SI9210098B - Benzimidazoles, drugs with this compounds, and process for their preparation - Google Patents

Benzimidazoles, drugs with this compounds, and process for their preparation Download PDF

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SI9210098B
SI9210098B SI9210098A SI9210098A SI9210098B SI 9210098 B SI9210098 B SI 9210098B SI 9210098 A SI9210098 A SI 9210098A SI 9210098 A SI9210098 A SI 9210098A SI 9210098 B SI9210098 B SI 9210098B
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methyl
imidazo
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carbon atoms
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SI9210098A
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SI9210098A (en
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Norbert Hauel
Berthold Narr
Uwe Ries
Meel Jacques Van
Wolfgang Wienen
Michael Entzeroth
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Dr. Karl Thomae
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Priority claimed from DE4103492A external-priority patent/DE4103492A1/en
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Abstract

1-Biphenylylmethyl-benzimidazole derivs. of formula (I) and their salts are new. (A) where: R1 = F, Cl, Br, 1-4C alkyl, cycloalkyl, CH2F, CHF2 or CF3 and is in the 4 position; R2 = R2 or may also be R2 when R4 = 1H-tetrazolyl; R'2 = 3-5C alkoxy substd. in the 3, 4 or 5 position by imidazolyl, or 2-5C alkoxy substd. in the 2, 3, 4 or 5 position by benzimidazolyl or tetrahydrobenzimidazolyl; R2 = e.g. (a) 2-(1-imadazolyl)ethoxy, 1-4C alkylsulphonyloxy, OSO2Ph or phenylalkylsulphonyloxy; (b) acylamino opt. N-substd. by 1-6C alkyl, Ph, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenylyl, where acyl is 1-7C alkanoyl, 2-4C alkoxycarbonyl, 1-6C alkylsulphonyl, benzoyl, phenylsulphonyl, phenylalkylsulphonyl, naphthylsulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl, where phenyl rings are opt. substd. by 1-2 of F, Cl, Br, Me and OMe, or 3-oxopyridazylinyl or (l) 3-oxodihydropyridazinyl, opt. 2-substd. by alkyl or phenylalkyl and opt. further C-substd. by 1-2 alkyl gps., Het = a C- or imino-bonded 5-membered heteroaromatic ring or a C-bonded 6-membered heteroaromatic ring. (B) where: R1 = H or F, Cl, Br, 1-4C alkyl, CH2F, CHF2 or CF3 in the 5, 6 or 7 position; R2 = Het or a gp. as defined in (l) above; R3 and R4 are as defined in (A); provided that: (a) R2 is not 3-methylimidazo (4,5-b)pyridin-2-yl or 3-n-hexylimidazo(4,5-b) pyridin-2-yl in the 6 position when R1 = H, R3 = n-Pr and R4 = COOH; (b) R2 is not benzoxazol-2-yl in the 5 or 6 position when R1 = H, R3 = n-Pr or n-Bu and R4 = 1H-tetrazolyl; (c) R2 is not 1-methyl-2-benzimidazolyl in the 5 or 6 position or 1-n-butyl-2-benzimidazolyl, 1,5-dimethyl-2-benzimidazolyl or 1-methyl-5-trifluoromethyl -2-benzimidazolyl in the 6 postion when R1 = H, R3 = n-Pr and R4 = COOH; (d) R2 is not 1-methyl-2-benzimidazolyl in the 6 position when R1 = H, R3 = n-Bu and R4 = COOH or 1H-tetrazolyl; (e) R2 is not 2-benzimidazolyl in the 6 position when R1 = H, R3 = n-Bu and R4 = COOH; unless otherwise stated, alkanoyl, alkyl and alkoxy gps. are 1-3C and cycloalkyl gps. are 3-7C.

