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WO1998008844A1 - Nouveaux derives de thiazol s'utilisant comme inhibiteurs selectifs de la pde-iv - Google Patents

Nouveaux derives de thiazol s'utilisant comme inhibiteurs selectifs de la pde-iv Download PDF

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Publication number
WO1998008844A1
WO1998008844A1 PCT/EP1997/004397 EP9704397W WO9808844A1 WO 1998008844 A1 WO1998008844 A1 WO 1998008844A1 EP 9704397 W EP9704397 W EP 9704397W WO 9808844 A1 WO9808844 A1 WO 9808844A1
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Prior art keywords
alkoxy
hydroxy
mono
hydrogen
alkyl
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PCT/EP1997/004397
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German (de)
English (en)
Inventor
Thomas Bär
Wolf-Rüdiger Ulrich
Hermann Amschler
Thomas Martin
Dieter Flockerzi
Beate Gutterer
Ulrich Thibaut
Armin Hatzelmann
Hildegard Boss
Dietrich Häfner
Hans-Peter Kley
Rolf Beume
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Byk Gulden Lomberg Chemische Fabrik Gmbh
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Priority to AU42989/97A priority Critical patent/AU4298997A/en
Publication of WO1998008844A1 publication Critical patent/WO1998008844A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms

Definitions

  • the invention relates to new thiazole derivatives which are used in the pharmaceutical industry for the manufacture of medicaments.
  • Japanese patent JP 46-15935 describes substituted 4- (carboxyphenyl) thiazoles and their use for the treatment of thrombosis, arteriosclerosis, gastric ulcers and hypersecretion.
  • European patent applications EP 0 513 387 and EP 0 600 092 describe, inter alia, 4- (substituted phenyl) thiazole derivatives and their use as inhibitors of oxygen radical release by neutrophils. The compounds are therefore described as being suitable for the treatment of acute inflammatory processes such as ischemia and reperfusion damage.
  • the invention thus relates to compounds of the formula I (see attached formula sheet), in which
  • R1 is hydroxy, 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy
  • R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, phenyl-1-4C-alkoxy, 2-indanyloxy, 2-tetrahydronaphthalinyloxy or 2-norbornanyloxy,
  • R3 represents hydrogen or halogen
  • R4 represents a phenyl or naphthyl ring substituted by R41, R42 and R43, represents a mono- or bicyclic heterocycle substituted by R44, R45 and R46, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, Pyrimidine, pyrazine, pyridazine, quinoxaline, quinazoline, cinnoline, benzimidazole, thiophene and furan or a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyrazole, imidazole, purine, oxazole, isoxazole, thiazole and isothiazole, where
  • R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,
  • R42 is hydrogen, wholly or predominantly fluorine-substituted 1-4C-alkoxy, hydroxy, amino, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-alkyl or 1 -4C-alkoxy,
  • R43 is hydrogen, 1-4C-alkoxy, halogen or hydroxy
  • R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,
  • R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkoxy and
  • R46 is hydrogen, halogen, 1-4C-alkoxy or 1-4C-alkyl, n is 0, 1 or 2, where n is not 1 or 2, if R4 is phenyl, the salts of these compounds and the N-oxides of pyridines , Quinolines, isoquinolines, pyrimidines,
  • 1-4C-alkoxy represents a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • alkyl radicals having 1 to 4 carbon atoms are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 3-5C-Cycloalkoxy stands for example for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
  • 3-7C-Cycloalkoxy stands for example for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 3-7C-Cycloalkylmethoxy stands for example for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
  • Phenyl-1-4C-alkoxy stands for one of the above-mentioned 1-4C-alkoxy radicals which is substituted by the phenyl radical.
  • the benzyloxy and phenethoxy radicals may be mentioned as examples.
  • Halogen in the sense of the invention is fluorine, chlorine, bromine and iodine.
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • Examples of mono- or di-1-4C-alkylamino radicals are the methylamino, the dimethylamino, the ethylamino, the diethylamino, the propylamino and the isopropylamino radical.
  • Mono- or di-1-4C-alkylaminocarbonyl stands for a carbonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino radicals is attached.
  • the methylaminocarbonyl, the dimethylaminocarbonyl and the ethylaminocarbonyl radical may be mentioned as examples.
  • Mono- or di-1-4C-alkylaminosulfonyl stands for a sulfonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino residues is bonded.
  • Examples include the methylaminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl radicals.
  • the 1-4C-alkylcarbonylamino radical may be mentioned, for example, the acetylamino radical (-NH-CO-CH 3 ).
  • 1-4C-alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. Examples include the methoxycarbonyl (CH 3 O-CO-) and ethoxycarbonyl (CH 3 CH 2 0-CO-) radicals.
  • 1-4C-alkylcarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkyl radicals is attached.
  • the acetyl radical (CH 3 CO-) may be mentioned.
  • 1-4C-alkylcarbonyloxy radicals contain a 1-4C-alkylcarbonyl radical.
  • the acetoxy residue (CH 3 CO-O-) may be mentioned.
