HRP940752A2 - Benzimidazol, medicaments containing them and process for their preparation - Google Patents

Benzimidazol, medicaments containing them and process for their preparation Download PDF

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HRP940752A2
HRP940752A2 HRP-98/92A HRP940752A HRP940752A2 HR P940752 A2 HRP940752 A2 HR P940752A2 HR P940752 A HRP940752 A HR P940752A HR P940752 A2 HRP940752 A2 HR P940752A2
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methyl
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imidazo
benzimidazol
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Norbert Hauel
Berthold Narr
Uwe Ries
Jacques Van Meel
Wolfgang Wienen
Michael Entzeroth
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Thomae Gmbh Dr K
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Priority claimed from DE4103492A external-priority patent/DE4103492A1/en
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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.

Description

U EP-A-0 392 317 su već opisani benzimidazoli koji predstavljaju dragocjene antagoniste angiontenzina. EP-A-0 392 317 has already described benzimidazoles which are valuable angiotensin antagonists.

Sada smo utvrdili da novi benzimidazoli opće formule We have now established that new benzimidazoles of the general formula

[image] [image]

njihove 1-, 3-izomerne smjese kao također i njihove soli, osobito njihove soli s anorganskim ili organskim kiselinama ili s bazama, podnošljive za faramceutsku upotrebu, predstavljaju također dragocjene antagoniste angiontenzina, osobito angiontenzin-II-antagoniste. their 1-, 3-isomeric mixtures as well as their salts, especially their salts with inorganic or organic acids or with bases, acceptable for pharmaceutical use, are also valuable angiotensin antagonists, especially angiotensin-II antagonists.

U gornjoj općoj formuli I In the general formula I above

R1 u položaju 4 predstavlja atom fluora, klora ili broma, alkilnu skupinu s 1 do 4 ugljikova atoma, ciklo-alkilnu, fluormetilnu, difluormetilnu ili trifluormetilnu skupinu i R1 in position 4 represents a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and

R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma, koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetrahidro-benzimidazolilnom skupinom, ili također, ako R4 predstavlja 1H-tetrazolilnu skupinu, R2 predstavlja 2-(imidazol-1-il)-etoksi skupinu, R2 represents an alkoxy group with 3 to 5 carbon atoms, which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms, which is substituted in position 2, 3, 4 or 5 with a benzimidazilyl group, or by a tetrahydro-benzimidazolyl group, or also, if R4 represents a 1H-tetrazolyl group, R2 represents a 2-(imidazol-1-yl)-ethoxy group,

alkilsulfoniloksi skupinu s 1 do 4 ugljikova atoma, benzensulfoniloksi ili fenilalkan sulfoniloksi skupinu, alkylsulfonyloxy group with 1 to 4 carbon atoms, benzenesulfonyloxy or phenylalkane sulfonyloxy group,

acilamino skupinu, u kojoj acilni ostatak predstavlja alkanoilnu skupinu s 1 do 7 ugljikova atoma, u datom slučaju supstituiranu na atomu dušika s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma, s fenilnom, ciklo-alkilnom, fenilalkilnom, cikloalkilalkilnom, biciklo-heksilnom ili bifenilnom skupinom, alkoksikarbonilnu skupinu s ukupno 2 do 4 ugljikova atoma, alkilsulfonilnu skupinu s 1 do 6 ugljikova atoma, benzoilnu, benzen-sulfonilnu, fenilalkansulfonilnu, naftalensulfonilnu, cikloalkilkarbonilnu, fenilalkanoilnu ili cikloalkil-alkanoilnu skupinu, pri čemu prethodno spomenuta fenilna jezgra može biti mono- ili disupstituirana s atomom fluora, klora ili broma, s metilnom ili metoksi skupinom, a supstituenti mogu biti jednaki ili različiti, an acylamino group, in which the acyl residue represents an alkanoyl group with 1 to 7 carbon atoms, in a given case substituted on the nitrogen atom with an alkyl group having 1 to 6 carbon atoms, with phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or by a biphenyl group, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, an alkylsulfonyl group with 1 to 6 carbon atoms, a benzoyl, benzenesulfonyl, phenylalkanesulfonyl, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkyl-alkanoyl group, whereby the aforementioned phenyl nucleus can be mono - or disubstituted with a fluorine, chlorine or bromine atom, with a methyl or methoxy group, and the substituents can be the same or different,

ftalimino, homoftalimino, 2-karboksifenilkarbonilamino ili 2-karoksifenilmetilamino skupinu, pri čemu je karbonilna skupina u ftalimino skupini nadomještena s metilenskom, alkilmetilenskom ili dialkilmetilenskom skupinom, a također metilenska skupina u homoftalimino skupini može biti supstituirana s jednom ili dvije alkilne skupine, i dodatno prethodno spomenute fenilne jezgre su mono- ili disupstituirane s alkilnim ili alkoksi skupinama, pri čemu supstituenti mogu biti jednaki ili različiti i istovremeno mogu biti potpuno ili djelomično hidrirani, phthalimino, homophthalimino, 2-carboxyphenylcarbonylamino or 2-carboxyphenylmethylamino group, wherein the carbonyl group in the phthalimino group is replaced by a methylene, alkylmethylene or dialkylmethylene group, and also the methylene group in the homophthalimino group can be substituted with one or two alkyl groups, and additionally previously the mentioned phenyl nuclei are mono- or disubstituted with alkyl or alkoxy groups, whereby the substituents may be the same or different and at the same time may be fully or partially hydrogenated,

peteročlanu, šesteročlanu ili sedmeročlanu alkilimino ili alkilenimino skupinu, u kojoj metilenska skupina može biti nadomještena s karbonilnom ili sulfonilnom skupinom, u datom slučaju supstituiranu s jednom ili dvije alkilne skupine ili s tetrametilenskom ili pentametilenskom skupinom, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group, in which the methylene group can be substituted with a carbonyl or sulfonyl group, in a given case substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group,

imino skupinu bicikloalkan-2,3-dikarboksilne kiseline ili imino skupinu bicikloalken-2,3-dikarbonske kiseline, u kojoj bicikloalkanski i bicikloalkenski dio sadrži 9 ili 10 ugljikovih atoma, koja može biti supstituirana s 1, 2 ili 3 metilne skupine i endometilenska skupina može biti nadomještena s atomom kisika, imino group of bicycloalkane-2,3-dicarboxylic acid or imino group of bicycloalkene-2,3-dicarboxylic acid, in which the bicycloalkane and bicycloalkene part contains 9 or 10 carbon atoms, which can be substituted with 1, 2 or 3 methyl groups and an endomethylene group can be substituted with an oxygen atom,

amidino skupinu u datom slučaju supstituiranu s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 6 ugljikovih atom, an amidino group substituted in a given case with one or two alkyl groups, each of which has 1 to 6 carbon atoms,

imino skupinu glutarne kiseline, u kojoj je n-propilenska skupina perfluorirana, koja može biti supstituirana s jednom ili dvije alkilne skupina ili s tetrametilenskom ili pentametilenskom skupinom, the imino group of glutaric acid, in which the n-propylene group is perfluorinated, which can be substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group,

imido skupinu maleinske kiseline, u datom slučaju mono- ili disupstituiranu s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different,

peteročlani heteroatomni prsten, povezan preko ugljikovog atoma ili preko imino skupine, koji sadrži imino skupinu, atom kisika, ili sumpora, ili imino skupinu i atom kisika, sumpora, ili dušika, ili šesteročlani heteroatomni prsten povezan preko ugljikovog atoma, koji sadrži 1 ili 2 dušikova atoma, pri čemu prethodno spomenuti hetero-aromatski prstenovi u ugljikovoj strukturi mogu biti supstituirani s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili s fenilalkilnom skupinom i povezani su na šesteročlane heteroatomne prstenove preko dvaju susjednih ugljikova atoma n-propilenske ili n-butilenske skupine ili su vezani također na peteročlane, kao također na šesteročlane heteroatomne prstenove preko dvaju susjednih ugljikovih atoma, 1,3-butadienilne skupine ili preko imino skupine i susjednog ugljikovog atoma n-butilenske ili 1,3-butadienilne skupine i u tako nastalom aneliranom piridinskom prstenu metilenska skupina može biti nadomještena s dušikovim atomom, a vinilenska skupina u položaju 3, 4 prema atomu dušika nastalog piridinskog prstena, s atomom sumpora, ili u tako nastalom aneliranom fenilnom prstenu jedna ili dvije metinske skupine mogu biti nadomještene s dušikovim atomom, pri čemu dodatno prethodno spomenuti dokondenzirani aromatski ili heteroaromatski prstenovi u ugljikovoj strukturi mogu biti mono-supstituirani s atomom fluora, klora ili broma, s alkilnom, alkoksi, hidroksi, fenilnom, nitro, amino, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksi-karbonilnom, aminokarbonilnom, alkilaminokarbonilnom, dialkilaminokarbonilnom, fluormetilnom, difluormetilnom, trifluormetilnom, alkanoilnom, aminosulfonilnom, alkil-aminosulfonilnom, ili a five-membered heteroatomic ring, connected through a carbon atom or through an imino group, containing an imino group, an oxygen, or sulfur atom, or an imino group and an oxygen, sulfur, or nitrogen atom, or a six-membered heteroatomic ring connected through a carbon atom, containing 1 or 2 of nitrogen atoms, whereby the previously mentioned hetero-aromatic rings in the carbon structure can be substituted with an alkyl group having 1 to 6 carbon atoms or with a phenylalkyl group and connected to six-membered heteroatomic rings via two adjacent n-propylene or n-butylene carbon atoms groups or are attached also to five-membered, as well as to six-membered heteroatomic rings via two adjacent carbon atoms, 1,3-butadienyl group or via an imino group and an adjacent carbon atom of an n-butylene or 1,3-butadienyl group and in the resulting annealed pyridine ring the methylene group can be substituted with a nitrogen atom, and the vinylene group in p deposit 3, 4 according to the nitrogen atom of the resulting pyridine ring, with a sulfur atom, or in the resulting annealed phenyl ring, one or two methine groups can be substituted with a nitrogen atom, whereby additionally the previously mentioned co-condensed aromatic or heteroaromatic rings in the carbon structure can be mono -substituted with a fluorine, chlorine or bromine atom, with alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxy-carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkanoyl , aminosulfonyl, alkyl-aminosulfonyl, or

dialkilaminosulfonilnom skupinom, ili disupstituirani s atomom fluora ili klora, s metilnim, metoksi ili hidroksi skupinama, kao što također dva metilna supstituenta, jedan prema drugom u položaju 1,2, mogu biti međusobno povezani s metilenskim ili etilenskim mostom, i u datom slučaju NH skupina prisutna u imidazolnom prstenu može biti supstituirana s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma, s fenilalkilnom skupinom ili sa ciklo-alkilnom skupinom, ili with a dialkylaminosulfonyl group, or disubstituted with a fluorine or chlorine atom, with methyl, methoxy or hydroxy groups, as well as two methyl substituents, one to the other in the 1,2 position, can be connected to each other with a methylene or ethylene bridge, and in a given case an NH group present in the imidazole ring may be substituted with an alkyl group having 1 to 6 carbon atoms, with a phenylalkyl group or with a cycloalkyl group, or

preko ugljikova atoma povezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina susjedna dušikovom atomu u pirolidinskom ili piperidinskom prstenu mogu biti nadomješteni s karbonilnom skupinom, a pyrrolidine, piperidine or pyridine ring connected via carbon atoms, whereby the phenyl residue condensed onto the pyridine ring via two adjacent carbon atoms and the methylene group adjacent to the nitrogen atom in the pyrrolidine or piperidine ring can be replaced with a carbonyl group,

imidazolidindion skupinu u datom slučaju supstituiranu s alkilnom, fenilalkilnom, tetrametilenskom, penta-metilenskom ili heksametilenskom skupinom, an imidazolidinedione group optionally substituted with an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group,

piridazin-3-on ili dihidro-piridazin-3-on skupinu koja u položaju 2 može biti supstituirana u datom slučaju s alkilnom skupinom supstituiranom s fenilnom skupinom, i dodatno u ugljikovoj strukturi s 1 ili 2 alkilne skupine, pyridazin-3-one or dihydro-pyridazin-3-one group which in position 2 can be substituted in a given case with an alkyl group substituted with a phenyl group, and additionally in the carbon structure with 1 or 2 alkyl groups,

R7-NR6-CO-NR5 skupinu u kojoj R7-NR6-CO-NR5 group in which

R5 predstavlja vodikov atom, alkilnu skupinu s 1 do 8 ugljikovih atoma, cikloalkilnu skupinu s 5 do 7 ugljikovih atoma ili fenilnu skupinu, R5 represents a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or a phenyl group,

R6 predstavlja vodikov atom, alkilnu skupinu s 1 do 8 ugljikovih atoma, alkenilnu skupinu s 3 do 5 ugljikovih atoma, fenilnu skupinu, fenilalkilnu skupinu ili ciklo-alkilnu skupinu s 5 do 7 ugljikovih atoma, R6 represents a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a phenyl group, a phenylalkyl group or a cycloalkyl group with 5 to 7 carbon atoms,

R7 predstavlja vodikov atom ili alkilnu skupinu s 1 do 6 ugljikovih atoma ili R7 represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms or

jedan od ostataka R5, R6 ili R7 također predstavlja bicikloheksilnu ili bifenilnu skupinu ili one of the residues R5, R6 or R7 also represents a bicyclohexyl or biphenyl group or

R6 i R7 zajedno s atomom dušika, koji se nalazi između njih, tvore alkenilimino skupinu sa 4 do 6 ugljikovih atoma ravnog lanca ili morfolino skupinu ili R6 and R7 together with the nitrogen atom located between them form an alkenylimino group with 4 to 6 straight chain carbon atoms or a morpholino group or

R5 i R6 zajedno tvore alkilensku skupinu koja ima 2 do 4 ugljikova atoma, R5 and R6 together form an alkylene group having 2 to 4 carbon atoms,

1H,3H-kinazolin-2,4-dion-3-ilnu ili pentametilen-oksazolin-2-ilnu skupinu ili 1H,3H-quinazolin-2,4-dion-3-yl or pentamethylene-oxazolin-2-yl group or

R1 predstavlja vodikov atom ili u položaju 5, 6 ili 7 atom fluora, klora ili broma, alkilnu skupinu s 1 do 4 ugljikova atoma, fluormetilnu, difluormetilnu ili trifluor-metilnu skupinu i R1 represents a hydrogen atom or in position 5, 6 or 7 a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, a fluoromethyl, difluoromethyl or trifluoromethyl group and

R2 predstavlja preko ugljikovog atoma ili preko imino skupine povezan peteročlani heteroaromatski prsten, koji sadrži imino skupinu, atom kisika ili sumpora ili imino skupinu i atom kisika, sumpora ili dušika, ili preko ugljikovog atoma povezan šesteročlani heteroaromatski prsten koji sadrži 1 ili 2 dušikova atoma, pri čemu prethodno spomenuti heteroaromatski prstenovi mogu biti supstituirani u ugljikovoj strukturi s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili s fenilalkilnom skupinom i povezani su na šesteročlane heteroaromatske prstenove preko dvaju susjednih ugljikova atoma n-propilenske ili n-butilenske skupine, ili su vezani kako na peteročlane tako također i na šesteročlane heteroaromatske prstenove preko dvaju susjednih ugljikova atoma 1,3-butadienske skupine ili preko imino skupine i susjednog ugljikovog atoma n-butilenske ili 1,3-butadienske skupine, i u tako nastalom aneliranom piridinskom prstenu metinska skupina nadomještena je s dušikovim atomom, a vinilenska skupina u položaju 3,4 prema dušikovom atomu nastalog piridinskog prstena, s atomom sumpora, ili su u tako nastalom aneliranom fenilnom prstenu jedna ili dvije metinske skupine nadomještene s dušikovim atomima, pri čemu dodatno prethodno spomenuti dokondenzirani aromatski ili heteroaromatski prstenovi u ugljikovoj strukturi mogu biti monosupstituirani s atomom fluora, klora ili broma, s alkilnom, alkoksi, hidroksi, fenilnom, nitro, animo, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksikarbonilnom, aminokarbonilnom, alkilamino-karbonilnom, dialkilaminokarbonilnom, fluormetilnom, di-fluormetilnom, trifluormetilnom, alkanoilnom, amino-sulfonilnom, alkilaminosulfonilnom ili dialkilamino-sulfonilnom skupinom, ili mogu biti supstituirani s atomom fluora ili klora, s metilnim, metoksi ili hidroksi skupinama, kao što također dva metilna supstituenta, jedan prema drugom u položaju 1, 2, mogu biti međusobno povezani s metilenksim ili etilenskim mostom, i u datom slučaju NH skupina, prisutna u imidazolnom prstenu, može biti supstituirana s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma, s fenilalkilnom skupinom ili sa ciklo-alkilnom skupinom, pri čemu ako R2 represents a five-membered heteroaromatic ring connected via a carbon atom or an imino group, containing an imino group, an oxygen or sulfur atom or an imino group and an oxygen, sulfur or nitrogen atom, or a six-membered heteroaromatic ring connected via a carbon atom containing 1 or 2 nitrogen atoms, whereby the previously mentioned heteroaromatic rings can be substituted in the carbon structure with an alkyl group having 1 to 6 carbon atoms or with a phenylalkyl group and are connected to six-membered heteroaromatic rings via two adjacent carbon atoms of the n-propylene or n-butylene group, or are attached both to five-membered and also to six-membered heteroaromatic rings via two adjacent carbon atoms of the 1,3-butadiene group or via an imino group and an adjacent carbon atom of an n-butylene or 1,3-butadiene group, and in the annealed pyridine ring thus formed, the methine group is replaced with a nitrogen atom, and vinylene sk upin in the 3,4 position to the nitrogen atom of the resulting pyridine ring, with a sulfur atom, or in the resulting annealed phenyl ring, one or two methine groups are substituted with nitrogen atoms, whereby additionally the previously mentioned co-condensed aromatic or heteroaromatic rings in the carbon structure can be monosubstituted with a fluorine, chlorine or bromine atom, with alkyl, alkoxy, hydroxy, phenyl, nitro, animo, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl, fluoromethyl, di-fluoromethyl, trifluoromethyl, an alkanoyl, amino-sulfonyl, alkylaminosulfonyl or dialkylamino-sulfonyl group, or they can be substituted with a fluorine or chlorine atom, with methyl, methoxy or hydroxy groups, as well as two methyl substituents, one to the other in position 1, 2, can be mutually linked by a methylenexime or ethylene bridge, and in a given case NH costly na, present in the imidazole ring, can be substituted with an alkyl group having 1 to 6 carbon atoms, with a phenylalkyl group or with a cycloalkyl group, whereby if

(i) R1 predstavlja atom vodika, R3 je n-propilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati 3-metil-imidazo[4,5-b]-2-ilnu ili 3-n-heksil-imidazo[4,5-b]piridin-2-ilnu skupine ili ako (i) R1 represents a hydrogen atom, R3 is an n-propyl group and R4 is a carboxy group, R2 in position 6 cannot represent 3-methyl-imidazo[4,5-b]-2-yl or 3-n-hexyl- imidazo[4,5-b]pyridin-2-yl group or if

(ii) R1 predstavlja vodikov atom, R3 je n-propilna ili b-butilna skupina i R4 je 1H-tetrazolilna skupina, R2 u položaju 5 ili 6 ne može predstavljati benzoksazol-2-ilnu skupinu, ili ako (ii) R1 represents a hydrogen atom, R3 is an n-propyl or b-butyl group and R4 is a 1H-tetrazolyl group, R2 in position 5 or 6 cannot represent a benzoxazol-2-yl group, or if

(iii) R1 predstavlja vodikov atom, R3 je n-propilna skupina, a R4 je karboksi skupina, R2 u položaju 5 ili 6 ne može predstavljati 1-metilbenzimidazol-2-ilnu skupinu ili u položaju 6 ne može predstavljati 1-n-butilbenzimidazol-2-ilnu, 1,5-dimetilbenzimidazol-2-ilnu ili 1-metil-5-tri-fluormetilbenzimidazol-2-ilnu skupinu ili ako (iii) R1 represents a hydrogen atom, R3 is an n-propyl group and R4 is a carboxy group, R2 in position 5 or 6 cannot represent a 1-methylbenzimidazol-2-yl group or in position 6 cannot represent 1-n-butylbenzimidazole -2-yl, 1,5-dimethylbenzimidazol-2-yl or 1-methyl-5-trifluoromethylbenzimidazol-2-yl group or if

(iv) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi ili 1H-tetrazolina skupina, R2 u položaju 6 ne može predstavljati 1-metilbenzimidazol-2-ilnu skupinu, ili ako (iv) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy or 1H-tetrazoline group, R2 in position 6 cannot represent a 1-methylbenzimidazol-2-yl group, or if

(v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group,

ili preko ugljikovog atoma povezan pirolidinski, piperidinski ili piridinski prsten, pri čemu na piridinski prsten preko dvaju susjednih ugljikovih atoma dokondenzirani fenilni ostatak i metilenska skupina susjedna dušikovom atomu u pirolidinskom ili piperidinskom prstenu, mogu biti nadomješteni s karbonilnom skupinom, or a pyrrolidine, piperidine or pyridine ring connected via a carbon atom, whereby the phenyl residue condensed on the pyridine ring via two adjacent carbon atoms and the methylene group adjacent to the nitrogen atom in the pyrrolidine or piperidine ring can be replaced with a carbonyl group,

R3 predstavlja vodikov atom, alkilnu skupinu s 1 do 5 ugljikovih atoma u kojoj metilenska skupina može biti nadomještena s kisikovim atomom ili sumpornim atomom ili sa cikloalkilnom skupinom koja ima 3 do 5 ugljikova atoma i R3 represents a hydrogen atom, an alkyl group with 1 to 5 carbon atoms in which the methylene group can be substituted with an oxygen atom or a sulfur atom or with a cycloalkyl group having 3 to 5 carbon atoms and

R4 predstavlja karboksi, cijano, 1H-tetrazolilnu ili 1-trifenilmetiltetrazolilnu skupinu, alkoksi karbonilnu skupinu s ukupno 2 do 5 ugljikovih atoma, alkansulfonil-aminokarbonilnu, arilsulfonilaminokarbonilnu ili trifluor-metansulfonilaminokarbonilnu skupinu, R4 represents a carboxy, cyano, 1H-tetrazolyl or 1-triphenylmethyltetrazolyl group, an alkoxy carbonyl group with a total of 2 to 5 carbon atoms, an alkanesulfonyl-aminocarbonyl, arylsulfonylaminocarbonyl or trifluoro-methanesulfonylaminocarbonyl group,

pri čemu ako nije navedeno drugačije, pretodno spomenuti alkanoilni, alkilni ili alkoksi dio može sadržavati 1 do 3 ugljikova atoma, kao također prthodno spomenuti ciklo-alkilni dio može sadržati po 3 do 7 ugljikovih atoma. wherein, unless stated otherwise, the previously mentioned alkanoyl, alkyl or alkoxy part may contain 1 to 3 carbon atoms, as well as the previously mentioned cyclo-alkyl part may contain 3 to 7 carbon atoms each.

Za ostatke koji imaju značenja navedena gore pri definiciji za ostatke R1 do R3 dolaze u obzir npr. slijedeći: For the residues having the meanings given above in the definition for residues R1 to R3, the following are considered, for example:

R1: atom vodika, flora, klora ili broma, metil, etil, n-propil, izopropil, izobutil, n-butil, 1-metil-n-propil, 2-metil-n-propil, terc.butil, ciklo-propil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, fluormetil, difluormetil ili trifluor-metil, R1: hydrogen, fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, 1-methyl-n-propyl, 2-methyl-n-propyl, tert.butyl, cyclo-propyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethyl,