Claims (9)

1 PATENTNI ZAHTEVKI 1. Benzimidazoli s splošno formulo1 CLAIMS 1. Benzimidazoles of general formula v kateri pomenijo Ri atom fluora, klora ali broma, alkilno, cikloalkilno, fluormetilno, difluormetilno ali trifluormetilno skupino, R2 po izbiri z eno ali dvema alkilna skupinama ali s tetrametilensko ali pentametilensko skupino substituirano 5-, 6- ali 7-člensko alkilenimino- ali alkenilenimino skupino, v kateri je metilenska skupina nadomeščena s karbonilno ali sulfonilno skupino, po izbiri z alkilno ali fenilno skupino mono- ali disubstituirano imido skupino maleinske kisline, pri čemer so lahko substituenti enaki ali različni, po izbiri v položaju 1 z alkilno skupino z 1 do 6 atomi ogljika ali cikloalkilno skupino substituirano benzimidazol-2-ilno ali 4,5,6,7-tetrahidro-benzimidazol-2-ilno skupino, pri čemer je lahko fenilno jedro ene od predhodno navedenih benzimidazolnih skupin dodatno substituirano z atomom fluora, metilno ali trifluormetilno skupino, imidazo[2. l-b]tiazol-6-ilno imidazo[1.2-a]piridin-2-ilno, 5,6,7,8-tetrahidro-imidazo[ 1.2-a]piridin-2-ilno, imidazo-[ 1.2-a]pirimidin-2-ilno, imdazo[4.5-b]piridin-2-ilno, imidazo[4.5-c]piridin-2-ilno, imidazo[1.2-c]pirimidin-2-ilno, imidazo[1.2-a]pirazin-2-ilno, imidazo[1.2-b]piridazin-2-ilno, purin-8-ilno, imdazo[4.5-b]pirazin-2-ilno, imidazo[4.5-c]piridazin-2-ilno ali imidazo[4.5-d]piridazin-2-ilno skupino, piridilno skupino, ali 2 po izbiri v položaju 1 z alkilno ali benzilno skupino preko atoma ogljika vezano imidazolilno skupino, ki je lahko dodatno v ogljikovem ogrodju substituirana z alkilno skupino, R3 alkilno skupino z 1 do 5 atomi ogljika ali cikloalkilno skupino s 3 do 5 atomi ogljika, in R4 karboksi ali lH-tetrazolilno skupino, in njihove soli z anorganskimi ali organskimi kislinami ali bazami, pri čemer, če ni drugače navedeno, lahko predhodno navedeni alkilni del vsebuje vsakokrat 1 do 3 atome ogljika, predhodno navedeni cikloalkilni del pa vsakokrat 3 do 7 atomov ogljika.in which R 1 represents a fluorine, chlorine or bromine atom, an alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, R 2 is optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group substituted 5-, 6- or 7-membered alkyleneimino- or an alkenyleneimine group in which the methylene group is replaced by a carbonyl or sulfonyl group, an mono- or disubstituted imido maleic group optionally substituted by an alkyl or phenyl group, the substituents being the same or different, optionally in position 1 with an alkyl group of 1 up to 6 carbon atoms or a cycloalkyl group substituted by a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group, the phenyl nucleus of one of the aforementioned benzimidazole groups being additionally substituted by a fluorine atom, methyl or a trifluoromethyl group, imidazo [2. 1b] Thiazol-6-yl imidazo [1,2-a] pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridin-2-yl, imidazo- [1,2-a] pyrimidine- 2-yl, imdazo [4.5-b] pyridin-2-yl, imidazo [4.5-c] pyridin-2-yl, imidazo [1,2-c] pyrimidin-2-yl, imidazo [1.2-a] pyrazin-2- yl, imidazo [1,2-b] pyridazin-2-yl, purin-8-yl, imdazo [4.5-b] pyrazin-2-yl, imidazo [4.5-c] pyridazin-2-yl or imidazo [4.5-d] a pyridazin-2-yl group, a pyridyl group, or 2 an imidazolyl group optionally in position 1 with an alkyl or benzyl group attached via a carbon atom, which may be further substituted in the carbon backbone by an alkyl group, an R3 alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, and R4 a carboxy or 1H-tetrazolyl group, and salts thereof with inorganic or organic acids or bases, wherein, unless otherwise indicated, the aforementioned alkyl moiety may each contain 1 to 3 carbon atoms. , and the aforementioned cycloalkyl moiety is in each case 3 to 7 carbon atoms. 