IE921936A1 - Bicyclic-substituted vinylimidazoles, -triazoles and¹-tetrazoles - Google Patents

Abstract

The invention relates to bicyclic-substituted vinylimidazoles, -triazoles and -tetrazoles of the general formula I having improved aromatase-inhibiting action.i

Description

Bicvclic-substituted vinyl imida zoles, -triazoles and -tetrazoles The present invention relates to bicyclic-substituted vinylimidazoles, -triazoles and -tetrazoles of the general formula I in which X, Y and Z, together with the two nitrogen atoms, form an imidazole, triazole or tetrazole radical, A and B are identical or different and each denote a hydrogen atom, a straight- or branched-chain Ci-C^-alkyl group or an optionally substituted aryl group or either A or B denotes a hydrogen atom and the other substituent B or A in each case denotes an optionally esterified carboxyl group, an optionally substituted carboxamide group, an alkyl or aryl ketone group or a nitrile group or A and B together denote a cycloalkylidene or polycycloalkylidene radical, which in each case can be monoor polysubstituted by Cj-Ce-alkyl groups or halogen atoms, and U either denotes the radical >CH-OH or the group >C=D, where D represents an oxygen atom or a radical ®N-ORX and -V-w- represents an alkylene radical -(CH2)nwhere n = 2, 3 or 4, or U denotes the group >C-RZ which is doubly bonded to V, where V represents the radical ?C-R3 and W represents the radical >N-R4, or U denotes a nitrogen atom doubly bonded to V, where V then likewise denotes a nitrogen atom or the group ^C-R5 and W represents the group >N-R6 where Rx, M PUS. Τ R fl (MON>06.15.’92 11:25 NO . 22 PAGE R2, R3, R4, R5 and R6 in each case denote a hydrogen atom or a straight- or branched-chain C1-C12-alkyl group.

As a result of these definitions indicated for U, V and W, the following ring systems thus result for the bicyclic substituents on the vinylic double bond: tr (benzotriazole) If A or B represent an aryl radical, this should preferably be a phenyl, naphthyl or heteroaryl radical such as, for example, a thiophene, furan, pyridine, thiazole, oxazole or diazine ring which can optionally be substituted by one or more lower alkyl radicals (1 to 4 C atoms) or halogen atoms, preferably fluorine, chlorine or bromine.

If A or B represents an esterified carboxyl group, this is primarily esterified with a straight- or branched-chain or cyclic O-alkyl radical having up to 10 carbon atoms, with an O-aryl radical, where aryl is a phenyl or naphthyl radical optionally substituted by one or more lower alkyl groups (1-4 carbon atoms) or halogen atoms (F, Cl, Br, I) or an 0-aralkyl radical, where in this the aryl and alkyl fragments have the abovementioned meaning.

Particularly preferred in this connection are the methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, OH P ij 5 . TRi.r.£_wT I ONS ( Π Ο N>06. 15. ’9 2 11:26 NO PAGE 4 tert-butoxy, cyclohexyloxy, cyclopentyloxy, phenoxy or 2,6-dichlorophenoxy radical.

If A or B is a substituted carboxamide group, this is primarily substituted by one or two, in the last case identical or different, radicals. These radicals can be straight- or branched-chain alkyl radicals having 1 to 10 carbon atoms, or aryl radicals having 6 to 10 carbon atoms and optionally substituted by alkyl groups or halogen atoms. In addition, the amide nitrogen atom can also be part of a 5- to 8-membered ring which can also contain >N-R7 where R7 denotes a hydrogen atom or a straight- or branched-chain alkyl group having 1 to 6 carbon atoms, 0 or S as a ring member.

Very particularly to be emphasised is the sub15 stitution of the carboxamide group by a methyl, ethyl, propyl, tert-butyl, phenyl or benzyl radical, two methyl, ethyl or propyl radicals, one phenyl and one methyl, one phenyl and one ethyl and also one benzyl and one methyl radical or a pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring formed together with the amide nitrogen atom.

A preferred alkyl ketone group A or B is the radical -CO-R8, where R8 denotes a straight- or branchedchain alkyl radical having 1 to 10 or a cycloalkyl radical having 3 to 12 carbon atoms and a preferred aryl ketone group is the radical -CO-R9, where R9 denotes a phenyl, naphthyl or heteroaryl radical optionally substituted by alkyl, halogen, hydroxyl or alkoxy radicals, such as, for example, a thiophene, furan, pyridine, thiazole, oxazole or diazine ring.

