-Trifluoracetessigsäureestern um gesetzt werden, worin R⁴ ein Wasserstoffatom bedeutet, gemäß dem folgenden Reaktionsschema:In analogy to R.E. Ireland, J.A. Marshall; J. Am. Chem. Soc. 81, 2907 (1959) can also be substituted in the 2-position ized malonic acid monoester, wherein R⁴ is a hydrogen atom means with reactive trifluoroacetic acid derivatives under Elimination of CO₂ to 4,4,4-trifluoroacetoacetic acid esters are set in which R⁴ represents a hydrogen atom, according to the following reaction scheme:
Kondensation von 4,4,4-Trifluoracetessigsäureestern, worin R³ und R⁴ ein Wasserstoffatom bedeuten, mit Alde hyden oder Ketonen der allgemeinen Formel RyRzC=O analog "Organikum", Organisch-chemisches Grundpraktikum, VEB Deutscher Verlag der Wissenschaften, 16. Auflage, Berlin 1986, S. 459 und nachfolgende katalytische Hydrierung führen gemäß dem folgenden Reaktionsschema ebenfalls zu Verbindungen der allgemeinen Formel III. Die Reste Ry und Rz sind dabei so gewählt, daß bei der katalytischen Hydrierung aus dem Rest RyRzC= der Rest R³ mit den in An spruch 1 genannten Bedeutungen gebildet wird.Condensation of 4,4,4-trifluoroacetoacetic acid esters, in which R³ and R⁴ represent a hydrogen atom, with alde hydene or ketones of the general formula R y R z C = O analogous to "organics", basic organic chemistry internship, VEB German Publishing House of Sciences, 16 Edition, Berlin 1986, p. 459 and subsequent catalytic hydrogenation also lead to compounds of the general formula III according to the following reaction scheme. The radicals R y and R z are chosen so that in the catalytic hydrogenation from the radical R y R z C = the radical R³ with the meanings given in claim 1 is formed.
Aus der Gruppe der am Amidstickstoffatom aromatisch sub stituierten 4,4,4-Trifluoracetessigsäreamide sind einzel ne Verbindungen bekannt geworden. So werden in einigen Patentschriften Vertreter der 4,4,4-Trifluoracetessig säureamide als Zwischenstufen bei der Synthese heterocyc lischer Verbindungen bzw. für Azokupplungsreaktionen be schrieben (BE-PS 634 930, GB-PS 993 749, US-PS 2 857 373).From the group of aromatically sub at the amide nitrogen atom substituted 4,4,4-trifluoroacetoacetic acid amides are single ne connections become known. So in some Patent specifications representative of 4,4,4-trifluoroacetic vinegar acid amides as intermediates in the synthesis of heterocyc lical compounds or for azo coupling reactions wrote (BE-PS 634 930, GB-PS 993 749, US-PS 2 857 373).
Pharmakologische Wirkungen sind von diesen bekannten Ver bindungen nicht bekannt geworden.Pharmacological effects are known from these known ver ties not known.
Im Zusammenhang mit der vorliegenden Erfindung wurde überraschenderweise gefunden, daß die erfindungsgemäßen Verbindungen wertvolle pharmakologische Eigenschaften aufweisen. In connection with the present invention Surprisingly found that the invention Compounds valuable pharmacological properties exhibit.
