WO1989011479A1 - Nouveaux composes fluores d'alkoxyde - Google Patents
Nouveaux composes fluores d'alkoxyde Download PDFInfo
- Publication number
- WO1989011479A1 WO1989011479A1 PCT/EP1989/000567 EP8900567W WO8911479A1 WO 1989011479 A1 WO1989011479 A1 WO 1989011479A1 EP 8900567 W EP8900567 W EP 8900567W WO 8911479 A1 WO8911479 A1 WO 8911479A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- compounds
- methyl
- formula
- trifluoroethoxy
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 100
- -1 phenoxy, phenoxy Chemical group 0.000 claims description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 36
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 25
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000000229 (C1-C4)alkoxy group Chemical class 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 230000004962 physiological condition Effects 0.000 claims description 10
- 210000002784 stomach Anatomy 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 150000001556 benzimidazoles Chemical class 0.000 claims description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
- 230000027119 gastric acid secretion Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical group 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- 210000000936 intestine Anatomy 0.000 claims description 2
- 150000004987 o-phenylenediamines Chemical class 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
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004789 chlorodifluoromethoxy group Chemical group ClC(O*)(F)F 0.000 claims 2
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical class C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 claims 1
- 230000000026 anti-ulcerogenic effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
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- 238000006243 chemical reaction Methods 0.000 description 20
- 239000002253 acid Substances 0.000 description 15
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
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- 238000009835 boiling Methods 0.000 description 8
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
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- 208000025865 Ulcer Diseases 0.000 description 6
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- 231100000397 ulcer Toxicity 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 108010079943 Pentagastrin Proteins 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 230000009858 acid secretion Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 3
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Definitions
- the invention relates to new fluoroalkoxy compounds, processes for their preparation, their use and medicaments containing them.
- the compounds according to the invention are used in the pharmaceutical industry as intermediates and for the manufacture of medicaments.
- the invention relates to new fluoroalkoxy compounds of the formula I.
- Rl, R2 and R3 can be at any position in the benzo part of the benzimidazole and wherein
- R1 hydrogen, halogen, trifluoromethyl, 1- ⁇ C-alkyl, 1-6C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-aloxy, phenyl, phenoxy , Phenoxy-1-4C-alkyl, phenoxy-1-4C-alkoxy, phen-1-4C-al yl or phen-1-4C-alkoxy,
- R2 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1, 1,2-trifluoroethoxy or together with R3 in whole or in part Is fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy,
- R3 is completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,2,2-trifluoroethoxy or together with R2 completely or partly fluorine-substituted 1,2-alkylenedioxy or chlorotrifluoroethylenedioxy,
- R4 denotes hydrogen or a group which can easily be split off under physiological conditions
- R5 denotes hydrogen or 1-6C-alkyl
- R6 represents hydrogen or 1-6C-alkyl
- R7 denotes hydrogen, 1-6C-alkyl, 1-6C-alkoxy, 2-5C-alkenyloxy, 2-5C-alkynyloxy or 1-4C-alkoxy-1-4C-alkoxy,
- R8 is completely or predominantly fluorine-substituted 1-4C-alkoxy and n represents the number 0 or 1, and the salts of these compounds.
- Halogen in the sense of the present invention is bromine, chlorine and fluorine.
- 1-6C-Alkyl stands for straight-chain and branched AI ylreste.
- Straight-chain alkyl radicals are the hexyl, pentyl, butyl, propyl, ethyl and in particular the methyl radical.
- Branched AI kylreste are, for example, the neopentyl, i-butyl, see. -Butyl, t-butyl and the isopropyl radical.
- 1-6C-Alkoxy stands for straight-chain or branched alkoxy radicals. Examples include the hexyl oxy, neopentyl oxy, butoxy, i-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
- 1-4C-Alkoxy stands for straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and especially the methoxy radical.
- 1-4C-A1kyl represents straight-chain or branched alkyl radicals; For example, the butyl, i-butyl, see.-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
- 1-4C-Alkoxy-1-4C-alkyl represents 1-4C-alkyl which is substituted by 1-4C-alkoxy.
- the ethoxymethyl, propoxybutyl, methoxymethyl and especially the methoxyethyl and ethoxyethyl radicals may be mentioned.