  • Hydroxy-1-4C-alkyl stands for the aforementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group.
  • the hydroxyethyl and hydroxymethyl radicals may be mentioned.
  • 1-4C-Alkylsulfonyl stands for a sulfonyl group to which one of the above-mentioned 1-4C-alkyl radicals is attached.
  • the methylsulfonyl radical (CH 3 S0 2 -) may be mentioned.
  • 1-4C-alkoxysulfonyl stands for a sulfonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. Examples include the methoxysulfonyl (CH 3 0-S0 2 -) and ethoxysulfonyl (CH 3 CH 2 0-S0 2 -) groups.
  • the substituent R4 can be attached to the rest of the compounds of the formula I via any suitable ring position of the phenyl or naphthyl ring or of the heterocycle, the attachment of the heterocycles not taking place via a ring heteroatom.
  • R4 are phenyl, 3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3- Methoxy-4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-ethoxycarbonylphenyl, 3,4-diethoxyphenyl, 3,4-dimethylphenyl, 4-fluorophenyl, 3-chloro-4- methylphenyl, 3-nitrophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 3,4-dibutoxyphenyl, 3,4-dipropoxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-bromo-4,5-dimethoxyphenyl, 3, 4-diacetoxyphenyl, 4-dimethylamin
  • Suitable salts for compounds of the formula I - depending on the substitution - are all acid addition salts or all salts with bases. Particularly noteworthy are the pharmacologically acceptable ones Salts of the inorganic and organic acids and bases commonly used in galenics. Suitable as such are on the one hand water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid , Lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether
  • salts with bases can also be used.
  • examples of salts with bases which may be mentioned are alkali (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meluminum or guanidinium salts, the salt production also being used here Bases are used in the equimolar or a different ratio.
  • Pharmacologically incompatible salts which may initially be obtained as process products in the preparation 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.
  • R1 is hydroxy, 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
  • R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, phenyl-1-4C-alkoxy or 2-indanyloxy,
  • R3 represents hydrogen or halogen
  • R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, pyrimidine, pyrazine, pyridazine, py - razole, imidazole, quinoxaiine, quinazoline, cinnoline, benzimidazole, oxazole, isoxazole, thiazole and isothiazole, where
  • R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,
  • R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy,
  • R44 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or Di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy,
  • 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and R45 are hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 means when R4 is phenyl, the salts of these compounds and the N-oxides of pyridines, quinolines, isoquinolines, pyrimidines, imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.
  • R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
  • R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 2-indanyloxy,
  • R3 means hydrogen
  • R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine and pyrazine, where
  • R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylami ⁇ o, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,
  • R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy,
  • R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and
  • R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 if R4 is phenyl, the salts of these compounds and the N-oxides of pyridines, quinolines and isoquinolines and their
  • Preferred compounds of formula I are those in which
  • R1 is 1-4C-alkoxy or completely or predominantly substituted by fluorine-1-4C-alkoxy
  • R2 is 3-5C-cycloalkoxy or 2-indanyloxy
  • R3 means hydrogen
  • R4 represents a phenyl ring substituted by R41 and R42 or represents pyridine or pyrazine substituted by R44 and R45, where
  • R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,
  • R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy,
  • R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and
  • R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 if R4 is phenyl, the salts of these compounds and the N-oxides of pyridines and their salts.
  • R1 is 1-4C-alkoxy
  • R2 means cyclopentyloxy or 2-indanyloxy
  • R3 means hydrogen
  • R4 represents a phenyl ring substituted by R41 or represents pyridine or pyrazine substituted by R44, where
  • R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl or hydroxy and
  • R44 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl or hydroxy, n is 0 or 1, where n is not 1 if R4 is phenyl, and the salts of these compounds.
  • R1 means methoxy
  • R2 means cyclopentyloxy or 2-indanyloxy
  • R3 means hydrogen
  • R4 represents pyridine or pyrazine substituted by R44, where
  • R44 denotes hydrogen or 1-4C-alkoxycarbonyl
  • n denotes 0 or 1
  • the salts of these compounds