R2: 3-(imidazol-1-il)-propioksi, 4-(imidazol-1-il)-butoksi, 5-(imidazol-1-il)-pentoksi, 2-(benzimidazol-1-il)etoksi, 3-(benzimidazol-1-il)-propoksi, 4-(benzimidazol-1-il)-butoksi, 5-(benzimidazol-1-il)-pentoksi, 2-(tetra-hidro-benzimidazol-1-il)-etoksi, 3-(tetrahidrobenzimidazol-1-il)-propoksi, 4-(tetrahidrobenzimidazol-1-il)-butoksi, 5-(tetrshidrobenzimidazol-1-il)-pentoksi, metansulfoniloksi, etansulfoniloksi, n-propansulfoniloksi, izopropan-sulfonil-oksi, n-butansulfoniloksi, benzensulfoniloksi, 4-fluor-benzensulfoniloksi, 4-brombenzensulfoniloksi, 4-metil-benzensulfoniloksi, 4-metoksibenzensulfoniloksi, 3,4-di-klorbenzensulfoniloksi, fenilmetansulfoniloksi, 2-fenil-etansulfoniloksi, 3-fenilpropansulfoniloksi, formilamino, acetilamino, propionilamino, butanoilamino, izobutanoil-amino, pentanoilamino, 3-metilbutanoilamino, heksanoil-amino, metoksikarbonilamino, etoksikarbonilamino, n-propoksikarbonilamino, izopropoksikarbonilamino, metan-sulfonilamino, etansulfonilamino, n-propansulfonilamino, izopropansulfonilamino, n-butansulfonilamino, n-pentan-sulfonilamino, n-heksansulfonilamino, benzamido, benzen-sulfonilamido, 4-fluorbenzensulfonilamido, 4-klorbenzen-sulfonilamido, 4-brombenzensulfonilamido, 4-metilbenzen-sulfonilamido, 4-metoksibenzensulfonilamido, fenilmetan-sulfonilamido, 2-feniletansulfonilamido, 3-fenilpropan-sulfonilamido, naftalen-1-il-sulfonilamido, naftalen-2-il-sulfonilamido, ciklopentilkarbonilamido, cikloheksil-karbonilamido, cikloheptilkarbonilamido, fenilacetilamido, 2-fenilpropionilamido, ciklopentilacetilamido, 3-ciklo-pentilpropionilamido, cikloheksilacetamido, 3-cikloheksil-propionilamido, cikloheptilacetilamido, 3-cikloheptil-propionilamido, N-metil-formilamino, N-metil-acetilamino, N-metil-propionilamino, N-metil-butanoilamino, N-metil-izobutanoilamino, N-metil-pentanoilamino, N-metil-3-metil-butanoilamino, N-metil-heksanoilamino, N-metil-metoksi-karbonilamino, N-metil-etoksikarbonilamino, N-metil-n-propoksikarbonilamino, N-metil-izopropoksikarbonilamino, N-metil-metansulfonilamino, N-metil-etansulfonilamino, N-metil-n-propansulfonilamino, N-metil-izopropansulfonil-amino, N-metil-n-butansulfonilamino, N-metil-n-pentan-sulfonilamno, N-metil-n-heksansulfonilamino, N-metil-benz-amido, N-metil-benzensulfonilamido, N-metil-4-fluor-benzen-sulfonamido, N-metil-4-klorbenzen-sulfonamido, N-metil-4-brombenzensulfonamido, 4-metil-benzensulfonamido, N-metil-4-metoksibenzensulfonamido, N-metil-fenilmetan-sulfonil-amido, N-metil-2-feniletansulfonilamido, N-metil-3-fenil-propansulfonilamido, N-metil-naftalen-1-il-sulfon-amido, N-metil-naftalen-2-il-sulfonilamido, N-metil-ciklopentil-karbonilamido, N-metil-cikloheksilkarbonilamido, N-metil-cikloheptilkarbonilamido, N-metil-fenilacetilamido, N-metil-3-fenilpropionilamido, N-metil-ciklopentilacetil-amido, N-metil-3-ciklopentilpropionilamido, N-metil-ciklo-heksilacetamido, N-metil-3-cikloheksilpropionilamido, N-metil-cikloheptilacetilamido, N-metil-3-cikloheptil-propionilamido, N-etil-formilamino, N-etil-acetilamino, N-etil-propionilamino, N-etil-butanoilamino, N-etil-izobutanoilamino, N-etil-pentanoilamino, N-etil-3-metil-butanoilamino, N-etil-heksanoilamino, N-etil-metoksi-karbonilamino, N-etil-etoksikarbonilamino, N-etil-n-propoksikarbonilamino, N-etil-izopropoksikarbonilamino, N-etil-metansulfonilamino, N-etil-etansulfonilamino, N-etil-n-propansulfonilamino, N-etil-izopropansulfonilamino, N-etil-n-butansulfonilamino, N-etil-n-pentansulfonilamino, N-etil-n-heksansulfonilamino, N-etil-benzamido, N-etil-benzensulfonilamido, N-etil-4-fluorbenzensulfonamido, N-etil-4-klorbenzensulfonamido, N-etil-4-brombenzensulfon-amido, N-etil-4-metilbenzensulfonamido, N-etil-4-metoksi-benzensulfonamido, N-etil-fenilmetansulfonilamido, N-etil-2-feniletansulfonilamido, N-etil-3-fenilpropansulfonil-amido, N-etil-naftalen-1-il-sulfonamido, N-etil-naftalen-2-il-sulfonilamido, N-etil-ciklopentilkarbonilamido, N-etil-cikloheksilkarbonilamido, N-etil-cikloheptilkarbonilamido, N-etil-fenilacetilamido, N-etil-3-fenilpropionilamido, N-etil-ciklopentilacetilamido, N-etil-3-ciklopentilpropionil-amido, N-etil-cikloheksilacetamido, N-etil-3-cikloheksil-propionilamido, N-etil-cikloheptilacetilamido, N-etil-3-cikloheptilpropionilamido, N-n-propil-formilamino, N-n-propil-acetilamino, N-n-propil-propionilamino, N-n-propil-butanoilamino, N-n-propil-izobutanoilamino, N-n-propil-pentanoilamino, N-n-propil-(3-metilbutanoil)amino, N-n-propil-heksanoilamino, N-izopropil-formilamino, N-izopropil-acetilamino, N-izopropil-propionilamino, N-izopropil-butanoilamino, N-izopropil-izobutanoilamino, N-izopropil-pentanoilamino, N-izopropil-(3-metilbutanoil)-amino, N-izopropil-heksanoilamino, N-n-butil-formilamino, N-n-butil-acetilamino, N-n-butil-propionilamino, N-n-butil-butanoilamino, N-n-butil-izobutanoilamino, N-n-butil-pentanoilamino, N-n-butil-(3-metilbutanoil)amino, N-n-butil-heksanoilamino, N-izobutil-formilamino, N-izobutil-acetilamino, N-izobutil-propionilamino, N-izobutil-butanoilamino, N-izobutil-izobutanoilamino, N-izobutil-pentanoilamino, N-n-pentil-formilamino, N-n-pentil-acetil-amino, N-n-pentil-propionilamino, N-n-pentil-butanoilamino, N-n-pentil-izobutanoilamino, N-n-pentil-izobutanoilamino, N-n-pentil-pentanoilamino, N-(1-metil-butil)-formilamino, N-(1-metil-butil)-acetilamino, N-(1-metil-butil)-propionil-amino, N-(1-metil-butil)-butanoilamino, N-(1-metil-butil)-izobutanoilamino, N-(1-metil-butil)-pentanoilamino, N-(2-metil-butil)-formilamino, N-(2-metil-butil)-acetilamino, N-(2-metil-butil)-propionilamino, N-(2-metil-butil)-butanoil-amino, N-(2-metil-butil)-izobutanoilamino, N-(2-metil-butil)-pentanoilamino, N-(3-metil-butil)-formilamino, N-(3-metil-butil)-acetilamino, N-(3-metil-butil)-propionilamino, N-(3-metil-butil)-butanoilamino, N-(3-metil-butil)-izobutanoilamino, N-(3-metil-butil)-pentanoilamino, N-n-heksil-formilamino, N-n-heksil-acetilamino, N-n-heksil-propionilamino, N-n-heksil-butanoilamino, N-n-heksil-izobutanoilamino, N-n-heksil-pentanoilamino, N-n-propil-cikloheksilkarbonilamino, N-n-propil-cikloheksilacetil-amino, N-n-propil-(3-cikloheksil)propionilamino, N-n-izopropil-cikloheksilkarbonilamino, N-izopropil-ciklo-heksilacetilamino, N-izopropil-3-(cikloheksil)propionil-amino, N-butil-cikloheksilarbonilamino, N-n-butil-ciklo-heksilacetilamino, N-butil-3-(cikloheksil)propionilamino, N-izobutil-cikloheksilkarbonilamino, N-izobutil-ciklo-heksilkarbonilamino, N-izobutil-cikloheksilacetilamino, N-izobutil-3-(cikloheksil)propionilamino, N-n-pentil-ciklo-heksilkarbonilamino, N-n-pentil-cikloheksilacetilamino, N-n-pentil-3-(cikloheksil)propiomilamino, N-n-heksil-ciklo-heksilkarbonilamino, N-n-heksil-cikloheksilacetil-amino, N-n-heksil-3-(cikloheksil)propionilamino, ftalimino, 5-metoksi-ftalimino, 5,6-dimetoksiftalimino, 6-metoksi-ftalimino homoftalimino, 4,4-dimetil-homoftalimino, 7-metoksihomoftalimino, 6,7-dimetoksi-homoftalimino, 7-metoksi-4,4-dimetil-homoftalmino, 6,7-dimetoksi-4,4-dimetil-homoftalimino, 1,2,3,6-tetrahidro-ftalimino, heksa-hidroftalimino, cis-heksahidroftalimino, trans-heksahidro-ftalimino, 1-okso-izoindolin-2-il, 3,4-dimetil-ftalimino, 4,5-dimetil-1,2,3,6-tetrahidroftalimino, 4,5-dimetil-heksa-hidroftalimino, 4,5-dimetil-1-okso-izoindolin-2-il, 3,4-dimetoksi-ftalimino, 4,5-dimetoksi-1,2,3,4-tetrahidro-ftalimino, 4,5-dimetoksi-heksahidroftalimino, 4,5-di-metoksi-1-okso-izoindolin-2-il, 2-karboksifenil-metil-amino, 2-karboksifenilmetilen-karbonilamino, pirolidino, 2-metilpirolidino, 3-etilpirolidino, 3-izopropilpirolidino, piperidino, 3-metilpiperidino, 4-metilpiperidino, 4-etil-piperidino, 4-izopropilpiperidino, heksametilenimino, 3-metilheksametilenimino, 4-metilheksametilenimino, 3-etil-heksametilenimino, 4-izopropilheksametilenimino, 3,3-dimetil-pirolidino, 3,4-dimetilpirolidino, 3,4-dimetil-piperidino, 3,4-dimetil-piperidino, 4,4-dimetil-piperidino, 3,3-dimetil-heksametilenimino, 3,4-dimetil-heksametilen-imino, 4,4-dimetil-heksametilenimino, 3,5-dimetil-heksa-metilenimino, 3,3-tetrametilen-pirolidino, 3,3-penta-metilen-pirolidino, 3,3-tetrametilenpiperidino, 3,3-penta-metilenpiperidino, 4,4-tetrametilen-piperidino, 4,4-penta-metilen-piperidino, 3,3-tetrametilen-heksametilenimino, 3,3-pentametilen-heksametilenimino, 4,4-tetrametilen-heksa-metilenimino, 4,4-pentametilen-heksametilenimino, 2-okso-pirolidino, 2-okso-piperidino, 2-okso-heksametilenimino, propansultan-1-il, butansultam-1-il, pentansultam-1-il, imino skupina endo-biciklo[2.2.2]okt-5-en-2,3-dikarboksilne kiseline, imino skupina metil-5-norbornen-2,3-dikarbonske kiseline, 3,6-endoksi-1,2,3,6-tetrahidroftalimino skupina, imino skupina 5-norbornen-endo-2,3-dikarbonske kiseline, glutarimino, 3,3-tetrametilen-glutarimino, 3,3-penta-metilen-glutarimino, 2,2-dimetilglutarimino, 3-metil-glutarimino, 3,3-dimetil-glutarimino, 3-etil-glutarimino, 3-etil-3-metil-glutarimino, 1,3-ciklopentadikarbonil-imino, 2,4-dimetil-glutarimino, 2,4-di-n-propil-glutarimino, glutaramino, 3,3-tetrametilen-glutaramino, 3,3-penta-metilen-glutaramino, 2,2-dimetilglutaramino, 3-metil-glutaramino, 3,3-dimetil-glutaramino, 3-etil-glutaramino, 3-etil-3-metil-glutarimino, 1,3-ciklopentadikarbonil-amino, 2,4-dimetil-glutaramino, 2,4-di-n-propil-glutaramino, maleinamido, maleinimido, 2-metil-maleinamido, 3-metil-maleinamido, 2-metil-maleinimido, 2-fenil-maleinamido, 3-fenil-maleinimido, 2-fenil-maleinimido, 2,3-dimetil-maleinamido, 3-metil-2-fenil-maleinamido, 2-metil-3-fenil-maleinamido, 2-metil-3-fenil-maleinimido, 2,3-difenil-maleinamido, 2,3-difenil-maleinamido, pirolidin-2-il, pirolidin-2-on-5-il, piperidin-2-il, piperidin-2-on-1-il, piperidin-2-on-6-il, kinolin-2-il, izokinolin-1-il, izokinolin-3-il, piridin-2-il, 4-metilimidazol-2-il, 1-metilimidazol-4-il, 1-metilimidazol-5-il, 1-n-heksil-imidazol-4-il, 1-n-heksilimidazol-5-il, 1-benzilimidazol-4-il, 1-benzilimidazol-5-il, 1,2-dimetilimidazol-4-il, 1,2-dimetilimidazol-5-il, 1-n-pentil-2-metil-imidazol-4-il, 1-n-pentil-2-metil-imidazol-5-il, 1-n-butil-2-metil-imidazol-4-il, 1-n-butil-2-metil-imidazol-5-il, 1-benzil-2-metil-imidazol-4-il, 1-benzil-2-metil-imidazol-5-il, benzimid-azol-2-il, 1-metilbenzimidazol-2-il, 1-etilbenzimidazol-2-il, 1-n-propilbenzimidazol-2-il, 1-izoproilbenzimidazol-2-il, 1-n-butilbenzimidazol-2-il, 1-izobutilbenzimidazol-2-il, 1,-pentilbenzimidazol-2-il, 1-n-heksilbenzimidazol-2-il, 1-ciklopropilbenzimidazol-2-il, 1-ciklobutilbenzimid-azol-2-il, 1-ciklopentilbenzimidazol-2-il, 1-cikloheksil-benzimidazol-2-il, 5-nitrobenzimidazol-2-il, 5-aminobenz-imidazol-2-il, 5-acetamidobenzimidazol-2-il, 5-metil-benz-imidazol-2-il, 5-metoksi-benzimidazol-2-il, 5-etoksi-benzimidazol-2-il, 1-metil-5-metoksi-benzimidazol-2-il, 1,5-dimetilbenzimidazol-2-il, 1,6-dimetilbenzimidazol-2-il, 1,4-dimetil-benzimidazol-2-il, 5,6-dimetil-benzimidazol-2-il, 1,5,6-trimetil-benzimidazol-2-il, 5-klor-benzimidazol-2-il, 5-klor-1-metil-benzimidazol-2-il, 6-klor-1-metil-benzimidazol-2-il, 5,6-diklor-1-metilbenzimidazol-2-il, 5-dimetilaminobenzimidazol-2-il, 5-dimetil-1-etil-benzimid-azol-2-il, 5,6-dimetoksi-1-metil-benzimidazol-2-il, 5,6-dimetoksi-1-etil-benzimidazol-2-il, 5-fluor-1-metil-benz-imidazol-2-il, 6-fluor-1-metil-benzimidazol-2-il, 5-tri-fluormetilbenzimidazol-2-il, 5-trifluor-1-metil-benzimid-azol-2-il, 4-cijano-1-metil-benzimidazol-2-il, 5-karboksi-1-metil-benzimidazol-2-il, 5-aminokarbonilbenzimidazol-2-il, 5-aminokarboni-1-metil-benzimidazol-2-il, 5-dimetil-aminosulfonil-1-metil-benzimidazol-2-il, 5-metoksikarbonil-1-metil-benzimidazol-2-il, 5-metilaminokarbonil-1-metil-benzimidazol-2-il, 5-dimetilaminokarbonil-1-metilbenzimid-azol-2-il, 4,6-difluor-1-metil-benzimidazol-2-il, 5-acetil-1-metil-benzimidazol-2-il, 5,6-dihidroksi-1-metil-benzimid-azol-2-il, imidazo[1,2-a]piridin-2-il, 5-metil-imidazo[1,2-a]piridin-2-il, 6-metil-imidazo[1,2-a]piridin-2-il, 7-metil-imidazo[1,2-a]piridin-2-il, 8-metil-imidazo[1,2-a]piridin-2-il, 5,7-dimetil-imidazo[1,2-a]piridin-2-il, 6-amino-karbonil-imidazo[1,2-a]piridin-2-il, 6-klor-imidazo[1,2-a]-piridin-2-il, 6-brom-imidazo[1,2-a]piridin-2-il, 5,6,7,8,-tetrahidro-imidazo[1,2-a]pirimidin-2-il, imidazo[1,2-a]-pirimidin-2-il, 5,7-dimetil-imidazo[1,2-a]piridin-2-il, R2: 3-(imidazol-1-yl)-propyoxy, 4-(imidazol-1-yl)-butoxy, 5-(imidazol-1-yl)-pentoxy, 2-(benzimidazol-1-yl)ethoxy, 3 -(benzimidazol-1-yl)-propoxy, 4-(benzimidazol-1-yl)-butoxy, 5-(benzimidazol-1-yl)-pentoxy, 2-(tetra-hydro-benzimidazol-1-yl)-ethoxy , 3-(tetrahydrobenzimidazol-1-yl)-propoxy, 4-(tetrahydrobenzimidazol-1-yl)-butoxy, 5-(tetrahydrobenzimidazol-1-yl)-pentoxy, methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropane-sulfonyloxy . , propionylamino, butanoylamino, isobutanoyl-amino, pentanoylamino, 3-methylbutanoylamino, hexanoyl-amino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino onylamino, isopropanesulfonylamino, n-butanesulfonylamino, n-pentanesulfonylamino, n-hexanesulfonylamino, benzamido, benzenesulfonylamido, 4-fluorobenzenesulfonylamido, 4-chlorobenzenesulfonylamido, 4-bromobenzenesulfonylamido, 4-methylbenzenesulfonylamido, 4-methoxybenzenesulfonylamido, phenylmethane- sulfonylamido, 2-phenylethanesulfonylamido, 3-phenylpropane-sulfonylamido, naphthalen-1-yl-sulfonylamido, naphthalen-2-yl-sulfonylamido, cyclopentylcarbonylamido, cyclohexyl-carbonylamido, cycloheptylcarbonylamido, phenylacetylamido, 2-phenylpropionylamido, cyclopentylacetylamido, 3-cyclopentylpropionylamido, cyclohexylacetamido, 3-cyclohexyl-propionylamido, cycloheptylacetylamido, 3-cycloheptyl-propionylamido, N-methyl-formylamino, N-methyl-acetylamino, N-methyl-propionylamino, N-methyl-butanoylamino, N-methyl-isobutanoylamino, N-methyl- pentanoylamino, N-methyl-3-methyl-butanoylamino, N-methyl-hexanoylamino, N-methyl-methoxy-carbonylamino, N-methyl-ethoxycarbonylamino, N-methyl-n-propoxycarbonylamino, N-methyl-isoprop oxycarbonylamino, N-methyl-methanesulfonylamino, N-methyl-ethanesulfonylamino, N-methyl-n-propanesulfonylamino, N-methyl-isopropanesulfonyl-amino, N-methyl-n-butanesulfonylamino, N-methyl-n-pentane-sulfonylamino, N- methyl-n-hexanesulfonylamino, N-methyl-benz-amido, N-methyl-benzenesulfonylamido, N-methyl-4-fluoro-benzenesulfonamido, N-methyl-4-chlorobenzenesulfonamido, N-methyl-4-bromobenzenesulfonamido, 4-methyl-benzenesulfonamido, N-methyl-4-methoxybenzenesulfonamido, N-methyl-phenylmethane-sulfonyl-amido, N-methyl-2-phenylethanesulfonylamido, N-methyl-3-phenyl-propanesulfonylamido, N-methyl-naphthalene-1- yl-sulfonamido, N-methyl-naphthalen-2-yl-sulfonylamido, N-methyl-cyclopentyl-carbonylamido, N-methyl-cyclohexylcarbonylamido, N-methyl-cycloheptylcarbonylamido, N-methyl-phenylacetylamido, N-methyl-3- phenylpropionylamido, N-methyl-cyclopentylacetyl-amido, N-methyl-3-cyclopentylpropionylamido, N-methyl-cyclo-hexylacetamido, N-methyl-3-cyclohexylpropionylamido, N-methyl-cycloheptylacetylamido, N-methyl-3-cycloheptyl-propionylamido, N-ethyl-f ormylamino, N-ethyl-acetylamino, N-ethyl-propionylamino, N-ethyl-butanoylamino, N-ethyl-isobutanoylamino, N-ethyl-pentanoylamino, N-ethyl-3-methyl-butanoylamino, N-ethyl-hexanoylamino, N- ethyl-methoxy-carbonylamino, N-ethyl-ethoxycarbonylamino, N-ethyl-n-propoxycarbonylamino, N-ethyl-isopropoxycarbonylamino, N-ethyl-methanesulfonylamino, N-ethyl-ethanesulfonylamino, N-ethyl-n-propanesulfonylamino, N-ethyl- isopropanesulfonylamino, N-ethyl-n-butanesulfonylamino, N-ethyl-n-pentanesulfonylamino, N-ethyl-n-hexanesulfonylamino, N-ethyl-benzamido, N-ethyl-benzenesulfonylamido, N-ethyl-4-fluorobenzenesulfonamido, N-ethyl- 4-chlorobenzenesulfonamido, N-ethyl-4-bromobenzenesulfonamido, N-ethyl-4-methylbenzenesulfonamido, N-ethyl-4-methoxy-benzenesulfonamido, N-ethyl-phenylmethanesulfonamido, N-ethyl-2-phenylethanesulfonamido, N-ethyl- 3-phenylpropanesulfonyl-amido, N-ethyl-naphthalen-1-yl-sulfonamido, N-ethyl-naphthalen-2-yl-sulfonylamido, N-ethyl-cyclopentylcarbonylamido, N-ethyl-cyclohexylcarbonylamido, N-ethyl-cycloheptylcarbonylamido, N- ethyl-phenyl cetylamido, N-ethyl-3-phenylpropionylamido, N-ethyl-cyclopentylacetylamido, N-ethyl-3-cyclopentylpropionyl-amido, N-ethyl-cyclohexylacetamido, N-ethyl-3-cyclohexyl-propionylamido, N-ethyl-cycloheptylacetylamido, N- ethyl-3-cycloheptylpropionylamido, N-n-propyl-formylamino, N-n-propyl-acetylamino, N-n-propyl-propionylamino, N-n-propyl-butanoylamino, N-n-propyl-isobutanoylamino, N-n-propyl-pentanoylamino, N-n-propyl-(3-methylbutanoyl) )amino, N-n-propyl-hexanoylamino, N-isopropyl-formylamino, N-isopropyl-acetylamino, N-isopropyl-propionylamino, N-isopropyl-butanoylamino, N-isopropyl-isobutanoylamino, N-isopropyl-pentanoylamino, N-isopropyl-( 3-methylbutanoyl)-amino, N-isopropyl-hexanoylamino, N-n-butyl-formylamino, N-n-butyl-acetylamino, N-n-butyl-propionylamino, N-n-butyl-butanoylamino, N-n-butyl-isobutanoylamino, N-n-butyl-pentanoylamino, N-n -butyl-(3-methylbutanoyl)amino, N-n-butyl-hexanoylamino, N-isobutyl-formylamino, N-isobutyl-acetylamino, N-isobutyl-propionylamino, N-isobutyl-butanoylamino , N-isobutyl-isobutanoylamino, N-isobutyl-pentanoylamino, N-n-pentyl-formylamino, N-n-pentyl-acetyl-amino, N-n-pentyl-propionylamino, N-n-pentyl-butanoylamino, N-n-pentyl-isobutanoylamino, N-n-pentyl-isobutanoylamino , N-n-pentyl-pentanoylamino, N-(1-methyl-butyl)-formylamino, N-(1-methyl-butyl)-acetylamino, N-(1-methyl-butyl)-propionyl-amino, N-(1- methyl-butyl)-butanoylamino, N-(1-methyl-butyl)-isobutanoylamino, N-(1-methyl-butyl)-pentanoylamino, N-(2-methyl-butyl)-formylamino, N-(2-methyl- butyl)-acetylamino, N-(2-methyl-butyl)-propionylamino, N-(2-methyl-butyl)-butanoyl-amino, N-(2-methyl-butyl)-isobutanoylamino, N-(2-methyl- butyl)-pentanoylamino, N-(3-methyl-butyl)-formylamino, N-(3-methyl-butyl)-acetylamino, N-(3-methyl-butyl)-propionylamino, N-(3-methyl-butyl) -butanoylamino, N-(3-methyl-butyl)-isobutanoylamino, N-(3-methyl-butyl)-pentanoylamino, N-n-hexyl-formylamino, N-n-hexyl-acetylamino, N-n-hexyl-propionylamino, N-n-hexyl-butanoylamino , N-n-hexyl-isobutanoylamino, N-n-hexyl-pentanoylamino, N-n-propyl-cyclohexylcarbonylamino, N-n-propyl-cyclohexylacetyl-amino, N-n-propyl-(3-cyclohexyl)propionylamino, N-n-isopropyl-cyclohexylcarbonylamino, N-isopropyl-cyclohexylacetylamino, N-isopropyl-3-(cyclohexyl)propionyl-amino amino, N-butyl-cyclohexylcarbonylamino, N-n-butyl-cyclohexylacetylamino, N-butyl-3-(cyclohexyl)propionylamino, N-isobutyl-cyclohexylcarbonylamino, N-isobutyl-cyclohexylcarbonylamino, N-isobutyl-cyclohexylacetylamino, N-isobutyl -3-(cyclohexyl)propionylamino, N-n-pentyl-cyclohexylcarbonylamino, N-n-pentyl-cyclohexylacetylamino, N-n-pentyl-3-(cyclohexyl)propiomylamino, N-n-hexyl-cyclohexylcarbonylamino, N-n-hexyl-cyclohexylacetylamino, N-n-pentyl-3-(cyclohexyl)propionylamino -hexyl-3-(cyclohexyl)propionylamino, phthalimino, 5-methoxy-phthalimino, 5,6-dimethoxyphthalimino, 6-methoxy-phthalimino homophthalimino, 4,4-dimethyl-homophthalimino, 7-methoxyhomophthalimino, 6,7-dimethoxy-homophthalimino , 7-methoxy-4,4-dimethyl-homophthalimino, 6,7-dimethoxy-4,4-dimethyl-homophthalimino, 1,2,3,6-tetrahydro-phthalim ino, hexahydrophthalimino, cis-hexahydrophthalimino, trans-hexahydro-phthalimino, 1-oxo-isoindolin-2-yl, 3,4-dimethyl-phthalimino, 4,5-dimethyl-1,2,3,6-tetrahydrophthalimino, 4,5-dimethyl-hexa-hydrophthalimino, 4,5-dimethyl-1-oxo-isoindolin-2-yl, 3,4-dimethoxy-phthalimino, 4,5-dimethoxy-1,2,3,4-tetrahydro- phthalimino, 4,5-dimethoxy-hexahydrophthalimino, 4,5-di-methoxy-1-oxo-isoindolin-2-yl, 2-carboxyphenyl-methyl-amino, 2-carboxyphenylmethylene-carbonylamino, pyrrolidino, 2-methylpyrrolidino, 3- ethylpyrrolidino, 3-isopropylpyrrolidino, piperidino, 3-methylpiperidino, 4-methylpiperidino, 4-ethyl-piperidino, 4-isopropylpiperidino, hexamethyleneimino, 3-methylhexamethyleneimino, 4-methylhexamethyleneimino, 3-ethyl-hexamethyleneimino, 3,3- dimethyl-pyrrolidino, 3,4-dimethylpyrrolidino, 3,4-dimethyl-piperidino, 3,4-dimethyl-piperidino, 4,4-dimethyl-piperidino, 3,3-dimethyl-hexamethyleneimino, 3,4-dimethyl-hexamethylene- imino, 4,4-dimethyl-hexamethyleneimino, 3,5-dimethyl-hexa-methyleneimino, 3,3-tetramethylene -pyrrolidino, 3,3-penta-methylene-pyrrolidino, 3,3-tetramethylenepiperidino, 3,3-penta-methylenepiperidino, 4,4-tetramethylene-piperidino, 4,4-penta-methylene-piperidino, 3,3-tetramethylene -hexamethyleneimino, 3,3-pentamethylene-hexamethyleneimino, 4,4-tetramethylene-hexamethyleneimino, 4,4-pentamethylene-hexamethyleneimino, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino, propansultan-1 -yl, butansultam-1-yl, pentasultam-1-yl, imino group of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic acid, imino group of methyl-5-norbornene-2,3- dicarboxylic acids, 3,6-endoxy-1,2,3,6-tetrahydrophthalimino group, imino group 5-norbornene-endo-2,3-dicarboxylic acid, glutarimino, 3,3-tetramethylene-glutarimino, 3,3-penta -methylene-glutarimino, 2,2-dimethylglutarimino, 3-methyl-glutarimino, 3,3-dimethyl-glutarimino, 3-ethyl-glutarimino, 3-ethyl-3-methyl-glutarimino, 1,3-cyclopentadicarbonyl-imino, 2 ,4-dimethyl-glutarimino, 2,4-di-n-propyl-glutarimino, glutaramino, 3,3-tetramethylene-glutaramino, 3,3-penta-methylene-glu taramino, 2,2-dimethylglutaramino, 3-methyl-glutaramino, 3,3-dimethyl-glutaramino, 3-ethyl-glutaramino, 3-ethyl-3-methyl-glutarimino, 1,3-cyclopentadicarbonyl-amino, 2,4- dimethyl-glutaramino, 2,4-di-n-propyl-glutaramino, maleinamido, maleinimido, 2-methyl-maleinamido, 3-methyl-maleinamido, 2-methyl-maleinimido, 2-phenyl-maleinamido, 3-phenyl-maleinimido, 2-phenyl-maleinimido, 2,3-dimethyl-maleinamido, 3-methyl-2-phenyl-maleinamido, 2-methyl-3-phenyl-maleinamido, 2-methyl-3-phenyl-maleinimido, 2,3-diphenyl- maleinamido, 2,3-diphenyl-maleinamido, pyrrolidin-2-yl, pyrrolidin-2-on-5-yl, piperidin-2-yl, piperidin-2-on-1-yl, piperidin-2-on-6- yl, quinolin-2-yl, isoquinolin-1-yl, isoquinolin-3-yl, pyridin-2-yl, 4-methylimidazol-2-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 1-n-hexyl-imidazol-4-yl, 1-n-hexylimidazol-5-yl, 1-benzylimidazol-4-yl, 1-benzylimidazol-5-yl, 1,2-dimethylimidazol-4-yl, 1, 2-dimethylimidazol-5-yl, 1-n-pentyl-2-methyl-imidazol-4-yl, 1-n-pentyl-2-methyl-imidazol-5-yl, 1-n-butyl-2-methyl- imidazol-4-yl, 1-n-butyl-2-methyl-imidazol-5-yl, 1-benzyl-2-methyl-imidazol-4-yl, 1-benzyl-2-methyl-imidazol-5-yl, benzimid-azole-2- yl, 1-methylbenzimidazol-2-yl, 1-ethylbenzimidazol-2-yl, 1-n-propylbenzimidazol-2-yl, 1-isopropylbenzimidazol-2-yl, 1-n-butylbenzimidazol-2-yl, 1-isobutylbenzimidazol-2-yl 2-yl, 1,-pentylbenzimidazol-2-yl, 1-n-hexylbenzimidazol-2-yl, 1-cyclopropylbenzimidazol-2-yl, 1-cyclobutylbenzimidazol-2-yl, 1-cyclopentylbenzimidazol-2-yl, 1 -cyclohexyl-benzimidazol-2-yl, 5-nitrobenzimidazol-2-yl, 5-aminobenzimidazol-2-yl, 5-acetamidobenzimidazol-2-yl, 5-methyl-benzimidazol-2-yl, 5-methoxy -benzimidazol-2-yl, 5-ethoxy-benzimidazol-2-yl, 1-methyl-5-methoxy-benzimidazol-2-yl, 1,5-dimethylbenzimidazol-2-yl, 1,6-dimethylbenzimidazol-2-yl , 1,4-dimethyl-benzimidazol-2-yl, 5,6-dimethyl-benzimidazol-2-yl, 1,5,6-trimethyl-benzimidazol-2-yl, 5-chloro-benzimidazol-2-yl, 5 -chloro-1-methyl-benzimidazol-2-yl, 6-chloro-1-methyl-benzimidazol-2-yl, 5,6-dichloro-1-methylbenzimidazol-2-yl, 5-dimethylaminobenzimidazol-2-yl, 5 -smoke ethyl-1-ethyl-benzimidazol-2-yl, 5,6-dimethoxy-1-methyl-benzimidazol-2-yl, 5,6-dimethoxy-1-ethyl-benzimidazol-2-yl, 5-fluoro- 1-methyl-benzimidazol-2-yl, 6-fluoro-1-methyl-benzimidazol-2-yl, 5-tri-fluoromethylbenzimidazol-2-yl, 5-trifluoro-1-methyl-benzimidazole-2- yl, 4-cyano-1-methyl-benzimidazol-2-yl, 5-carboxy-1-methyl-benzimidazol-2-yl, 5-aminocarbonylbenzimidazol-2-yl, 5-aminocarbonyl-1-methyl-benzimidazol-2- yl, 5-dimethyl-aminosulfonyl-1-methyl-benzimidazol-2-yl, 5-methoxycarbonyl-1-methyl-benzimidazol-2-yl, 5-methylaminocarbonyl-1-methyl-benzimidazol-2-yl, 5-dimethylaminocarbonyl- 1-methylbenzimidazol-2-yl, 4,6-difluoro-1-methyl-benzimidazol-2-yl, 5-acetyl-1-methyl-benzimidazol-2-yl, 5,6-dihydroxy-1-methyl- benzimid-azol-2-yl, imidazo[1,2-a]pyridin-2-yl, 5-methyl-imidazo[1,2-a]pyridin-2-yl, 6-methyl-imidazo[1,2- a]pyridin-2-yl, 7-methyl-imidazo[1,2-a]pyridin-2-yl, 8-methyl-imidazo[1,2-a]pyridin-2-yl, 5,7-dimethyl- imidazo[1,2-a]pyridin-2-yl, 6-amino-carbonyl-imidazo[1,2-a]pyridin-2-yl, 6-chloro-imidazo[1,2-a]-p Iridin-2-yl, 6-bromo-imidazo[1,2-a]pyridin-2-yl, 5,6,7,8,-tetrahydro-imidazo[1,2-a]pyrimidin-2-yl, imidazo [1,2-a]-pyrimidin-2-yl, 5,7-dimethyl-imidazo[1,2-a]pyridin-2-yl,

imidazo[4,5-b]piridin-2-il, 1-metil-imidazo[4,5-b]piridin-2-il, 1-n-heksil-imidazo[4,5-b]piridin-2-il, 1-ciklopropil-imidazo[4,5-b]piridin-2-il, 1-cikloheksil-imidazo[4,5-b]-piridin-2-il, 4-metil-imidazo[4,5-b]piridin-2-il, 6-metil-imidazo[4,5-b]piridin-2-il, 1,4-dimetil-imidazo[4,5-b]-piridin-2-il, 1,6-dimetil-imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]piridin-2-il, 1-metil-imidazo[4,5-c]piridin-2-il, 1-n-heksil-imidazo[4,5-c]piridin-2-il, 1-ciklopropil-imidazo[4,5-c]piridin-2-il, 1-cikloheksil-imidazo[4,5-c]-piridin-2-il, imidazo[2,1-b]tiazol-6-il, 3-metil-imidazo-[2,1-b]tiazol-6-il, 2-fenil-imidazo[2,1-b]tiazol-6-il, 3-fenil-imidazo[2,1-b]tiazol-6-il, 2,3-dimetil-imidazo[2,1-b]-tiazol-6-il, 2,3-trimetilen-imidazo[2,1-b]tiazol-6-il, 2,3-tetrametilen-imidazo[2,1-b]tiazol-6-il, imidazo[2,1-c]-pirimidin-2-il, imidazo[1,2-a]pirazin-2-il, imidazo[1,2-b]-piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]-piridazin-2-il, imidazo[4,5-d]piridazin-2-il, imidazolidin-2,4-dion-3-il, 5-metil-imidazolidin-2,4-dion-3-il, 5-etil-imidazolidin-2,4-dion-3-il, 5-n-propil-imidazolidin-2,4-dion-3-il, 5-benzil-imidazolidin-2,4-dion-3-il, 5-(2-feniletil)-imidazolidin-2,4-dion-3-il, 5-(3-fenil-propil)-imidazolidin-2,4-dion-3-il, 5,5-tetrametilen-imidazolidin-2,4-dion-3-il, 5,5-pentametilen-imidazolidin-2,4-dion-3-il, 5,5-heksametilen-imidazolidin-2,4-dion-3-il, 1-metil-imidazolidin-2,4-dion-3-il, 1-benzil-imidazolidin-2,4-dion-3-il, 4,5-dihidro-2H-piridazin-3-on-6-il, 2-metil-4,5-dihidro-2H-piridazin-3-on-6-il, 2-etil-4,5-dihidro-2H-piridazin-3-on-6-il, 2-n-propil-4,5-dihidro-2H-piridazin-3-on-6-il, 2-izopropil-4,5-dihidro-2H-piridazin-3-on-6-il, 2-benzil-4,5-dihidro-2H-piridazin-3-on-6-il, 2-(2-fenetil)-4,5-dihidro-2H-piridazin-3-on-6-il, 2-(3-fenilpropil)-4,5-dihidro-2H-piridazin-3-on-6-il, 4-metil-4,5-dihidro-2H-piridazin-3-on-6-il, 5-metil-4,5-dihidro-2H-piridazin-3-on-6-il, 4,4-dimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 5,5-dimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 4,5-dimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 2,4-dimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 2,5-dimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 2,4,5-trimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 2,4,4-trimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 2,5,5-trimetil-4,5-dihidro-2H-piridazin-3-on-6-il, 2H-piridazin-3-on-6-il, 2-metil-piridazin-3-on-6-il, 2-etil-piridazin-3-on-6-il, 2-n-propil-piridazin-3-on-6-il, 2-izopropil-piridazin-3-on-6-il, 2-benzil-piridazin-3-on-6-il, 2-(2-(feniletil)-piridazin-3-on-6-il, 2-(3-fenil-propil)-piridazin-3-on-6-il, 4-metil-piridazin-3-on-6-il, 5-metil-piridazin-3-on-6-il, 4,5-dimetil-piridazin-3-on-6-il, 2,4-dimetil-piridazin-3-on-6-il, 2,5-dimetil-piridazin-3-on-6-il, 2,4,5-trimetil-piridazin-3-on-6-il, amino-karbonilamino, metilaminokarbonilamino, dimetilamino-karbonilamino, N-metilaminokarbonil-metilamino, N-(dimetil-aminokarbonil)-metilamino, N-dimetilaminokarbonil-etil-amino, N-dimetilaminokarbonil-izopropilamino, N-(dimetil-aminokarbonil)-n-pentilamino, N-metilaminokarbonil-etil-amino, N-metilaminokarbonil-n-pentilamino, N-metilmino-karbonil-n-heksilamino, N-metilaminokarbonil-n-oktilamino, N-metil-aminokarbonil-cikloheksilamino, etilaminokarbonil-amino, N-etilaminokarbonil-metilamino, N-etilaminokarbonil-etilamino, N-etilaminokarbonil-n-heksilamino, N-etilamino-karbonil-n-heptilamino, N-etilaminokarbonil-cikloheksil-amino, dietilaminokarbonilamino, N-(dietilaminokarbonil)-metilamino, N-(dietilaminokarbonil)-etilamino, N-(dietil-aminokarbonil)-n-butilamino, N-(dietilaminokarbonil)-n-heksilamino, N-(dietilaminokarbonil)-n-oktilamino, izopropilaminokarbonilamino, N-izopropilaminokarbonil-metilamino, n-butilaminokarbonilamino, N-(n-butilamino-karbonil)-metilamino, N-(n-butilaminokarbonil)-etilamino, N-(n-butilaminokarbonil)-izopropilamino, N-(n-butilamino-karbonil)-n-butilamino, N-(n-butilaminokarbonil)-n-heksil-amino, N-(n-butilaminokarbonil)-cikloheksilamino, N-(di-(n-butil)-aminokarbonil)-amino, N-(di-(n-butil)-amino-karbonil)-metilamino, N-(di-(n-butil)-aminokarbonil)-etil-amino, N-(di-(n-butil)-aminokarbonil)-n-butilamino, N-(di-(n-butil)-aminokarbonil)-n-heksilamino, N-(n-pentil)-amino-karbonil)-metilamino, N-(n-pentil)-aminokarbonil)-etil-amino, N-(n-heksilaminokarbonil)-etilamino, n-heksilamino-karbonilamino, n-heptilaminokarbonilamino, n-oktilamino-karbonilamino, N-(n-heksilaminokarbonil)-n-butilamino, N-(n-heksilaminokarbonil)-n-pentilamino, N-(n-heksilamino-karbonil)-n-heksilamino, N-(n-heksilaminokarbonil)-ciklo-heksilamino, di-(n-heksil)-aminokarbonilamino, N-(di-(n-heksil)-aminokarbonil)-metilamino, N-((n-heksil)-metil-aminokarbonil)-amino, cikloheksilmetilaminokarbonilamino, N-cikloheksil-aminokarbonil-metilamino, N-cikloheksil-aminokarbonil-etilamino, N-cikloheksil-aminokarbonil-n-butilamino, N-cikloheksil-aminokarbonil-izobutilamino, N-cikloheksil-aminokarbonil-n-pentilamino, N-cikloheksil-aminokarbonil-n-heksil-amino, N-cikloheksil-aminokarbonil-cikloheksilamino, N-(etilcikloheksil-aminokarbonil)-metilamino, N-propil-cikloheksil-aminokarbonil-metilamino, N-(n-butil-cikloheksil-aminokarbonil)-metilamino, alil-aminokarbonilamino, benzilaminokarbonilamino, N-benzil-aminokarbonil-izobutilamino, fenil-aminokarbonilamino, pirolidinokarbonilamino, pirolidinokarbonilmetilamino, piperidinokarbonilamino, heksametileniminokarbonilamino, morfolinokarbonilamino, 3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-metil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-etil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-n-propil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-izopropil-3,4,5,6-tetra-hidro-2-pirimidon-1-il, 3-n-butil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-izobutil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-n-pentil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-n-heksil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-ciklopentil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-cikloheksil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-cikloheptil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3-benzil-3,4,5,6-tetrahidro-2-pirimidon-1-il, 3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il, 3-metil-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il, 3-metil-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il, 3-etil-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il, 3-n-propil-3,4,5,6-tetra-hidro-2(1H)-pirimidon-1-il, 3-izopropil-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il, 3-benzil-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il, 3-(2-feniletil)-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il ili 3-(3-fenilpropil)-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il i imidazo[4,5-b]pyridin-2-yl, 1-methyl-imidazo[4,5-b]pyridin-2-yl, 1-n-hexyl-imidazo[4,5-b]pyridin-2- yl, 1-cyclopropyl-imidazo[4,5-b]pyridin-2-yl, 1-cyclohexyl-imidazo[4,5-b]-pyridin-2-yl, 4-methyl-imidazo[4,5-b ]pyridin-2-yl, 6-methyl-imidazo[4,5-b]pyridin-2-yl, 1,4-dimethyl-imidazo[4,5-b]-pyridin-2-yl, 1,6- dimethyl-imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, 1-methyl-imidazo[4,5-c]pyridin-2-yl, 1- n-hexyl-imidazo[4,5-c]pyridin-2-yl, 1-cyclopropyl-imidazo[4,5-c]pyridin-2-yl, 1-cyclohexyl-imidazo[4,5-c]-pyridine -2-yl, imidazo[2,1-b]thiazol-6-yl, 3-methyl-imidazo-[2,1-b]thiazol-6-yl, 2-phenyl-imidazo[2,1-b] thiazol-6-yl, 3-phenyl-imidazo[2,1-b]thiazol-6-yl, 2,3-dimethyl-imidazo[2,1-b]-thiazol-6-yl, 2,3-trimethylene -imidazo[2,1-b]thiazol-6-yl, 2,3-tetramethylene-imidazo[2,1-b]thiazol-6-yl, imidazo[2,1-c]-pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]-pyridin-2-yl, purin-8-yl, imidazo[4,5-b]-pyrazin-2-yl, imidazo[4,5-c]-pyridazin-2-yl, imidazo[4,5-d]pyridase in-2-yl, imidazolidin-2,4-dion-3-yl, 5-methyl-imidazolidin-2,4-dion-3-yl, 5-ethyl-imidazolidin-2,4-dion-3-yl, 5-n-propyl-imidazolidin-2,4-dion-3-yl, 5-benzyl-imidazolidin-2,4-dion-3-yl, 5-(2-phenylethyl)-imidazolidin-2,4-dione- 3-yl, 5-(3-phenyl-propyl)-imidazolidin-2,4-dion-3-yl, 5,5-tetramethylene-imidazolidin-2,4-dion-3-yl, 5,5-pentamethylene- imidazolidin-2,4-dion-3-yl, 5,5-hexamethylene-imidazolidin-2,4-dion-3-yl, 1-methyl-imidazolidin-2,4-dion-3-yl, 1-benzyl- imidazolidin-2,4-dion-3-yl, 4,5-dihydro-2H-pyridazin-3-one-6-yl, 2-methyl-4,5-dihydro-2H-pyridazin-3-one-6- yl, 2-ethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-n-propyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2- isopropyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-(2-phenethyl)- 4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-(3-phenylpropyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4-methyl-4, 5-dihydro-2H-pyridazin-3-on-6-yl, 5-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4,4-dimethyl-4,5-dihydro- 2H-pyridazin-3-on-6-yl, 5,5-dimethyl-4, 5-dihydro-2H-pyridazin-3-on-6-yl, 4,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,4-dimethyl-4,5- dihydro-2H-pyridazin-3-on-6-yl, 2,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,4,5-trimethyl-4,5- dihydro-2H-pyridazin-3-on-6-yl, 2,4,4-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,5,5-trimethyl-4, 5-dihydro-2H-pyridazin-3-on-6-yl, 2H-pyridazin-3-on-6-yl, 2-methyl-pyridazin-3-on-6-yl, 2-ethyl-pyridazin-3- on-6-yl, 2-n-propyl-pyridazin-3-on-6-yl, 2-isopropyl-pyridazin-3-on-6-yl, 2-benzyl-pyridazin-3-on-6-yl, 2-(2-(phenylethyl)-pyridazin-3-on-6-yl, 2-(3-phenyl-propyl)-pyridazin-3-on-6-yl, 4-methyl-pyridazin-3-one-6 -yl, 5-methyl-pyridazin-3-on-6-yl, 4,5-dimethyl-pyridazin-3-on-6-yl, 2,4-dimethyl-pyridazin-3-on-6-yl, 2 ,5-dimethyl-pyridazin-3-on-6-yl, 2,4,5-trimethyl-pyridazin-3-on-6-yl, amino-carbonylamino, methylaminocarbonylamino, dimethylamino-carbonylamino, N-methylaminocarbonyl-methylamino, N -(dimethyl-aminocarbonyl)-methylamino, N-dimethylaminocarbonyl-ethyl-amino, N-dimethylaminocarbonyl-isopropylamino, N-( dimethyl-aminocarbonyl)-n-pentylamino, N-methylaminocarbonyl-ethyl-amino, N-methylaminocarbonyl-n-pentylamino, N-methylamino-carbonyl-n-hexylamino, N-methylaminocarbonyl-n-octylamino, N-methyl-aminocarbonyl-cyclohexylamino , ethylaminocarbonyl-amino, N-ethylaminocarbonyl-methylamino, N-ethylaminocarbonyl-ethylamino, N-ethylaminocarbonyl-n-hexylamino, N-ethylamino-carbonyl-n-heptylamino, N-ethylaminocarbonyl-cyclohexyl-amino, diethylaminocarbonylamino, N-(diethylaminocarbonyl) -methylamino, N-(diethylaminocarbonyl)-ethylamino, N-(diethylaminocarbonyl)-n-butylamino, N-(diethylaminocarbonyl)-n-hexylamino, N-(diethylaminocarbonyl)-n-octylamino, isopropylaminocarbonylamino, N-isopropylaminocarbonyl-methylamino , n-butylaminocarbonylamino, N-(n-butylamino-carbonyl)-methylamino, N-(n-butylaminocarbonyl)-ethylamino, N-(n-butylaminocarbonyl)-isopropylamino, N-(n-butylamino-carbonyl)-n-butylamino , N-(n-butylaminocarbonyl)-n-hexyl-amino, N-(n-butylaminocarbonyl)-cyclohexylamino, N-(di-(n-butyl)-aminocarbonyl)-amino, N -(di-(n-butyl)-amino-carbonyl)-methylamino, N-(di-(n-butyl)-aminocarbonyl)-ethyl-amino, N-(di-(n-butyl)-aminocarbonyl)-n -butylamino, N-(di-(n-butyl)-aminocarbonyl)-n-hexylamino, N-(n-pentyl)-amino-carbonyl)-methylamino, N-(n-pentyl)-aminocarbonyl)-ethyl-amino , N-(n-hexylaminocarbonyl)-ethylamino, n-hexylamino-carbonylamino, n-heptylaminocarbonylamino, n-octylamino-carbonylamino, N-(n-hexylaminocarbonyl)-n-butylamino, N-(n-hexylaminocarbonyl)-n-pentylamino , N-(n-hexylamino-carbonyl)-n-hexylamino, N-(n-hexylaminocarbonyl)-cyclohexylamino, di-(n-hexyl)-aminocarbonylamino, N-(di-(n-hexyl)-aminocarbonyl) -methylamino, N-((n-hexyl)-methyl-aminocarbonyl)-amino, cyclohexylmethylaminocarbonylamino, N-cyclohexyl-aminocarbonyl-methylamino, N-cyclohexyl-aminocarbonyl-ethylamino, N-cyclohexyl-aminocarbonyl-n-butylamino, N-cyclohexyl -aminocarbonyl-isobutylamino, N-cyclohexyl-aminocarbonyl-n-pentylamino, N-cyclohexyl-aminocarbonyl-n-hexyl-amino, N-cyclohexyl-aminocarbonyl-cyclohexylamino, N-(ethylcyclohexyl-aminocarbonyl)-methylamino, N-propyl-cyclohexyl-aminocarbonyl-methylamino, N-(n-butyl-cyclohexyl-aminocarbonyl)-methylamino, allyl-aminocarbonylamino, benzylaminocarbonylamino, N-benzyl-aminocarbonyl-isobutylamino, phenyl- aminocarbonylamino, pyrrolidinocarbonylamino, pyrrolidinocarbonylmethylamino, piperidinocarbonylamino, hexamethyleneiminocarbonylamino, morpholinocarbonylamino, 3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-methyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl yl, 3-ethyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3- isopropyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-butyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-isobutyl- 3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-pentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-hexyl-3, 4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-cyclopentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-cyclohexyl-3,4,5,6- tetrahydro-2-pyrimidon-1-yl, 3-cycloheptyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-benzyl-3,4,5,6-tetrahydro-2-pyrimide on-1-yl, 3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1- yl, 3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1- yl, 3-n-propyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-isopropyl-3,4,5,6-tetrahydro-2(1H)- pyrimidon-1-yl, 3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-(2-phenylethyl)-3,4,5,6-tetrahydro-2 (1H)-pyrimidon-1-yl or 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl and

R3: vodikov atom, metil, etil, n-propil, izopropil, n-butil, izobutil, terc.butil, n-pentil, 1-metil-butil, 2-metilbutil, 3-metil-butil, ciklopropil, ciklobutil, ciklopentil, metoksi, etoksi, n-propoksi, izobutoksi, n-butoksi, metilmerkapto, etilmerkapto, n-propil-merkapto, izopropilmerkapto ili n-butilmerkapto skupina. R3: hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, 1-methyl-butyl, 2-methylbutyl, 3-methyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl , methoxy, ethoxy, n-propoxy, isobutoxy, n-butoxy, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto or n-butylmercapto group.