- 1-4C-Alkoxy-1-4C-alkoxy stands for 1-4C-alkoxy which is substituted by 1-4C-alkoxy.
- methoxypropoxy, ethoxymethoxy and in particular the ethoxyethoxy and methoxyethoxy radicals may be mentioned.
- Phenoxy-1-4C-alkyl stands for 1-4C-alkyl which is substituted by a phenoxy radical.
- phenoxypropyl and the phenoxyethyl radical may be mentioned.
- Phenoxy-l-4C-alkoxy stands for l-4C-alkoxy which is substituted by a phenoxy radical. Examples include phenoxyethoxy and phenoxypropoxy.
- Phen-1-4C-al yl stands for 1-4C-alkyl which is substituted by a phenyl radical.
- the phenethyl and especially the benzyl radical may be mentioned.
- Phen-1-4C-alkoxy stands for 1-4C-alkoxy which is substituted by a phenyl radical. Examples include the 2-phenyl-ethoxy and the benzyloxy radical.
- 1,1-difluoroethylenedioxy- (-0-CF 2 -CH 2 -0-), 1,1,2,2-tetra-fluoroethylenedioxy- (as wholly or partly substituted by fluorine substituted by fluorine are -0-CF 2 -CF 2 -0-) and in particular the difluoroethylenedioxy- (_0-CF 2 -0-) and the 1,1,2-trifluoroethylenedioxy radical (-0-CF 2 -CHF-0-).
- a group R4 which can easily be split off under physiological conditions, is a substituent which is separated from the nitrogen atom by formation of an NH bond by — optionally enzymatically catalyzed — hydrolysis pharmacologically acceptable compound is converted.
- substituted carbonyl groups such as the AI ylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group, may be mentioned in particular as the R4 groups which can be split off.
- R4 groups which can be split off. Examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and the dimethylcarbonyl group.
- 2-5C-alkenyloxy represents alkenyloxy radicals such as the pent-2-enyloxy, but-1-enyloxy and in particular the allyloxy radical.
- 2-5C-alkynyloxy represents alkynyloxy radicals such as the ethynyloxy and in particular the prop-2-ynyloxy radical.
- Suitable salts for compounds of the formula I in which n denotes the number 0 (sulfides), preferably alTe acid addition salts, are suitable.
- Pharmacologically incompatible salts which may initially be obtained as process products in the production of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
- Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, carbonate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosal cylate, maleate, laurate, malate , Fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
- water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, carbonate, gluconate, benzoate, hibenzate, fendizoate, butyrate
- preferred salts are basic salts, in particular pharmacologically acceptable salts with inorganic and organic bases commonly used in galenics.
- Lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts may be mentioned as examples of basic salts.
- Rl is hydrogen
- R2 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-l, 1,2-tri fluoroethoxy or together with R3 difluoromethylene dioxy , 1,1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene dioxy,
- R3 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-l, l, 2-trifluoroethoxy or together with R2 difluoromethyl methylenedioxy, 1,1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene-dioxy means
- R4 means hydrogen
- R5 denotes hydrogen, methyl or ethyl
- R6 denotes hydrogen or 1-4C-A1 kyl
- R7 is hydrogen, 1-4C-A1kyl or 1-4C-alkoxy
- R8 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy and n represents the number 0 or 1, and the salts of these compounds.
- Another noteworthy embodiment of the invention are compounds of the formula Ib
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration, and their salts.
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration a, and their salts.
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration a, and their salts.
- Preferred compounds according to the invention are those of the formulas I, Ia and I in those
- Rl is hydrogen
- R2 is hydrogen or together with R3 difluoromethylene dioxy
- R3 is 2,2,2-trifluoroethoxy, difluoromethoxy or together with R3 is difluoromethylene methylene
- R4 is hydrogen
- R5 is hydrogen
- R6 is hydrogen
- R7 represents hydrogen, methyl or methoxy
- R8 represents 2,2,2-trifluoroethoxy
- n represents the number 0 or 1
- the salts of these compounds
- Another object of the invention is a process for the preparation of the compounds of formula I, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given above, and their salts.