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the process is characterized in that compounds of the formula II (see attached formula sheet) in which R1, R2 and R3 have the meanings indicated above and Y represents a suitable leaving group with compounds of the formula III (see attached formula sheet) in which R4 and n has the meanings given above and Z represents the group -C (S) -NH 2 , and that, if desired, subsequently obtained compounds of the formula I in their salts or, if desired, subsequently obtained salts of the compounds of the formula I in the transferred free connections.
  • Suitable solvents are, for example, alcohols such as methanol, ethanol or propanol, cyclic hydrocarbons such as toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dioxane, halogenated hydrocarbons such as dichloromethane or chloroform, polar solvents such as dimethylformamide, acetonitrile or dimethyl sulfoxide or, if desired, mixtures of the solvents mentioned.
  • Preferred bases that are used are nitrogen bases such as triethylamine, ethyldiisopropylamine, N-methylmorpholine or pyridine. The bases can be added in an equimolar ratio (based on compounds of the formula II) or preferably in excess.
  • compounds of the formula I obtained can also be converted into other compounds of the formula I by using methods known to those skilled in the art.
  • the preparation of carboxamides of the formula I from the corresponding carboxylic acids of the formula I may be mentioned as an example.
  • the carboxylic acids of the formula I can be reacted with suitable amines in a manner known to those skilled in the art for the synthesis of carboxamides.
  • the carboxylic acid of the formula I is converted into a suitably activated derivative, for example a corresponding acid halide, before the aminolysis.
  • suitable amines which can be used are ammonia, methylamine or ethylamine.
  • carboxylic acids of the formula I from corresponding esters of the formula I may also be mentioned, for example by saponification in a manner known to the person skilled in the art.
  • quinolines, isoquinolines, pyrimidines, pyrazines, imidazoles, quinoxalines, quinazolines, benzimidazoles and in particular pyridines of the formula I obtained can also be converted into the corresponding N-oxides or their salts.
  • the N-oxidation takes place in a manner also familiar to the person skilled in the art, e.g. with the help of m-chloroperoxibenzoic acid in dichloromethane at room temperature.
  • the person skilled in the art is familiar with the reaction conditions which are required for carrying out the process in detail on the basis of his specialist knowledge.
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
  • Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is subsequently added.
  • a suitable solvent e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is subsequently added.
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
  • Salts obtained can be converted into the free compounds by alkalization or acidification, which in turn can be converted into salts. In this way, pharmacologically incompatible salts can be converted into pharmacologically
  • the compounds of the formula II in which R1, R2 and R3 have the meanings given above and Y is in particular chlorine or bromine are either known or can be obtained in a known manner, for example by chlorination or bromination of corresponding compounds of the formula II, in which Y is hydrogen.
  • compounds of the formula II in which R1 and R2 have the meanings given above, R3 is hydrogen and Y is in particular chlorine or bromine also by reacting compounds of the formula Ha (see attached formula sheet) in which R1 and R2 have the abovementioned Have meanings and A is a suitable leaving group, in particular chlorine or bromine, can be obtained with diazomethane and subsequent treatment with HCl or HBr.
  • the reactions are otherwise carried out, for example, as described in the examples below, or in a manner familiar to the person skilled in the art.
  • radicals R1 and / or R2 in compounds of the formula V are not stable under the acylation conditions, compounds of the formula V in which R1 and / or R2 represents a base-unprotected hydroxyl group can, if desired, be used as starting products.
  • the protective groups are removed and, if desired, from the compounds of the formula II, in which R1 and / or R2 is hydroxy, in a manner known to the person skilled in the art, the desired compounds in the formula II, in which R1 and R2 are the abovementioned Have meanings.
  • the person skilled in the art knows which protective groups are suitable.
  • the chloroacetyl protective group may be mentioned, for example, as a suitable base-labile hydroxy protective group.
  • the protective groups are attached or removed according to suitable, known standard methods (for example as described by T.W. Green in “Protective Groups in Organic Synthesis", John Wiley and Sons, 1981).
  • the compounds of formula V in which R1 and R2 have the meanings given above can also be obtained in a known manner from pyrocatechol.
  • the compounds of the formula III, in which R4 and n have the meanings given above and Z represents the group —C (S) —NH 2 are either known (for example from EP 0 513 387 or EP 0 600 092) or can be analogous or other ways known to the person skilled in the art, for example by adding hydrogen sulfide to corresponding compounds of the formula III in which Z is cyano (-CN) [W. Christ, D. Rakow, S. Strauss, J. Heterocycl. Chem. 11, 397 (1974)].
  • mp stands for melting point, h for hour (s), RT for room temperature, min for minute (s), Toi. for toluene, EA for ethyl acetate, PE for petroleum ether, DMF for dimethylformamide, CCI 4 for carbon tetrachloride and THF for tetrahydrofuran.
