RU2104276C1 - Heterocyclic compounds, pharmaceutical composition showing antagonistic activity with respect to angiotensin-ii and a method of antagonization of angiotensin-ii in mammals - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: invention relates to new derivatives of benzimidazole. Product: 1-[[2'-(2,5-dihydro-5- -oxo-1,2,4-oxadiazole-3-yl)-biphenyl-4-yl] -methyl]-2-propylbe- -nzimidazole-7-carboxylic acid, yield is 90%, m. p. is 169-171 C, empirical formula is $$$. The synthesized compounds can be used in medicine, in part, in therapy and cardiology. EFFECT: improved method of synthesis. 29 cl, 1 tbl

Description

 The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds that are used for the synthesis of these compounds.

где R₁ может быть замещенным остатком углеводорода, возможно связанным через гетероатом; R₂ может быть остатком замещенного 5-7-членного гетероцикла, содержащего в качестве заместителя карбонильную группу, тиокарбонильную группу, возможен окисленный атом серы или группа, которую можно в них превратить; X - прямая связь "спейсер", содержащая два или менее атомов между циклами Y и W; W и Y независимо могут быть остатками замещенного ароматического углеводорода, возможно содержащего гетероатом или остаток замещенного гетероцикла; n = 1-2; a и b, входящие в состав гетероциклического состава, представляют собой разные один или два возможно замещенные атомы углерода или гетероатомы; c может быть замещенным атомом углерода или гетероатомом; и в группе формулы

заместители у соседних атомов вместе с двумя атомами цикла образуют 5-6-членный цикл, или их соль.In particular, the invention relates to compounds of the general formula

where R ₁ may be substituted by a hydrocarbon residue, optionally linked via a heteroatom; R ₂ may be a residue of a substituted 5-7 membered heterocycle containing a carbonyl group, a thiocarbonyl group as a substituent, an oxidized sulfur atom or a group that can be converted into them is possible; X is a direct spacer bond containing two or less atoms between Y and W cycles; W and Y independently may be residues of a substituted aromatic hydrocarbon, possibly containing a heteroatom or a residue of a substituted heterocycle; n is 1-2; a and b, which are part of the heterocyclic composition, are different one or two possibly substituted carbon atoms or heteroatoms; c may be substituted by a carbon atom or a heteroatom; and in the group of the formula

substituents at adjacent atoms together with two atoms of the cycle form a 5-6 membered ring, or their salt.

The chymosin-angiotensin system takes part in the homeostatic functioning of the body, controlling blood pressure, fluid volume, balance between electrolytes, etc., which are associated with the aldosterone system. The relationship between the chymosin-angiotensin system and high blood pressure was established in the production of angiotensin II (A II), converting enzyme inhibitors (ACE inhibitor), which leads to the production of angiotensin II, which has a strong vasoconstrictor effect. Since angiotensin II constricts a blood vessel, which leads to an increase in blood pressure through angiotensin II receptors acting on cell membranes, substances of the opposite effect, such as ACE inhibitors, can be used to treat hypertension, which is caused by angiotensin. It is known that a number of analogues of angiotensin II, such as salarasin, (Sar ¹ , Ile ⁸ ) A II and the like, have a possible activity opposite to that of angiotensin II. However, it is also known that peptide antagonists that are not prescribed orally do not have a prolonged effect, and when administered orally, they are ineffective (MA Ondetti, DW Cushman, Annual Reports in Medicinal Chemistry, 13, 82-91, 1978).

 On the other hand, to solve the problems associated with these peptide angiotensin II antagonists, studies have been conducted of non-peptide angiotensin II antagonists. Previously, imidazole derivatives having antitensin II antagonist activity have been described in Japanese Patent Applications S56 N 71073, 1981, S56 N 71074, 1981, S57 N 98270, 1982, S58 N 157768, 1983, US Pat. Nos. 4,350,040 and 4,340,598, etc. . More recently, improved imidazole derivatives have been described in EP 0253310, EP 0291969, EP 0324377, EP 403158, WO 9100277, Japanese application S63 N 23868, 1988 and Japanese application HI N 117876, 1989; derivatives of pyrrole, pyrazole and triazole are described in EP 0323841, EP 0409332 and Japanese application HI N 287071, 1989; benzimidazole derivatives are described in US patent 4880804, EP 0392317, EP 0399732, EP 0400835 and Japanese application NZ N 632264, 1991, azoinden derivatives in EP 0399731; pyrimidone derivatives - in EP 0407342; quinazolinone derivatives - in EP 0441766, as angiotensin II antagonists.

 However, in order to become useful for drug therapy, angiotensin II antagonists must have a strong long-term opposite effect of angiotensin II when taken orally. As is known from literature, strong antagonists have an acid group, for example tetrazole or carboxy, on the side of the biphenyl chain, a tetrazole group is particularly preferred, and a clinical test of compounds having a tetrazole group as antihypertensive agents is known (Y. Christen, B. Waeber, J. Nussberger, RJ Lee, PBMWM Timmermans, HR Brunner, Am. J. Hypertens, 4, 350 S, 1991). However, it is known that compounds containing the tetrazole cycle and azide compounds easily explode, which becomes a serious problem for their production on a large scale.

 The invention aims to obtain a new compound containing a heterocyclic residue, which can be substituted on a tetrazole or carboxyl group, and having a strong effect opposite to that of angiotensin II and antihypertensive effect when administered orally and which can be used as a useful therapeutic agent.

 The inventors believe that compounds that block the action of the chymosin-angiotensin system, which are clinically useful for the treatment of circulatory diseases, such as hypertension, heart disease (tachycardia, heart failure, myocardial infarction, etc.), cerebrovascular accident, nephritis , atherosclerosis, etc. must have potential activity opposite to the action of the angiotensin II receptor and have a strong long-term effect of antagonistic angiotensin II and peripheral arterial effect when administered orally. They conducted intensive studies of these compounds having the antagonistic effect of angiotensin II for a long time.

 As a result, it was found that the new heterocyclic compounds I have potential activity opposite to the action of the angiotensin II receptor, and also have a strong long-term effect, opposite to the action of angiotensin II and antihypertensive effects when administered orally.

где R₁ может быть остатком замещенного углеводорода, возможно связанным через гетероатом; R₂ может быть остатком замещенного 5-7-членного гетероцикла, содержащего в качестве заместителя карбонильную группу, тиокарбонильную группу, возможен окисленный атом серы или группа, которую можно в них превратить; X - прямая связь или спейсер, содержащий два или менее атомов между циклами I и W; W и Y независимо могут быть остатками замещенного ароматического углеводорода, возможно содержащего гетероатом или остаток замещенного гетероцикла; n = 1-2; a и b, входящие в состав гетероциклического остатка, представляют собой разные один или два возможно замещенные атомы углерода или гетероатомы; c может быть замещенным атомом углерода или гетероатомом; и в группе формулы

заместители у соседних атомов цикла возможно связаны друг с другом и с двумя другими атомами цикла образуют кольцо, или к его соли, более преимущественно соединение (2) формулы

где R₁ может быть остатком замещенного углеводорода, возможно связанным через гетероатом; R₂ может быть остатком замещенного 5-7-членного гетероцикла, содержащего в качестве заместителя карбонильную группу, тиокарбонильную группу, возможен окисленный атом серы или группа, которую в них можно превратить; X - прямая связь или спейсер, содержащий два или менее атомов между циклами Y и W; W и Y независимо могут быть остатками замещенного ароматического углеводорода, возможно содержащего гетероатом или остаток замещенного гетероцикла; n = 1-2; a и b, входящие в состав гетероциклического остатка, представляют собой разные один или два возможно замещенные атомы углерода или гетероатомы; c может быть замещенным атомом углерода или гетероатомом; и когда a может быть замещенным атомом углерода, R₁ и a возможно могут быть связаны друг с другом, образуя группу формулы

образуя цикл, или его соль или соединение (3) формулы

где R₁ может быть остатком замещенного углеводорода, возможно связанным через гетероатом; R₂ может быть остатком замещенного 5-7-членного гетероцикла, содержащего в качестве заместителя карбонильную группу, тиокарбонильную группу, возможен окисленный атом серы или группа, которую в них можно превратить; X - первая связь или "спейсер", содержащий два или менее атомов между циклами Y и W; W и Y независимо могут быть остатками замещенного ароматического углеводорода, возможно содержащего гетероатом или остаток замещенного гетероцикла; a и e, образующие гетероциклический остаток независимо один или два возможно замещенных углерода или гетероатома; d и f, образующие гетероциклический остаток, независимо один возможно замещенный углерод или гетероатом; b и c независимо один возможно замещенный углерод или атом азота; n = 1-2; когда a - возможно замещенный атом углерода, R₁ и a возможно могут быть связаны друг с другом, образуя группу формулы

образующую цикл, или его соль.More specifically, the invention relates to a compound of the formula

where R ₁ may be a substituted hydrocarbon residue, optionally linked via a heteroatom; R ₂ may be a residue of a substituted 5-7 membered heterocycle containing a carbonyl group, a thiocarbonyl group as a substituent, an oxidized sulfur atom or a group that can be converted into them is possible; X is a direct bond or spacer containing two or less atoms between cycles I and W; W and Y independently may be residues of a substituted aromatic hydrocarbon, possibly containing a heteroatom or a residue of a substituted heterocycle; n is 1-2; a and b, which are part of the heterocyclic radical, are different one or two possibly substituted carbon atoms or heteroatoms; c may be substituted by a carbon atom or a heteroatom; and in the group of the formula

substituents at adjacent atoms of the ring are possibly bonded to each other and form a ring or its salt with two other atoms of the ring, more preferably compound (2) of the formula

where R ₁ may be a substituted hydrocarbon residue, optionally linked via a heteroatom; R ₂ may be a residue of a substituted 5-7 membered heterocycle containing a carbonyl group, a thiocarbonyl group as a substituent, an oxidized sulfur atom or a group that can be converted into them is possible; X is a direct bond or spacer containing two or less atoms between Y and W cycles; W and Y independently may be residues of a substituted aromatic hydrocarbon, possibly containing a heteroatom or a residue of a substituted heterocycle; n is 1-2; a and b, which are part of the heterocyclic radical, are different one or two possibly substituted carbon atoms or heteroatoms; c may be substituted by a carbon atom or a heteroatom; and when a may be substituted by a carbon atom, R ₁ and a may optionally be bonded to each other, forming a group of the formula

forming a cycle, or its salt or compound (3) of the formula

where R ₁ may be a substituted hydrocarbon residue, optionally linked via a heteroatom; R ₂ may be a residue of a substituted 5-7 membered heterocycle containing a carbonyl group, a thiocarbonyl group as a substituent, an oxidized sulfur atom or a group that can be converted into them is possible; X is the first bond or "spacer" containing two or less atoms between the cycles Y and W; W and Y independently may be residues of a substituted aromatic hydrocarbon, possibly containing a heteroatom or a residue of a substituted heterocycle; a and e forming a heterocyclic radical independently one or two possibly substituted carbon or heteroatoms; d and f forming a heterocyclic residue, independently one possibly substituted carbon or heteroatom; b and c independently one possibly substituted carbon or nitrogen atom; n is 1-2; when a is a possibly substituted carbon atom, R ₁ and a may possibly be bonded to each other, forming a group of the formula

forming a cycle, or its salt.

In the general formula I, examples of the hydrocarbon residue designated R ₁ may be alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl. Among them, preferred are alkyl, alkenyl and cycloalkyl. The hydrocarbon residue may be linked to the ring via a heteroatom or may in turn be a substituted hydrocarbon residue linked via a heteroatom.

The alkyl group depicted as R ₁ may be a straight or branched lower alkyl group containing 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso- pentyl, hexyl, heptyl or octyl.

The alkenyl group depicted as R ₁ may be a straight or branched lower alkenyl group containing 2-8 carbon atoms, for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.

The alkenyl group depicted as R ₁ may be a straight or branched lower alkynyl group containing 2-8 carbon atoms, for example ethynyl, 2-propyl, 2-butyl, 2-pentyl or 2-octyl.

The cycloalkyl group depicted as R ₁ may be a lower cycloalkyl group containing 3-6 hydrocarbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The aforementioned alkyl, alkenyl, alkyl or cycloalkyl group may be substituted, for example, by a hydroxyl group, an amino group, for example amino, N-lower (1-4C) alkylamino or N, N ¹ -di-lower (1-4C) alkylamino, halogen, lower (1-4C) alkoxy group or lower (1-4C) alkylthio group.

The aralkyl group depicted as R ₁ may be, for example, phenyl lower (1-4C) alkyl, such as benzyl or phenethyl, and the aryl group depicted as R ₁ may be, for example, phenyl.

 The aforementioned aralkyl or alkyl group may possibly have in its benzene ring, for example, halogen, for example F, CI or Br), a nitro, possibly substituted amino group, for example amino, N-lower (1-4C) alkyl amino, or N, N -di lower (1-4C) alkyl amino; lower (1-4C) alkoxy, for example methoxy, or ethoxy; lower (1-4C) alkylthio, for example methylthio or ethylthio, or lower (1-4C) alkyl, for example methyl or ethyl.

Among the above groups represented by R ₁ , substituted alkyl or alkenyl groups are possible, for example lower (1-5C) alkyl or lower (2-5C) alkenyl group optionally substituted with hydroxyl, amino, halogen or lower (1-4C) alkoxy group are preferred.

The aforementioned R ₁ group may be bonded via a heteroatom, for example nitrogen (N (R ₉ ) (R ₉ ) is hydrogen or lower (1-4C) alkyl), oxygen or sulfur (-S (O) _m - (m = 0 -2), etc.), among them there may be substituted alkyl or alkenyl bonded via a heteroatom, for example methylamino, ethylamino, propylamino, propenylamino, isopropylamino, allylamino, butylamino, isobutylamino, dimethylamino, methylethylamino, methoxy, ethoxy, propoxy, isopropoxy , propenyloxy, allyloxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-butenyloxy, 3-butenyloxy, isobutenyloxy, ne ntoxy, isopentoxy, hexyloxy, methyl, thio, ethylthio, propylthio, isopropylthio, allylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, 2-butenylthio, 3-butenylthio, isobutylthio, pentylthio, pentylthio, pentylthio ., preferred.

 Examples of a possibly substituted aromatic hydrocarbon or heterocyclic residues, possibly containing heteroatoms represented by Y and W, are aromatic hydrocarbon residues such as phenyl, 4- and 7-membered monocyclic and fused heterocyclic residues containing one or more N, S and O, for example, pyridyl, pyrimidinyl, pyradazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, benzofuranyl, isobenzofuranyl, indolisinyl, isondolyl, 3H-indolyl, indolyl, 1 zolil, Pirin, 4H-quinolizinyl, isoquinolyl, quinolyl, ftalizinil, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl and pteridinyl, preferably phenyl.

Кроме связи углерод-углерод, как это показано выше, группа, представленная R₂, может быть связана с возможно замещенным ароматическим углеводородным или гетероциклицеским остатком, возможно содержащим гетероатом, который представлен как Y в случае g = -NH- в вышеприведенной формуле через один из многих существующих атомов азота.The aforementioned aromatic hydrocarbon or heterocyclic residues, possibly containing a heteroatom, which are represented as Y, have a substituent depicted as R ₂ , examples of which are optionally substituted 5- and 7-membered, preferably 5- and 6-membered, monocyclic heterocyclic radicals containing one or more N, S and O atoms, preferably an N-containing heterocyclic residue having a hydrogen atom that can be protonated, or a group that can be converted into it. Groups represented by R ₂ :

In addition to the carbon-carbon bond, as shown above, the group represented by R ₂ may be linked to a possibly substituted aromatic hydrocarbon or heterocyclic residue, possibly containing a heteroatom, which is represented as Y in the case of g = —NH— in the above formula through one of many existing nitrogen atoms.

,
эту группу представляют

Примерами групп R₂, связанных через атом азота, являются

В вышеприведенной формуле g = CH₂-, -NR₉-, атом O или

; >=Z; >=Z' и >= Z", соответственно, обозначают карбонильную, тиокарбонильную группы или возможно окисленный атом серы, например S, S(O) и S(O₂), преимущественно карбонильная или тиокарбонильная группа, более предпочтительно карбонильная группа, m = 0,1 или 2 и R₉ обозначает атом водорода или возможно замещенный низший алкил.For example, when

,
this group is represented

Examples of R ₂ groups bonded through a nitrogen atom are

In the above formula, g = CH ₂ -, —NR ₉ -, an O atom, or

; > = Z; > = Z 'and> = Z ", respectively, denote a carbonyl, thiocarbonyl group or possibly an oxidized sulfur atom, for example S, S (O) and S (O ₂ ), preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group, m = 0.1 or 2 and R ₉ represents a hydrogen atom or optionally substituted lower alkyl.

где i = -O- или -S-, j >= O, >S или >S (O)_m, а m имеет то же самое значение, что и в формуле обозначенной выше. В том случае, когда Y, например, фенил, R₂ может иметь заместители в орто-, мета- или пара-положение, орто-положение предпочтительно.As R ₂ , groups such as an oxadiazole or thiazole ring containing an —NH or OH group as a proton donor and a carbonyl group, a thiocarbanyl group or a sulfinyl group as a proton acceptor at the same time are preferred. When the heterocyclic residue represented by R ₂ may form a fused ring due to the bonds of the substituents of the ring, preferably 5- and 6-membered heterocyclic residues, more preferably 5-membered rings. Among others, as R _{2, a} preferred group of the formula

where i = -O- or -S-, j> = O,> S or> S (O) _m , and m has the same meaning as in the formula indicated above. In the case where Y, for example, phenyl, R ₂ may have substituents in the ortho, meta or para position, the ortho position is preferred.

Когда Z = 0, g = 0,

гетероциклический остаток, представленный формулой

включает все вышеупомянутые a', b' и c'.When the aforementioned heterocyclic residue R ₂ can exist in tautomeric forms, as shown below, for example, in the form of three tautomers, a ', b' and c 'in

When Z = 0, g = 0,

heterocyclic residue represented by the formula

includes all of the above a ', b' and c '.

Примерами группы R₁₀, упомянутой выше, являются группы, представленные формулой CH(R₄)-OCOR₅, где R₄ - водород, прямая или разветвленная низшая C_1-6 алкильная группа, например метил, этил, н-пропил, изопропил, н-бутил, трет-бутил, н-пентил, изопентил или неопентил, C_2-6 прямая или разветвленная низшая алкенильная группа или C_3-8 циклоалкенильная группа, например циклопентил, циклогексил или циклогептил; R₅ - C_1-6 прямая или разветвленная низшая алкильная группа, например метил, этил, н-пропил, изопропил, н-бутил, изобутил, втор-бутил, трет-бутил, н-пентил, изопентил или неопентил, C_2-6 прямая или разветвленная низшая алкенильная группа, C_3-8 циклоалкильная группа, например циклопентил, циклогексил или циклогептил, C_1-3 низшая алкильная группа, замещенная циклоалкильной группой C_3-8, например циклопентил, циклогексил или циклогептил, или возможна замещенная арильная группа, такая, как фенил, например бензил, пара-хлорбензол, фенетил, циклопентилметил или циклогексилметил, C_2-3 низшая алкенильная группа, замещенная циклоалкилом C_3-8 или возможно замещенная арильная группа, такая, как фенил, например группа, имеющая алкенильный остаток, такая, как винил, например циннамил, пропенил, аллил или изопропенил, возможна замещенная арильная группа, такая, как фенил, например фенил, пара-толил или нафтил, C_1-6 прямая или разветвленная низшая алкоксигруппа, например метокси, этокси, н-пропокси, изопропокси, н-бутокси, изобутокси, втор-бутокси, трет-бутокси, н-пентилокси, изопентилокси или неопентилокси, C_2-8 прямая или разветвленная низшая алкенилоксигруппа, например аллилокси или изобутенилокси, C_3-8 циклоалкилокси группа, например циклопентенилокси, циклогексилокси или циклопентилокси, C_1-3 низшая алкоксигруппа, замещенная циклоалкилом C_3-8 , например циклопентил, циклогексил или циклогептил, или возможна замещенная арильная группа, такая, как фенил, например группа, имеющая алкокси остаток, такая, как метокси, этокси, н-пропокси или изопропокси, например бензилокси, фенетилокси, циклопентилметокси или циклогексилметилокси, C_2-3 низшая алкенилоксигруппа, замещенная циклоалкилом C_3-8, например циклопентил, циклогексил или циклогептил, или возможен замещенный арил, такой, как фенил, например группа, имеющая алкенилокси остаток, такой, как винилокси, например циннамилокси, пропенилокси, аллилокси или изопропенилокси, арилокси группа, включающая возможно замещенную феноксигруппу, например фенокси, пара-нитрофенокси или нафтилокси, и возможен замещенный алкил, например низший (C_1-4) алкил или ацил, например низший (C_2-5) алканоил, или возможен замещенный бензоил. Примерами R₁₀ являются метил, этил, пропил, трет-бутил, метоксиметил, трифенилметил, цианоэтил, ацетил, пропионил, пивалоилоксиметил, 1-(циклогексилоксикарбонилокси)этил, 5-метил-2-оксо-1,3-диоксолен-4-илметил, ацетоксиметил, пропионил-оксиметил, H-бутирилоксиметил, изобутирилоксиметил, 1-(этоксикарбонилокси)этил, 1-ацетилокси)этил, 1-(изобутирилокси)этил, циклогексилкарбонилоксиметил, бензилоксиметил, цианнамил и циклопентилкарбонилоксиметил. Такие группы могут иметь заместители, которые способны к легкому превращению в первоначальный гетероциклический остаток, представленный формулой

или химическим или биологическим путем, т.е. в физиологических условиях, например при реакции in vivo, такой, как окисление, восстановление или гидролиз, катализируемой энзимами in vivo, то, что называется пролекарством.And the aforementioned heterocyclic radical R ₂ may be substituted with a group R ₁₀

Examples of the R ₁₀ group mentioned above are those represented by the formula CH (R ₄ ) -OCOR ₅ , where R ₄ is hydrogen, a straight or branched lower C _1-6 alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, isopentyl or neopentyl, a C _2-6 straight or branched lower alkenyl group or a C _3-8 cycloalkenyl group, for example cyclopentyl, cyclohexyl or cycloheptyl; R ₅ is C _{1-6 a} straight or branched lower alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or neopentyl, C _{2- 6} straight or branched lower alkenyl group, C _3-8 cycloalkyl group, for example cyclopentyl, cyclohexyl or cycloheptyl, C _1-3 lower alkyl group substituted with C _3-8 cycloalkyl group, for example cyclopentyl, cyclohexyl or cycloheptyl, or optionally substituted aryl group such as phenyl, e.g. benzyl, para-chlorobenzene, phenethyl, cyclopentylmeth L or cyclohexylmethyl, C _2-3 lower alkenyl group substituted with C _3-8 cycloalkyl or optionally substituted aryl group such as phenyl, e.g. a group having alkenyl moiety such as vinyl, e.g. cinnamyl, propenyl, allyl or isopropenyl, a substituted aryl group is possible, such as phenyl, for example phenyl, para-tolyl or naphthyl, C _1-6 straight or branched lower alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy or neopentyl and, C _2-8 straight or branched lower alkenyloxy group such as allyloxy, or isobutenyloxy, C _3-8 cycloalkyloxy group such as cyclopentenyloxy, cyclopentyloxy or cyclohexyloxy, C _1-3 lower alkoxy group, a substituted cycloalkyl C _3-8, for example, cyclopentyl, cyclohexyl or cycloheptyl, or a possibly substituted aryl group, such as phenyl, for example a group having an alkoxy moiety, such as methoxy, ethoxy, n-propoxy or isopropoxy, for example benzyloxy, phenethyloxy, cyclopentylmethoxy or cyclohexylmethyloxy, C _2-3 lower an alkenyloxy group substituted with C _3-8 cycloalkyl, for example cyclopentyl, cyclohexyl or cycloheptyl, or optionally substituted aryl such as phenyl, for example a group having an alkenyloxy residue, such as vinyloxy, for example cinnamyloxy, propenyloxy, allyloxy or isopropenyloxy, aryloxy group, including a possibly substituted phenoxy group, for example phenoxy, para-nitrophenoxy or naphthyloxy, and optionally substituted alkyl, for example lower (C _1-4 ) alkyl or acyl, for example lower (C _2-5 ) alkanoyl, or substituted benzoyl is possible. Examples of R ₁₀ are methyl, ethyl, propyl, tert-butyl, methoxymethyl, triphenylmethyl, cyanoethyl, acetyl, propionyl, pivaloyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl , acetoxymethyl, propionyl-hydroxymethyl, H-butyryloxymethyl, isobutyryloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1-acetyloxy) ethyl, 1- (isobutyryloxy) ethyl, cyclohexylcarbonyloxymethyl, benzyloxymethyl, cyanamylcarbonylmethoxymethyl. Such groups may have substituents which are capable of being easily converted to the original heterocyclic residue represented by the formula

either chemically or biologically, i.e. under physiological conditions, for example, in an in vivo reaction such as oxidation, reduction or hydrolysis catalyzed by in vivo enzymes, what is called a prodrug.