2. Benzimidazoli s splošno formulo I po zahtevku 1 v kateri pomenijo Ri atom klora, alkilno skupino z 1 do 3 atomi ogljika ali trifluormetilno skupino R2 5-, 6- ali 7-člensko alkilenimino skupino, v kateri je lahko metilenska skupina nadomeščena s karbonilno ali sulfonilno skupino, po izbiri z alkilno skupino z 1 do 3 atomi ogljika ali s fenilno skupino mono- ali di-substituirano imido skupina maleinske kisline, pri čemer so lahko substituenti enaki ali različni, po izbiri v položaju 1 z alkilno skupino z 1 do 6 atomi ogljika ali cikloalkilno skupino substituirano bezimidazol-2-ilno ali 4,5,6,7-tetrahidro-benzimidazol-2-ilno skupino, pri čemer je lahko fenilno jedro ene od predhodno navedenih benzimidazolnih skupin dodatno substituirano z atomom fluora, metilno ali trifluormetilno skupino, imidazo[2. l-b]tiazol-6-ilno, imidazo[1.2-a]piridin-2-ilno, 5,6,7,8- tetrahidroimidazo[ 1,2-a]piridin-2-ilno, imidazo[ 1.2-a]pirimidin-2-ilno, imidazo[4.5-b]piridin-2-ilno, imidazo[4.5-c]piridin-2-ilno, imidazo[l .2-c]pirimidin-2-ilno, imidazo[1.2-a]pirazin-2-ilno, imidazo[1.2-b]piridazin-2-ilno, purin-8-ilno, imidazo[4.5-b]pirazin-2-ilno, imidazo[4.5-c]piridazin-2-ilno ali imidazo[4.5-d]piridazin-2-ilno skupino, piridilno skupino, ali v položaju 1 z alkilno skupino z 1 do 3 atomi ogljika ali z benzilno skupino substituirano imidazol-4-ilno skupino, ki je lahko dodatno v ogljikovem ogrodju substituirana z alkilno skupino z 1 do 3 atomi ogljika, 3 R3 alkilno skupino z 1 do 5 atomi ogljika ali cikloalkilno skupino s 3 do 5 atomi ogljika, in R4 karboksilno ali ΙΗ-tetrazolilno skupino, in njihove soli z anorganskimi ali organskimi kislinami ali bazami.Benzimidazoles of the general formula I according to Claim 1 in which R 1 represents a chlorine atom, an alkyl group having 1 to 3 carbon atoms or a trifluoromethyl group R 2 a 5-, 6- or 7-membered alkyleneimine group in which the methylene group may be replaced by a carbonyl group or a sulfonyl group, optionally with an alkyl group having 1 to 3 carbon atoms or with a phenyl group a mono- or di-substituted imido maleic acid group, the substituents being the same or different, optionally in position 1 with an alkyl group having 1 to 3 6 carbon atoms or a cycloalkyl group substituted by a bezimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group, the phenyl nucleus of one of the aforementioned benzimidazole groups being additionally substituted by a fluorine atom, methyl or trifluoromethyl group, imidazo [2. 1b] thiazol-6-yl, imidazo [1,2-a] pyridin-2-yl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidine- 2-yl, imidazo [4.5-b] pyridin-2-yl, imidazo [4.5-c] pyridin-2-yl, imidazo [1,2-c] pyrimidin-2-yl, imidazo [1,2-a] pyrazin- 2-yl, imidazo [1,2-b] pyridazin-2-yl, purin-8-yl, imidazo [4.5-b] pyrazin-2-yl, imidazo [4.5-c] pyridazin-2-yl or imidazo [4.5- d] a pyridazin-2-yl group, a pyridyl group, or in position 1 an alkyl group having 1 to 3 carbon atoms or a benzyl group substituted imidazol-4-yl group which may be additionally substituted in the carbon backbone by an alkyl group having 1 up to 3 carbon atoms, a 3 R3 alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, and R4 a carboxyl or N-tetrazolyl group, and salts thereof with inorganic or organic acids or bases. 