In particular, R8 is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, cyclopentyl or cyclohexyl radical and Rs is a phenyl, hydroxyphenyl, methoxy phenyl or chlorophenyl radical.

The compounds of the general formula I are inhibitors of oestrogen biosynthesis (aromatase inhibitors). They are thus suitable for the treatment of diseases which are caused by oestrogens or dependent on - Ο Μ PUS. TRANSLATIONS <ΜΟΝ)06.15.’92 11:27 NO . 22 PAGE 5 - 4 oestrogens. Thus, they are suitable for the treatment of oestrogen-induced or -stimulated tumours, such as, for example, carcinoma of the breast or prostate hyperplasia (The Lancet, 1984, 1237-1239, J. Med. Chem. 33, 1990, 2933).

The compounds according to the invention are also useful for affecting the fertility. Thus, a male infertility which results from increased oestrogen levels can be rectified using the novel active substances. In addition, the compounds can be used in women of reproductive age as an antifertility agent in order to inhibit ovulation by oestrogen withdrawal.

Probably aromatase inhibitors are also suitable for the treatment of imminent cardiac infarct, as in15 creased oestrogen levels in man can precede a cardiac infarct (US Patent 4,289,762).

Known substances having an aromatase-inhibiting action are, besides steroids, also non-steroidal substances, for example the various nitrogen hetero20 cycles described in European Patent Applications EP-A 0165777 to 0165784, the substituted glutarimides described in J. Med. Chem. 1986, 29, pages 1362-1369, the substituted imidazobenzenes described in European Patent Application EP 0165904, the heterocyclic-substituted toluonitriles described in European Patent Application EP-A 0236940 and the imida2o- and 5,6,7,8-tetrahydroimidazo[l,5a]pyridines carrying an optionally substituted phenyl ring, originating from US Patent US-A-4,728,465, from which in particular 5-(p-cyanophenyl)-5,6,7,8-tetra30 hydroimidazof1,5a]pyridine, hydrochloride stands out as a strongly active aromatase inhibitor {Cancer Res. 48, pp. 834-838, 1988).

The compounds of the present applications are distinguished compared to the previously known compounds by the fact that they more strongly and at the same time selectively inhibit the aromatase enzyme system. The selective action is shown by the fact that other enzyme systems are affected to a relatively small extent.

OM PUS. TRANSLATIONS 06.15.’92 1::23 NO. 22 PAGE 6 - 5 The amount of the compounds to be administered varies within a wide range and can cover any effective amount. Depending on the condition to be treated and the type of administration, the amount of the compounds administered can be 0.0001-10 mg/kg of body weight, preferably 0.001-1 mg/kg of body weight, per day.

For oral administration, capsules, pills, tablets, coated tablets etc. are suitable. Besides the active substance, the dosage units can contain a pharma10 ceutically tolerable excipient, such as, for example, starch, sugars, sorbitol, gelatin, lubricants, salicylic acid, talc etc. The individual dosage units for oral administration can contain, for example, 0.05-50 mg of the active substance (aromatase inhibitor).

For parenteral administration, the active substances can be dissolved or suspended in a physiologically tolerable diluent. Diluents used are very commonly oils with or without addition of a solubiliser, a surface-active agent, or a suspending or emulsifying mixture. Examples of oils used to be mentioned are: olive oil, groundnut oil, cotton oil, soya bean oil, castor oil and sesame oil.

The compounds can be administered in the form of a depot injection or an implant preparation, which can be formulated such that a sustained release of active substance is made possible.

As inert materials, for example, implants can contain biologically degradable polymers or synthetic silicones, such as, for example, silicone rubber. The active substances can additionally be incorporated for percutaneous application, for example in plaster.

The invention thus also relates to pharmaceutical preparations and the use of the compounds for the production of these preparations for the treatment of oestrogen-related diseases.