Since the above tautomers of the heterocyclic residues (a ', b' and c ') and the heterocyclic residue (a'',b''andc'') substituted with R ₁₀ are included in the heterocyclic residues represented as R ₂ in According to the invention, tautomers and their substituted compounds of various heterocyclic residues described below are in fact included in the substituent R _{2 of the} invention. A substituent R ₂ may also have substituents different from the substituents represented by R ₁₀ that have been described previously, for example, a substituted alkyl group, for example methyl, and triphenylmethyl, halogen, for example F, CI and Br, nitro, cyano, lower C _{1 -4} alkoxy and a possibly substituted amino group, for example amino, methylamino and dimethylamino, and others.

An aromatic hydrocarbon residue and a heterocyclic residue, possibly containing one or more N, O or S atom, may have substituents such as halogen, for example F, Cl and Br, nitro, cyano, lower C _1-4 alkoxy, possibly substituted amino group, for example amino, methylamino and dimethylamino.

X shows that an adjacent W ring, for example a phenylene group, is bonded to a Y ring, for example a phenyl group, directly or via a “spacer” containing two or less atoms, a direct bond is preferred. The spacer can be any divalent chain in which a straight chain is made up of one or two atoms and it can have a side chain, for example lower C _1-4 alkylene, -CO-, -O-, -S-, -NH, -CO-, -NH-, -O-CH ₂ -, -S-CH ₂ -, and -CH = CH-.

 n is an integer equal to 1 or -2, preferably 1.

предпочтительны соединения, изображенные следующими формулами, например

Типичные примеры гетероциклических соединений представлены формулой

Оказалось, что R₁ имеет то же самое значение, что и в приведенных выше, и R используется вместо формулы

Примерами соединений формулы II, как соединений, приведенных формулой

являются все приведенные ниже, но ими не ограничивается все их возможные варианты

где h >CH₂, >=O, >=S, >-(O)_m, -NR₉- и -O- и m и R₉ означают то же самое, что и в формулах, приведенных выше или как соединения формулы

где A обозначает остаток возможно замещенного ароматического углеводорода, возможно содержащий гетероатом или гетероциклический остаток, преимущественно такой ароматический углеводородный остаток, как фенил; h и h¹ каждый означает CH₂, >=O, >=S, >S-(O)_m, -NR₉- и -O-, а m и R₉ имеют то же самое значение, что и в формулах, приведенных выше. Примерами этих соединений являются следующие соединения:
формула

может означать гетероциклический цикл и трициклические гетероциклические соединения

где R и h имеют те же значения, что и в формулах, приведенных выше, а R_1a обозначает возможно замещенный углеводородный остаток, или бициклические гетероциклические соединения

где R, b и c имеют то же значение, что и в формулах, приведенных выше, R_1a обозначает возможно замещенный углеводородный остаток, а h" обозначает -O- или -S-.Among the compounds designated R ₂ , W, X, Y, and n described above, preferred are those given in the following formulas:

preferred compounds depicted by the following formulas, for example

Typical examples of heterocyclic compounds are represented by the formula

It turned out that R ₁ has the same meaning as in the above, and R is used instead of the formula

Examples of compounds of formula II, as compounds of the formula

are all of the following, but they are not limited to all their possible options

where h> CH ₂ ,> = O,> = S,> - (O) _m , -NR ₉ - and -O- and m and R ₉ mean the same as in the formulas above or as compounds of the formula

where A denotes a residue of a possibly substituted aromatic hydrocarbon, possibly containing a heteroatom or heterocyclic residue, preferably an aromatic hydrocarbon residue such as phenyl; h and h ¹ each means CH ₂ ,> = O,> = S,> S- (O) _m , -NR ₉ - and -O-, and m and R ₉ have the same meaning as in the formulas, given above. Examples of these compounds are the following compounds:
formula

may mean a heterocyclic ring and tricyclic heterocyclic compounds

where R and h have the same meanings as in the formulas above, and R _1a denotes a possibly substituted hydrocarbon residue, or bicyclic heterocyclic compounds

where R, b and c have the same meaning as in the formulas above, R _1a is a possibly substituted hydrocarbon residue, and h "is —O— or —S—.

The heterocyclic compound of formula II may be substituted, in addition to the groups designated as R, R ₁ and R _1a , with a group R ₃ that can form an anion or a group that can be converted into it. The substituent R ₃ is in a cycle that is adjacent to the cycle to which R is bonded, preferably in a position adjacent to R (atom f position).

Examples of an R ₃ group capable of forming an anion or a group that can be converted into it are possibly etherified or amidated carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide (-NHSO ₂ CF ₃ ), phosphoric acid and sulfuric acid. These groups may possibly be protected by a possibly substituted lower alkyl group or an acyl group, and this may be any group that can form an anion under biological or physiological conditions, for example, in an in vivo reaction, such as oxidation, reduction, or hydrolysis with in vivo enzymes, or chemically.

Examples of optionally esterified or amidated carboxyl groups of R ₃ are groups represented by the formula —CO — D, where D is a carboxyl group, a possibly substituted amino group, for example, amino, N-lower (1-4C) alkylamino, and N, N ′ - di-lower (1-4C) alkylamino) or a possibly substituted alkoxy, for example a lower (1-6C) alkoxy group, in which the alkyl residue is optionally substituted by a hydroxyl group, possibly substituted by an amino, for example amino, dimethylamino, diethylamino, piperidino and morpholino, halogen, lower (1-6C) alkoxy, lower (1-6C) alk ltio dioksolenilnuyu or optionally substituted, for example 5-methyl-2-oxo-1,3-dioxolen-4-yl, or a group represented by formula -O-CH (R ₄₎ -OCOR ₅ wherein R ₄ is hydrogen, C _{1 -6} straight or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and neopentyl, C _2-6 straight or branched lower alkenyl group or C _{3- 8 a} cycloalkyl group, for example cyclopentyl, cyclohexyl and cycloheptyl, R ₅ represents a straight or branched lower C _1-6 alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n -butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl, C _2-6 straight or branched lower alkenyl group, C _3-8 cycloallyl group, for example cyclopentyl, cyclohexyl and cycloheptyl, C _1-3 lower alkyl a group substituted with C _3-8 cycloalkyl, for example cyclopentyl, cyclohexyl and cycloheptyl, or a possibly substituted aryl group such as phenyl, such as benzyl, para-chlorobenzene, phenethyl, cyclopentylmethyl, cyclohexylmethyl, C _2-3 lower alkenyl group, possibly substituted cycloalkyl C _3-8 or optionally substituted aryl group PPA, such as phenyl, for example cinnamyl, etc., having an alkenyl radical such as vinyl, propenyl, allyl and isopropenyl, an aryl group such as possibly substituted phenyl, for example phenyl, para-tolyl and naphthyl, C _{1 -6} straight or branched lower alkoxy group, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isopropoxy, sec-butoxy, n-pentyloxy, isopentyloxy and neopentoxy, C _2-8 straight or branched lower alkenyloxy group, for example allyloxy and isobutenyloxy, C _3-8 tsikloalliloksi group such as cyclopentyloxy, tzik ogeksiloksi and cycloheptyloxy, C _1-3 lower alkoxy group, a substituted cycloalkyl C _3-8, for example, cyclopentyl, cyclohexyl, cycloheptyl or an aryl group such as optionally substituted phenyl, e.g., benzyloxy, phenethyloxy, tsiklopentilmetiloksi and cyclohexylmethyloxy having alkoxy moiety such as methoxy, ethoxy, n-propoxy and isopropoxy, C _2-3 lower alkenyloxy substituted with C _3-8 cycloalkyl, e.g. cyclopentyl, cyclohexyl and cycloheptyl, or an aryl group such as possibly substituted phenyl, e.g. cinnamyloxy, having an alkenyloxy residue, such as vinyloxy, propenyloxy, allyloxy and isopropenyloxy; and an aryloxy group, such as a possibly substituted phenoxy group, for example phenoxy, p-nitrophenoxy and naphthoxy. An example of an R ₃ group can also be a group that can form an anion or a group that can be converted into it, for example tetrazole, trifluoromethanesulfonic acid amide, phosphoric acid or sulfuric acid, possibly protected by alkyl, for example lower C _1-4 alkyl or acyl, for example lower C _2-5 alkanoyl and possibly protected benzoyl.

Examples of R ₃ are —COOH and its salt, —COOMe, —COOEt, —COO tert-Bu, —COOPr, pivaloylmethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolene-4- ylmethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyrylmethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycycloxycarbonyloxy cyclohexyloxycyloxycarbonyloxy cyclohexyloxycyloxycyloxycarbonyloxycarbonyloxymex As such groups, you can use any groups that can form an anion, for example, COO ^- and its derivatives, or a group that can be converted into it under biological or physiological conditions, for example, in an in vivo reaction, such as oxidation, reduction or hydrolysis, catalyzed by enzymes in vivo, or chemically. R ₃ may be a carboxyl or a prodrug thereof. R ₃ may also be a group converted to an anion in vivo, for example, by biological or chemical means.

Compounds in which R ₃ is a group that can form an anion or a group that can be converted into it, for example, a possibly protected carboxyl group, a tetrazolyl group, a carboaldehyde group, a hydroxymethyl group, a cyano group, chemically, for example, oxidation, reduction or hydrolysis, are useful in as intermediates for synthesis.

Among the R ₃ groups, a carboxyl, esterified carboxyl, for example methyl ester, ethyl ether or an ester formed by linking a group represented by the above formula —O — CH (R ₄ ) —OCOR ₅ to a carbonyl and optionally protected tetrazolyl, carbaldehyde and hydroxymethyl are preferred .

The heterocyclic compound of the formula II can have, in addition to the groups R, R ₁ , R _1a and R ₃ , also substituents, such as halogen, for example F, Cl and Br, nitro, cyano, a possibly substituted amino group, for example amino, N- lower (1-4C) alkylamino, for example methylamino, N, N-di-lower (1-4C) alkylamino, for example dimethylamino, N-arylamino, for example phenylamino, acyclic amino for example morpholino, piperidino, piperazino and N-phenylpiperazino, groups represented by the formula UR ₆ , where U is a —O—, —S— or —CO— bond and R ₆ is hydrogen, an optionally substituted lower alkyl group for example, a lower (1-4C) alkyl group substituted with hydroxyl, a possibly substituted amino group, for example amino, halogen, nitro, cyano or a lower (1-4C) alkoxy group, groups represented by the formula - (CH ₂ ) ₁ -CO-D ¹ where D is hydrogen, a hydroxyl group, a possibly substituted amino group, for example amino, N-lower (1-4C) alkylamino and N, N-di-lower (1-4C) alkylamino) or a possibly substituted alkoxy group, for example lower (1 -6C) alkoxy group, the alkyl residue of which is possibly substituted by a hydroxyl group, possibly substituted by an amino, for example amino, di ethylamino, diethylamino, piperidino and morpholono, halogen, lower (1-6C) alkoxy, lower (1-6C) alkylthio or possibly substituted dioxolenyl, for example 5-methyl-2-oxo-1,3-dioxolen-4-yl, or groups represented by the formula OCH (R ₇ ) OCOR ₈ , where R ₇ is hydrogen, 1-6C straight or branched lower alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- pentyl, isopentyl and neopentyl, or 5-7C cycloalkyl (cyclopentyl, cyclohexyl and cycloheptyl), R ₈ is 1-6C straight or branched lower alkyl, for example methyl, ethyl, n-propyl, isopropyl l, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl, 2-8C lower alkenyl group, vinyl, propenyl, allyl, isopropenyl, 5-7C cycloalkyl group, for example cyclopentyl, cyclohexyl and cycloheptyl, 1-3C lower alkyl group substituted with 5-7C cycloalkyl group, for example cyclopentyl, cyclohexyl and cycloheptyl, or an aryl group such as phenyl, for example benzyl, para-chlorobenzene, phenethyl, cyclopentylmethyl and cyclohexylmethyl, 2-3C lower alkenyl a group substituted by cycloalkyl 5-7C, for example cyclope nyl, cyclohexyl and cycloheptyl, or an aryl group such as phenyl, for example cinnamyl having an alkenyl radical such as vinyl, propenyl, allyl or isopropenyl, a substituted aryl group such as phenyl, for example phenyl, para-tolyl and naphthyl is possible , 1-6C straight or branched lower alkoxy, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentyloxy and neopentyloxy, 2-8C straight or branched lower alkenyloxy group, for example allyloxy and isobutenyloxy, 5-7C cycloalkyloxy group, for example cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, 1-3C lower alkoxy group, substituted with 5-7C cycloalkyl, for example cyclopentyl, cyclohexyl and cycloheptyl or an aryl group, such as possibly substituted phenyl, for example benzyloxy, phenethyloxy, cyclopentylmethoxy and cyclohexylmethyloxy having an alkoxy radical such as methoxy, ethoxy, n-propoxy and isopropoxy, a 2-3C alkenyloxy group substituted with 5-7C cycloalkyl, for example cyclopentyl, cyclohexyl and cycloheptyl or optionally substituted aryl group PA, such as phenyl, for example cinnamoxy, having an alkenyloxy residue, such as vinyloxy, propenyloxy, allyloxy and isopropenyloxy, and an aryloxy group, such as possibly substituted phenyloxy, for example, phenoxy, para-nitrile phenoxy and naphthoxy, and l = 0 or 1, or tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfuric acid, each optionally protected by alkyl, for example lower (1-4C) alkyl, or acyl, for example lower (2-5C) alkanoyl and optionally substituted benzoyl.

 One or two of these substituents may be substituted simultaneously in the ring. When two or more of these substituents exist, the advantage is the case when two substituents are located on the atoms forming the ring, next to each other in a, b and in the groups forming the ring, they can be connected to each other so that form A 5- and 6-membered, possibly substituted aromatic hydrocarbon residue or heterocyclic residue, preferably an aromatic ring, such as phenyl, possibly containing a heteroatom, taken together with two ring-forming atoms. These cycles may be further substituted by any of the above substituents.

в качестве конденсированных гетероциклических циклов, обозначенных формулой

предпочтительны

где R₁, R и R₃ и h имеют то же самое значение, что и в формулах, приведенных ранее, а в качестве гетероциклического цикла формулы

предпочтительны

где R, R₁, R₃ и R₉ имеют те же значения, что и в формулах, приведенных ранее.Among the compounds of the formula

as condensed heterocyclic rings indicated by the formula

preferred

where R ₁ , R and R ₃ and h have the same meaning as in the formulas given above, and as a heterocyclic ring of the formula

preferred

where R, R ₁ , R ₃ and R ₉ have the same meanings as in the formulas given above.

где R₁ обозначает возможно замещенный низший (1-5C) алкил, который может быть связан через гетероатом, например O, N (H) и S, предпочтителен низший (2-4C) алкил; R₂ обозначает оксадиазол или тиадиазол, возможно защищенный возможно замещенным низшим (1-4C) алкилом, например алкил, трифенилметил, метоксиметил, ацетоксиметил, метоксикарбонилоксиметил, этоксикарбонилоксиметил, циклогексилоксикарбонилоксиэтил и пивалоилоксиметил, или ацил, например, низший (2-5C)алканоил или бензоил; R₃ обозначает группы формулы -CO-D", где D" обозначает гидроксильную группу, аминогруппу, N-низшую (1-4C) алкиламино, N, N'-ди-низшую (1-4C)алкиламино или низшую (1-4C)алкоксигруппу, алкильный остаток которой возможно замещен гидроксилом, аминогруппой, галогеном, низшей (2-6C) алканоилоксигруппой, например ацетилокси и пивалоилокси, 1-низший (1-6C) алкоксикарбонил, например метоксикарбонилокси, этоксикарбонилокси и циклогексилоксикарбонилокси, или низшая (1-4C) алкокси группа, или тетразолил, возможно защищенный низшей (1-4C) алкил или ацильной группой, например низшей (2-5C) алканоил или бензоил, и изображает гетероциклическое кольцо формулы

Среди соединений Ib предпочтительны соединения формулы

где R₁ обозначает возможно замещенный низший (1-5C) алкил, который может быть связан через гетероатом, например O, N (H) и S, предпочтительно низший (2-4C) алкил; R₂ обозначает оксадиазол или тиадиазол, возможно защищенный возможно замещенным низшим (1-4C) алкилом, например метил, трифенилметил, метоксиметил, ацетоксиметил, метоксикарбонилоксиметил, этоксикарбонилоксиметил, циклогексилоксикарбонилоксиэтил и пивалоилоксиметил, или ацил, например низший (2-5C) алканоил и бензоил; R₃ обозначает водород, группы формулы -CO- D", где D" обозначает гидроксильную группу, аминогруппу, N-низшую (1-4C) алкиламино, N, N-ди-низшую (1-4C) алкиламино или низшую (1-4C) алкоксигруппу, алкильный остаток которой возможно замещен гидроксильной группой, аминогруппой, галогеном, низшей (2-6C) алканоилокси, например ацетилокси и пивалоилокси, 1-низший (1-6C) алкоксикарбонил, например метоксикарбонилокси, этоксикарбонилокси и циклогексилоксикарбонилокси, или низший (1-4C) алкокси или тетразолил, возможно защищенный низший (1-4C) алкилом или ацилом, например низший (2-5C) алканоил или бензоил, и конденсированное гетероциклическое кольцо, представленное формулой

показывает

которое может быть далее замещено вышеупомянутыми заместителями в дополнении к группам R, R₁ и R₃. В качестве соединения формулы (Iб) предпочтительны соединения, имеющие бензимидальную, тиенимидазольную или имидазопиридиновую структуру, более предпочтительны бензимидазол или тиенимидазол. А соединения формулы (Iа) или (Iб), где R₂ - гидроксииминокарбоксамид (-C(NH₂)= N-OH), могут быть использованы в качестве интермедиатов для синтеза соединений формул (Iа) и (Iб), где R₂ - оксадиазол или триадиазол.Among compounds Ia, preferred are compounds of the formula

where R ₁ denotes a possibly substituted lower (1-5C) alkyl, which may be linked via a heteroatom, for example O, N (H) and S, lower (2-4C) alkyl is preferred; R ₂ is oxadiazole or thiadiazole, optionally protected with optionally substituted lower (1-4C) alkyl, for example alkyl, triphenylmethyl, methoxymethyl, acetoxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, cyclohexyloxycarbonyloxyethyl and pivaloyloxymethyl, or acyl (2), for example ; R ₃ is a group of the formula —CO — D ″ wherein D ″ is a hydroxyl group, an amino group, an N-lower (1-4C) alkylamino, N, N'-di-lower (1-4C) alkylamino or lower (1-4C ) an alkoxy group, the alkyl radical of which is optionally substituted with hydroxyl, amino, halogen, a lower (2-6C) alkanoyloxy group, for example acetyloxy and pivaloyloxy, 1-lower (1-6C) alkoxycarbonyl, for example methoxycarbonyloxy, ethoxycarbonyloxy and cyclohexyloxycarbonyloxy, 1 or ) an alkoxy group, or tetrazolyl, possibly protected by a lower (1-4C) alkyl or acyl group, for example a lower (2-5C) alkanoyl or benzoyl, and shows heterocyclic ring of the formula

Among compounds Ib, compounds of the formula are preferred

where R ₁ denotes a possibly substituted lower (1-5C) alkyl, which may be bonded via a heteroatom, for example O, N (H) and S, preferably lower (2-4C) alkyl; R ₂ is oxadiazole or thiadiazole, optionally protected with optionally substituted lower (1-4C) alkyl, for example methyl, triphenylmethyl, methoxymethyl, acetoxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, cyclohexyloxycarbonyloxyethyl and pivaloyloxymethyl, or acyl 5 and lower acylo; R ₃ is hydrogen, groups of the formula —CO — D ″ wherein D ″ is a hydroxyl group, an amino group, an N-lower (1-4C) alkylamino, N, N-di-lower (1-4C) alkylamino, or lower (1- 4C) an alkoxy group, the alkyl residue of which is optionally substituted by a hydroxyl group, an amino group, a halogen, lower (2-6C) alkanoyloxy, e.g. acetyloxy and pivaloyloxy, 1-lower (1-6C) alkoxycarbonyl, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and cyclohexyloxycarbonyloxy, or -4C) alkoxy or tetrazolyl, optionally protected with lower (1-4C) alkyl or acyl, e.g. higher (2-5C) alkanoyl or benzoyl, and a fused heterocyclic ring represented by the formula

shows

which may be further substituted by the above substituents in addition to the groups R, R ₁ and R ₃ . As a compound of formula (Ib), compounds having a benzimide, thienimidazole or imidazopyridine structure are preferred, benzimidazole or thienimidazole are more preferred. And the compounds of formula (Ia) or (Ib), where R ₂ is hydroxyiminocarboxamide (-C (NH ₂ ) = N-OH), can be used as intermediates for the synthesis of compounds of formulas (Ia) and (Ib), where R ₂ - oxadiazole or triadiazole.