Spojevi gornje opće formule I su ponajprije oni u kojima Compounds of the above general formula I are primarily those in which

R1 u položaju 4 predstavlja atom fluora, klora ili broma, alkilnu skupinu s 1 do 3 ugljikova atoma, cikloalkilnu, fluormetilnu, difluormetilnu ili trifluor-metilnu skupinu i R1 in position 4 represents a fluorine, chlorine or bromine atom, an alkyl group with 1 to 3 carbon atoms, a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and

R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetrahidro-benzimidazolilnom skupinom, R2 represents an alkoxy group with 3 to 5 carbon atoms which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms which is substituted in position 2, 3, 4 or 5 with a benzimidazyl group or tetrahydro - benzimidazolyl group,

acilamino skupinu u kojoj acilni ostatak predstavlja alkanoilnu skupinu s 2 do 7 ugljikova atoma, u datom slučaju supstituiranu na atomu dušika s alkilnom skupinom koja ima 1 do 5 ugljikovih atoma, alkoksikarbonilnu skupinu s ukupno 2 do 4 ugljikova atoma, alkilsulfonilnu skupinu s 1 do 3 ugljikova atoma ili benzensulfonilnu skupinu, an acylamino group in which the acyl residue represents an alkanoyl group with 2 to 7 carbon atoms, in a given case substituted on the nitrogen atom with an alkyl group having 1 to 5 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, an alkylsulfonyl group with 1 to 3 carbon atoms or a benzenesulfonyl group,

ftalimino ili homoftalimino, pri čemu je karbonilna skupina u ftalimino skupini nadomještena s metilenskom skupinom, kao što također metilenska skupina u homoftalimino skupini može biti supstituirana s jednom ili dvije alkilne skupine, phthalimino or homophthalimino, wherein the carbonyl group in the phthalimino group is replaced by a methylene group, as well as the methylene group in the homophthalimino group can be substituted with one or two alkyl groups,

peteročlana, šesteročlana ili sedmeročlana alkilimino ili alkilenimino skupina, u datom slučaju supstituirana s jednom ili dvije alkilne skupine ili s tetrametilenskom ili pentametilenskom skupinom, u kojoj metilenska skupina može biti nadomještena s karbonilnom ili sulfonilnom skupinom, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group, in a given case substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, in which the methylene group can be replaced by a carbonyl or sulfonyl group,

imino skupina glutarne kiseline, u kojoj je n-propilenska skupina perfluorirana, koja može biti supstituirana s jednom ili dvije alkilne skupine ili s tetrametilenskom ili pentametilenskom skupinom, the imino group of glutaric acid, in which the n-propylene group is perfluorinated, which can be substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group,

imido skupina maleinske kiseline, u datom slučaju mono- ili disupstituirana s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different,

amidino skupina supstituirana u datom slučaju s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 4 ugljikova atoma, an amidino group substituted in a given case with one or two alkyl groups, each of which has 1 to 4 carbon atoms,

benzimidazol-2-ilna skupina koja je u datom slučaju supstituirana u položaju 1 s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili s cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, benzimidazol-2-yl group, which in a given case is substituted in position 1 with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group,

imidazo[2,5-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatakdokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina u pirolidinskom prstenu ili peperidinskom prstenu, koja je susjedna dušikovom atomu, mogu biti nadomješteni s karbonilnom skupinom, imidazo[2,5-b]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]pyrimidin-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, imidazo[4,5-c]-pyridin-2 -yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo[4,5-d]pyridazin-2- il group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue condensed to the pyridine ring via two adjacent carbon atoms and the methylene group in the pyrrolidine ring or peperidine ring, which is adjacent to the nitrogen atom, can be replaced with a carbonyl group,

imidazolilnu skupinu, vezanu preko ugljikovog atoma, u datom slučaju u položaju 1 supstituiranu s 1 do 3 ugljikova atoma ili s benzilnom skupinom, koja dodatno može biti supstituirana u ugljikovoj strukturi s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, an imidazolyl group, attached via a carbon atom, in a given case substituted in position 1 with 1 to 3 carbon atoms or with a benzyl group, which can additionally be substituted in the carbon structure with an alkyl group having 1 to 3 carbon atoms,

imidazolidinsku skupina u datom slučaju supstituiranu s alkilnom, fenilalkilnom, tetrametilenskom, penta-metilenskom ili heksametilenskom skupinom, an imidazolidine group optionally substituted with an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group,

piridazin-3-on ili dihidro-piridazin-on koji u položaju 2 može biti supstituiran s metilnom ili benzilnom skupinom, pyridazin-3-one or dihydro-pyridazin-one which in position 2 can be substituted with a methyl or benzyl group,

R7-NR6-CO-NR5 skupina u kojoj R7-NR6-CO-NR5 group in which

R5 predstavlja vodikov atom, alkilnu skupinu s 1 do 5 ugljikovih atoma, cikloalkilnu ili benzilnu skupinu, R5 represents a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, a cycloalkyl or benzyl group,

R6 predstavlja vodikov atom, alkilnu skupinu s 1 do 6 ugljikovih atoma, alilnu, cikloheksilnu, benzilnu ili fenilnu skupinu, R6 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, cyclohexyl, benzyl or phenyl group,

R7 predstavlja vodikov atom ili alkilnu skupinu s 1 do 3 ugljikova atoma ili R7 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms or

R6 i R7 zajedno s atomom dušika, koji se nalazi između njih, tvore alkenilimino skupinu sa 4 do 6 ugljikovih atoma ravnog lanca ili morfolino skupinu ili R6 and R7 together with the nitrogen atom located between them form an alkenylimino group with 4 to 6 straight chain carbon atoms or a morpholino group or

R5 i R6 zajedno tvore alkilensku skupinu koja ima 2 do 4 ugljikova atoma, ili R5 and R6 together form an alkylene group having 2 to 4 carbon atoms, or

R1 predstavlja vodikov atom ili u položaju 5, 6 ili 7 atom fluora, klora ili broma, alkilnu skupinu s 1 do 4 ugljikova atoma ili trifluormetilnu skupinu i R1 represents a hydrogen atom or in position 5, 6 or 7 a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms or a trifluoromethyl group and

R2 predstavlja benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili sa cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, R2 represents a benzimidazol-2-yl group in a given case substituted in position 1 with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group,

imidazo[2,5-b]tiazol-6-ilnu, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-ilnu, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo-[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina, koja je susjedna dušikovom atomu u pirolidinskom prstenu ili peperidinskom prstenu, mogu biti nadomješteni s karbonilnom skupinom, ili u datom slučaju u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, ili imidazolilnu skupinu, vezanu preko ugljikovog atoma, supstituiranu s benzilnom skupinom, koja dodatno u ugljikovoj strukturi može biti supstituirana s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, pri čemu ako imidazo[2,5-b]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]pyrimidin-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, imidazo[4,5-c]-pyridin-2 -yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo-[4,5-d]pyridazin- 2-yl group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue condensed to the pyridine ring via two adjacent carbon atoms and the methylene group, which is adjacent to the nitrogen atom in the pyrrolidine ring or peperidine ring, can be replaced with a carbonyl group, or in a given case in position 1 with an alkyl group having 1 to 3 carbon atoms, or an imidazolyl group, attached via a carbon atom, substituted with a benzyl group, which can additionally be substituted in the carbon structure with alk by a functional group having 1 to 3 carbon atoms, whereby if

(v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group,

R3 predstavlja alkilnu skupinu s 1 do 5 ugljikovih atoma ili cikloalkilnu skupinu koja ima 3 do 5 ugljikova atoma i R3 represents an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms and

R4 predstavlja karboksi ili 1H-tetrazolilnu skupinu, R4 represents a carboxy or 1H-tetrazolyl group,

njihove 1-, 3-izomerne smjese kao također i njihove soli, osobito za farmaceutsku upotrebu njihove fiziološki podnošljive soli s anorganskim ili organskim kiselinama ili bazana, their 1-, 3-isomeric mixtures as well as their salts, especially for pharmaceutical use of their physiologically tolerable salts with inorganic or organic acids or bases,

pri čemu ako nije navedeno drugačije, pri tome spomenuti alkanoilni, alkilni ili alkoksi dio može sadržavati uvijek 1 do 3 ugljikova atoma, kao također pri tome spomenuti cikloalkilni dio može sadržati uvijek po 3 do 7 ugljikovih atoma. wherein, unless stated otherwise, the mentioned alkanoyl, alkyl or alkoxy part can always contain 1 to 3 carbon atoms, and also the mentioned cycloalkyl part can always contain 3 to 7 carbon atoms.

Posebnu prednost daje se spojevima gornje opće formule I su u kojima Particular preference is given to compounds of the above general formula I in which

R1 u položaju 4 predstavlja atom klora, alkilnu skupinu s 1 do 3 ugljikova atoma ili trifluormetilnu skupinu i R1 in position 4 represents a chlorine atom, an alkyl group with 1 to 3 carbon atoms or a trifluoromethyl group and

R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma, koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetra-hidrobenzimidazolilnom skupinom, R2 represents an alkoxy group with 3 to 5 carbon atoms, which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms, which is substituted in position 2, 3, 4 or 5 with a benzimidazilyl group, or tetrahydrobenzimidazolyl group,

alkanoilamino skupinu s 2 do 5 ugljikovih atoma u alkanoilnom dijelu ili N-benzensulfonilmetilamino skupinu, an alkanoylamino group with 2 to 5 carbon atoms in the alkanoyl part or an N-benzenesulfonylmethylamino group,

ftalimino ili homoftalimino, pri čemu karbonilna skupina u ftalimino skupini može biti nadomještena s metilenskom skupinom, phthalimino or homophthalimino, whereby the carbonyl group in the phthalimino group can be replaced with a methylene group,

peteročlanu, šesteročlanu ili sedmeročlanu alkilimino ili alkilenimino skupinu u kojoj je metilenska skupina nadomještena s karbonilnom ili sulfonilnom skupinom, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group in which the methylene group is replaced by a carbonyl or sulfonyl group,

imino skupinu glutarne kiseline, u kojoj n-propilenska skupina može biti supstituirana s jednom ili dvije alkilne skupina ili s tetrametilenskom ili pentametilenskom skupinom, the imino group of glutaric acid, in which the n-propylene group can be substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group,

imido skupinu maleinske kiseline, u datom slučaju mono- ili disupstituiranu s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different,

benzimidazol-2-ilnu skupinu supstituiranu u datom slučaju s jednom alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili sa cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimid-azolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, imidazo-[2,1-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]-pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo-[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo-[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu je fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina, koja je susjedna dušikovom atomu u pirolidinskom prstenu ili peperidinskom prstenu, mogu biti naomješteni s karbonilnom skupinom, a benzimidazol-2-yl group substituted in a given case with one alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group , imidazo-[2,1-b]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]-pyrimidin-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, imidazo[4,5-c] -pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo-[4,5- d]pyridazin-2-yl group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue is condensed to the pyridine ring via two adjacent carbon atoms and a methylene group, which is adjacent to the nitrogen atom in the pyrrolidine ring or peperidine ring, can be equipped with a carbonyl group,

imidazol-4-ilnu skupinu supstituiranu u položaju 4 s 1 alkilnom skupinom koja ima 1 do 3 ugljikova atoma ili s benzilnom skupinom, koja dodatno u ugljikovoj strukturi može biti supstituirana s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, an imidazol-4-yl group substituted in position 4 with 1 alkyl group having 1 to 3 carbon atoms or with a benzyl group, which can additionally be substituted in the carbon structure with an alkyl group having 1 to 3 carbon atoms,

piridazin-3-on ili dihidro-piridazin-on koji u položaju 2 može biti supstituiran s metilnom ili benzilnom skupinom, pyridazin-3-one or dihydro-pyridazin-one which in position 2 can be substituted with a methyl or benzyl group,

R7-NR6-CO-NR5 skupinu u kojoj R7-NR6-CO-NR5 group in which

R5 predstavlja vodikov atom, alkilnu skupinu s 1 do 5 ugljikovih atoma, cikloalkilnu ili benzilnu skupinu, R5 represents a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, a cycloalkyl or benzyl group,

R6 predstavlja vodikov atom, alkilnu skupinu s 1 do 6 ugljikovih atoma, alilnu, cikloheksilnu, benzilnu ili fenilnu skupinu, R6 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, cyclohexyl, benzyl or phenyl group,

R7 predstavlja vodikov atom ili alkilnu skupinu s 1 do 3 ugljikovih atoma ili R7 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms or

R6 i R7 zajedno s atomom dušika, koji se nalazi između njih, tvore alkenilimino skupinu sa 4 do 6 ugljikovih atoma ravnog lanca ili morfolino skupinu ili R6 and R7 together with the nitrogen atom located between them form an alkenylimino group with 4 to 6 straight chain carbon atoms or a morpholino group or

R5 i R6 zajedno tvore alkilensku skupinu koja ima 2 do 4 ugljikova atoma, ili R5 and R6 together form an alkylene group having 2 to 4 carbon atoms, or

R1 predstavlja vodikov atom ili u položaju 5, 6 ili 7 alkilnu skupinu s 1 do 4 ugljikova atoma ili trifluor-metilnu skupinu i R1 represents a hydrogen atom or in position 5, 6 or 7 an alkyl group with 1 to 4 carbon atoms or a trifluoromethyl group and

R2 predstavlja benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili sa cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, imidazo[2,1-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo-[1,2-a]pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo-[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina, koja je susjedna dušikovom atomu u pirolidinskom prstenu ili peperidinskom prstenu, mogu biti nadomješteni s karbonilnom skupinom, ili u datom slučaju u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, ili imidazol-4-ilnu skupinu supstituiranu s benzilnom skupinom, koja dodatno u ugljikovoj strukturi može biti supstituirana s alkilnom skupinom s 1 do 3 ugljikova atoma, pri čemu ako R2 represents a benzimidazol-2-yl group in a given case substituted in position 1 with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group, imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine -2-yl, imidazo-[1,2-a]pyrimidin-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, imidazo[4,5-c] -pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo-[4,5- d]pyridazin-2-yl group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue is condensed to the pyridine ring via two adjacent carbon atoms and a methylene group, which is adjacent to the nitrogen atom in pyrrole diene ring or peperidine ring, can be substituted with a carbonyl group, or in a given case in position 1 with an alkyl group having 1 to 3 carbon atoms, or an imidazol-4-yl group substituted with a benzyl group, which additionally in the carbon structure can be substituted with an alkyl group with 1 to 3 carbon atoms, where if

(v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group,

R3 predstavlja alkilnu skupinu s 1 do 5 ugljikovih atoma ili cikloalkilnu skupinu koja ima 3 do 5 ugljikovih atoma i R3 represents an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms and

R4 predstavlja karboksi ili 1H-tetrazolilnu skupinu, R4 represents a carboxy or 1H-tetrazolyl group,

osobito oni spojevi gornje opće formule I, u kojoj especially those compounds of the above general formula I, in which

R1 u položaju 4 predstavlja metilnu skupinu ili atom klora i R1 in position 4 represents a methyl group or a chlorine atom and

R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetrahidro-benzimidazolilnom skupinom, R2 represents an alkoxy group with 3 to 5 carbon atoms which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms which is substituted in position 2, 3, 4 or 5 with a benzimidazyl group or tetrahydro - benzimidazolyl group,

alkanoilamino skupinu s 2 do 5 ugljikovih atoma u alkanoilnom dijelu ili N-benzensulfonil-metilamino skupinu, an alkanoylamino group with 2 to 5 carbon atoms in the alkanoyl part or an N-benzenesulfonyl-methylamino group,

ftalimino ili homoftalimino, pri čemu karbonilna skupina u ftalimino skupini može biti nadomještena s metilenskom skupinom, phthalimino or homophthalimino, whereby the carbonyl group in the phthalimino group can be replaced with a methylene group,

peteročlanu, šesteročlanu ili sedmeročlanu alkilimino ili alkilenimino skupina u kojoj je metilenska skupina nadomještena s karbonilnom ili sulfonilnom skupinom, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group in which the methylene group is replaced by a carbonyl or sulfonyl group,

imido skupinu maleinske kiseline, u datom slučaju mono- ili disupstituiranu s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different,

benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu s jednom alkilnom skupinom koja ima 1 do 3 ugljikova atoma, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, imidazo[2,5-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo-[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il ili imidazo[2,1-b]tiazol-6-il skupinu, benzimidazol-2-yl group in a given case substituted with one alkyl group having 1 to 3 carbon atoms, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, imidazo[2,5-b]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 ]pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group,

imidazol-4-ilnu skupinu supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, an imidazol-4-yl group substituted in position 1 with an alkyl group having 1 to 3 carbon atoms,

piridazin-3-on ili dihidro-piridazin-3-on skupinu koja u položaju 2 može biti supstituirana s metilnom ili benzilnom skupinom, ili pyridazin-3-one or dihydro-pyridazin-3-one group which can be substituted in position 2 with a methyl or benzyl group, or

R1 predstavlja vodikov atom ili u položaju 5, 6 ili metilnu skupinu i R1 represents a hydrogen atom or in position 5, 6 or a methyl group i

R2 predstavlja benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, koja u fenilnoj jezgri može biti dodatno supstituirana s atomom fluora, imidazol-4-ilnu skupinu ili imidazo[1,2-a]piridin-2-ilnu skupinu, pri čemu ako R2 represents a benzimidazol-2-yl group in a given case substituted in position 1 with an alkyl group having 1 to 3 carbon atoms, which in the phenyl nucleus can be additionally substituted with a fluorine atom, an imidazol-4-yl group or an imidazo[1,2 -a]pyridin-2-yl group, where if

(v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group,

R3 predstavlja alkilnu skupinu s 1 do 5 ugljikovih atoma ili cikloalkilnu skupinu koja ima 3 do 5 ugljikovih atoma i R3 represents an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms and

R4 predstavlja karboksi ili 1H-tetrazolilnu skupinu, R4 represents a carboxy or 1H-tetrazolyl group,

njihove 1-, 3-izomerne smjese kao također i njihove soli, s anorganskim ili organskim kiselinama ili bazana. their 1-, 3-isomeric mixtures as well as their salts, with inorganic or organic acids or bases.

U smislu izuma spojevi se mogu dobiti po slijedećim postupcima: In terms of the invention, the compounds can be obtained by the following procedures:

a) Ciklizacijom spoja opće formule a) By cyclization of the compound of the general formula

[image] [image]

u kojoj where

R1 i R2 imaju značenje definirano na početku, a jedan od ostataka X1 ili Y1 predstavlja skupinu opće formule R1 and R2 have the meaning defined at the beginning, and one of the residues X1 or Y1 represents a group of the general formula

[image] [image]

a drugi od ostataka X1 ili Y1 predstavlja skupinu opće formule and the second of the residues X1 or Y1 represents a group of the general formula

[image] [image]

pri čemu su at which they are

R2 i R4 su definirani kao na početku, R2 and R4 are defined as at the beginning,

R8 predstavlja vodikov atom ili R3CO skupinu, pri čemu je R8 represents a hydrogen atom or R3CO group, where

R3 definiran kao što je prethodno navedeno, R3 defined as previously stated,

Z1 i Z2, koji mogu biti jednaki ili različiti, u datom slučaju predstavljaju supstituirane amine skupine ili u datom slučaju hidroksi ili merkapto skupine supstituirane s nižim alkilnim skupinama, ili Z1 and Z2, which may be the same or different, in a given case represent substituted amine groups or in a given case hydroxy or mercapto groups substituted with lower alkyl groups, or

Z1 i Z2 zajedno predstavljaju atom kisika ili sumpora, Z1 and Z2 together represent an oxygen or sulfur atom,

imino skupinu, supstituiranu u datom slučaju s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, alkilendioksi ili alkilenditio skupinu sa 2 ili 3 ugljikova atoma, pri čemu jedan od ostataka X1 ili Y2 mora predstavljati skupinu opće formule an imino group, substituted in a given case with an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms, whereby one of the residues X1 or Y2 must represent a group of the general formula

[image] [image]

ili or

[image] [image]

Ciklizaciju se može smisleno provesti u otapalu ili u mješavini otapala, kao etanolu, izopropanolu, ledenoj octenoj kisleini, benzenu, klorbenzenu, toluenu, ksilenu, glikolu, glikolmonometileteru, diglikoldimetileteru, dimetilformamidu, tetralinu ili u suvišku sredstva za aciliranje koje se upotrebljava za pripravu spoja opće formule II, npr. u odgovarajućem nitrilu, kiselinskom halogenidu, esteru ili amidu, npr. pri temperaturama između 0 i 250oC, ponajprije pri temperaturi vrelišta reakcijske smjese, u datom slučaju u prisutnosti kondenzacijskog sredstva, kao fosfornog oksiklorida, tionilklorida, sulfurilklorida, sumporne kiseline, p-toluensulfonske kiseline, metansulfonske kiseline, klorovodične kiseline, fosforne kiseline, polifosforne kiseline, anhidrida octene kiseline, ili u datom slučaju također u prisutnosti kalijevog etilata, ili kalijevog terc.butilata. Ciklizaciju se može provesti također i bez otapala i/ili kondenzacijskog sredstva. The cyclization can conveniently be carried out in a solvent or mixed solvent, such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diglycoldimethylether, dimethylformamide, tetralin, or in excess of the acylating agent used to prepare the compound. of general formula II, e.g. in the corresponding nitrile, acid halide, ester or amide, e.g. at temperatures between 0 and 250oC, preferably at the temperature of the boiling point of the reaction mixture, in the given case in the presence of a condensation agent, such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfur acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride, or in the given case also in the presence of potassium ethylate or potassium tert.butylate. The cyclization can also be carried out without a solvent and/or condensing agent.

Kemijsku pretvorbu vrši se posebno korisno tako da se pripremi spoj opće formule II u reakcijskoj smjesi redukcijom odgovarajućeg o-nitro-amino spoja, u datom slučaju u prisutnosti karboksilne kiseline opće formule R3COOH ili aciliranjem odgovarajućeg o-diamino spoja. Po prekidu redukcije nitro skupinu u stupnju hidroksilamina dobije se kasnijom ciklizacijom N-oksidnog spoja opće formule I. Tako dobiven N-oksid prevede se zatim redukcijom u odgovarajući spoj opće formule I. The chemical conversion is carried out particularly advantageously by preparing the compound of the general formula II in the reaction mixture by reduction of the corresponding o-nitro-amino compound, in the given case in the presence of a carboxylic acid of the general formula R3COOH or by acylation of the corresponding o-diamino compound. After stopping the reduction, the nitro group in the hydroxylamine stage is obtained by subsequent cyclization of the N-oxide compound of general formula I. The N-oxide thus obtained is then converted into the corresponding compound of general formula I by reduction.

Kasniju redukciju tako dobivenog N-oksida formule I provodi se ponajprije u otapalu, kao u vodi, vodi/etanolu, metanolu, ledenoj octenoj kiselini, etilesteru octene kiseline ili dimetilformamidu s vodikom u prisutnosti katalizatora za hidriranje, kao Raney-nikla, platine ili paladij/ugljena s metalima kao željezom, kositrom ili cinkom, u prisutnosti kiseline kao octene kiseline, klorovodične kiseline ili sumporne kiseline, sa solima kao što su željezni(II) sulfat, kositreni(II) klorido ili natrijev ditionit, ili hidrozinom u prisutnosti Raney-nikla pri temperaturama između 0 i 50oC, ponajprije pri sobnoj temperaturi. The subsequent reduction of the thus obtained N-oxide of formula I is preferably carried out in a solvent, such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium /charcoal with metals such as iron, tin or zinc, in the presence of an acid such as acetic acid, hydrochloric acid or sulfuric acid, with salts such as iron(II) sulphate, tin(II) chloride or sodium dithionite, or hydrazine in the presence of Raney- nickel at temperatures between 0 and 50oC, preferably at room temperature.

b) Kemijskom pretvorbom benzimidazola opće formule b) Chemical conversion of benzimidazole of the general formula

[image] [image]

u kojoj where

R1 do R3 su definirani kao gore, s bifenilnim spojem opće formule R1 to R3 are defined as above, with a biphenyl compound of the general formula

[image] [image]

u kojoj where

R4 je definiran kao gore i R4 is defined as above and

Z3 predstavlja nukleofilnu polaznu skupinu, kao halogeni atom, npr. atom klora, broma ili joda, ili supstituiranu sulfoniloksi skupinu, npr. metansulfoniloksi, fenilsulfoniloksi ili p-toleunsulfoniloksi skupinu. Z3 represents a nucleophilic starting group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a substituted sulfonyloxy group, for example a methanesulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy group.

Kemijsku pretvorbu smisleno se provodi u otapalu ili u smjesi otapala, kao metilenkloridu, dietileteru, tetra-hidrofuranu, dioksanu, dimetilsulfoksidu, dimetilformamidu ili benzenu, u datom slučaju u prisutnosti sredstva za vezanje kiseline, kao natrijevog karbonata, kalijevog karbonata, natrijevog hidroksida, kalijevog terc.butilata, trietilamina ili piridina, pri čemu se obadva posljednja navedena spoja istovremeno upotrebljavaju i kao otapalo, ponajprije pri temperaturama između 0 i 100oC, npr. pri temperaturama između sobne temperature i 50oC. The chemical conversion is meaningfully carried out in a solvent or in a mixture of solvents, such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or benzene, in a given case in the presence of an acid binding agent, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium of tert.butylate, triethylamine or pyridine, whereby both of the latter compounds are simultaneously used as a solvent, preferably at temperatures between 0 and 100oC, for example at temperatures between room temperature and 50oC.

Pri kemijskoj pretvorbi dobije se ponajprije smjesu 1- i 3-izomera, koju se zatim po želji rastavlja u odgovarajući 1- i 3-izomer, ponajprije kromatografijom, primjenom nosača kao silika gela ili aluminijevog oksida. During the chemical conversion, a mixture of 1- and 3-isomers is obtained, which is then separated into the corresponding 1- and 3-isomers, preferably by chromatography, using a carrier such as silica gel or aluminum oxide.

c) Za pripravu spoja opće formule I, u kojoj R4 predstavlja karboksi skupinu: c) For the preparation of the compound of the general formula I, in which R4 represents a carboxy group:

Pretvorbom spoja opće formule By converting the compound of the general formula

[image] [image]

u kojoj where

R1 do R3 su kao gore definirani i R1 to R3 are as defined above and

R4’ predstavlja skupinu koju se hidrolizom, termolizom ili hidrogenolizom može prevesti u karboksi skupinu. R4' represents a group that can be converted into a carboxyl group by hydrolysis, thermolysis or hydrogenolysis.

Tako se npr. funkcionalni derivati karboksi skupine, kao njihovi nesupstituirani amidi, esteri, tiolni esteri, ortoesteri, iminoeteri, amidini ili anhidridi, nitrilna skupina ili tetrazolilna skupinu može hidrolizom prevesti u karboksi skupinu, esteri s tercijarnim alkoholima, npr. terc.butil ester, prevedu se termolizom u karboksi skupinu, s esteri s aralalkoholima, npr. benzil ester, prevedu se hidrogenolizom u karboksi skupinu. Thus, for example, functional derivatives of the carboxy group, such as their unsubstituted amides, esters, thiol esters, orthoesters, iminoethers, amidines or anhydrides, a nitrile group or a tetrazolyl group can be hydrolyzed into a carboxy group, esters with tertiary alcohols, e.g. tert.butyl ester , are converted to a carboxy group by thermolysis, with esters with aral alcohols, eg benzyl ester, are converted to a carboxy group by hydrogenolysis.

Hidrolizu se smisleno provodi u prisutnosti kiseline, kao što je klorovodična kiselina, sumporna kiselina, fosforna kiselina, trikloroctena kiselina ili trifluoroctena kiselina, u prisutnosti baze, kao natrijevog hidroksida ili kalijevog hidroksida u prikladnom otapalu, kao vodi, vodi/metanolu, etanolu, vodi/etanolu, vodi/izo-propanolu ili vodi/dioksanu, pri temperaturama između -10oC i 120oC, npr. pri temperaturama između sobne temperature i temperature vrelišta reakcijske smjese. The hydrolysis is meaningfully carried out in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, in the presence of a base, such as sodium hydroxide or potassium hydroxide in a suitable solvent, such as water, water/methanol, ethanol, water /ethanol, water/iso-propanol or water/dioxane, at temperatures between -10oC and 120oC, for example at temperatures between room temperature and the boiling temperature of the reaction mixture.

Kod hidrolize u prisutnosti nekih organskih kiselina, kao trikloroctene kiseline ili trifluoroctene kiselina, u datom slučaju prisutne alkoholne hidroksi skupine mogu se istovremeno prevesti u odgovarajuće aciloksi skupine, kao trifluor-acetoksi skupinu. During hydrolysis in the presence of some organic acids, such as trichloroacetic acid or trifluoroacetic acid, the alcoholic hydroxy groups present in a given case can be simultaneously converted into corresponding acyloxy groups, such as a trifluoroacetoxy group.

Ako R4’ u spoju opće formule V predstavlja cijano ili aminokarbonilnu skupinu, te se skupine mogu pretvoriti u karboksi skupine također s nitritom, npr. s natrijevim nitritom u prisutnosti kiseline, kao sumporne kiseline, pri čemu se nju smisleno može upotrijebiti istovremeno kao otapalo, pri temperaturama između 0 i 50oC. If R4' in the compound of the general formula V represents a cyano or aminocarbonyl group, these groups can be converted into carboxyl groups also with nitrite, for example with sodium nitrite in the presence of an acid, such as sulfuric acid, whereby it can meaningfully be used simultaneously as a solvent, at temperatures between 0 and 50oC.

Ako R4’ u spoju opće formule V predstavlja npr. terc.butiloksikarbonilnu skupinu, terc.butilnu skupinu se također može termički odcijepiti u datom slučaju u inertnom otapalu, kao metilenkloridu, kloroformu, benzenu, toluenu, tetrahidrofuranu ili dioksanu i ponajprije u prisutnosti katalitičke količine kiseline, kap p-toluensulfonske kiseline, sumporne kiseline, fosforne kiseline ili polifosforne kiseline, ponajprije pri temperaturi vrelišta upotrijebljenog otapala, npr. pri temperaturama između 40oC i 100oC. If R4' in the compound of the general formula V represents, for example, a tert.butyloxycarbonyl group, the tert.butyl group can also be cleaved off thermally in a given case in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount acid, a drop of p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the temperature of the boiling point of the solvent used, for example at temperatures between 40oC and 100oC.

Ako R4’ u spoju opće formule V predstavlja npr. benziloksikarbonilnu skupinu, tu benzilnu skupinu se također odcijepi hidrogenolitički u prisutnosti katalizatora za hidririranje, kao paladij/ugljena, u prikladnom otapalu, kao metanolu, etanolu, etanol/vodi, ledenoj octenoj kiselini, etilesteru octene kiseline, dioksanu ili dimetilformamidu, ponajprije pri temperaturama između 0 i 50oC, npr. pri sobnoj temperaturi i pod tlakom vodika od 1 do 5 bara. Kod hidrogenolize mogu se istovremeno reducirati i drugi ostaci, npr. nitro skupinu u amino skupinu, benziloksi skupinu u hidroksi skupinu, vinilidensku skupinu u odgovarajuću alkilidensku skupinu ili skupinu cimetne kiseline u odgovarajuću skupinu fenilpropionske kiseline ili se npr. halogeni atom nadomjesti s atomom vodika. If R4' in the compound of the general formula V represents, for example, a benzyloxycarbonyl group, this benzyl group is also cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl ester acetic acid, dioxane or dimethylformamide, preferably at temperatures between 0 and 50oC, for example at room temperature and under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other residues can be simultaneously reduced, e.g. a nitro group to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylidene group or a cinnamic acid group to a corresponding phenylpropionic acid group, or e.g. a halogen atom is replaced by a hydrogen atom.

d) Za pripravu spoja opće formule I u kojoj R4 predstavlja 1H-tetrazolilnu skupinu: d) For the preparation of the compound of the general formula I in which R4 represents the 1H-tetrazolyl group:

Odcijepanjem zaštitnog ostatka od spoja opće formule By cleaving the protective residue from the compound of the general formula

[image] [image]

u kojoj where

R1, R2 i R3 su kao gore definirani i R1, R2 and R3 are as defined above and

R4’’ predstavlja 1H-tetrazolilnu skupinu u položaju 1 ili 3 zaštićenu sa zaštitnim ostatkom. R4'' represents a 1H-tetrazolyl group in position 1 or 3 protected with a protective residue.

Kao zaštitni ostatak u obzir dolazi npr. trifenil-metil, kositrena tributil ili kositrena trifenil skupina. Examples of protective residues include triphenylmethyl, tin tributyl or tin triphenyl group.

Odcijepljenje upotrijebljenog zaštitnog ostatka odvija se ponajprije u prisutnosti halogenovodika, ponajprije u prisutnosti klorovodika, u prisutnosti baze, kao natrijevog hidroksida ili alkoholnog amonijaka i prikladnom otapalu, kao metilenkloridu, metanolu, metanol/amonijaku, etanolu ili izopropanolu pri temperaturama između 0 i 100oC, ponajprije pri sobnoj temperaturi, ili također u slučaju da se pretvorbu provodi u prisutnosti alkoholnog amonijaka, pri povišenim temperaturama, npr. pri temperaturama između 100 i 150oC, ponajprije pri temperaturama između 120 i 140oC. Cleavage of the protective residue used takes place preferably in the presence of hydrogen halide, preferably in the presence of hydrogen chloride, in the presence of a base such as sodium hydroxide or alcoholic ammonia and a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol at temperatures between 0 and 100oC, preferably at room temperature, or also in case the conversion is carried out in the presence of alcoholic ammonia, at elevated temperatures, for example at temperatures between 100 and 150oC, preferably at temperatures between 120 and 140oC.

e) Za pripravu spoja opće formule I, u kojoj R4 predstavlja 1H-tetrazolilnu skupinu: e) For the preparation of the compound of the general formula I, in which R4 represents the 1H-tetrazolyl group:

Kemijskom pretvorbom spoja opće formule By chemical conversion of the compound of the general formula

[image] [image]

u kojoj where

R1 do R3 su kao gore definirani, s dušikovodičnom kiselinom ili njenim solima. R1 to R3 are as defined above, with nitric acid or its salts.

