WO1983002613A1 - Composes oxazoiques a triple substitution - Google Patents

Composes oxazoiques a triple substitution Download PDF

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Publication number
WO1983002613A1
WO1983002613A1 PCT/CH1982/000009 CH8200009W WO8302613A1 WO 1983002613 A1 WO1983002613 A1 WO 1983002613A1 CH 8200009 W CH8200009 W CH 8200009W WO 8302613 A1 WO8302613 A1 WO 8302613A1
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Prior art keywords
phenyl
pyridyl
lower alkoxy
formula
substituted
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PCT/CH1982/000009
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German (de)
English (en)
Inventor
Ag Ciba-Ceigy
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Sallmann, Alfred
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Application filed by Sallmann, Alfred filed Critical Sallmann, Alfred
Priority to HU42982A priority Critical patent/HU188308B/hu
Priority to GB08324693A priority patent/GB2123831B/en
Priority to JP82500317A priority patent/JPS59500054A/ja
Priority to AU80022/82A priority patent/AU8002282A/en
Publication of WO1983002613A1 publication Critical patent/WO1983002613A1/fr
Priority to FI833280A priority patent/FI833280A0/fi
Priority to NO833350A priority patent/NO833350L/no
Priority to DK423683A priority patent/DK423683A/da

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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to new trisubstituted oxaza compounds, in particular compounds of the general formula
  • R 1 and R 2 represents heteroaryl and the other carbocyclic aryl or heteroaryl and A represents a divalent hydrocarbon radical and R 3 represents carboxy, esterified or amidated carboxy, their isomers and their salts, processes for their preparation, compounds containing them pharmaceutical preparations and the use of compounds of formula (I), their isomers and their salts as active pharmaceutical ingredients and / or for the production of pharmaceutical preparations.
  • Carbocyclic aryl is, for example, monocyclic carbocyclic aryl, such as optionally substituted phenyl.
  • Heteroaryl is, for example, monocyclic, preferably 5- or 6-membered heteroaryl, where at least one ring member represents a heteroatom, such as a nitrogen, oxygen or sulfur atom, it being possible for a nitrogen atom to also be present in oxidized form.
  • a heteroatom such as a nitrogen, oxygen or sulfur atom
  • Such 5-membered residues are e.g. Pyrrolyl, such as 2-pyrrolyl.
  • 6-membered heteroaryl examples include pyridyl, such as 2-, 3- or 4-pyridyl, 1-oxidopyridyl, such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, and pyrimidyl, such as 2-pyrimidyl Question.
  • suitable substituents for carbocyclic aryl, such as phenyl, or heteroaryl, such as pyridyl or 1-oxidopyridyl are halogen, lower alkyl, hydr ⁇ xy, lower alkoxy and / or acyloxy.
  • Acyloxy is derived, for example, from an organic carboxylic acid and means, for example, lower alkanoyloxy.
  • a hydrocarbon residue A is, for example, a divalent aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residue.
  • divalent aliphatic hydrocarbon radicals are lower alkylene, lower alkylidene, lower alkenyl or lower alkenylidene.
  • Divalent cycloaliphatic hydrocarbons are, for example, monocyclic 3- to 8-membered cycloalkylenes or cycloalkylidenes.
  • Cycloaliphatic-aliphatic hydrocarbon radicals are, for example, those which have a monocyclic 3- to 8-membered cycloaliphatic radical as the cycloaliphatic radical and lower alkylidene as the aliphatic radical, such as cycloalkyl-lower alkylidene.
  • Esterified carboxy is, for example, carboxy esterified with an optionally substituted aliphatic, cycloaliphatic or aromatic alcohol.
  • An aliphatic alcohol is, for example, a lower alkanol, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec- or tert-butanol, while the cycloaliphatic alcohol is, for example, a 3- to 8-membered cycloalkanol, such as cyclopentanol, hexanol or heptanol.
  • substituents such as lower alkanols or cycloalkanols, for example, hydroxy, mercapto, optionally substituted phenyl, lower alkoxy, optionally substituted in the phenyl phenyl-lower alkoxy, lower alkylthio, optionally substituted in the phenyl phenyl-lower alkylthio, Hydroxyniederalkoxy, Niederalkoxyniederalkoxy, optionally substituted in the phenyl moiety Phenylniederalkoxyniederalkoxy, hydroxy-hydroxyniederalkoxyniederalkoxy, Niederalkoxyniederalkoxynied ⁇ ralkoxy optionally come in the phenyl part substituted phenyl-lower alkoxy-lower alkoxy-lower alkoxy.
  • An aromatic alcohol is, for example, a phenol or heterocyclic alcohol, each of which can optionally be substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, in particular hydroxy pyridine, for example 2-, 3- or 4-hydroxypyridine.
  • Amidated carboxy is, for example, carbamoyl, monosubstituted by hydroxy, amino, or optionally substituted phenyl, mono- or disubstituted by lower alkyl or by 4- to 7-membered alkylene or 3-aza, 3-lower alkylza, 3-oxo or 3 -Thiaalkylene disubstituted carbamoyl.
  • Examples are carbamoyl, N-mono- or N, N-di-lower alkylcarbamoyl, such as N-methyl-, N-ethyl-, N, N-dimethyl-, N, N-diethyl- or N, N-dipropylcarbamoyl, pyrrolidino- or Piperidino-carbonyl, morpholino-, piperazino- or 4-methylpiperazino- and thiomorpholinocarbonyl, anilinocarbonyl or anilinocarbonyl substituted by lower alkyl, lower alkoxy and / or halogen.
  • lower organic radicals and compounds are preferably to be understood as meaning those which contain up to and with 7, especially up to and with 4 carbon atoms (carbon atoms).
  • Halogen is e.g. Halogen up to and with atom number 35, such as fluorine, chlorine or bromine, also iodine.
  • Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and also a pentyl, hexyl or heptyl radical.
  • Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.
  • Lower alkylthio is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butylthi ⁇ .
  • Phenyl lower alkoxy is e.g. Phenylmethoxy, phenylethoxy or phenylpropyloxy.
  • Phenyl lower alkylthio is e.g. Benzyl, phenylethyl or phenylpropylthio.
  • Hydroxy lower alkoxy is e.g. Hydroxyethoxy, hydroxypropyloxy or 1,2-dihydroxypropyloxy.
  • Lower alkoxy lower alkoxy is e.g. Methoxyethoxy, ethoxyethoxy, methoxypropyloxy or methoxybutyloxy.
  • Phenyl lower alkoxy lower alkoxy is e.g. 2-benzyloxyethoxy or 2- (2-phenylethoxy) ethoxy.
  • Lower alkanoyloxy is e.g. Acetyl, propionyl, butyryl _ iso .sec or tert-butyryloxy.
  • Lower alkylene is e.g. straight-chain, such as methylene, ethylene, 1,3-propylene or 1,4-butylene, - or branched, such as 1,2-propylene, 1,2- or l, 3- (2-methyl) -propylene or 1,2 -Butylene.
  • Lower alkylidene has a tertiary or in particular a quaternary carbon atom and is e.g. Ethylidene or 1,1- or 2,2-propylidene, furthermore 1,1- or 2,2-butylidene or 1,1-, 2,2- or 3,3-pentylidene.
  • Lower alkenylene is, for example, ethenylene, 1,2- or 1,3-propenylene or 1,2-, 1,3- or 1,4-buten-2-ylene.
  • Lower alkenylideh is, for example, ethenylidene, 1,1-propen-l-ylidene, 1,1-propen-2-ylidene, and also a butenylidene, such as 1,1-propen-3-ylidene.
  • Cycloalkylene is e.g. Cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2-, 1,3- or 1,4-cyclopentylene, also a cyclohexylene.
  • Cycloalkylidene is e.g. Cyclopropylidene, cyclobutylidene, cyclopentyl idene or cyclohexylidene.
  • Cycloalkyl-lower alkylidene is e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylmethylene, ethylidene or propylidene, and also a cyclohexylbutylidene.