 The method of obtaining.

 Compounds of the above formulas (I), (Ia) or (Ib) can be obtained, for example, by the methods described below.

где R₁, R₂, W, X, Y, a, b, c и n имеют тот же смысл, что и в формулах приведенных ранее; L обозначает атом галогена.Reaction (a)

where R ₁ , R ₂ , W, X, Y, a, b, c and n have the same meaning as in the formulas given above; L is a halogen atom.

 Reaction (a) above is an alkylation reaction using an alkylating agent in the presence of a base.

 Alkylation is carried out using approximately 1-3 mol of each of the bases and an alkylating agent per mol of compound (III), using dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone or methyl ethyl ketone as a solvent.

 Examples of bases are sodium hydride, potassium tert-butoxide, potassium carbonate and sodium carbonate.

 As the alkylating agent, for example, substituted halides, for example chlorides, bromides and iodides, and substituted sulfonic acid esters, for example paratoluene sulfonic acid ether, can be used.

Although the reaction conditions depend on the combination of a base and an alkylating agent, it is preferable to carry out the reaction at a temperature of from 0 ^° C. to room temperature for 1-10 hours.

 During alkylation, a mixture of regioisomers is obtained depending on the position of the N atom. Although the ratio of the components in the reaction products depends on the reaction conditions and on the substituents on the heterocyclic ring, these compounds can be easily obtained as pure products by conventional isolation and purification methods, for example, recrystallization and columnar chromatography.

где R₁, W, X, Y, a, b, c и n имеют тот же самый смысл, что и ранее.Reaction (b)

where R ₁ , W, X, Y, a, b, c and n have the same meaning as before.

 The aforementioned reaction (b) consists in preparing an oxadiazole compound (Ic) by converting the cyano compound (Ia) to an amido oxime (Ib) followed by ring closure.

 The reaction for the preparation of compound (Ib) is carried out using about 2-10 mol of hydroxylamine per 1 mol of compound (Ia), usually in an organic solvent.

 Examples of such solvents are amines, for example dimethylformamide and dimethylacetamide, sulfoxides, for example dimethyl sulfoxide, alcohols, for example methanol and ethanol, ethers, for example dioxane and tetrahydrofuran, and halogenated hydrocarbons, for example methylene chloride and chloroform.

When using hydroxylamine, the reaction is carried out in the presence of a suitable base, for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methanolate, sodium ethanolate and sodium hydride, in an almost equimolar ratio, using an inorganic acid salt, for example hydroxyl amine hydrochloride or hydroxyl amine sulfate or salts of an organic acid, for example, oxalite hydroxyl amine. Although the reaction conditions depend on the nature of the reagent and solvent, the reaction is preferably carried out at 50-100 ^° C. for 2-10 hours after the hydroxylamine hydrochloride is treated with sodium methoxide in dimethyl sulfoxide.

 The amidoxime (Ib) thus obtained is then treated with chloroformate, for example methyl ether and ethyl ether, in a conventional organic solvent, for example chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile and pyridine, in the presence of a base, for example triethylamine, pyridine, sodium carbonate and potassium carbonate , with the formation of o-acyl compounds.

Mostly the reaction is carried out at a ratio of ethyl formate and amidoxime (Ib) of 2-5 mol: 1 mol in the presence of 2-5 mol of triethylamine in tetrahydrofuran at a temperature of from 0 ^° C to room temperature for 1-5 hours.

 Upon heating the resulting o-acyl amidoxime in a conventional organic solvent, a cyclized compound (Ic) is formed.

 Examples of solvents are aromatic hydrocarbons, for example benzene, toluene and xylene, ethers, for example dioxane and tetrahydrufuran, and halogenated hydrocarbons, for example dichloroethane and chloroform. Preferably, oxadiazole is obtained by heating the o-acyl amido oxime under reflux for 1-3 hours in boiling xylene.

Реакция (с) состоит в получении оксадиазолона (Id) при гидролизе соединения (V), являющемся продуктом алкилирования соединения (III) алкилирующим агентом, полученным по реакции (m).Reaction (s)

Reaction (c) consists in the preparation of oxadiazolone (Id) by hydrolysis of compound (V), which is a product of the alkylation of compound (III) with an alkylating agent obtained by reaction (m).

 Examples of organic solvents are esters, for example dioxane and tetrahydrofuran, and alcohols, for example methanol and ethanol.

 As alkali, sodium hydroxide, potassium hydroxide and lithium hydroxide can be used.

Preferably, compound (V) is reacted at a temperature of from 0 ^° C. to room temperature for 0.5-2 hours with 2-10 mol 0.5-1 N. sodium hydroxide.

Реакция (d) состоит в получении соединения спирта (Ie) при восстановлении альдегида (If).Reaction (d)

Reaction (d) consists in obtaining the alcohol compound (Ie) by reducing the aldehyde (If).

 The reaction is carried out at a ratio of 2-5 mol of reducing agent per 1 mol of compound (Ie), usually in ether, for example tetrahydrofuran and dioxane, in alcohol, for example methanol and ethanol.

 As a reducing agent, metal complexes, for example sodium borohydride, can be used.

Preferably, the reaction is carried out by adding a reducing agent to a solution of compound (Ie) in methanol at a temperature of from 0 ^° C. to room temperature, followed by stirring for 0.5-2 hours.

где R₁, R₂, W, X, Y, a, b, c, d, e, f, n имеют тот же самый смысл, что и ранее; L обозначает атом галогена.Reaction (e)

where R ₁ , R ₂ , W, X, Y, a, b, c, d, e, f, n have the same meaning as before; L is a halogen atom.

 Reaction (e) consists in alkylation with an alkylating agent in the presence of a base.

 The reaction is carried out using 1-3 mol of the base and 1-3 mol of an alkylating agent per 1 mol of compound (III), usually in a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone or methyl ethyl ketone.

 Examples of bases are sodium hydride, potassium tert-butoxide, potassium carbonate and sodium carbonate.

 As the alkylating agent, substituted halides, for example chloride, bromide and iodide, and substituted sulfonic acid esters, for example para-toluenesulfonic acid ester, are used.

Although the reaction conditions depend on the combination of a base and an alkylating agent, it is preferable to carry out the reaction at a temperature of from 0 ^° C. to room temperature for 1-10 hours.

 By alkylation, a mixture of regioisomers is obtained, the composition of which depends on the position of the N atom, which undergoes alkylation. Although the ratio of the components in the reaction mixture depends on the reaction conditions and on the nature of the heterocycle substituent, compound (Ib) can be easily obtained in pure form by conventional isolation and purification techniques, for example, recrystallization and column chromatography.

где R₁, W, X, Y, a, b, c, d, e, f, n имеют тот же самый смысл, что и ранее.Reaction (f)

where R ₁ , W, X, Y, a, b, c, d, e, f, n have the same meaning as before.

Reaction (f) consists in producing oxadiazole (I ^b c) by converting the cyano compound (I ^b a) into an amidoxime (I ^b b) followed by crystallization.

The reaction of obtaining the compound (I ^b b) is carried out using 2-10 mol of hydroxylamine per 1 mol of compound (I ^b a) in a conventional organic solvent.

 Examples of the solvent are amides, for example dimethylforamide and dimethylacetamide, sulfoxides, for example dimethyl sulfoxide, alcohols, for example methanol and ethanol, ethers, for example dioxane and tetrahydrofuran, and halogenated hydrocarbons, for example methylene chloride and chloroform.

 When using hydroxylamine, the reaction is carried out in the presence of a suitable base, for example potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methanolate, sodium ethanolate and sodium hydride, in an almost equimolar ratio, using an inorganic acid salt, for example hydroxylamine hydrochloride or hydroxylamine sulfate, or salts of an organic acid, for example hydroxylamine oxalate.

Although the reaction conditions depend on the nature of the reagent and solvent, the reaction is preferably carried out at a temperature of 50-100 ^° C. for 2-10 hours, then the hydroxylamine hydrochloride is treated with sodium methoxide in dimethyl sulfoxide.

The amidoxime (I ^b b) thus obtained is treated with chloroformate, for example methyl ether and ethyl ether, in a conventional organic solvent, for example chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile and pyridine, in the presence of a base, for example triethylamine, pyridine, potassium carbonate and sodium carbonate to form an o-acyl compound.

Preferably, the reaction is carried out using 2-5 mol of ethyl chloroformate salts per 1 mol of amidoxime (I ^b b) in the presence of 2-5 mol of triethylamine in tetrahydrofuran at a temperature of from 0 ^° C. to room temperature for 1-5 hours.

 By heating the amidoxime thus obtained in a conventional organic solvent, the cyclized compound (Ic) is readily obtained.

 Examples of the solvent are aromatic hydrocarbons, for example benzene, toluene and xylene, ethers, for example dioxane and tetrahydrofuran, and halogenated hydrocarbons, for example dichloroethane and chloroform. Preferably heating o-acyl amidoxime for 1-3 hours in boiling xylene.

где R₁, R₂, R₉, W, Y, a, b, c, d, e, X и n имеют те же значения, что и в формулах, приведенных выше.Reaction (g)

where R ₁ , R ₂ , R ₉ , W, Y, a, b, c, d, e, X and n have the same meanings as in the formulas above.

Reaction (g) consists in producing a carboxylic acid (I ^b e) by alkaline hydrolysis of an ester (I ^b d).

This reaction is carried out at a ratio of alkali: compound (I ^b d) = (1-3): 1 (mol), usually in a solvent such as aqueous alcohol, for example methanol, ethanol and methyl cellulose.

 Examples of alkali are lithium hydroxide, sodium hydroxide and potassium hydroxide.

The reaction is carried out at a temperature from room temperature to about 100 ^° C. for 1-10 hours, preferably at a boiling point of the solvent for 3-5 hours

где R₁, R₂, W, X, Y, a, b, c, d, e и n имеют то же самое значение, что и в формулах, приведенных выше; R₁₁ обозначает возможно замещенную алкильную группу, аналогичную вышеупомянутой.Reaction (h)

where R ₁ , R ₂ , W, X, Y, a, b, c, d, e and n have the same meaning as in the formulas above; R ₁₁ denotes a possibly substituted alkyl group similar to the above.

 Reaction (h) is an alkylation reaction with an alkylating agent in the presence of a base.

Alkylation is carried out using 1-3 mol of base and 1-3 mol of alkylating agent per 1 mol of compound (I ^b e), usually in a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone and ethyl methyl ketone.

 Examples of the base are sodium hydride, potassium tert-butoxide, potassium carbonate and sodium carbonate.

 Examples of an alkylating agent are substituted halides, for example chloride, bromide and iodide, and substituted sulfonic acid esters, for example para-toluenesulfonic acid ester.

Although the reaction conditions depend on the nature of the base and the alkylating agent, it is preferable to carry out the reaction at a temperature of from 0 ^° C. to room temperature for 1-10 hours.

 When using chloride or bromide as the alkylating agent, it is preferable to add potassium iodide or sodium iodide to the reaction system to increase the reaction rate.

где R₁, W, X, Y, a, b, c, d, e, f и n имеют тот же самый смысл, что и в формулах, приведенных ранее.Reaction (i)

where R ₁ , W, X, Y, a, b, c, d, e, f and n have the same meaning as in the formulas given above.

Reaction (i) consists in the preparation of oxathiadiazole (I ^b g) by cyclization of the aldoxime (I ^b b) obtained by reaction (f). The compound (I ^b g) is obtained by cyclization of the aldoxime (I ^b b) with thionyl chloride in a conventional organic solvent, for example dichloromethane, chloroform, dioxane and tetrahydrofuran, in the presence of a base, for example pyridine and triethylamine.

It is preferable to carry out the reaction in the presence of 2-10 mol of thionyl chloride while cooling to 0-30 ^° C in the presence of 1-3 mol of pyridine per 1 mol of aldoxime (I ^b b), using dichloromethane as a solvent for 0.5-1 hours.

Вышеприведенная реакция (j) состоит в получении диамино производного (VIII), которое предполагает депротонирование нитропроизводного (VII), полученного по методике ЕП 434038 и ЕП 459136, обычным методом с последующей обработкой восстановителем, например каталитическим восстановлением с использованием никеля Ренея или палладия углерода, железо-хлористоводородной кислоты, хлорным железо-гидразином, хлоридом олова, борогидридом натрия-хлорид никеля и т.д. Затем диамино производное реагирует с карбоновой кислотой или ее производным, например эфиром, ангидридом или галоидангидридом, орто-эфиром, иминоэфиром или имино-тиоэфиром с образованием конденсированного цикла, превращая таким образом диамино производное (VIII) в соединение (IX).Reaction (j)

The above reaction (j) consists in the preparation of a diamino derivative (VIII), which involves the deprotonation of a nitro derivative (VII) obtained by the method of EP 434038 and EP 459136, by the usual method, followed by reduction with a reducing agent, for example, by catalytic reduction using Raney nickel or carbon palladium, iron hydrochloric acid, ferric chloride, tin chloride, sodium borohydride, nickel chloride, etc. Then, the diamino derivative reacts with a carboxylic acid or its derivative, for example, ether, anhydride or acid halide, ortho ether, iminoether or imino-thioether to form a condensed ring, thereby converting diamine derivative (VIII) into compound (IX).

Compound (IX) obtained in this way reacts with a 1-2-fold excess of triethyloxonium tetrafluoroborate in a halogenated hydrocarbon, for example methylene chloride or chloroform, at a temperature of from 0 ^° C to room temperature for 30 minutes to 2 hours to form imino ether (X) with good exit.

Then, the imino-ester (X) is reacted with a 1-2-fold excess of chloroformate, for example chloromethyl formate or chloroethyl formate, in a common organic solvent, for example benzene, toluene, methylene chloride, chloroform, dioxane or pyridine, in the presence of 1-2- a multiple excess of base, for example 2,4,6-trimethylpyridine, triethylamine, trimethylpyridine, methylpyridine, diethylaniline, etc. In particular, the reaction is carried out in toluene at 80-100 ^° C. for 1-3 hours to obtain N-alkoxycarbonyl (XI) in good yield.

The acylamino ester (XI) thus obtained reacts with a twofold excess of hydroxylamine hydrochloride and a base, for example sodium methoxide, sodium ethoxide, potassium carbonate, in alcohol, for example methanol or ethanol, to close the ring. This reaction is carried out mainly at a temperature of from about 50 ^o C to the boiling point of the solvent for 3-10 hours

.Reaction (k)

.

Reaction (k) involves the conversion of a nitrile derivative (XII) synthesized in accordance with the procedures of EP 434038 and EP 459136 into aldoxime (XIII), obtained by reaction of the same reaction above (b), followed by the reaction of aldoxime (XIII) with 1-2- a multiple excess of chloroformate, for example chloromethyl formate or chloroethyl formate, in the presence of 1-2 mol of a base, for example triethylamine or pyridine, in a common non-protic organic solvent, for example benzene, toluene, methylene chloride, chloroform, dioxane or pyridine, in the same way as in the above reaction (b). When carrying out the reaction in tetrahydrofuran, the reaction is carried out at a temperature of from 0 ^° C. to room temperature to obtain O-alkoxycarbonyl (XV) in good yield.

The resulting compound (XV) is reacted in a conventional organic solvent, for example methanol, ethanol, ethyl acetate, benzene, acetonitrile, acetone or N, N-dimethylformamide, in the presence of a base, for example potassium carbonate, sodium carbonate, sodium hydride, potassium tert-butoxide or 1 , 8-diazabicyclo [5, 4, 0] undecene-7 (DBU). This reaction is preferably carried out at a temperature from room temperature to the boiling point of the solvent for 1-20 hours. When the reaction is carried out in ethyl acetate using DBU at 50-80 ^° C. for 1-2 hours, the ring closure product can be obtained in good yield (I ^b c).

По реакции (l) получают тиадиазольное производное (I^bc), проводя замыкание кольца альдоксима (I^bb).Reaction (l)

By reaction (l), a thiadiazole derivative (I ^b c) is obtained by shorting the aldoxime ring (I ^b b).

This reaction is carried out in a conventional organic solvent, using 1 to 2 mol of 1,1'-thiocarbonyl diimidazole per 1 mol of compound (I ^b b).

 The solvent used is, for example, ethers, for example dioxane or tetrahydrofuran, or halogenated hydrocarbons, for example methylene chloride or chloroform.

This reaction is preferably carried out by dissolving the compound (I ^b b) in the aforementioned solvent, followed by adding a solution of 1,1'-thiocarbonyldiimidazole with stirring at a temperature from 0 ^° C. to room temperature.

 The reaction products obtained from reactions (a) to (l), as shown above, can be easily isolated by conventional isolation and purification methods, for example, column chromatography and recrystallization.

 In this case, these compounds (I) can be converted by conventional methods into salts with physiologically acceptable acids or bases. For example, these salts include salts with inorganic acids, such as hydrochloric acid, sulfuric acid and nitric acid, and, depending on the compounds, salts with organic acids, such as acetic acid, nitric acid, succinic acid and maleic acid, salts with alkali metals such as sodium and potassium; and salts with an alkaline earth metal such as calcium.

 The starting compounds can be prepared by the following methods.

где L имеет то же значение, что и раньше.Reaction (m)

where L has the same meaning as before.

 Compound (IVd) is obtained by reaction (m) by the conversion of compound (IVa) containing a cyano group to aldoxime (IVb) under the same conditions as during reaction (b), followed by cyclization of the aldoxime (IVb) to form oxadiazole (IVc) followed by halogenation of oxadiazole (IVc).

 The following example is a preferred embodiment of the reaction.

Aldoxime (IVb) is obtained from compound (IVa) in a manner analogous to that described in reaction (f), which consists in reacting 1-10 mol of trichloroacetic anhydride or hexachloroacetone with 1 mol of aldoxime (IVb) in accordance with the known method (F. Eloy, et. al., Helv. Chim. Acta, 49, 1430, 1966) to form oxadiazole (IVc), then (IVc) are halogenated with an agent such as N-bromosuccinimide or N-bromoacetamide (molar ratio from 1/1 to 1 / 1.5) in a halogenated hydrocarbon, for example carbon tetrachloride, at a temperature from 50 ^o C to the reflux temperature pa -solvent for 1-3 hours in the presence of a catalytic amount of an initiator such as benzoyl peroxide and azobisisobutyronitrile. This reaction can be carried out when exposed to light.

,
где R¹³ - произвольно замещенная алкильная группа, аналогичная вышеупомянутой R¹⁰, например трифенилметил, метоксиметил и цианоэтил, или трет-бутилдиметилсилильная группа и имеет то же значение, что и ранее.Reaction (n)

,
where R ¹³ is an optionally substituted alkyl group similar to the aforementioned R ¹⁰ , for example triphenylmethyl, methoxymethyl and cyanoethyl, or a tert-butyldimethylsilyl group and has the same meaning as before.

 The reaction (n) of producing oxadiazole (IVh) involves adding a carboxylic acid to the acyl isothiocyanate in an acceptable manner by reacting the latter with an alcohol to form carbonylthiocarbamate (IVf), methylating compound (IVf) to form carbonate (IVg), reacting compound (IVg) with hydroxylamine, followed by cyclization when heated.

In the reaction for producing carbonylthiocarbamate (IVf) from a carboxylic acid (IVe), the compound (IVe) is reacted with a halogenating agent, for example thionyl chloride (molar ratio 1: about 2-5) in a halogenated hydrocarbon, for example chloroform or methylene chloride, for 1-5 hours at a temperature of from 50 ^o C to the boiling point of the solvent used. The obtained acid chloride is reacted with 2-5 mol of thiocyanate, for example, sodium salt or potassium salt, in ether, for example, in dioxane and tetrahydrofuran, at a temperature of from 50 ^° C. to the boiling point of the solvent used, for 1-3 hours, with the formation isocyanate. It is preferable to subject the thus obtained isothiocyanate to heating together with 2-10 mol of alcohol, for example methanol and ethanol, at 50 ^° C. to the boiling point of the solvent used for 15 minutes to 1 hour.

In the reaction for producing iminothiocarbonate (IVg) from compound (IVf), it is preferable to react compound (IVf) with methyl iodide (molar ratio 1: (1-2)) in an organic solvent, for example methanol, ethanol, dimethylformamide (DMF) and acetonitrile, in the presence of 1-2 mol, in relation to 1 mol (IVf) of the base, for example NaOMe, Na ₂ CO ₃ and K ₂ CO ₃ , at a temperature of from room temperature to 50 ^o C for 10-24 hours

When carrying out the reaction for producing oxadiazole (IVh) from compound (IVg), it is preferable to react (IVg) with hydroxyamine (molar ratio 1: about 1-2) in alcohol, for example methanol or ethanol, at a temperature of from room temperature to 50 ^° C. for about 10-20 hours, followed by heating the reaction mixture in an organic solvent such as toluene and benzene, in the presence of about a catalytic amount of acid such as p-toluenesulfonic acid, at a temperature from 50 ^o C to the reflux temperature of the solution is ator for 1-3 hours.

When carrying out the reaction for producing dimethylated compound (IVi) from compound (IVh), it is preferable to subject an excess of pyridinium chloride and (IVh) to melting in a nitrogen atmosphere at a temperature of about 150-160 ^° C. for about 30 minutes to 1 hour.

When carrying out the reaction for preparing compound (IVj) from compound (Vj), it is preferable to react compound (IVi) with an alkylating agent, for example triphenylmethyl chloride, methoxymethyl chloride and cyanoethyl chloride (molar ratio 1: about 1-2) in an organic solvent, for example chloroform, methylene chloride , dioxane, tetrahydrofuran and pyridine, in the presence of 1-2 mol of a base, for example potassium carbonate, sodium carbonate, triethylamine and pyridine, at a temperature of from 0 ^o C to room temperature for 1-3 hours

 The reaction for preparing compound (IVk) by halogenating compound (IVj) can be carried out in the same way as the reaction for producing compound (IVd) from compound (IVc) according to reaction (m).

где R¹³ и L имеют те же самые значения, что и раньше.Reaction (o)

where R ¹³ and L have the same meanings as before.

 Reaction (o) involves the conversion of carboxylic acid (IVe) to semicarbazide (IVm) via hydrazide (IVl) in an acceptable manner, then dehydrocyclization (IVm) to form oxadiazole (IVn) in a further conversion (IVn) leads to a halogen-containing compound (IVp).