Kemijsku pretvorbu provodi se ponajprije u otapalu, kao benzenu, toluenu ili dimetilformamidu, pri temperaturama između 80 i 150oC, ponajprije pri 125oC. Pri tome smisleno je osloboditi dušikovodičnu kiselinu tijekom pretvorbe alkalijskog azida, npr. iz natrijevog azida u prisutnosti slabe kiseline, kao amonijevog klorida, ili tetrazolilnu sol dobivenu u smjesi pri pretvorbi sa soli dušikovodične kiseline, ponajprije s aluminijevim azidom, ili tributilkositrenim azidom, koju se pored toga smisleno pripremi u reakcijskoj smjesi pretvorbom aluminijevog klorida ili tributilkositrenog klorida s alkalijskim azodom, kao natrijevim azidom, zatim se oslobodi zakiseljavanjem s razrijeđenom kiselinom kao 2N klorovodičnom kiselinom ili 2N sumpornom kiselinom. The chemical conversion is preferably carried out in a solvent, such as benzene, toluene or dimethylformamide, at temperatures between 80 and 150oC, preferably at 125oC. In this case, it makes sense to liberate nitric acid during the conversion of alkaline azide, for example from sodium azide in the presence of a weak acid, such as ammonium chloride, or the tetrazolyl salt obtained in a mixture during the conversion from the salt of nitric acid, preferably with aluminum azide, or tributyltin azide, which in addition, it is meaningfully prepared in the reaction mixture by converting aluminum chloride or tributyltin chloride with an alkaline azide, such as sodium azide, then liberated by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulfuric acid.

f) Za pripravu spojeva opće formule I u kojoj R2 predstavlja jednu od gore spomenutih skupina: imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il, imidazo[1,2-c]-pirimidin-2-il, imidazo[1,2-a]pirazin-2-il, imidazo[1,2-b]-piridazin-2-il ili imidazo[2,1-b]tiazol-6-il: f) For the preparation of compounds of the general formula I in which R2 represents one of the aforementioned groups: imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[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-il:

Kemijskom pretvorbom spoja opće formule By chemical conversion of the compound of the general formula

[image] [image]

u kojoj where

jedan od ostataka A, B, C ili D predstavlja metinsku skupinu ili dušikov atom i one of the residues A, B, C or D represents a methine group or a nitrogen atom and

preostali od ostataka A, B, C i D predstavljaju metinske skupine, ili A i B predstavljaju metinske skupine, a -C=D-skupina predstavlja sumporni atom, the rest of the residues A, B, C and D represent methine groups, or A and B represent methine groups, and the -C=D-group represents a sulfur atom,

R9 predstavlja vodikov atom, fluor, klor ili brom, alkilnu, alkoksi, hidroksi, fenilnu, nitro, amino, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksikarbonilnu, aminokarbonilnu, alkilaminokarbonilnu, dialkilaminokarbonilnu, trifluormetilnu, alkanoilnu, amino-sulfonilnu, alkilaminosulfonilnu ili dialkilaminosulfonilnu akupinu i R9 represents a hydrogen atom, fluorine, chlorine or bromine, alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl acupine and

R10 je atom vodika, fluora ili klora, metil, metoksi ili hidroksi skupina, pri čemu u slučaju da R9 i R10 predstavljaju susjedne metilne skupine, one međusobno mogu biti povezane s metilenskom ili etilenskom skupinom, R10 is a hydrogen, fluorine or chlorine atom, a methyl, methoxy or hydroxy group, where in case R9 and R10 represent adjacent methyl groups, they can be connected to each other with a methylene or ethylene group,

sa spojem opće formule with a compound of the general formula

[image] [image]

u kojoj where

R1, R3 i R4 su definirani kao gore, a R1, R3 and R4 are defined as above, a

Z predstavlja nukleofilnu polaznu skupinu, kao halogeni atom, npr. atom klora ili broma. Z represents a nucleophilic starting group, such as a halogen atom, for example a chlorine or bromine atom.

Kemijsku pretvorbu smisleno se provodi u otapalu ili u mješavini otapala, kao etanolu, izopropanolu, benzenu, glikolu, glikolmonometileteru, dimetilformamidu ili dioksanu, npr. pri temperaturama između 20 i 100oC. Kemijsku pretvorbu može se provesti i bez otapala. The chemical conversion is meaningfully carried out in a solvent or a mixture of solvents, such as ethanol, isopropanol, benzene, glycol, glycolmonomethylether, dimethylformamide or dioxane, for example at temperatures between 20 and 100oC. The chemical conversion can also be carried out without solvents.

g) Za pripravu spoja opće formule I u kojoj R2 predstavlja jednu od gore spomenutih skupina: benzimidazol-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]piridin-2-il, imidazo[4,5-b]pirazin-2-il, imidazo[4,5-c]piridazin-2-il, imidazo[4,5-d]piridazin-2-il ili purin-8-il skupinu: g) For the preparation of compounds of the general formula I in which R2 represents one of the above-mentioned groups: benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2- yl, 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 group :

Ciklizacijom spoje opće formule By cyclization of compounds of general formula

[image] [image]

u kojoj where

nijedan, jedan ili dva od ostataka A1, B1, C1 ili D1 predstavljaju dušikov atom, a prestali od ostataka A1, B1, C1 ili D1 predstavljaju metinske skupine, none, one or two of the residues A1, B1, C1 or D1 represent a nitrogen atom, and the remainder of the residues A1, B1, C1 or D1 represent methine groups,

R11 je atom vodika, fluora, klora ili broma, alkil, alkoksi, hidroksi, fenil, nitro, amino, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksi-karbonil, aminokarbonil, alkilaminokarbonil, dialkilamino-karbonil, trifluormetil, alkanoil, aminosulfonil, alkil-aminosulfonil ili dialkilaminosulfonil akupina i R11 is a hydrogen, fluorine, chlorine or bromine atom, alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulfonyl , alkylaminosulfonyl or dialkylaminosulfonyl acupine and

R12 je atom vodika, fluora ili klora, metil, metoksi ili hidroksi skupina, jedan od ostataka X2 ili Y2 predstavlja R13-NH skupinu, a drugi od ostataka X2 ili Y3 predstavlja skupinu opće formule R12 is a hydrogen, fluorine or chlorine atom, a methyl, methoxy or hydroxy group, one of the residues X2 or Y2 represents the R13-NH group, and the other of the residues X2 or Y3 represents a group of the general formula

[image] [image]

pri čemu su R1, R3 i R4 kao gore definirani, a jedan od ostataka R13 ili R14 predstavlja vodikov atom, dok drugi od ostataka R13 ili R14 predstavlja vodikov atom, alkilnu skupinu s 1 do 6 ugljikovih atoma ili cikloalkilnu skupinu, wherein R1, R3 and R4 are as defined above, and one of the residues R13 or R14 represents a hydrogen atom, while the other of the residues R13 or R14 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a cycloalkyl group,

Z5 i Z6, koji mogu biti jednaki ili različiti, predstavljaju u datom slučaju supstituirane amino skupine ili u datom slučaju hidroksi ili merkapto skupine supstiruirane s nižim alkilnim skupinama ili Z5 and Z6, which may be the same or different, represent in a given case substituted amino groups or in a given case hydroxy or mercapto groups substituted with lower alkyl groups or

Z5 i Z6 zajedno predstavljaju atom kisika ili sumpora ili imino skupinu, u datom slučaju supstituiranu s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, alkilendioksi ili alkilenditio skupinu od kojih svaka ima 2 ili 3 ugljikova atoma, i zatim, u datom slučaju, hidrolizu. Z5 and Z6 together represent an oxygen or sulfur atom or an imino group, optionally substituted with an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or an alkylenedithio group each having 2 or 3 carbon atoms, and then, optionally, hydrolysis .

Ciklizaciju se smisleno provodi u otapalu ili u mješavini otapala, kao etanolu, izopropanolu, ledenoj octenoj kiselini, benzenu, klorbenzenu, toluenu, ksilenu, glikolu, glikolmonometileteru, dietilenglikol dimetileteru, sulfolanu, dimetilformamidu, tetralinu ili u suvišku sredstva za aciliranje koje se upotrebljava za pripravu spoja opće formule X, npr. u odgovarajućem nitrilu, anhidridu, kiselinskom halogenidu, esteru ili amidu, npr. pri temperaturama između 0 i 250oC, ponajprije pri temperaturi vrelišta reakcijske smjese, u datom slučaju u prisutnosti sredstva za kondenzaciju, kao fosfornog oksiklorida, tionilklorida, sulfurilklorida, sumporne kiseline, p-toluensulfonske kiseline, metansulfonske kiseline, klorovodične kiseline, fosforne kiseline, polifosforne kiseine, anhidrida octene kiseline ili u datom slučaju također u prisutnosti baze, kao kalijevog etilata ili kalijevog terc.butilata. The cyclization is conveniently carried out in a solvent or mixed solvent such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin, or in an excess of an acylating agent used for preparation of a compound of the general formula X, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250oC, preferably at the temperature of the boiling point of the reaction mixture, in the given case in the presence of a condensation agent, such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or in the given case also in the presence of a base, such as potassium ethylate or potassium tert.butylate.

Ciklizaciju se također može provesti i bez otapala i/ili sredstva za kondenzaciju. The cyclization can also be carried out without a solvent and/or condensing agent.

Posebno korisno kemijsku pretvorbu provodi se tako, da se spoj opće formule X pripremi u reakcijskoj smjesi, redukcijom odgovarajućeg o-nitro-amino spoja, u datom slučaju u prisutnosti karboksilne kiseline opće formule A particularly useful chemical conversion is carried out by preparing the compound of the general formula X in the reaction mixture, by reducing the corresponding o-nitro-amino compound, in the given case in the presence of a carboxylic acid of the general formula

[image] [image]

u kojoj where

R1, R3 i R4 su definirani kao gore, ili aciliranjem odgovarajućeg o-diamino spoja s karboksilnom kiselinom opće formule XI. R 1 , R 3 and R 4 are defined as above, or by acylation of the corresponding o-diamino compound with a carboxylic acid of general formula XI.

Kod prekida redukcije nitro skupine u hidroksilno aminskom stupnju pri kasnijoj ciklizaciji dobiju se N-oksidni spojevi opće formule I. Tako dobiveni N-oksid prevodi se zatim redukcijom u odgovarajući spoj opće formule I. When the reduction of the nitro group is interrupted in the hydroxyl amine stage during subsequent cyclization, N-oxide compounds of the general formula I are obtained. The N-oxide thus obtained is then converted into the corresponding compound of the general formula I by reduction.

Kasniju redukciju tako dobivenog N-oksida provodi se ponajprije u otapalu, kao vodi, voda/etanolu, metanolu, ledenoj octenoj kiselini, etilesteru octene kiseline ili dimetilformamidu s vodikom u prisutnosti katalizatora za hidriranje, kao Raney-nikla, platine ili paladij/ugljena s metalima, kao željezom, kositrom ili cinkom u prisutnosti kiseline, kao octene kiseline, klorovodične kiseline ili sumporne kiseline, sa solima kao željeznim(II) sulfatom, kositrenim(II) kloridom ili natrijevim ditionitom ili s hidrazinom u prisutnosti Raney-nikla pri temperaturama između 0 i 50oC, ponajprije pri sobnoj temperaturi. The subsequent reduction of the thus obtained N-oxide is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, acetic acid ethyl ester or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/carbon with metals, such as iron, tin or zinc in the presence of an acid, such as acetic acid, hydrochloric acid or sulfuric acid, with salts such as iron(II) sulphate, stannous(II) chloride or sodium dithionite or with hydrazine in the presence of Raney-nickel at temperatures between 0 and 50oC, preferably at room temperature.

Kasniju hidrolizu vrši se smisleno u prisutnosti kiseline, kao klorovodične kiseline, sumporne kiseline, fosforne kiseline, trikloroctene kiseline ili trifluor-octene kiseline i u prisutnosti baze, kao natrijevog hidroksida ili kalijevog hidroksida u prikladnom otapalu, kao vodi, voda/metanolu, tanolu, voda/etanolu, voda/izo-propanolu ili voda/dioksanu, pri temperaturama između -10oC i 120oC, npr. pri temperaturama između sobne temperature i vrelišta reakcijske smjese. Kod hidrolize u prisutnosti organskih kiselina, kao trokloroctene kiseline ili trifluoroctene kiseline, u datom slučaju može se istovremeno prevesti prisutnu alkoholnu hidroksi skupinu u odgovarajuću aciloksi skupinu, kao trifluoracetoksi skupinu. Subsequent hydrolysis is meaningfully carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid and in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water /ethanol, water/iso-propanol or water/dioxane, at temperatures between -10oC and 120oC, eg at temperatures between room temperature and the boiling point of the reaction mixture. During hydrolysis in the presence of organic acids, such as trichloroacetic acid or trifluoroacetic acid, in a given case, the present alcoholic hydroxy group can be simultaneously converted into a corresponding acyloxy group, such as a trifluoroacetoxy group.

) Za pripravu spojeva opće formule I u kojoj R2 predstavlja dihidro-piridazin-3-on ili piridazin-3-on skupinu, koja može biti supstituirana u položaju 2 s alkilnom skupinom koja 1 do 3 ugljikova atoma, u datom slučaju supstituiranom s fenilnom skupinom, ili može biti supstituirana u ugljikovoj strukturi s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma: ) For the preparation of compounds of the general formula I in which R2 represents a dihydro-pyridazin-3-one or pyridazin-3-one group, which can be substituted in position 2 with an alkyl group having 1 to 3 carbon atoms, in this case substituted with a phenyl group , or it can be substituted in the carbon structure with one or two alkyl groups, each of which has 1 to 3 carbon atoms:

Kemijskom pretvorbom kiseline opće formule By chemical conversion of an acid of the general formula

[image] [image]

u kojoj where

R1, R3 i R4 su kao gore definirani, a R1, R3 and R4 are as defined above, a

E predstavlja etilensku ili etenilensku skupinu, u datom slučaju supstituiranu s jednom ili dvije alkilne skupine od kojih svaka ima po 1 do 3 ugljikova atoma, ili njenih kiselinskih derivata sposobnih za reakciju, kao njenih estera, amida ili halogenida, s hidroazinom opće formule E represents an ethylene or ethenylene group, in a given case substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms, or its acid derivatives capable of reacting, as its esters, amides or halides, with hydrazine of the general formula

H2N-NHR15(XIII) H2N-NHR15(XIII)

u kojoj where

R15 predstavlja atom vodika ili u datom slučaju alkilnu skupinu koja ima 1 do 3 ugljikova atoma supstituiranu s fenilnom skupinom. R15 represents a hydrogen atom or, in a given case, an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group.

Kemijsku pretvorbu vrši se smisleno u otapalu, kao metanolu, etanolu, izopropanolu, ledenoj octenoj kiselini, propionskoj kiselini i/ili suvišku upotrijebljenog hidrazina, odnosno hidrazin hidrata, pri temperaturama između 0oC i 200oC, npr. pri temperaturama između 20 i 150oC, a ponajprije pri vrelištu reakcijske smjese i u datom slučaju u prisutnosti kiseline, kao sumporne kiseline ili p-toluensulfonske kiseline kao sredstva za kondenzaciju. Kemijsku pretvorbu može se provesti i bez otapala. The chemical conversion is meaningfully carried out in a solvent, such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and/or an excess of used hydrazine, i.e. hydrazine hydrate, at temperatures between 0oC and 200oC, for example at temperatures between 20 and 150oC, and preferably at the boiling point of the reaction mixture and in the given case in the presence of an acid, such as sulfuric acid or p-toluenesulfonic acid as a condensation agent. The chemical conversion can also be carried out without solvents.

Kod prethodno opisanih kemijskih pretvorbi u datom slučaju prisutne reaktivne skupine, kao hidroksi, amino ili alkilamino skupine tijekom pretvorbe se zaštite s uobičajenim zaštitinim skupinama koje se nakon pretvorbe opet odcijepe. In the previously described chemical conversions, the reactive groups present in the given case, such as hydroxy, amino or alkylamino groups, are protected during the conversion with the usual protective groups, which are cleaved off again after the conversion.

Kao zaštitne skupine za hidroksi skupinu u obzir dolaze npr. trimetilsilil, acetil, benzoil, metil, terc.butil, benzil ili tetrahidropiranil skupina, a kao zaštitna skupina za amino, alkilamino i imino skupinu u obzir dolaze acetil, benzoil, etoksikarbonil ili benzil skupina. Suitable protective groups for the hydroxy group include, for example, trimethylsilyl, acetyl, benzoyl, methyl, tert.butyl, benzyl or tetrahydropyranyl groups, and suitable protective groups for amino, alkylamino and imino groups include acetyl, benzoyl, ethoxycarbonyl or benzyl groups .

U datom slučaju kasnije odcjepljenje upotrijebljenog zaštitnog ostatka odvija se ponajprije hidrolitički u vodenom otapalu, npr. u vodi, izopropanol/vodi, tetrahidrofuran/vodi ili dioksan/vodi u prisutnosti kiseline, kao klorovodične kiseline ili sumporne kiseline, ili u prisutnosti alkalijske baze, kao natrijevg hidroksida ili kalijevog hidroksida pri temperaturama između 0 i 100oC, ponajprije pri temperaturi vrelišta reakcijske smjese. Odcjepljenje benzilnog ostatka odvija se međutim ponajprije hidrogenolitički, npr. s vodikom u prisutnosti katalizatora, kao paladij/ugljena, u otapalu, kao metanolu, etanolu, etilesteru ostene kiseline ili ledenoj octenoj kiselini u datom slučaju uz dodatak kiseline, kao klorovodične kiseline pri temperaturama između 0 i 50oC, ponajprije pri sobnoj temperaturi i pod tlakom vodika od 1 do 7 bara, ponajprije od 3 do 5 bara. In this case, the subsequent cleavage of the protective residue used takes place primarily hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water in the presence of an acid, such as hydrochloric acid or sulfuric acid, or in the presence of an alkaline base, such as of sodium hydroxide or potassium hydroxide at temperatures between 0 and 100oC, preferably at the temperature of the boiling point of the reaction mixture. However, the removal of the benzyl residue takes place primarily hydrogenolytically, e.g. with hydrogen in the presence of a catalyst, such as palladium/charcoal, in a solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid in a given case with the addition of an acid, such as hydrochloric acid at temperatures between 0 and 50oC, preferably at room temperature and under a hydrogen pressure of 1 to 7 bar, preferably from 3 to 5 bar.

Tako dobivenu izomernu smjesu spojeva opće formule I može se po želji korisno rastaviti kromatografski upotrebom nosača, kao silika gela ili aluminijevog oksida. The thus obtained isomeric mixture of compounds of the general formula I can, if desired, be advantageously resolved chromatographically using a carrier such as silica gel or aluminum oxide.

Nadalje, tako dobiveni spojevi opće formule I mogu se prevesti u njihove kiselinske adicijske soli, osobito u njihove fiziološki podnošljive soli s anorganskim ili organskim kiselinama za farmaceutsku upotrebu. Kao kiseline za tu svrhu u obzir dolaze npr. klorovodična kiselina, bromovodična kiselina, sumporna kiselina, fosforna kiselina, fumarna kiselina, jantarna kiselina, mliječna kiselina, limunska kiselina, vinska kiselina ili maleinska kiselina. Furthermore, the thus obtained compounds of the general formula I can be translated into their acid addition salts, especially into their physiologically tolerable salts with inorganic or organic acids for pharmaceutical use. Acids for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Osim toga, tako dobiveni novi spojevi opće formule I, u slučaju da sadrže karboksi ili 1H-tetrazolilnu skupinu, po želji, mogu se zatim prevesti u njihove soli s anorganskim ili organskim bazama, osobito u njihove fiziološki podnošljive soli za farmaceutsku upotrebu. Kao baze za tu svrhu u obzir dolaze npr. natrijev hidroksid, kalijev hidroksid, cikloheksilamin, etanolamin, dietanol-amin i trietanolamin. In addition, the thus obtained new compounds of the general formula I, in case they contain a carboxy or 1H-tetrazolyl group, can then be converted into their salts with inorganic or organic bases, especially into their physiologically tolerable salts for pharmaceutical use, if desired. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Spojevi općih formula II do XIII, koji se upotrebljavaju kao polazne tvari, djelomično su poznati iz literature ili se mogu dobiti po postupcima poznatim iz literature. The compounds of the general formulas II to XIII, which are used as starting materials, are partly known from the literature or can be obtained by procedures known from the literature.

Tako se npr. spoj opće formule II može dobiti alkiliranjem odgovarajućeg o-aminonitro spoja i zatim redukcijom nitro skupine. Thus, for example, a compound of the general formula II can be obtained by alkylating the corresponding o-aminonitro compound and then reducing the nitro group.

Spojevi općih formula III, V, VI, VII, IX, X ili XII, koji se upotrebljavaju kao polazne tvari, dobiju se aciliranjem odgovarajućeg o-fenilendiamina ili odgovarajućeg o-aminonitro spoja, zatim redukcijom nitro skupine i naknadnom ciklizacijom tako dobivenog o-diamino-fenilnog spoja, i u datom slučaju kasnijim odcjepljenjem upotrijebljenog zaštitnog ostatka ili ciklizacijom odgovarajuće supstituiranog benzimidazola s odgovarajućim aminom ili NH-alkiliranjem odgovarajućeg 1H-benzimidazola, pri čemu se tako dobivenu smjesu izomera može zatim rastaviti uobičajenim metodama, npr. kromatografijom. Pri tome spomenuti polazni spojevi djelomično su opisani u EP-A-0 392 317. Compounds of the general formulas III, V, VI, VII, IX, X or XII, which are used as starting substances, are obtained by acylation of the corresponding o-phenylenediamine or the corresponding o-aminonitro compound, then by reduction of the nitro group and subsequent cyclization of the thus obtained o-diamino -phenyl compound, and in the given case by subsequent removal of the protective residue used or by cyclization of the appropriately substituted benzimidazole with the appropriate amine or NH-alkylation of the appropriate 1H-benzimidazole, whereby the mixture of isomers thus obtained can then be separated by usual methods, e.g. chromatography. The aforementioned starting compounds are partially described in EP-A-0 392 317.

Tako se npr. 2-n-butil-5-(imidazo[1,2-a]piridin-2-il)-3H-benzimidazol dobije pretvorbom p-amino-acetofenona s kloridom maslačne kiseline, kasnijim nitriranjem, bromiranjem, ciklizacijom s 2-aminopiridinom u 6-n-butanoilamido-3-(imidazo[1,2-a]piridin-2-il)nitrobenzen, kojeg se zatim, nakon redukcije nitro skupine, prevede ciklizacijom u željeni spoj ili Thus, for example, 2-n-butyl-5-(imidazo[1,2-a]pyridin-2-yl)-3H-benzimidazole is obtained by converting p-amino-acetophenone with butyric acid chloride, subsequent nitration, bromination, cyclization with with 2-aminopyridine in 6-n-butanoylamido-3-(imidazo[1,2-a]pyridin-2-yl)nitrobenzene, which is then, after reduction of the nitro group, cyclized into the desired compound or

2-n-butil-4-metil-6-(1-metilbenzimidazol-2-il)-1H-benzimidazol nitriranjem metil estera 3-metil-4-n-butanoil-amido-benzojeve kiseline, zatim redukcijom nitro skupine i ciklizacijom u 2-n-butil-4-metil-6-metoksikarbonil-1H-benzimidazol, kojeg se zatim prevede s 2-metilamino-anilinom ciklizacijom u željeni spoj. 2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-1H-benzimidazole by nitration of methyl ester of 3-methyl-4-n-butanoyl-amido-benzoic acid, then by reduction of the nitro group and cyclization in 2-n-butyl-4-methyl-6-methoxycarbonyl-1H-benzimidazole, which is then converted with 2-methylamino-aniline cyclization into the desired compound.

Benzimidazol, u kojem je alkoksi skupina u položaju 2, 3, 4 ili 5 supstituirana s imidazolnim ostatkom, dobije se npr. pretvorbom odgovarajućeg 7-hidroksi-benzimidazola, koji je opisan u EP-A-0 392 317, kemijskom pretvorbom s odgovarajućim α,ω-dihalogenalkanom i zatim pretvorbom s odgovarajućim imidazolom. Benzimidazole, in which the 2-, 3-, 4- or 5-position alkoxy group is substituted with an imidazole residue, is obtained, for example, by converting the corresponding 7-hydroxy-benzimidazole, which is described in EP-A-0 392 317, by chemical conversion with the corresponding α ,ω-dihaloalkane and then conversion with the corresponding imidazole.

Novi spojevi opće formule I i njihove fiziološki podnošljive soli imaju dragocjena farmakološka svojstva. Oni predstavljaju antagoniste angiotenzina, osobito antagoniste angiotenzina II. New compounds of the general formula I and their physiologically tolerable salts have valuable pharmacological properties. They represent angiotensin antagonists, especially angiotensin II antagonists.

Slijedeći spojevi bili su ispitani s obzirom na njihove biološke učinke: The following compounds were tested for their biological effects:

A = 4’-[[2-n-butil-7-[3-(imidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, A = 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

B = trifluoracetat 4’-[[2-n-butil-7-[3-(imidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]metil]bifenil-2-karboksilne kiseline, B = 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid trifluoroacetate,

C = 4’-[[2-n-butil-7-[4-(tetrahidrobenzimidazol-1-il)-butil-oksi]benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, C = 4'-[[2-n-butyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyl-oxy]benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

D = 4’-[[2-n-propil-4-metil-6-(metilbenzimidazol-2-il)benz-imidazol-1-il]metil]bifenil-2-karboksilna kiselina, D = 4'-[[2-n-propyl-4-methyl-6-(methylbenzimidazol-2-yl)benz-imidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

E = 4’-[[2-n-propil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, E = 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl ,

F = 4’-[[2-n-propil-4-metil-6-(1-okso-izoindolin-2-il)-benz-imidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, F = 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benz-imidazol-1-yl]methyl]-2-(1H-tetrazol-5 -yl)biphenyl,

G = 4’-[[2-n-propil-4-metil-6-(butansultam-1-il)benzimid-azol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, G = 4'-[[2-n-propyl-4-methyl-6-(butansultam-1-yl)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl,

H = semihidrat 4’-[[2-n-butil-6-(2,3-dimetilmaleinskakiselina)-4-metilbenzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, H = 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid)-4-methylbenzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid hemihydrate,

I = 4’-[[2-n-butil-6-(izopropilkarbonilamino)-4-metil-benz-imidazol-1-il]metil]bifenil-2-karboksilna kiselina, I = 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benz-imidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

J = 4’-[[2-n-butil-4-metil-6-(morfolinokarbonilamino)-benz-imidazol-1-il]metil]bifenil-2-karboksilna kiselina, J = 4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benz-imidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

K = semitrifluoracetat 4’-[[2-n-butil-6-(cikloheksilamino-karbonilamino)-4-metil-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, K = semitrifluoroacetate 4'-[[2-n-butyl-6-(cyclohexylamino-carbonylamino)-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

L = 4’-[[2-n-butil-7-[3-imidazol-1-il)propiloksi]-4-metil-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, L = 4'-[[2-n-butyl-7-[3-imidazol-1-yl)propyloxy]-4-methyl-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl )biphenyl,

M = 4’-[(2-ciklopropil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, M = 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

N = 4’-[(2-n-propil-4-metil-6-(1-metil-5-fluor-benzimid-azol-2-il)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, N = 4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid ,

O = 4’-[(2-n-propil-4-metil-6-(imidazo[1,2-a]pirimidin-2-il)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, O = 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)benzimidazol-1-yl]methyl]-2-(1H-tetrazol- 5-yl)biphenyl,

P = 4’-[(2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo-[1,2-a]piridin-2-il)-benzimidazol-1-il-metil]-2-bifenil-2-karboksilna kiselina, P = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1- yl-methyl]-2-biphenyl-2-carboxylic acid,

Q = 4’-[(2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo-[1,2-a]piridin-2-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)bifenil, Q = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1- yl)-methyl]-2-(1H-tetrazol-5-yl)biphenyl,

R = 4’-[(2-n-propil-4-klor-6-(1-metilbenzimidazol-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)bifenil-hidroklorid i R = 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl) biphenyl hydrochloride i

S = 4’-[(2-n-propil-4-metil-6-(imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il)-metil]-2-bifenil-2-karboksilna kiselina. S = 4'-[(2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl)-methyl]-2-biphenyl-2 -carboxylic acid.

Opis metode ispitivanja receptorskog vezanja angiotenzina Description of the angiotensin receptor binding test method

II II

Tkivo (pluća štakora) se homogenizira u tris puferu (50 mmolova tris, 150 mmolova NaCl, 5 mmolova EDTA, pH 7,40) i centrifugira se 2 puta po 20 minuta pri 20000 x g. Dobiveni talog ponovno se suspendira u inkubacijskom puferu (50 mmolova tris, 5 mmolova MgCl2, 0,2% BSA, pH 7,40) 1:75, s obzirom na masu vlažnog tkiva. Po 0,1 ml homogenata inkubira se 60 minuta pri 37oC s 50 pM [125J]-angiotenzina II (NEN, Dreieich, FRG) s rastućim koncentracijama ispitne tvari u ukupnom volumenu od 0,25 ml. Inkubaciju se završi s brzom filtracijom kroz filterski preplet od staklenih vlakana. Filter se ispere sa po 4 ml ledeno hladnog pufera (25 mmolova tris, 2,5 mmolova MgCl2, 0,1% BSA, pH 7,40). Vezanu radioaktivnost odredi se pomoću gama brojača. Pripadne vrijednosti IC50 odrede se iz krivulje doza-učinak. The tissue (rat lung) is homogenized in Tris buffer (50 mmol Tris, 150 mmol NaCl, 5 mmol EDTA, pH 7.40) and centrifuged 2 times for 20 minutes at 20,000 x g. The resulting precipitate is resuspended in incubation buffer ( 50 mmol Tris, 5 mmol MgCl2, 0.2% BSA, pH 7.40) 1:75, with respect to wet tissue mass. Each 0.1 ml homogenate is incubated for 60 minutes at 37oC with 50 pM [125J]-angiotensin II (NEN, Dreieich, FRG) with increasing concentrations of the test substance in a total volume of 0.25 ml. Incubation is finished with rapid filtration through a mesh of glass fibers. The filter is washed with 4 ml of ice-cold buffer (25 mmol Tris, 2.5 mmol MgCl2, 0.1% BSA, pH 7.40). The bound radioactivity is determined using a gamma counter. The corresponding IC50 values are determined from the dose-response curve.

U opisanom ispitivanju tvari A do S pokazuju slijedeće IC50 vrijednosti: In the described test, substances A to S show the following IC50 values:

[image] [image]

Dodatno, učinak spojeva D, E, F, G, H, M i O nakon oralnog davanja ispitan je na budnim renalno hipertenzivnim štakorima, po metodama poznatim iz literature. Kod doze od 10 mg/kg spojevi pokazuju učinak sniženja krvnog tlaka. Additionally, the effect of compounds D, E, F, G, H, M and O after oral administration was tested on awake renally hypertensive rats, using methods known from the literature. At a dose of 10 mg/kg, the compounds show a blood pressure lowering effect.

Nadalje, pri i.v. aplikaciji prethodno navedenih spojeva dozom od 30 mg/kg ne opažaju se nikakvi toksični učinci, npr. nikakav inotropni učinak i nikakav poremećaj srčanog ritma. Spojevi se dakle dobro podnose. Furthermore, at i.v. application of the aforementioned compounds at a dose of 30 mg/kg did not show any toxic effects, eg no inotropic effect and no heart rhythm disturbance. The compounds are therefore well tolerated.

Na osnovi njihovih farmakoloških svojstava novi spojevi i njihove fiziološki podnošljive soli prikladni su za liječenje hipertonije i srčane insuficijencije, nadalje za liječenje ishemijskih perifernih poremećaja prokrvljenosti, miokardijalne ishemije (angine), za preventivu progresije srčane insuficijencije nakon miokardijalnog infarkta, za liječenje dijabetične nefropatije, glaukoma, gastrointestinalnih oboljenja i oboljenja mjehura. Based on their pharmacological properties, new compounds and their physiologically tolerable salts are suitable for the treatment of hypertension and heart failure, furthermore for the treatment of ischemic peripheral blood supply disorders, myocardial ischemia (angina), for the prevention of the progression of heart failure after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma , gastrointestinal diseases and bladder diseases.

Nadalje, novi spojevi i njihove fiziološki podnošljive soli prikladni su za liječenje plućnih oboljenja, npr. plućnih edema i kroničnog bronhitisa, za preventivu arterijske restenoze nakon angioplastije, odebljanja stijenki žila nakon operacije žila, arterioskleroze i dijabetične angiopatije. Zbog utjecaja angiotenzina na oslobađanje acetil holina i dopamina u mozgu novi antagonisti angiotenzina prikladni su također za uklanjanje poremećaja središnjeg živčanog sustava, npr. depresije, Alzheimerove bolesti, Parkinsonovog sindroma, bulimije kao također poremećaja kognitivnih funkcija. Furthermore, the new compounds and their physiologically tolerable salts are suitable for the treatment of pulmonary diseases, eg pulmonary edema and chronic bronchitis, for the prevention of arterial restenosis after angioplasty, thickening of vessel walls after vessel surgery, arteriosclerosis and diabetic angiopathy. Due to the influence of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also suitable for the elimination of disorders of the central nervous system, eg depression, Alzheimer's disease, Parkinson's syndrome, bulimia, as well as disorders of cognitive functions.

Doziranje, potrebno za postizanje odgovarajućeg učinka kod odraslih, iznosi smisleno kod intravenskog davanja 20 do 100 mg, ponajprije 30 do 70 mg, a kod oralnog davanja 50 do 200 mg, ponajprije 75 do 150 mg 1 do 3 puta na dan. U tu svrhu daju se spojevi opće formule I pripremljeni u skladu s izumom, u datom slučaju u kombinaciji s drugim aktivnim tvarima, kao npr. sa sredstvima za sniženje krvnog tlaka, diureticima i/ili kalcijevim antagonistima, zajedno s jednim ili više inertnih uobičajenih nosača i/ili sredstava za razređenje, npr. s kukuruznim škrobom, mliječnim šećerom, sirovim šećerom, mikrokristaliničnom celulozom, magnezijevim stearatom, polivinilpirolidonom, limunskom kiselinom, vinskom kiselinom, vodom, voda/etanolom, voda/glicerinom, voda/sorbitom, voda/polietilenglikolom, propilenglikolom, cetilstearilalkoholom, karboksimetil-celulozom ili tvarima koje sadrže mast, kao čvrstom masti ili njihovim prikladnim mješavinama, pomiješane u uobičajene galenske pripravke, kao tablete, dražeje, kapsule, praške, suspenzije ili čepiće. The dosage required to achieve the appropriate effect in adults is meaningfully for intravenous administration 20 to 100 mg, preferably 30 to 70 mg, and for oral administration 50 to 200 mg, preferably 75 to 150 mg 1 to 3 times a day. For this purpose, compounds of the general formula I prepared in accordance with the invention are administered, in a given case in combination with other active substances, such as, for example, blood pressure lowering agents, diuretics and/or calcium antagonists, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, milk sugar, raw sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol , propylene glycol, cetylstearyl alcohol, carboxymethyl-cellulose or fat-containing substances, as a solid fat or suitable mixtures thereof, mixed in the usual galenic preparations, as tablets, dragees, capsules, powders, suspensions or suppositories.