  • Carboxy lower alkoxy is e.g. Carboxymethoxy, 2-carboxyethoxy, 2-, 3-carboxypropyloxy, l-carboxy-2-propyloxy, 2-, 3- or 4-carboxy-n-butyl-oxy, l-Carboxy ⁇ 2-methyl-propyl-3-oxy or l -Carboxy-2-methyl-propyl-2-oxy.
  • Lower alkoxycarbonyl-lower alk'oxy each contains, independently of one another, the meanings listed above under lower alkoxy in the lower alkoxy part.
  • Salts of compounds of the formula I according to the invention are preferably pharmaceutically usable salts, such as pharmaceutically usable salts
  • Acid addition salts and / or, when R 3 is carboxy, internal salts or salts with bases.
  • Suitable acid addition salts are, for example, salts with inorganic acids, such as mineral acid, with sulfamic acids, such as cyclohexylsulfamic acid, with organic carboxylic acids, such as lower alkane carboxylic acids, optionally unsaturated dicarboxylic acids, with carboxylic acids substituted by hydroxy and / or oxo, or with sulfonic acids, for example sulfates or hydrohalides or such as hydrobromides Hydrochloride, oxalates, malonates, fumarates or maleinates, tartrates, pyruvates or citrates, sulfonates, such as methane, benzene or p-toluenesulfonates.
  • Suitable salts with bases are, for example, alkali or alkaline earth metal salts, for example sodium, potassium or magnesium salts, pharmaceutically usable transition metal salts, such as zinc or copper salts, or salts with ammonia or substituted organic amines, such as cyclic amines, for example morpholine, thiomorpholine, piperidine , Pyrrolidine, such as mono-, di- or tri-lower alkylamines or mono-, di- or trihydroxy-lower alkylamines, for example mono-, di- or triethanolamine.
  • Mono-lower alkyl arynes are, for example, ethyl or tert-butylamine.
  • Di ⁇ iederalkylamine are, for example, diethyl or diisopropylamine, and triethylamine is suitable as tri-lower alkylamine.
  • the new compounds of formula I and their pharmaceutically usable salts have valuable pharmacological properties. In particular, e.g. when used locally, a pronounced anti-inflammatory effect.
  • This property can be detected, for example, according to the method developed by G. Tonelli, L. Thibault, Endocrinology 77, 625 (1965) by inhibiting the rat ear edema induced by croton oil in the normal rat in the dose range from about 1 to about 100 mg / ml.
  • an ED 50 value of 17 mg / ml was determined in the test described above.
  • the compounds of the formula I according to the invention are therefore used as medicaments, in particular external (topical) dermatological agents for the treatment of inflammatory dermatoses of any origin, such as mild skin irritations, contact dermatitis, rashes, burns, and as mucosal agents for the treatment of mucosal infections, e.g. of the eyes, nose, lips, genital, anal region, suitable.
  • external (topical) dermatological agents for the treatment of inflammatory dermatoses of any origin, such as mild skin irritations, contact dermatitis, rashes, burns, and as mucosal agents for the treatment of mucosal infections, e.g. of the eyes, nose, lips, genital, anal region, suitable.
  • the compounds can also be used as sunscreens.
  • the invention relates, for example, to compounds of the formula I in which one of the radicals R 1 and R 2 is a 5- or 6-membered heteroaryl which has nitrogen as the heteroatom (s) and which is unsubstituted or by Halogen, lower alkyl, hydroxy; Lower alkoxy and / or lower alkanoyloxy may be substituted, and the other is unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyl or a 5- or 6-membered heteroaryl group containing nitrogen as heteroatom (s) which is unsubstituted or can be substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyl,
  • A means lower alkylene, lower alkylidene, nie deralkenylene, lower alkenylidene, cycloalkylene, cycloalkylidene or cycloalkyl lower alkylidene and R
  • 4- to 7-membered alkylene or 3-aza, 3-lower alkylza, 3-oxa- or 3-thiaalkylene means disubstituted carbamoyl, a lower alkanol being unsubstituted or substituted by hydroxy, mercapto, optionally substituted phenyl, lower alkoxy, optionally in the phenyl part substituted phenyl-lower alkoxy, lower alkylthio, optionally substituted in the phenyl phenyl-lower alkylthio, Hydroxyniederalkoxy, Niederalkoxyniederalkoxy, optionally substituted in the phenyl moiety Phenylniederalkoxyniederalkoxy, Hydroxyniederalkoxyniederalkoxy, Lower alkoxyniederalkoxyniederalkoxy optionally substituted in the phenyl moiety Phenylniederalkoxyniederalkoxy, Hydroxyniederal
  • the invention relates, for example, to compounds of the formula I in which one of the radicals R 1 and R 1 is pyridyl or 1-oxidopyridyl, which may be unsubstituted and / or substituted in each case by halogen, hydroxyl, lower alkyl, lower alkoxy and / or lower alkanoyloxy, and the other phenyl, pyridyl or 1-oxidopyridyl, which may be unsubstituted and / or substituted in each case by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy, means A lower alkylene with up to and with 4 carbon atoms, such as methylene, lower alkylidene to and with 7 carbon atoms, such as 2,2-propylidene, lower alkenyls with up to and with 4 carbon atoms, such as 1,3-propen-2-ylene, lower alkenylidene with up to and 7 carbon atom
  • the invention relates, for example, to compounds of the formula I in which one of the radicals R 1 and R 2 is unsubstituted or, in the second place, halogen with an atom number up to and including 35, such as chlorine, hydroxyl, lower alkyl having up to and 4 carbon atoms, such as methyl, and / or lower alkoxy with up and phenyl substituted with 4 carbon atoms, such as methoxy, and the other being pyridyl, such as 3-pyridyl, or 1-oxido-pyridyl, such as 1-oxido-3-pyridyl, each of which is unsubstituted or secondarily by halogen with atomic numbers up to and including 35, such as chlorine, hydroxyl and / or lower alkoxy, can be substituted with up to and with 4 carbon atoms, such as methoxy,
  • the invention relates first and foremost to compounds of the formula I in which one of the radicals R 1 and R 2 is unsubstituted or, in the second place, halogen with an atom number up to and including 35, such as chlorine, hydroxy or lower alkoxy with up to 4 carbon atoms, such as Methoxy, substituted phenyl and the other pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as 1-oxido-3-pyridyl or l-oxido-4-pyridyl, A is lower alkylidene with up to and with 4 C. -Atoms, such as 2,2-propylidene, and R 3 represents lower alkoxycarbonyl with up to and with 5 C atoms, such as ethoxycarbonyl, their isomers and their salts.
  • the invention relates first and foremost to compounds of the formula I in which one of the radicals R 1 and R 2 is unsubstituted or, in the second place, halogen with an atom number up to and including 35, such as chlorine, hydroxy or lower alkoxy with up to 4 carbon atoms, such as Methoxy substituted phenyl and the other pyridyl, such as 3- or 4-pyridyl, or 1-oxido-pyridyl, such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A is a lower alkylidene having a quaternary carbon atom to and with 4 carbon atoms, such as 2,2-propylidene, the quaternary carbon atom being bonded directly to the imidazole ring, and R 3 being lower alkoxycarbonyl having up to and with 5 carbon atoms, such as ethoxycarbonyl, their isomers as well as their salts.
  • R 1 and R 2 is unsubsti
  • the invention relates first and foremost to compounds of the formula I in which R 1 is phenyl, R 2 is 1-oxidopyridyl, such as 1-oxido-3-pyridyl, A is 2,2-propylidene and R 3 is lower alkoxycarbonyl with up to and with 5 C atoms, such as ethoxycarbonyl, represents their isomers and their salts.
  • the invention relates in particular to the new compounds mentioned in the examples and their salts, in particular pharmaceutically usable salts of such compounds with salt-forming groups, and to the preparation processes listed in the examples.