When carrying out the reaction for producing hydrazide (IVl) from carboxylic acid (IVe), (IVe) it reacts with approximately 2-5 mol of a halogenating agent, for example oxalyl chloride and thionyl chloride, in an organic solvent, for example tetrahydrofuran, chloroform and methylene chloride, at a temperature from room temperature to boiling the solvent used for 1-20 hours. In this case, it is preferable to add a catalytic amount of dimethylformamide to accelerate the reaction. The resulting acid halide is reacted with about 2-5 mol of hydrazine hydrate in an organic solvent, for example tetrahydrofuran and dioxane, at a temperature of from room temperature to 50 ^° C. for 1-10 hours to form compound (IVl). When carrying out the reaction for the preparation of semicarbazide (IVm) from hydrazide (IVl), it is preferable to react (IVe) with approximately 2-5 mol of isocyanate, for example, sodium or potassium salt, in an aqueous solution in the presence of an acid, for example, hydrochloric or sulfuric, in an amount equivalent to the amount of isocyanate used, at a temperature of from 0 ^o C to room for 1-5 hours

 When carrying out the reaction for the preparation of oxadiazole (IVn) from semicarbazide (IVm), it is preferable to heat (IVm) in an organic solvent, for example benzene and xylene, at a boiling point of the solvent for 5-20 hours.

 When carrying out the reaction for producing the halogen-containing compound (IVp) from oxadiazole (IVn), it is preferable to carry out it by a method similar to that described for reaction (n).

Реакция (p) получения амида (IVq) проводится по существу тем же способом, что и при проведении реакции (o).Reaction (p)

The amide (IVq) reaction (p) is carried out essentially in the same manner as in the reaction (o).

Carboxylic acid (IVe) is reacted with about 2-5 mol of a halogenating agent, for example oxalyl chloride or thionyl chloride, in an organic solvent, for example tetrahydrofuran, chloroform or methylene chloride, at room temperature to the boiling point of the solvent used for about 1-20 hours It is preferred to accelerate this reaction by adding catalytic amounts of dimethylformamide. The resulting acid halide is preferably reacted with an excess of aqueous ammonium hydroxide in an organic solvent, for example tetrahydrofuran or dioxane, at a temperature of from 0 ^° C. to room temperature for about 1-10 hours with a good yield of amide derivative (IVq).

 The reaction for producing a halogenated derivative (IVr) from the obtained amide derivative (IVq) is preferably carried out essentially in the same manner as in the case of reaction (m) or (n).

 Compounds (I) and their salts are less toxic, are more effective inhibitors against vasoconstriction and the hypertensive effect of angiotensin II, contribute to the hypotensive effect in animals, especially warm-blooded animals, for example, humans, dogs, rabbits and rats, and therefore they are useful as therapeutic not only in the case of hypertension, but also in the case of diseases of the circulatory system, such as impaired cardiac activity, cardiac hypertrophy, heart failure, heart attack or similar disorders TWA, cerebral hemorrhage and nephropathy. Compound (I) also has CNS activity for the treatment of Alzheimer's disease and senile dementia and has the properties of a tranquilizer and antidepressant.

 When used as a therapeutic agent, especially in the case noted above, compound (I) and its salts can be administered orally, non-orally, by inhalation, rectally or topically as pharmaceutical compositions or forms, for example, powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions or solutions, including at least one of the varieties of the compounds of this invention, in pure form or in admixture with pharmaceutically acceptable carriers, adjuvants, excipients and / or and thinners.

 Pharmaceutical compositions may be formulated in accordance with conventional operations. In this specification, the term “non-oral” includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or instillation. Injectable preparations, for example sterile injectable aqueous or oily suspensions, may be prepared by a method known in the art using a suitable dispersant, wetting or dispersing agent. Injections can be in the form of, for example, a solution or suspension, which can be obtained with a non-toxic diluent used non-orally, for example in the form of an aqueous solution, or with a solvent suitable for sterile injection. Examples of excipients or acceptable solvents used include water, Ringer's solution and isotonic aqueous saline. Further, sterile fixed oil can usually be used as a solvent or suspending agent. Any non-volatile oil or fatty acid may be used for this purpose, including natural, synthetic or artificial fatty oil or fatty acid, or synthetic or artificial mono-, di- or triglycerides.

 Rectal suppositories can be prepared by mixing the drug with an acceptable non-irritating carrier, such as coconut oil and polyethylene glycol, which is in the solid state at ordinary temperature, in the liquid state at intestinal temperature and melts in the rectum with the release of the drug.

 As a solid form for oral administration, powders, granules, tablets, pills and capsules can be used, as noted above. In such forms, the examples of which are given above, the active component of the compound can be mixed with at least one additive, for example, sucrose, lactose, cellulose sugar, mannitol, malt sugar, dextrin, starch, agar, alginate, chitin, chitosan, pectin, resin tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or artificial polymer or glyceride. These forms may contain further additives, for example, an inactive diluent, a lubricant, such as magnesium stearate, a preservative disintegrant, a binder, a thickener, a buffer, a sweetener, a flavoring, and a flavoring agent. Tablets and pills may be coated. Examples of liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and a solution that may contain an inactive diluent, for example water, which is commonly used in the art.

 The dose for each patient is prescribed depending on his age, weight, general health, gender, interval between doses, method of administration, speed of elimination, combination of drugs and the course of diseases that are being treated, and other factors that must be taken into account.

 The dose may vary depending on the nature of the disease, the conditions of their course, the condition of the patients and the methods of administration, while it is preferable that the daily dose is 1-50 mg for oral administration or 1-30 mg for intravenous injection, which can be taken once or can be divided into 2-3 doses, when used as a therapeutic agent for hypertension in an adult.

 Working examples.

 The following claims, working examples, experimental examples and comparative examples, the invention is illustrated more specifically and there is no need to say that they can not be construed as limitations of this invention.

 When the compound (I) of the invention is used as a therapeutic agent for the treatment of circulatory disorders, such as hypertension, heart disease, cerebral palsy and nephritis, it can be used, for example, in accordance with the following prescriptions.

1. Capsules, mg:
(1) 2-Ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-] methyl] benzimidazole-7-carboxylic acid - ten
(2) Lactose - 90
(3) Microcrystalline cellulose - 70
(4) Magnesium Stearate - 10
One capsule - 180
(1), (2), (3) and half (4) are mixed and granulated. The remainder (4) is added to the granules and the whole is placed in gelatin capsules.

2. Tablets, mg:
(1) 2-Ethoxy-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid - ten
(2) Lactose - 35
(3) Wheat Starch - 150
(4) Microcrystalline cellulose - 30
(5) Magnesium Stearate - 5
One tablet - 230
(1), (2), (3), two-thirds (4) and half (5) are mixed and granulated. The pellets add the residue (4) and (5), followed by injection molding of the resulting mixture.

3. Injection, mg:
(1) 2-Ethoxyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid disodium salt - 10
(2) Inositol - 100
(3) Benzyl alcohol - 20
One ampoule - 130
(1), (2) and (3) are dissolved in distilled water for injection to obtain a full volume of 2 ml, which is filled in the ampoule. All operations are carried out under sterile conditions.

4. Capsules, mg:
(1) 2-Butyl-4-chloro-5-hydroxymethyl-1 - [[2 '(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] imidazole - 10
(2) Lactose - 90
(3) Microcrystalline cellulose - 70
(4) Magnesium Stearate - 10
One capsule - 180
(1), (2), (3) and half (4) are mixed and granulated. The remainder (4) is added to the granules and the gelatin capsules are filled with all of this.

5. Tablets, mg:
(1) 2-Butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl ] methyl] imidazole - 10
(2) Lactose - 35
(3) Wheat Starch - 150
(4) Microcrystalline cellulose - 30
(5) Magnesium Stearate - 5
One tablet - 230
(1), (2), (3), two-thirds (4) and half (5) are mixed and granulated. The pellets add the residue (4) and (5), followed by molding the mixture under pressure.

6. Injection, mg:
(1) 2-Butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl ] methyl] imidazole sodium salt - 10
(2) Inositol - 100
(3) Benzyl alcohol - 20
One ampoule - 130
(1), (2) and (3) are dissolved in distilled water for injection to obtain a total volume of 2 ml, which is filled in the ampoule. All operations are carried out under sterile conditions.

7. Capsules, mg:
(1) 2-Ethoxy-1 - [[2'-2,5-dihydro-5-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid - 10
(2) Lactose - 90
(3) Microcrystalline cellulose - 70
(4) Magnesium Stearate - 10
One capsule - 180
(1), (2), (3) and half (4) are mixed and granulated. The remainder (4) is added to the granules and the gelatin capsules are filled with all of this.

8. Tablets, mg:
(1) 2-Ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) -biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid - 10
(2) Lactose - 35
(3) Wheat Starch - 50
(4) Microcrystalline cellulose - 30
(5) Magnesium Stearate - 5
One tablet - 230
(1), (2), (3), two-thirds (4) and half (5) are mixed and granulated. The pellets add the residue (4) and (5), followed by molding the mixture under pressure.

9. Injection, mg:
(1) 2-Ethoxy-1 - [[2'-dihydro-5-oxo-1,2.4-thiadiazol-3-yl) - biphenyl-4-] methyl] benzimidazole-7 carboxylic acid disodium salt - 10
(2) Inositol
100
Benzyl alcohol - 20
One ampoule - 130
(1), (2) and (3) are dissolved in distilled water for injection until a total volume of 2 ml is obtained with which the ampoule is filled. All operations are carried out under sterile conditions.

 Working Example 1. 2-Ethoxy-1 [[2 '- (2,5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

 1a) Methyl-3-amino-2 - [[2'-cyanobiphenyl-4-yl) methylamino] benzoate.

A mixture of methyl-2 - [[2'-cyanobiphenyl-4-yl) methyl] methyl] amino] -3-nitrobenzoate (10 g), synthesized in accordance with the method described in the official newspaper EP-0425921, FeCl ₃ • 6H ₂ O (0.1 g) and activated carbon (1 g) in a mixture of methanol (100 ml) and THF (50 ml) were refluxed for 30 minutes. Hydrazine hydrate (7.2 ml) was added dropwise to the reaction mixture, followed by heating for 14 hours at the boil. Insoluble matters were filtered off to dryness. An aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, the solvent was removed to dryness, and the residue was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from isopropyl ether to form pale yellow needles (6.0 g, 64%).

T. pl. 110-111 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 3.97 (2H, br s), 4.23 (2H, d), 6.39 (1H, t) 6.84-6.93 (2H, m), 7.26-7.55 (8H, m), 7.64 (1H, dt), 7.77 (1H, dd).

 1b) Methyl-1 - [[2'-cyanophenyl-4-yl) methyl] -2-ethoxybenzimidazole carboxylate.

To a solution of methyl 3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] amino benzoate (2.03 g) in ethyl orthocarbonate (5 ml) was added acetic acid (0.37 g) and the mixture was stirred in for 1 h at 80 ^o C. the Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous sodium hydrogen carbonate solution and water. The solvent was removed by drying to form crystals. Recrystallization of the crystals from ethyl acetate-hexane gave colorless crystals (2.01 g, 86%).

T. pl. 168.5-169.5 ^o C.

Elemental analysis of C ₂₅ H ₂₁ N ₃ O ₃ :
Calculated,%: C 72.98; H 5.14; N 10.21.

Found,%: C 72.71; H 5.12; N 9.97
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 3.71 (3H, s), 4.63 (2H, q, J = 7.1 Hz), 5.59 (2H, s), 7.09 (2H, d, J = 8.4 Hz), 7.20 (1H, t, J = 7.9 Hz), 7.45-7.59 (5H, m), 7.69-7.80 (2H, m), 7.92 (IH , dd, J = 1.4, 7.8 Hz).

IR (KBr), cm ^-1 : 2225, 1725, 1550, 1480, 1430, 1350, 1280, 1250, 1040, 760, 750.

 1c) Methyl 2-ethoxy-1 [[2'-hydroxycarbamimidoyl) biphenyl) -4-yl] methyl 1H-benzimidazole-7-carboxylate.

To a mixture of hydroxylamine hydrochloride (6.95 g) in dimethyl sulfoxide (DMSO) (80 ml) was added a solution of 28% NaOMe in methanol (5.2 g) with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes, then the compound obtained in working example (1b) (8.2 g) was added and the mixture was stirred for 4 hours at 90 ^° C. Water (50 ml) was added to the stirred reaction mixture at room temperature . The resulting crystalline precipitate was collected by filtration, washed with water and dried to give a white powder (8.0 g, 90%).

¹ H-NMR (90 MHz, CDCl ₃ ): 1.43 (3H, t), 3.73 (3H, t), 3.73 (3H, s), 4.67 (2H, q), 5.63 (2H, s) 6.97-7.80 (IIH, m).

IR (Nuiol), cm ^-1 : 3430, 3320, 1720, 1545, 1430, 1280, 1040, 750.

 1d) Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate.

 To a stirred suspension of the compound obtained in working example (1c) and triethylamine (0.2 g) in GTP tetrahydrofuran (30 ml) was added dropwise a solution of methylene chloride (2 ml) of ethyl chlorocarbonate (0.22 g) under ice cooling. The mixture was stirred for 2 hours at room temperature, then the insoluble products were filtered off and the filtrate was concentrated to dryness. A mixture of the residue in xylene (10 ml) was heated for 1.5 h at boiling. Ethyl acetate was added to the reaction mixture, washed with water, dried and concentrated by drying. The residue was purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate with isopropyl ether gave colorless prisms (0.22 g, 23%).

T. pl. 195-197 ^o C.

Elemental analysis of C ₂₆ H ₂₂ N ₄ O ₅ :
Calculated,%: C 66.38; H 4.71; N, 11.91.

 Found,%: C 66.17; H 4.66; N, 11.84.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.43 (3H, s), 3.77 (3H, s), 4.60 (2H, s), 5.63 (2H, s), 7.00-7.73 (11H, m )
IR (Nuiol), cm ^-1 : 2740, 2670, 1775, 1720, 1545, 1450, 1435, 1275, 1040, 750.

 1e) 2-Ethoxy-I [[2'-2,5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl] biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

 The compound obtained in working example (1d) (0.165 g) was dissolved in methanol (122 ml), 2N was added to the solution. an aqueous solution of LiOH (1 ml), then everything was heated to boiling and kept at this temperature under reflux for 3 hours. Then the pH of the reaction mixture was brought to 3 with 2 N. HCl, then the solvent was evaporated to dryness. The residue was dissolved in a mixture of water (20 ml) and chloroform (50 ml), then the organic layer was washed with water and dried. The solvent was evaporated to dryness, the crystalline product was crystallized from ethyl acetate to give colorless prisms (0.135 g, 84%).

Mp 156-157 ^o C.

Elemental analysis for C ₂₅ H ₂₀ N ₄ O ₅ • 1 / 2C ₄ H ₈ O ₂ • 1 / 5H ₂ O:
Calculated,%: C 64.33; H 4.88; N 11.11.

 Found,%: C 64.37; H 4.89; N 11.04.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.47 (3H, t), 4.60 (2H, s), 5.65 (2H, s), 6.97-7-77 (11H, m).

IR (Nuiol), cm ^-1 : 1775, 1730, 1685, 1540, 1425, 1270, 1030, 750.

 Working Example 2. Methyl 2-butyl-1 [[2 '- (2-oxo-3H-1, 2, 3, 5-oxathiadiazol-4-yl) biphenyl] methyl] benzimidazole-7-carboxylate.

In DMSO (3 ml) was dissolved methyl 2-butyl-1 [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (1.27 g), synthesized in accordance with the method published in the official newspaper EP-0425921, and hydroxylamine hydrochloride (0.35 g). A 28% solution of sodium methoxide in methanol (0.965 g) was added to the solution, and the mixture was stirred for 3 hours at 90-100 ^° C. Water (20 ml) was added to the reaction mixture, and the resulting precipitate was filtered off. The filtrate was concentrated to dryness and the precipitate was purified by silica gel column chromatography to give a light brown powdery product. The product (0.427) and pyridine (9.183 g) were dissolved in methylene chloride (3 ml). Thionyl chloride (1.19 g) was added dropwise to the solution under cooling from -20 ^° C to -25 ^° C. The mixture was stirred for some time, then water (3 ml) was added to it at a temperature of from -5 ^° C to -10 ^° C. Water (15 ml) was then added to the reaction mixture, the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography. The resulting crude crystals were recrystallized from isopropyl ether to form prisms (0.12 g, 7%).

T. pl. 124-125 ^o C.

Elementary analysis for C ₂₇ H ₂₆ N ₄ O ₄ S • 1 / 5C ₆ H ₁₄ O • 1 / 5H ₂ O:
Calculated,%: C 64.02; H 5.56; N, 10.59.

 Found,%: C 64.11; H 5.52; N, 10.51.

¹ H-NMR (90 MHz, CDCl ₃ δ: 0.90 (3H, t), 1.20-2.00 (4H, m), 2.63 (2H, t), 3.70 (3H, s,) 5.63 (2H, s) 6.73 (2H, d), 7.00-7.70 (8H, m), 7.83-7.93 (1H, m).

IR (Nuiol), cm ^-1 : 1725, 1520, 1435, 1410, 1290, 1180.

MS m \ z: 502 (M ⁺ ), 438, 423, 381, 192, 64.

 Working Example 3. Methyl-2-ethoxy-1 - [(2 '- (2-oxo-3H-1,2,3,5-oximadiazol-4-yl) biphenyl methyl [benzimidazole-7-carboxylate.

 Pyridine (0.711 g) was added to a solution of the compound (2.0 g) obtained in working example (1c) in THF (100 ml). The mixture was added dropwise over 45 minutes while cooling with ice to a solution in methylene chloride (20 ml) of thionyl chloride (0.536 g). An ox (15 ml) was added dropwise to the mixture under ice-cooling. The solvent was evaporated to dryness. Water (50 ml) was added to the residue, and the mixture was extracted with chloroform (100 ml). The extract was concentrated to dryness and the residue was purified by column chromatography. The resulting crystals were recrystallized from ethyl acetate to give colorless prisms (0.35 g, 16%).

T. pl. 109-111 ^o C.

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₅ S • 1 / 5H ₂ O:
Calculated,%: C 60.77; H 4.53; N, 11.34; S 6.49.

 Found,%: C 60.76; H 4.49; N 11.11; S 6.49.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.47 (3H, t), 3.73 (2 H, s), 4.53 (2 H, s) 5.60 (2H, s), 6.90-7, 93 (11 H, m).

IR (Nuiol), cm ^-1 : 1720, 1545, 1430, 1280, 1040, 750.

 Working Example 4. 1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

The compound obtained in working example (1e) was dissolved in dimethylformamide (8) ml). To the solution was added 1- (cyclohexyloxycarbonyloxy) ethyl chloride (0.3 g), potassium carbonate (0.4) and potassium iodide (0.04). The mixture was stirred for 15 hours at 80 ^° C. The solvent was evaporated to dryness. Chloroform (100 ml), water (5 ml), ethanol (5 ml) were added to the residue, and the mixture was shaken. The lower layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. Recrystallization from isopropyl ether gave the title compound as colorless prisms (0.2 g, 36%).

T. pl. 108-109 ^o C.

Elemental analysis of C ₃₄ H ₃₄ N ₄ O ₈ • 5H ₂ O:
Calculated,%: C 64.24; H 5.55; N, 8.81.

 Found,%: C 64.34; H 5.50; N, 8.79.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.07-2.00 (16H, m), 4.03-4.67 (3H, m), 5.67 (2H, s), 6.57.90 (12H, m), 10.57 (1H , wide.).

IR (Nuiol), cm ^-1 : 1780, 1750, 1545, 1275, 1235, 1070, 1030.

 Working Example 5. 2-Ethylthio-4-methyl-1 - [[2 '- (2, dihydro-3-oxo-1,2,4-oxdiazol-5-yl) bifunil-4-yl] methyl] -1H thieno [3,4-d] imidazole-6-carboxylic acid.

 5a) 0-methyl (4'-methylbiphenyl-2-yl) carbonylthiocarbamate.

 (4'-methylbiphenyl-2-yl) carboxylic acid (10 g) was dissolved in chloroform (40 ml). Thionyl chloride (7 ml) was added to the solution and the mixture was kept at reflux for 3 hours. The reaction mixture was poured into ice water, then the organic layer was separated, washed with water and concentrated to dryness to form a syrup, which was dissolved in dioxane (80 ml) . Powdered potassium thiocyanate (9.16) was added to the solution, and the mixture was heated for 1 h at the boil under reflux. The reaction mixture was cooled and the insoluble portion was filtered off. After adding methanol (15 ml) to the filtrate, the solution was heated for 15 min to boiling under reflux. The reaction solution was concentrated to dryness and the resulting crystals were recrystallized from isopropyl ether to give the product as white plates (7.4 g, 55%).

T. pl. 149-150 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.50 (3H, s), 4.01 (3H, s), 7.23-7.34 (4H, m), 7.38-7.60 (3H, m), 7.47 (1H, dd ), 8.37 (1H, broad s).

 5b) Dimethyl (4'-methylbiphenyl-2-yl) carbonyliminonothiocarbamate.

 To a solution of the compound (7.4 g) obtained in working example (5a) in methanol (35 ml) was added methyl iodide (4.0 g) and a 28% solution of sodium methoxide in methanol (5.5 g), and then the mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated to dryness, then the residue was extracted with ethyl acetate-water. The organic layer was washed with water and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain a colorless syrup (4.4 g, 57%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.29 (3H, s), 3.36 (3 H, s), 2.37 (3H, s), 7.13-7.27 (4H, m), 7.32-7.53 ( 3H, m), 7.93 (1H, m).

 5c) 3-Methoxy-5- (4'-methylbiphenyl-2-yl) -1,2,4-oxadiazole.

 To a solution of potassium hydroxide (1.1 g) in methanol (20 ml) was added powdered hydroxylamine hydrochloride (1.2 g) and the mixture was well shaken. The mixture was added to a solution of the compound (4.4 g) obtained in working example (5b) in 95% ethanol (10 ml) and the resulting mixture was stirred for 18 h at room temperature. The reaction mixture was concentrated to dryness and chloroform was added to the precipitate. The insoluble portion was filtered to dryness and the residue was dissolved in toluene (50%). The solution was heated to boiling under reflux for 2 hours with a catalytic amount of n-toluenesulfonic acid, followed by concentration to dryness. The residue was purified by silica gel column chromatography to obtain a colorless syrup (2.5 g, 64%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.38 (3H, s), 4.08 (3H, s), 7.11-7.21 (4H, m), 7.41-7.62 (3H, m), 7.96 (1H, dd )

 5d) 5- (4'-methylbiphenyl-2-yl) -1,2,4-oxadiazolin-3 (2H) -one.