Za gore spomenute kombinacije kao daljnje aktivne tvari dolaze u obzir, npr., bendroflumetazid, klortiazid, hidroklortiazid, spironolakton, benztiazid, ciklotiazid, etakrinska kiselina, furozemid, metoprolol, prazozin, atenolol, propanolol, (di)hidralazin-hidroklorid, diltiazem, felodipin, nikardipin, nifedipin, nizoldipin i nitredipin. Pri tome, doza te aktivne tvari smisleno iznosi 1/5 uobičajenog preporučenog najnižeg doziranja do 1/1 normalno preporučenog doziranja, dakle npr. 15 do 200 mg hidroklortiazida, 125 do 2000 mg klortiazida, 15 do 200 mg etakrinske kiseline, 5 do 80 mg furozemida, 20 do 480 mg propranolola, 5 do 60 mg felodipina, 5 do 60 mg nifedipina ili 5 do 60 mg nitredipina. For the above-mentioned combinations, as further active substances come into consideration, for example, bendroflumetazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclothiazide, ethacrynic acid, furosemide, metoprolol, prazosin, atenolol, propanolol, (di)hydralazine hydrochloride, diltiazem, felodipine , nicardipine, nifedipine, nisoldipine and nitredipine. At the same time, the dose of this active substance meaningfully amounts to 1/5 of the usual recommended lowest dosage to 1/1 of the normally recommended dosage, i.e. 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 15 to 200 mg of ethacrynic acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felodipine, 5 to 60 mg nifedipine, or 5 to 60 mg nitridipine.

Slijedeći primjeri pobliže objašnjavaju izum. The following examples explain the invention in more detail.

Primjer 1 Example 1

Hidrat 4’-[[2-n-butil-7-[5-(imidazol-1-il)-pentiloksi]-4-metil-benzimidazol-1-il]metil]bifenil-2-karboksilne kiseline 4'-[[2-n-butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid hydrate

0,7 g (1,15 mmola) terc.butilestera 4’-[[2-n-butil-7-[5-(imidazol-1-il)-pentiloksi]-4-metil-benzimidazol-1-il]- 0.7 g (1.15 mmol) tert.butyl ester 4'-[[2-n-butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl] -

metil]bifenil-2-karboksilne kiseline otopi se u 35 ml metilenklorida, doda se 5 ml trifluoroctene kiseline i miješa se 12 sati pri sobnoj temperaturi. Razrijedi se s metilenkloridom i promućka s vodom i sa zasićenom otopinom natrijevog bikarbonata. Tako dobiven sirov proizvod očisti se kroz kolonu silika gela (veličina zrna: 0,063-0,02 mm, etilacetat/etanol/amonijak = 90/10/0,1) i izkristalizira iz acetona. of methyl]biphenyl-2-carboxylic acid is dissolved in 35 ml of methylene chloride, 5 ml of trifluoroacetic acid is added and stirred for 12 hours at room temperature. It is diluted with methylene chloride and shaken with water and saturated sodium bicarbonate solution. The crude product thus obtained is purified through a silica gel column (grain size: 0.063-0.02 mm, ethyl acetate/ethanol/ammonia = 90/10/0.1) and crystallized from acetone.

Dobitak: 0,19 g (29,9 % od teorijskog). Gain: 0.19 g (29.9% of theoretical).

Talište: 185-187oC. Melting point: 185-187oC.

C34H38N4O3·H2O (550,70) C34H38N4O3·H2O (550.70)

[image] Maseni spektar: M/e = M+ 550 [image] Mass spectrum: M/e = M+ 550

Analogono kao u primjeru 1 dobiveni su slijedeći spojevi: Analogous to example 1, the following compounds were obtained:

4’-[[2-n-butil-4-metil-6-(4,5-dihidro-2H-piridazin-3-on-6-il)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(4,5-dihidro-2H-piridazin-3-on-6-il)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-etil-4-metil-6-(4,5-dihidro-2H-piridazin-3-on-6-il)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-ethyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-butil-4-metil-6-(fenilaminokarbonilamino)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(phenylaminocarbonylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-etil-4-metil-6-(cikloheksilaminokarbonilamino)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-ethyl-4-methyl-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-amino)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-butil-4-metil-6-(cikloheksilaminokarbonil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(metilaminokarbonil-metil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-methyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(n-pentilaminokarbonil-metilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(n-pentilaminokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(n-butilaminokarbonil-metil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(n-butylaminocarbonyl-methyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(benzilaminokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(benzylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(alilaminokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-metilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(dimetilaminokarbonil-metil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-methyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(dimetilaminokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-n-butilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-n-butylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(metilaminokarbonil-cikloheksilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(metilaminokarbonil-benzil-amino)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-benzyl-amino)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(n-heksilaminokarbonil-cikloheksilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(n-hexylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-etilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-ethylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(dimetilaminokarbonil-n-pentilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(morfolinokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(pirolidinokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(pirolidinokarbonil-metil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonyl-methyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(piperidinokarbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(piperidinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(3-benzil-3,4,5,6-tetrahidro-2(1H)-pirimidon-1-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina. 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl)-benzimidazol-1-yl] -methyl]-biphenyl-2-carboxylic acid.

Primjer 2 Example 2

4’-[[2-n-butil-7-[3-(imidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[3-(imidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 69,4 % od teorijskog. Gain: 69.4% of the theoretical.

Talište: 208-210oC. Melting point: 208-210oC.

C32H34N4O3 (522,64) C32H34N4O3 (522.64)

[image] Rf vrijednost: 0,50 (silika gel; etilacetat/etanol/amonijak = 50/45/5). [image] Rf value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia = 50/45/5).

Primjer 3 Example 3

Trifluoracetat 4’-[[2-n-butil-7-[3-(benzimidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2- Trifluoroacetate 4'-[[2-n-butyl-7-[3-(benzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-

karboksilne kiseline carboxylic acids

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[3-(benzimidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[3-(benzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 87,8 % od teorijskog. Gain: 87.8% of the theoretical.

Talište: 221-223oC. Melting point: 221-223oC.

C36H36N4O3·CF3COOH (686,72) C36H36N4O3·CF3COOH (686.72)

[image] Rf vrijednost: 0,50 (silika gel; etilacetat/etanol/amonijak = 50/45/5). [image] Rf value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia = 50/45/5).

Primjer 4 Example 4

Hidrat 4’-[[2-n-butil-7-[4-(imidazol-1-il)-butiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline 4'-[[2-n-butyl-7-[4-(imidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid hydrate

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[4-(imidazol-1-il)-butiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[4-(imidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 68,5 % od teorijskog. Gain: 68.5% of the theoretical.

Talište: 126-128oC. Melting point: 126-128oC.

C33H36N4O3·H2O (554,68) C33H36N4O3·H2O (554.68)

[image] Maseni spektar: M/e = 536 [image] Mass spectrum: M/e = 536

Primjer 5 Example 5

4’-[[2-n-butil-7-[2-(benzimidazol-1-il)-etoksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[2-(benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[2-(benzimidazol-1-il)-etoksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[2-(benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 78,1 % od teorijskog. Gain: 78.1% of the theoretical.

Talište: 167-169oC. Melting point: 167-169oC.

C35H34N4O3 (558,68) C35H34N4O3 (558.68)

[image] [image]

Primjer 6 Example 6

4’-[[2-n-butil-7-[5-(benzimidazol-1-il)-pentiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[5-(benzimidazol-1-il)-pentiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 7 Example 7

4’-[[2-n-butil-7-[4-(benzimidazol-1-il)-butiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[4-(benzimidazol-1-il)-butiloksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 8 Example 8

4’-[[2-n-butil-7-[4-(tetrahidrobenzimidazol-1-il)-butiloksi]-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-butil-7-[4-(tetrahidrobenzimidazol-1-il)-butiloksi]-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-benzimidazol-1-yl]-methyl]-biphenyl -2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 86 % od teorijskog. Gain: 86% of the theoretical.

Talište: 229-231oC. Melting point: 229-231oC.

C37H42N4O3 (590,76) C37H42N4O3 (590.76)

[image] [image]

Primjer 9 Example 9

4’-[[2-n-propil-4-metil-6-(1-metil-benzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil estera 4’-[[2-n-propil-4-metil-6-(1-metil-benzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl] -biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 63,9 % od teorijskog. Gain: 63.9% of the theoretical.

Talište: 261-263oC. Melting point: 261-263oC.

C33H30N4O2 (514,60) C33H30N4O2 (514.60)

[image] [image]

Analogono kao u primjeru 9 dobiveni su slijedeći spojevi: Analogous to example 9, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(1-n-propil-benzimidazol-2-il)-benzimidazol-1-il]metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(1-n-propyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(1-n-heksil-benzimidazol-2-il)-benzimidazol-1-il]metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(1-ciklopropil-benzimidazol-2-il)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(1-cikloheksil-benzimidazol-2-il)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina. 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid.

Primjer 10 Example 10

4’-[[2-n-propil-4-metil-6-(1-metil-benzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

K otopini od 1,60 g (3,3 mmola) 4’-[[2-n-propil-4-metil-6-(1-metil-benzimidazol-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila u 50 ml dimetilformamida doda se 4,3 g (66 mmolova) natrijevog azida i 3,5 g (66 mmolova) amonijevog klorida i smjesu se miješa 24 sata pri 140oC. Zatim se doda vodu i talog se odsisa. Tako dobiveni proizvod očisti se kromatografijom preko silika gela (300 g silika gela, metilenklorid + 6% etanola). To a solution of 1.60 g (3.3 mmol) 4'-[[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl ]-2-cyano-biphenyl in 50 ml of dimethylformamide, 4.3 g (66 mmol) of sodium azide and 3.5 g (66 mmol) of ammonium chloride are added and the mixture is stirred for 24 hours at 140°C. Then water is added and the precipitate is suctioned off. The product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride + 6% ethanol).

Dobitak: 900 g (51 % od teorijskog. Gain: 900 g (51% of the theoretical.

Talište: 228-230oC. Melting point: 228-230oC.

C33H30N8 (538,70) C33H30N8 (538.70)

[image] [image]

Analogono kao u primjeru 10 dobiveni su slijedeći spojevi: Analogous to example 10, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(1-n-heksil-benzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(1-ciklobutil-benzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(1-cyclobutyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl,

4’-[[2-n-propil-4-metil-6-(1-cikloheksil-benzimidazol-2-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)- biphenyl,

4’-[[2-n-butil-4-metil-7-[2-(imidazol-1-il)-etoksi]-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-7-[2-(imidazol-1-yl)-ethoxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[[2-n-butil-7-[3-(imidazol-1-il)-propiloksi]-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl,

4’-[[2-n-butil-7-[4-imidazol-1-il)-butiloksi]-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[4-imidazol-1-yl)-butyloxy]-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)- biphenyl,

4’-[[2-n-butil-4-metil-7-[5-(imidazol-1-il)-pentiloksi]-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-7-[5-(imidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[[2-n-butil-7-[2-benzimidazol-1-il)-etoksi]-4-metil-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[2-benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl )-biphenyl,

4’-[[2-n-butil-4-metil-7-[3-benzimidazol-1-il)-propil-oksi]-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-7-[3-benzimidazol-1-yl)-propyl-oxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5 -yl)-biphenyl,

4’-[[2-n-butil-7-[4-(benzimidazol-1-il)-butiloksi]-4-metil-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl )-biphenyl,

4’-[[2-n-butil-4-metil-7-[5-(benzimidazol-1-il)-pentil-oksi]-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-7-[5-(benzimidazol-1-yl)-pentyl-oxy]-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5 -yl)-biphenyl,

4’-[[2-n-butil-7-[2-(4,5,6,7-tetrahidrobezimidazol-1-il)-etiloksi]-4-metil-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[2-(4,5,6,7-tetrahydrobezimidazol-1-yl)-ethyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2 -(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-7-[3-(tetrahidrobezimidazol-1-il)-propiloksi]benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[3-(tetrahydrobezimidazol-1-yl)-propyloxy]benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-7-[4-(tetrahidrobezimidazol-1-il)-butil-oksi]-4-metil-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-7-[4-(tetrahydrobezimidazol-1-yl)-butyl-oxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl,

4’-[[2-n-butil-4-metil-7-[5-(tetrahidrobezimidazol-1-il)-pentiloksi]-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobezimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[[2-n-butil-4-metil-6-(fenilaminokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(phenylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-etil-4-metil-6-(cikloheksilaminokarbonil-amino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-ethyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-propil-4-metil-6-(cikloheksilaminokarbonil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-propyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-4-metil-6-(cikloheksilaminokarbonil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(metilaminokarbonil-metil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-methyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(n-pentilaminokarbonil-metil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonyl-methyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(n-pentilaminokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(n-butilaminokarbonil-metil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(n-butylaminocarbonyl-methyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(benzilaminokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(benzylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(alilaminokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-metilamino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-methylamino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(dimetilaminokarbonil-metil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-methyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(dimetilaminokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-n-butilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-n-butylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(metilaminokarbonil-cikloheksilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(metilaminokarbonil-benzil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-benzyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(n-heksilaminokarbonil-cikloheksilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(n-hexylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(cikloheksilaminokarbonil-etilamino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-ethylamino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(dimetilaminokarbonil-n-pentilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(morfolinokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(pirolidinokarbonilamino)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(pirolidinokarbonil-metil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonyl-methyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(piperidinokarbonil-metil-amino)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(piperidinocarbonyl-methyl-amino)benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(3-benzil-3,4,5,6-tetrahidro-2(1H)-pirimidinon-1-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl] -methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

Primjer 11 Example 11

4’-[[2-n-propil-4-metil-6-ftalamino-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-phthalamino-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-ftalamino-benzimidazol-1-il)-cijano- It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-phthalamino-benzimidazol-1-yl)-cyano-

bifenila i natrijevog azida u dimetilformamidu. of biphenyl and sodium azide in dimethylformamide.

Dobitak: 6,8 % od teorijskog. Gain: 6.8% of the theoretical.

Talište: 160oC, sinterira. Melting point: 160oC, sintered.

C33H27N7O2 (553,60) C33H27N7O2 (553.60)

[image] [image]

Primjer 12 Example 12

4’-[[2-n-butil-4-metil-6-ftalamino-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-phthalamino-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-ftalamino-benzimidazol-1-il)-cijano- It is prepared analogously as in example 10 from 4'-[[2-n-butyl-4-methyl-6-phthalamino-benzimidazol-1-yl)-cyano-

bifenila i natrijevog azida u dimetilformamidu. of biphenyl and sodium azide in dimethylformamide.

Dobitak: 7,1 % od teorijskog. Gain: 7.1% of the theoretical.

Talište: iznad 150oC sinterira. Melting point: above 150oC sinters.

C34H29N7O2 (567,70) C34H29N7O2 (567.70)

[image] [image]

Primjer 13 Example 13

4’-[[2-n-propil-4-metil-6-(1-okso-izoindolin-2-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(1-okso-izoindolin-2-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. Prepare analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 25,0 % od teorijskog. Gain: 25.0% of the theoretical.

Talište: 170oC sinterira. Melting point: 170oC sintered.

C33H29N7O (539,60) C33H29N7O (539.60)

[image] [image]

Primjer 14 Example 14

4’-[[2-n-butil-4-metil-6-(1-okso-izoindolin-2-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-(1-okso-izoindolin-2-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. Prepare analogously as in example 10 from 4'-[[2-n-butyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 21,0 % od teorijskog. Gain: 21.0% of the theoretical.

Talište: 165oC, sinterira. Melting point: 165oC, sintered.

C34H31N7O (553,70) C34H31N7O (553.70)

[image] [image]

Primjer 15 Example 15

4’-[[2-n-propil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 49,0 % od teorijskog. Gain: 49.0% of the theoretical.

Talište: iznad 186oC sinterira. Melting point: above 186oC sinters.

C29H31N7O2S (541,70) C29H31N7O2S (541.70)

[image] [image]

Primjer 16 Example 16

4’-[[2-etil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-ethyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-etil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. Prepare analogously as in example 10 from 4'-[[2-ethyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 60,0 % od teorijskog. Gain: 60.0% of the theoretical.

Talište: amorfan, iznad 194oC sinterira. Melting point: amorphous, sintered above 194oC.

C28H29N7O2S (527,70) C28H29N7O2S (527.70)

[image] [image]

Primjer 17 Example 17

4’-[[2-n-butil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-butyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 48,0 % od teorijskog. Gain: 48.0% of the theoretical.

Talište: amorfan, iznad 183oC sinterira. Melting point: amorphous, sintered above 183oC.

C30H33N7O2S (555,70) C30H33N7O2S (555.70)

[image] [image]

Primjer 18 Example 18

4’-[[2-n-propil-4-etil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-ethyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-etil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-ethyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 27,0 % od teorijskog. Gain: 27.0% of the theoretical.

Talište: amorfan, iznad 189oC sinterira. Melting point: amorphous, sintered above 189oC.

C30H33N7O2S (555,70) C30H33N7O2S (555.70)

[image] [image]

Primjer 19 Example 19

4’-[[2-etil-4-etil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-ethyl-4-ethyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-etil-4-etil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-ethyl-4-ethyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 39,0 % od teorijskog. Gain: 39.0% of the theoretical.

Talište: amorfan, iznad 212oC sinterira. Melting point: amorphous, sintered above 212oC.

C29H31N7O2S (541,70) C29H31N7O2S (541.70)

[image] [image]

Primjer 20 Example 20

4’-[[2-n-propil-4-izopropil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-isopropyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-izopropil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-isopropyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 22,0 % od teorijskog. Gain: 22.0% of the theoretical.

Talište: amorfan. Melting point: amorphous.

C31H35N7O2S (569,70) C31H35N7O2S (569.70)

[image] [image]

Primjer 21 Example 21

4’-[[2-etil-4-izopropil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-ethyl-4-isopropyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-etil-4-izopropil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. Prepare analogously as in example 10 from 4'-[[2-ethyl-4-isopropyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 24,0 % od teorijskog. Gain: 24.0% of the theoretical.

Talište: amorfan, iznad 209oC sinterira. Melting point: amorphous, sintered above 209oC.

C30H33N7O2S (555,70) C30H33N7O2S (555.70)

[image] [image]

Primjer 22 Example 22

4’-[[2-n-propil-4-trifluormetil-6-(butansultam-1-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-trifluoromethyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-trifluormetil-6-(butansultam-1-il)-benzimidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-trifluoromethyl-6-(butansultam-1-yl)-benzimidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 17,0 % od teorijskog. Gain: 17.0% of the theoretical.

Talište: 199-203oC. Melting point: 199-203oC.

C29H28F3N7O2S (595,70) C29H28F3N7O2S (595.70)

[image] [image]

Primjer 23 Example 23

4’-[[2-n-propil-4-metil-6-(N-benzensulfonil-metilamino)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(N-benzensulfonil-metilamino)-benz-imidazol-1-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. Prepare analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(N-benzenesulfonyl-methylamino)-benz-imidazol-1-yl)-cyano-biphenyl and sodium azide in dimethylformamide .

Dobitak: 42,0 % od teorijskog. Gain: 42.0% of the theoretical.

Talište: 161-163oC. Melting point: 161-163oC.

C32H31N7O2S (577,70) C32H31N7O2S (577.70)

[image] [image]

Primjer 24 Example 24

4’-[[2-n-butil-4-metil-6-(N-benzensulfonil-metilamino)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-(N-benzendulfonil-metilamino)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 10 from 4'-[[2-n-butyl-4-methyl-6-(N-benzenesulfonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium of azide in dimethylformamide.

Dobitak: 37,0 % od teorijskog. Gain: 37.0% of the theoretical.

Talište: 150-153oC. Melting point: 150-153oC.

C33H33N7O2S (591,70) C33H33N7O2S (591.70)

[image] [image]

Analogno kao u primjeru 24 dobiveni su slijedeći spojevi: Analogous to example 24, the following compounds were obtained:

4’-[[2-etil-4-metil-6-(4,5-dihidro-2H-piridazin-3-on-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-ethyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H- tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(4,5-dihidro-2H-piridazin-3-on-6-il)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-1-yl]methyl]-2-(1H- tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-4-metil-6-(4,5-dihidro-2H-piridazin-3-on-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-2-( 1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(3-benzil-3,4,5,6-tetrahidro-2(1H)-pirimidinon-1-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl] -methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-etil-4-metil-6-(3-benzil-3,4,5,6-tetrahidro-2(1H)-pirimidinon-1-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-ethyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl ]-2-(1H-tetrazol-5-yl)-biphenyl.

Primjer 25 Example 25

4’-[[2-n-butil-4-metil-6-(1-metilbenzilimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzylimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-4-metil-6-(1-metilbenzil-imidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzyl-imidazol-2-yl)-benzimidazol-1-yl]-methyl ]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 48,0 % od teorijskog. Gain: 48.0% of the theoretical.

Talište: 233-235oC. Melting point: 233-235oC.

C34H32N4O2 (528,70) C34H32N4O2 (528.70)

[image] [image]

Primjer 26 Example 26

4’-[[2-n-butil-4-metil-6-(1-metilbenzimidazol-2-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 10 from 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 41,0 % od teorijskog. Gain: 41.0% of the theoretical.

Talište: 235-237oC. Melting point: 235-237oC.

C34H32N8 (552,70) C34H32N8 (552.70)

[image] [image]

Analogno kao u primjeru 26 dobiveni su slijedeći spojevi: Analogous to example 26, the following compounds were obtained:

4’-[[2-n-butil-4-metil-6-(1-etilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(1-ethylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl ,

4’-[[2-n-butil-4-metil-6-(1-ciklopropilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl ,

4’-[[2-n-butil-4-metil-6-(1-n-pentilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(1-n-pentylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl,

4’-[[2-n-butil-4-metil-6-(1-ciklopentilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-n-butyl-4-methyl-6-(1-cyclopentylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl .

Primjer 27 Example 27

4’-[[2-n-propil-4-metil-6-(2-okso-piperidin-1-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(2-okso-piperidin-1-il)benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilform-amidu. It is prepared analogously to example 10 from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)benzimidazol-1-yl]-methyl]-2-cyano- of biphenyl and sodium azide in dimethylformamide.

Dobitak: 51,0 % od teorijskog. Gain: 51.0% of the theoretical.

Talište: amorfan, iznad 140oC sinterira. Melting point: amorphous, sintered above 140oC.

C30H31N7O (505,60) C30H31N7O (505.60)

[image] [image]

Primjer 28 Example 28

4’-[[2-n-butil-4-metil-6-(2-okso-piperidin-1-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-(2-okso-piperidin-1-il)benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilform-amidu. It is prepared analogously to example 10 from 4'-[[2-n-butyl-4-methyl-6-(2-oxo-piperidin-1-yl)benzimidazol-1-yl]-methyl]-2-cyano- of biphenyl and sodium azide in dimethylformamide.

Dobitak: 39,0 % od teorijskog. Gain: 39.0% of the theoretical.

Talište: amorfan, iznad 128oC sinterira. Melting point: amorphous, sintered above 128oC.

C31H33N7O (519,70) C31H33N7O (519.70)

[image] [image]

Primjer 29 Example 29

4’-[[2-n-propil-4-metil-6-(2-okso-piperidin-1-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl

Pripremi se iz 4’-[[2-n-propil-4-metil-6-(2-okso-piperidin-1-il)benzimidazol-1-il]-metil]-2-(2-trifenil-tetrazol-5-il)-bifenila odcjepljenjem trifenilmetilne skupine s metanolnom klorovodičnom kiselinom. Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)benzimidazol-1-yl]-methyl]-2-(2-triphenyl-tetrazol- 5-yl)-biphenyl by removing the triphenylmethyl group with methanolic hydrochloric acid.

Dobitak: 51,0 % od teorijskog. Gain: 51.0% of the theoretical.

Talište: amorfan, iznad 115oC sinterira. Melting point: amorphous, sintered above 115oC.

C30H31N7O (505,60) C30H31N7O (505.60)

[image] [image]

Primjer 30 Example 30

4’-[[2-n-propil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-6-(imidazo[1,2-a]-piridin-2-il)-benz-imidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benz-imidazol-1-yl ]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 54,0 % od teorijskog. Gain: 54.0% of the theoretical.

Talište: 202-204oC. Melting point: 202-204oC.

C31H26N4O2 (486,60) C31H26N4O2 (486.60)

[image] [image]

Analogno kao u primjeru 30 dobiveni su slijedeći spojevi: Analogous to example 30, the following compounds were obtained:

4’-[[2-n-propil-6-(8-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(8-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid ,

4’-[[2-n-butil-6-(6-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-6-(6-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid ,

4’-[[2-n-propil-6-(5,7-dimetil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-6-(6-aminokarbonil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(6-aminocarbonyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid ,

4’-[[2-n-propil-6-(6-klor-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(6-chloro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid ,

4’-[[2-n-propil-6-(imidazo[1,2-a]-piridin-2-il)-benz-imidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benz-imidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-6-(imidazo[2,1-b]tiazol-6-il)-benz-imidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(imidazo[2,1-b]thiazol-6-yl)-benz-imidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-butil-6-(2,3-dimetil-imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina. 4'-[[2-n-butyl-6-(2,3-dimethyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid.

Primjer 31 Example 31

4’-[[2-n-butil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-6-(imidazo[1,2-a]-piridin-2-il)-benz-imidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benz-imidazol-1-yl ]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 41,0 % od teorijskog. Gain: 41.0% of the theoretical.

Talište: 193-195oC. Melting point: 193-195oC.

C32H28N4O2 (500,60) C32H28N4O2 (500.60)

[image] [image]

Primjer 32 Example 32

4’-[[2-n-propil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl )-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilform-amidu. It is prepared analogously to example 10 from 4'-[[2-n-propyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2- of cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 28,0 % od teorijskog. Gain: 28.0% of the theoretical.

Talište: 187-189oC. Melting point: 187-189oC.

C31H26N8 (510,60) C31H26N8 (510.60)

[image] [image]

Analogno kao u primjeru 32 dobiveni su slijedeći spojevi: Analogous to example 32, the following compounds were obtained:

4’-[[2-n-propil-6-(7-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(7-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazole -5-yl)-biphenyl,

4’-[[2-n-propil-6-(5-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(5-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazole -5-yl)-biphenyl,

4’-[[2-n-butil-6-(6-brom-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-6-(6-bromo-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazole -5-yl)-biphenyl,

4’-[[2-n-propil-6-(5,7-dimetil-imidazo[1,2-a]-pirimidin-2-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]-pyrimidin-2-yl)-benzimidazol-1-yl]methyl]-2-(1H- tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-6-(3-metil-imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl,

4’-[[2-n-propil-6-(2-fenil-imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl,

Primjer 33 Example 33

4’-[[2-n-butil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl )-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilform-amidu. It is prepared analogously to example 10 from 4'-[[2-n-butyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2- of cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 23,0 % od teorijskog. Gain: 23.0% of the theoretical.

Talište: 170-173oC. Melting point: 170-173oC.

C32H28N8 (524,60) C32H28N8 (524.60)

[image] [image]

Primjer 34 Example 34

4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1 -yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 38,0 % od teorijskog. Gain: 38.0% of the theoretical.

Talište: 195-197oC (nakon isparavanja otapala). Melting point: 195-197oC (after evaporation of the solvent).

Talište: 299-303oC (metilenklorid/metanol = 20/1). Melting point: 299-303oC (methylene chloride/methanol = 20/1).

C32H28N4O2 (500,60) C32H28N4O2 (500.60)

[image] [image]

Analogno kao u primjeru 34 dobiveni su slijedeći spojevi: Analogous to example 34, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(8-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acid,

4’-[[2-n-butil-4-metil-6-(7-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(7-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acid,

4’-[[2-n-butil-4-metil-6-(6-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(6-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(5-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(5-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(5,7-dimetil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(5,7-dimethyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]- biphenyl-2-carboxylic acid,

4’-[[2-etil-4-metil-6-(6-aminokarbonil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-ethyl-4-methyl-6-(6-aminocarbonyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2- carboxylic acid,

4’-[[2-etil-4-metil-6-(6-klor-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]metil]-bifenil-2-karboksilna kiselina. 4'-[[2-ethyl-4-methyl-6-(6-chloro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid.

Primjer 35 Example 35

4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benz-imidazol-1-yl]-methyl]-2-(1H -tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously to example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl ]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 21,0 % od teorijskog. Gain: 21.0% of the theoretical.

Talište: iznad 181oC sinterira. Melting point: above 181oC sinters.

C32H28N8 (524,60) C32H28N8 (524.60)

[image] [image]

Analogno kao u primjeru 35 dobiveni su slijedeći spojevi: Analogous to example 35, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(5-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(5-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2- (1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-pirimidin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazole -5-yl)-biphenyl.

Primjer 36 Example 36

4’-[[2-n-butil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1 -yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 51,0 % od teorijskog. Gain: 51.0% of the theoretical.

Talište: 194-197oC. Melting point: 194-197oC.

C33H30N4O2 (514,60) C33H30N4O2 (514.60)

[image] [image]

Analogno kao u primjeru 35 dobiveni su slijedeći spojevi: Analogous to example 35, the following compounds were obtained:

4’-[[2-n-propil-6-(pirolidin-2-on-5-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(pyrrolidin-2-on-5-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-6-(pirolidin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(pyrrolidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-6-(kinolin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-butil-6-(kinolin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-6-(izokinolin-3-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-etil-6-(izokinolin-3-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina. 4'-[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid.

Primjer 37 Example 37

4’-[[2-n-butil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benz-imidazol-1-yl]-methyl]-2-(1H -tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-butil-4-metil-6-(imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously to example 10 from 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl ]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.

Dobitak: 26,0 % od teorijskog. Gain: 26.0% of the theoretical.

C33H30N8 (538,60) C33H30N8 (538.60)

[image] [image]

Analogno kao u primjeru 37 dobiveni su slijedeći spojevi: Analogous to example 37, the following compounds were obtained:

4’-[[2-n-propil-6-(pirolidin-2-on-5-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(pyrrolidin-2-on-5-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-6-(pirolidin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(pyrrolidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-6-(pirolidin-2-on-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(pyrrolidin-2-on-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-6-(piperidin-2-on-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-6-(piperidin-2-on-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-6-(piperidin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(piperidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-6-(piperidin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-6-(piperidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-etil-6-(piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-ethyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-6-(piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-6-(piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-6-(kinolin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-6-(kinolin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-6-(izokinolin-3-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-etil-6-(izokinolin-3-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

Primjer 38 Example 38

4’-[[2-n-butil-4-metil-6-(2,2-dimetilpropionilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-4-methyl-6-(2,2-dimethylpropionylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-4-metil-6-(2,2-dimetil-propionil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilen-kloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-4-methyl-6-(2,2-dimethyl-propionyl-amino)-benzimidazol-1-yl]-methyl ]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 39 Example 39

4’-[[2-n-butil-7-[2-(tetrahidrobenzimidazol-1-il)-etoksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-7-[2-(tetrahidrobenzimidazol-1-il)-etoksi]-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilen-kloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl] -methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 81,0 % od teorijskog. Gain: 81.0% of the theoretical.

Talište: 236-237oC. Melting point: 236-237oC.

C35H38N4O3 (562,71) C35H38N4O3 (562.71)

[image] [image]

Primjer 40 Example 40

4’-[[2-n-butil-4-metil-7-[5-(tetrahidrobenzimidazol-1-il)-pentiloksi]-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-4-metil-7-[5-(tetrahidrobenzimidazol-1-il)-pentiloksi]-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilen-kloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl] -methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 41 Example 41

4’-[[2-n-butil-7-[3-(tetrahidrobenzimidazol-1-il)-propil-oksi]benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyl-oxy]benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-7-[3-(tetrahidrobenz-imidazol-1-il)-propiloksi]-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-benzimidazol-1-yl]-methyl ]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 42 Example 42

4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-pirimidin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]-pirimidin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]-pyrimidin-2-yl)-benzimidazol-1 -yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 47,0 % od teorijskog. Gain: 47.0% of the theoretical.

Talište: 224-226oC (nakon isparavanja otapala). Melting point: 224-226oC (after evaporation of the solvent).

Talište: 294-297oC (metilenklorid/etanola = 20/1). Melting point: 294-297oC (methylene chloride/ethanol = 20/1).

C31H27N5O2 (501,60) C31H27N5O2 (501.60)

[image] [image]

Primjer 43 Example 43

4’-[[2-n-propil-4-metil-6-(imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1- yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 43 % od teorijskog. Gain: 43% of the theoretical.

Talište: 192-195oC (nakon isparavanja otapala). Melting point: 192-195oC (after evaporation of the solvent).

Talište: >300oC (metilenklorid/etanola = 20/1). Melting point: >300oC (methylene chloride/ethanol = 20/1).

C30H26N4O2S (506,64) C30H26N4O2S (506.64)

[image] [image]

Analogno kao u primjeru 43 dobiveni su slijedeći spojevi: Analogous to example 43, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(3-metil-imidazo[2,1-b]tiazol-6-il)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid ,

4’-[[2-n-propil-4-metil-6-(2,3-dimetil-imidazo[2,1-b]-tiazol-6-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(2,3-dimethyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]- biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(2,3-tetrametilen-imidazo-[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(2,3-tetramethylene-imidazo-[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]- biphenyl-2-carboxylic acid,

4’-[[2-n-butil-4-metil-6-(2,3-trimetilen-imidazo[2,1-b]-tiazol-6-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(2,3-trimethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]- biphenyl-2-carboxylic acid,

4’-[[2-etil-4-metil-6-(2-fenil-imidazo[2,1-b]tiazol-6-il)benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina. 4'-[[2-ethyl-4-methyl-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid .

Primjer 44 Example 44

4’-[[2-n-propil-4-metil-6-(imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously to example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl] of -2-cyano-biphenyl and sodium azide in dimethyl-formamide.

Dobitak: 21,0 % od teorijskog. Gain: 21.0% of the theoretical.

Talište: amorfan, iznad 196oC sinterira. Melting point: amorphous, sintered above 196oC.

C30H26N8S (530,67) C30H26N8S (530.67)

[image] [image]

Analogno kao u primjeru 44 dobiveni su slijedeći spojevi: Analogous to example 44, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(3-metil-imidazo[2,1-b]tiazol-6-il)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)benzimidazol-1-yl]methyl]-2-(1H- tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-4-metil-6-(2,3-dimetil-imidazo[2,1-b]-tiazol-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(2,3-dimethyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]- 2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-4-metil-6-(2,3-trimetilen-imidazo[2,1-b]-tiazol-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(2,3-trimethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]- 2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-etil-4-metil-6-(2,3-tetrametilen-imidazo[2,1-b]-tiazol-6-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-ethyl-4-methyl-6-(2,3-tetramethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2- (1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(2-fenil-imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]methyl]-2-(1H -tetrazol-5-yl)-biphenyl,

Primjer 45 Example 45

4’-[[2-n-propil-4-metil-6-(benzimidazo-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(benzimidazo-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(benzimidazo-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously to example 10 from 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- of 5-yl)-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 28,0 % od teorijskog. Gain: 28.0% of the theoretical.

Talište: 202-205oC. Melting point: 202-205oC.

[image] [image]

Analogno kao u primjeru 45 dobiveni su slijedeći spojevi: Analogous to example 45, the following compounds were obtained:

4’-[[2-etil-4-metil-6-(benzimidazo-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-ethyl-4-methyl-6-(benzimidazo-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-butil-4-metil-6-(benzimidazo-2-il)-benzimid-azol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(benzimidazo-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl ,

4’-[[2-n-propil-4-metil-6-(1-n-heksil-benzimidazo-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(1-ciklopropil-benzimidazo-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl,

4’-[[2-n-propil-4-metil-6-(1-cikloheksil-benzimidazo-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl.

Primjer 46 Example 46

4’-[[2-n-propil-4-metil-6-(benzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(benzimidazol-2-il)-benz-imidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benz-imidazol-1-yl]-methyl]- of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 43 % od teorijskog. Gain: 43% of the theoretical.

Talište: 239-242oC. Melting point: 239-242oC.

C32H28N4O2 (500,61) C32H28N4O2 (500.61)

[image] [image]

Analogno kao u primjeru 46 dobiveni su slijedeći spojevi: Analogous to example 46, the following compounds were obtained:

4’-[[2-etil-4-metil-6-(benzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-butil-4-metil-6-(benzimidazol-2-il)-benzimid-azol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(1-n-heksil-benzimidazol-2-il)-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(1-ciklopropil-benzimidazol-2-il)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(1-cikloheksil-benzimidazol-2-il)benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina. 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid.

Primjer 47 Example 47

4’-[[2-n-butil-7-metil-[3-(imidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-butyl-7-methyl-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl

Pripremi se iz 4’-[[2-n-butil-7-metil-[3-(imidazol-1-il)-propiloksi]-4-metil-benzimidazol-1-il]-metil]-2-(1- Prepared from 4'-[[2-n-butyl-7-methyl-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1 -

trifenilmetiltetrazol-5-il)-bifenila odcjepljenjem 1-trifenilmetanske skupine s etanol/klorovodičnom kiselinom. of triphenylmethyltetrazol-5-yl)-biphenyl by cleavage of the 1-triphenylmethane group with ethanol/hydrochloric acid.

Dobitak: 89,8 % od teorijskog. Gain: 89.8% of the theoretical.

Talište: 83-87oC. Melting point: 83-87oC.