The tumour-inhibitory action of imidazole derivatives is based on inhibition of P-450-dependent enzyme systems (cf., for example, J. P. Van Wanne and OM RUS. TRANSLATIONS (MON>06.15.’92 11:23 NO.22 PAGE 7 -6ρ. A. J. Janssen, J. Med. Chem. 32, 1988, 2231). In addition, the action of antifungal therapeutics from the imidazole and triazole derivative series is based on a blockade of p-450-dependent biochemical reactions (loc. cit.). In addition, it has also been disclosed in the patent literature that azole derivatives have both antifungal and antitumour action at the same time (for this cf. EPA 0165777, Eli Lilly). The compounds according to the invention should therefore also have an antifungal action against human-, animal- and phytopathogenic microorganisms.

The present invention additionally relates to a process for the preparation of the compounds of the general formula I. In this process, either a) a compound of the general formula II in which V, W, X, Y and z have the meaning indicated in formula I, U' denotes the radical >CH-OH or ^“N-OR1, where R1 has the meaning indicated in formula I and the hydroxy group in ϋ' is optionally protected, and the H atoms of the methylene group bridging the two ring systems are acidic, is reacted with a ketone of the general formula III 0=<A (III) in which A and B have the meaning indicated in formula I, in the presence of a base to give a compound of the general formula IV Ο« R«S,. TRANSLATIONS < Μ Ο Ν ) 0 6 . 1 5 . ’ 9 2 11:29 NO. 22 PAGE 3 and this is converted with a dehydrating agent, and after removal of the protective group in U' which may be necessary, to a compound of the general formula I or b) a compound of th® general formula V in which V, W, X, Y and Z have the meaning indicated in formula I and U' represents the radical >CH-0H or >C=N-OR1, where Rx has the meaning indicated in formula X is reacted with a Wittig reagent of the general formula VI I in which A' or B' denotes a hydrogen atom and the other substituent B' or A' in each case denotes an optionally esterified carboxyl group, an optionally substituted carboxamide group, an alkyl or aryl ketone group or a nitrile group and E denotes a phenyl radical optionally substituted by one or more straight- or branched-chain 0Π R Id S . 'PflNSL^TIONS 96.15.’92 11:30 NO. 22 POSE 9 Cj-Ce-alJcyl radicals or halogen atoms, or a straight- or branched-chain Cj-Cg-alkyl radical, in an inert solvent between room temperature and the boiling point of the solvent used or c) a compound of the general formula VII in which A, Β, X, Y, Z and R6 have the meaning indicated in formula I, is reacted in a manner known per se with an acid R5-COOH or an aldehyde R5-CHO, in which R5 has the meaning indicated in formula I, in the case of the aldehyde under mild oxidising conditions, or with nitrous acid or its esters.

In process variant a) according to the invention, it is to be noted that the corresponding starting compounds of the general formula II must have no acidic hydrogen atoms in O', V and W.

The reaction with a ketone of the general formula III is carried out after deprotonation of the corresponding compound of the general formula II with one or two equivalents of a strong base such as, for example, lithium diisopropylamide, or primary, secondary or tertiary butyllithium. Two equivalents of a strong base are necessary if Z represents a methine group >CH, as first its proton and only then a proton of the methylene group bridging the two ring systems is removed.

The compound of the formula IV obtained is converted to a compound of the general formula I, optionally after conversion of the hydroxy group to a better leaving group, either by heating or by addition of a base, if appropriate with additional heating, by OM RUS. TRANSLATIONS (MON >06.15.’92 11:30 N 0.2 2 PAGE 10 - 9 elimination of HOH or, if the hydroxy group was converted to a leaving group Ab, by removal of HAb.

Preferably, before the introduction of the double bond the hydroxy group is converted to a chlorine function by reaction of the hydroxy compound, for example with thionyl chloride. The subsequent elimination of hydrogen chloride can then be simply effected by further heating in a chlorinating agent.

In general, however, it is expedient to perform 10 the introduction of the double bond by removal of HOH or HAb under the action of a base. Suitable bases are, besides others, for example, moderately concentrated aqueous sodium hydroxide solution or triethylamine.

Process variant b) according to the invention 15 leads by reaction of an acylazole of the general formula V with a phosphorane of the formula VII to the compounds of the general formula lb (Wittig reaction). Inert solvents used are, for example, benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide or dimethyl sulphoxide. The reaction temperature selected is preferably above 60’C.