Die erfindungsgemäßen Verbindungen zeichnen sich durch eine starke antientzündliche Wirkung aus. Außerdem haben diese Verbindungen antithrombotische, analgetische und antipyretische Eigenschaften. Besonders überraschend ist die hohe antithrombotische Wirksamkeit der erfindungsge mäßen Verbindungen. Die erfindungsgemäßen Verbindungen eignen sich daher zur Behandlung entzündlicher und schmerz hafter Erkrankungen bei Mensch und Tier. Die Krankheits bilder, die mit den erfindungsgemäßen Verbindungen behan delt werden können, umfassen alle entzündlichen Zustände, wie zum Beispiel Entzündungen der Haut wie Radiodermati tis, Psoriasis, Akne, Ekzeme, Entzündungen am Auge wie zum Beispiel Conjunktivitis, Entzündungen im Hals-Nasen- Ohren-Bereich wie zum Beispiel katarralische Infektionen der oberen Luftwege und Sinusitis, entzündliche Erkran kungen des Gefäßsystems wie Thrombophlebitis oder Vasku litis und Entzündungen des Nervensystems wie zum Beispiel Neuralgien oder Neuritiden. Bevorzugt zu behandelnde ent zündliche Erkrankungen sind Entzündungen im Bereich des Bewegungsapparates wie Arthritiden, Arthrose, Tendinitis, Tendopathien, Kontusionen und Distorsionen, Weichteil rheumatismus, Gicht und Lumbalgien. Die erfindungsgemäßen Verbindungen eignen sich auch besonders zur Behandlung von bestimmten Erkrankungen oder Störungen, bei denen der Schmerz im Vordergrund steht. Hier sind postoperative Schmerzzustände, Schmerzen nach Zahnextraktion und Migräne zu nennen. Ferner eignen sich die erfindungsgemäßen Ver bindungen zur Prophylaxe und zur Behandlung thromboembo lischer Erkrankungen.The compounds according to the invention are notable for a strong anti-inflammatory effect. Also have these compounds are antithrombotic, analgesic and antipyretic properties. It is particularly surprising the high antithrombotic effectiveness of the fiction moderate connections. The compounds of the invention are therefore suitable for the treatment of inflammatory and pain serious diseases in humans and animals. The disease pictures that behan with the compounds of the invention can include all inflammatory conditions, such as inflammation of the skin such as radiodermatitis tis, psoriasis, acne, eczema, eye inflammation like for example conjunctivitis, inflammation in the ear, nose and throat Ear area such as catarral infections the upper airways and sinusitis, inflammatory crane vascular system such as thrombophlebitis or vascu litis and inflammation of the nervous system such as Neuralgia or neuritis. Ent to be treated preferentially inflammatory diseases are inflammations in the area of Musculoskeletal system such as arthritis, arthrosis, tendonitis, Tendopathies, contusions and distortions, soft tissue rheumatism, gout and low back pain. The invention Compounds are also particularly suitable for treatment of certain diseases or disorders in which the Pain is in the foreground. Here are post-operative ones Pain conditions, pain after tooth extraction and migraines to call. The Ver according to the invention are also suitable prophylaxis and thromboembo treatment diseases.
In Untersuchungen auf antientzündliche Wirkung (gemäß C. A. Winter, E. A. Risley, G. W. Nuss; Proc. Soc. Exp. Biol. Med. 111, 544 (1962)) an Gruppen mit je zehn Wistar-Rat ten erwiesen sich erfindungsgemäße Verbindungen als stark antientzündlich wirksam.In tests for anti-inflammatory effects (according to C.A. Winter, E. A. Risley, G. W. Nuss; Proc. Soc. Exp. Biol. Med. 111, 544 (1962)) to groups with ten Wistar Councils each Compounds according to the invention proved to be strong anti-inflammatory.
Die nachstehende Tabelle zeigt die Ergeb nisse für erfindungsgemäße Verbindungen:The table below shows the results nisse for compounds according to the invention:
Gegenstand der Erfindung sind auch Arzneimittel zur Behand lung von Mensch und Tier, bestehend aus oder enthaltend eine oder mehrere Verbindungen der allgemeinen Formel I, gegebenenfalls zusammen mit üblichen Träger- und Hilfs stoffen.The invention also relates to medicaments for treatment development of humans and animals, consisting of or containing one or more compounds of the general formula I, optionally together with usual carrier and auxiliary fabrics.
Die erfindungsgemäßen Verbindungen können in einer Viel zahl pharmazeutischer Zubereitungsformen und Formulie rungen appliziert werden, wie zum Beispiel Tabletten, Dragees, Kapseln, Pillen, Granulate, flüssige oral einzu nehmende Zubereitungen, Suppositorien, Lösungen, Suspen sionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lo tions, Pflaster, Injektionslösungen, Puder, Sprays oder Aerosole, wobei allgemein übliche Träger- und Hilfsstoffe verwendet werden können, die mit den erfindungsgemäßen Verbindungen verträglich sind.The compounds of the invention can be used in a variety of ways number of pharmaceutical forms and formulations such as tablets, Dragees, capsules, pills, granules, liquid orally taking preparations, suppositories, solutions, suspensions sions and emulsions, pastes, ointments, gels, creams, lo tions, plasters, solutions for injection, powder, sprays or Aerosols, generally common carriers and auxiliaries can be used with the invention Connections are compatible.