  • a procedure for the preparation of compounds of the formula (I) is characterized, for example, in that a compound of the formula
  • Tautomers of compounds of formula (II) are, for example, those in which there is a partial enol or enamine group in the form of the corresponding tautomeric keto or ketimine form and vice versa, the respective tautomers being in equilibrium with one another.
  • cyclization of a compound of the formula II, a tautomer and / or salt thereof is carried out in a conventional manner, in particular in the manner known from the literature for analogous reactions, if necessary with heating, such as in a temperature range from about 20 ° to about 250 ° C. under Pressure and / or in the presence of a catalytic agent, preferably an acid or an acid anhydride.
  • Suitable acids are, for example, inorganic acids, such as mineral acids, e.g. Sulfuric acid, polyphosphoric acid or hydrohalic acid such as hydrochloric acid or organic acids such as lower alkane carboxylic acids e.g. Acetic acid.
  • acid anhydrides are Mineral anhydrides such as sulfuryl or phosphorus (oxy) halides, e.g. Phosphorus oxychloride.
  • an inert solvent for example an optionally halogenated hydrocarbon, such as chloroform, chlorobenzene, hexane, pyridine or toluene, a lower alkanol, such as methanol, e.g. Dimethylformamide or formamide, or a lower alkane carboxylic acid, such as formic or acetic acid, and / or under an inert gas, such as nitrogen.
  • an optionally halogenated hydrocarbon such as chloroform, chlorobenzene, hexane, pyridine or toluene
  • a lower alkanol such as methanol, e.g. Dimethylformamide or formamide
  • a lower alkane carboxylic acid such as formic or acetic acid
  • an inert gas such as nitrogen.
  • the starting materials of the formula II, their tautomers and / or salts are predominantly formed in situ by processes known per se and further reacted under the reaction conditions without isolation to the compound of the formula I.
  • the cyclization can take place after an upstream condensation.
  • a corresponding compound of formula (II) or a tautomer thereof can be formed, which further reacts according to the invention under the reaction conditions.
  • salts of compounds of the formula (II) and (Ila) are, for example, acid addition salts, such as hydrohalides.
  • Functionally modified hydroxy Y 1 is, for example, amino or reactive esterified hydroxy, such as hydroxyl esterified with an inorganic mineral acid, for example hydrohalic acid, or with an organic sulphonic acid, for example optionally substituted benzenesulfonic acid.
  • reactive esterified hydroxy are primarily halogen, for example chlorine or bromine, or sulfonyloxy, for example p-toluenesulfonyloxy.
  • Functionally modified carboxy Y 2 is, for example, anhydridized carboxy, such as halocarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbonyl, carbamoyl or amidino.
  • Reactive esterified hydroxy is, for example, preferably with strong inorganic or organic acids such as mineral acids, e.g. Hydrohalic acids, e.g. Bromic or hydrochloric acid, or organic sulfonic acids, such as. optionally substituted benzenesulfonic acids, e.g. p-toluenesulfonic acid, esterified hydroxy.
  • strong inorganic or organic acids such as mineral acids, e.g. Hydrohalic acids, e.g. Bromic or hydrochloric acid, or organic sulfonic acids, such as. optionally substituted benzenesulfonic acids, e.g. p-toluenesulfonic acid, esterified hydroxy.
  • Functionally modified carboxy derivatives of the formula (IIc) are, for example, corresponding optionally esterified, amidated or anhydridized carboxy compounds, such as corresponding lower alkoxycarbonyl, optionally substituted carbamoyl or halocarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbonyl derivatives.
  • Suitable condensing agents include, for example, strong protonic acids, such as mineral acids, for example sulfuric acid, hydrohalic acids, phosphoric acids, sulfonic acids, such as optionally substituted benzenesulfonic acids, or carboxylic acids, such as lower alkane carboxylic acids, or anhydrides of mineral acids, such as corresponding anhydrides of phosphoric acids, carbonic acid or sulfuric acid, for example phosphorus pentachloride, , Phosphorus pentoxide, thionyl chloride or phosgene.
  • the reaction is carried out in a conventional manner, if necessary with heating and in an inert solvent, such as a halogenated hydrocarbon.
  • compounds of the formula (II) in which X 1 and X 2 each represent oxy are obtained by reacting compounds of the formula (Ila) in which Y 1 is hydroxy with acid halides of the formula (IIc), in particular the corresponding ones Acid halides.
  • the corresponding compounds of the formula (Ild) can be formed with ammonia in the presence of an acid, such as glacial acetic acid, the corresponding compounds of the formula (I).
  • compounds of the formula (II) in which X 1 is oxy and X 2 are imino are obtained by reacting a compound of the formula (Ila) in which Y 1 is esterified hydroxy, primarily halogen, with a corresponding compound of the formula (Ilb), in which Y 2 is carbamoyl, is reacted under the reaction conditions given above.
  • compounds of the formula (II) in which X 1 is imino and X 2 are oxo are obtained by reacting a compound of the formula (Ila) in which Y 1 is amino, a salt and / or tau tomers thereof with a compound of the formula (Ilb), in which Y 2 is anhydride-carboxy, primarily halocarbonyl under the reaction conditions indicated.
  • compounds of the formula (Ila) preferably by ester condensation of esterified acids of the formulas R 1 -CH 2 -COOH or R 2 -CH 2 - COOH with esterified acids of the formulas R 1 -COOH or R 2 -COOH obtained in the presence of a base.
  • the resulting ⁇ -methylene ketone of the formula (IIe) is brominated, for example, and thus converted into a compound of the formula (Ila) or a salt thereof, for example hydrohalide, in which Y 1 is bromine.
  • the reduction takes place according to methods known per se.
  • compounds of the formula (III) or their salts are treated with hydrogen in the presence of a hydrogenation catalyst or with a dithionite, for example sodium dithionite, or with a phosphorus halide, for example phosphorus trichloride.
  • a hydrogenation catalyst for example, elements of subgroup VIII and derivatives thereof, such as platinum, palladium or palladium chloride, are optionally present a conventional carrier material, such as activated carbon or alkaline earth metal compounds, for example barium carbonate, or Raney nickel.
  • the reduction can likewise be carried out using a system composed of a suitable base metal and a protonic acid, for example using zinc / glacial acetic acid.
  • the reduction can be carried out, if necessary, with cooling or heating, for example in a temperature range from about 0 ° to about 150 ° C, in an inert solvent such as a halogenated hydrocarbon, e.g. Chloroform, carbon tetrachloride or chlorobenzene, or an ether such as dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran, and / or under inert gas, e.g. Nitrogen.
  • a halogenated hydrocarbon e.g. Chloroform, carbon tetrachloride or chlorobenzene
  • an ether such as dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran
  • inert gas e.g. Nitrogen.
  • a tautomer or a salt thereof with an aldehyde of the formula R 3 -AC ( O) -H (Illb), if appropriate at elevated temperature and in the presence of an acid such as mineral acid, for example hydrochloric acid, sulfonic acid, for example p-toluenesulfonic acid, or carboxylic acid , for example acetic acid.
  • mineral acid for example hydrochloric acid, sulfonic acid, for example p-toluenesulfonic acid, or carboxylic acid , for example acetic acid.
  • R ' 3 is a radical which can be converted into R 3
  • the radical R' 3 is converted into a radical R 3
  • the free compound of the formula (I) obtainable according to the process is converted into another free compound, a free compound obtainable according to the process into a salt or converting a salt obtainable according to the process into the free compound or into another salt and, if desired, separating a mixture of isomers obtainable according to the process into its components.
  • Such groups R ' 3 are, for example, groups which can be converted into esterified or amidated carboxy R 3 by solvolysis or oxidation.
  • solvolysis can be converted into R 3 groups 3 different functionally modified carboxy come from R in question; to be mentioned first and foremost cyano, anhydridized carboxy, such as halocarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyl oxycarbonyl, optionally substituted amidino, such as lower alkyl amidino, optionally esterified thiocarboxy, such as lower alkylthio carbonyl, optionally esterified dithiocarboxy, optionally substituted thiocarbamoyamoyl-mono- or mono- , optionally esterified or anhydridized carboximidoyl, such as lower alkoxy or haloiminocarbonyl, or residues derived from ortho-formic acid esters, such as tri-lower alkoxy or trihal
  • Solvolysis agents are, for example, water, alcohols corresponding to the desired esterified carboxy group, ammonia or amines corresponding to the desired amidated carboxy group.