The fact that acylazoles react with a phosphorane in the sense of a Wittig reaction was described for the first time in German Patent Application P 40 39 559.6. As acylazoles are good acylating agents (Comprehensive Heterocyclic Chemistry, Eds. A. R. Katritzky, K. T. Potts, Permagon Press 1984, Volume 4A, page 451 et seq.), an acylation of the Wittig reagent (phosphorane) of the general formula VI on the methylene carbon atom would also rather have been expected in the reaction b) according to the invention.

The acylazoles of the general formula V required as a starting material are prepared in a manner known per se from the corresponding carboxylic acids of the formula ROM R W S . TRANSLATIONS < MON )06. 15. ’92 11:31 NO PAGE 11 or derivatives of these carboxylic acids, preferably the acid chlorides, by reaction with suitable azole derivatives such as carbonyl- or sulphinyldiazole, trialklylsilylazole or else the azole itself or a metal salt of the azole. The reactions mentioned are preferably performed in inert solvents such as diethyl ether, tetrahydrofuran, dichloromethane or toluene at temperatures between 0eC and 50eC, as a rule at room temperature. Suitable azole metal salts are preferably alkali metal and alkaline earth metal or silver salts.

For the synthesis of the compounds of the general formula VII as starting materials for process variant c) according to the invention, precursors of the general formulae VIII or IX are used in which K and L represent groups which can easily be converted to amino groups, or in the case of L, also to an alkylamino group. Primarily to be considered here are nitro groups, which can be converted to amino groups by reduction according to standard processes. If K is a nitro group and L a fluorine atom, the fluorine atom can be replaced by an alkylamino group by nucleophilic substitution and, after reduction, an amino group is obtained for K but an alkylamino group -NHR6 for E.

The compounds of the general formula VIII itself can be prepared from the corresponding carboxylic acids OM PUS. TRANSLATIONS (MON>06. 15. ’ 92 :::32 NO. 22 PAGE 12 - 11 or their derivatives by the method indicated in the description of the process variant b). They can be converted into the compounds of the general formula VII analogously to variant b) . Compounds of the general formula IX are obtained by N-alkylation of an azole with the appropriate benzyl halide by customary processes. Reaction analagous to variant a) then leads to the compounds of the general formula VII.

The following examples serve to illustrate the 10 invention in greater detail.

Example 1 tert-Butyl 3-(1-imidazolyl)-3-(l-methyl-6-benzotriazolyl) acrylate Methyl benzotriazole-5-carboxylate is methylated 15 with potassium carbonate/methyl iodide in tetrahydrofuran. The product is separated by chromatography into: methyl l-methylbenzotriazole-5-carboxylate and methyl l-methylbenzotriazole-6-carboxylate, m.p. 154-156°C. 1.8 g of methyl 1-methylbenzotriazole-6-carboxylate are boiled under reflux for 3 hours with 100 ml of potassium hydroxide in methanol (10% W/V). After stripping off the solvent, the residue is dissolved in a little water and the acid is precipitated by addition of 6M hydrochloric acid. 1.6 g of the acid are boiled under reflux for one hour with 20 ml of thionyl chloride. After complete evaporation, the acid chloride remains as a pale brown crystal mass. This is dissolved in 60 ml of tetrahydro30 furan and stirred for 0,5 hours with 1.4 g of N-trimethylsilylimidazole. After evaporation of the solvent in vacuo, the residue is dissolved in 120 ml of tetrahydrofuran and boiled under reflux for 16 hours with 3.38 g of tert-butoxycarbonyltriphenylphosphorane. 240 ml of IM hydrochloric acid are added, the mixture is extracted with ether, and the water phase is rendered alkaline with potassium carbonate and extracted again with ethyl acetate. After drying the ethyl acetate phase (NazSOA) and US. TRANSLATIONS 06. 15.

NO. 22 PAGE - 12 evaporating, the residue is crystallised from ether. 630 mg of a Z/E mixture of the title compound are obtained. Recrystallisation from cyclohexane/ethanol gives 320 mg of the E isomer, m.p. 184-185“C.