Die erfindungsgemäßen Arzneimittel enthalten neben den Verbindungen der allgemeinen Formel I bevorzugt nicht toxische, inerte pharmazeutisch geeignete Träger- und Hilfsstoffe.The pharmaceuticals according to the invention contain in addition to Compounds of the general formula I are preferably not toxic, inert pharmaceutically acceptable carrier and Auxiliaries.
Unter nicht toxischen, inerten pharmazeutisch geeigneten Träger- und Hilfsstoffen sind feste, halbfeste oder flüs sige Verdünnungsmittel, Füllstoffe und Formulierungshilfs mittel jeder Art zu verstehen.Among non-toxic, inert pharmaceutically suitable Carriers and auxiliaries are solid, semi-solid or liquid diluents, fillers and formulation aids to understand means of any kind.
Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten. Dazu gehören a) Füll- und Streckmittel, zum Beispiel Stärken, Milchzucker, Rohrzucker, Glucose, Mannit und Kieselsäure, b) Bindemittel, zum Beispiel Carboxyme thylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, c) Feuchthaltemittel, zum Beispiel Glycerin, d) Spreng mittel, zum Beispiel Agar-Agar, Calciumcarbonat und Na triumbicarbonat, e) Lösungsverzögerer, zum Beispiel Pa raffin, f) Resorptionsbeschleuniger, g) Netzmittel, zum Beispiel Cetylalkohol, Glycerinmonostearat, h) Adsorptions mittel, zum Beispiel Kaolin und Bentonit und i) Gleitmit tel, zum Beispiel Talkum, Calcium- und Magnesiumstearat und feste Polyethylenglycole oder Gemische der unter a) bis i) aufgeführten Stoffe.Tablets, coated tablets, capsules, pills and granules can the active ingredient or ingredients in addition to the usual carriers contain. These include a) fillers and extenders, to Example starches, milk sugar, cane sugar, glucose, mannitol and silica, b) binders, for example carboxyme ethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, c) humectant, for example glycerin, d) explosive medium, for example agar-agar, calcium carbonate and Na triumbicarbonate, e) retarders, e.g. Pa raffin, f) absorption accelerator, g) wetting agent, for Example cetyl alcohol, glycerol monostearate, h) adsorption medium, for example kaolin and bentonite and i) lubricant tel, for example talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of those under a) to i) listed substances.
Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit üblichen gegebenenfalls Opalisierungsmittel enthaltenden Überzügen, zum Beispiel Zucker, Überzugs lacken, versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil des Intestinaltraktes, gegebenen falls verzögert abgeben, wobei als Einbettungsmassen zum Beispiel Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can with usual opalizing agents if necessary containing coatings, for example sugar, coating paint, be provided and also be composed, that they only or preferably the active ingredient (s) in a certain part of the intestinal tract if delayed deliver, using as embedding materials for Example polymer substances and waxes can be used can.
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der eben angegebenen Trägerstoffe auch in mikroverkapselter Form vorliegen.The active ingredient (s) can optionally be combined with a or more of the carriers just specified also in microencapsulated form.
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Träger stoffe enthalten, zum Beispiel Polyethylenglycole, Fette, zum Beispiel Kakaofett und höhere Ester (zum Beispiel C₁₄-Alkohol mit C₁₆-Fettsäure oder Gemische dieser Stof fe).Suppositories can in addition to the active ingredient (s) usual water-soluble or water-insoluble carrier contain substances, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C₁₄ alcohol with C₁₆ fatty acid or mixtures of these substances fe).