A mixture of the compound (0.5 g) obtained in working example (5c) and pyridinium chloride (5 g) was heated to 155 ^° C. for 30 minutes in a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate-water. The organic layer was washed with water and concentrated to dryness to form pale yellow prisms (0.5 g, 100%).

T. pl. 145-150 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.36 (3H, s), 7.09-7.20 (4H, m) 7.44-7.53 (2H, m) 7.58-7.67 (1H, m), 7.88 (1H, dd )

IR (Nuiol), cm ^-1 : 1605, 1590, 1480, 1340, 815, 750.

 5e) 5- (4'-Methylbiphenyl-2-yl) -2-trityl-1,2,4-oxadiazole-3 (2H) -one.

 To a solution of the compound (1 g) obtained in working example (5d) and trityl chloride in dichloromethane (20 ml) was added dropwise with stirring. Then the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness and the residue was purified by silica gel column chromatography to obtain colorless prisms (0.9 g, 45%).

T. pl. 181-184 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 7.06 (4H, s), 7.16-7.43 (17H, m), 7.52-7.60 (1H, m), 7.79 (1H, dd )

IR (Nuiol), cm ^-1 : 1745, 1595, 1580, 1440, 1335, 1160.

 5f) 5- (4-Bromomethylbiphenyl-2-yl) -2-trityl-1,2,4-oxdiazol-3 (2H) -one.

 A mixture of the compound (0.9 g) obtained in working example (5e), N-bromosuccinimide (0.3 g) and a catalytic amount of benzoyl peroxide was heated to boiling for 1 h in carbon tetrachloride (20 ml) under light irradiation. The reaction mixture was cooled, then the precipitate was filtered. The filtrate was dried to dryness to afford the title compound as a pale yellow amorphous powder (1.0 g, 99%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.47 (2H, s), 7.06-7.63 (22H, m), 7.85 (1H, dd).

 5g) Methyl-2-ethylthio-4-Methyl-1 - [[2 '- (2,3-dihydro-3-oxo-2-trityl-1,2,4-oxadiazol-5-yl) -4-yl ] methyl] -1H-thieno [3,4-d]] imidazole-6-carboxylate.

 To a stirred solution of methyl 2-ethylthio-4-methyl-1H-thieno [3,4-d] imidazole-6-carboxylate (0.4 g) in dimethylformamide (10 ml) was added portionwise sodium hydride (60% dispersion in mineral oil; 70 mg) under ice cooling. The mixture was further stirred for 30 minutes at room temperature. The compound (1 g) obtained in working example (5f) was added to the reaction mixture, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate-water. The organic layer was washed with water, then concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the title compound as a yellow amorphous powder (0.6 g, 50%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.32 (3H, s), 2.66 (3H, s), 3.61 (3H, s), 3.25 (3H, s), 5.75 (2H, s), 7.10 ( H, c), 7.19 (15H, s), 7.26-7.43 (2H, m), 7.53-7.60 (1H, m), 7.70 (1H, dd).

IR (Nuiol), cm ^-1 : 1740, 1685, 1595, 1330, 1315, 1160, 1080.

 5h) Methyl-2-ethylthio-1]] 2 '- (2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl) -biphenyl-4-yl] methyl] -4-methyl -1H-thieno [3,4-d] imidazole-6-carboxylate.

 The compound (0.6 g) obtained in the working example (5g) was dissolved in methanol (15 ml) and chloroform (10 ml). 1N was added to the solution. HCl (0.9 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness, the residue was partitioned between chloroform-water. The organic layer was washed with water and concentrated to dryness. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow amorphous powder (0.4 g, 95%).

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₄ S ₂ • 2/5 CH ₂ Cl ₂ .

 Calculated,%: C 56.64; H 4.25; N, 10.36.

 Found,%: C 56.56; H 4.18; N 10.26.

¹ H-NMR (200 MHz, d ₆ -DMCO) δ: 1.35 (3H, t), 2.56 (3H, s), 3.70 (3H, s), 3.26 (2H, s) 5.67 (2H, c) 7.12 (2H, d), 7.12 (2H, d), 7.12 (2H, d), 7.41-7.68 (3H, m), 7.80 (1H, d).

IR (Nuiol), cm ^-1 : 1685, 1590, 1530, 1355, 1315, 1230, 1160, 1085.

 5i) 2-Ethylthio-1 - [[2 '- (2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] -4-methyl- 1H-thieno [3,4-d] imidazole-6-carboxylic acid.

 The compound (0.1 g) obtained in working example (5h) was dissolved in tetrahydrofuran (2 ml) and water (1 ml). Hydroxidolithium monohydrate (25 mg) was added to the solution, and the mixture was kept at reflux for 17 hours. The reaction mixture was concentrated to dryness, water was added thereto, and then insoluble products were filtered off. The filtrate was acidified with 1 N. HCl and the resulting precipitate were collected by filtration to obtain the indicated powder compound (60 mg, 62%).

T. pl. 144-147 ^o C.

Elemental analysis of C ₂₄ H ₂₀ N ₄ O ₄ S ₂ :
Calculated,%: C 58.52; H 4.09; N, 11.37.

 Found,%: C 58.47; H 4.25; N, 11.33.

¹ H-NMR (200 MHz, d ₆ -DMCO) δ: 1.34 (3H, t), 2.54 (3H, s), 3.25 (2H, s), 5.70 (2H, s), 7 16 (2H, d), 7.20 (2H, d), 7.45-7.73 (3H, m), 7.88 (1H, d).

IR (Nuiol), cm ^-1 : 1650, 1590, 1525, 1310, 1160, 1085.

 Working Example 6. 2-Butyl-1 [[2 '- (2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4yl] methyl] benzimidazole-7-carboxylic acid .

 6a) 4'-methylbiphenyl-2-carbohydrazide.

 To a solution of 4-methylbiphenyl-2-carboxylic acid (6.4 g) in tetrahydrofuran (50 ml) was added N, N-dimethylformamide (two drops) and oxalyl chloride (4.4 g). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated to dryness under reduced pressure to give an oil, which was added dropwise to a solution of hydrazine monohydrate (7.5 g) in tetrahydrofuran (50 g) with stirring, followed by stirring for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure. The precipitate was purified by silica gel column chromatography to give crude crystals. Recrystallization from chloroform-isopropyl ether gave the title compound as colorless needles (4.3 g, 63%).

T. pl. 98-99 ^o C.

Elemental analysis of C ₁₄ H ₁₄ N ₂ O:
Calculated,%: C 74.31; H 6.24; N, 12.38.

 Found,%: C 74.17; H 6.17; N, 12.46.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: (3H s), 2.65 (2H, broad), 7.20-7.31 (4H, m), 7.35-7.55 (3H, m), 7.67 (1H, dd).

IR (KBr), cm ^-1 : 3280, 3220, 1670, 1610, 1520, 1320, 1185, 1100, 820, 755.

 6b) 1- [2- (4'-Methylphenyl) benzoyl] semicarbazide.

 To a solution of the compound (4.3 g) obtained in working example (6a), in 1N. HCl (20 ml) was added dropwise an aqueous solution (20 ml) of sodium isocyanate (1.7 g) and the mixture was stirred for 3.5 hours. The resulting crystalline precipitate was collected by crystallization of colorless needles (4.5 g, 87%).

T. pl. 183-184 ^o C (decomp.).

Elemental analysis of C ₁₅ H ₁₅ N ₃ O ₂ • 2H ₂ O:
Calculated,%: C 65.79; H 5.61; N, 15.38.

 Found,%: C 65.79; H 5.61; N, 15.38.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.33 (3H, s), 5.71 (2H, broad), 7.18 (2H, d), 7.33-7.56 ( 6H, m) 7.84 (1H, s), 9.84 (1H, broad).

IR (KBr), cm ^-1 : 3260, 3230, 1700, 1650, 1520, 1305, 820, 765.

 6c) 2,3-dihydro-5- (4'-methylbiphenyl-2-yl) -1,3,4-oxadiazol-2 (3H) -one.

 The compound (4.0 g) obtained in working example (6b) was suspended in acid (100 ml) and the mixture was refluxed for 18 hours. The solvent was distilled off to dryness under reduced pressure and the residue was purified by silica gel column chromatography with the formation of crude crystals. Recrystallization from ethyl acetate-hexane gave the title compound as colorless needles (2.0 g, 53%).

T. pl. 130-131 ^o C.

Elemental analysis of C ₁₅ H ₁₂ N ₂ O ₂ :
Calculated,%: C 71.42; H 4.79; N, 11.10.

 Found,%: C 71.45; H 4.79; N, 11.05.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 7.19 (4H, s), 7.37-7.60 (3H, s), 7.77 (1H, dd), 8.89 (1H, broad).

IR (KBr), cm ^-1 : 1765, 1600, 1490, 1330, 1240, 1035, 960, 925, 815, 770, 750, 715, 700.

 6b) 2,3-dihydro-5- (4'-methylbiphenyl-2-yl) -3-triphenylmethyl-1,3,4-oxadiazole-2 (3H) -one.

 To a solution of the compound (2.0 g) obtained in working example (6c) in methylene chloride (25 ml) was added triethylamine (0.89 g) and triphenylmethyl chloride (2.5 g) and the mixture was stirred. The reaction mixture was washed with water, then dried. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as a colorless amorphous powder (4.0 g, 100%).

T. pl. 60-63 ^o C.

Elemental analysis of C ₃₄ H ₂₆ N ₂ O:
Calculated,%: C 82.57; H 5.30; N, 5.66.

 Found,%: C 82.67; H 5.37; N, 5.20.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.31 (3H, s), 7.00 (2H, d), 7.05-7.54 (20H, m), 7.68 (1H, dd).

IR (KBr), cm ^-1 : 1780, 1490, 1445, 1335, 1280, 1005, 875, 820, 770, 755, 740, 700.

 6e) 5- (4'-Bromomethylphenyl-2-yl) -2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2 (3H) one.

 To a solution of the compound (4.0 g) obtained in working example (6d) in carbon tetrachloride (50 ml) was added N-bromosuccinimide (1.4 g) and benzoyl peroxide (19 mg) and the reaction mixture was refluxed for 1 h when exposed to light. Insoluble products were filtered off and the filtrate was concentrated under reduced pressure. The resulting precipitate was purified by silica gel column chromatography to give the title compound as a colorless amorphous powder (4.3 g, 93%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.42 (2H, s), 7.10-7.56 (22H, m), 7.72 (1H, dd).

IR (KBr), cm ^-1 : 1780, 1490, 1440, 1335, 1260, 1215, 1000, 870, 765, 740, 700.

 6f) Methyl-2- [N [2 '- (2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl-N-valeryl] amino 3-nitrobenzoate.

To a solution of the compound (0.86 g) obtained in working example (6e) in acetonitrile (10 ml) was added methyl 3-nitro-2-valerylaminobenzoate (0.42 g) and potassium carbonate (0.26 g) and the mixture was refluxed for 36 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The oily product thus obtained was dissolved in trifluoroacetic acid (5 ml), the solution was stirred for 30 minutes at 60 ^° C. Trifluoroacetic acid was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and dried. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the indicated oily product (0.50 g, 63%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.85 (3H, t), 1.18-1.36 (2H, m), 1.58-1.71 (2H, m), 2.05- 2.15 (2H, m), 3.69 (3H, s), 4.58 (1H, d), 4.95 (1H, d), 7.06-7.16 (4H, m), 7 34 (1H, dd), 7.41-7.54 (2H, m), 7.62 (1H, t), 7.77 (1H, dd), 8.02 (1H, dd), 8, 17 (1H, dd), 8.97 (1H, broad).

IR (undiluted), cm ^-1 : 1815, 1780, 1730, 1660, 1530, 1445, 1390, 1370, 1340, 1285, 1260, 1230, 750.

 6g) Methyl-2-butyl-1 [[2 '- (2, 3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7- cabroxylate.

 To a solution of the compound (0.50 g) obtained in working example (6f) in methanol (10 ml) was conc. HCl (1 ml) and iron powder (0.34 g). The mixture was refluxed for 24 hours. Insoluble products were filtered off, the filtrate was concentrated to dryness. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The crude crystals thus obtained were recrystallized from ethyl acetate-chloroform to give the title compound as colorless crystals (73 mg, 16%).

T. pl. 204-205 ^o C.

Elemental analysis of C ₂₈ H ₂₆ N ₄ O ₄ :
Calculated,%: C 69.70; H 5.43; N, 11.61.

 Found,%: C 69.43; H 5.49; N, 11.59.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94 (3H, t, 1.36-1.55 (2H, m), 1.79-1.94 (2H, m), 2.94 (2H, t), 3.73 (3H, s), 5.78 (2H, s), 6.84 (2H, d) 7.16 (2H, d) 7.21-7.36 (2H, m), 7.41-7.57 (2H, m), 7.64 (1h, dd), 7.96 (1H, dd), 9.35 (1H, broad).

IR (KBr), cm ^-1 : 1760, 1710, 1600, 1430, 1405, 1335, 1270, 750.

 6h) 2-Butyl-1 - [[2 '- (2, 3-dihydro-2-oxo-1, 3, 4-oxadiazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid .

 To a solution of the compound (30 g) obtained in the working example (6g) in methanol (1 ml) was added 1 N. NaOH (0.5 ml), then the mixture was refluxed for 1.5 hours. After evaporation of the solvent, the residue was washed with water, the pH was adjusted to 3-4 with 1 N. HCl, while crystals precipitated. The crystals were collected by filtration, recrystallized from ethyl acetate-methanol to give the title compound as colorless needles (16 mg, 54%).

T. pl. 247-248 ^o C.

Elemental analysis of C ₂₇ H ₂₄ N ₄ O ₄ • 0.5H ₂ O:
Calculated,%: C 67.91; H 5.28; N, 11.73.

 Found,%: C 68.19; H 5.21; N, 11.89.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.98 (3H t), 1.40-1.60 (2H, m), 1.81-1.97 (2H, m), 3.05 (2H, t), 5.87 (2H, s), 6.86 (2H, d), 7.17 (2H, d), 7.28 (1H, t), 7.36-7.62 ( 3H, m), 7.67 (1H, dd), 7.83 (1H, dd), 7.99 (1H, dd).

IR (KBr), cm ^-1 : 1770, 1700, 1600, 1410, 1230, 740.

 Working Example 7. 2-Ethylthio-1 - [[2 '- (2, 3-dihydro-2-oxo-1, 3, 4-oxadiazol-5-yl) biphenyl-4-yl] methyl] -4-methylthieno [3, 4-d] imidazole-6-carboxylic acid.

 7a) Methyl-2-ethylthio-1 - [[2 '- (2, 3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylate.

To an ice-cooled solution of methyl 2-ethylthio-4-methylthieno [3, 4-d] imidazole-6-carboxylate (0.26 g) in N, N-dimethylformamide (2 ml) was added sodium hydride (60% dispersion in mineral oil; 44 mg) and the mixture was stirred for 15 min, then 5- (4'-bromomethylbiphenyl-2-yl) -2,3-dimethyl-3-triphenylmethyl-1,3,4-oxadiazol-2-one (0, 57 g). The reaction mixture was stirred for 2 hours at room temperature, then diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure, and the residue was dissolved in trifluoroacetic acid (5 ml). The solution was stirred for 30 minutes at 60 ^° C. and concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate and dried. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate gave the title compound as yellow prisms (0.17 g, 33%).

T. pl. 220-221 ^o C.

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₄ S ₂ :
Calculated,%: C 59.27; H 4.38; N, 11.06.

 Found,%: C 59.18; H 4.50; N, 10.91.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.62 (3H, s), 3.30 (2H, s), 3.75 (3H, s), 5 70 (2H, s), 7.13-7.23 (4H, m), 7.34-7.58 (3H, m), 7.77 (1H, dd), 8.82 (1H, broad )

IR (undiluted), cm ^-1 : 1770, 1695, 1600, 1530, 1445, 1340 1320, 1240, 1195, 1165, 1085, 1000, 750.

 7b) 2-Ethylthio-1 - [[2 '- (2,3-dihydro-2-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4 -d] imidazole-6-carboxylic acid.

To a solution of the compound (0.12 g) obtained in working example (7a) in tetrahydrofuran (6 ml) was added a solution of lithium hydroxide monohydrate (60 mg) in water (3 ml). The mixture was stirred for 60 minutes at 50-60 ^° C. The solvent was evaporated to dryness under reduced pressure. The residue was diluted with water, the pH of the solution was adjusted to 3-4 with 1 N. HCl to precipitate crystals. The crystals were collected by filtration in recrystallization from a mixture of ethyl acetate-methanol, and the title compound was obtained as yellow prisms (72 mg, 60%).

T. pl. 195-196 ^° C (decomp.).

Elemental analysis of C ₂₄ H ₂₀ N ₄ O ₄ S ₂ • H ₂ O:
Calculated,%: C 58.10; H 4.14; N, 11.29.

 Found,%: C 58.13; H 4.22; N, 11.22.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.34 (3H, t), 2.55 (3H, s), 3.25 (2H, s), 7.19 (2H, d), 7.28 (2H d) 7.42 (1H, dd), 7.49-7.62 (2H, m), 7.76 (1H, dd), 12.40 (1H, broad).

IR (KBr), cm ^-1 : 1760, 1685, 1600, 1440, 1330, 1185, 1160, 1080, 960, 925, 760, 750.

 Working Example 8. 2-Ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 8a) Methyl 2-ethyltyl-4-methyl-1- [2 '- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methylthieno [3,4-d] imidazole- 6-carboxylate.

 To an ice-cooled solution of methyl 2-ethylthio-4-methylthieno [3.4-d] imidazole-6-carboxylate (3 g) in DMF (20 ml) was added a solution of sodium hydride (60%, oil) (0.56 g) and the mixture was stirred for 10 minutes [2 '- (5-Trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl bromide (6.1 g) was added to the ice-cooled mixture, and the mixture was stirred at room temperature for 2 hours. water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a pale yellow syrupy product (4.15 g, 58%).

^I H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.62 (3H, s), 3.29 (2H, s), 3.77 (2H, s), 3.77 (3H, s), 5.71 ( 2H, s), 7.16 (4H, s), 7.42-7.62 (3H, m), 7.83-7.88 (1H, m).

IR (undiluted), cm ^-1 : 1690, 1600, 1450, 1430, 1345, 1330, 1315, 1230, 1190, 1160, 1090, 850, 820, 800, 755, 730.

 8b) Methyl-2-ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylate.

To a solution of the compound (4.15 g) obtained in working example (8a) in MeOH (50 ml) - CHCl ₃ (10 ml) was added 1N. NaOH (10 ml) and the mixture was stirred for 30 min at room temperature. The reaction mixture was acidified to pH 4 with 1 N. HCl, then water was added thereto, followed by extraction with CHCl ₃ . The extract was washed with water, dried and the solvent was distilled off under reduced pressure to dryness to form crude crystals. Recrystallization from ethyl acetate-methanol-hexane gave the title compound as colorless prisms (3.15 g, 91%).

T. pl. 240-241 ^o C (decomp.).

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₄ S ₂ :
Calculated,%: C 59.27; H 4.38; N 11.06
Found,%: C 59.07; H 4.26; N 11.00
^I H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.61 (3H, s) 3.29 (2H, s), 3.75 (2H, s) 3.75 (3H, s), 5.74 (2H, c) 7.26 (4H, s), 7.42 (1H, dt), 7.51 (1H, dd), 7.61 (1H, dt), 7.85 (1H, dd), 7.90 (1H, broad s).

IR (KBr), cm ^-1 : 1760, 1680, 1595, 1455, 1450, 1430, 1315, 1230, 11.60, 1085, 755.

 8c) 2-Ethylthio-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3, 4-d] imidazole-6-carboxylic acid.

To a solution of the compound (0.5 g) obtained in working example (8b) in tetrahydrofuran (THF) (5 ml) and H ₂ O (2.5 ml) was added sodium monoxide hydrate (0.12 g) and the mixture was boiled under reflux for 7 hours. Water was added to the reaction mixture and the mixture was acidified to pH 3 with 1N. HCl. The resulting crystals were collected by filtration and recrystallized from a mixture of chloroform-methanol to form the indicated compound as colorless needles (0.36 g, 73%).

T. pl. 217-219 ^o C (decomp.).

Elemental analysis of C ₂₄ H ₂₀ N ₄ O ₄ S • 3H ₂ O:
Calculated,%: C 57.89; H 4.17; N, 11.25.

 Found,%: C 57.89; H 4.02; N 11.08.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.34 (3H, s), 2.55 (3H, s), 3.24 (3H, s) 5.71 (2H, s), 7.19 (2H, d) 7.28 (2H, d); 7.28 (2H, d); 7.49-7.72 (4H, m).

IR (KBr), cm ^-1 : 1750, 1640, 1620, 1585, 1520, 1450, 1305, 1250, 1235, 1155, 760, 750.

 Working Example 9. 2-Methoxy-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 9a) Methyl 2-ethylsulfinyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2.4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3, 4-d] imidazole-6-carboxylate.

 To a solution of the compound (3.15 g) obtained in working example (8b) in methylene chloride (100 ml) was added m-chloroperbenzoate (13 g) and the mixture was stirred for 20 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness and the residue was purified on silica gel using column chromatography to give crude crystals. Recrystallization from ethyl acetate-methanol-hexane gave the title compound as colorless needles (2.60 g, 80%).

T. pl. 206-208 ^o C (decomp.).

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₅ S ₂ :
Calculated,%: C 57.46; H 4.24; N, 10.72.

 Found,%: C 57.28; H 4.27; N, 10.45.

^I H-NMR (200 MHz, CDCl ₃ ) δ: 1.27 (3H, s), 2.71 (3H, s), 3.38 (2H, s), 3.82 (3H, s), 5.98 (1H , d), 6.40 (1H, d), 7.26 (3H, m), 7.41-7.64 (3H, m), 7.81 (1H, dd), 8.75 (1H, broad s)
IR (KBr), cm ^-1 : 1770, 1685, 1450, 1420, 1315, 1235, 1090, 1050, 1040, 1020, 780, 750.

 9b) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methyloxy-4-methylthieno [3,4-d] imidazole-6-carboxylate.

 To a suspension of the compound (0.79 g) obtained in working example (9a) in methanol (20 ml) was added sodium methoxide (28%, methanol solution) (0.88 g) and the mixture was stirred for 30 min at room temperature . Water was added to the reaction mixture, and the pH of the mixture was adjusted to 4 with 1N. HCl, then extracted with ethyl acetate, then washed with saturated aqueous saline and dried. The solution was distilled off to dryness under reduced pressure to give crude crystals. Recrystallization from ethyl acetate-hexane gave the title compound as colorless needles (0.71 g, 98%).