- the process to be prepared are product products - that compounds of the formula I in which R4 is hydrogen are reacted with compounds of the formula R4'-Y ' (XIII), in which R4 'is the desired group which can easily be split off under physiological conditions or is a precursor together with Y' i and, if desired, is subsequently converted into the salts, or
- Y, Y ' 1 , 1, V and 1 represent suitable leaving groups
- Y' represents a leaving or reactive group
- M stands for an alkali metal atom (Li, Na or K)
- M ' stands for the equivalent of a metal atom
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given above.
- the compounds II-XIV can be used as such or, if appropriate, in the form of their salts.
- a suitable leaving group Y is, for example, a group which, together with the sulfinyl group to which it is attached, forms a reactive sulfinic acid derivative.
- suitable leaving groups Y include alkoxy, dialkylamino or alkyl mercapto groups.
- a suitable leaving or reactive group Y ' is a group which is able to react with a secondary amino group with elimination of HY' or with addition.
- Y' is, for example, a leaving group which, together with the carbonyl group to which it is attached, forms a reactive carboxylic acid derivative, for example an acid halide.
- the general formula R4'-Y '(XIII) also includes those compounds (precursors of the group R4 which can easily be split off under physiological conditions) in which Y 1 represents a reactive group (for example isonitriles) which are involved in the reaction with the secondary amino group, there is no condensation with elimination of HY 'but an addition to form the desired removable group R4.
- the leaving group Y 11 is a group familiar to the person skilled in the art for alkylation reactions, which goes off during the alkylation - for example with dialkyl sulfate, fluorosulfonic acid alkyl ester or alkyl iodide.
- Suitable leaving groups Z, V or 1 are, for example, halogen atoms, in particular chlorine atoms, or hydroxyl groups activated by esterification (e.g. with p-toluenesulfonic acid).
- a metal atom M ' is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg) which is substituted by a halogen atom (eg Br, Grignard reagent) or any other, optionally substituted Metal atom, which is known to react in the case of substitution reactions of organometallic compounds, such as the metals mentioned above.
- a metal atom M is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg) which is substituted by a halogen atom (eg Br, Grignard reagent) or any other, optionally substituted Metal atom, which is known to react in the case of substitution reactions of organometallic compounds, such as the metals mentioned above.
- the reaction of II with III is carried out in suitable, preferably polar, protic or aprotic solvents (such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile) with or without water. It is carried out, for example, in the presence of a proton acceptor.
- suitable, preferably polar, protic or aprotic solvents such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile
- a proton acceptor Alkali metal hydroxides, such as sodium hydroxide, alkali metal carbonates, such as potassium carbonate, or tertiary amines, such as pyridine, triethylamine or ethyldiisopropylamine, are suitable as such.
- reaction can also be carried out without a proton acceptor, it being possible, depending on the nature of the starting compounds, first of all to separate off the acid addition salts in a particularly pure form.
- the reaction temperature can be between 0 and 150 ° C, temperatures in the presence of proton acceptors between 20 and 80 ° C and without proton acceptors between 60 and 120 ° C
- the boiling point of the solvents used - are preferred.
- the response times are between 0.5 and 12 hours.
- the reaction of VI with VII is preferably carried out in polar, optionally water-containing solvents in the presence of a strong acid, for example hydrochloric acid, in particular at the boiling point of the solvent used.
- a strong acid for example hydrochloric acid
- the oxidation of sulfides VIII takes place under the conditions known to the person skilled in the art for the oxidation of sulfides to sulfoxides (see, for example, J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2) , 45-89 (1982) or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E. Part 1, pp. 539-608, John Wiley and Sons (Interscience Publication), 1980.
- oxidizing agents reagents commonly used for the oxidation of sulfides to sulfoxides in particular peroxy acids, such as peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid, magnesium monoperoxiphthalate or preferably m-chloroperoxybenzoic acid.
- the reaction temperature (depending on the reactivity of the oxidizing agent and degree of dilution) is between -70 C and the boiling temperature of the solvent used, but preferably between -30 and +20 C. Also advantageous is the oxidation with halogens or with hypohalites (eg with aqueous sodium hypochlorite solution), which is expediently carried out at temperatures between 0 and 50 ° C.
- the reaction is conveniently carried out in inert solvents, e.g. B. aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dioxane.
- the reaction of IX with X is preferably carried out in inert solvents, as are usually used for the reaction of enolate ions with alkylating agents.