  • the treatment with an appropriate solvolysis agent is optionally carried out in the presence of an acid or base, optionally with cooling or heating or, if necessary, in an inert solvent or diluent.
  • Suitable acids are, for example, inorganic or organic protonic acids, such as mineral acids, for example sulfuric acid or hydrohalic acid, such as sulfonic acid, for example lower alkane or optionally substituted benzenesulfonic acid, or such as carboxylic acids, such as lower alkane carboxylic acids.
  • bases can for example hydroxides, such as alkali metal hydroxides, can be used.
  • the cyano group, optionally esterified thiocarboxy, optionally esterified dithiocarboxy, optionally substituted thiocarbamoyl, optionally esterified or anhydridized carboximidoyl, or residues R ' 3 derived from orthoformic acid, optionally in the presence of a protonic acid, are hydrolyzed to carboxy R 3 , for example cyano, optionally S-esterified thiocarboxy or anhydridized carboxy R ' 3 with a suitable alcohol, optionally in the presence of a protonic acid, can be alcoholysed to esterified carboxy R 3 .
  • Amidated carboxy R 3 can also be obtained, for example, by aminolysis or by treatment with a suitable amine from cyano, for example in the presence of a Lewis acid, such as aluminum chloride, or anhydridized carboxy.
  • Further groups which can be converted into carboxy or esterified carboxy R 3 are, for example, radicals which can be converted into these groups, such as hydrated or acetalized formyl, if appropriate.
  • This can advantageously be formed in situ in the course of the oxidation reaction, for example from the acyl group of an ⁇ , ⁇ -unsaturated or ⁇ , ⁇ -dihydroxylated aliphatic or araliphatic carboxylic acid, a formyl group which may be esterified on the hydroxyl group, or from one of its functional derivatives, for example one of its Acetals, acylals or imines are set free.
  • Acyl groups of ⁇ , ⁇ -unsaturated or ⁇ , ⁇ -dihydroxylated carboxylic acids are, for example, acyl groups of ⁇ , ⁇ -unsaturated aliphatic mono- or dicarboxylic acids, for example acryloyl, crotonyl or the acyl group of the functionally modified fumaric or maleic acid, acyl groups of ⁇ , ⁇ unsaturated araliphatic carboxylic acids, eg optionally substituted cinnamoyl, or acyl groups of aliphatic ⁇ , ⁇ -dihydroxydicarboxylic acids, such as tartaric acid, or monofunctional carboxy derivatives, such as esters or amides, of the same.
  • Esterified hydroxymethyl groups are, for example, on the hydroxyl group with a mineral acid, such as a hydrohalic acid, for example with hydrochloric or hydrobromic acid, or with a carboxylic acid, for example with acetic acid or the optionally substituted benzoic acid, esterified groups.
  • a mineral acid such as a hydrohalic acid, for example with hydrochloric or hydrobromic acid, or with a carboxylic acid, for example with acetic acid or the optionally substituted benzoic acid, esterified groups.
  • Acetalized formyl groups are, for example, acetalized formyl groups with lower alkanols or a lower alkanediol, such as dimethoxy, diethoxy or ethylenedioximethyl.
  • Acylalized formyl groups are, for example, diniederalkanoyloxymethyl or dihalomethyl groups, such as diacetoxymethyl or dichloromethyl.
  • Imines of formyl groups are, for example, optionally substituted N-benzylimines or N- (2-benzothiazolyl) imines thereof or imines with 3,4-di-tert-butyl-o-quinone.
  • Further radicals which can be converted into the carboxy group are, for example, optionally substituted 2-furoyl groups, such as those in the 5-position of an acetalized formyl group, such as diethoxymethyl.
  • Groups which can be oxidized to esterified carboxy groups are etherified hydroxymethyl or dihydroxymethyl groups, such as lower alkoxymethyl or diniederalkoxymethyl groups.
  • the oxidation of such groups R ' 3 takes place in a manner known per se, for example by reaction in a suitable oxidizing agent, for example in an inert solvent such as a lower alkane carboxylic acid, for example acetic acid, a ketone, for example acetone, an ether, for example tetrahydrofuran, a heterocyclic aromatic, for example pyridine, or water or a mixture thereof, if necessary with cooling or heating, for example from about 0 ° to about 150 ° C.
  • oxidizing agents are, for example, oxidizing transition metal compounds, in particular those with elements of subgroups I, VI, VII, or VIII.
  • Examples include: silver compounds, such as silver nitrate, oxide or picolinate, chromium compounds, such as chromium trioxide or potassium dichromate, manganese compounds, such as potassium ferrate, tetrabutylammonium or benzyl (triethyl) ammonium permanganate.
  • Other oxidizing agents are, for example, suitable compounds with elements of main group 4, such as lead dioxide, or halogen-oxygen compounds, such as sodium iodate or potassium periodate.
  • the oxidation of hydroxymethyl or of hydroxymethyl etherified with a lower alkanol leads to carboxy or to carboxy R esterified with a lower alkanol.
  • This reaction is advantageously carried out, for example, with potassium permanganate in acetone or aqueous pyridine at room temperature.
  • the oxidation of optionally hydrated formyl to carboxy R 3 takes place accordingly, for example with iodine in a methanolic potassium hydroxide solution.
  • bromine or N-bromosuccinimide in particular is used as the oxidizing agent.
  • (IVa) exposes and sets this with a compound of the formula R ' 3 -A-Y' 2 (IVb) or a salt thereof, in which Y ' 2 optionally represents functionally modified carboxy, or R' 3 -A-COOH, a functional derivative or salt thereof and ammonia in an inert solvent and with heating in situ to the compound of formula (IV) without isolation of intermediates.
  • ammonia which is predominantly added in excess
  • ammonia-releasing agents are ammonium salts of lower alkanecarboxylic acids, preferably ammonium acetate, and a suitable lower alkanecarboxamide, in particular formamide.
  • the compounds of the formula (IIIc) can be prepared, for example, by reacting 2-methyl-2,4-pentanediol with a nitrile of the formula R 3 -A-CN in the presence of sulfuric acid.
  • the correspondingly substituted dihydro-1,3-oxazine thus formed is converted to the tetrahydro-1,3-oxazine of the formula () in a mixture of tetrahydrofuran and ethanol at -45 ° C. and a pH of about 7 under the action of sodium borohydride. IIIc) reduced.
  • a compound obtainable according to the invention can be converted in a conventional manner into another compound of the formula I.
  • free and esterified carboxy groups R 3 can be converted into one another in compounds of the formula I obtainable according to the invention.
  • a free carboxyl group R 3 can be obtained, for example, in a customary manner, for example by treatment with a diazo-lower alkane, di-lower alkyl formamide acetal, alkyl halide or tri-lower alkyl oxonium, tri-lower alkyl carboxonium or di-lower alkyl carbonium salts, such as hexachloroantimonate or hexafluorophosphate, or above all by reaction with the corresponding alcohol or a reactive compound , such as a carbon, phosphorous, sulfurous or carbonic acid ester, for example a lower alkane carboxylic acid ester, tri-lower alkyl phosphite, di-lower alkyl sulfite or the pyrocarbonate, or one
  • Mineral acid or sulfonic acid ester e.g. the chlorine or bromine water Esterified carbonic acid or sulfuric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid ester, the corresponding alcohol or an olefin derived therefrom, to an esterified carboxyl group R 3 .
  • the reaction with the corresponding alcohol itself can advantageously take place in the presence of an acidic catalyst such as a protonic acid, e.g. of hydrochloric or hydrobromic, sulfuric, phosphoric, boric, benzenesulfonic and / or toluenesulfonic acid, or a Lewis acid, e.g. boron trifluoride etherate, in an inert solvent, especially an excess of the alcohol used and, if necessary, in the presence of a water-binding agent and / or under distillative, e.g. azeotropic, removal of the reaction water and / or at elevated temperature.