T. pl. 207-209 ^o C (decomp.).

Elemental analysis of C ₂₄ H ₂₀ N ₄ O ₅ S:
Calculated,%: C 60.49; H 4.23; N, 11.76.

 Found,%: C 60.23; H 4.29; N, 11.49.

^I H-NMR (200 MHz, CLCl ₃ ) δ: 2.37 (3H, s) 3.73 (3H, s), 3.99 (3H, s), 5.59 (2H, s), 7.25 (4H, s), 7.38 (1H, dd), 7.59 (1H, dt), 7.61 (1H, dt), 7.83 (1H, dd), 8.79 (1H, broad s).

IR (KBr), cm ^-1 : 1750-1685, 1610, 1570, 1525, 1450, 1440, 1430, 1375, 1330, 1230, 1055, 750.

 9c) 1 - [[2 '- (2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] 2-methoxy-4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 To a mixture of the compound (0.6 g) obtained in working example (9b) in a mixture of THF (10 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.16 g). The mixture was refluxed for 8 hours. Water was added to the reaction mixture and the mixture was acidified to pH 4 with 1N. HCl, after which the mixture was extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure to give crude crystals. Recrystallization from ethyl acetate-methanol gave the title compound as colorless needles (0.35 g, 54%).

T. pl. 183-186 ^o C (decomp.).

Elemental analysis of C ₂₃ H ₁₈ N ₄ O ₅ S • 0 / 5AcOEt:
Calculated,%: C 59.28; H 4.38; N 11.06.

 Found,%: C 58.94; H 4.15; N, 11.18.

^I H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.48 (3H, s), 4.06 (3H, s), 5/56 (2H, s), 7.21-7.31 (4H, m), 7.49-7.72 (4H, m).

IR (KBr), cm ^-1 : 1800, 1660, 1650, 1570, 1450, 1380, 1370, 1330, 1240, 760, 730.

 Working Example 10. 2-Ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 10a) Methyl-2-ethoxy-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylate.

 To a solution of sodium (0.1 g) in ethanol (20 ml) was added the compound (0.7 g) obtained in working example (9a), and the mixture was stirred for 30 min at room temperature. Water was added to the reaction mixture, and the mixture was acidified with 1N. HCl to pH 4, then it was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure to form crystals, which were suspended in methanol. Sodium methoxide (28%, solution in methanol) (0.65%) was added to the suspension, and the mixture was refluxed for 7 hours. After adding water, the mixture was acidified to pH 4 with 1N. HCl, then extracted with ethyl acetate. The extract was washed with water and dried, the solvent was evaporated to dryness under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate-methanol-hexane gave the title compound as pale yellow prisms (0.5 g, 76%).

T. pl. 215-217 ^o C (decomp.).

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₅ :
Calculated,%: C 61.21; H 4.52; N, 11.42.

 Found,%: C 61.02; H 4.32; N, 11.28.

^I H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.45 (3H, s), 3.75 (3H, s), 4.45 (2H, s), 5.59 (2H, s), 7.23-7.33 (4H, m), 7.38 (1H, dd), 7.49 (1H, dt), 7.60 (1H, dt), 7.84 (1H, dd), 8.27 (1H, broad, s).

IR (KBr), cm ^-1 : 1760, 1685, 1610, 1570, 1460, 1445, 1435, 1410, 1380, 1330, 1230, 1100, 1060, 760.

 10b) 2-Ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 To a suspension of the compound (0.4 g) obtained in working example (10a) in a mixture of THF (10 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.1 g), then the mixture was refluxed for 12 h. Water was added to the reaction mixture, then the mixture was acidified to pH 4 with 1N. HCl. Recrystallization of the obtained crystals from ethyl acetate-methanol gave the title compound as colorless prisms (0.31 g, 79%).

Mp. 206-208 ^o C (decomp.).

Elemental analysis of C ₂₄ H ₂₀ N ₄ O ₅ S:
Calculated,%: C 60.49; H 4.23; N, 11.76.

 Found,%: C 60.27; H 4.15; N, 11.70.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.32 (3H, t), 2.46 (3H, s), 4.47 (2H, s), 5.56 (2H, s), 7.27 (4H, s), 7.49-7.72 (4H, m).

IR (KBr), cm ^-1 : 1760, 1650, 1600, 1570, 1525, 1460, 1445, 1330, 1240, 760.

 Working Example 11. 1- [2 '- (2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl-4-methyl-2-p-propoxythieno [3,4-d] imidazole-6-carboxylic acid.

 11a) Methyl-12 - [[2 '- (2,5-dihydro-5-oxo-1,2,4, oxadiazol-3-yl] biphenyl-4-yl] methyl-4-methyl-2-p- propoxythieno [3,4-d] imidazole-5-carboxylate.

 To a solution of sodium (0.1 g) in isopropanol (20 ml) was added the compound (0.7 g) obtained in working example (9a), and the mixture was stirred for 30 min at room temperature. Water was added to the reaction mixture, acidified to pH 4 with 1N. HCl, then the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure to form crystals. The crystals were suspended in methanol and sodium methoxide (28%, solution in methanol) (0.65 g) was added to the suspension. The mixture was refluxed for 7 hours. Water was added to the reaction mixture, and the mixture was acidified to pH 4 with 1N. HCl, then the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure to give crude crystals. Recrystallization from ethyl acetate-methanol-hexane gave the title compound as pale yellow prisms (0.5 g, 74%).

T. pl. 213-215 ^o C (decomp.).

Elemental analysis of C ₂₆ H ₂₄ N ₄ O ₅ S:
Calculated,%: C 61.89; H 4.79; N 11.10.

 Found,%: C 61.73; H 4.63; N, 10.93.

¹ H-NMR (200 MHz, CDCl ₃ ): 0.98 (3H, t), 1.71-1.91 (2H, m), 2.47 (3H, s), 4.37 (2H, s), 7.23-7.34 (4H, m) , 7.37 (1H, dt), 7.49 (1H, dt), 7.60 (1H, dt), 7.83 (1H, dd), 8.22 (1H, broad s)
IR (KBr), cm ^-1 : 1760, 1690, 1615, 1570, 1530, 1460, 1445, 1430, 1410, 1360, 1330, 1230, 1100, 1060, 755.

 11b) 1- [2 '- (2,5-Dihydro-5-oxo-1,2,4oxadiazol-3-yl) biphenyl-4-yl] methyl-4-methyl-2-p-propoxythieno [3,4 -d] imidazole-6-carboxylic acid.

 To a suspension of the compound (0.4 g) obtained in working example (11a) in a mixture of THF (10 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.1 g), then the mixture was refluxed for 12 hours. water was added to the reaction mixture, the mixture was acidified to pH 4 with 1N. HCl. The resulting crystals were collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound as colorless needles (0.28 g, 72%).

T. pl. 208-209 ^o C (decomp.).

Elemental analysis of C ₂₅ H ₂₂ N ₄ O ₅ S • 0.3H ₂ O:
Calculated,%: C 60.55; H 4.59; N 11.30.

 Found,%: C 60.58; H 4.43; N, 11.39.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.89 (3H, t), 1.65-1.82 (2H, m), 2.48 (3H, s), 4.38 (2H, t), 5.59 (2H, s ), 7.28 (4H, s), 7.49-7.74 (4H, m).

IR (KBr), cm ^-1 : 1760, 1650, 1645, 1605, 1570, 1530, 1460, 1445, 1325, 1240, 760.

 Working Example 12. 2-Ethylamino-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-5yl] methyl] -4-methylthieno [3 , 4-d] imidazole-6-carboxylic acid.

 12b) Methyl-2-ethylamino-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylate.

A mixture of the compound (0.60 g) obtained in working example (9a) and a 70% aqueous solution of ethylamine (10 ml) was heated at 80 ^° C. in an autoclave for 2 hours. The reaction mixture was concentrated to dryness and acidified to pH 4 with 1 n . HCl. The mixture was extracted with chloroform, the extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate-methanol-hexane gave the title compound as pale orange needles (0.28 g, 45%).

T. pl. 219-221 ^o C (decomp.).

Elemental analysis of C ₂₅ H ₂₃ N ₅ O ₄ S • 0.5 AcOEt (533.60):
Calculated,%: C 60.78; H 5.10; N 13.12
Found,%: C 60.52; H 5.15; N 12.93
¹ H-NMR (200 MHz, CLCl ₃ ) δ: 1.26 (3H, s). 2.40 (3H, s), 3.31 (2H, s), 3.67 (3H, s), 5.61 (2H, s), 7.16 (2H, d), 7.23 (2H, d), 7.38 (2H, dt), 7.47 (1H, dd) 7.58 (1H, dt), 7.72 (1H, dd).

IR (KBr), cm ^-1 : 3325, 1740, 1690, 1610, 1590, 1540, 1460, 1435, 1335, 1230, 1090, 765.

 12b) 2-Ethylamino-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 To a suspension of the compound (0.2 g) obtained in working example (12b) in a mixture of THF (5 ml) and water (2.5 ml) was added lithium hydroxide monohydrate (51 mg), the mixture was refluxed for 24 hours. water was added to the mixture, then the mixture was acidified to pH 4 with 1N. HCl. The crystals which precipitated in this case were collected by filtration and recrystallized from a mixture of chloroform-methanol to give the title compound as pale yellow crystals. (0.12 g, 67%).

T. pl. 189-192 ^o C (decomp.).

Elemental analysis of C ₂₄ H ₂₁ n ₅ O ₄ S • 1.0 MeOH (507.56):
Calculated,%: C 59.16; H 4.96; N, 13.80.

 Found,%: C 59.34; H 4.76; N 14.00.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.13 (3H, s), 2.34 (3H, s), 3.28 (2H, s), 5.84 (2H, s), 7.06 (2H, s), 7.22 (2H, d), 7.28 (1H, dd), 7.34-7.43 (2H, m), 7.47 (1H, dd).

IR (KBr), cm ^-1 : 1700, 1680, 1670, 1650, 1635, 1560, 1540, 1510.

 Working Example 13. Acetoxymethyl-1 [[2 '- (4-acetoxymethyl-4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] - 2-ethoxybenzimidazole-7-carboxylate.

 Triethylamine (413 mg) was added to a solution of the compound (1.02 g) obtained in working example (1) in DMF (4 ml). Acetoxymethyl chloride (444 mg) was added to the stirred mixture at room temperature, then the mixture was stirred for another 20 hours under the same conditions. Dichloromethane (40 ml), water (25 ml) and 2N were added to the reaction mixture. HCl (3 ml) and the mixture was shaken. The organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give crude crystals. Recrystallization from ether-isopropyl ether gave the title compound as colorless prisms (350 mg, 30%).

T. pl. 132-133 ^o C.

Elemental analysis of C ₃₁ H ₂₈ N ₄ O ₉ :
Calculated,%: C 62.00; H 4.70; N, 9.33.

 Found,%: C 62.08; H 4.60; N, 9.29.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.47 (3H, t), 1.77 (3H, s), 2.10 (3H, s). 4.67 (2H, s), 4.87 (2H, s), 5.70 (2H, s), 5.87 (2H, s), 7.00-7.83 (11H, m).

IR (Nuiol), cm ^-1 : 1790, 1760, 1730, 1200, 1035, 980.

 Working Example 14. Acetoxymethyl 2-ethoxy-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) butenyl-4-yl] methyl] benzimidazole-7- carboxylate.

 The same reaction was carried out as in working example 13, and the reaction mixture was purified using column chromatography on silica gel with the formation of crude crystals. Recrystallization from ethyl acetate-isopropyl ether gave the title compound as colorless prisms (250 mg, 29%).

T. pl. 111-112 ^o C.

Elemental analysis of C ₂₈ H ₂₄ N ₄ O ₇ • 1 / 30C ₆ H ₁₄ O • 1 / 5H ₂ O:
Calculated,%: C 63.24; H 4.68; N, 10.46.

 Found,%: C 63.31; H 4.64; N 10.20.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.40 (3H, s), 2.00 (3H, s), 4.40 (2H, s), 5.67 (2H, s), 5.70 (2H, s), 6.87- 7.90 (11H, m).

IR (Nuiol), cm ^-1 : 1780, 1730, 1545.

 Working Example 15. 1 - [[2 '- (4-Acetoxymethyl-4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -2 ethoxybenzimidazole-7-carboxylate.

 The same reaction was carried out as in working example 13, and the reaction mixture was purified by silica gel column chromatography to give crude crystals, followed by recrystallization from ethyl acetate to give the title compound as colorless prisms (50 mg, 5%).

T. pl. 177-179 ^o C.

Elemental analysis of C ₂₈ H ₂₄ N ₄ O ₇ • 1/3 H ₂ O:
Calculated,%: C 62.92; H 4.65; N, 10.48.

 Found,%: C 62.86; H 4.44; N, 10.35.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.47 (3H, s), 1.77 (3H, s), 4.70 (2H, s), 4.80 (2H, s), 5.70 (2H, s), 6.97- 7.83 (11H, m).

IR (Nuiol), cm ^-1 : 1785, 1760, 1690, 1550, 1205, 1035.

 Working Example 16. 1 - [[2 '- (2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylpyrazolo [1,5 -b] [1,2,4] triazole-7-carboxylic acid.

 16a) Ethyl 1 - [[2 '- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylpyrazolo [1,5-b] [1,2 , 4] triazole-7-carboxylate.

 To a solution of ethyl 2-propyl-1H-pyrazolo [1,5-b] [1,2,4] triazole-7-carboxylate (0.4 g), cooled in ice, in N, N-dimethylformamide (7 ml) was added sodium hydride (60%, oil; 72 mg) under nitrogen and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added a solution of the compound (1.15 g) obtained in working example (22c) in N, N-dimethylfamamide (7 ml). The mixture was stirred for 1 hour while cooling with ice, then 3 hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white amorphous powder (0.92 g, 89%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.01 (3H, t), 1.30 (3H, t), 1.70-1.88 (2H, m), 2.67 (2H, t), 4.27 (2H, q), 5.72 (2H, s), 7.14 (2H, d), 7.24 (2H, d), 7.40-7.60 (3H, m), 7.90-7.94 (1H, m), 8.00 (1H, s).

IR (KBr), cm ^-1 : 2970, 1692, 1600, 1538, 1470.

 16b) Ethyl 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylpyrazolo [1,5- b] [1,2,4] triazole-7-carboxylate.

 To a solution cooled by ice of a compound (0.92 g) obtained in working example (16a), in a mixture of dioxane (8 ml) and water (2 ml) was added 1N. NaOH (1.7 ml) and the mixture was stirred for 15 minutes while cooling with ice. 1N was added to the reaction mixture. HCl (2.5 ml) and water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent was evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate-ether to give the title compound as colorless crystals (0.666 g, 88%).

T. pl. 227-228 ^o C.

Elemental analysis of C ₂₅ H ₂₄ N ₆ O ₄ :
Calculated,%: C 63.55; H 5.12; N, 17.79.

 Found,%: C 63.53; H 5.20; N, 17.67.

¹ H-NMR (200 MHz, DMCO - d ₆ ) δ: 0.91 (3H, t), 1.16 (3H, t), 1.54-1.73 (2H, m), 2.73 (2H, t), 4.16 (2H, q ), 5.75 (2H, s), 7.26 (2H, d), 7.32 (2H, d), 7.48-7.73 (4H, m), 7.96 (1H, s).

IR (KBr), cm ^-1 : 3100, 2980, 1795, 1702, 1602, 1540, 1468.

 16c) 1 - [[2 '- (2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -2-propylpyrazolo [1,5- b] [1,2,4] -triazole-7-carboxylic acid.

 To a mixture of the compound (0.2 g) obtained in working example (16b) in a mixture of methanol (5 ml), tetrahydrofuran (5 ml) and water (5 ml) was added 2N. NaOH (2.1 ml) and the mixture was refluxed for 3 hours. The reaction mixture was cooled, 2N was added to it. HCl (3.0 ml) and water, then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (0.17 g, 90%).

T. pl. 223-225 ^o C.

Elemental analysis of C ₂₃ H ₂₀ N ₆ O ₄ • 0.2 AcOEt:
Calculated,%: C 61.87; H 4.71; N 18.19.

 Found,%: C 61.81; H 4.66; N, 18.28.

¹ H-NMR (200 MHz, DMCO - d ₆ ) δ: 0.90 (3H, t), 1.52-1.70 (2H, m), 2.71 (2H, t), 5.79 (2H, s), 7.32 (4H, s ), 7.50-7.73 (4H, m), 7.92 (1H, s), 12.35 (1H, broad s).

IR (KBr), cm ^-1 : 3060, 2960, 2700-2200, 1783, 1668, 1590, 1540, 1483.

 Working Example 17. 1 - [[2 '- (2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl-2-propylimidazo [1,2- b] pyrazole-7-carboxylic acid.

 17a) Ethyl-2-propyl - [[2 '- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] imidazole [1,2-b] pyrazol-7 carboxylate.

 By a reaction similar to that in working example (16a), the compound was obtained as a pale yellow oil (0.16 g, 47%) from ethyl 2-propyl-1H-imidazo [1,2-b] pyrazole-7-carboxylate (0.132 g).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.98 (3H, t), 1.28 (3H, t), 1.53-1.72 (2H, m), 2.46 (2H, t), 4.23 (2H, q), 5.75 (2H, s), 7.05 (2H, d), 7.14 (1H, s), 7.18 (2H, d), 7.41-7.63 (3H, m), 7.86-7.91 (1H, m), 8.01 (1H, from).

IR (undiluted), cm ^-1 : 2975, 1702, 1690, 1603, 1582, 1562, 1562, 1495.

 17b) Ethyl-1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylimidazo [1,2- b] pyrazole-7-carboxylate.

By carrying out a reaction similar to that described in working example (16b), the indicated compound was obtained in the form of colorless crystals (84 mg, 68%), mp 204-206 ^o C (ethyl acetate-ether), from the compound obtained in working example (17a) (0.15 g).

Elemental analysis of C ₂₆ H ₂₅ N ₅ O ₄ • 0.5H ₂ O:
Calculated,%: C 64.99; H 5.45; N, 14.57.

 Found,%: C 65.27; H 5.50; N, 14.38.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.99 (3H, t), 1.27 (3H, t), 1.53-1.72 (2H, m), 2.48 (2H, q), 5.74 (2H, s), 7.13 (2H, d), 7.27 (2H, d), 7.38-7.65 (3H, m), 7.80-7.84 (1H, m), 7.92 (1H, s), 8.31 (1H, broad).

IR (KBr), cm ^-1 : 3125, 2960, 1780, 1705, 1600, 1585, 1492, 1470.

 17c) 1 - [[2 '- (2,5-Dihydro-5-oxo-1,2,4-oxdiazol-3-yl) biphenyl-4-yl] methyl] -2-propylimidazo [1,2-b ] pyrazole-7-carboxylic acid.

By carrying out reactions similar to those described in working example (16c), the indicated compound was obtained in the form of colorless crystals (48 mg, 57%), mp 191-196 ^o C (decomp.) (Methanol-water), from the compound obtained in working example (17b) (90 mg).

Elemental analysis of C ₂₄ H ₂₁ N ₅ O ₄ :
Calculated,%: C 65.00; H 4.77; N, 15.79.

 Found,%: C 65.28; H 4.68; N, 15.72.

¹ H-NMR (200 MHz, DMCO - d ₆ ) δ: 0.89 (3H, t), 1.43-1.62 (2H, m), 2.43-2.51 (2H, m), 5.80 (2H, s), 7.18 (2H d), 7.29 (2H, d), 7.50-7.72 (5H, m), 11.87 (1H, broad s).

IR (KBr), cm ^-1 : 3025, 2960, 1700-2200, 1780, 1634, 1595, 1580, 1498.

 Working Example 18. Ethyl-2-ethyl-4,7-dihydro-7 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4- yl] methyl] -4-oxo-thieno [2,3-b] pyridine-5-carboxylate.

 18a) Ethyl-7 - [[2 '- (5-trichloromethyl-1,2,4-oxodiazol-3-yl) biphenyl-4-yl] methyl] -2-ethyl-4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylate.

 To an ice-cooled solution of ethyl 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-carboxylate (0.25 g) in N, N-dimethylfomamide (DMF) (7 ml) was added under a nitrogen atmosphere (60 % in oil; 40 mg) and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of the compound obtained in working example (22c) (0.6 g) in N, N-dimethylformamide (4 ml), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, the solvent was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white powder (0.5 g, 83%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.32 (3H, t), 1.41 (3H, t), 2.82 (2H, dc), 4.40 (2H, s), 5.22 (2H, s), 7.23-7.33 (5H, m), 7.43-7.65 (3H, m), 7.93-7.98 (1H, m), 8.39 (1H, s).

IR (KBr), cm ^-1 : 2975, 1672, 1580, 1493.

 Ethyl-2-ethyl-4,7-dihydro-7 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-oxo-thieno [2,3-b] pyridin-5-carboxylate.

 To an ice-cooled solution of the compound (0.49 g) obtained in working example (18a) in a mixture of dioxane (8 ml), tetrahydrofuran THF (8 ml) and water (4 ml) was added 1N NaOH (0.9 ml). After moving for 40 minutes under ice cooling, 1N was added to the mixture. NaOH (0.4 ml) and the mixture was stirred for 20 min under ice cooling. 1N was added to the reaction mixture. NaCl (2.0 ml) and water and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent was evaporated to dryness under reduced pressure. The residue was crystallized from methanol to give the title compound as colorless crystals (0.278 g, 68%).

T. pl. 243-235 ^o C.

Elemental analysis of C ₂₇ H ₂₃ N ₃ O ₅ S:
Calculated,%: C 64.66; H 4.62; N, 8.33.

 Found,%: C 64.70; H 4.70; N, 8.33.

¹ H-NMR (200 MHz, DMCO - d ₆ ) δ: 1.22 (3H, t), 1.29 (3H, t), 2.79 (2H, dc), 4.23 (2H, q), 5.50 (2H, s ), 7.10 (1H, t), 7.31-7.40 (4H, m), 8.77 (1H, s), 12.37 (1H, broad s.).

IR (KBr), cm ^-1 : 3430, 2980, 1782, 1727, 1602, 1542, 1500.

 Working Example 19. 3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propyl-4- ( 3H) -quinazolinone.

 19a) 3 - [[2- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propyl-4- (3H) -quinazolinone.