- aromatic solvents such as benzene or toluene may be mentioned.
- the reaction temperature is (depending on the type of Al alimeo o tallatoms M and the leaving group Z) generally between 0 and 120 C, the boiling point of the solvent used is preferred.
- M represents Li (lithium) and Z Cl (chlorine) and the reaction is carried out in benzene o] the boiling point of benzene (80 ° C.) is preferred.
- the compounds XI are reacted with the compounds XII in a manner known per se, as is known to the person skilled in the art for the reaction of organometallic compounds.
- reaction according to process variant f) is carried out in a manner known to the person skilled in the art in suitable solvents such as tetrahydrofuran or acetonitrile, optionally with the addition of a base (if Y 'represents a leaving group) or also without base addition (if Y 'represents a reactive group).
- suitable solvents such as tetrahydrofuran or acetonitrile
- Y 'represents a leaving group or also without base addition (if Y 'represents a reactive group).
- this reaction gives isomeric mixtures which have to be separated by suitable separation processes (for example chromatography).
- Solvolysis according to process variant g) is carried out in a manner known to those skilled in the art in suitable water-containing or water-splitting alkaline or acidic solutions, at room temperature or, if desired, with heating to the boiling point of the solvent used.
- the alkylation according to process variant h) is carried out - if appropriate after prior deprotonation - in a manner familiar to the person skilled in the art in suitable inert solvents.
- the compounds according to the invention are initially obtained either as such or in the form of their salts.
- the salts are obtained by dissolving the free compounds in a suitable solvent, e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether (diisopropyl ether), a ketone (acetone) or water, which contains the desired acid or base, or which contains the desired acid or Base - optionally in the precisely calculated stoichiometric amount - is then added.
- a chlorinated hydrocarbon such as methylene chloride or chloroform
- a low molecular weight aliphatic alcohol ethanol, isopropanol
- an ether diisopropyl ether
- a ketone acetone
- the salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent.
- Salts obtained can be converted into the free compounds by alkalization or acidification, for example with aqueous sodium bicarbonate or with dilute hydrochloric acid, which in turn can be converted into the salts. In this way, the compounds can be purified or pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
- the sulfox de invention are optically active compounds. Depending on the nature of the substituents Rl to R8, there may be additional chiral centers in the molecule (eg if R5 is not hydrogen). The invention therefore includes both the enantiomers and d astereomers and their mixtures and racemates.
- the enantiomers can be separated in a manner known per se (for example by producing and separating corresponding diastereoisomeric compounds).
- the enantiomers can also be obtained by asymmetric synthesis, for example by enantioselective oxidation of the sulfides, for example using tert-butyl hydroperoxide with the addition of optically pure tartaric acid, or for example by reacting optically active pure compounds XI or diastereoisomerically pure compounds XI with compounds XII are produced [see KK Andersen, Tetrahedron Lett., 93 (1962)].
- the compounds according to the invention are preferably synthesized by reacting II with III and, if appropriate, subsequent oxidation of the sulfide VIII formed.
- Compounds II, IV, VI, IX and XI are e.g. known from W086 / 02646, EP 134400 or EP 127763.
- the compounds III are known from EP 174726 and EP 208452, or they can be prepared in an analogous manner.
- the compounds V, VII and XII are prepared, for example, starting from the compounds III in ways known to those skilled in the art.
- Example 1 The procedure described in Example 1 is obtained by reacting 0.66 g of 5-difluoromethoxy-2-mercapto-1H-benzimiazole with 0.78 g of 2-chloromethyI-4- (2,2,2-trifluoroethoxy ) -3-methylpy ⁇ d ⁇ nium chloride with the addition of 3.1 ml of 2N sodium hydroxide solution in ethanol / water after crystallization from methylene chloride / di-isopropyl ether 1.18 g (80% of theory) of the title compound as a colorless powder of mp 148 -149 C.
- the compounds of the formula I according to the invention and their salts have valuable pharmacological properties which make them commercially usable. They clearly inhibit gastric acid secretion from warm-blooded animals and, moreover, have an excellent gastric and intestinal protective effect in warm-blooded animals. This gastric and intestinal protective effect is sometimes already observed when doses are administered which are below the acid secretion-inhibiting doses.