  • an acidic catalyst such as a protonic acid, e.g. of hydrochloric or hydrobromic, sulfuric, phosphoric, boric, benzenesulfonic and / or toluenesulfonic acid, or a Lewis acid, e.g. boron trifluoride etherate, in an inert solvent, especially
  • reaction with a reactive derivative of the corresponding alcohol can be carried out in a customary manner, starting from a carbonic, phosphorous, sulfurous or carbonic acid ester, for example in the presence of an acidic catalyst, such as one of the above, in an inert solvent, such as an aromatic Hydrocarbon, for example in benzene or toluene, or an excess of the alcohol derivative used or the corresponding alcohol.
  • an acidic catalyst such as one of the above
  • an inert solvent such as an aromatic Hydrocarbon, for example in benzene or toluene, or an excess of the alcohol derivative used or the corresponding alcohol.
  • the acid to be esterified is advantageously used in the form of a salt, for example the sodium or potassium salt, and, if necessary, is carried out in the presence of a basic condensing agent, such as an inorganic base, for example sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, for example of triethylamine or pyridine, and / or in an inert solvent, such as one of the above tertiary nitrogen bases or a polar solvent, for example in dirnethylformamide and / or at elevated temperature.
  • a basic condensing agent such as an inorganic base, for example sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, for example of triethylamine or pyridine
  • an inert solvent such as one of the above tertiary nitrogen bases or a polar solvent, for example in dirnethylformamide and / or at elevated temperature.
  • reaction with a di-lower alkyl formamide acetal such as dimethyl formamide acetal
  • a base such as an amine, for example triethylamine
  • the reaction with an olefin can be carried out, for example, in the presence of an acid catalyst, e.g. a Lewis acid such as boron fluoride, a sulfonic acid e.g. p-toluenesulfonic acid, or especially a basic catalyst e.g. of sodium or potassium hydroxide, advantageously in an inert solvent such as an ether, e.g. Diethyl ether or tetrahydrofuran.
  • an acid catalyst e.g. a Lewis acid such as boron fluoride, a sulfonic acid e.g. p-toluenesulfonic acid, or especially a basic catalyst e.g. of sodium or potassium hydroxide, advantageously in an inert solvent such as an ether, e.g. Diethyl ether or tetrahydrofuran.
  • a Lewis acid such as boron fluoride
  • a sulfonic acid e
  • An esterified carboxyl group R 3 can be released in the usual way, for example by hydrolysis in the presence of a catalyst, for example a basic or acidic agent, such as a strong base, for example sodium or potassium hydroxide, or a mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid Carboxyl group R 3 are transferred.
  • a catalyst for example a basic or acidic agent, such as a strong base, for example sodium or potassium hydroxide, or a mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid Carboxyl group R 3 are transferred.
  • An esterified carboxyl group R 3 can be used in a customary manner, for example by reaction with a metal salt, such as sodium or potassium salt, with an appropriate alcohol or with the same
  • a catalyst for example a strong base, for example sodium or potassium hydroxide, or a strong acid, for example a mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, or an organic sulfonic acid, for example p-toluenesulfonic acid, or a Lewis acid, for example of Boron trifluoride etherate, to be transesterified to another esterified carboxyl group R 3 .
  • a catalyst for example a strong base, for example sodium or potassium hydroxide, or a strong acid, for example a mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, or an organic sulfonic acid, for example p-toluenesulfonic acid, or a Lewis acid, for example of Boron trifluoride etherate, to be transesterified to another esterified carboxyl group R 3 .
  • free carboxy or reactive functional carboxy derivatives can be converted into a desired amidated form by solvolysis with ammonia or a primary or secondary amine, and hydroxylamines or hydrazines can also be used, with dehydration, if appropriate in the presence of a condensing agent .
  • Bases are preferably used as the condensing agent, for example inorganic bases such as alkali metal hydroxides, e.g. Sodium or potassium hydroxide, organic nitrogen bases such as tertiary amines, e.g. Pyridine, tributylamine or N-dimethyl aniline, or tetrahalosilanes, such as tetrachlorosilane.
  • compounds of the formula I, in which R denotes amidated carboxy which are obtainable according to the invention, cleave the amide bond by methods known per se and thus convert the carbamoyl to free carboxy. This is done in the presence of a catalyst, for example a base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium, potassium or calcium hydroxide or carbonate, or an acid such as a mineral acid e.g. Hydrochloric acid, sulfuric acid or phosphoric acid.
  • a catalyst for example a base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium, potassium or calcium hydroxide or carbonate, or an acid such as a mineral acid e.g. Hydrochloric acid, sulfuric acid or phosphoric acid.
  • substituents R 1 , R 2 and R 3 contains hydroxy as additional substituents, this can be etherified in a manner known per se.
  • the reaction with an alcohol component for example with a lower alkanol, such as ethanol, in the presence of acids, For example, mineral acid, such as sulfuric acid, or dehydrating agents, such as dicyclohexylcarbodiimide, leads to lower alkoxy.
  • acids for example, mineral acid, such as sulfuric acid, or dehydrating agents, such as dicyclohexylcarbodiimide
  • bases such as alkali metal hydroxides or carbonates, for example sodium hydroxide or potassium carbonate
  • diazo-lower alkanes diazo-lower alkanes or convert alkyl or aryl halides into corresponding lower alkylphenyl ether or arylphenyl ether.
  • ethers can be split into alcohols.
  • aromatic alcohols are formed from alkoxyaryl compounds by the ether cleavage using acids, such as mineral acids, for example hydrohalic acid, such as hydrobromic acid, or Lewis acids, for example halides of elements of the 3rd main group, such as boron tribromide, or using bases, for example lower alkyl amines, such as methylamine , performs.
  • Hydroxy can also be converted to lower alkanoyloxy, for example by reaction with a desired lower alkanecarboxylic acid, such as acetic acid or a reactive derivative thereof, for example in the presence of an acid, such as a protonic acid, e.g. Chloric, hydrobromic, sulfuric, phosphoric or a benzene sulfonic acid, in the presence of a Lewis acid, e.g. of boron trifluoride etherate, or in the presence of a water-binding agent.
  • a desired lower alkanecarboxylic acid such as acetic acid or a reactive derivative thereof
  • an acid such as a protonic acid, e.g. Chloric, hydrobromic, sulfuric, phosphoric or a benzene sulfonic acid
  • a Lewis acid e.g. of boron trifluoride etherate
  • esterified hydroxy e.g. by base catalysis, can be volysed to hydroxy sol
  • Free compounds of the formula I obtained can be converted into salts in a manner known per se.
  • Hydroxy-containing groups R 1 and R 2 and carboxy R 3 are converted with appropriate bases, such as alkali metal hydroxides, into the salts with bases mentioned at the beginning, or by treatment with an acid forming acid addition salts as mentioned above to form acid addition salts.
  • Salts obtained can be converted into the free compounds in a manner known per se, for example by treatment with an acidic reagent, such as a mineral acid, or a base, for example alkali metal hydroxide.
  • an acidic reagent such as a mineral acid, or a base, for example alkali metal hydroxide.
  • the compound can be in the form of one of the possible isomers or as mixtures thereof.
  • the compound, including its salts, can also be obtained in the form of its hydrates or include other solvents used for crystallization.
  • the compounds can be in the form of one of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, mixtures of diastereoisomers or racemates, and also as tautomers.
  • Obtained diastereomer mixtures and racemate mixtures can be separated into the pure isomers, diastereomers or racemates in a known manner on the basis of the physico-chemical differences between the constituents, for example by chromatography and / or fractional crystallization. Racemates obtained can furthermore be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reacting an acidic end product with an optically active base which forms salts with the racemic acid and separating the in this way obtained salts, for example due to their different solubilities, broken down into the diastereomers from which the antipodes can be released by the action of suitable agents.