Example 2 6-[Cyclohexylidene(1-imidazolyl)methyl]-1-methylbenzotriazole g of methyl l-methylbenzotriazole-6-carboxylate (see Example 1) are dissolved in 1 1 of tetrahydro10 furan and treated in portions with 4 g of lithium aluminium hydride at room temperature. After 2.5 hours, 200 ml of ethyl acetate are added dropwise at O’C, the precipitate is filtered off with suction, and the filtrate is dried and evaporated. 18.2 g of (1-methyl15 benzotriazol-6-yl)methanol are obtained. 4.75 g of this are dissolved in 125 ml of carbon tetrachloride and 44 ml of acetonitrile and treated at O’C with 12.6 g of triphenylphospine. After 2.5 hours at O’C, the mixture is diluted with ethyl acetate, washed with water and sodium chloride solution, dried (Na2SOJ and evaporated. The residue is chromatographed on silica gel. Using hexane/ ethyl acetate (1:1), 1.6 g of 6-chloromethyl-l-methylbenzotriazole are eluted.

This is dissolved in 20 ml of dimethylformamide and, after addition of 1.35 g of imidazole, treated in portions with 576 mg of sodium hydride (60% strength in mineral oil). After one hour at room temperature, the mixture is diluted with ethyl acetate, washed with sodium chloride solution, dried and evaporated, and the residue is crystallised from ethyl acetate. 6-(l-Imidazolylmethyl)-1-methylbenzotriazole, m.p. 157*C, is thus obtained. 1.9 g of this are dissolved in 86 ml of dry tetrahydrofuran and treated at -70’C with 12.2 ml of a 1.4 M solution of tert-butyllithium in pentane. After stirring for 0.5 hours at a temperature rising from -70’C to -50C, 0.92 ml of cyclohexanone is added dropwise at -50’C. After one hour at -50C, solid ammonium chloride R U S. TRANSLATIONS (MON )06. 15. ’92 11:3 NO . 22 PAGE 14 - 13 and then water are added and the mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried (NazSO4) and evaporated. The residue is dissolved in 25 ml of methylene chloride and slowly treated at O’C with 1.12 ml of thionyl chloride. After stirring for one hour at room temperature, the mixture is diluted with ethyl acetate, then rendered alkaline with 2M sodium hydroxide solution at 0*C, stirred for a further hour and added to water.

After extraction with ethyl acetate, drying (NazSOA) and evaporation, 2.1 g of a crude product are obtained, which is chromatographed on 200 g of silica gel. It is eluted with methylene chloride with the addition of amounts of methanol and 2% triethylamine rising to 15% (V/V). 140 mg of the title compound are thus obtained which, recrystallised from hexane, melts at 127-130’C.