- the compounds according to the invention are distinguished by the absence of significant side effects and a large therapeutic breadth.
- Another aspect essential to the invention is that the compounds of the formula I have high chemical stability and a significant maximum activity in the pH range desired in each case.
- “Stomach and intestinal protection” in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastrititis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins , Drugs (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), stomach acid or stressful situations can be caused.
- gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastrititis, hyperacid or drug-induced irritable stomach
- Drugs eg certain anti-inflammatory drugs and anti-rheumatic drugs
- chemicals eg ethanol
- stomach acid or stressful situations can be caused.
- the compounds according to the invention surprisingly prove to be significantly superior to the compounds known from the prior art.
- the compounds according to the invention and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, in particular for the treatment and prophylaxis of diseases of the stomach and intestine and those diseases which are exaggerated Gastric acid secretion are based, be used ver.
- the high storage stability of the compounds according to the invention enables their problem-free use in pharmaceutical preparations.
- the invention further relates to the compounds according to the invention for use in the treatment and prophylaxis of the abovementioned diseases.
- the invention also includes the use of the compounds according to the invention in the manufacture of medicinal products which are used for the treatment and prophylaxis of the abovementioned diseases.
- the invention further relates to medicaments which contain one or more compounds of the formula I according to the invention and / or their pharmacologically tolerable salts.
- the medicaments are produced according to known processes known to the person skilled in the art.
- auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
- solvents for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or in particular performance promoters and complexing agents (e.g. cyclodextrins) can be used.
- the active ingredients can be administered orally, parenterally or percutaneously.
- the active ingredient (s) when administered orally in a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg of body weight ⁇ if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
- a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg of body weight ⁇ if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
- parenteral treatment similar or (in particular in the case of intravenous administration of the active substances) generally lower doses can be used. Any person skilled in the art can easily determine the optimum dosage and mode of application of the active ingredients required on the basis of his or her specialist knowledge.
- the pharmaceutically preparations also include one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics such as Bietamiverin, Camylofin; Anticholi ergica, such as, for example, Oxyphencycli in, phencarbamide; Local anesthetics, such as tetracaine, procaine; Antibiotics such as penicillins, tetracyeline, etc .; optionally also contain ferments, vitamins or amino acids.
- antacids for example aluminum hydroxide, magnesium aluminate
- Tranquilizers such as benzodiazepines, for example diazepam
- Antispasmodics such as Bietamiverin, Camylofin
- Anticholi ergica such as, for example, Oxyphencycl
- H 2 blockers for example cimetidine, ranitidine
- peripheral anticholinergics for example pirenzepin, telenzepin, zolenzepin
- gastrin antagonists with the aim of increasing the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further with antibacterially active substances (such as cephalosporins, tetracyclines, nalidixic acid, penicillins etc .) to combat Ca pylobacter pyloridis.
- the excellent stomach protection effect and the gastric secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on models of animal experiments.
- the compounds according to the invention investigated in the models listed below have been given numbers which correspond to the example numbers.
- Table 1 below shows the influence of the compounds according to the invention after oral (p. O.) Administration on lesion formation and acid excretion in the modified Shay rat.
- ED50 dose (interpolated) that reduces the lesion index or the HCl secretion of the rat stomach in the treated group compared to the control group by 50%.
- the ulcer provocation is carried out on 24 hours fasting rats (female, 180-200 g, 4 animals per cage on a high grating) by pyloric acid (under diethyl ether anesthesia) and oral application of 100 mg / lOml / kg acetylsalicylic acid.
- the substances to be tested are administered orally (10 ml / kg) one hour before the pylorus ligature.
- the wound is closed using Miehe! lammer made. 4 hours later, the animals were killed in etheric intoxication by atlas displacement and gastric resection.
- the stomach is opened along the large curvature and stretched out on a cork plate after the amount of the secreted gastric juice (volume) and later its HCl content (titration with sodium hydroxide solution) is determined.
- the product of the severity (according to the following scale of points) and the number of ulcers serves as an individual lesion index.
- the ED50 is the dose that reduces the mean lesion index or HCl secretion by 50% compared to the control.
- Table 2 shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.
- ED50 Dosi s (interpolated), which causes a maximum inhibition of the HCl secretion IO ⁇ u 50%.
- anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened by a median upper abdominal incision and a PVC catheter transorally in the esophagus and another via The pylorus was fixed in such a way that the ends of the tube were just protruding into the gastric lumen.
- the catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall.
- the stomach was continuously flowed through with 37 C warm physiological NaCl solution (0.5 ml / min, pH 6.8-6.9; Braun-Unita I).
- p 7 Dosimat 655 Metrohm
- the maximum decrease in acid excretion (15 min fractions) of each treated group compared to that of the untreated control group ( 100%) served as a measure of the secretion-inhibiting effect.
- the ED50 denotes the dose that causes a maximum inhibition of HCl secretion by 50%.
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Abstract
Des composés fluorés d'alkoxyde ayant la formule (I), dans laquelle les substituants et les symboles ont la signification donnée dans la description, sont de nouveaux composés qui présentent des propriétés anti-ulcérogènes.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CH197788 | 1988-05-25 | ||
CH1977/88-5 | 1988-05-25 |
Publications (1)
Publication Number | Publication Date |
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WO1989011479A1 true WO1989011479A1 (fr) | 1989-11-30 |
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ID=4223038
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP1989/000567 WO1989011479A1 (fr) | 1988-05-25 | 1989-05-23 | Nouveaux composes fluores d'alkoxyde |
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Country | Link |
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EP (1) | EP0415990A1 (fr) |
JP (1) | JPH03504497A (fr) |
AU (1) | AU3690289A (fr) |
WO (1) | WO1989011479A1 (fr) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT394368B (de) * | 1990-08-07 | 1992-03-25 | Byk Gulden Lomberg Chem Fab | Verfahren zur herstellung von 3,4-dialkoxypyridinen |
WO1992004898A1 (fr) * | 1990-09-14 | 1992-04-02 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Utilisation de derives de pyridylmethylsulfinyl-1h-benzimidazol pour le traitement de maladies provoquees par helicobacter |
EP0481764A1 (fr) * | 1990-10-17 | 1992-04-22 | Takeda Chemical Industries, Ltd. | Dérivés de pyridine, leur préparation et utilisation |
AP215A (en) * | 1990-06-20 | 1992-09-02 | Ab Astra | Substituted benzimidazoles, process for their preparation and their pharmaceutical use. |
AP253A (en) * | 1990-06-20 | 1993-05-03 | Ab Astra | Dialkoxy-pyridinyl-benzimidazole derivatives process for their preparation and thei phamaceutical use. |
EP0893445A1 (fr) * | 1997-07-24 | 1999-01-27 | Bayer Ag | Procédé pour la préparation des dérivés de 2-chlorobenzimidazole |
US6051570A (en) * | 1997-05-30 | 2000-04-18 | Dr. Reddy's Research Foundation | Benzimidazole derivatives as antiulcer agents, process for their preparation and pharmaceutical compositions containing them |
JP3163382B2 (ja) | 1990-10-17 | 2001-05-08 | 武田薬品工業株式会社 | ピリジン誘導体およびその製造法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0127763A1 (fr) * | 1983-05-03 | 1984-12-12 | Byk Gulden Lomberg Chemische Fabrik GmbH | Ethers tricycliques, procédé pour leur préparation, leur utilisation et médicaments les contenant |
EP0134400A2 (fr) * | 1983-05-03 | 1985-03-20 | Byk Gulden Lomberg Chemische Fabrik GmbH | Pyridylméthylthio-(ou sulfinyl-)benzimidazoles substitués par fluoroalkoxy à activité sécrétolytique |
EP0174726A1 (fr) * | 1984-08-16 | 1986-03-19 | Takeda Chemical Industries, Ltd. | Dérivés de pyridine et leur préparation |
WO1986002646A1 (fr) * | 1984-10-31 | 1986-05-09 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft M | Nouveaux derives de picoline, leur procede de preparation, leur utilisation et medicaments les contenant |