3. Benzimidazoli s splošno formulo I po zahtevku 1, v kateri pomenijo Ri merilno skupino ali atom klora, R2 5-, 6- ali 7-člensko alkilenimino skupino, v kateri je lahko metilenska skupina nadomeščena s karbonilno ali sulfonilno skupino, po izbiri z alkilno skupino z 1 do 3 atomi ogljika ali s fenilno skupino mono- ali di-substituirano imido skupino maleinske kisline, pri čemer so lahko substituenti enaki ali različni, po izbiri v položaju 1 z alkilno skupino z 1 do 3 atomi ogljika substituirano benzimidazol-2-ilno ali 4,5,6,7-tetrahidrobenzimidazol-2-ilno skupino, pri čemer je lahko fenilno jedro ene od predhodno navedenih benzimidazolnih skupin dodatno substituirano z atomom fluora, imdazo[1.2-a]piridin-2-ilno, 5,6,7,8-tetrahidro-imidazo[1.2-a]piridin-2-ilno, imidazo[1.2-a]pirimidin-2-ilno ali imidazo[2. l-b]tiazol-6-ilno skupino, ali v položaju 1 z alkilno skupino z 1 do 3 atomi ogljika substituirano imidazol-4-ilno skupino, R3 alkilno skupino z 1 do 5 atomi ogljika ali cikloalkilno skupino s 3 do 5 atomi ogljika, in R4 karboksilno ali ΙΗ-tetrazolilno skupino, in njihove soli z anorganskimi ali organskimi kislinami ali bazami.Benzimidazoles of the general formula I according to Claim 1, in which R 1 represents a measuring group or a chlorine atom, R 2 a 5-, 6- or 7-membered alkyleneimine group in which the methylene group may be replaced by a carbonyl or sulphonyl group, optionally by an alkyl group having 1 to 3 carbon atoms or a phenyl group having a mono- or di-substituted imido group of maleic acid, the substituents being the same or different, optionally in position 1 with an alkyl group having 1 to 3 carbon atoms substituted by benzimidazole-2 -yl or 4,5,6,7-tetrahydrobenzimidazol-2-yl group, wherein the phenyl nucleus of one of the aforementioned benzimidazole groups may be further substituted by a fluorine atom, imdazo [1,2-a] pyridin-2-yl, 5, 6,7,8-tetrahydro-imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyrimidin-2-yl or imidazo [2. 1b] a thiazol-6-yl group, or in position 1 an alkyl group having 1 to 3 carbon atoms substituted by an imidazol-4-yl group, an R 3 alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, and R4 is a carboxyl or N-tetrazolyl group, and their salts with inorganic or organic acids or bases. 4. Naslednji benzimidazoli s splošno formulo I po zahtevku 1: (a) 4'-[[2-n-propil-4-metil-6-(l-metilbenzimidazol-2-il)-benzimidazol-l-il]metil]bifenil-2-karboksilna kislina (b) 4'-[[2-n-propil-4-metil-6-( l-metilbenzimidazol-2-il)-benzimidazol- l-il]metil]-2-(1 H-tetrazol-5-il)bifenil (c) 4'-[[2-n-propil-4-meril-6-(butansultam-l-il)-benzimidazol-l-il]metil]-2-(1 H-tetrazol-5-il)bifenil 4 (e) 4'-[(2-ciklopropil-4-metil-6-(l-metilbenzimidazol-2-il)benzimidazol-1 -il)-metil]biefnil-2-karboksilna kislina (f) 4’-[(2-n-propil-4-metil-6-( lmetil-5-fluor-benzimidazol-2-il)benzi-midazol- l-il)metil]bifenil-2-karboksilna kislina (g) 4'-[(2-n-propil-4-metil-6-(imidazo[1.2-a]pirimidin-2-il)benzimidazol-l-il)metil]-2-(1 H-tetrazol-5-il)bifenil (h) 4'-[(2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-iniidazo[ 1,2-a]-piridin-2-il)benzimidazol- l-il)metil]bifenil-2-karboksilna kislina (i) 4'-[(2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[ 1,2-a]-piridin-2-il)benzimidazol- l-il)metil]-2-( lH-tetrazol-5-il)bifenil (j) 4'-[(2-n-propil-4-klor-6-(l-metilbenzimidazol-2-il)benzimidazol-l-il)metil]-2-(lH-tetrazol-5-il)bifenil (k) 4'-[[2-n-propil-4-metil-6-(imidazo[2. l-b]tiazol-6-il)benzimidazol-l-il]metil]bifenil-2-karboksilna kislina (l) 4'-[[2-etil-4-metil-6-(butansultam-l-il)benzimidazol- l-il]metil]-2-( 1H-tetrazol-5-il)bifenil (m) 4'-[[2-n-butil-4-metil-6-(l-metilbenzimidazol-2-il)benzimidazol-l-il]metil]-2-(lH-tetrazol-5 -il)bifenil (n) 4'-[[2-n-propil-4-metil-6-(imidazo[ 1 2-a]piridin-2-il)benzimidazol- 1- il]metil]bifenil-2-karboksilna kislina (o) 4'-[[2-n-propil-4-metil-6-(imidazo[ 1.2-a]piridin-2-il)benzimidazol- l-il]metil]- 2- ( lH-tetrazol-5-il)bifenil (P) 4'-[[2-n-propil-4-metil-6-(imidazo[2. l-b]tiazol-6-il)benzimidazol- l-il]metil]-2-( 1 H-tetrazol-5-il)bifenil (q) 4'-[[2-n-propil-4-metil-6-(l-metil-6-fluor-benzimidazol-2-il)benzimidazol- 1- il)metil]bifenil-2-karboksilna kislina, in njihove soli z anorganskimi ali organskimi kislinami ali bazami.The following benzimidazoles of general formula I according to claim 1: (a) 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid (b) 4 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] -2- (1 H -tetrazol-5-yl) biphenyl (c) 4 '- [[2-n-propyl-4-meryl-6- (butansultam-1-yl) -benzoimidazol-1-yl] methyl] -2- (1 H -tetrazol-5-yl) biphenyl 4 (e) 4 '- [(2-cyclopropyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) -methyl] biphenyl-2-carboxylic (f) 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-5-fluoro-benzimidazol-2-yl) benzymidazol-1-yl) methyl] biphenyl-2-carboxylic acid (g) 4 '- [(2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyrimidin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazole- 5-yl) biphenyl (h) 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-inidazo [1,2-a] -pyridin-2-yl (benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid (i) 4 '- [(2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-imidazo] [1, 2-alkyl-pyridin-2-yl) benzimidazol-1-yl) methyl] -2- (1H-tetr azol-5-yl) biphenyl (j) 4 '- [(2-n-propyl-4-chloro-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) methyl] -2- (1H- tetrazol-5-yl) biphenyl (k) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2. 1b] thiazol-6-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid (1) 4 '- [[2-ethyl-4-methyl-6- (butansultam-1-yl) benzimidazol-1 -yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl (m) 4 '- [[2-n-butyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1 -yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl (n) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1 2-a] pyridin-2- yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid (o) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [1,2-a] pyridin-2-yl) benzimidazole - 1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl (P) 4 '- [[2-n-propyl-4-methyl-6- (imidazo [2,1b] thiazol-6 -yl) benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) biphenyl (q) 4 '- [[2-n-propyl-4-methyl-6- (1-methyl- 6-fluoro-benzimidazol-2-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, and their salts with inorganic or organic acids or bases. 5. 4'-[ [2-n-propil-4-metil-6-( 1 -metilbenzimidazol-2-il)benzimidazol-1 -il]metil]bifenil- 2- karboksilna kislina in njene soli z anorganskimi ali organskimi kislinami ali bazami. 54 '- [[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and its salts with inorganic or organic acids or bases. 5 6. Fiziološko prenesljive soli spojin po vsaj enem od zahtevkov 1 do 5 z anorganskimi ali organskimi kislinami ali bazami.Physiologically tolerable salts of the compounds according to at least one of Claims 1 to 5 with inorganic or organic acids or bases. 