  • EA ethyl acetate
  • PE petroleum ether
  • DMF dimethylformamide
  • CCI 4 for carbon tetrachloride
  • THF tetrahydrofuran
  • the cleaning is carried out by boiling the residue in 2.0 l of petroleum ether with the addition of 20 g of Tonsil (Südchemie AG Kunststoff). After filtration, 199 g (85%) of the title compound, mp. 59-60 ° C., crystallize.
  • the compounds according to the invention have valuable pharmacological properties which make them commercially usable.
  • PDE selective cyclic nucleotide phosphodiesterase
  • they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions due to their dilating but also due to their respiratory rate or respiratory drive increasing effect) and for the eradication of erectile dysfunction due to the vasodilating effect, on the other hand, however, primarily for the treatment of diseases, in particular inflammatory in nature, for example the respiratory tract (asthma prophylaxis), the skin, the intestine, the eyes and the joints, which are mediated by mediators such as histamine, PAF (platelet activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines , alpha, beta and gamma interferon, tumor necrosis factor (TNF) or oxygen radicals and protea
  • mediators such
  • the compounds according to the invention can be used as therapeutic agents in human and veterinary medicine, for example they can be used for the treatment and prophylaxis of the following diseases: Acute and chronic (in particular inflammatory and allergen-induced) respiratory diseases of various origins (bronchitis, allergic Bronchitis, bronchial asthma); Dermatoses (especially proliferative, inflammatory and allergic) such as psoriasis (vulgaris), toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, lying simplex, sunburn, pruritus in the genital area, alopecia areata, hypertrophic scars, discoid lupus follicular and extensive pyoderma, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin diseases; Diseases that are based on an excessive release of TNF and leukotrienes, such as diseases from bronchitis, allergic Bronchitis
  • Another object of the invention is a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases.
  • the method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.
  • the invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the diseases mentioned.
  • the invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned.
  • the invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention.
  • the pharmaceuticals are produced by methods known per se and familiar 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, preservatives, solubilizers or permeation promoters can be used.
  • the compounds according to the invention are preferably also administered by inhalation.
  • these are administered either directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions containing them.
  • atomizing solutions or suspensions containing them are administered either directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions containing them.
  • the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
  • the pharmaceuticals according to the invention are produced by methods known per se.
  • the active ingredients are dosed in the order of magnitude customary for PDE inhibitors.
  • topical forms of application such as ointments
  • the dose for inhalation is usually between 0.01 and 1 mg per spray.
  • the usual dose for systemic therapy po or iv is between 0.1 and 200 mg per application.
  • Activation of inflammatory cells is of particular importance when studying PDE IV inhibition at the cellular level.
  • An example is the FMLP (N-formyl-methionyl-leucyl-phenylalanine) -induced superoxide production of neutrophil granulocytes, which can be measured as luminol-enhanced chemiluminescence.
  • Mc Phail LC, Strum SL, Leone PA and Sozzani S The neutrophil respiratory burst mechanism.
  • Coffey RG Marcel Decker, Inc., New York-Basel-Hong Kong
  • Substances which inhibit chemiluminescence and the cytokine secretion and the secretion of inflammation-increasing mediators on inflammatory cells are those which inhibit PDE IV.
  • This isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation.
  • the PDE IV inhibition by the substances according to the invention is thus a central indicator for the suppression of inflammatory processes.
  • the activity test was carried out according to the Bauer and Schwabe method, which was adapted to microtiter plates (Naunyn-Schmiedeberg's Arch. Pharmacol. 311, 193-198, 1980).
  • the PDE reaction takes place in the first step.
  • the resulting 5'-nucleotide is cleaved by a 5'-nucleotidase of the snake venom from ophiophagus hannah (King Cobra) to the uncharged nucleoside.
  • the nucleoside is separated from the remaining charged substrate on ion exchange columns. The columns are eluted with 2 ml of 30 mM ammonium formate (pH 6.0) directly in minivials, into which 2 ml of scintillator liquid is added for counting.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de la formule (I) dans laquelle R1, R2, R3, R4 et n ont la signification mentionnée dans la description. Ces composés sont de nouveaux agents thérapeutiques bronchiques actifs.
PCT/EP1997/004397 1996-08-26 1997-08-13 Nouveaux derives de thiazol s'utilisant comme inhibiteurs selectifs de la pde-iv WO1998008844A1 (fr)