EP0237200A2 (fr) * | 1986-02-13 | 1987-09-16 | Takeda Chemical Industries, Ltd. | Utilisation de sels basiques mineraux de magnesium ou calcium pour la stabilisation de derives du benzimidazole |
EP0298440A1 (fr) * | 1987-07-10 | 1989-01-11 | Hoechst Aktiengesellschaft | Benzimidazoles substitués, procédé pour leur préparation, compositions pharmaceutiques les contenant et leur application |
-
1989
- 1989-05-23 AU AU36902/89A patent/AU3690289A/en not_active Abandoned
- 1989-05-23 JP JP1505495A patent/JPH03504497A/ja active Pending
- 1989-05-23 EP EP89906099A patent/EP0415990A1/fr not_active Withdrawn
- 1989-05-23 WO PCT/EP1989/000567 patent/WO1989011479A1/fr not_active Application Discontinuation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0127763A1 (fr) * | 1983-05-03 | 1984-12-12 | Byk Gulden Lomberg Chemische Fabrik GmbH | Ethers tricycliques, procédé pour leur préparation, leur utilisation et médicaments les contenant |
EP0134400A2 (fr) * | 1983-05-03 | 1985-03-20 | Byk Gulden Lomberg Chemische Fabrik GmbH | Pyridylméthylthio-(ou sulfinyl-)benzimidazoles substitués par fluoroalkoxy à activité sécrétolytique |
EP0174726A1 (fr) * | 1984-08-16 | 1986-03-19 | Takeda Chemical Industries, Ltd. | Dérivés de pyridine et leur préparation |
WO1986002646A1 (fr) * | 1984-10-31 | 1986-05-09 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft M | Nouveaux derives de picoline, leur procede de preparation, leur utilisation et medicaments les contenant |
EP0237200A2 (fr) * | 1986-02-13 | 1987-09-16 | Takeda Chemical Industries, Ltd. | Utilisation de sels basiques mineraux de magnesium ou calcium pour la stabilisation de derives du benzimidazole |
EP0298440A1 (fr) * | 1987-07-10 | 1989-01-11 | Hoechst Aktiengesellschaft | Benzimidazoles substitués, procédé pour leur préparation, compositions pharmaceutiques les contenant et leur application |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AP215A (en) * | 1990-06-20 | 1992-09-02 | Ab Astra | Substituted benzimidazoles, process for their preparation and their pharmaceutical use. |
AP253A (en) * | 1990-06-20 | 1993-05-03 | Ab Astra | Dialkoxy-pyridinyl-benzimidazole derivatives process for their preparation and thei phamaceutical use. |
AT394368B (de) * | 1990-08-07 | 1992-03-25 | Byk Gulden Lomberg Chem Fab | Verfahren zur herstellung von 3,4-dialkoxypyridinen |
WO1992004898A1 (fr) * | 1990-09-14 | 1992-04-02 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Utilisation de derives de pyridylmethylsulfinyl-1h-benzimidazol pour le traitement de maladies provoquees par helicobacter |
EP0481764A1 (fr) * | 1990-10-17 | 1992-04-22 | Takeda Chemical Industries, Ltd. | Dérivés de pyridine, leur préparation et utilisation |
US5312824A (en) * | 1990-10-17 | 1994-05-17 | Takeda Chemical Industries, Ltd. | Certain 2-[(4-difluoromethoxy-2-pyridyl)-methylthio or methylsulfinyl-5-benzimidazoles useful for treating peptic ulcers |
JP3163382B2 (ja) | 1990-10-17 | 2001-05-08 | 武田薬品工業株式会社 | ピリジン誘導体およびその製造法 |
US6051570A (en) * | 1997-05-30 | 2000-04-18 | Dr. Reddy's Research Foundation | Benzimidazole derivatives as antiulcer agents, process for their preparation and pharmaceutical compositions containing them |
US6028200A (en) * | 1997-07-22 | 2000-02-22 | Bayer Aktiengesellschaft | Process for preparing 2-chloro-benzimidazole derivatives |
US6054589A (en) * | 1997-07-22 | 2000-04-25 | Bayer Aktiengesellschaft | Process for preparing 2-chloro-benzimidazole derivatives |
EP0893445A1 (fr) * | 1997-07-24 | 1999-01-27 | Bayer Ag | Procédé pour la préparation des dérivés de 2-chlorobenzimidazole |
Also Published As
Publication number | Publication date |
---|---|
AU3690289A (en) | 1989-12-12 |
JPH03504497A (ja) | 1991-10-03 |
EP0415990A1 (fr) | 1991-03-13 |
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