Example 3 tert-Butyl (E)-3-(1-imidazolyl)-3-(1-methoxyimino20 1,2,3,4-tetrahydro-6-naphthyl) acrylate 2.48 g of S-oxo-5,6,7,8-tetrahydro-2hydroxynaphthoic acid (Chem. Pharm. Bull. 32 (1984) 130) in 20 ml of pyridine are treated with 1.26 g of O-methylhydroxylamine hydrochloride. After 3 hours at room temperature, the mixture is added to IM hydrochloric acid, extracted with ethyl acetate, dried (Na2S0*) and evaporated. The crystalline residue is stirred at room temperature for 15 minutes with 10 ml of thionyl chloride. The thionyl chloride is then distilled off in vacuo at 30“C. The mixture is distilled a further two times with 10 ml of methylene chloride each time, and the residue is dissolved in 30 ml of tetrahydrofuran and treated with 1.9 ml of N-trimethylsilylimidazole. After 15 minutes at room temperature, the mixture is completely evaporated in vacuo and the residue is dissolved again in ml of tetrahydrofuran and treated with 5.8 g of tertbutoxy-carbonyl triphenylphosphorane . After boiling for 17 hours under reflux, the mixture is added to IM Off RUS. TRANSLATIONS < MON )36. 15. ’92 11:34 NO. 22 PAGE 15 - 14 hydrochloric acid and extracted with ethyl acetate. The hydrochloric acid phase is rendered alkaline with potassium carbonate and extracted with ethyl acetate. After drying and evaporation of the ethyl acetate phase 4.1 g of crude product remain, which is chromatographed on 60 g of silica gel. Using methylene chloride/methanol (99si), 2.3 gof product are eluted, from which 930 mg of the pure E isomer of the title compound are obtained by crystallisation; m.p. 128e-l35‘C Example 4 tert-Butyl (E/Z)-3-(1-hydroxy-l,2,3,4-tetrahydro-6naphthyl)-3-(1-imidazolyl) acrylate 1.14 g of 5-oxo-5,ο,7,8-tetrahydro-2hydroxynaphthoic acid in 20 ml of dioxane/water (9:1, V/V) are slowly treated with 800 mg of sodium borohydride with ice-cooling. After stirring for one hour at room temperature, the mixture is added to 2M hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate phase with sodium chloride solution, drying (Na2SO(,) and evaporation, 1.13 g of the hydroxy acid are obtained, which is dissolved in 10 ml of pyridine and treated with 1 ml of acetic anhydride. After 4 days at room temperature ethyl acetate is added, the mixture is washed three times with ice-cold IM hydrochloric acid and the ethyl acetate phase is dried (Na2SO4) and evaporated. After filtering off the crystalline residue with suction using hexane, 1.2 g of 5-acetoxy-5,6,7,8-tetrahydro-2hydroxynaphthoic acid are obtained. 1.1 g of this are stirred at room temperature for one hour with 10 ml of thionyl chloride; the mixture is then evaporated in vacuo and redistilled twice with methylene chloride. The residue is dissolved in 10 ml of tetrahydrofuran and treated with 0.73 ml of N-trimethylsilylimidazole. Further reaction with 1.9 g of tert-butoxycarbonyltri35 phenylphosphorane (6 hours' reflux), working-up and chromatography is carried out analogously to Example 3. 0.8 g of the acetate of the title compound is obtained as a colourless oil. 700 mg of this are allowed to stand at PUS. TRflrSLflTIONS HO. 22 POSE 16 - 15 room temperature for 1 hour in 10 ml of methanolic potassium hydroxide solution (10% W/V). The mixture is added to water, extracted with ethyl acetate, dried (Na2SOA) and evaporated.

The residue is redistilled a further two times with methylene chloride. The residue is chromatographed on 20 g of silica gel. Using methylene chloride/methanol (99:1), 394 mg of the title compound are obtained as a colourless resin.

Example 5 tert-Butyl (E/Z)-3-(1-imidazolyl)-3-(1-oxo-1,2,3,4-tetrahydro-6 -naphthyl ) acrylate 140 mg of the final compound described in Example 4 are dissolved in 5 ml of methylene chloride and the solution is stirred at room temperature for 18 hours with 800 mg of manganese dioxide. After filtering off the manganese dioxide and evaporating, a crude product remains which, after purification by thick layer chromatography (eluent methylene chloride/methanol 9:1) gives 64 mg of the title compound as a thick oil.

Example 6 tert-Butyl e-3-(l-methyl-6-benzotriazolyl)-3-(1,2,4triazol-1-yl)acrylate 2.8 g of l-methylbenzotria2ole-6-carboxylic acid (Example 1) are reacted analogously to Example l, but using 2.35 g of l-trimethylsilyl-l,2,4-triazole. Chromatographic separation on silica gel (eluent dichloromethane/2-propanol 99:1) gives the title compound in pure form.

M.p.: 145-150’C Example 7 tert-Butyl E- and 2-3-( l-methyl-6-benzirnidazolyl )-3-( 1imidazolyl) acrylate g of l-methylbenzimida2ole-6-carboxylic acid are reacted analogously to Example 1. After separation by means of HPLC, the E isomer of the title compound (m.p.: 183-185’C) and the Z isomer (m.p.: 69-71*C) are obtained in pure form.

'J “ PUS. TRANSLATIONS (MON>06.I5.’92 11:36 NO . 22 PAGE 17 - 16 The required l-methylbenzimidazole-6-carboxylic acid is obtained by permanganate oxidation of 1,6-dimethylbenzimidazole.

Example 8 tert-Butyl 3-{l-methyl-6-indazolyl)-3-(1-imidazolyl)acrylate The title compound is obtained from 1-methylindazole-6-carboxylic acid analogously to Example 1. l-Methylindazole-6-carboxylic acid is obtained from 1,610 dimethylindazole by permanganate oxidation.