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Application Number Priority Date Filing Date Title
AU42989/97A AU4298997A (en) 1996-08-26 1997-08-13 Thiazole derivatives useful as selective inhibitors of pde-iv

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DE19634409 1996-08-26
DE19634409.3 1996-08-26
EP96113738.7 1996-08-28
EP96113738 1996-08-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1348701A1 (fr) * 2002-03-28 2003-10-01 Warner-Lambert Company LLC Thiazol-5-yl-amines 2,4-disubstituées comme inhibiteurs de la PDE7
EP1348706A4 (fr) * 2000-12-08 2005-08-10 Takeda Pharmaceutical Derives thiazole substitues porteurs de groupes 3-pyridyl, procede d'elaboration et leur utilisation
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1248070A (en) * 1968-12-16 1971-09-29 Science Union & Cie Thiazolyl-benzoic acid derivatives and process for preparing them
EP0097323A2 (fr) * 1982-06-22 1984-01-04 Schering Corporation Dérivés de 2-(4-pyridyl)-thiazole
EP0411718A2 (fr) * 1989-08-04 1991-02-06 Shell Internationale Researchmaatschappij B.V. Dérivés de thiazole, leur préparation et leur utilisation comme fongicides
EP0513387A1 (fr) * 1990-11-30 1992-11-19 Otsuka Pharmaceutical Co., Ltd. Inhibiteur d'oxygene actif
EP0600092A1 (fr) * 1992-05-29 1994-06-08 Otsuka Pharmaceutical Co., Ltd. Derive de thiazole
WO1994012461A1 (fr) * 1992-12-02 1994-06-09 Pfizer Inc. Diethers de pyrocatechine utilises comme inhibiteurs selectifs de la pde¿iv?
JPH07215952A (ja) * 1993-12-06 1995-08-15 Otsuka Pharmaceut Factory Inc カテコール誘導体

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1248070A (en) * 1968-12-16 1971-09-29 Science Union & Cie Thiazolyl-benzoic acid derivatives and process for preparing them
EP0097323A2 (fr) * 1982-06-22 1984-01-04 Schering Corporation Dérivés de 2-(4-pyridyl)-thiazole
EP0411718A2 (fr) * 1989-08-04 1991-02-06 Shell Internationale Researchmaatschappij B.V. Dérivés de thiazole, leur préparation et leur utilisation comme fongicides
EP0513387A1 (fr) * 1990-11-30 1992-11-19 Otsuka Pharmaceutical Co., Ltd. Inhibiteur d'oxygene actif
EP0600092A1 (fr) * 1992-05-29 1994-06-08 Otsuka Pharmaceutical Co., Ltd. Derive de thiazole
WO1994012461A1 (fr) * 1992-12-02 1994-06-09 Pfizer Inc. Diethers de pyrocatechine utilises comme inhibiteurs selectifs de la pde¿iv?
JPH07215952A (ja) * 1993-12-06 1995-08-15 Otsuka Pharmaceut Factory Inc カテコール誘導体

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
EP1348706A4 (fr) * 2000-12-08 2005-08-10 Takeda Pharmaceutical Derives thiazole substitues porteurs de groupes 3-pyridyl, procede d'elaboration et leur utilisation
US7067537B2 (en) 2000-12-08 2006-06-27 Takeda Pharmaceutical Company Limited Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof
EP1348701A1 (fr) * 2002-03-28 2003-10-01 Warner-Lambert Company LLC Thiazol-5-yl-amines 2,4-disubstituées comme inhibiteurs de la PDE7
WO2003082839A1 (fr) * 2002-03-28 2003-10-09 Warner-Lambert Company Llc Composes (4,2-disubstitue-thiazol-5-yle)amine convenant comme inhibiteurs pde7
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility

Also Published As

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