Cremes enthalten neben dem oder den Wirkstoffen als ölige Grundlage in erster Linie Fettalkohole, zum Beispiel Lauryl-, Cetyl-, Stearylalkohol, Fettsäuren, zum Beispiel Palmi tin- oder Stearinsäure, flüssige bis feste Wachse, zum Beispiel Isopropylmyristat, Wollwachse oder Bienenwachs und/oder Kohlenwasserstoffe, zum Beispiel Vaseline (Petro latum) oder Paraffinöl. Als Emulgatoren verwendet man bevorzugt solche mit vorwiegend hydrophilen Eigenschaf ten, zum Beispiel nichtionische Emulgatoren wie Fettsäure ester von Polyalkoholen, Ethylenoxidaddukte davon wie Polyglycerinfettsäureester oder Polyoxyethylensorbitan fettsäureester (Tweens) oder ionische Emulgatoren wie Alkalimetallsalze von Fettalkoholsulfaten, zum Beispiel Natriumlaurylsulfat, Natriumcetylsulfat oder Natriumstea rylsulfat. Zur Wasserphase können Mittel zugesetzt werden, welche die Austrocknung der Creme verhindern, zum Bei spiel Polyalkohole wie Glycerin, Sorbit, Propylenglycol und/oder Polyethylenglycole.In addition to the active ingredient (s), creams contain oily substances The basis is primarily fatty alcohols, for example lauryl, Cetyl, stearyl alcohol, fatty acids, for example palmi tin or stearic acid, liquid to solid waxes, for Example isopropyl myristate, wool waxes or beeswax and / or hydrocarbons, for example petroleum jelly (Petro latum) or paraffin oil. One uses as emulsifiers preferably those with predominantly hydrophilic properties ten, for example nonionic emulsifiers such as fatty acid esters of polyalcohols, ethylene oxide adducts thereof as Polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (tweens) or ionic emulsifiers such as Alkali metal salts of fatty alcohol sulfates, for example Sodium lauryl sulfate, sodium cetyl sulfate or sodium stea ryl sulfate. Agents can be added to the water phase which prevent the cream from drying out play polyalcohols such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols.
Für Salben kommen neben dem oder den Wirkstoffen als Trä gerstoffe in erster Linie Kohlenwasserstoffe, zum Bei spiel Vaseline oder Paraffinöl in Frage, die zur Verbesse rung des Wasserbindungsvermögens vorzugsweise geeignete Fettalkohole oder Ester davon, zum Beispiel Cetylalkohol oder Wollwachse enthalten. Emulgatoren sind entsprechende lipophile Substanzen wie Sorbitanfettsäureester. Zur Was serphase können Feuchthaltungsmittel wie zum Beispiel Glycerin oder Propylenglycol zugesetzt werden.For ointments come next to the active ingredient (s) as a Trä hydrocarbons, for the Play petroleum jelly or paraffin oil in question, which can be improved tion of the water binding capacity is preferably suitable Fatty alcohols or esters thereof, for example cetyl alcohol or wool waxes. Emulsifiers are corresponding lipophilic substances such as sorbitan fatty acid esters. For what This phase can contain humectants such as Glycerin or propylene glycol can be added.
Sprays und Puder können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, zum Beispiel Milch zucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calcium silicat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treibmittel enthal ten.Sprays and powders can be used in addition to the active ingredient (s) contain the usual carriers, for example milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual blowing agents ten.
Lösungen und Emulsionen können neben dem oder den Wirk stoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, zum Beispiel Wasser, Ethanol, Isopropanol, Ethylcarbonat, Benzylalkohol, Benzyl benzoat, Propylenglycol, 1,3-Butylenglycol, Öle, insbe sondere Baumwollsaatöl, Erdnußöl, Maisöl, Ricinusöl, Cashewnußöl und Sesamöl, Glycerin, Glycerinformal, Poly ethylenglycole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten. Solutions and emulsions can be in addition to the or the effect substances the usual carriers such as solvents, Solubilizers and emulsifiers, for example water, Ethanol, isopropanol, ethyl carbonate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, esp special cottonseed oil, peanut oil, corn oil, castor oil, Cashew nut oil and sesame oil, glycerin, glycerin formal, poly ethylene glycols and fatty acid esters of sorbitan or Mixtures of these substances contain.
Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, zum Beispiel Ethanol, Propylenglycol, Suspendiermittel, zum Beispiel ethoxylierte Isostearylalkohole, Polyoxyethylen sorbit- und Sorbitanester, mikrokristalline Cellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar oder Traganth oder Gemische dieser Stoffe enthalten.In addition to the active ingredient or suspensions, the usual carriers such as liquid diluents for Example ethanol, propylene glycol, suspending agent for Example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminum metahydroxide, bentonite, agar-agar or tragacanth or mixtures of these substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbes sernde Zusätze, zum Beispiel Pfefferminzöl und Eucalyp tusöl und Süßmittel, zum Beispiel Saccharin enthalten.The formulation forms mentioned can also contain colorants, Preservatives as well as odor and taste enhancers additives such as peppermint oil and eucalyptus tus oil and sweeteners, for example saccharin.
Die therapeutisch wirksamen Verbindungen sollen in den oben aufgeführten pharmazeutischen Zubereitungen vorzugs weise in einer Konzentration von etwa 0.1 bis 99.5, be sonders bevorzugt von etwa 0.5 bis 95 Nasse-% der Gesamt mischung vorhanden sein.The therapeutically active compounds should be in the preferred pharmaceutical preparations listed above as in a concentration of about 0.1 to 99.5, be particularly preferably from about 0.5 to 95% by wet of the total mixture be present.
Die oben aufgeführten pharmazeutischen Zubereitungen kön nen außer den erfindungsgemäßen Wirkstoffen auch weitere pharmazeutische Wirkstoffe enthalten.The pharmaceutical preparations listed above can In addition to the active compounds according to the invention, other compounds contain active pharmaceutical ingredients.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, zum Beispiel durch Mischen der Wirkstoffe mit den Trägerstoffen.The manufacture of the pharmaceutical listed above Preparations are carried out in the usual way according to known Methods, for example by mixing the active ingredients with the carriers.
Die vorliegenden Wirkstoffe bzw. pharmazeutischen Zube reitungen, die einen oder mehrere Wirkstoffe enthalten, können in der Human- und Veterinärmedizin zur Verhütung, Besserung und/oder Heilung entzündlicher Krankheiten ein gesetzt werden.The present active ingredients or pharmaceutical accessories horse rides that contain one or more active ingredients, can be used in human and veterinary medicine for contraception, Improvement and / or healing of inflammatory diseases be set.
Im allgemeinen erweist es sich als vorteilhaft, in der Humanmedizin den oder die erfindungsgemäßen Wirkstoffe in Gesamtdosen von etwa 1 bis etwa 1000 mg, vorzugsweise 5 bis 200 mg pro Dosiseinheit bei Verabreichung von ein bis vier Dosiseinheiten pro Tag zur Erzielung der gewünschten Ergebnisse zu applizieren.In general, it proves to be advantageous in the Human medicine or the active ingredients according to the invention in Total doses from about 1 to about 1000 mg, preferably 5 up to 200 mg per dose unit when administered from one to four dose units per day to achieve the desired Apply results.
Es kann jedoch erforderlich sein, von den genannten Do sierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Objektes, der Art und der Schwere der Erkrankung, der Art der Zube reitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabrei chung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der oben genannten Wirkstoffmenge auszukommen, während in anderen Fällen die oben angeführ te Menge Wirkstoff überschritten werden muß.However, it may be necessary to do so from the above deviations, depending on the Type and body weight of the object to be treated, the type and severity of the disease, the type of accessories equation and the application of the drug as well as the Period or interval within which the administration is done. So in some cases it may be sufficient be with less than the above amount of active ingredient get along, while in other cases the above te amount of active ingredient must be exceeded.
Die nachfolgenden Beispiele erläutern die Erfindung näher, ohne ihren Umfang darauf zu beschränken.The following examples explain the invention in more detail, without limiting its scope to it.
25 g 4,4,4-Trifluoracetessigsäuremethylester und 14.72 g
(1 eq) 2-Aminothiazol werden in Xylol solange erhitzt, bis
kein bei der Reaktion freiwerdender Methylalkohol mehr ab
destilliert. Abziehen des Lösungsmittels, anschließende
Chromatographie mit einer Essigsäureethylester/Ameisen
säuremischung (50/l) und zuletzt Umkristallisation aus Es
sigsäureethylester liefert die Titelverbindung in 20%-
iger Ausbeute.
beige Kristalle; Schmp.: 193-194°C.