 To an ice-cooled solution of 2-propyl-4 (3H) -quinazoline (0.283 g) in N, N-dimethylfomamide (8 ml) was added sodium hydride (60% in oil; 60 mg) under nitrogen atmosphere and the mixture was stirred within 30 minutes To the reaction mixture was added a solution of the compound (0.78 g) obtained in working example (22c) in N, N-dimethylformamide (5 ml) and stirred for 4 hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated to dryness under reduced pressure. The precipitate was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.50 g, 62%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.02 (3H, t), 1.75-1.94 (2H, m), 2.75 (2h, t), 5.44 (2H, c0, 7.16 (2H, d), 7.41-7.79 (6H, m), 7.87-7.92 (1H, m), 8.28-8.32 (1H, m).

IR (neat), cm ^-1 : 2960, 1668, 1595, 1567.

 19b) 3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] - 2-propyl-4 (3H) - quinazolinone.

 To a mixture of the compound (0.42 g) obtained in working example (19a) with a mixture of dioxane (6 ml) and water (1.5 ml) was added 1N under ice-cooling. NaOH (1.0 ml). The mixture was stirred for 30 minutes while cooling with ice. 1N was added to the reaction mixture. HCl (2.0 ml) and water, and then the mixture was extracted with ethyl acetate.

 The organic layer was washed with water and dried, and the solvent was evaporated to dryness under reduced pressure. The precipitate was recrystallized from ethyl acetate-ether to give the title compound as colorless crystals (0.311 g, 91%).

T. pl. 251-253 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₃ :
Calculated,%: C 81.22, H 5.06, N 12.78.

 Found,%: C 70.93, H 5.04, H 12.72.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: (3H, t), 1.63-1.82 (2H, m), 2.74 (2H, t), 5.45 (2H, d ), 7.31 (2H, d), 7.49-7.74 (6H, m), 7.80-7.88 (1H, m), 8.16-8.20 (1H, m), 12.38 (1H, n.)
IR (KBr), cm ^-1 : 3120, 2970, 1768, 1638, 1605, 1590.

 Working Example 20. Methyl-2-butyl-1 - [[2- (4,4-dihydro-5-oxo-6H-1,2,4-oxadiazin-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

 20a) Methyl-2-butyl-1- [2 - (- ethoxycarbonylmethyl (hydroxycarbamimidoyl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

A mixture of the compound (20.0 g) obtained in working example (1c), ethyl bromoacetate (0.84 g) and potassium carbonate (0.67 g) in acetonitrile (20 ml) was stirred for 15 minutes at room temperature. Saturated aqueous saline was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (Mgso ₄ ), and then the solvent was evaporated in vacuo. The precipitate was purified by silica gel column chromatography (80 g) to obtain the title compound (1.10 g, 42%) as an oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.4 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.48 (2H , m), 1.49 (2H, m), 2.94 (2H, t, J = 7.6 Hz), 3.74 (3H, s), 4.20 (2H, q, J = 7, 2 Hz), 4.45 (2H, br.s), 4.56 (2H, s) 5.77 (H, s), 6.89 (2H, d, J = 0.8 Hz), 7, 19-7.70 (8H, m), 7.94 (1H, dd, J = 1.2 Hz, 7.8 Hz).

IR (neat), cm ^-1 : 3480, 3375, 1750, 1725, 1715, 1635, 1600.

 20b) Methyl-2-butyl-1 - [[2 '- (4,5, -dihydro-5-oxo-6H-1,2,4-oxadiazin-3-yl) biphenyl-4-yl] methyl] benzimidazole -7-carboxylate.

A mixture of the compound (1.10 g) obtained in working example (20a) and p-toluenesulfonic acid chloride (0.1 g) in toluene (20 ml) was boiled under reflux for 18 hours. The reaction mixture was concentrated to dryness and a precipitate extracted with chloroform. The extract was washed with water and dried (MgSO ₄ ), and then the solvent was evaporated in vacuo. The precipitate was purified by silica gel column chromatography (80 g) to obtain the title compound as colorless crystals (0.25 g, 25%).

T. pl. 226-227 ^o C.

Elemental analysis for C ₂₉ H ₂₈ N ₄ O ₄ • 1/2 H ₂ O
Calculated,%: C 68.90; H 5.78; N, 11.08.

 Found,%: C 69.06; H 5.78; N, 10.73.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.40 (2H, m), 1.77 (2H, m), 2 88 (2H, t, J = 7.4 Hz), 3.65 (2H, s), 4.15 (2H, s), 5.72 (H, s), 6.89 (2H, d, J = 8.4 Hz), 7.27-7.64 (8H, m), 7.87 (1H, dd, J = 1.0 Hz, 8.0 Hz), 10.91 (1H, br. from.).

 Working Example 21. 2-butyl-1 - [[2 '- (2,4,-dioxothiazolidin-5-yl) biphenyl-4-yl] methyl] benzimidazole.

 21a) 2-butyl-1 [[2'-hydroxymethylbiphenyl-4-yl] methyl] benzimidazole.

A mixed solution of 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] benzimidazole (1.50 g) in benzene (30 ml) was added dropwise to sodium dihydro-bis (2-methoxyethoxy) aluminate (70 % solution in toluene). The mixture was moved 1 h at room temperature and then boiled for 10 min under reflux. The reaction mixture was cooled, poured 2 N. HCl and was extracted with dichloromethane. The extract was washed with water and dried (MgSO ₄ ), and the solvent was evaporated in vacuo. The precipitate was purified by silica gel column chromatography (80 g) to obtain the title compound (0.67 g, 46%) as an oil, which was crystallized from ethyl acetate-ether to give pale yellow prisms.

T. pl. 162-163 ^o C.

Elemental analysis for C ₂₅ H ₂₆ N ₂ O • 1 / 3H ₂ O:
Calculated,%: C 79.75; H 7.14; N, 7.44.

 Found,%: C 78.75; H 7.01; N, 7.29.

¹ H (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t, J = 7.2 Hz), 1.43 (2H, m), 1.83 (2H, m), 1.86 (1H , s), 2.87 (2H, t, J = 7.4 Hz), 4.57 (2H, s), 5.39 (2H, s), 7.09 (2H, d, J = 8, 4 Hz), 7.19-7.61 (9H, m), 7.72-7.81 (1H, m).

IR (Nujol), cm ^-1 : 3170.

 21b) 2-butyl-1 - [(2-formylbiphenyl-4-yl) methyl] benzimidazole.

 A mixture of the alcohol (0.65 g) obtained in working example (21a) and pyridinium dichromate (0.67 g) in dichloromethane (20 ml) was stirred for 15 hours at room temperature. Insoluble material was filtered off and the filtrate was concentrated to dryness. The precipitate was purified by silica gel column chromatography (60 g) to obtain the indicated product as an oil (0.52 g, 80%), which was crystallized from isopropyl ether to form colorless crystals (0.46 g, 71%).

T. pl. 117-118 ^o C.

Elemental analysis for C ₂₅ H ₂₄ N ₂ O • 1 / 5H ₂ O:
Calculated,%: C 80.72; H 6.61; N, 7.53.

 Found,%: C 80.73; H 6.55; N, 7.41.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.2 Hz), 1.45 (2H, m), 1.86 (2H, m), 2.88 (2H, t, J = 7.4 Hz), 5.42 (2H, s), 7.14 (2H, d, J = 7.8 Hz), 7.21-7.68 (8H, m) 7.76-7.83 (1H, m), 8.01 (1H, dd, J = 1.6 Hz, 7.6 Hz), 9.94 (1H, s).

IR (Nujol), cm ^-1 : 1690, 1655, 1615, 1595.

 21c) 2-butyl-1 - [[2 '- (2,4-dioxothiazolin-5-yl) biphenyl-4-yl] methyl] benzimidazole.

To a mixed mixture of the aldehyde obtained in working example 21 (b), (0.44 g) in ethyl acetate (4 ml) and tetrahydrofuran (4 ml) was added an aqueous solution (2 ml) of sodium sulfate and an aqueous solution (1.2 ml) potassium cyanate (0.78 g). The reaction mixture was stirred for 4 hours at room temperature and then another 1 hour at 60 ^° C. The reaction mixture was concentrated in vacuo and water was added to the precipitate, and then extracted with chloroform. The extract was washed with water and dried (MgSO ₄ ), and the solvent was evaporated in vacuo. The precipitate crystallized from ether to form cyanohydrin (0.43 g, 91%) as colorless crystals. The product was used for the corresponding reactions without further purification.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (3H, t, J = 7.4 Hz), 1.25 (2H, m0, 1.61 (2H, m), 2.69 ( 2H, t, J = 7.6 Hz), 5.32 (2H, s), 5.51 (1H, s), 7.03 (2H, d, J = 8.0 Hz), 7.11- 7.60 (9H, m), 7.92 (1H, dd, J = 1.8 Hz).

IR (Nujol), cm ^-1 : 3420, 2230, 1615.

Thionyl chloride (0.11 ml) was added to a solution of cyanhydride (0.41 g) obtained by the above reaction in chloroform (2.5 ml). The mixture was refluxed with constant stirring for 1.5 hours. The reaction mixture was concentrated to dryness to give an oil. A mixture of oil and thiourea (88 mg) in ethanol (10 ml) was refluxed for 1 h. 2N was added to the reaction mixture. HCl (10 ml) and refluxed overnight (16 h). The reaction mixture was cooled, water was added and extracted with chloroform. The extract was washed with water and dried (MgSO ₄ ), and then evaporated in vacuo. The precipitate was purified by silica gel column chromatography (70 g) to obtain crystals. Recrystallization from ethyl acetate gave the title compound (0.31 g, 66%) as colorless prisms.

T. pl. 249-250 ^o C.

Elemental analysis for C ₂₇ H ₂₅ N ₃ O ₂ :
Calculated,%: C 71.18; H 5.53; N, 9.22.

 Found,%: C 70.93; H 5.51; N, 9.09.

¹ H-NMR (200 MHz, DMCl-d ₆ ) δ: 0.88 (3H, t, J = 7.4 Hz), 1.38 (2H, m), 1.74 (2H, m), 2 87 (2H, t, J = 7.4 Hz), 5.52 (1H, s), 5.56 (2H, s), 7.13-7.64 (12H, m), 12.20 (1H, w).

IR (Nujol), cm ^-1 : 1690.

 Working Example 22. 2-butyl-4-chloro-5-formyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4- ml] methyl] imidazole.

 22a) 4'-methylbiphenyl-2-carboxamidoxime.

To a solution of hydroxylamine hydrochloride (17.9 g) in dimethyl sulfoxide (120 ml) was added a methanol solution of sodium methoxide obtained from sodium metal (5.92 g) and anhydrous methanol (50 ml). The mixture was stirred for 10 minutes at room temperature and 2'-cyano-4-methylbiphenyl (10 g) was added. The reaction mixture was stirred for 5 hours at 100 ^° C. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous solution was extracted with ethyl acetate. The organic layers were combined, washed with water and dried, and then the solvent was evaporated in vacuo. The precipitate was purified by silica gel column chromatography, and the indicated amorphous product compound (11.2 g, 96%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 4.42 (2H, br s), 7.22 (2H, d), 7.31-7.50 ( 5H, m), 7.56-7.60 (1H, m).

IR (KBr), cm ^-1 : 3490, 3380, 1642, 1575, 1568.

 22b) 5-trichloromethyl-3- (4'-methylbiphenyl-2-id) -1,2,4-oxadiazole.

 Trichloroacetic anhydride was added dropwise to a solution of the compound (10 g) obtained according to working example (22a) in benzene (100 ml), and the reaction mixture was then refluxed for 2 hours. The reaction mixture was cooled and concentrated to dryness. The residue was partitioned between ether and water. The aqueous layer was extracted with ether. The organic layers were combined, washed with water and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil (12 g, 77%).

¹ H-NMR (200 MHz, CDCl ₃ ), delta: 2.38 (3H, s), 7.16 (4H, s), 7.44-7.64 (3H, m), 7.88-7 93 (1H, m).

IR (neat), cm ^-1 : 3025, 1600, 1580, 1561, 1508.

 22c) 3- (4'-bromomethylbiphenyl-2-yl) -5-trichloromethyl-1,2,4-oxadiazole.

 To a solution of the compound (24.8 g) obtained in working example (22b) in carbon tetrachloride (300 ml) was added N-bromosuccinimide (12.5 g) and α, α-azobisisobutyronitrile (1.15 g) and the mixture was boiled 2 hours under reflux. The reaction mixture was cooled and insoluble materials were filtered. The filtrate was dissolved in dichloromethane. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was pericrystallized from an ether-hexane mixture to give the title compound as colorless crystals (23.0 g, 76%).

T. pl. 77-79 ^o C.

Elemental analysis for C ₁₆ H ₁₀ N ₂ OBCl ₃ • 0.5H ₂ O:
Calculated,%: C 43.52; H 2.51; N, 6.34.

 Found,%: C: 43.76; H 2.33; N, 6.31.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.52 (2H, s), 7.23 (2H, d), (2H, d), 7.44-7.65 (3H, m), 7.91-7.95 (1H, m).

IR (KBr), cm ^-1 : 1600, 1560, 1475, 1428, 1332.

 22d) 2-butyl-4-chloro-1 - [[2- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5-formylimidazole.

 To a cooled solution of sodium metal (26 mg) in anhydrous methanol (2 ml) was added dropwise a solution of 2-butyl-4-chloro-5-formylimidazole (0.2 g) in methanol (3 ml) in a nitrogen atmosphere. The mixture was stirred for 1 h at room temperature and concentrated to dryness. To a solution of the residue in N, N-dimethylformamide (2 ml) was added dropwise a solution of the compound (0.56 g) obtained in working example (22c) in N, N-dimethylformamide (3 ml) while cooling the mixture with ice. The reaction mixture was stirred for 2.5 hours at room temperature and concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the indicated product was obtained as a colorless oil (0.44 g, 76%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.91 (3H, t), 1.28-1.46 (2H, m), 1.63-1.78 (2H, m), 2, 65 (2H, t), 5.59 (2H, s), 7.05 (2H, d), 7.23 (2H, d), 7.41-7.65 (3H, m), 7.90 -7.95 (1H, m); 9.77 (1H, s).

IR (neat), cm ^-1 : 2960, 1670, 1652, 1580, 1565, 1510.

 22e) 2-butyl-4-chloro-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5 Formylimidazole

 To a solution of the compound obtained in working example (22d) in a mixture of dioxane (4 ml) and water (1 ml) was added 1N NaOH (0.75 ml) under ice cooling. The mixture was stirred for 30 minutes while cooling with ice. 1N was added to the reaction mixture. HCl (1 ml) and water, and then extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was evaporated under reduced pressure. The residue was crystallized from ether-hexane to give the title compound as white crystals (0.255 g, 87%).

T. pl. 181-183 ^o C.

Elemental analysis for C ₂₃ H ₂₁ N ₄ O ₃ Cl • 0.2H ₂ O:
Calculated,%: C 62.71; H 4.90; N, 12.72.

 Found,%: C 62.71; H 4.79; N, 12.62.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.91 (3H, t), 1.29-1.48 (2H, m), 1.63-1.79 (2H, m), 2, 68 (2H, t), 5.55 (2H, s), 7.10 (2H, d), 7.31 (2H, d), 7.38-7.67 (3H, m), 7.80 (1H, dd), 8.50 (1H, br), 9.68 (1H, s).

IR (KBr), cm ^-1 : 2960, 1772, 1673, 1522, 1490, 1460.

 Working Example 23. 2-Butyl-4-chloro-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl ] -5-hydroxymethylimidazole.

 Sodium hydroxide (16 mg) was added to a solution of the compound (0.15 g) obtained in working example (22e) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) and the mixture was stirred at room temperature for 1 h. ice-water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was evaporated in vacuo under reduced pressure. The residue was recrystallized from ether-hexane to give the title compound as white crystals (67 mg, 45%).

T. pl. 202-205 ^o C.

Elemental analysis for C ₂₃ H ₂₃ N ₄ O ₃ Cl • 0.1Et ₂ O • 0.5H ₂ O:
Calculated,%: C 61.73; H 5.53; N, 12.30.

 Found,%: C 61.81; H 5.56; N, 12.07.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.80 (3H, t), 1.16-1.34 (2H, m), 1.40-1.55 (2H, m), 2.45-2.52 (2H, m), 4.34-4.36 (2H, m), 5.25 (1H, s), 5.29 (2H, s), 7.14 (2H, d) 7.48-7.72 (4H, m).

HK (KBr), cm ^-1 : 3470, 2960, 1755, 1501, 1463.

 Working Example 24. 5-Butyl-3-ethoxycarbonyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] pyrazole.

 24a) 5-butyl-3-ethoxycarbonyl-1 - [[2 '- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] pyrazole.

 Sodium hydride (60%) was added to an ice-cooled solution of 3-butyl-5-ethoxycarbonylpyrazole (0.3 g) and the compound (0.95 g) obtained in working example (22c) in anhydrous tetrahydrofuran (100 ml) under nitrogen atmosphere , 61 mg). The mixture was stirred for 10 minutes at room temperature and then refluxed for 3 hours. The reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil (0.29 g, 35%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t), 1.26-1.44 (2H, m), 1.40 (3H, t), 1.50-1, 68 (2H, m), 2.49 (2H, s), 4.41 (2H, s), 5.41 (2H, s), 6.64 (1H, s), 7.08 (2H, d) ), 7.20 (2H, d), 7.40-7.63 (3H, m), 7.88-7.92 (1H, m).

IR (neat), cm ^-1 : 2950, 1715, 1578, 1565.

 24b) 5-butyl-3-ethoxycarbonyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxodiazol-3-yl) biphenyl-4-yl] methyl] pyrazole.

 To a solution of the compound (0.27 g) obtained in working example (24a) in a mixture of dioxane (4 ml) and water (1 ml) was added 1N under ice cooling. NaOH (0.6 ml). The mixture was stirred for 20 minutes while cooling with ice. 1N was added to the reaction mixture. HCl (0.9 ml) and water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was recrystallized from ether-hexane to give the title compound as colorless crystals (0.176 g, 80%).

T. pl. 166-168 ^o C.

Elemental analysis for C ₂₅ H ₂₆ N ₄ O ₄ :
Calculated,%: C 67.25; H 5.87; N, 12.55.

 Found,%: C 66.99; H 5.91; N, 12.45.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: (3H, t), 1.28-1.46 (2H, m), 1.37 (3H, t), 1.53-1.68 (2H , m), 2.56 (2H, s), 4.35 (2H, s), 5.36 (2H, s), 6.64 (1H, s), 7.15 (2H, d), 7 30 (2H, d), 7.37-7.65 (3H, m), 7.79-7.83 (1H, m), 8.49 (1H, m), 8.49 (1H, br )

IR (KBr), cm ^-1 : 2960, 1725, 1600, 1485.

 Working Example 25. 2-butyl-4-chloro-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl ] imidazole-5-carboxylic acid.

 An aqueous solution (2.5 ml) of potassium permanganate (0.147 g) was added to a solution of the compound (0.27 g) obtained in working example (22e) in pyridine (5 ml). The mixture was stirred for 3 hours at room temperature. Then the reaction mixture was concentrated to dryness under reduced pressure. Ethyl acetate and dilute hydrochloric acid were added to the residue. The resulting suspension was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, and the product was crystallized from ethyl acetate-isopropyl ether to give the title compound as colorless crystals (0.17 g, 61%).

T. pl. 188-189 ^o C (decomposition).

Elemental analysis for C ₂₃ H ₂₁ N ₄ O ₄ Cl • 0.1AcOEt • 2.9H ₂ O:
Calculated,%: C 54.69; H 5.41; N, 10.90.

 Found,%: C 54.91; H 5.17; N, 10.62.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.80 (3H, t), 1.16-1.35 (2H, m), 1.43-1.58 (2H, m), 2.46-2.53 (2H, m), 5.80 (2H, s), 6.95 (2H, d), 7.25 (2H, d), 7.29-7.51 (4H, m).

IR (KBr), cm ^-1 : 3390, 2960, 1765, 1648, 1590, 1525, 1488.

 Working Example 26. 2-butyl-4-chloro-1 - [[2 '- (2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] imidazole-5-carbaldehyde.

Sodium hydride (60% in oil; 44 mg) was added to an ice-cooled solution of 2-butyl-4-chlorimidazole-5-carbaldehyde (0.19 g) in N, N-dimethylformamide (1 ml), and the mixture was stirred for 10 min. Then, 5- (4'-bromomethylbiphenyl-2-yl) 2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2-one (0.57 g) was added to the mixture. The reaction mixture was stirred for 1.5 hours at room temperature, then diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. The crude product thus obtained was dissolved in trifluoroacetic acid (4 ml), and the solution was stirred at 60 ^° C. for 30 minutes. Trifluoroacetic acid was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with an aqueous solution of sodium bicarbonate and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. The crude crystals thus obtained were recrystallized from an ethyl acetate-hexane mixture to give the title compound as colorless prisms (0.12 g, 27%).

T. pl. 178-179 ^o C.

Elemental analysis for C ₂₃ H ₂₁ N ₄ ClO ₃ :
Calculated,%: C 63.23; H 4.84; N, 12.83.

 Found,%: C 63.07; H 4.87; N, 12.69.

¹ H-NMR (200 MHz, CLCl ₃ ) δ: 0.90 (3H, t), 1.28-1.46 (2H, m), 1.62-1.78 (2H, m), 2, 68 (2H, t), 5.59 (2H, s), 7.08 (2H, d), 7.26 (2H, d), 7.35 (1H, dd), 7.43 7.60 ( 2H, m), 7.79 (1H, dd), 8.85 (1H, br), 9.76 (1H, s).

IR (neat), cm ^-1 : 1810, 1775, 1660, 1455, 1340, 1275, 900, 840, 770, 750.

 Working Example 27. 2-butyl-4-chloro-1 - [[2 '- (2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] -5-imidazolemethanol.

To a solution of the compound (50 mg) obtained in working example 26 in methanol (5 ml) was added sodium borohydride (4 mg) and the mixture was stirred for 1 h at 0 ^° C. The solvent was evaporated under reduced pressure and the pH of the residue was adjusted to 3- 4 1 n. HCl. The crystalline precipitate was filtered off and recrystallized from ethyl acetate-hexane to give the title compound as colorless prisms (47 mg, 94%).

T. pl. 163-164 ^o C.

Elemental analysis for C ₂₃ H ₂₃ N ₄ ClO ₃ :
Calculated,%: C 62.94; H 5.28; N, 12.76.

 Found,%: C 62.76; H 5.16; N, 12.54.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.25-1.41 (2H, m), 1.58-1.70 (2H, m), 2, 62 (2H, t), 4.50 (2H, s), 5.24 (2H, s), 7.06 (2H, d), 7.27 (2H, d), 7/37 (1H, dd ), 7.43-7.59 (2H, m), 7.81 (1H, dd), 9.93 (1H, br).

IR (KBr), cm ^-1 : 3400, 1800, 1775, 1455, 1410, 1340, 1260, 1000, 900, 770, 750.