7. Zdravilo, ki vsebuje spojino po vsaj enem od zahtevkov 1 do 5 ali fiziološko prenesljivo sol po zahtevku 6 poleg po izbiri enega ali več inertnih nosilcev in/ali razredčil.Medicament comprising a compound according to at least one of Claims 1 to 5 or a physiologically tolerable salt according to Claim 6, in addition to optionally one or more inert carriers and / or diluents. 8. Uporaba spojine po vsaj enem od zahtevkov 1 do 6 za pripravo zdravila z angiotenzinskim antagonističnim učinkom.Use of a compound according to at least one of claims 1 to 6 for the preparation of a medicament with an angiotensin antagonist effect. 9. Postopek za pripravo zdravila po zahtevku 7, označen s tem, da na nekemični način vdelamo spojino po vsaj enem od zahtevkov 1 do 6 v enega ali več inertnih nosilcev in/ali razredčil.Process for the preparation of a medicament according to Claim 7, characterized in that the compound according to at least one of Claims 1 to 6 is incorporated in a non-chemical manner into one or more inert carriers and / or diluents. 10. Postopek za pripravo benzimidazolov po zahtevkih 1 do 6, označen s tem, da a) cikliziramo spojino s splošno formuloProcess for the preparation of benzimidazoles according to Claims 1 to 6, characterized in that a) the compound of the general formula is cyclized (II) , v kateri sta Ri in R2, kot je definirano v zahtevkih 1 do 5, eden od ostankov Xi ali Yi pomeni skupino s splošno formulo,(II) in which R 1 and R 2, as defined in claims 1 to 5, one of the residues X 1 or Y 1 represents a group of general formula, 6 drugi od ostankov X! ali Yi pa skupino s splošno formulo, 66 second of the remains of X! or Yi is a group of general formula, 6 Z 2 R3 pri čemer sta R3 in R4, kot je definirano v zahtevkih 1 do 5, Rg je atom vodika ali R3CO-skupina, pri čemer je R3, kot je definirano predhodno, Zi in Z2, ki sta lahko enaka ah različna, pomenita po izbiri substituirane amino skupine ah po izbiri z nižjimi alkilnimi skupinami substituirane hidroksi ah merkapto skupine, ah Zi in Z2 skupaj pomenita atom kisika ah žvepla, po izbiri z alkilno skupino z 1 do 3 atomi ogljika substituirano imino skupino, alkilendioksi ah alkilenditio skupino z vsakokrat 2 ah 3 atomi ogljika, pri čemer mora eden od ostankov Xi ah Yi pomeniti skupino s splošno formulo ahZ 2 is R 3 wherein R 3 and R 4 are as defined in claims 1 to 5, R 8 is a hydrogen atom or an R 3 CO group, wherein R 3 is as defined above, Z 1 and Z 2, which may be the same or different, mean optionally substituted amino groups ah optionally substituted lower alkyl groups hydroxy ah mercapto groups, ah Z1 and Z2 together represent an oxygen atom ah sulfur, optionally an alkyl group having 1 to 3 carbon atoms substituted imino group, alkylenedioxy ah alkylenedithio group with each 2 ah 3 carbon atoms, one of the residues Xi ah Yi must represent a group of general formula ah in po izbiri tako dobljeni ustrezni N-oksid reduciramo, ah b) benzimidazol s splošno formulo (III),and optionally reducing the corresponding N-oxide thus obtained, ah b) benzimidazole of general formula (III), 7 R7 R H v kateri so Ri do R3, kot je definirano v zahtevkih 1 do 5, presnovimo z bifenilno spojino s splošno formuloH in which R 1 to R 3 are as defined in claims 1 to 5 is reacted with a biphenyl compound of general formula / (IV) , v kateri je Rt, kot je definirano v zahtevkih 1 do 5 in Z3 pomeni nukleofilno izstopno skupino, ali c) za pripravo spojine s splošno formulo I, v kateri R4 pomeni karboksi skupino, spojino s splošno formulo R/ (IV) in which R 1 is as defined in claims 1 to 5 and Z 3 represents a nucleophilic leaving group, or c) for the preparation of a compound of general formula I in which R 4 represents a carboxy