¹H-NR (d₆-Aceton): δ = 3.08 (s, 2H, 2-CH₂-Keto); 6.13 (s,
1H, 2-CH-Enol); 7.10-7.63 (4d, 2H, Ar-H); 10.00 (s-breit,
2H, NH und Enol-OH); Keto : Enol = 1 : 2.3.
IR (KBr): 3130, 1670, 1600, 1585, 1540, 1440, 1405, 1320,
1285, 1275, 1170, 1120, 1085, 1065, 970, 900, 865, 800,
750, 735, 725 cm-1.
MS: m/e = 238 (M⁺), 169, 139, 100 (100%), 73, 69, 58.25 g of 4,4,4-trifluoroacetoacetic acid methyl ester and 14.72 g (1 eq) of 2-aminothiazole are heated in xylene until no more methyl alcohol released during the reaction is distilled off. Removal of the solvent, subsequent chromatography with an ethyl acetate / ants acid mixture (50 / l) and finally recrystallization from ethyl acetate gives the title compound in 20% yield.
beige crystals; Mp: 193-194 ° C.
¹H-NR (d₆-acetone): δ = 3.08 (s, 2H, 2-CH₂-keto); 6.13 (s, 1H, 2-CH-enol); 7.10-7.63 (4d, 2H, Ar-H); 10.00 (broad s, 2H, NH and enol-OH); Keto: enol = 1: 2.3.
IR (KBr): 3130, 1670, 1600, 1585, 1540, 1440, 1405, 1320, 1285, 1275, 1170, 1120, 1085, 1065, 970, 900, 865, 800, 750, 735, 725 cm -1 .
MS: m / e = 238 (M⁺), 169, 139, 100 (100%), 73, 69, 58.
50 g 4,4,4-Trifluoracetessigsäuremethylester und 13.83 g
(1 eq) 2-Aminopyridin werden in Xylol solange erhitzt, bis
kein bei der Umsetzung freiwerdender Methylalkohol mehr
abdestilliert. Die Lösung wird im Eisbad abgekühlt, der
dabei entstandene Niederschlag abgenutscht und mit Xylol
nachgewaschen. Chromatographie über Kieselgel mit Essig
säureethylester und anschließende Umkristallisation mit
Essigsäureethylester liefert die Titelverbindung in 21%
iger Ausbeute.
beige Kristalle; Schmp.: 164-165°C.
¹H-NMR (d₆-DMSO): δ = 2.89 (s, 2H, 2-CH₂-Keto); 5.76 (s, 1H,
2-CH-Enol); 7.00-8.53 (m, 4H, Ar-H); 10.48 (s-breit, 1H,
NH); 11.56 (s-breit, 1H, Enol-OH); Keto : Enol = 3 : 1.
IR (KBr): 3080, 1650, 1615, 1580, 1565, 1420, 1360, 1320,
1275, 1185, 1165, 1155, 1115, 1085, 1000, 970, 900, 850,
820, 780, 770, 735 cm-1.
MS: m/e = 232 (M⁺), 163, 135, 121, 95, 94,. 78, 69 (100%), 51.50 g of methyl 4,4,4-trifluoroacetoacetate and 13.83 g (1 eq) of 2-aminopyridine are heated in xylene until no more methyl alcohol liberated during the reaction is distilled off. The solution is cooled in an ice bath, the resulting precipitate is filtered off and washed with xylene. Chromatography on silica gel with ethyl acetate and subsequent recrystallization with ethyl acetate gives the title compound in 21% yield.
beige crystals; Mp: 164-165 ° C.
1 H-NMR (d₆-DMSO): δ = 2.89 (s, 2H, 2-CH₂-keto); 5.76 (s, 1H, 2-CH-enol); 7.00-8.53 (m, 4H, Ar-H); 10.48 (s broad, 1H, NH); 11.56 (s broad, 1H, enol-OH); Keto: enol = 3: 1.