  • the invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or in particular forms under the reaction conditions.
  • the pharmaceutical preparations according to the invention which contain at least one active ingredient or a pharmaceutically acceptable salt thereof, are preferably those for topical use on warm-blooded animals, the pharmacological active ingredient being contained alone or together with a pharmaceutically acceptable carrier material.
  • the daily dosage of the active ingredient depends on the age and individual condition as well as on the mode of administration.
  • Corresponding agents with a concentration range of about 1 to about 10% w / w, e.g. in the form of creams, ointments or solutions, for example, can be applied 2 to 3 times a day.
  • topical pharmaceutical preparations that can be used are primarily creams, ointments, pastes, foams, tinctures and solutions which contain from about 0.1 to about 10% of the active ingredient.
  • Creams are oil-in-water emulsions that contain more than 50% water.
  • the main oils used are fatty alcohols, e.g. lauryl, cetyl or stearyl alcohol, fatty acids, e.g. palmitic or stearic acid, liquid to solid waxes, e.g. isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. petroleum jelly (Petrolatum) or paraffin oil.
  • Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid ester of polyalcohols or ethylene oxide adducts thereof, such as Polyglycerinfesklareester or polyoxyethylene (Tweens), and also Polyoxyethylenfcttalkoholether or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example, Sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol.
  • corresponding nonionic emulsifiers for example fatty acid ester of polyalcohols or ethylene oxide adducts thereof, such as Polyglycerinfesklareester or polyoxyethylene (T
  • Additives to the water phase include agents which reduce the drying out of the cream, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
  • Ointments are water-in-oil emulsions which contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases.
  • the fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins
  • the hydroxyl compounds such as fatty alcohols or esters thereof, which are preferably suitable for improving the water binding capacity, e.g. Cetyl alcohol or wool wax alcohols or wool wax.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), e.g. Sorbitan oleate and / or sorbitan isostearate.
  • Additions to the water phase include Humectants such as polyalcohols e.g. Glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.
  • Fatty ointments are anhydrous and contain in particular hydrocarbon, for example paraffin, petroleum jelly and / or liquid paraffins, as well as natural or partially synthetic fat, for example coconut fatty acid triglyceride, or preferably hardened oils; for example hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, for example glycerol mono- and distearate, and for example the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments which increase the water absorption capacity.
  • Pastes are creams and ointments with secretion-absorbing powder components, such as metallic oxides, for example titanium oxide or zinc oxide, and also talc and / or aluminum silicates, which have the task of binding moisture or secretions present.
  • Foams are e.g. administered from pressure vessels and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents.
  • the oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes.
  • the emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual additives such as preservatives, etc.
  • Tinctures and solutions mostly have an aqueous-ethanolic base, which among other things Polyalcohols, e.g. Glycerin, glycols and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances, such as fatty acid esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol and, if necessary, other auxiliary substances and additives are added.
  • Polyalcohols e.g. Glycerin, glycols and / or polyethylene glycol, as humectants to reduce evaporation
  • refatting substances such as fatty acid esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol and, if necessary, other auxiliary substances and additives are added.
  • topically usable pharmaceutical preparations are prepared in a manner known per se, for example by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary.
  • active ingredient When the active ingredient is processed as a solution, it is usually dissolved in one of the two phases before emulsification; at ver Working as a suspension, it is mixed with part of the base after the emulsification and then added to the rest of the formulation.
  • Example 1 A solution of 39.0 g of l-phenyl-2- (3-pyridyl) glyoxal (freshly distilled) in 500 ml of methanol is mixed in portions with stirring at 0 ° for 5 hours with 2.5 g of sodium borohydride. After the addition has ended, the mixture is stirred for a further 2 hours at 0 °, left for 15 hours at 0 ° and then with 200 ml of 2-n. Hydrochloric acid added. The suspension is concentrated to dryness under reduced pressure, ice is added to the residue and the mixture is made up by adding 2-n. Alkaline sodium carbonate solution. The aqueous suspension is extracted three times with 200 ml of ethyl acetate.
  • the ⁇ -hydroxy-benzyl— (3-pyridyl) ketone melts at 109-111 °.
  • Fractions 5 and 6 eluted with 1000 ml each of toluene-ethyl acetate (1: 1), are discarded.
  • Fractions 7-14 eluted with 1000 ml each of toluene-ethyl acetate (40:60), are combined and evaporated to dryness under reduced pressure. The residue is crystallized from ether-petroleum ether.
  • the ⁇ -hydroxy-phenyl - [(3-pyridyl) methyl] ketone melts at 93 to 95 °.
  • Example 2 A mixture of 6.0 g of ⁇ -hydroxy ⁇ henyl- [(3-pyridyl) methyl] ketone and 1 ml of triethylamine in 80 ml of anhydrous benzene is stirred at 10 ° with a solution of 6. 0 g of dimethyl malonic acid mono-ethyl ester chloride in 30 ml of anhydrous benzene, mixed for 20 minutes, stirred for three hours at room temperature, mixed with 30 ml of ethyl acetate and 90 ml of water and stirred again for one hour at room temperature. The aqueous phase is separated off and washed twice with 20 ml of ethyl acetate.
  • Example 3 A mixture of 3.1 g of dimethylmalonic acid monoethyl ester [ ⁇ -benzoyl (3-pyridylmethyl) ester, 2.4 g of ammonium acetate and 24 ml of glacial acetic acid is stirred for 2 hours at a bath temperature stirred by 140 °. The mixture is cooled and the reaction mixture is poured to 100 ml of ice water and adjust to pH 8.0 with concentrated aqueous ammonia solution. It is extracted three times with 70 ml of ethyl acetate and the ethyl acetate extracts are washed twice with 20 ml of water. The combined organic phases are dried over magnesium sulfate and evaporated to dryness under reduced pressure.
  • Example 4 A solution of 1.6 g of 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid ethyl ester in 20 ml of methylene chloride is added dropwise with stirring at 0 ° Solution of 1.0 g m-chlorine perbenzoic acid in 20 ml methylene chloride. The mixture is stirred at 0 ° for two hours, another 0.1 g of m-chloro perbenzoic acid is added and the mixture is stirred at 0 ° for 30 minutes. The mixture is twice with 10 ml of 2-n. Washed potassium bicarbonate solution, dried over magnesium sulfate and under reduced pressure
  • the solution is stirred for 5 hours at room temperature and evaporated to dryness under reduced pressure.
  • the residue is dissolved in 50 ml of water and the aqueous solution is extracted with 20 ml of methylene chloride. Then the aqueous phase is separated off and treated with 2-n. Hydrochloric acid precisely adjusted to pH 4.0.
  • the suspension is stirred at O ⁇ for 5 minutes and filtered off.
  • the 2- [4-phenyl-5- (l-oxido-3-pyridyl) -oxazo1-2-yl] -2-r ⁇ ethyl-propionic acid melts at 136-137 °.
  • Example 6 In a suspension of 11.3 g of ⁇ -oximobenzyl- (3-pyridyl) ketone and 12.2 g of 2- (2, 2-dimethyl-carbethoxymethyl) -4,4,6-trimethyl-2,3 , 5,6-tetrahydro-1,3-oxime in 300 ml glacial acetic acid is introduced without cooling and with good stirring hydrochloric acid gas. The temperature rises to 45 ° and a clear solution is created.
  • Hydrochloric acid gas is introduced into the solution at 115 ° for 30 minutes, then the solution is heated at 115 ° for 15 hours, cooled and evaporated to dryness at 50 ° under reduced pressure.
  • the residue is dissolved in 300 ml of water.
  • the aqueous solution is made alkaline with concentrated aqueous ammonia solution and the crystals which have separated out are dissolved with 300 ml of ethyl acetate-methylene chloride (1: 1).
  • the organic phase is washed with 50 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure.
  • the residue is crystallized from methanol ether.