C32H34N8O2·1,5H2O (573,69) C32H34N8O2·1.5H2O (573.69)

[image] [image]

Primjer 48 Example 48

4’-[[6-(N-benzosulfonil-metilamino)-2-n-butil-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[6-(N-benzosulfonyl-methylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[6-(N-benzosulfonil-metilamino)-2-n-butil-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[6-(N-benzosulfonyl-methylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acids and trifluoroacetic acids in methylene chloride.

Dobitak: 95,6 % od teorijskog. Gain: 95.6% of the theoretical.

Talište: 211-212oC. Melting point: 211-212oC.

C33H33N3O4S (567,70) C33H33N3O4S (567.70)

[image] [image]

Primjer 49 Example 49

4’-[[6-(N-benzosulfonil-n-pentilamino)-2-n-butil-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[6-(N-benzosulfonyl-n-pentylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[6-(N-benzosulfonil-n-pentilamino)-2-n-butil-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[6-(N-benzosulfonyl-n-pentylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]- of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 81,8 % od teorijskog. Gain: 81.8% of the theoretical.

Talište: 232-233oC. Melting point: 232-233oC.

C37H41N3O4S (623,81) C37H41N3O4S (623.81)

[image] [image]

Primjer 50 Example 50

4’-[[2-n-butil-6-(izopropilkarbonilamino)-4-metil-benzimid-azol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimid-azol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-6-(izopropilkarbonilamino)-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid tert.butyl ester and trifluoroacetic acid in methylene chloride.

Dobitak: 86,3 % od teorijskog. Gain: 86.3% of the theoretical.

Talište: 313-315oC. Melting point: 313-315oC.

C30H33N3O3 (483,61) C30H33N3O3 (483.61)

[image] [image]

Primjer 51 Example 51

Semihidrat 4’-[[2-n-butil-6-(2,3-dimetilmaleinimino)-4-metilbenzimidazol-1-il]metil]bifenil-2-karboksilne kiseline 4'-[[2-n-butyl-6-(2,3-dimethylmaleinimino)-4-methylbenzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid semihydrate

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-6-(2,3-dimetilmaleinimino)-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-6-(2,3-dimethylmaleinimino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acids and trifluoroacetic acids in methylene chloride.

Dobitak: 88,9 % od teorijskog. Gain: 88.9% of the theoretical.

Talište: 321-322oC. Melting point: 321-322oC.

C32H31N3O4·0,5H2O (530,62) C32H31N3O4·0.5H2O (530.62)

[image] [image]

Primjer 52 Example 52

Semihidrat 4’-[[6-(2,3-dimetilmaleinimino)-2-n-propil-4-metilbenzimidazol-1-il]metil]bifenil-2-karboksilna kiselina 4'-[[6-(2,3-Dimethylmaleimino)-2-n-propyl-4-methylbenzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid semihydrate

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[6-(2,3-dimetilmaleinimino)-2-n-propil-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[6-(2,3-dimethylmaleinimino)-2-n-propyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acids and trifluoroacetic acids in methylene chloride.

Dobitak: 75,4 % od teorijskog. Gain: 75.4% of the theoretical.

Talište: 329-331oC. Melting point: 329-331oC.

C31H29N3O4·0,5H2O (516,60) C31H29N3O4·0.5H2O (516.60)

[image] [image]

Primjer 53 Example 53

Trifluoracetat-semihidrat 4’-[[(6-acetamino-2-n-butil-4-metil-benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina Trifluoroacetate-semihydrate 4'-[[(6-acetamino-2-n-butyl-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[6-(acetamino-2-n-butil-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester of 4'-[[6-(acetamino-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 95,7 % od teorijskog. Gain: 95.7% of the theoretical.

Talište: 112-114oC (amorfan). Melting point: 112-114oC (amorphous).

C28H29N3O3·CF3COOH·0,5H2O (578,59) C28H29N3O3·CF3COOH·0.5H2O (578.59)

[image] [image]

Primjer 54 Example 54

4’-[[2-n-butil-4-metil-6-(morfolinokarbonilamino)-benzimid-azol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimid-azol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-4-metil-6-(morfolino-karbonilamino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-4-methyl-6-(morpholino-carbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2- carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 80,9 % od teorijskog. Gain: 80.9% of the theoretical.

Talište: 279-281oC. Melting point: 279-281oC.

C31H34N4O4 (526,64) C31H34N4O4 (526.64)

[image] [image]

Primjer 55 Example 55

Semitrifluoracetat 4’-[[2-n-butil-6-(cikloheksilamino-karbonilamino)-4-metil-benzimidazol-1-il]-metil]-bifenil-2- Semitrifluoroacetate 4'-[[2-n-butyl-6-(cyclohexylamino-carbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-

karboksilne kiseline carboxylic acids

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-butil-6-(cikloheksilamino-karbonilamino)-4-metil-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-butyl-6-(cyclohexylamino-carbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2- carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 76,9 % od teorijskog. Gain: 76.9% of the theoretical.

Talište: 288-289oC. Melting point: 288-289oC.

C33H38N4O3·0,5CF3COOH (595,70) C33H38N4O3·0.5CF3COOH (595.70)

[image] [image]

Primjer 56 Example 56

4’-[[2-n-propil-4-izopropil-6-(1-okso-izoindolinil-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolinyl-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-izopropil-6-(1-okso-izoindolinil-2-il)-benzimid-azol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolinyl-2-yl)-benzimidazol-1-yl]-methyl]-2 -cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 14 % od teorijskog. Gain: 14% of the theoretical.

Talište: amorfan. Melting point: amorphous.

C35H33N7O (567,71) C35H33N7O (567.71)

[image] Maseni spektar: M+ = 567 [image] Mass spectrum: M+ = 567

Primjer 57 Example 57

4’-[[2-n-propil-5-(imidazo[1,2-a]piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-5-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-5-(imidazo[1,2-a]piridin-2-il)-benz-imidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-5-(imidazo[1,2-a]pyridin-2-yl)-benz-imidazol-1-yl] -methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 32 % od teorijskog. Gain: 32% of the theoretical.

Talište: 250-253oC. Melting point: 250-253oC.

C31H26N4O2 (486,60) C31H26N4O2 (486.60)

[image] [image]

Primjer 58 Example 58

4’-[[2-n-propil-4-etil-6-(1-metilbenzimidazo-2-il)-benzimid-azol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-ethyl-6-(1-methylbenzimidazo-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-etil-6-(1-metilbenzimidazo-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-ethyl-6-(1-methylbenzimidazo-2-yl)-benzimidazol-1-yl]-methyl]- of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 64 % od teorijskog. Gain: 64% of the theoretical.

Talište: 217-219oC. Melting point: 217-219oC.

C34H32N4O2 (528,70) C34H32N4O2 (528.70)

[image] [image]

Primjer 59 Example 59

4’-[[2-n-propil-4-etil-6-(1-metilbenzimidazol-2-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-etil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 15 % od teorijskog. Gain: 15% of the theoretical.

Talište: 215-217oC. Melting point: 215-217oC.

C34H32N8 (552,70) C34H32N8 (552.70)

[image] [image]

Primjer 60 Example 60

4’-[[2-ciklopropil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-ciklopropil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acids and trifluoroacetic acids in methylene chloride.

Dobitak: 52 % od teorijskog. Gain: 52% of the theoretical.

Talište: 244-246oC. Melting point: 244-246oC.

C33H28N4O2 (512,60) C33H28N4O2 (512.60)

[image] [image]

Primjer 61 Example 61

4’-[[2-ciklopropil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-ciklopropil-4-metil-6-(1-okso-metilbenzimidazol-2-il)-benz-imidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously to example 10 from 4'-[[2-cyclopropyl-4-methyl-6-(1-oxo-methylbenzimidazol-2-yl)-benz-imidazol-1-yl]-methyl]-2-cyano -biphenyl and sodium azide in dimethylformamide.

Dobitak: 59 % od teorijskog. Gain: 59% of the theoretical.

Talište: 245-247oC. Melting point: 245-247oC.

C33H28N8 (536,65) C33H28N8 (536.65)

[image] [image]

Primjer 62 Example 62

4’-[[2-ciklobutil-4-metil-6-(1-metilbenzimidazol-2-il)- 4'-[[2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-

benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz 4’-[[2-ciklobutil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimid-azol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluor-octene kiseline u metilenkloridu. It is prepared analogously to example 1 from 4'-[[2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 63 % od teorijskog. Gain: 63% of the theoretical.

Talište: 189-191oC. Melting point: 189-191oC.

C34H30N4O2 (526,60) C34H30N4O2 (526.60)

[image] [image]

Primjer 63 Example 63

4’-[[2-ciklobutil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-ciklobutil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimid-azol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 61 % od teorijskog. Gain: 61% of the theoretical.

Talište: 197-199oC. Melting point: 197-199oC.

C34H30N8 (550,70) C34H30N8 (550.70)

[image] [image]

Primjer 64 Example 64

4’-[[2-n-propil-4-metil-6-(1-metil-5-fluor-benzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-propil-4-metil-6-(1-metil-5-fluor-benzimid-azol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1- yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 34 % od teorijskog. Gain: 34% of the theoretical.

Talište: 250-252oC. Melting point: 250-252oC.

C33H29FN4O2 (532,60) C33H29FN4O2 (532.60)

[image] [image]

Analogno kao u primjeru 64 dobiveni su slijedeći spojevi: Analogous to example 64, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(kinolin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(izokinolin-3-il)-benzimid-azol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-metil-6-(izokinolin-1-il)-benzimid-azol-1-il]-metil]-bifenil-2-karboksilna kiselina. 4'-[[2-n-propyl-4-methyl-6-(isoquinolin-1-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid.

Primjer 65 Example 65

4’-[[2-n-propil-4-metil-6-(imidazol[1,2-a]pirimidin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(imidazol[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol- 5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(imidazol[1,2-a]pirimidin-2-il)-benzimid-azol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazol[1,2-a]pyrimidin-2-yl)-benzimid-azol-1-yl]- of methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 16,5 % od teorijskog. Gain: 16.5% of the theoretical.

Talište: iznad 275oC (raspad). Melting point: above 275oC (decomposition).

C31H27N9·H2O (543,65) C31H27N9·H2O (543.65)

[image] [image]

Analogno kao u primjeru 65 dobiveni su slijedeći spojevi: Analogous to example 65, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(piridin-2-il)-benzimidazol-1-il]-metil]-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(kinolin-2-il)-benzimidazol-1-il]-metil]-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(izokinolin-3-il)-benzimid-azol-1-il]-metil]-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(isoquinolin-3-yl)-benzimid-azol-1-yl]-methyl]-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-n-propil-4-metil-6-(izokinolin-1-il)-benzimid-azol-1-il]-metil]-(1H-tetrazol-5-il)-bifenil. 4'-[[2-n-propyl-4-methyl-6-(isoquinolin-1-yl)-benzimidazol-1-yl]-methyl]-(1H-tetrazol-5-yl)-biphenyl.

Primjer 66 Example 66

4’-[[2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl] -methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imid-azo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilen-kloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imid-azo[1,2-a ]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 67 % od teorijskog. Gain: 67% of the theoretical.

Talište: iznad 240oC (sinterira). Melting point: above 240oC (sinters).

C33H32N4O2 (504,64) C33H32N4O2 (504.64)

[image] [image]

Analogno kao u primjeru 66 dobiveni su slijedeći spojevi: Analogous to example 66, the following compounds were obtained:

4’-[[2-n-butil-4-metil-6-(5,6,7,8-tetrahidro-imidazo-[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, 4'-[[2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl ]-methyl]-biphenyl-2-carboxylic acid,

4’-[[2-etil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina. 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl ]biphenyl-2-carboxylic acid.

Primjer 67 Example 67

4’-[[2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl] -methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin- It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridine-

benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. of benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 73,5 % od teorijskog. Gain: 73.5% of the theoretical.

Talište: 275oC (raspad). Melting point: 275oC (decomposition).

C32H32N8 (528,67) C32H32N8 (528.67)

[image] [image]

Analogno kao u primjeru 67 dobiveni su slijedeći spojevi: Analogous to example 67, the following compounds were obtained:

4’-[[2-n-butil-4-metil-6-(5,6,7,8-tetrahidro-imidazo-[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl ]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

4’-[[2-etil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl ]-2-(1H-tetrazol-5-yl)-biphenyl.

Primjer 68 Example 68

4’-[[2-n-propil-4-metil-6-(1-metil-6-fluor-benzimidazol-2-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(1-metil-6-fluor-benzimid-azol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol- 1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 76 % od teorijskog. Gain: 76% of the theoretical.

Talište: 243-245oC. Melting point: 243-245oC.

C33H29FN4O2 (532,60) C33H29FN4O2 (532.60)

[image] Maseni spektar: m/e = 532 [image] Mass spectrum: m/e = 532

Primjer 69 Example 69

4’-[[2-n-propil-4-klor-6-(1-okso-izoindolin-2-il)-benzimid-azol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-klor-6-(1-okso-izoindolin-2-il)- It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-

benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. of benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 7,5 % od teorijskog. Gain: 7.5% of the theoretical.

Talište: 209-210oC. Melting point: 209-210oC.

C32H26ClN3O3 (536,04) C32H26ClN3O3 (536.04)

Maseni spektar: m/e = 535/537 Mass spectrum: m/e = 535/537

Rf vrijednost: 0,25 (silika gel; metilenklorid/etanol = 9/1). Rf value: 0.25 (silica gel; methylene chloride/ethanol = 9/1).

Primjer 70 Example 70

4’-[[2-n-propil-4-klor-6-(1-metilbenzimidazol-2-il)-benz-imidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benz-imidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-klor-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]- of biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 52,7 % od teorijskog. Gain: 52.7% of the theoretical.

Talište: 292-295oC. Melting point: 292-295oC.

C32H27ClN4O2 (535,06) C32H27ClN4O2 (535.06)

Rf vrijednost: 0,30 (silika gel; metilenklorid/etanol = 19/1). Rf value: 0.30 (silica gel; methylene chloride/ethanol = 19/1).

[image] [image]

Primjer 71 Example 71

4’-[[2-n-propil-4-klor-6-(1-metilbenzimidazol-2-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil-hidroklorid 4'-[[2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl hydrochloride

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-klor-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 54,8 % od teorijskog. Gain: 54.8% of the theoretical.

Talište: iznad 204oC sinterira. Melting point: above 204oC sinters.

C32H27ClN8·HCl (595,55) C32H27ClN8·HCl (595.55)

Rf vrijednost: 0,20 (silika gel; petroleter/etil acetat = 1/1 u 1%-tnoj ledenoj octenoj kiselini). Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 1/1 in 1% glacial acetic acid).

[image] [image]

Primjer 72 Example 72

4’-[[2-n-propil-4-klor-6-(1-okso-izoindolin-2-il)-benzimid-azol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-klor-6-(1-okso-izoindolin-2-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously to example 10 from 4'-[[2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano -biphenyl and sodium azide in dimethylformamide.

Dobitak: 24,6 % od teorijskog. Gain: 24.6% of the theoretical.

Talište: 246-248oC. Melting point: 246-248oC.

C32H26ClN7O (560,08) C32H26ClN7O (560.08)

Rf vrijednost: 0,15 (silika gel; metilenklorid/etanol = 9/1). Rf value: 0.15 (silica gel; methylene chloride/ethanol = 9/1).

[image] [image]

Analogno kao u primjeru 72 dobiveni su slijedeći spojevi: Analogous to example 72, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(1-metil-imidazol-2-il)-benz-imidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[[2-n-propyl-4-methyl-6-(1-methyl-imidazol-2-yl)-benz-imidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[[2-n-propil-4-klor-6-(4,5,6,7-tetrahidro-benzimid-azol-2-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil. 4'-[[2-n-propyl-4-chloro-6-(4,5,6,7-tetrahydro-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-( 1H-tetrazol-5-yl)-biphenyl.

Primjer 73 Example 73

4’-[[2-n-propil-4-klor-6-(cikloheksilaminokarbonilamino)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-chloro-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-klor-6-(cikloheksilamino-karbonil-amino)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-chloro-6-(cyclohexylamino-carbonyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acids and trifluoroacetic acids in methylene chloride.

Dobitak: 75 % od teorijskog. Gain: 75% of the theoretical.

Talište: 222-224oC. Melting point: 222-224oC.

C31H33ClN4O3 (545,09) C31H33ClN4O3 (545.09)

Rf vrijednost: 0,15 (silika gel; metilenklorid/etanol = 19/1). Rf value: 0.15 (silica gel; methylene chloride/ethanol = 19/1).

[image] [image]

Primjer 74 Example 74

Hidrat 4’-[[2-n-propil-4-metil-6-amidino-benzimidazol-1-il]-metil]bifenil-2-karboksilne kiseline 4'-[[2-n-propyl-4-methyl-6-amidino-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid hydrate

a) Metil ester 4’-[[2-n-propil-4-metil-6-amidino-benzimid-azol-1-il]-metil]bifenil-2-karboksilne kiseline a) Methyl ester of 4'-[[2-n-propyl-4-methyl-6-amidino-benzimid-azol-1-yl]-methyl]biphenyl-2-carboxylic acid

2,1 g (5 mmolova) metil estera 4’-[[2-n-propil-4-metil-6-cijano-benzimidazol-1-il]-metil]bifenil-2-karboksilne kiseline otopi se uz miješanje u 250 ml metanola pri sobnoj tempraturi. Klorovodik se dovodi uz hlađenje ledom pri 10-20oC. Zatim se miješa još 3 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, ostatak se pomiješa dva puta s eterom i isperi. Natali imino eter preuzme se u 250 ml metanola i doda se 10,0 g amonijevog karbonata. Reakcijsku smjesu miješa se 12 sati pri sobnoj temperaturi. Nakon oduzimanja otapala ostatak se očisti kroz kolonu silika gela (veličina zrna 0,063-0,032 mm), pri čemu se kao sredstvo za ispiranje koristi mješavinu metilenklorida i metanola s rastućom polarnošću (9:1 i 8:2). Sjedinjene frakcije se ispare u vakuumu. 2.1 g (5 mmol) of methyl ester of 4'-[[2-n-propyl-4-methyl-6-cyano-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid is dissolved with stirring in 250 ml of methanol at room temperature. Hydrogen chloride is supplied with ice cooling at 10-20oC. Then it is stirred for another 3 hours at room temperature. The solvent was removed in vacuo, the residue was mixed twice with ether and washed. Natali imino ether is taken up in 250 ml of methanol and 10.0 g of ammonium carbonate is added. The reaction mixture was stirred for 12 hours at room temperature. After removing the solvent, the residue is purified through a silica gel column (grain size 0.063-0.032 mm), using a mixture of methylene chloride and methanol with increasing polarity (9:1 and 8:2) as a washing agent. The combined fractions are evaporated in vacuo.

Dobitak: 1,5 g (58 % od teorijskog). Gain: 1.5 g (58% of theoretical).

Rf vrijednost: 0,15 (silika gel; sredstvo za ispiranje: metilenklorid/metanol = 9/1). Rf value: 0.15 (silica gel; eluent: methylene chloride/methanol = 9/1).

b) 4’-[[2-n-propil-4-metil-6-amidino-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina b) 4'-[[2-n-propyl-4-methyl-6-amidino-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

0,51 g (1,0 mmol) metil estera 4’-[[2-n-propil-4-metil-6-amidino-benzimidazol-1-il]-metil]bifenil-2-karboksilne kiseline otopi se u 6 ml tetrahidrofurana, doda se 2,8 ml 1,4 M vodene otopine litijevog hidroksida i 3 ml vode i miješa se 2 dana pri sobnoj temperaturi. Zatim se doda 300 mg amonijevog klorida u 4 ml vode. Smjesu se miješa 5 minuta, nastali talog se odsisa, ispere s acetonom i osuši preko kalijevog hidroksida. 0.51 g (1.0 mmol) of 4'-[[2-n-propyl-4-methyl-6-amidino-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid methyl ester is dissolved in 6 ml of tetrahydrofuran, 2.8 ml of 1.4 M aqueous solution of lithium hydroxide and 3 ml of water are added and stirred for 2 days at room temperature. Then 300 mg of ammonium chloride in 4 ml of water is added. The mixture is stirred for 5 minutes, the resulting precipitate is suctioned off, washed with acetone and dried over potassium hydroxide.

Dobitak: 0,25 g (59 % od teorijskog). Gain: 0.25 g (59% of theoretical).

Talište: 270-271oC. Melting point: 270-271oC.

C26H26N4O2·H2O (426,53) C26H26N4O2·H2O (426.53)

[image] Rf vrijednost: 0,55 (silika gel; sredstvo za ispiranje: metilenklorid/metanol/amonijak = 2/1/0,25). [image] Rf value: 0.55 (silica gel; eluent: methylene chloride/methanol/ammonia = 2/1/0.25).

Analogno kao u primjeru 74 dobiveni su slijedeći spojevi: Analogous to example 74, the following compounds were obtained:

4’-[[2-n-propil-4-metil-6-(3-metil-imidazol-2-il)-benz-imidazol-1-il]-metil]-2-bifenil-2-karboksilna kiselina, 4'-[[2-n-propyl-4-methyl-6-(3-methyl-imidazol-2-yl)-benz-imidazol-1-yl]-methyl]-2-biphenyl-2-carboxylic acid,

4’-[[2-n-propil-4-klor-6-(4,5,6,7-tetrahidro-benzimid-azol-2-il)-benzimidazol-1-il]-metil]-2-bifenil-karboksilna kiselina. 4'-[[2-n-propyl-4-chloro-6-(4,5,6,7-tetrahydro-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-biphenyl -carboxylic acid.

Primjer 75 Example 75

4’-[[2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benzimid-azol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

a) 3-metil-4-butirilamino-5-nitro-acetofenon a) 3-methyl-4-butyrylamino-5-nitro-acetophenone

32,6 g (148 mmolova) 3-metil-4-butirilamino-aceto-fenona doda se uz miješanje u obrocima pri -15oC u 300 ml dimeće dušične kiseline i miješa se daljnjih 30 minuta pri -15oC. Zatim se reakcijsku smjesu uz miješnje prelije na 3 l leda, izlučeni sirovi proizvod se odsisa, ispre sa 400 ml vode, osuši i očisti prekristalizacijom iz etanol/dietil-etera (1:1). 32.6 g (148 mmol) of 3-methyl-4-butyrylamino-aceto-phenone was added with stirring in portions at -15°C to 300 ml of fuming nitric acid and stirred for a further 30 minutes at -15°C. Then, with stirring, the reaction mixture is poured onto 3 l of ice, the secreted crude product is filtered off with suction, washed with 400 ml of water, dried and purified by recrystallization from ethanol/diethyl ether (1:1).

Dobitak: 23,8 g (61,0% od teorijskog). Gain: 23.8 g (61.0% of theoretical).

Rf vrijednost: 0,32 (silika gel; metilenklorid); Rf value: 0.32 (silica gel; methylene chloride);

Rf vrijednost: 0,48 (silika gel; metilenklorid/metanol = 50/1). Rf value: 0.48 (silica gel; methylene chloride/methanol = 50/1).

b) 3-metil-4-butirilamino-5-nitro-1-bromacetofenon b) 3-methyl-4-butyrylamino-5-nitro-1-bromoacetophenone

K otopini od 23,8 g (90 mmolova) 3-metil-4-butiril-amino-5-acetofenona u 900 ml diklormetana pri sobnoj temperaturi uz miješanje dokaplje se otopinu od 16,0 g (200 mmolova) broma u 140 ml dioksana tako polako, da dođe do konstatnog potpunog obezbojenja reakcijske smjese. Zatim se miješa slijedeća dva sata, i zatim se reakcijsku smjesu ispari u vakuumu do suhog. Tako dobiveni ostatak protare se s pribl. 20 ml diklormetan/dietiletera (1:1), odsisa i zatim osuši. Tako se dobije 23 g (74% od teor.) 3-metil-4-butirilamino-5-nitro-ω-brom-acetofenona, koji sadrži još pribl. 10% polaznog materijala. Proizvod se bez daljnjeg čišćenja dalje kemijski pretvara. A solution of 16.0 g (200 mmol) of bromine in 140 ml of dioxane is added dropwise to a solution of 23.8 g (90 mmol) of 3-methyl-4-butyryl-amino-5-acetophenone in 900 ml of dichloromethane at room temperature with stirring. so slowly, that the constant complete discoloration of the reaction mixture occurs. It is then stirred for the next two hours, and then the reaction mixture is evaporated to dryness under vacuum. The resulting residue is rubbed with approx. 20 ml of dichloromethane/diethylether (1:1), suction and then dry. Thus, 23 g (74% of theory) of 3-methyl-4-butyrylamino-5-nitro-ω-bromo-acetophenone is obtained, which also contains approx. 10% of the starting material. The product is further chemically transformed without further cleaning.

Rf vrijednost: 0,69 (silika gel; metilenklorid/metanol = 50:1); Rf value: 0.69 (silica gel; methylene chloride/methanol = 50:1);

Rf vrijednost: 0,84 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.84 (silica gel; methylene chloride/methanol = 9:1).

c) 2-butirilamino-3-nitro-5-imidazo-4-il)-toluen c) 2-butyrylamino-3-nitro-5-imidazo-4-yl)-toluene

Otopinu od 6,8 g (20 mmolova) 3-metil-4-butirilamino-5-nitro-ω-brom-acetofenona u 20 ml formamida grije se 2 sata pri 140oC. Ohlađenu otopinu prelije se zatim u pribl. 50 ml 1N amonijaka i miješa se 15 minuta. Izlučen sirovi proizvod se odsisa, ispere s pribl. 50 ml vode i osuši. Tako se dobije 4,4 g (75% od teor.) proizvoda koji se bez daljnjeg čišćenja dalje kemijski pretvara. A solution of 6.8 g (20 mmol) of 3-methyl-4-butyrylamino-5-nitro-ω-bromo-acetophenone in 20 ml of formamide is heated for 2 hours at 140oC. The cooled solution is then poured into approx. 50 ml of 1N ammonia and stir for 15 minutes. The excreted crude product is suctioned off, washed with approx. 50 ml of water and dry. Thus, 4.4 g (75% of theory) of the product is obtained, which is further chemically converted without further purification.

Rf vrijednost: 0,29 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.29 (silica gel; methylene chloride/methanol = 9:1).

d) 2-butirilamino-3-nitro-5-(1-metil-imidazo-4-il)-toluen d) 2-butyrylamino-3-nitro-5-(1-methyl-imidazo-4-yl)-toluene

K otopini od 2,5 g (8,7 mmolova) 2-butirilamino-3-nitro-5-imidazo-4-il)-toluena i 5,2 g (30 mmolova) dihidrata kalijevog karbonata u 30 ml dimetilsulfoksida dokaplje se 1,3 g (9,5 mmolova) metiljodida pri sobnoj temperaturi i zatim se miješa 2 sata. Reakcijsku smjesu se zatim pomiješa s pribl. 150 ml vode i zatim se ekstrahira 4 puta sa po 25 ml etilacetata. Organske ekstrakte se ispere s pribl. 30 ml vode, osuši i ispari. Tako dobiven sirovi proizvod se očisti kromatografijom u koloni (300 g silika gela, sredstvo za ispiranje: metilenklorid/metanol = 30:1). To a solution of 2.5 g (8.7 mmol) of 2-butyrylamino-3-nitro-5-imidazo-4-yl)-toluene and 5.2 g (30 mmol) of potassium carbonate dihydrate in 30 ml of dimethylsulfoxide, 1 .3 g (9.5 mmol) of methyl iodide at room temperature and then stirred for 2 hours. The reaction mixture is then mixed with approx. 150 ml of water and then extracted 4 times with 25 ml of ethyl acetate each. The organic extracts are washed with approx. 30 ml of water, dry and evaporate. The crude product thus obtained is purified by column chromatography (300 g of silica gel, eluent: methylene chloride/methanol = 30:1).

Dobitak: 640 mg (24% od teor.). Gain: 640 mg (24% of theory).

Rf vrijednost: 0,54 (silika gel; metilenklorid/metanol = 9:1) Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1)

e) 2-butirilamino-3-amino-5-(1-metil-imidazo-4-il)-toluen e) 2-butyrylamino-3-amino-5-(1-methyl-imidazo-4-yl)-toluene

640 mg (2,1 mmol) 2-butirilamino-3-nitro-5-(1-metil-imidazo-4-il)-toluena hidrira se u 30 ml metanola nakon dodatka pribl. 200 mg paladij/ugljena (20%) pri sobnoj temperaturi i pod tlakom vodika od 5 bara. Nakon prestanka uzimanja vodika katalizator se odfiltrira i filtrat se ispari. Tako dobiven sirovi proizvod dalje se kemijski pretvara bez daljnjeg čišćenja. 640 mg (2.1 mmol) of 2-butyrylamino-3-nitro-5-(1-methyl-imidazo-4-yl)-toluene is hydrogenated in 30 ml of methanol after the addition of approx. 200 mg of palladium/charcoal (20%) at room temperature and under a hydrogen pressure of 5 bar. After the hydrogen uptake has stopped, the catalyst is filtered off and the filtrate is evaporated. The raw product thus obtained is further chemically converted without further purification.

Dobitak: 600 mg (100% od teor.). Gain: 600 mg (100% of theory).

Rf vrijednost: 0,23 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.23 (silica gel; methylene chloride/methanol = 9:1).

f) 2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benzimidazol f) 2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole

600 mg (2,1 mmola) 2-butirilamino-3-amino-5-(1-metil-imidazol-4-il)-toluena grije se u 10 ml ledene octene kiseline 1 sat pod refluksom. Zatim se u vakuumu ispari do suhog, ostatak se pomiješa s pribl. 15 ml vode, s amonijakom se namjesti na lužnato i četiri puta se ekstrahira sa po pribl. 10 ml etil acetata. Organski ekstrakti se isperu s pribl. 15 ml vode, osuše i zatim ispare. Tako dobiven sirovi proizvod dalje se kemijski pretvara bez daljnjeg čišćenja. 600 mg (2.1 mmol) of 2-butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene is heated in 10 ml of glacial acetic acid for 1 hour under reflux. It is then evaporated to dryness under vacuum, the residue is mixed with approx. 15 ml of water, made alkaline with ammonia and extracted four times with approx. 10 ml of ethyl acetate. The organic extracts are washed with approx. 15 ml of water, dry and then evaporate. The raw product thus obtained is further chemically converted without further purification.

Dobitak: 420 mg (79% od teor.). Yield: 420 mg (79% of theory).

Rf vrijednost: 0,37 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.37 (silica gel; methylene chloride/methanol = 9:1).

g) Terc.butil ester 4’-[(2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benzimidazol-1-il)-metil]-bifenil-2-karboksilne kiseline g) Tert.butyl ester 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid

K otopini od 200 mg (0,79 mmola) 2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benzimidazola i 90 mg (0,8 mmola) kalijevog terc.butilata u 5 ml dimetilsulfoksida doda se 280 mg (0,8 mmola) terc.butil estera 4’-bromfenil-bifenil-2-karboksilne kiseline i smjesu se miješa 90 minuta pri sobnoj temperaturi, zatim se umiješa pribl. 40 ml vode, ekstrahira se 4 puta sa po pribl. 10 ml etilacetata, zatim se organski ekstrakti isperu sa po 10 ml vode, osuše i ispare do suhog. Tako dobiven sirovi proizvod očisti se kromatografijom u koloni (100 g silika gela, sredstvo za ispiranje: diklormetan/metanol = 30:1). A solution of 200 mg (0.79 mmol) of 2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg (0.8 mmol) of potassium tert.butylate in 280 mg (0.8 mmol) of tert.butyl ester of 4'-bromophenyl-biphenyl-2-carboxylic acid is added to 5 ml of dimethylsulfoxide and the mixture is stirred for 90 minutes at room temperature, then approx. 40 ml of water, extracted 4 times with approx. 10 ml of ethyl acetate, then the organic extracts are washed with 10 ml of water each, dried and evaporated to dryness. The thus obtained crude product is purified by column chromatography (100 g silica gel, eluent: dichloromethane/methanol = 30:1).

h) 4’-[(2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benz-imidazol-1-il)-metil]-bifenil-2-karboksilna kiselina h) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benz-imidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid

Otopinu od 230 mg (0,44 mmola) terc.butil estera 4’-[(2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benzimid-azol-1-il)-metil]-bifenil-2-karboksilne kiseline i 2 ml trifluoroctene kiseline u 10 ml diklormetana miješa se preko noći pri sobnoj temperaturi i zatim se ispari do suhog. Ostatak se otopi u pribl. 5 ml razrijeđenog natrijevog hidroksida, otopinu se neutralizira s octenom kiselinom, izlučeni talog se odsisa, ispere s vodom i osuši. A solution of 230 mg (0.44 mmol) tert.butyl ester 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimid-azol-1-yl) )-methyl]-biphenyl-2-carboxylic acid and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane were stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in approx. 5 ml of diluted sodium hydroxide, the solution is neutralized with acetic acid, the excreted precipitate is sucked off, washed with water and dried.

Dobitak: 120 mg (59% od teor.). Yield: 120 mg (59% of theory).

Talište: 293-295oC. Melting point: 293-295oC.

Rf vrijednost: 0,39 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.39 (silica gel; methylene chloride/methanol = 9:1).

Analogno kao u primjeru 77 dobiveni su slijedeći spojevi: Analogous to example 77, the following compounds were obtained:

4’-[(2-n-propil-4-metil-6-(1-etil-imidazol-4-il)-benz-imidazol-1-il)-metil]-bifenil-2-karboksilna kiselina, 4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-benz-imidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

4’-[(2-n-propil-4-metil-6-(1-n-heksil-imidazol-4-il)-benzimidazol-1-il)-metil]-bifenil-2-karboksilna kiselina, 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

4’-[(2-n-propil-4-metil-6-(1-benzil-imidazol-4-il)-benzimidazol-1-il)-metil]-bifenil-2-karboksilna kiselina, 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

4’-[(2-n-propil-4-metil-6-(1-izopropil-imidazol-4-il)-benzimidazol-1-il)-metil]-bifenil-2-karboksilna kiselina, 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid,

4’-[(2-n-propil-4-metil-6-(1-cikloheksil-imidazol-4-il)-benzimidazol-1-il)-metil]bifenil-2-karboksilna kiselina. 4'-[(2-n-propyl-4-methyl-6-(1-cyclohexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid.

Primjer 76 Example 76

4’-[(2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benz-imidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benz-imidazol-1-yl)-methyl]-2-(1H-tetrazol-5- yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(1-metil-imidazol-4-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]-2-cyano -biphenyl and sodium azide in dimethylformamide.

Dobitak: 24 % od teorijskog. Gain: 24% of the theoretical.

Talište: 255-257oC. Melting point: 255-257oC.

Rf vrijednost: 0,24 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.24 (silica gel; methylene chloride/methanol = 9:1).

C29H28N8·H2O (506,62) C29H28N8·H2O (506.62)

[image] [image]

Analogno kao u primjeru 76 dobiveni su slijedeći spojevi: Analogous to example 76, the following compounds were obtained:

4’-[(2-n-propil-4-metil-6-(1-etil-imidazol-4-il)-benz-imidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil, 4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-benz-imidazol-1-yl)-methyl]-2-(1H-tetrazol-5- yl)-biphenyl,

4’-[(2-n-propil-4-metil-6-(1-n-heksil-imidazol-4-il)-benzimidazol-1-il)-metil]-2-bifenil-karboksilna kiselina, 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-biphenyl-carboxylic acid,

4’-[(2-n-propil-4-metil-6-(1-benzil-imidazol-4-il)-benzimidazol-1-il)-metil]-2-bifenil-karboksilna kiselina, 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-biphenyl-carboxylic acid,

4’-[(2-n-propil-4-metil-6-(1-izopropil-imidazol-4-il)-benzimidazol-1-il)-metil]-2-(1-H-tetrazol)-bifenil, 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1-H-tetrazole)-biphenyl ,

4’-[(2-n-propil-4-metil-6-(1-cikloheksil-imidazol-4-il)-benzimidazol-1-il)-metil]-2-(1-H-tetrazol)-bifenil. 4'-[(2-n-propyl-4-methyl-6-(1-cyclohexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1-H-tetrazole)-biphenyl .

Primjer 77 Example 77

4’-[(2-etil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl ]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[(2-etil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il)-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously to example 10 from 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)- of benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 21 % od teorijskog. Gain: 21% of the theoretical.

Talište: amorfan. Melting point: amorphous.

Rf vrijednost: 0,27 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.27 (silica gel; methylene chloride/methanol = 9:1).

C31H30N8 (514,64) C31H30N8 (514.64)

[image] [image]

Primjer 78 Example 78

4’-[[2-n-propil-4-metil-6-(8-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]biphenyl-2 -carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(8-metil-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilen-kloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]-pyridin-2-yl) -benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 87 % od teorijskog. Gain: 87% of the theoretical.