group, a compound of general formula R (V) , v kateri so Ri do R3, kot je definirano v zahtevkih 1 do 5, in je(V), wherein R 1 to R 3 are as defined in claims 1 to 5, and is 8 RV skupina, ki se da prevesti v karboksi skupino s hidrolizo, termolizo ali hidrogenolizo, presnovimo v ustrezno karboksi spojino, ali d) za pripravo spojine s splošno formulo I, v kateri R4 pomeni lH-tetrazolilno skupino, odcepimo zaščitni ostanek spojine s splošno formulo8 The RV group which can be converted to the carboxy group by hydrolysis, thermolysis or hydrogenolysis is converted into the corresponding carboxy compound, or d) to prepare a compound of general formula I in which R 4 represents a 1H-tetrazolyl group, the protecting residue of the compound of general formula (vi) . v kateri so Ri, R2 in R3, kot je definirano v zahtevkih 1 do 5 in R4" pomeni lH-tetrazolilno skupino, zaščiteno v 1- ali 3-položaju z zaščitnim ostankom, ali e) za pripravo spojine s splošno formulo I, v kateri R4 pomeni lH-tetrazolilno skupino, spojino s splošno formulo(vi). wherein R 1, R 2 and R 3 are as defined in claims 1 to 5 and R 4 " means a 1H-tetrazolyl group protected in the 1- or 3-position with a protecting residue, or e) for the preparation of a compound of general formula I in which R4 represents a 1H-tetrazolyl group, a compound of general formula CN (VII), v kateri so Ri do R3, kot je definirano v zahtevkih 1 do 5, presnovimo z dušikvodikovo kislino ali njenimi solmi, ali 9 f) za pripravo spojin s splošno formulo I, v kateri R2 pomeni eno od skupin: imidazol[1.2-a]piridin-2-ilno, imidazol[ 1.2-a]pirimidin-2-ilno, imidazol[1.2-c]pirimidin-2-ilno, imidazo[1.2-a]pirazin-2-ilno, imidazo[1.2-b]piridazin-2-ilno ali imidazo[2.1-b]tiazol-6-ilno, navedenih v zahtevkih 1 do 5, presnovimo spojino s splošno formuloCN (VII) in which R 1 to R 3 are as defined in claims 1 to 5 are reacted with hydrochloric acid or its salts, or 9 f) for the preparation of compounds of general formula I in which R 2 represents one of the groups: imidazole [1,2-a] pyridin-2-yl, imidazole [1,2-a] pyrimidin-2-yl, imidazole [1,2-c] pyrimidin-2-yl, imidazo [1.2-a] pyrazin-2-yl, imidazo [1.2 -b] pyridazin-2-yl or imidazo [2.1-b] thiazol-6-yl, as claimed in claims 1 to 5, is a compound of general formula 9 B N (VIII), S) nh2 v kateri pomenijo eden od ostankov A, B, C ali D po izbiri z merilno skupino substituirano metinsko skupino ali atom dušika, in drugi ostanki A, B, C ali D metinske skupine, ali A in B vsakokrat metinsko skupino, in -C=D-skupina atom žvepla, s spojino s splošno formulo9 BN (VIII), S) nh2 in which one of the radicals A, B, C or D is optionally substituted by a methyl group substituted methine group or a nitrogen atom, and the other radicals A, B, C or D of a methine group, or A and B is in each case a methine group, and a -C = D-group a sulfur atom, with a compound of general formula (IX) , v kateri so Ri, R.3 in R4, kot je definirano v zahtevkih 1 do 5 in Z4 pomeni nukleofilno izstopno skupino, kot je atom halogena, npr. atom klora ali broma, ali g) za pripravo spojin s splošno formulo I, v kateri R2 pomeni eno od skupin: benzimidazol-2-ilno, imidazo[4.5-b]piridin-2-ilno, imidazo[4.5-c]piridin-2-ilno, 10 imidazo[4.5-b]pirazin-2-ilno, imidazo[4.5-c]piridazin-2-ilno, imidazo[4.5-d]piridazin-2-ilno ali purin-8-ilno, navedenih v zahtevkih 1 do 5, cikliziramo spojino s splošno formulo 10(IX) wherein R 1, R 3 and R 4 are as defined in claims 1 to 5 and Z 4 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, or g) for the preparation of