  • the 2- [4-phenyl-5- (3-pyridyl) - (3-oxido-oxazol) -2-yl] -2-methyl-propionic acid ethyl ester melts at 195-210 °.
  • Example 7 A solution of 1.2 g of 2- [4-phenyl-5- (3-pyrido) - (3-oxido-oxazol) -2-yl] -2-methyl-propionic acid ethyl ester in 10 ml of glacial acetic acid is added at 10 ° added 1.2 g of zinc dust in portions with stirring. When the addition is complete, 0.05 ml of concentrated hydrochloric acid are added. The mixture is heated at 90 ° for one hour and cooled , filtered and washed with 5 ml of glacial acetic acid. The filtrate is evaporated to dryness at 50 ° under reduced pressure. The residue is dissolved in 20 ml of water.
  • the aqueous solution is made alkaline with aqueous concentrated ammonia solution.
  • the suspension is extracted three times with 30 ml of ethyl acetate each.
  • the combined organic phases are washed with 10 ml of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure.
  • the residue is chromatographed on 80 g of silica gel. Fractions 1-5, eluted with 50 ml of chloroform each, are discarded. Fractions 6-9, eluted with 50 ml of chloroform each, are combined and evaporated to dryness under reduced pressure. The residue crystallizes after rubbing with petroleum ether.
  • Example 8 A mixture of 3.6 g of ⁇ -bromo-benzyl (3-pyridyl) ketone, 1.7 g of dimethylmalonic acid monoethyl ester monoamide and 1.3 g of colüdin in 100 ml of xylene is used for 15 hours heated at 120-130 °, the water formed being separated off with a water separator. The reaction mixture is then evaporated to dryness under reduced pressure.
  • Example 9 A mixture of 3.56 g of ⁇ -bromo-benzyl- (3-pyridyl) ketone hydrobromide and 3.66 g of dimethylmalonic acid monoethyl ester sodium salt in 100 ml of aqueous ethanol is heated to reflux with stirring . After adding 1 ml of concentrated sulfuric acid, the solution is stirred under reflux for one hour and at 50 ° for 15 hours. The mixture is cooled and concentrated to dryness under reduced pressure. The residue, an oil, is chromatographed on 250 g of silica gel.
  • Methyl-malonic acid mono-ethyl ester [ ⁇ -nicotinoyl-benzyl] ester (oil), starting from ⁇ -brorn-benzyl- (3-pyridyl) ketone hydrobromide and methyl-malonic acid mono-ethyl ester sodium salt.
  • Example 10 A mixture of 6.5 g of dimethyl malonic acid monoethyl ester [ ⁇ -nicotinoyl benzyl] ester, 4.8 g of ammonium acetate and 50 ml of glacial acetic acid. is stirred for 2 hours at a bath temperature of 140 °. It is cooled, the reaction mixture is poured onto 400 ml of ice water and the pH is adjusted to 8.0 with concentrated aqueous ammonia solution. It is extracted three times with 100 ml of ethyl acetate and the ethyl acetate extracts are washed twice with 30 ml of saturated saline. The combined organic phases are dried over magnesium sulfate and evaporated to dryness under reduced pressure.
  • Example 12 A solution of 6.2 g of ⁇ -aminobenzyl- (3-pyridyl) ketone in 100 ml of anhydrous tetrahydrofuran is mixed with 8.8 g of dimethyl-malonic acid monoethyl ester chloride and 7.2 with stirring and introducing nitrogen ml of N, N-diisopropylethylamine were added. The mixture is stirred for 15 hours and evaporated to dryness under reduced pressure. The residue is chromatographed on 500 g of silica gel. Fractions 1-6, eluted with 400 ml of chloroform each, are discarded.
  • Example 13 A solution of 2.1 g of N- [ ⁇ - (3-pyridyl) phenacyl] dimethyl malonic acid monoethyl ester mono amide in 40 ml of phosphorus oxychloride is heated under reflux for 4 hours. The mixture is cooled and the mixture is poured onto ice. The oil which has separated out is extracted with 100 ml of ethyl acetate. The ethyl acetate solution is twice with 20 ml of water, twice with 20 ml of 1-n. Sodium carbonate solution and extracted again with 20 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on 70 g of silica gel.
  • Fractions 1-5 eluted with 80 ml of chloroform each, are discarded.
  • Fractions 6-8 eluted with 80 ml of chloroform each, are combined and evaporated to dryness under reduced pressure. The residue is triturated with petroleum ether, the ethyl 2- [4-phenyl] 5- (3-pyridyl) -oxazol-2-yl] -2-methyl-propionate crystallizing. 70-71 °.
  • ⁇ -Amino-benzyl- (3-pyridyl) ketone can be produced in the following way: 10.8 g of benzyl (3-pyridyl) ketone are stirred together with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine at 100 ° for 6 hours. The reaction mixture is poured onto ice / water and stirred for 15 minutes. The precipitated crystals are filtered off, washed with water and dried in a high vacuum. The benzyl (3-pyridyl) ketone oxime of mp 122-126 ° is obtained.
  • a solution of 7.7 g of p-toluenesulfochloride in 15 ml of pyridine is added dropwise to a solution of 8.5 g of benzyl- (3-pyridyl) ketone oxime in 20 ml of pyridine which is stirred at -10 ° within 5 minutes.
  • the reaction mixture is kept in the refrigerator for 24 hours and then poured onto ice / water. After stirring and rubbing in a little, the precipitated oil solidifies to crystals. These are filtered off, washed with water and dried in a high vacuum.
  • the benzyl- (3-pyridyl) -ketone-oxime-p-toluenesulfonic acid ester is obtained, which is used in the next step without further purification.
  • Example 14 An ointment containing 5% of 2- [4-phenyl-5- (l-oxido-3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid ethyl ester can be prepared as follows: Composition:
  • Sorbitan sesquioleate 5.0% p-hydroxybenzoic acid ester 0.2%
  • the fatty substances and emulsifiers are melted together.
  • the preservative is dissolved in water and the solution is emulsified into the fat melt at elevated temperature. After cooling, a suspension of the active ingredient is incorporated into part of the fat melt in the emulsion.
  • Example 15 A cream containing 10% ethyl 2- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methyl-propionate can be prepared as follows:
  • Triethanolamine added, whereby a mucus is obtained.
  • a mixture of isopropyl palmitate, cetyl palmitate, silicone oil, sorbitan monostearate and polysorbate is heated to approximately 75 ° and incorporated into the mucus, which is likewise heated to approximately 75 °, with stirring.
  • the cream base cooled to room temperature is then used to produce a concentrate with the active ingredient.
  • the concentrate is homogenized by means of a continuous homogenizer and then added to the base as a proton.
  • Example 16 A cream containing 5% ethyl 2- [4-phenyl-5- (l-oxido-3-pyridyl) oxazol-2-yl] -2-methyl-propionate can be obtained as follows.
  • Triglyceride mixture of saturated medium-fat fatty acids 5.0%
  • Cetomacrogol 1000 1.0% microcrystalline cellulose 0.5%
  • Cetyl alcohol, cetyl palmitate, the triglyceride mixture, stearic acid and glycerol stearate are melted together.
  • the microcrystalline cellulose is dispersed in part of the water.
  • Cetomacrogol is dissolved in the remaining part of the water and so is the propylene glycol like the slime mixed into it.
  • the fat phase is then added to the water phase with stirring and stirred cold. Finally, the active ingredient is rubbed with part of the base and the rubbing is then incorporated into the rest of the cream.
  • Example 17 A transparent hydrogel containing 5% ethyl 2- [4-phenyl5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methyl-propionate is prepared as follows:
  • the hydroxypropyl methyl cellulose is swollen in the water.
  • the active ingredient is dissolved in a mixture of isopropanol and propylene glycol.
  • the active ingredient solution is then mixed with a swollen cellulose derivative and, if desired, with fragrances (0.1%).
  • Example 18 A transparent hydrogel containing 5% ethyl 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methyl propionate is prepared as follows:
  • the active ingredient is dissolved in a mixture of isopropanol and propylene glycol.