IR (KBr): 3080, 1650, 1615, 1580, 1565, 1420, 1360, 1320, 1275, 1185, 1165, 1155, 1115, 1085, 1000, 970, 900, 850, 820, 780, 770, 735 cm - 1st
MS: m / e = 232 (M⁺), 163, 135, 121, 95, 94 ,. 78, 69 (100%), 51.
Elementaranalyse:
ber.: C 46.56%; H 3.04%; N 12.07%; F 24.55%;
gef.: C 46.57%; H 3.02%; N 12.06%; F 24.38%.Elemental analysis:
calc .: C 46.56%; H 3.04%; N 12.07%; F 24.55%;
Found: C 46.57%; H 3.02%; N 12.06%; F 24.38%.
Durch Umsetzung der in der folgenden Tabelle genannten Edukte der allgemeinen Formel IV mit 4,4,4-Trifluoracet essigsäureethylester analog den Beispielen 1 und 2 erhält man die in derselben Tabelle genannten Titelverbindungen.By implementing the ones listed in the following table Educts of the general formula IV with 4,4,4-trifluoroacet ethyl acetate analogous to Examples 1 and 2 the title compounds mentioned in the same table.
Claims (3)
R¹ einen Phenylrest, einen 4-Methylphenylrest, einen 4- Methyloxyphenylrest, einen 2,4-Dimethyloxyphenylrest, ei nen 2,5-Dimethyloxyphenylrest, einen 2-Fluorphenylrest, einen 4-Fluorphenylrest, einen 4-Chlorphenylrest, einen 2,4-Dichlorphenylrest, einen 2,6-Dichlorphenylrest, einen 3-Trifluormethylphenylrest, einen 4-N,N-Dimethylaminophe nylrest oder einen 4-N,N-Diethylaminophenylrest bedeutet, oder
worin
R¹ einen 2-Imidazolylrest, einen 2-Thiazolylrest, einen 5-Methyl-2-thiazolylrest, einen 5-Trifluoromethyl-1,3,4- thiadiazol-2-ylrest, einen 5-Methyl-3-isoxazolylrest, ei nen 2-Benzimidazolylrest, einen 2-Benzothiazolylrest, ei nen 6-Methyloxy-2-benzothiazolylrest, einen 5-Chlor-2- benzoxazolylrest, einen 2-Pyridylrest, einen 5-Chlor-2- pyridylrest- einen 2-Pyrimidylrest- einen 3-Chinolinylrest oder einen 1-Isochinolinylrest bedeutet und
worin
R² ein Wasserstoffatom oder einen C₁- bis C₆-Niedrig alkylrest bedeutet,
R³ und R⁴ unabhängig voneinander ein Wasserstoffatom, einen Rest der allgemeinen Formel II, einen C₁- bis C₆- Niedrigalkylrest oder C₁- bis C₆-Niedrigalkylrest, ver bunden mit einem Rest der allgemeinen Formel II, be deuten,
wobei Ra für einen Rest mit einer der folgenden Bedeutungen steht:
C₁- bis C₆-Niedrigalkylreste, Hydroxylreste, C₁- bis C₆- Niedrigalkyloxyreste, Mercaptoreste, C₁- bis C₆-Niedrig alkylthioreste, Halogenatome, Nitrogruppen, Trifluor methylreste, Cyanoreste, Sulfonsäurereste, Carbonsäure gruppen, C₁- bis C₆-Niedrigalkyloxycarbonylreste oder un substituierte, einfach oder zweifach mit C₁- bis C₆-Nie drigalkylresten substituierte Aminoreste, und
wobei
n gleich 0, 1, 2 oder 3 ist, und
worin
X ein Sauerstoffatom bedeutet,
sowie deren Salze mit physiologisch verträglichen Säuren und Basen,
ausgenommen
N-Methyl-N-phenyl-4,4,4-trifluoracetessigsäureamid,
und mit der Maßgabe, daß wenn R², R³ und R⁴ gleichzeitig ein Wasserstoffatom bedeuten, in diesem Falle R¹ von einem Phenylrest, einem 4-Methyloxyphenylrest, einem 4- Methylphenylrest, einem 4-Chlorphenylrest oder einem 2,4- Dichlorphenylrest verschieden ist.1. Compounds of the general formula I, wherein
R¹ is a phenyl group, a 4-methylphenyl group, a 4-methyloxyphenyl group, a 2,4-dimethyloxyphenyl group, a 2,5-dimethyloxyphenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group , a 2,6-dichlorophenyl radical, a 3-trifluoromethylphenyl radical, a 4-N, N-dimethylaminophenyl radical or a 4-N, N-diethylaminophenyl radical, or