Claims (6)

1. PATENT CLAIMS

1. Bicyclic-substituted vinylimidazoles, -triazoles and -tetrazoles of the general formula I (I) 5 in which X, Y and Z, together with the two nitrogen atoms, form an imidazole, triazole or tetrazole radical, A and B are identical or different and each denote a hydrogen atom, a straight- or branched-chain Cx-Cia-alkyl 10 group or an optionally substituted aryl group or either A or 3 denotes a hydrogen atom and the other substituent B or A in each case denotes an optionally esterified carboxyl group, an optionally substituted carboxamide group, an alkyl or aryl ketone group or a nitrile group 15 or A and B together denote a cycloaikyl or poly-cycloalkyl radical, which in each case can be mono-or polysubstituted by Gj-Cg-alkyl groups or halogen atoms, and U either denotes the radical >CH-OH or the group >C-D, where D represents an oxygen atom or a radical 20 =N-OR X and -V-W- represents an alkylene radical -(CH 2 ) n where n = 2, 3 or 4, or U denotes the group >C-R 2 which is doubly bonded to V, where V represents the radical >C-R 3 and W represents the radical >N-R 4 , or U denotes a nitrogen atom doubly bonded 25 to V, where V then likewise denotes a nitrogen atom or the group £c-R s and W represents the group >N-R 6 where R 1 , R 2 , R 3 , R*, R 5 and R 6 in each case denote a hydrogen atom or a straight- or branched-chain Cx-C^-alkyl group.

2. Vinylazoles of the general formula I, in which X, 30 Y and Z each denote a >CH- group. rlT I ONS 06.:5.'92 11:

3. ? NO . 22 PAGE 19 - 18 3. Vinylazoles of the general formula I, in which, if R 1 or R 2 and/or R 3 and/or R 4 or R 5 and/or R e denote alkyl groups, these alkyl groups have 1 to 8 carbon atoms.

4. Process for the preparation of the compounds of 5 the general formula I, characterised in that either a) a compound of the general formula II in which V, W, X, Y and Z have the meaning indicated in formula I, 10 U' denotes the radical >CH-OH or >C=N-OR 1 , where R 1 has the meaning indicated in formula I and the hydroxy group in U' is optionally protected, and the H atoms of the methylene group bridging the two ring systems are acidic, is reacted with a ketone of the general formula III (HI) in which A and B have the meaning indicated in formula I, in the presence of a base to give a compound of the general formula IV K- (IV) ο. TRANSLATIONS (Μ 0Ν ) 06. 15. ’ 92 11:38 NO. 22 PAGE 20 and this is converted with a dehydrating agent, and after removal of the protective group in U' which may be necessary, to a compound of the general formula I or b) a compound of the general formula V (V) in which w V, W, X, Y and Z have the meaning indicated in formula I and U' represents the radical >CH-OH or XMI-OR 1 , where R 1 has the meaning indicated in formula I is reacted with a 10 Wittig reagent of the general formula VI in which A' or B' denotes a hydrogen atom and the other substituent B' or A' in each case denotes an optionally esterified carboxyl group, an optionally substituted 15 carboxamide group, an alkyl or aryl ketone group or a nitrile group and E denotes a phenyl radical optionally substituted by one or more straight- or branched-chain Ci-C 6 -alkyl radicals or halogen atoms, or a straight- or branched-chain C 1 -C 5 -alkyl radical, in an inert solvent 20 between room temperature and the boiling point of the solvent used or c) a compound of the general formula VII <ΜΟΝ)0ό.13.’92 11:33 NO . 22 PAGE 2 in. which A, Β, X, Y, 2 and R 6 have the meaning indicated in formula I, is reacted in a manner known per se with an acid R 5 -C00H or an aldehyde R S -CHO, in which R 5 has the 5. Meaning indicated in formula I, in the case of the aldehyde under mild oxidising conditions, or with nitrous acid or its esters.

5. Pharmaceutical preparations which contain at least one compound according to Claims 1 to 3 and a pharmaceutically tolerable excipient.

6. Use of the compounds according to Claims 1 to 3 for the production of medicaments. -218. 8. 9. 9. 10. 10. A compound substantially as hereinbefore described with reference to the Examples. A process substantially as hereinbefore described with reference to the Examples. A pharmaceutical preparation substantially as hereinbefore described with reference to the Examples. A use substantially as hereinbefore described with reference to the Examples.