compounds of general formula I in which R2 represents one of the groups: benzimidazol-2-yl, imidazo [4.5-b] pyridin-2-yl, imidazo [4.5-c] pyridin- 2-yl, 10 imidazo [4.5-b] pyrazin-2-yl, imidazo [4.5-c] pyridazin-2-yl, imidazo [4.5-d] pyridazin-2-yl or purin-8-yl claimed in claims 1 to 5, cyclize a compound of general formula 10 C (X) ,C (X), v kateri pomenijo nobeden, eden ali dva od ostankov Ai, Bb Q ali Di atom dušika in drugi ostanki od ostankov Ai, Bi, Ci ali Di metinske skupine kot tudi Ri j atom vodika ali fluora, metilno ali trifluormetilno skupino, eden od ostankov X2 ali Y2 pomeni Ri3-NH-skupino in drugi od ostankov X2 ali Y2 skupino s splošno formuloin which none, one or two of the residues Ai, Bb Q or Di represent a nitrogen atom and other residues of the residues Ai, Bi, Ci or Di methine group as well as Ri j a hydrogen or fluorine atom, a methyl or trifluoromethyl group, one of the residues X2 or Y2 represents a R3-NH group and the other of the residues X2 or Y2 a group of general formula pri čemer so Rj, R3 in R4, kot je definirano v zahtevkih 1 do 5, eden od ostankov Ri3 ali R14 pomeni atom vodika in drugi od ostankov Ri3 ali Ru atom vodika, alkilno skupino z 1 do 6 atomi ogljika ali cikloalkilno skupino s 3 do 7 atomi ogljika, Z5 in Zg, ki sta lahko enaka ali različna, pomenita po izbiri substituirane amino skupine ali po izbiri z nižjimi alkilnimi skupinami substituirane hidroksi ali merkapto skupine, ali Z5 in Z6 pomenita skupaj atom kisika ali žvepla, po izbiri z alkilno skupino z 1 do 3 atomi ogljika substituirano imino skupino, alkilendioksi ali alkilenditio skupino z 11 vsakokrat 2 ali 3 atomi ogljika, in po izbiri tako dobljeni ustrezni N-oksid reduciramo in tako dobljeno spojino po izbiri nato hidroliziramo in po potrebi odcepimo zaščitni ostanek, uporabljen za zaščito reaktivnih skupin pri presnovah a) do g), in/ali po potrebi tako dobljeno izomemo zmes ločimo v njene izomere in/ali tako dobljeno spojino s splošno formulo I prevedemo v njeno sol, zlasti za farmacevtsko uporabo v njeno fiziološko prenesljivo sol z anorganskimi ali organskimi kislinami ali bazami. Za Dr. KARL THOMAE Gesellschaft mit beschrankter Haftung:wherein R 1, R 3 and R 4, as defined in claims 1 to 5, one of the residues R 13 or R 14 is a hydrogen atom and the other of the residues R 3 or R 1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, Z5 and Zg, which may be the same or different, represent an optionally substituted amino group or optionally substituted lower alkyl groups hydroxy or mercapto groups, or Z5 and Z6 together represent an oxygen or sulfur atom, optionally alkyl. a group of 1 to 3 carbon atoms substituted imino group, an alkylenedioxy or alkylenedithio group of 11 each 2 or 3 carbon atoms, and optionally the corresponding N-oxide thus obtained is reduced and the compound thus obtained is then optionally hydrolyzed and, if necessary, cleaved off. to protect the reactive groups in metabolites a) to g), and / or, if necessary, separate the isomeric mixture thus obtained into its isomers and / or convert the compound thus obtained of the general formula I into its salt, in particular for pharmaceutical use in its physiologically tolerable salt with inorganic or organic acids or bases. For Dr. KARL THOMAE Company with limited liability:
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SI9210098A (en) 1994-12-31
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PL293387A1 (en) 1993-01-25
SK279261B6 (en) 1998-08-05
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