Talište: 295-297oC. Melting point: 295-297oC.

Rf vrijednost: 0,34 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.34 (silica gel; methylene chloride/methanol = 9:1).

C33H30N4O2·H2O (532,65) C33H30N4O2·H2O (532.65)

[image] [image]

Primjer 79 Example 79

4’-[(2-n-propil-4-metil-6-(2-piridil)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[(2-n-propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[(2-n-propil-4-metil-6-(2-piridil)-benzimidazol-1-il)-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously to example 10 from 4'-[(2-n-propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 56 % od teorijskog. Gain: 56% of the theoretical.

Talište: iznad 136oC (raspad). Melting point: above 136oC (decomposition).

C30H27N7·0,5H2O (494,60) C30H27N7·0.5H2O (494.60)

[image] [image]

Primjer 80 Example 80

4’-[(2-n-propil-4-metil-6-(8-metil-imidazo[1,2-a]piridin-2-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[(2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-( 1H-tetrazol-5-yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[(2-n-propil-4-metil-6-(8-metil-imidazo[1,2-a]piridin-2-il)-benz-imidazol-1-il)-metil]-2-cijano-bifenila i natrijevog azida u dimetilformamidu. It is prepared analogously as in example 10 from 4'-[(2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benz-imidazol-1 -yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.

Dobitak: 19 % od teorijskog. Gain: 19% of the theoretical.

Talište: amorfan. Melting point: amorphous.

Rf vrijednost: 0,36 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.36 (silica gel; methylene chloride/methanol = 9:1).

C33H30N8 (538,61) C33H30N8 (538.61)

Maseni spektar: m/e = 538 Mass spectrum: m/e = 538

Primjer 81 Example 81

4’-[[2-etil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl ]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-etil-4-metil-6-(5,6,7,8-tetrahidro-imidazo-[1,2-a]-piridin-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilen-kloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]-pyridine -2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 50 % od teorijskog. Gain: 50% of the theoretical.

Talište: >300oC. Melting point: >300oC.

Rf vrijednost: 0,16 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.16 (silica gel; methylene chloride/methanol = 9:1).

Primjer 82 Example 82

4’-[[2-n-propil-4-metil-6-(1-izopropil-imidazol-4-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(1-izopropil-imidazol-4-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl ]biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Dobitak: 84 % od teorijskog. Gain: 84% of the theoretical.

Talište: 285-286oC. Melting point: 285-286oC.

Rf vrijednost: 0,55 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.55 (silica gel; methylene chloride/methanol = 9:1).

Primjer 83 Example 83

4’-[(2-n-propil-4-metil-6-(1-izopropil-imidazol-4-il)-benzimidazol-1-il)-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[(2-n-propil-4-metil-6-(1-izopropil-imidazol-4-il)-benzimidazol-1-il)-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously to example 10 from 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano -biphenyl and sodium azide in dimethylformamide.

Dobitak: 18 % od teorijskog. Gain: 18% of the theoretical.

Talište: amorfan. Melting point: amorphous.

Rf vrijednost: 0,29 (silika gel; metilenklorid/metanol = 9:1). Rf value: 0.29 (silica gel; methylene chloride/methanol = 9:1).

C31H32N8 (516,66) C31H32N8 (516.66)

Maseni spektar: m/e = 516 Mass spectrum: m/e = 516

Primjer 84 Example 84

4’-[[2-n-propil-4-metil-6-(1-n-heksil-imidazol-4-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(1-n-heksil-imidazol-4-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl] -methyl]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 85 Example 85

4’-[[2-n-propil-4-metil-6-(1-benzil-imidazol-4-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina 4'-[[2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid

Pripremi se analogno kao u primjeru 1 iz terc.butil-estera 4’-[[2-n-propil-4-metil-6-(1-benzil-imidazol-4-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilne kiseline i trifluoroctene kiseline u metilenkloridu. It is prepared analogously as in example 1 from tert.butyl ester 4'-[[2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl ]-biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Primjer 86 Example 86

4’-[[2-n-propil-4-metil-6-(1-n-heksil-imidazol-4-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5- yl)-biphenyl

Pripremi se analogno kao u primjeru 10 iz 4’-[[2-n-propil-4-metil-6-(1-n-heksil-imidazol-4-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 10 from 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]-2 -cyano-biphenyl and sodium azide in dimethyl-formamide.

Primjer 87 Example 87

4’-[[2-n-propil-4-metil-6-(1-benzil-imidazol-4-il)-benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil 4'-[[2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl

Pripremi se analogno kao u primjeru 1 iz 4’-[[2-n-propil-4-metil-6-(1-benzil-imidazol-4-il)-benzimidazol-1-il]-metil]-2-cijano-bifenila i natrijevog azida u dimetil-formamidu. It is prepared analogously as in example 1 from 4'-[[2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl]-methyl]-2-cyano -biphenyl and sodium azide in dimethylformamide.

U slijedećim faramceutskim primjerima upotrebe, kao aktivnu tvar može se upotrijebiti svaki prikladni spoj formule I, osobito oni u kojima R 4 predstavlja karboksi ili 1H-tetrazolilnu skupinu. In the following pharmaceutical examples of use, any suitable compound of formula I can be used as an active substance, especially those in which R 4 represents a carboxy or 1H-tetrazolyl group.

Primjer I Examples

Ampule koje u 5 ml sadrže 50 mg aktivne tvari Ampoules containing 50 mg of active substance in 5 ml

[image] Priprava: [image] Preparation:

U jednom dijelu vode otope se puferne tvari i izotonično sredstvo. Doda se aktivnu tvar i nakon potpunog otapanja nadolije se s vodm do nomilanog volumena. Buffer substances and an isotonic agent are dissolved in one part of the water. The active substance is added and after complete dissolution, it is poured with water up to the nominal volume.

Primjer II Example II

Ampule koje u 5 ml sadrže 100 mg aktivne tvari Ampoules containing 100 mg of active substance in 5 ml

[image] [image]

Priprava: Preparation:

U jednom dijelu vode otopi se metilglukamin i aktivnu tvar se doda uz miješanje i grijanje otopine. Nakon dodatka otapala nadolije se s vodom na nominalni volumen. Methylglucamine is dissolved in one part of water and the active substance is added while stirring and heating the solution. After adding the solvent, it is topped up with water to the nominal volume.

Primjer III Example III

Tablete koja sadrže 50 mg aktivne tvari Tablets containing 50 mg of active substance

[image] Priprava: [image] Preparation:

Aktivnu tvar, CaHPO4, mliječni šećer i kukurzni škrob jednakomjerno se navlaže s vodenom otopinom PVP-a. Masu se prosije kroz sito 2 mm, osuši pri 50oC u sušilici u zraku i ponovno prosije. The active substance, CaHPO4, milk sugar and corn starch are evenly moistened with an aqueous solution of PVP. The mass is sieved through a 2 mm sieve, dried at 50oC in an air dryer and sieved again.

Zatim se umiješa lubrikant i granulat se ispreša na stroju za tabletiranje. Then the lubricant is mixed in and the granulate is crushed on a tableting machine.

Primjer IV Example IV

Dražeje koje sadrže 50 mg aktivne tvari Dragees containing 50 mg of active substance

[image] Priprava: [image] Preparation:

Aktivnu tvar pomiješa se s pomoćnim tvarima i navlaži s vodenom otopinom želatine. Nakon sijanja i sušenja granulat se pomiješa s magnezijevim stearatom i ispreša u jezgre dražeja. The active substance is mixed with excipients and moistened with an aqueous solution of gelatin. After sowing and drying, the granulate is mixed with magnesium stearate and pressed into dragee cores.

Tako pripremljene jezgre prevuču se s prevlakom na poznat način. Suspenziji ili otopini za dražeje doda se bojilo. The cores prepared in this way are covered with a coating in a known manner. A dye is added to the suspension or solution for dragees.

Primjer V Example V

Dražeje koje sadrže 100 mg aktivne tvari Dragees containing 100 mg of active substance

[image] [image]

Priprava: Preparation:

Aktivnu tvar pomiješa se s pomoćnim tvarima i navlaži s vodenom otopinom PVP-a. Vlažnu masu prosije se kroz sito 1,5 mm i osuši pri 45oC. Nakon sušenja ponovno se prosije i umiješa se magnezijev stearat. Tu smjesu spreša se u jezgre dražeja. The active substance is mixed with excipients and moistened with an aqueous solution of PVP. The wet mass is sieved through a 1.5 mm sieve and dried at 45oC. After drying, it is sieved again and magnesium stearate is mixed in. This mixture is pressed into the dragee cores.

Tako pripremljene jezgre prevuču se s prevlakom na poznat način. Suspenziji ili otopini za dražeje doda se bojilo. The cores prepared in this way are covered with a coating in a known manner. A dye is added to the suspension or solution for dragees.

Primjer VI Example VI

Kapsule koje sadrže 250 mg aktivne tvari Capsules containing 250 mg of active substance

[image] [image]

Priprava: Preparation:

Aktivnu tvar i kukuruzni škrob se pomiješa i navlaži s vodom. Vlažnu masu se prosije i osuši. Suhi granulat se prosije i pomiješa s magenzijevim stearatom. Dobivenu smjesu puni se u kapsule od tvrde želatine veličine 1. The active substance and corn starch are mixed and moistened with water. The wet mass is sieved and dried. The dry granulate is sieved and mixed with magnesium stearate. The resulting mixture is filled into hard gelatin capsules of size 1.

Primjer VII Example VII

Oralne suspenzije koje u 5 ml sadrže 50 mg aktine tvari Oral suspensions containing 50 mg of actin substance in 5 ml

[image] [image]

Priprava: Preparation:

Destiliranu vodu zagrije se na 70oC. U njoj se uz miješanje otopi hidroksietilcelulozu. Nakon dodatka otopine sorbita i glicerina ohladi se na sobnu temperaturu. Pri sobnoj temperaturi doda se sorbinsku kiselinu, aromu i aktivnu tvar. Za odzračivanje suspenziju se evakuira uz miješanje. 5,0 ml sadrži dozu od 50 mg. Distilled water is heated to 70oC. Hydroxyethyl cellulose is dissolved in it with stirring. After adding the sorbitol and glycerine solution, cool to room temperature. Add sorbic acid, aroma and active substance at room temperature. For deaeration, the suspension is evacuated with stirring. 5.0 ml contains a dose of 50 mg.

Primjer VIII Example VIII

Čepići koji sadrže 100 mg aktivne tvari Suppositories containing 100 mg of active substance

[image] [image]

Priprava: Preparation:

Čvrstu mast se rastali. Pri 40oC homogeno se dispergira smljevenu aktivnu tvar u talinu. Ohladi se na 38oC i izlije u malo podhlađene kalupe za čepiće. Melt the solid fat. At 40oC, the ground active substance is homogeneously dispersed in the melt. Cool to 38oC and pour into slightly cooled suppository molds.

Claims (10)