wherein
R¹ is a 2-imidazolyl group, a 2-thiazolyl group, a 5-methyl-2-thiazolyl group, a 5-trifluoromethyl-1,3,4-thiadiazol-2-yl group, a 5-methyl-3-isoxazolyl group, a 2- Benzimidazolyl, a 2-benzothiazolyl, 6-methyloxy-2-benzothiazolyl, 5-chloro-2-benzoxazolyl, 2-pyridyl, 5-chloro-2-pyridyl, 2-pyrimidyl, 3-quinolinyl, or represents a 1-isoquinolinyl radical and
wherein
R² represents a hydrogen atom or a C₁ to C₆ lower alkyl radical,
R³ and R⁴ independently of one another are a hydrogen atom, a radical of the general formula II, a C₁- to C₆- lower alkyl radical or C₁- to C₆-lower alkyl radical, related to a radical of the general formula II, be,
in which Ra stands for a residue with one of the following meanings:
C₁ to C₆ lower alkyl radicals, hydroxyl radicals, C₁ to C₆ lower alkyloxy radicals, mercapto radicals, C₁ to C₆ lower alkylthio radicals, halogen atoms, nitro groups, trifluoromethyl radicals, cyano radicals, sulfonic acid radicals, carboxylic acid groups, C₁ to C₆ lower alkyloxy substituted carbonyl radicals, amino radicals substituted once or twice with C₁- to C₆-never drigalkyl radicals, and
in which
n is 0, 1, 2 or 3, and
wherein
X represents an oxygen atom,
as well as their salts with physiologically compatible acids and bases,
except
N-methyl-N-phenyl-4,4,4-trifluoroacetoacetic acid amide,
and with the proviso that when R², R³ and R⁴ simultaneously represent a hydrogen atom, in this case R¹ is different from a phenyl radical, a 4-methyloxyphenyl radical, a 4-methylphenyl radical, a 4-chlorophenyl radical or a 2,4-dichlorophenyl radical.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19924218159 DE4218159C2 (en) | 1992-06-02 | 1992-06-02 | 4,4,4-trifluoroacetoacetic acid amides, process for their preparation and pharmaceuticals |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19924218159 DE4218159C2 (en) | 1992-06-02 | 1992-06-02 | 4,4,4-trifluoroacetoacetic acid amides, process for their preparation and pharmaceuticals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE4218159A1 DE4218159A1 (en) | 1993-12-09 |
| DE4218159C2 true DE4218159C2 (en) | 1997-07-31 |
Family
ID=6460220
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| DE19924218159 Expired - Fee Related DE4218159C2 (en) | 1992-06-02 | 1992-06-02 | 4,4,4-trifluoroacetoacetic acid amides, process for their preparation and pharmaceuticals |
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| DE (1) | DE4218159C2 (en) |
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| MC2447A1 (en) * | 1996-06-24 | 1998-03-16 | Trabelsi Hedi | Processes for obtaining biomedical perfluoroalkzyl glycosidic surfactants and their precursors |
| DE19652955A1 (en) * | 1996-12-19 | 1998-06-25 | Bayer Ag | Process for the preparation of trifluoroacetoacetic acid anilides |
| US6121300A (en) * | 1998-11-10 | 2000-09-19 | Wagle; Dilip R. | Reversing advanced glycosylation cross-links using heterocyclic-substituted thiazolium salts |
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| US2857373A (en) * | 1955-03-01 | 1958-10-21 | Eastman Kodak Co | Benzothiazole azo compounds containing a reactive methylene coupling component |
| FR79706E (en) * | 1959-11-13 | 1963-04-17 |
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