  • the active ingredient solution is then mixed with the gel, it being possible, if desired, to add fragrance (0.1%).
  • Example 19 A foam spray containing 1% 2- [4-phenyl-5- (l-oxido-3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid can be produced as follows:
  • Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan stearate are melted together. Methyl and propyl paraben are dissolved in hot water. The melt and the solution are then mixed. The active ingredient, suspended in propylene glycol, is incorporated into the base. Chemoderm is then added and water is added to the final weight.
  • Example 20 A mixture of 4.0 g of ⁇ -hydroxyphenyl - [(3-pyridyl) methyl] ketone and 0.6 ml of triethylamine in 70 ml of anhydrous benzene is stirred at 10 ° with a solution of 3.7 g of 2-ethoxymethyl-2-methyl-propionic acid chloride in 20 ml of anhydrous benzene were added over the course of 20 minutes.
  • the mixture is then stirred for three hours at room temperature, mixed with 30 ml of ethyl acetate and 60 ml of water and stirred for another hour at room temperature.
  • the aqueous phase is separated off and washed twice with 20 ml of ethyl acetate.
  • the combined organic phases are washed with 20 ml saturated saline, 20 ml 2-n. Potassium bicarbonate solution and again 20 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure.
  • Example 21 A solution of 2.0 g (2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl -2-methyl-1-ethoxy- ⁇ ropan in 40 ml acetone and 12 ml water Potassium permanganate is added in portions at room temperature with vigorous stirring until no more discoloration can be observed. The mixture is then stirred for 10 hours at room temperature and then filtered off. The filtrate is concentrated to dryness under 11 torr at 50 °. The residue is mixed with 15 ml of ice water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure.
  • Example 22 A mixture of 1.0 g of 2- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid, 0.6 g of triethylene glycol monomethyl ether and 40 mg of 4-dimethylaminopyridine in 30 ml of methylene chloride are mixed with 0.7 g of dicyclohexylcarbodiimide at room temperature while stirring well and introducing nitrogen. The mixture is stirred at room temperature for 48 hours, 40 ml of toluene are added and the mixture is filtered off. The filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 20 ml of methylene chloride.
  • Example 23 A solution of 1.43 g of diethylene glycol monochlorohydrin in 6 ml of hexamethylphosphoric triamide is stirred at 50-60 ° with 3.46 g of 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] - 2-methylpropionic acid sodium salt added. The mixture is stirred at 100 ° for 4 hours, cooled and poured onto 50 ml of ice water. The oil which has separated out is extracted with 100 ml of ether. The ether phase is mixed with 20 ml water, 20 ml 2-n. Potassium hydrogen carbonate solution and again 20 ml of water, dried over magnesium sulfate and evaporated under reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Nouveaux composés oxazoïques à triple substitution, notamment les composés ayant la formule générale:$(10,)$Un des restes R1 et R2 représente de l'hétéroaryle, et l'autre de l'aryle carbocyclique ou de l'hétéroaryle, A un hydrocarbure bivalent résiduel et R3 du carboxyle, du carboxyle estérifié ou amidifié, ses isomères et ses sels. Les composés ayant la formule (I), qui peuvent être utilisés comme anti-phlogistiques épidermiques, sont produits selon des procédés de fabrication connus.
PCT/CH1982/000009 1981-07-20 1982-01-22 Composes oxazoiques a triple substitution WO1983002613A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
HU42982A HU188308B (en) 1982-01-22 1982-01-22 Process for producing trisubstituted oxazole derivatives and pharmaceutical compositions containing them
GB08324693A GB2123831B (en) 1981-07-20 1982-01-22 Trisubstituted oxazo compounds
JP82500317A JPS59500054A (ja) 1982-01-22 1982-01-22 三置換オキサザ化合物
AU80022/82A AU8002282A (en) 1982-01-22 1982-01-22 Trisubstituted oxazo compounds
FI833280A FI833280A0 (fi) 1982-01-22 1983-09-14 Trisubstituerade oxazafoereningar
NO833350A NO833350L (no) 1982-01-22 1983-09-16 Trisubstituerte oksazaforbindelser
DK423683A DK423683A (da) 1982-01-22 1983-09-16 Fremgangsmaade til fremstilling af trisubstitueret oxazaforbindelser eller isomere eller salte deraf

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US28523181A 1981-07-20 1981-07-20

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WO1983002613A1 true WO1983002613A1 (fr) 1983-08-04

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PCT/CH1982/000011 WO1983002611A1 (fr) 1981-07-20 1982-01-25 Composes diazoiques a triple substitution

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EP1306377A2 (fr) * 1993-11-08 2003-05-02 Smithkline Beecham Corporation Pyridyl-oxazoles et leur utilisation comme inhibiteurs de cytokines

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JP2636819B2 (ja) 1994-12-20 1997-07-30 日本たばこ産業株式会社 オキサゾール系複素環式芳香族化合物
WO1998056788A1 (fr) 1997-06-12 1998-12-17 Rhone-Poulenc Rorer Limited Acetals cycliques imidazolyle
AU1924699A (en) 1997-12-19 1999-07-12 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositionsand uses
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
US6982270B1 (en) 1999-11-23 2006-01-03 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
WO2001038314A1 (fr) 1999-11-23 2001-05-31 Smithkline Beecham Corporation Composes de 3,4-dihydro-(1h)quinazolin-2-one utilises comme inhibiteurs de kinase csbp/p38
AU1781601A (en) 1999-11-23 2001-06-04 Smithkline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
MXPA03003612A (es) 2000-10-23 2003-06-19 Smithkline Beecham Corp Compuestos novedosos.
AU2003225072A1 (en) 2002-04-19 2003-11-03 Smithkline Beecham Corporation Novel compounds
JP2008535822A (ja) 2005-03-25 2008-09-04 グラクソ グループ リミテッド 新規化合物
TWI389690B (zh) 2005-03-25 2013-03-21 Glaxo Group Ltd 新穎化合物（一）
TW200724142A (en) 2005-03-25 2007-07-01 Glaxo Group Ltd Novel compounds
KR20080002865A (ko) 2005-03-25 2008-01-04 글락소 그룹 리미티드 피리도[２,３-ｄ]피리미딘-７-온 및３,４-디히드로피리미도[４,５-ｄ]피리미딘-２(１ｈ)-온유도체의 제조 방법

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US3578671A (en) * 1967-11-06 1971-05-11 Wyeth John & Brother Ltd Oxazoles
CH561718A5 (fr) * 1971-05-10 1975-05-15 Ciba Geigy Ag
GB1542315A (en) * 1976-08-13 1979-03-14 Wyeth John & Brother Ltd Process for preparing oxazoles
EP0045081A2 (fr) * 1980-07-25 1982-02-03 Ciba-Geigy Ag Dérivés d'imidazole trisubstitués, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation

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US3578671A (en) * 1967-11-06 1971-05-11 Wyeth John & Brother Ltd Oxazoles
CH561718A5 (fr) * 1971-05-10 1975-05-15 Ciba Geigy Ag
GB1542315A (en) * 1976-08-13 1979-03-14 Wyeth John & Brother Ltd Process for preparing oxazoles
EP0045081A2 (fr) * 1980-07-25 1982-02-03 Ciba-Geigy Ag Dérivés d'imidazole trisubstitués, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation

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Publication number Priority date Publication date Assignee Title
EP1306377A2 (fr) * 1993-11-08 2003-05-02 Smithkline Beecham Corporation Pyridyl-oxazoles et leur utilisation comme inhibiteurs de cytokines
EP1306377A3 (fr) * 1993-11-08 2003-05-07 Smithkline Beecham Corporation Pyridyl-oxazoles et leur utilisation comme inhibiteurs de cytokines

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GB2123830A (en) 1984-02-08
GB8324692D0 (en) 1983-10-19
GB2123831B (en) 1986-01-15
GB8324693D0 (en) 1983-10-19
GB2123831A (en) 1984-02-08

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