1. Benzimidazoli opće formule [image] naznačeni time, da R1 u položaju 4 predstavlja atom fluora, klora ili broma, alkilnu skupinu s 1 do 4 ugljikova atoma, ciklo-alkilnu, fluormetilnu, difluormetilnu ili trifluormetilnu skupinu i R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma, koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetrahidro-benzimidazolilnom skupinom, ili također, ako R4 predstavlja 1H-tetrazolilnu skupinu, R2 predstavlja 2-(imidazol-1-il)-etoksi skupinu, alkilsulfoniloksi skupinu s 1 do 4 ugljikova atoma, benzensulfoniloksi ili fenilalkan sulfoniloksi skupinu, acilamino skupinu, u kojoj acilni ostatak predstavlja alkanoilnu skupinu s 1 do 7 ugljikova atoma, u datom slučaju supstituiranu na atomu dušika s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma, s fenilnom, ciklo-alkilnom, fenilalkilnom, cikloalkilalkilnom, biciklo-heksilnom ili bifenilnom skupinom, alkoksikarbonilnu skupinu s ukupno 2 do 4 ugljikova atoma, alkilsulfonilnu skupinu s 1 do 6 ugljikova atoma, benzoilnu, benzen-sulfonilnu, fenilalkan-sulfonilnu, naftalensulfonilnu, cikloalkilkarbonilnu, fenilalkanoilnu ili cikloalkil-alkanoilnu skupinu, pri čemu prethodno spomenuta fenilna jezgra može biti mono- ili disupstituirana s atomom fluora, klora ili broma, s metilnom ili metoksi skupinom, a supstituenti mogu biti jednaki ili različiti, ftalimino, homoftalimino, 2-karboksifenilkarbonilamino ili 2-karoksifenilmetilamino skupinu, pri čemu je karbonilna skupina u ftalimino skupini nadomještena s metilenskom, alkilmetilenskom ili dialkilmetilenskom skupinom, a također metilenska skupina u homoftalimino skupini može biti supstituirana s jednom ili dvije alkilne skupine, i dodatno prethodno spomenute fenilne jezgre su mono- ili disupstituirane s alkilnim ili alkoksi skupinama, pri čemu supstituenti mogu biti jednaki ili različiti i istovremeno mogu biti potpuno ili djelomično hidrirani, peteročlanu, šesteročlanu ili sedmeročlanu alkilimino ili alkilenimino skupinu, u kojoj metilenska skupina može biti nadomještena s karbonilnom ili sulfonilnom skupinom, u datom slučaju supstituiranu s jednom ili dvije alkilne skupine ili s tetrametilenskom ili pentametilenskom skupinom, imino skupinu bicikloalkan-2,3-dikarboksilne kiseline ili imino skupinu bicikloalken-2,3-dikarbonske kiseline, u kojoj bicikloalkanski i bicikloalkenski dio sadrži 9 ili 10 ugljikovih atoma, koja može biti supstituirana s 1, 2 ili 3 metilne skupine i endometilenska skupina može biti nadomještena s atomom kisika, amidino skupinu u datom slučaju supstituiranu s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 6 ugljikovih atom, imino skupinu glutarne kiseline, u kojoj je n-propilenska skupina perfluorirana, koja može biti supstituirana s jednom ili dvije alkilne skupina ili s tetrametilenskom ili pentametilenskom skupinom, imido skupinu maleinske kiseline, u datom slučaju mono- ili disupstituiranu s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, peteročlani heteroatomni prsten, povezan preko ugljikovog atoma ili preko imino skupine, koji sadrži imino skupinu, atom kisika, ili sumpora, ili imino skupinu i atom kisika, sumpora, ili dušika, ili šesteročlani heteroatomni prsten povezan preko ugljikovog atoma, koji sadrži 1 ili 2 dušikova atoma, pri čemu prethodno spomenuti hetero-aromatski prstenovi u ugljikovoj strukturi mogu biti supstituirani s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili s fenilalkilnom skupinom i povezani su na šesteročlane heteroatomne prstenove preko dvaju susjednih ugljikova atoma n-propilenske ili n-butilenske skupine ili su vezani također na peteročlane, kao također na šesteročlane heteroatomne prstenove preko dvaju susjednih ugljikovih atoma, 1,3-butadienilne skupine ili preko imino skupine i susjednog ugljikovog atoma n-butilenske ili 1,3-butadienilne skupine i u tako nastalom aneliranom piridinskom prstenu metilenska skupina može biti nadomještena s dušikovim atomom, a vinilenska skupina u položaju 3, 4 prema atomu dušika nastalog piridinskog prstena, s atomom sumpora, ili u tako nastalom aneliranom fenilnom prstenu jedna ili dvije metinske skupine mogu biti nadomještene s dušikovim atomom, pri čemu dodatno prethodno spomenuti dokondenzirani aromatski ili heteroaromatski prstenovi u ugljikovoj strukturi mogu biti mono-supstituirani s atomom fluora, klora ili broma, s alkilnom, alkoksi, hidroksi, fenilnom, nitro, amino, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksi-karbonilnom, aminokarbonilnom, alkilaminokarbonilnom, dialkilaminokarbonilnom, fluormetilnom, difluormetilnom, trifluormetilnom, alkanoilnom, aminosulfonilnom, alkil-aminosulfonilnom, ili dialkilaminosulfonilnom skupinom, ili disupstituirani s atomom fluora ili klora, s metilnim, metoksi ili hidroksi skupinama, kao što također dva metilna supstituenta, jedan prema drugom u položaju 1,2, mogu biti međusobno povezani s metilenskim ili etilenskim mostom, i u datom slučaju NH skupina prisutna u imidazolnom prstenu može biti supstituirana s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma, s fenilalkilnom skupinom ili sa ciklo-alkilnom skupinom, ili preko ugljikovog atoma povezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina susjedna dušikovom atomu u pirolidinskom ili piperidinskom prstenu mogu biti nadomješteni s karbonilnom skupinom, imidazolidindionsku skupinu u datom slučaju supstituiranu s alkilnom, fenilalkilnom, tetrametilenskom, pentametilenskom ili heksametilenskom skupinom, piridazin-3-onsku ili dihidro-piridazin-3-onsku skupinu koja u položaju 2 može biti supstituirana u datom slučaju s alkilnom skupinom supstituiranom s fenilnom skupinom, i dodatno u ugljikovoj strukturi s 1 ili 2 alkilne skupine, R7-NR6-CO-NR5 skupinu u kojoj R5 predstavlja vodikov atom, alkilnu skupinu s 1 do 8 ugljikovih atoma, cikloalkilnu skupinu s 5 do 7 ugljikovih atoma ili fenilnu skupinu, R6 predstavlja vodikov atom, alkilnu skupinu s 1 do 8 ugljikovih atoma, alkenilnu skupinu s 3 do 5 ugljikovih atoma, fenilnu skupinu, fenilalkilnu skupinu ili ciklo-alkilnu skupinu s 5 do 7 ugljikovih atoma, R7 predstavlja vodikov atom ili alkilnu skupinu s 1 do 6 ugljikovih atoma ili jedan od ostataka R5, R6 ili R7 također predstavlja bicikloheksilnu ili bifenilnu skupinu ili R6 i R7 zajedno s atomom dušika, koji se nalazi između njih, tvore alkenilimino skupinu sa 4 do 6 ugljikovih atoma ravnog lanca ili morfolino skupinu ili R5 i R6 zajedno tvore alkilensku skupinu koja ima 2 do 4 ugljikova atoma, 1H,3H-kinazolin-2,4-dion-3-ilnu ili pentametilen-oksazolin-2-ilnu skupinu ili R1 predstavlja vodikov atom ili u položaju 5, 6 ili 7 atom fluora, klora ili broma, alkilnu skupinu s 1 do 4 ugljikova atoma, fluormetilnu, difluormetilnu ili trifluor-metilnu skupinu i R2 predstavlja preko ugljikovog atoma ili preko imino skupine povezan peteročlani heteroaromatski prsten, koji sadrži imino skupinu, atom kisika ili sumpora ili imino skupinu i atom kisika, sumpora ili dušika, ili preko ugljikovog atoma povezan šesteročlani heteroaromatski prsten koji sadrži 1 ili 2 dušikova atoma, pri čemu prethodno spomenuti heteroaromatski prstenovi mogu biti supstituirani u ugljikovoj strukturi s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili s fenilalkilnom skupinom i povezani su na šesteročlane heteroaromatske prstenove preko dvaju susjednih ugljikova atoma n-propilenske ili n-butilenske skupine, ili su vezani kako na peteročlane tako također i na šesteročlane heteroaromatske prstenove preko dvaju susjednih ugljikova atoma 1,3-butadienske skupine ili preko imino skupine i susjednog ugljikovog atoma n-butilenske ili 1,3-butadienske skupine, i u tako nastalom aneliranom piridinskom prstenu metinska skupina nadomještena je s dušikovim atomom, a vinilenska skupina u položaju 3,4 prema dušikovom atomu nastalog piridinskog prstena, s atomom sumpora, ili su u tako nastalom aneliranom fenilnom prstenu jedna ili dvije metinske skupine nadomještene s dušikovim atomima, pri čemu dodatno prethodno spomenuti dokondenzirani aromatski ili heteroaromatski prstenovi u ugljikovoj strukturi mogu biti monosupstituirani s atomom fluora, klora ili broma, s alkilnom, alkoksi, hidroksi, fenilnom, nitro, animo, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksikarbonilnom, aminokarbonilnom, alkilamino-karbonilnom, dialkilaminokarbonilnom, fluormetilnom, di-fluormetilnom , trifluormetilnom, alkanoilnom, amino-sulfonilnom, alkilaminosulfonilnom ili dialkilamino-sulfonilnom skupinom, ili mogu biti supstituirani s atomom fluora ili klora, s metilnim, metoksi ili hidroksi skupinama, kao što također dva metilna supstituenta, jedan prema drugom u položaju 1, 2, mogu biti međusobno povezani s metilenksim ili etilenskim mostom, i u datom slučaju NH skupina, prisutna u imidazolnom prstenu, može biti supstituirana s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma, s fenilalkilnom skupinom ili sa ciklo-alkilnom skupinom, pri čemu ako (i) R1 predstavlja atom vodika, R3 je n-propilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati 3-metil-imidazo[4,5-b]-2-ilnu ili 3-n-heksil-imidazo[4,5-b]piridin-2-ilnu skupine ili ako (ii) R1 predstavlja vodikov atom, R3 je n-propilna ili b-butilna skupina i R4 je 1H-tetrazolilna skupina, R2 u položaju 5 ili 6 ne može predstavljati benzoksazol-2-ilnu skupinu, ili ako (iii) R1 predstavlja vodikov atom, R3 je n-propilna skupina, a R4 je karboksi skupina, R2 u položaju 5 ili 6 ne može predstavljati 1-metilbenzimidazol-2-ilnu skupinu ili u položaju 6 ne može predstavljati 1-n-butilbenzimidazol-2-ilnu, 1,5-dimetilbenzimidazol-2-ilnu ili 1-metil-5-tri-fluormetilbenzimidazol-2-ilnu skupinu ili ako (iv) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi ili 1H-tetrazolina skupina, R2 u položaju 6 ne može predstavljati 1-metilbenzimidazol-2-ilnu skupinu, ili ako (v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, ili preko ugljikovog atoma povezan pirolidinski, piperidinski ili piridinski prsten, pri čemu na piridinski prsten preko dvaju susjednih ugljikovih atoma dokondenzirani fenilni ostatak i metilenska skupina susjedna dušikovom atomu u pirolidinskom ili piperidinskom prstenu, mogu biti nadomješteni s karbonilnom skupinom, R3 predstavlja vodikov atom, alkilnu skupinu s 1 do 5 ugljikovih atoma u kojoj metilenska skupina može biti nadomještena s kisikovim atomom ili sumpornim atomom ili sa cikloalkilnom skupinom koja ima 3 do 5 ugljikova atoma i R4 predstavlja karboksi, cijano, 1H-tetrazolilnu ili 1-trifenilmetiltetrazolilnu skupinu, alkoksi karbonilnu skupinu s ukupno 2 do 5 ugljikovih atoma, alkansulfonil-aminokarbonilnu, arilsulfonilaminokarbonilnu ili trifluor-metansulfonilaminokarbonilnu skupinu, njihove 1-, 3-izomerne smjese i njihove soli s anorganskim ili organskim kiselinama ili bazama, pri čemu ako nije navedeno drugačije, pretodno spomenuti alkanoilni, alkilni ili alkoksi dio može sadržavati 1 do 3 ugljikova atoma, kao također prthodno spomenuti ciklo-alkilni dio može sadržati po 3 do 7 ugljikovih atoma.1. Benzimidazoles of the general formula [image] indicated by that R1 in position 4 represents a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and R2 represents an alkoxy group with 3 to 5 carbon atoms, which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms, which is substituted in position 2, 3, 4 or 5 with a benzimidazilyl group, or by a tetrahydro-benzimidazolyl group, or also, if R4 represents a 1H-tetrazolyl group, R2 represents a 2-(imidazol-1-yl)-ethoxy group, alkylsulfonyloxy group with 1 to 4 carbon atoms, benzenesulfonyloxy or phenylalkane sulfonyloxy group, an acylamino group, in which the acyl residue represents an alkanoyl group with 1 to 7 carbon atoms, in a given case substituted on the nitrogen atom with an alkyl group having 1 to 6 carbon atoms, with phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or by a biphenyl group, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, an alkylsulfonyl group with 1 to 6 carbon atoms, a benzoyl, benzenesulfonyl, phenylalkanesulfonyl, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkyl-alkanoyl group, whereby the previously mentioned phenyl nucleus can be mono- or disubstituted with a fluorine, chlorine or bromine atom, with a methyl or methoxy group, and the substituents may be the same or different, phthalimino, homophthalimino, 2-carboxyphenylcarbonylamino or 2-carboxyphenylmethylamino group, wherein the carbonyl group in the phthalimino group is replaced by a methylene, alkylmethylene or dialkylmethylene group, and also the methylene group in the homophthalimino group can be substituted with one or two alkyl groups, and additionally previously the mentioned phenyl nuclei are mono- or disubstituted with alkyl or alkoxy groups, whereby the substituents may be the same or different and at the same time may be fully or partially hydrogenated, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group, in which the methylene group can be substituted with a carbonyl or sulfonyl group, in a given case substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, imino group of bicycloalkane-2,3-dicarboxylic acid or imino group of bicycloalkene-2,3-dicarboxylic acid, in which the bicycloalkane and bicycloalkene part contains 9 or 10 carbon atoms, which can be substituted with 1, 2 or 3 methyl groups and an endomethylene group can be substituted with an oxygen atom, an amidino group substituted in a given case with one or two alkyl groups, each of which has 1 to 6 carbon atoms, the imino group of glutaric acid, in which the n-propylene group is perfluorinated, which can be substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different, a five-membered heteroatomic ring, connected through a carbon atom or through an imino group, containing an imino group, an oxygen, or sulfur atom, or an imino group and an oxygen, sulfur, or nitrogen atom, or a six-membered heteroatomic ring connected through a carbon atom, containing 1 or 2 of nitrogen atoms, whereby the previously mentioned hetero-aromatic rings in the carbon structure can be substituted with an alkyl group having 1 to 6 carbon atoms or with a phenylalkyl group and connected to six-membered heteroatomic rings via two adjacent n-propylene or n-butylene carbon atoms groups or are attached also to five-membered, as well as to six-membered heteroatomic rings via two adjacent carbon atoms, 1,3-butadienyl group or via an imino group and an adjacent carbon atom of an n-butylene or 1,3-butadienyl group and in the resulting annealed pyridine ring the methylene group can be substituted with a nitrogen atom, and the vinylene group in p deposit 3, 4 according to the nitrogen atom of the resulting pyridine ring, with a sulfur atom, or in the resulting annealed phenyl ring, one or two methine groups can be substituted with a nitrogen atom, whereby additionally the previously mentioned co-condensed aromatic or heteroaromatic rings in the carbon structure can be mono -substituted with a fluorine, chlorine or bromine atom, with alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxy-carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkanoyl , aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl group, or disubstituted with a fluorine or chlorine atom, with methyl, methoxy or hydroxy groups, as well as two methyl substituents, one to the other in position 1,2, can be interconnected with methylene or ethylene bridge, and in the given case the NH group present in the imidazole ring can be substituted with an alkyl group having 1 to 6 carbon atoms, with a phenylalkyl group or with a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring connected via a carbon atom, whereby the phenyl residue condensed to the pyridine ring via two adjacent carbon atoms and the methylene group adjacent to the nitrogen atom in the pyrrolidine or piperidine ring can be replaced with a carbonyl group, imidazolidinedione group substituted in a given case with an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, a pyridazin-3-one or dihydro-pyridazin-3-one group which in position 2 can be substituted in a given case with an alkyl group substituted with a phenyl group, and additionally in the carbon structure with 1 or 2 alkyl groups, R7-NR6-CO-NR5 group in which R5 represents a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or a phenyl group, R6 represents a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a phenyl group, a phenylalkyl group or a cycloalkyl group with 5 to 7 carbon atoms, R7 represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms or one of the residues R5, R6 or R7 also represents a bicyclohexyl or biphenyl group or R6 and R7 together with the nitrogen atom located between them form an alkenylimino group with 4 to 6 straight chain carbon atoms or a morpholino group or R5 and R6 together form an alkylene group having 2 to 4 carbon atoms, 1H,3H-quinazolin-2,4-dion-3-yl or pentamethylene-oxazolin-2-yl group or R1 represents a hydrogen atom or in position 5, 6 or 7 a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, a fluoromethyl, difluoromethyl or trifluoromethyl group and R2 represents a five-membered heteroaromatic ring connected via a carbon atom or an imino group, containing an imino group, an oxygen or sulfur atom or an imino group and an oxygen, sulfur or nitrogen atom, or a six-membered heteroaromatic ring connected via a carbon atom containing 1 or 2 nitrogen atoms, whereby the previously mentioned heteroaromatic rings can be substituted in the carbon structure with an alkyl group having 1 to 6 carbon atoms or with a phenylalkyl group and are connected to six-membered heteroaromatic rings via two adjacent carbon atoms of the n-propylene or n-butylene group, or are attached both to five-membered and also to six-membered heteroaromatic rings via two adjacent carbon atoms of the 1,3-butadiene group or via an imino group and an adjacent carbon atom of an n-butylene or 1,3-butadiene group, and in the annealed pyridine ring thus formed, the methine group is replaced with a nitrogen atom, and vinylene sk upin in the 3,4 position to the nitrogen atom of the resulting pyridine ring, with a sulfur atom, or in the resulting annealed phenyl ring, one or two methine groups are substituted with nitrogen atoms, whereby additionally the previously mentioned co-condensed aromatic or heteroaromatic rings in the carbon structure can be monosubstituted with a fluorine, chlorine or bromine atom, with alkyl, alkoxy, hydroxy, phenyl, nitro, animo, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl, fluoromethyl, di-fluoromethyl, trifluoromethyl, an alkanoyl, amino-sulfonyl, alkylaminosulfonyl or dialkylamino-sulfonyl group, or they can be substituted with a fluorine or chlorine atom, with methyl, methoxy or hydroxy groups, as well as two methyl substituents, one to the other in position 1, 2, can be mutually linked by a methylenex or ethylene bridge, and in a given case an NH group ina, present in the imidazole ring, can be substituted with an alkyl group having 1 to 6 carbon atoms, with a phenylalkyl group or with a cyclo-alkyl group, whereby if (i) R1 represents a hydrogen atom, R3 is an n-propyl group and R4 is a carboxy group, R2 in position 6 cannot represent 3-methyl-imidazo[4,5-b]-2-yl or 3-n-hexyl- imidazo[4,5-b]pyridin-2-yl group or if (ii) R1 represents a hydrogen atom, R3 is an n-propyl or b-butyl group and R4 is a 1H-tetrazolyl group, R2 in position 5 or 6 cannot represent a benzoxazol-2-yl group, or if (iii) R1 represents a hydrogen atom, R3 is an n-propyl group and R4 is a carboxy group, R2 in position 5 or 6 cannot represent a 1-methylbenzimidazol-2-yl group or in position 6 cannot represent 1-n-butylbenzimidazole -2-yl, 1,5-dimethylbenzimidazol-2-yl or 1-methyl-5-trifluoromethylbenzimidazol-2-yl group or if (iv) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy or 1H-tetrazoline group, R2 in position 6 cannot represent a 1-methylbenzimidazol-2-yl group, or if (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group, or a pyrrolidine, piperidine or pyridine ring connected via a carbon atom, whereby the phenyl residue condensed on the pyridine ring via two adjacent carbon atoms and the methylene group adjacent to the nitrogen atom in the pyrrolidine or piperidine ring can be replaced with a carbonyl group, R3 represents a hydrogen atom, an alkyl group with 1 to 5 carbon atoms in which the methylene group can be substituted with an oxygen atom or a sulfur atom or with a cycloalkyl group having 3 to 5 carbon atoms and R4 represents a carboxy, cyano, 1H-tetrazolyl or 1-triphenylmethyltetrazolyl group, an alkoxy carbonyl group with a total of 2 to 5 carbon atoms, an alkanesulfonyl-aminocarbonyl, arylsulfonylaminocarbonyl or trifluoro-methanesulfonylaminocarbonyl group, their 1-, 3-isomeric mixtures and their salts with inorganic or organic acids or bases, wherein, unless stated otherwise, the previously mentioned alkanoyl, alkyl or alkoxy part may contain 1 to 3 carbon atoms, as well as the previously mentioned cyclo-alkyl part may contain 3 to 7 carbon atoms each. 2. Benzimidazoli opće formule I prema zahtjevu 1, naznačeni time, da R1 u položaju 4 predstavlja atom fluora, klora ili broma, alkilnu skupinu s 1 do 3 ugljikova atoma, cikloalkilnu, fluormetilnu, difluormetilnu ili trifluor-metilnu skupinu i R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetrahidro-benzimidazolilnom skupinom, acilamino skupinu u kojoj acilni ostatak predstavlja alkanoilnu skupinu s 2 do 7 ugljikova atoma, u datom slučaju supstituiranu na atomu dušika s alkilnom skupinom koja ima 1 do 5 ugljikovih atoma, alkoksikarbonilnu skupinu s ukupno 2 do 4 ugljikova atoma, alkilsulfonilnu skupinu s 1 do 3 ugljikova atoma ili benzensulfonilnu skupinu, ftalimino ili homoftalimino, pri čemu je karbonilna skupina u ftalimino skupini nadomještena s metilenskom skupinom, kao što također metilenska skupina u homoftalimino skupini može biti supstituirana s jednom ili dvije alkilne skupine, peteročlanu, šesteročlanu ili sedmeročlanu alkilimino ili alkilenimino skupina, u datom slučaju supstituiranu s jednom ili dvije alkilne skupine ili s tetrametilenskom ili pentametilenskom skupinom, u kojoj metilenska skupina može biti nadomještena s karbonilnom ili sulfonilnom skupinom, imino skupinu glutarne kiseline, u kojoj je n-propilenska skupina perfluorirana, koja može biti supstituirana s jednom ili dvije alkilne skupine ili s tetrametilenskom ili pentametilenskom skupinom, imido skupinu maleinske kiseline, u datom slučaju mono- ili disupstituirana s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, amidino skupina supstituirana u datom slučaju s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 4 ugljikova atoma, benzimidazol-2-ilnu skupina koja je u datom slučaju supstituirana u položaju 1 s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili s cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, imidazo[2,5-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatakdokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina u pirolidinskom prstenu ili peperidinskom prstenu, koja je susjedna dušikovom atomu, mogu biti nadomješteni s karbonilnom skupinom, imidazolilnu skupinu, vezanu preko ugljikovog atoma, u datom slučaju u položaju 1 supstituiranu s 1 do 3 ugljikova atoma ili s benzilnom skupinom, koja dodatno može biti supstituirana u ugljikovoj strukturi s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, imidazolidinsku skupina u datom slučaju supstituiranu s alkilnom, fenilalkilnom, tetrametilenskom, penta-metilenskom ili heksametilenskom skupinom, piridazin-3-on ili dihidro-piridazin-on koji u položaju 2 može biti supstituiran s metilnom ili benzilnom skupinom, R7-NR6-CO-NR5 skupinu u kojoj R5 predstavlja vodikov atom, alkilnu skupinu s 1 do 5 ugljikovih atoma, cikloalkilnu ili benzilnu skupinu, R6 predstavlja vodikov atom, alkilnu skupinu s 1 do 6 ugljikovih atoma, alilnu, cikloheksilnu, benzilnu ili fenilnu skupinu, R7 predstavlja vodikov atom ili alkilnu skupinu s 1 do 3 ugljikovih atoma ili R6 i R7 zajedno s atomom dušika, koji se nalazi između njih, tvore alkenilimino skupinu sa 4 do 6 ugljikovih atoma ravnog lanca ili morfolino skupinu ili R5 i R6 zajedno tvore alkilensku skupinu koja ima 2 do 4 ugljikova atoma, ili R1 predstavlja vodikov atom ili u položaju 5, 6 ili 7 atom fluora, klora ili broma, alkilnu skupinu s 1 do 4 ugljikova atoma ili trifluormetilnu skupinu i R2 predstavlja benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili sa cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, imidazo[2,5-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo-[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina, koja je susjedna dušikovom atomu u pirolidinskom prstenu ili peperidinskom prstenu, mogu biti nadomješteni s karbonilnom skupinom, ili u datom slučaju u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma ili imidazolilnu skupinu, vezanu preko ugljikovog atoma, supstituiranu s benzilnom skupinom, koja dodatno u ugljikovoj strukturi može biti supstituirana s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, pri čemu ako (v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, R3 predstavlja alkilnu skupinu s 1 do 5 ugljikovih atoma ili cikloalkilnu skupinu koja ima 3 do 5 ugljikova atoma i R4 predstavlja karboksi ili 1H-tetrazolilnu skupinu, njihove 1-, 3-izomerne smjese kao također i njihove soli, osobito za farmaceutsku upotrebu njihove fiziološki podnošljive soli s anorganskim ili organskim kiselinama ili bazana, pri čemu ako nije navedeno drugačije, pri tome spomenuti alkanoilni, alkilni ili alkoksi dio može sadržavati uvijek 1 do 3 ugljikova atoma kao također pri tome spomenuti cikloalkilni dio može sadržati uvijek po 3 do 7 ugljikovih atoma.2. Benzimidazoles of the general formula I according to claim 1, characterized in that R1 in position 4 represents a fluorine, chlorine or bromine atom, an alkyl group with 1 to 3 carbon atoms, a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and R2 represents an alkoxy group with 3 to 5 carbon atoms which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms which is substituted in position 2, 3, 4 or 5 with a benzimidazyl group or tetrahydro - benzimidazolyl group, an acylamino group in which the acyl residue represents an alkanoyl group with 2 to 7 carbon atoms, in a given case substituted on the nitrogen atom with an alkyl group having 1 to 5 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, an alkylsulfonyl group with 1 to 3 carbon atoms or a benzenesulfonyl group, phthalimino or homophthalimino, wherein the carbonyl group in the phthalimino group is replaced by a methylene group, as well as the methylene group in the homophthalimino group can be substituted with one or two alkyl groups, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group, in a given case substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, in which the methylene group can be replaced by a carbonyl or sulfonyl group, the imino group of glutaric acid, in which the n-propylene group is perfluorinated, which can be substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different, an amidino group substituted in a given case with one or two alkyl groups, each of which has 1 to 4 carbon atoms, a benzimidazol-2-yl group, which in a given case is substituted in position 1 with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group, imidazo[2,5-b]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]pyrimidin-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, imidazo[4,5-c]-pyridin-2 -yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo[4,5-d]pyridazin-2- il group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue condensed to the pyridine ring via two adjacent carbon atoms and the methylene group in the pyrrolidine ring or peperidine ring, which is adjacent to the nitrogen atom, can be replaced with a carbonyl group, an imidazolyl group, attached via a carbon atom, in a given case substituted in position 1 with 1 to 3 carbon atoms or with a benzyl group, which can additionally be substituted in the carbon structure with an alkyl group having 1 to 3 carbon atoms, an imidazolidine group optionally substituted with an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, pyridazin-3-one or dihydro-pyridazin-one which in position 2 can be substituted with a methyl or benzyl group, R7-NR6-CO-NR5 group in which R5 represents a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, a cycloalkyl or benzyl group, R6 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms or R6 and R7 together with the nitrogen atom located between them form an alkenylimino group with 4 to 6 straight chain carbon atoms or a morpholino group or R5 and R6 together form an alkylene group having 2 to 4 carbon atoms, or R1 represents a hydrogen atom or in position 5, 6 or 7 a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms or a trifluoromethyl group and R2 represents a benzimidazol-2-yl group in a given case substituted in position 1 with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group, imidazo[2,5-b]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]pyrimidin-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, imidazo[4,5-c]-pyridin-2 -yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo[4,5-d]pyridazin- 2-yl group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue condensed to the pyridine ring via two adjacent carbon atoms and the methylene group, which is adjacent to the nitrogen atom in the pyrrolidine ring or peperidine ring, can be replaced with a carbonyl group, or in a given case in position 1 with an alkyl group having 1 to 3 carbon atoms or an imidazolyl group, attached via a carbon atom, substituted with a benzyl group, which can additionally be substituted in the carbon structure with an alkyl by a group having 1 to 3 carbon atoms, whereby if (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group, R3 represents an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms and R4 represents a carboxy or 1H-tetrazolyl group, their 1-, 3-isomeric mixtures as well as their salts, especially for pharmaceutical use of their physiologically tolerable salts with inorganic or organic acids or bases, wherein, unless stated otherwise, the mentioned alkanoyl, alkyl or alkoxy part can always contain 1 to 3 carbon atoms, and also the mentioned cycloalkyl part can always contain 3 to 7 carbon atoms. 3. Benzimidazoli opće formule I prema zahtjevu 1, naznačeni time, da R1 u položaju 4 predstavlja atom klora, alkilnu skupinu s 1 do 3 ugljikova atoma ili trifluormetilnu skupinu i R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benzimidazililnom skupinom ili tetra-hidrobenzimidazolilnom skupinom, alkanoilamino skupinu s 2 do 5 ugljikovih atoma u alkanoilnom dijelu ili N-benzensulfonilmetilamino skupinu, ftalimino ili homoftalimino, pri čemu karbonilna skupina u ftalimino skupini može biti nadomještena s metilenskom skupinom, peteročlanu, šesteročlanu ili sedmeročlanu alkilimino ili alkilenimino skupinu u kojoj je metilenska skupina nadomještena s karbonilnom ili sulfonilnom skupinom, imino skupinu glutarne kiseline, u kojoj n-propilenska skupina može biti supstituirana s jednom ili dvije alkilne skupina ili s tetrametilenskom ili pentametilenskom skupinom, imido skupinu maleinske kiseline, u datom slučaju mono- ili disupstituiranu s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, benzimidazol-2-ilnu skupinu supstituiranu u datom slučaju s jednom alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili sa cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimid-azolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, imidazo-[2,1-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]-pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo-[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo-[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu je fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina, koja je susjedna dušikovom atomu u pirolidinskom prstenu ili peperidinskom prstenu, mogu biti naomješteni s karbonilnom skupinom, imidazol-4-ilnu skupinu supstituiranu u položaju 4 s 1 alkilnom skupinom koja ima 1 do 3 ugljikova atoma ili s benzilnom skupinom, koja dodatno u ugljikovoj strukturi može biti supstituirana s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, piridazin-3-on ili dihidro-piridazin-on koji u položaju 2 može biti supstituiran s metilnom ili benzilnom skupinom, R7-NR6-CO-NR5 skupinu u kojoj R5 predstavlja vodikov atom, alkilnu skupinu s 1 do 5 ugljikovih atoma, cikloalkilnu ili benzilnu skupinu, R6 predstavlja vodikov atom, alkilnu skupinu koja ima 1 do 6 ugljikovih atoma, alilnu, cikloheksilnu, benzilnu ili fenilnu skupinu, R7 predstavlja vodikov atom ili alkilnu skupinu koja ima 1 do 3 ugljikova atoma ili R6 i R7 zajedno s atomom dušika, koji se nalazi između njih, tvore alkenilimino skupinu sa 4 do 6 ugljikovih atoma ravnog lanca ili morfolino skupinu ili R5 i R6 zajedno tvore alkilensku skupinu koja ima 2 do 4 ugljikova atoma, ili R1 predstavlja vodikov atom ili u položaju 5, 6 ili 7 alkilnu skupinu s 1 do 4 ugljikova atoma ili trifluor-metilnu skupinu i R2 predstavlja benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 6 ugljikovih atoma ili sa cikloalkilnom skupinom, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, metilnom ili trifluormetilnom skupinom, imidazo[2,1-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo-[1,2-a]pirimidin-2-il, imidazo[4,5-b]piridin-2-il, imidazo[4,5-c]-piridin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]-pirazin-2-il, imidazo[1,2-b]piridazin-2-il, imidazo[4,5-c]-piridin-2-il, purin-8-il, imidazo[4,5-b]-pirazin-2-il, imidazo[4,5-c]piridazin-2-il, ili imidazo-[4,5-d]piridazin-2-il skupinu, preko ugljikovog atoma vezan pirolidinski, piperidinski ili piridinski prsten, pri čemu fenilni ostatak dokondenziran na piridinski prsten preko dvaju susjednih ugljikovih atoma i metilenska skupina, koja je susjedna dušikovom atomu u pirolidinskom prstenu ili peperidinskom prstenu, mogu biti nadomješteni s karbonilnom skupinom, ili u datom slučaju u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, ili imidazol-4-ilnu skupinu supstituiranu s benzilnom skupinom, koja dodatno u ugljikovoj strukturi može biti supstituirana s alkilnom skupinom s 1 do 3 ugljikova atoma, pri čemu ako (v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benzimidazol-2-ilnu skupinu, R3 predstavlja alkilnu skupinu s 1 do 5 ugljikovih atoma ili cikloalkilnu skupinu koja ima 3 do 5 ugljikovih atoma i R4 predstavlja karboksi ili 1H-tetrazolilnu skupinu, njihove 1-, 3-izomerne smjese kao također i njihove soli s anorganskim ili organskim kiselinama ili bazana.3. Benzimidazoles of the general formula I according to claim 1, characterized in that R1 in position 4 represents a chlorine atom, an alkyl group with 1 to 3 carbon atoms or a trifluoromethyl group and R2 represents an alkoxy group with 3 to 5 carbon atoms which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms which is substituted in position 2, 3, 4 or 5 with a benzimidazyl group or tetra -hydrobenzimidazolyl group, an alkanoylamino group with 2 to 5 carbon atoms in the alkanoyl part or an N-benzenesulfonylmethylamino group, phthalimino or homophthalimino, whereby the carbonyl group in the phthalimino group can be replaced with a methylene group, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group in which the methylene group is replaced by a carbonyl or sulfonyl group, the imino group of glutaric acid, in which the n-propylene group can be substituted with one or two alkyl groups or with a tetramethylene or pentamethylene group, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different, a benzimidazol-2-yl group substituted in a given case with one alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group , imidazo-[2,1-b]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]-pyrimidin-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, imidazo[4,5-c] -pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo-[4,5- d]pyridazin-2-yl group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue is condensed to the pyridine ring via two adjacent carbon atoms and a methylene group, which is adjacent to the nitrogen atom in the pyrrolidine ring or peperidine ring, can be equipped with a carbonyl group, an imidazol-4-yl group substituted in position 4 with 1 alkyl group having 1 to 3 carbon atoms or with a benzyl group, which can additionally be substituted in the carbon structure with an alkyl group having 1 to 3 carbon atoms, pyridazin-3-one or dihydro-pyridazin-one which in position 2 can be substituted with a methyl or benzyl group, R7-NR6-CO-NR5 group in which R5 represents a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, a cycloalkyl or benzyl group, R6 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms or R6 and R7 together with the nitrogen atom located between them form an alkenylimino group with 4 to 6 straight chain carbon atoms or a morpholino group or R5 and R6 together form an alkylene group having 2 to 4 carbon atoms, or R1 represents a hydrogen atom or in position 5, 6 or 7 an alkyl group with 1 to 4 carbon atoms or a trifluoromethyl group and R2 represents a benzimidazol-2-yl group in a given case substituted in position 1 with an alkyl group having 1 to 6 carbon atoms or with a cycloalkyl group, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can be additionally substituted with a fluorine atom, methyl or trifluoromethyl group, imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine -2-yl, imidazo-[1,2-a]pyrimidin-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, imidazo[4,5-c] -pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, or imidazo-[4,5- d]pyridazin-2-yl group, a pyrrolidine, piperidine or pyridine ring attached via a carbon atom, whereby the phenyl residue is condensed to the pyridine ring via two adjacent carbon atoms and a methylene group, which is adjacent to the nitrogen atom in pyrrole diene ring or peperidine ring, can be substituted with a carbonyl group, or in a given case in position 1 with an alkyl group having 1 to 3 carbon atoms, or an imidazol-4-yl group substituted with a benzyl group, which additionally in the carbon structure can be substituted with an alkyl group with 1 to 3 carbon atoms, where if (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group, R3 represents an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms and R4 represents a carboxy or 1H-tetrazolyl group, their 1-, 3-isomeric mixtures as well as their salts with inorganic or organic acids or bases. 4. Benzimidazoli opće formule I prema zahtjevu 1, naznačeni time, da R1 u položaju 4 predstavlja metilnu skupinu ili atom klora i R2 predstavlja alkoksi skupinu s 3 do 5 ugljikovih atoma koja je u položaju 3, 4 ili 5 supstituirana s imidazolilnom skupinom, alkoksi skupinom s 2 do 5 ugljikovih atoma, koja je u položaju 2, 3, 4 ili 5 supstituirana s benziimidazililnom skupinom ili tetrahidrobenzimidazolilnom skupinom, alkanoilamino skupinu s 2 do 5 ugljikovih atoma u alkanoilnom dijelu ili N-benzensulfonilmetilamino skupinu, ftalimino ili homoftalimino, pri čemu karbonilna skupina u ftalimino skupini može biti nadomještena s metilenskom skupinom, peteročlana, šesteročlana ili sedmeročlana alkilimino ili alkilenimino skupina u kojoj je metilenska skupina nadomještena s karbonilnom ili sulfonilnom skupinom, imido skupina maleinske kiseline, u datom slučaju mono- ili disupstituirana s alkilnom ili fenilnom skupinom, pri čemu supstituenti mogu biti jednaki ili različiti, benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu s jednom alkilnom skupinom koja ima 1 do 3 ugljikovih atoma, pri čemu fenilna jezgra jedne od prethodno spomenutih benzimidazolnih skupina može dodatno biti supstituirana s atomom fluora, imidazo[2,5-b]tiazol-6-il, imidazo[1,2-a]piridin-2-il, 5,6,7,8-tetrahidro-imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il ili imidazo[1,2-b]tiazol-6-il skupinu, imidazol-4-ilnu skupinu supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, piridazin-3-on ili dihidro-piridazin-on skupinu koja u položaju 2 može biti supstituirana s metilnom ili benzilnom skupinom, ili R1 predstavlja vodikov atom ili u položaju 5, 6 ili metilnu skupinu i R2 predstavlja benzimidazol-2-ilnu skupinu u datom slučaju supstituiranu u položaju 1 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, koja u fenilnoj jezgri može biti dodatno supstituirana s atomom fluora, imidazol-4-ilnu skupinu ili imidazo[1,2-a]piridin-2-ilnu skupinu, pri čemu ako (v) R1 predstavlja vodikov atom, R3 je n-butilna skupina i R4 je karboksi skupina, R2 u položaju 6 ne može predstavljati benziimidazol-2-ilnu skupinu, R3 predstavlja alkilnu skupinu s 1 do 5 ugljikovih atoma ili cikloalkilnu skupinu koja ima 3 do 5 ugljikova atoma i R4 predstavlja karboksi ili 1H-tetrazolilnu skupinu, njihove 1-, 3-izomerne smjese kao također i njihove soli, s anorganskim ili organskim kiselinama ili bazana.4. Benzimidazoles of the general formula I according to claim 1, characterized in that R1 in position 4 represents a methyl group or a chlorine atom and R2 represents an alkoxy group with 3 to 5 carbon atoms which is substituted in position 3, 4 or 5 with an imidazolyl group, an alkoxy group with 2 to 5 carbon atoms which is substituted in position 2, 3, 4 or 5 with a benzimidazilyl group or a tetrahydrobenzimidazolyl group group, an alkanoylamino group with 2 to 5 carbon atoms in the alkanoyl part or an N-benzenesulfonylmethylamino group, phthalimino or homophthalimino, whereby the carbonyl group in the phthalimino group can be replaced with a methylene group, a five-membered, six-membered or seven-membered alkylimino or alkyleneimino group in which the methylene group is replaced by a carbonyl or sulfonyl group, the imido group of maleic acid, in a given case mono- or disubstituted with an alkyl or phenyl group, whereby the substituents may be the same or different, a benzimidazol-2-yl group in a given case substituted with one alkyl group having 1 to 3 carbon atoms, whereby the phenyl nucleus of one of the aforementioned benzimidazole groups can additionally be substituted with a fluorine atom, imidazo[2,5-b]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]pyrimidin-2-yl or imidazo[1,2-b]thiazol-6-yl group, an imidazol-4-yl group substituted in position 1 with an alkyl group having 1 to 3 carbon atoms, pyridazin-3-one or dihydro-pyridazin-one group which can be substituted in position 2 with a methyl or benzyl group, or R1 represents a hydrogen atom or in position 5, 6 or a methyl group i R2 represents a benzimidazol-2-yl group in a given case substituted in position 1 with an alkyl group having 1 to 3 carbon atoms, which in the phenyl nucleus can be additionally substituted with a fluorine atom, an imidazol-4-yl group or an imidazo[1,2 -a]pyridin-2-yl group, where if (v) R1 represents a hydrogen atom, R3 is an n-butyl group and R4 is a carboxy group, R2 in position 6 cannot represent a benzimidazol-2-yl group, R3 represents an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms and R4 represents a carboxy or 1H-tetrazolyl group, their 1-, 3-isomeric mixtures as well as their salts, with inorganic or organic acids or bases. 5. Benzimidazoli opće formule I prema zahtjevu 1, naznačeni time, da su: (a) 4’-[[2-n-propil-4-metil-6-(1-metilbenzimidazol-2-il)- benzimidazol-1-il]metil]bifenil-2-karboksilna kiselina, (b) 4’-[[2-n-propil-4-metil-6-(1-metilbenzimidazol-2-il)- benzimidazol-1-il]-metil]-2-(1H-tetrazol-5-il)-bifenil, (c) 4’-[[2-n-propil-4-metil-6-(1-okso-izoindolin-2-il)- benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, (d) 4’-[[2-n-propil-4-metil-6-(butansultam-1-il)-benz- imidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, (e) 4’-[[2-n-butil-6-(2,3-iminodimetilmaleinska kiselina)-4- metil-benzimidazol-1-il]metil]bifenil-2-karboksilnakiselina, (f) 4’-[[2-n-butil-6-(izopropilkarbonilamino)-4-metil-benz-imidazol-1-il]metil]bifenil-2-karboksilna kiselina, (g) 4’-[[2-n-butil-4-metil-6-(morfolinokarbonilamino)-benz-imidazol-1-il]metil]bifenil-2-karboksilna kiselina, (h) 4’-[[2-n-butil-6-(cikloheksilaminokarbonilamino)-4-metil-benzimidazol-1-il]metil]bifenil-2-karboksilnakiselina, (i) 4’-[(2-ciklopropil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, (j) 4’-[(2-n-propil-4-metil-6-(1-metil-5-fluor-benz-imidazol-2-il)-benzimidazol-1-il]-metil]-bifenil-2-karboksilna kiselina, (k) 4’-[(2-n-propil-4-metil-6-(imidazo[1,2-a]pirimidin-2-il)benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)-bifenil, (l) 4’-[(2-n-propil-4-metil-6-(4,5,6,7-tetrahidro-imidazo-[1,2-a]pirimidin-2-il)benzimidazol-1-il)metil]-2-bifenil-2-karboksilna kiselina, (m) 4’-[(2-n-propil-4-metil-6-(4,5,6,7-tetrahidro-imidazo-[1,2-a]piridin-2-il)benzimidazol-1-il)metil]-2-(1H-tetrazol-5-il)bifenil, (n) 4’-[(2-n-propil-4-klor-6-(1-metil-benzimidazol-1-il)-benzimidazol-1-il]-2-(1H-tetrazol-5-il)bifenil, (o) 4’-[(2-n-propil-4-metil-6-(imidazo[1,2-b]tiazol-6-il)-benzimidazol-1-il)-metil]-2-bifenil-2-karboksilna kiselina, (p) 4’-[[2-etil-4-metil-6-(butansultam-1-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, (q) 4’-[[2-n-butil-4-metil-6-(1-metilbenzimidazol-2-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, (r) 4’-[[2-n-propil-6-(imidazo[1,2-a]piridin-2-il)-benz-imidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, (s) 4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]piridin-2-il)-benzimidazol-1-il]-metil]bifenil-2-karboksilna kiselina, (t) 4’-[[2-n-propil-4-metil-6-(imidazo[1,2-a]piridin-2-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil, (u) 4’-[[2-n-propil-4-metil-6-(imidazo[2,1-b]tiazol-6-il)-benzimidazol-1-il]metil]-2-(1H-tetrazol-5-il)bifenil i (v) 4’-[[2-n-propil-4-metil-6-(1-metil-6-fluor-benzimidazol-2-il)benzimidazol-1-il)metil]bifenil-2-karboksilna kiselina, i njihove 1-, 3-izomerne smjese i njihove soli, s anorganskim ili organskim kiselinama ili bazana.5. Benzimidazoles of the general formula I according to claim 1, characterized in that they are: (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-(1H-tetrazol-5-yl )-biphenyl, (c) 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5- yl)-biphenyl, (d) 4'-[[2-n-propyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl) -biphenyl, (e) 4'-[[2-n-butyl-6-(2,3-iminodimethylmaleic acid)-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid, (f) 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benz-imidazol-1-yl]methyl]biphenyl-2-carboxylic acid, (g) 4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benz-imidazol-1-yl]methyl]biphenyl-2-carboxylic acid, (h) 4'-[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid, (i) 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, (j) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzi-imidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl- 2-carboxylic acid, (k) 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)benzimidazol-1-yl]methyl]-2-(1H-tetrazole -5-yl)-biphenyl, (l) 4'-[(2-n-propyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo-[1,2-a]pyrimidin-2-yl)benzimidazol-1- yl)methyl]-2-biphenyl-2-carboxylic acid, (m) 4'-[(2-n-propyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)benzimidazol-1- yl)methyl]-2-(1H-tetrazol-5-yl)biphenyl, (n) 4'-[(2-n-propyl-4-chloro-6-(1-methyl-benzimidazol-1-yl)-benzimidazol-1-yl]-2-(1H-tetrazol-5-yl) biphenyl, (o) 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-b]thiazol-6-yl)-benzimidazol-1-yl)-methyl]-2-biphenyl- 2-carboxylic acid, (p) 4'-[[2-ethyl-4-methyl-6-(butansultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl, (q) 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl) biphenyl, (r) 4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benz-imidazol-1-yl]methyl]-2-(1H-tetrazol- 5-yl)biphenyl, (s) 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid, (t) 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]methyl]-2-(1H- tetrazol-5-yl)biphenyl, (u) 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]methyl]-2-(1H- tetrazol-5-yl)biphenyl and (v) 4'-[[2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid, and their 1-, 3-isomeric mixtures and their salts, with inorganic or organic acids or bases. 6. Fiziološki podnošljive soli, naznačene time, da sadrže spojeve prema barem jednom od zahtjeva 1 do 5 s anorganskim ili organskim kiselinama ili bazana.6. Physiologically tolerable salts, characterized in that they contain compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases. 7. Lijekovi, naznačeni time, da pored u datom slučaju jednog ili više inertnih nosača i/ili sredstava za razređenje sadrže spoj prema barem jednom od zahtjeva 1 do 5 ili fiziološki podnošljivu sol prema zahtjevu 6.7. Medicines, characterized by the fact that, in addition to one or more inert carriers and/or diluting agents, they contain a compound according to at least one of claims 1 to 5 or a physiologically tolerable salt according to claim 6. 8. Upotreba spojeva prema barem jednom od zahtjeva 1 do 6, naznačena time, da se oni koriste za pripravu lijeka s učinkom antagonista angiotenzina.8. Use of compounds according to at least one of claims 1 to 6, characterized in that they are used for the preparation of a drug with an angiotensin antagonist effect. 9. Postupak za pripravu lijeka prema zahtjevu 8, naznačen time, da se na nekemijski način pomiješa spoj prema barem jednom od zahtjeva 1 do 6 s jednim ili više inertnih nosača i/ili sredstava za razređenje.9. The method for the preparation of the medicine according to claim 8, characterized in that the compound according to at least one of claims 1 to 6 is mixed non-chemically with one or more inert carriers and/or diluting agents. 10. Postupak za pripravu benzimidazola prema zahtjevima 1 do 6, naznačen time, da a) spoj opće formule [image] u kojoj R1 i R2 imaju značenje definirano u zahtjevima 1 do 5, jedan od ostataka X1 ili Y1 predstavlja skupinu opće formule [image] a drugi od ostataka X1 ili Y1 predstavlja skupinu opće formule [image] pri čemu R2 i R4 su definirani u zahtjevima 1 do 5, R8 predstavlja vodikov atom ili R3CO skupinu, pri čemu R3 je definiran kako je prethodno navedeno, Z1 i Z2, koji mogu biti jednaki ili različiti, u datom slučaju predstavljaju supstituirane amino, ili hidroksi ili merkapto skupine, supstituirane u datom slučaju s nižim alkilnim skupinama, ili Z1 i Z2 zajedno predstavljaju atom kisika ili sumpora, imino skupinu, supstituiranu u datom slučaju s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, alkilendioksi ili alkilenditio skupinu sa 2 ili 3 ugljikova atoma, pri čemu jedan od ostataka X1 ili Y2 mora predstavljati skupinu opće formule [image] ili [image] ciklizira se i u datom slučaju tako dobiven odgovarajući N-oksid se reducira ili b) benzimidazol opće formule [image] u kojoj R1 do R3 su definirani u zahtjevima 1 do 5, kemijski se pretvara s bifenilnim spojem opće formule [image] u kojoj R4 je definiran kao u zahtjevima 1 do 5, a Z3 predstavlja nukleofilnu polaznu skupinu, ili c) za pripravu spoja opće formule I, u kojoj R4 predstavlja karboksi skupinu, spoj opće formule [image] u kojoj R1 do R3 su definirani u zahtjevima 1 do 5, R4‘ predstavlja skupinu koju se hidrolizom, termolizom ili hidrogenolizom može prevesti u karboksi skupinu, prevede se u odgovarajući karboksi spoj, d) za pripravu spoja opće formule I u kojoj R4 predstavlja 1H-tetrazolilnu skupinu, odcijepi se zaštitni ostatak spoja opće formule [image] u kojoj R1, R2 i R3 su definirani u zahtjevima 1 do 5, a R4’’ predstavlja 1H-tetrazolilnu skupinu zaštićenu sa zaštitnim ostatkom u položaju 1 ili 3, ili e) za pripravu spoja opće formule I, u kojoj R4 predstavlja 1H-tetrazolilnu skupinu, spoj opće formule [image] u kojoj R1 do R3 su definirani u zahtjevima 1 do 5, kemijski se pretvori s dušikovodičnom kiselinom ili s njenim solima, ili f) za pripravu spojeva opće formule I, u kojoj R2 predstavlja jednu od skupina navedenih u zahtjevima 1 do 5, imidazo[1,2-a]piridin-2-il, imidazo[1,2-a]pirimidin-2-il, imidazo[1,2-c]pirimidin-2-il, imidazo[1,2-a]pirazin-2-il, imidazo[1,2-b]piridazin-2-il ili imidazo[2,1-b]tiazol-6-il, kemijski se pretvori sa spojem opće formule [image] u kojoj jedan od ostataka A, B, C ili D predstavlja metinsku skupinu ili dušikov atom i preostali od ostataka A, B, C i D predstavljaju metinske skupine, ili A i B predstavljaju metinske skupine, a -C=D-skupina predstavlja sumporni atom, R9 predstavlja vodikov atom, fluor, klor ili brom, alkilnu, alkoksi, hidroksi, fenilnu, nitro, amino, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksikarbonilnu, aminokarbonilnu, alkilaminokarbonilnu, dialkil aminokarbonilnu, trifluormetilnu, alkanoilnu, amino-sulfonilnu, alkilaminosulfonilnu ili dialkil aminosulfonilnu akupinu i R10 je atom vodika, fluora ili klora, metilna, metoksi ili hidroksi skupina, pri čemu u slučaju da R9 i R10 predstavljaju susjedne metilne skupine, one međusobno mogu biti povezane s metilenskom ili etilenskom skupinom, sa spojem opće formule [image] u kojoj R1, R3 i R4 su definirani kao u zahtjevima 1 do 5, Z predstavlja nukleofilnu polaznu skupinu, kao halogeni atom, npr. atom klora ili broma, g) za pripravu spoja opće formule I u kojoj R2 predstavlja jednu od gore spomenutih skupina: benzimidazol-2-il, imidazo[4,5-b]piridin-2-il, imidazo-[4,5-c]piridin-2-il, imidazo[4,5-b]pirazin-2-il, imidazo[4,5-c]piridazin-2-il, imidazo[4,5-d]piridazin-2-il ili purin-8-il, ciklizira se spoj opće formule [image] u kojoj nijedan, jedan ili dva od ostataka A1, B1, C1 ili D1 predstavljaju dušikov atom, a prestali od ostataka A1, B1, C1 ili D1 predstavljaju metinske skupine, R11 predstavlja atom vodika, fluora, klora ili broma, alkilnu, alkoksi, hidroksi, fenilnu, nitro, amino, alkilamino, dialkilamino, alkanoilamino, cijano, karboksi, alkoksikarbonilnu, amnokarbonilnu, alkilaminokarbonilnu, dialkilaminokarbonilnu, trifluormetilnu, alkanoilna, amino-sulfonilnu, alkilaminosulfonilnu ili dialkilaminosulfonilnu akupinu i R12 predstavlja atom vodika, fluora ili klora, metilnu, metoksi ili hidroksi skupinu, jedan od ostataka X2 ili Y2 predstavlja R13-NH skupinu, a drugi od ostataka X2 ili Y3 predstavlja skupinu opće formule [image] pri čemu su R1, R3 i R4 definirani kao ua zahtjevima 1 do 5, a jedan od ostataka R13 ili R14 predstavlja vodikov atom, dok drugi od ostataka R13 ili R14 predstavlja vodikov atom, alkilnu skupinu koja ima 1 do 6 ugljikovih atoma ili cikloalkilnu skupinu, Z5 i Z6, koji mogu biti jednaki ili različiti, predstavljaju u datom slučaju supstituirane amino skupine, ili u datom slučaju hidroksi ili merkapto skupine supstiruirane s nižim alkilnim skupinama, ili Z5 i Z6 zajedno predstavljaju atom kisika ili sumpora ili imino skupinu, u datom slučaju supstituiranu s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, alkilendioksi ili alkilenditio skupinu, od kojih svaka ima 2 ili 3 ugljikova atoma, i u datom slučaju, tako dobiveni N-oksid se reducira i zatim se tako dobiveni spoj, u datom slučaju, hidrolizira, h) za pripravu spojeva opće formule I u kojoj R2 predstavlja dihidropiridazin-3-on ili piridazin-3-on skupinu, koja u datom slučaju može biti supstituirana u položaju 2 s alkilnom skupinom koja ima 1 do 3 ugljikova atoma, supstituiranom s fenilnom skupinom, ili može biti supstituirana u ugljikovoj strukturi s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma, kemijski se pretvara kiselinu opće formule [image] u kojoj R1, R3 i R4 su definirani kao u zahtjevima 1 do 5, E predstavlja etilensku ili etenilensku skupinu, u datom slučaju supstituiranu s jednom ili dvije alkilne skupine od kojih svaka ima po 1 do 3 ugljikova atoma, ili njene kiselinske derivate sposobne za reakciju, kao njen ester, amid ili halogenid, s hidrazinom opće formule H2N-NHR15(XIII) u kojoj R15 predstavlja atom vodika ili u datom slučaju alkilnu skupinu, koja ima 1 do 3 ugljikova atoma, supstituiranu s fenilnom skupinom, i po potrebi između pretvorbi a) do h) zaštitni ostatak upotrijebljen za zaštitu reaktivnih skupina se odcijepi i/ili po želji, zatim se tako dobivenu 1-, 3-izomernu smjesu spoja opće formule I rastavlajnjem izomera rastavi na njegov 1- i 3-izomer ili se tako dobiven spoj opće formule I prevede u svoju sol, osobito u farmaceutski upotrebljivu i fiziološki podnošljivu sol s anorganskom ili organskom kiselinom ili bazom.10. Process for the preparation of benzimidazole according to claims 1 to 6, characterized in that a) a compound of the general formula [image] where R1 and R2 have the meaning defined in claims 1 to 5, one of the residues X1 or Y1 represents a group of the general formula [image] and the second of the residues X1 or Y1 represents a group of the general formula [image] whereby R2 and R4 are defined in claims 1 to 5, R8 represents a hydrogen atom or R3CO group, where R3 is defined as previously stated, Z1 and Z2, which may be the same or different, in a given case represent substituted amino, or hydroxy or mercapto groups, substituted in a given case with lower alkyl groups, or Z1 and Z2 together represent an oxygen or sulfur atom, an imino group, substituted in a given case with an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms, whereby one of the residues X1 or Y2 must represent a group of the general formula [image] or [image] is cyclized and in the given case the corresponding N-oxide thus obtained is reduced or b) benzimidazole of the general formula [image] where R1 to R3 are defined in claims 1 to 5, chemically converted with a biphenyl compound of the general formula [image] where R4 is defined as in claims 1 to 5, a Z3 represents a nucleophilic starting group, or c) for the preparation of a compound of the general formula I, in which R4 represents a carboxy group, a compound of the general formula [image] where R1 to R3 are defined in claims 1 to 5, R4' represents a group that can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, is translated into the corresponding carboxy compound, d) for the preparation of the compound of the general formula I in which R4 represents a 1H-tetrazolyl group, the protective residue of the compound of the general formula is cleaved off [image] where R1, R2 and R3 are defined in claims 1 to 5, a R4'' represents a 1H-tetrazolyl group protected with a protecting residue in position 1 or 3, or e) for the preparation of a compound of the general formula I, in which R4 represents a 1H-tetrazolyl group, a compound of the general formula [image] where R1 to R3 are defined in claims 1 to 5, chemically converted with nitric acid or its salts, or f) for the preparation of compounds of the general formula I, in which R2 represents one of the groups specified in claims 1 to 5, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl , imidazo[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, is chemically converted with a compound of the general formula [image] where one of the residues A, B, C or D represents a methine group or a nitrogen atom and the rest of the residues A, B, C and D represent methine groups, or A and B represent methine groups, and the -C=D-group represents a sulfur atom, R9 represents a hydrogen atom, fluorine, chlorine or bromine, alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkyl aminocarbonyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminosulfonyl or dialkyl aminosulfonyl acupine and R10 is a hydrogen, fluorine or chlorine atom, a methyl, methoxy or hydroxy group, where in case R9 and R10 represent adjacent methyl groups, they can be connected to each other with a methylene or ethylene group, with a compound of the general formula [image] where R1, R3 and R4 are defined as in claims 1 to 5, Z represents a nucleophilic starting group, such as a halogen atom, for example a chlorine or bromine atom, g) for the preparation of a compound of the general formula I in which R2 represents one of the above-mentioned groups: benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo-[4,5-c]pyridin-2-yl, 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, the compound of the general formula is cyclized [image] where none, one or two of the residues A1, B1, C1 or D1 represent a nitrogen atom, and the remainder of the residues A1, B1, C1 or D1 represent methine groups, R11 represents a hydrogen, fluorine, chlorine or bromine atom, alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl acupine and R12 represents a hydrogen, fluorine or chlorine atom, a methyl, methoxy or hydroxy group, one of the residues X2 or Y2 represents the R13-NH group, and the other of the residues X2 or Y3 represents a group of the general formula [image] wherein R1, R3 and R4 are defined as in claims 1 to 5, and one of the residues R13 or R14 represents a hydrogen atom, while the other of the residues R13 or R14 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group , Z5 and Z6, which may be the same or different, represent in a given case substituted amino groups, or in a given case hydroxy or mercapto groups substituted with lower alkyl groups, or Z5 and Z6 together represent an oxygen or sulfur atom or an imino group, in a given case substituted with an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or an alkylenedithio group, each having 2 or 3 carbon atoms, and in a given case, the resulting N -oxide is reduced and then the thus obtained compound, in the given case, is hydrolyzed, h) for the preparation of compounds of the general formula I in which R2 represents a dihydropyridazin-3-one or a pyridazin-3-one group, which in a given case can be substituted in position 2 with an alkyl group having 1 to 3 carbon atoms, substituted with a phenyl group , or it can be substituted in the carbon structure with one or two alkyl groups, each of which has 1 to 3 carbon atoms, it is chemically converted to an acid of the general formula [image] where R1, R3 and R4 are defined as in claims 1 to 5, E represents an ethylene or ethenylene group, in a given case substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms, or its acid derivatives capable of reacting, such as its ester, amide or halide, with hydrazine of the general formula H2N-NHR15(XIII) where R15 represents a hydrogen atom or, in a given case, an alkyl group, having 1 to 3 carbon atoms, substituted with a phenyl group, and if necessary between conversions a) to h) the protective residue used to protect reactive groups is cleaved off and/or if desired, then the thus obtained 1-, 3-isomer mixture of the compound of the general formula I is separated into its 1- and 3-isomers by resolving the isomers, or the thus obtained compound of the general formula I is converted into its salt, especially into a pharmaceutically usable and physiologically tolerable salt with inorganic or organic acid or base.
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DE4103492A DE4103492A1 (en) 1991-02-06 1991-02-06 New 1-(1,4-bi:phenyl-methyl) benzimidazole(s) as angiotensin II antagonists
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DE4137812A DE4137812A1 (en) 1991-02-06 1991-11-16 New 1-(1,4-bi:phenyl-methyl) benzimidazole(s) as angiotensin II antagonists
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