 Working Example 28. 1,2,4,5-ethoxycarbonyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4- (3H) -pyrimidinone.

28a) 2-butyl-5-ethoxycarbonyl-3 - [[2 '- (5-trichloromethyl-1,2,3-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4 (3H) -pyrimidinone
To an ice-cooled solution of 2-butyl-5-ethoxycarbonyl-4-hydroxypyrimidine (0.36 g) in anhydrous tetrahydrofuran (8 ml) under nitrogen atmosphere was added sodium hydride (60% in oil, 65 mg) and the mixture was stirred for 15 min at room temperature. To the reaction mixture was added a solution of the compound (1.02 g) obtained in working example (22c) in anhydrous tetrahydrofuran (5 ml), and the mixture was refluxed for 6 hours. The reaction mixture was then cooled, added to water and extracted with ethyl acetate. . The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.18 g, 20%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t), 1.29-1.47 (2H, m), 1.39 (3H, t), 1.64-1, 79 (2H, m), 2.75 (2H, t), 4.39 (2H, q), 5.38 (2H, s), 7.19 (2H, d), 7.25 (2H, d) ), 7.41-7.65 (3H, m), 7.93 (1H, dd), 8.64 (1H, s).

IR (neat), cm ^-1 : 2960, 1748, 1705, 1685, 1580, 1521.

 28b) 2-butyl-5-ethoxycarbonyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4 (3H) -pyrimidinone.

 The compound (0.18 g) obtained in working example (28a) was dissolved in a mixture of dioxane (4 ml) and water (1 ml). 1N was added to the ice-cooled solution. NaOH (0.4 ml) and the reaction mixture were stirred for 30 minutes under ice-cooling. After adding 1 N. HCl (0.6 ml) and water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was evaporated under reduced pressure. The residue was purified on a silica gel column. The crude product thus obtained was recrystallized from ethyl acetate-isopropyl ether to give the title compound as colorless crystals (62 mg, 42%).

T. pl. 151-154 ^o C).

Elemental analysis for C ₂₆ H ₂₆ N ₄ O ₅ • 0.1H ₂ O:
Calculated,%: C 65.56; H 5.54; N, 11.76.

 Found,%: C 65.41; H 5.68; N, 11.62.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.91 (3H, t), 1.28-1.48 (2H, m), 1.34 (3H, t), 1.65-1, 80 (2H, m), 2.79 (2H, t), 4.31 (2H, q), 5.30 (2H, s), 7.22 (2H, d), 7.32 (2H, d) ), 7.37-7.65 (3H, m), 7.78 (1H, dd), 8.61 (1H, s).

IR (KBr), cm ^-1 : 3210, 2960, 1795, 1705, 1660, 1523.

 Working Example 29. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -6-propoxy-3-propyluracil .

 29a) 6-chloro-1 - [[2- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] - 3-propyluracil.

 Sodium hydride (60% in oil; 43 mg) was added to a ice-cooled solution of 6-chloro-3-propyluracil (0.2 g) in N, N-dimethylformamide (4 ml) under nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added a solution of the compound (0.64 g) obtained in working example (22c) in N, N-dimethylformamide (4 ml). The mixture was stirred for 2.5 hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue, and then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.43 g, 75%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95 (3H, t), 1.56-1.76 (2H, m), 3.91 (2H, t), 5.29 (2Y, s), 5.93 (1H, s), 7.24 (2H, d), 7.31 (2H, d), 7.43-7.64 (3H, m), 7.89-7.93 (1H, m).

IR (neat), cm ^-1 : 2960, 1712, 1668, 1608, 1582, 1568, 1508.

 29b) 1 - [[2 '- (2,4-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -6-propoxy-3-propyluracil.

To a solution of the compound (0.42 g) obtained in working example (29a) in a mixture of dioxane (4 ml) and water (1 ml) was added ice-cold 1 N NaOH. The mixture was stirred for 30 minutes while cooling with ice, and then 1N was added to the reaction mixture. HCl (1.5 ml) and water and was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of propanol (4 ml) and N, N-dimethylformamide (4 ml). A solution of sodium peroxide prepared from sodium metal (72 mg) and propanol (2 ml) were added dropwise to an ice-cooled solution, and then the solution was heated for 1.5 hours at 100-110 ^° C. The reaction mixture was cooled and then concentrated to dryness under reduced pressure. Diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography. The crude product thus obtained was recrystallized from ethyl acetate-hexane to give the title compound as colorless crystals (0.223 g, 63%).

T. pl. 129 - 132 ^o C.

Elemental analysis for C ₂₅ H ₂₆ N ₄ O ₅ :
Calculated,%: C 64.92; H 5.67; N, 12.11.

 Found,%: C 64.82; H 5.77; N, 11.91.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t), 1.00 (3H, t), 1.56-1.76 (2H, m), 1.74-1, 93 (2H, m), 3.85 (2H, t), 3.98 (2H, t), 55.11 (2H, s), 5.15 (1H, s), 7.28-7.67 (7H, m), 7.81-7.86 (1H, m), 8.15 (1H, br.s.).

IR (KBr), cm ^-1 : 3120, 2970, 1775, 1705, 1638, 1472.

 Working Example 30. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylbenzimidazol-7- carboxylic acid.

 30a) Methyl-1 - [[2-cyannobiphenyl-4-yl) methyl] -2-propylbenzimidazole-7-carboxylate.

To a solution of methyl-3-amino-2- [2'-cyanobiphenyl-4-yl) methyl] benzoate (1.43 g) in dioxane (8 ml) was added oil aldehyde (950 mg) and the solution was stirred for 3 hours at room temperature and then another 2 hours at 110 ^° C. Concentrated HCl (1 ml) was added to the reaction mixture and the mixture was stirred for 15 hours at 80 ^° C. The reaction mixture was partitioned between ethyl acetate (150 ml) and aqueous sodium bicarbonate (70 ml) ) The top layer was washed twice with water (50 ml) and concentrated under reduced pressure. The crystalline product was recrystallized from ethyl acetate-ether to give the title compound as colorless prisms (1.4 g, 85%).

T. pl. 128 - 129 ^o C.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.10 (3H, t), 1.77-2.10 (2H, m), 2.87 (3H, t), 3.67 (3H, s), 5.77 (2H, s), 6.93 (2H, d), 7.13-7.77 (8H, m), 7.93 (1H, d).

IR (Nujol), cm ^-1 : 2225, 1710, 1450, 1280, 1270, 1200, 1130, 760.

 30b) Methyl-1 - [(2 ') - hydroxycarbamimidoyl) biphenyl-4-yl) methyl] -2-propylbenzimidazole-7-carboxylate.

To a solution of hydroxylamine hydrochloride (2.78 g) in DMCO (12 ml) was added triethylamine (4.04 g) and tetrahydrofuran (15 ml), and then the resulting crystals were filtered. The filtrate was concentrated to dryness under reduced pressure. To the residue were added methyl-1 - [(2'-cyano-biphenyl-4-yl) methyl] -2-propylbenzimidazole-7-carboxylate (1.6 g) and triethylamine (1 g). The mixture was stirred for 15 hours at 75 ^° C. and then dissolved in ethyl acetate (200 ml). The solution was washed with water (200 ml and 50 ml x 3), dried and evaporated under reduced pressure. At the end of these operations, the indicated compound was obtained in the form of a pale yellow product (1.57 g, 89%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.10 (3H, t), 1.73-2.10 (2H, m), 2.90 (2H, t), 3.70 (3H, s), 4.33 (2H, s), 5.73 (2H, s), 6.87 (2H, d), 7.10-7.67 (8H, m), 7.93 (1H, d) )

IR (Nujol), cm ^-1 : 1720, 1440, 1380, 1290, 1265.

 30c) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylbenzimidazole-7-carboxylate .

 To a solution of methyl-1 - [(2'-N-hydroxyamidinobiphenyl-4-yl) methyl] -2-propylbenzimidazole-7-carboxylate (1.5 g) in DMF (8 ml) was added pyridine (240 mg) and 2- chloroformate ethylhexyl ester (556 mg) with constant stirring and cooling in an ice bath. The mixture was stirred under these conditions for 0.5 h, then methanol (3 ml) was added and the mixture was stirred for another 0.5 h at room temperature. The reaction mixture was dissolved in ethyl acetate (250 ml) and the solution was washed with water (200 ml and 50 ml x 3). Ethyl acetate was evaporated under reduced pressure. The residue was dissolved in xylene (150 ml) and the solution was boiled under reflux for 4 hours. The reaction mixture was then allowed to stand at room temperature for 20 hours and the indicated compound was obtained as colorless prisms (1.03 g, 58%).

T. pl. 224 - 226 ^o C.

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₄ • 1/2 C ₈ H ₁₀ :
Calculated,%: C 71.46; H 5.60; N, 10.74.

 Found,%: C 71.41; H 5.44; N, 10.53.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 0.90 (3H, t), 1.13-1.73 (2H, m), 2.43 (2H, t), 3.57 (3H, s), 5.57 (2H, s), 6.50-7.93 (11H, m).

IR (Nujol), cm ^-1 : 1770, 1720, 1267.

 30d) 1 - [[2 '- (2,5-dihydro-2-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylbenzimidazole-7-carboxylic acid .

Mixture of methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadisol-3-yl) -biphenyl-4-yl] methyl] -2-propylbenzimidazole-7-carboxylate (703 mg) in 0.3 n. NaOH (12 ml) was stirred 1 h at 60 ^o C and then 0.1 N. HCl adjusted the pH of the mixture to 3. The resulting precipitate was extracted with a mixture of chloroform: ethanol (10: 1, 150 ml). The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol to give the title compound as colorless prisms (550 mg, 90%).

T. pl. 169-171 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₄ :
Calculated,%: C 67.38; H 5.00; N, 12.09.

 Found,%: C 67.39; H 4.85; N, 11.91.

¹ H-NMR (90 MHz, DMCO d ₆ -CDCl ₃ ) δ: 1.03 (3H, t), 1.67-2.10 (2H, m), 2.83 (2H, t), 5, 97 (2H, s), 7.00 (2H, d), 7.20-8.03 (9H, m).

IR (Nujol), cm ^-1 : 1785, 1710, 1500, 1380, 760.

 Working Example 31. 2-ethyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 -carboxylic acid.

 31a) Methyl-1- [2'-cyanobiphenyl-4-yl) methyl] -2-ethylbenzimidazole-7-carboxylate.

 Methyl 3-amino-2- [2'-cyanobiphenyl-4-yl) methyl] benzoate (1.79 g) was treated with propionic anhydride (1.04 g) similarly to the method described in working example (30a). The product was recrystallized from ethyl acetate to give the title compound as colorless prisms (1.5 g, 76%).

T. pl. 153-154 ^o C.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.47 (3H, t), 2.90 (2H, s), 3.73 (3H, s), 5.83 (2H, s), 6 97 (2H, d), 7.30-7.83 (9H, m), 7.97 (1H, d).

IR (Nujol), cm ^-1 : 2225, 1725, 1710, 1480, 1440, 1285, 1250, 1205, 1120.

 31b) Methyl-2-ethyl-1 - [(2 '- (hydroxycarbamimidoyl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate.

 Methyl-1 - [(2 '- (cyanobiphenyl-4-yl) methyl] -2-ethylbenzimidazole-7-carboxylate (2 g) was subjected to the same reaction as described in working example (30b), and as a result, the above compound in the form of a pale yellow gummy substance (1.85 g, 85%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.43 (3H, t), 2.97 (2H, q), 3.73 (3H, s), 4.40 (2H, w), 5 73 (2H, s), 6.90 (2H, d), 7.17-7.80 (8H, m), 7.97 (1H, d).

IR (Nujol), cm ^-1 : 1720, 1380, 1290, 1265.

 Working Example 32. 2-Cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 32a) Methyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-cyclopropylbenzimidazole-7-carboxylate.

 Methyl-3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] benzoate (1.79 g) was treated with cyclopropanecarboxylic anhydride (1.3 g) according to the method described in working example (30a), with the formation the specified compound in the form of an orange syrup (1.85 g, 91%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.00-1.40 (4H, m), 1.87-2.23 (1H, m), 3.70 (3H, s), 5, 93 (2H, s), 7.00-7.93 (11H, m).

IR (Neat), cm ^-1 : 2225, 1720, 1710, 1525, 1440, 1285.

 32b) Methyl-2-cyclopropyl-1 - [(2- (hydroxycarbamimidoyl) biphenyl-4-yl) methyl-benzimidazole-7-carboxylate.

 Methyl-1 - [(2'-cyanobiphenyl-4-yl) methyl) -2-cyclopropylbenzimidazole-7-carboxylate (1.8 g) was subjected to the same reaction as described in working example (32b), resulting in the specified compound as a pale yellow syrup (1.75 g, 90%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 0.97-1.43 (4H, m), 1.80-2.17 (1H, m), 3.70 (3H, s), 4, 33 (2H, br), 5.87 (2H, s), 6.87 (2H, d), 7.10-7.63 (8H, m), 7.87 (1H, d).

IR (Nujol), cm ^-1 : 1720, 1440, 1380, 1290, 1265, 760.

 32c) Methyl-2-cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate.

 Methyl-2-cyclopropyl-1 - [(2'-N-hydroxyiminocarboxamide biphenyl-4-yl) methyl] benzimidazole-7-carboxylate (1.7 g) was subjected to the same reaction as described in working example (30c). Xylene was evaporated from the reaction mixture under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as colorless prisms (780 mg, 48%).

T. pl. 188-190 ^o C.

Elemental analysis for C ₂₇ H ₂₂ N ₄ O ₄ :
Calculated,%: C 69.52; H 4.75; N, 12.01.

 Found,%: C 69.52; H 4.77; N, 11.90.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 0.87 - 1.07 (4H, m), 1.53-1.80 (1H, m), 3.73 (3H, s), 5, 87 (2H, s), 6.83-7.87 (11H, m).

IR (Nujol), cm ^-1 : 1778, 1765, 1728, 1716, 1211.

 32d) 2-cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

 Methyl-2-cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate ( 550 mg) was subjected to the same reaction as described in working example (30d). The product was recrystallized from ethyl acetate to give the title compound as colorless prisms (480 mg, 90%).

T. pl. 199-200 ^o C.

Elemental analysis for C ₂₈ H ₂₀ N ₄ O ₄ • 1/3 H ₂ O:
Calculated,%: C 68.11; H 4.54; N, 12.22.

 Found,%: C 68.16; H 4.61; N, 12.03.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 0.93-1.30 (4H, m), 2.07-2.40 (1H, m), 6.07 (2H, s), 7.00-7.83 (11H, m), 12.27 (1H, br).

IR (Nujol), cm ^-1 : 1755, 1703, 1699, 1257.

 Working Example 33. 2-butyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 Methyl ether (0.53 g) obtained in working example 2 was subjected to the same reaction as described in working example (30d), followed by the formation of the indicated compound as colorless prisms (0.36 g, 64%).

T. pl. 165-167 ^o C.

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₄ • 1/3 CHCl ₃ :
Calculated,%: C 64.59; H 4.83; N, 11.02.

 Found,%: C 64.76; H 4.95; N, 10.83.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 0.90 (3H, t), 1.13-2.00 (4H, m), 2.83 (2H, t), 5.93 ( 2H, s), 6.93 (2H, d), 7.13-7.90 (9H, m).

IR (Nujol), cm ^-1 : 1770, 1440, 1420, 1250, 765.

 Working Example 34. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylthiobenzimidazole-7-carboxylic acid.

 34a) Methyl-2- (2'-cyanobiphenyl-4-yl) methylamino-3-methoxycarbonylaminobenzoate.

 Methyl chloroformate (9.0 ml) was added dropwise to a ice-cooled solution of the compound (10.0 g) obtained in working example (1a) in pyridine (50 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated to dryness and water was added to the residue. After extraction with ethyl acetate, the extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-hexane to give pale yellow crystals (10.5 g, 90%).

T. pl. 113-115 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.80 (3H, s), 3.83 (3H, s), 4.11 (2H, d), 6.29 (1H, br s) 7.09 (1H, t); 7.40 - 7.80 (10H, m); 8.19 (1H, d).

 34b) Methyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -2,3-dihydro-2-oxobenzimidazole-7-carboxylate.

 To a suspension of the compound (10.5 g) obtained in working example (34a) in methanol (100 ml) was added a solution of 28% sodium methoxide in methanol (10 g). The mixture was boiled for 21 hours under reflux. The introduction of 1 n. HCl adjusted the pH of the reaction mixture to 3 and then concentrated to dryness. After adding water to the residue, the mixture was extracted with chloroform. The extract was dried and concentrated to dryness. The residue was crystallized from chloroform-methanol to give colorless needle crystals (8.7 g, 90%).

T. pl. 250-253 ^o C.

¹ H-NMR (200 MHz, DMCO d ₆ ) δ: 3.65 (3H, s), 5.35 (2H, s), 7.04-7.76 (1H, dt), 7.92 (1H , dd).

IR (KBr), cm ^-1 : 2210, 1720, 1690, 1635, 1430, 1390, 1270, 1255, 760, 750, 730, 690.

 34c) Methyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-propylthiobenzimidazole-7-carboxylate.

 A mixture of the compound (11 g) obtained in working example (34b) with phosphorus oxychloride (90 g) was boiled under reflux for 10 hours, and then, after standard processing, methyl-2-chloro-1- (2'-cyanobiphenyl) was obtained -4-yl) methylbenzimidazole-7-carboxylate (11.37 g). Propyl mercaptan (2.4 g) and a 28% solution of sodium metaxide in methanol (6.4 g) were added to a solution of the compound in dioxane (100 ml). The mixture was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (300 ml) and water (150 ml), and then the top layer was washed with water (50 ml x 1). Ethyl acetate was evaporated under reduced pressure. After adding methanol (50 ml) to the residue, the resulting crystalline precipitate was filtered off, washed with methanol, dried, and the indicated compound was obtained as pale yellow prisms (10 g, 80%).

T. pl. 107-108 ^o C.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.07 (3H, t), 1.63-2.03 (2H, m), 3.40 (2H, t), 3.73 (3H, s), 5.80 (2H, s), 7.00-7.93 (11H, m).

IR (Nyjol), cm ^-1 : 2220, 1725, 1280.

 34d) Methyl-1 - [(2 '- (hydroxycarbamimidoyl) biphenyl-4-yl) methyl] -2-propylthiobenzimidazole-7-carboxylate.

Triethylamine (3.9 g) was added to a solution of hydroxylamine hydrochloride (20.85 g) in DMCO (200 ml) and the mixture was stirred for 30 minutes at room temperature. Compound (16 g) obtained in Example (34c) was added to the reaction mixture, and the mixture was stirred 60 h at 70 ^° C. Tetrahydrofuran (100 ml) was added to the resulting mixture. After removal of the crystalline precipitate by filtration, the filtrate was concentrated to dryness. The residue was partitioned between water (1.2 L) and ethyl acetate (350 ml), and then the top layer was washed with water (70 ml x 3). Ethyl acetate was evaporated under reduced pressure, and methanol (70 ml) was added to the residue. The resulting crystalline precipitate was filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound as a pale yellow syrup (13.0 g, 76%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.07 (3H, t), 1.63-2.03 (2H, m), 3.40 (2H, t), 3.73 (3H, s), 4.37 (2H, broad), 5.13 (1H, broad) 5.73 (2H, s), 6.97 (2H, d), 7.10-7.60 (8H, m) 7.87 (2H, d).

IR (Nujol), cm ^-1 : 1720, 1645, 1280, 755.

 34e) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylthiobenzimidazole-7-carboxylate .

To a mixed solution of the compound (13.0 g) obtained in working example (3d) in DMF (20 ml) was added pyridine (2.2 g) and 2-ethylhexyl chloroformate (4.83 g) successively while cooling in an ice bath. The mixture was stirred for 30 minutes under the same conditions, then methanol (5 ml) was added and stirred for another 30 minutes at room temperature. The reaction mixture was partitioned between ethyl acetate (250 ml) and water (250 ml). The top layer was washed with water (150 ml x 3) and concentrated to dryness under reduced pressure. The residue was dissolved in xylene (180 ml) and the solution was stirred with heating in a bath at 160 ^° C. for 70 minutes. The solution was concentrated to dryness under reduced pressure. Methanol (70 ml) was added to the residue, and the title compound was isolated as pale yellow prisms (7.16 g, 57%).

T. pl. 220-221 ^o C.

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₄ S:
Calculated,%: C 64.7; H 4.83; N, 11.19.

 Found,%: C 64.54; H 4.92; N, 10.89.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.03 (3H, t), 1.60-2.00 (2H, m), 3.27 (2H, t), 3.73 (3H, c), 5.73 (2H, s), 6.90-7.87 (11H, m).

IR (Nujol), cm ^-1 : 1760, 1720, 1280, 1260.

 34f) 1 - [[2- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4] methyl] -2-propylthiobenzimidazole-7-carboxylic acid.

To a solution of the compound (0.3 g) obtained in working example (34e) in tetrahydrofuran (10 ml) were added 2N. NaOH (2 ml) and methanol (5 ml). The mixture was stirred for 3 hours at 80 ^° C. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by an aqueous 2N solution. HCl was adjusted to pH 3. The resulting precipitate was filtered and recrystallized from ethyl acetate to give colorless prisms (0.19 g, 65%).

T. pl. 228-229 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₄ S:
Calculated,%: C 64.18; H 4.56; N, 11.52.

 Found,%: C 64.15; H 4.62; N, 11.56.

¹ H-NMR (90 MHz, CDCl-CD ₃ OD) δ: 1.07 (3H, t), 1.63-2.03 (2H, m), 3.37 (2H, t), 5.87 (2H, s), 6.97-7.90 (11, m).

IR (Nujol), cm ^-1 : 1795, 1700, 1455, 1280, 755.

Working Example 35. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylsulfinylbenzimidazole-7-carboxylate
35a) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] propylsulfinylbenzimidazole-7-carboxylate.

 To a mixed solution of the compound (2.5 g) obtained in working example (34e) in dichloromethane (60 ml) was added portionwise while cooling in an ice bath metachloroperbenzoic acid (1.1 g). The mixture was stirred under these conditions for 1 h, and then washed with a solution of sodium bicarbonate (500 mg) in water (50 ml). The organic layer was washed with water (30 ml x 1) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound as a pale yellow syrup (2.58 g, 100%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.03 (3H, t), 1.57-2.00 (2H, m), 3.13-3.63 (2H, m), 3, 77 (3H, s), 6.07 (1H, d), 6.17 (1H, d), 6.93 (2H, d) 7.17-8.03 (9H, m).

IR (Nujol), cm ^-1 : 1780, 1720, 1285, 1260, 755.

 35b) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxybenzimidazole-7-carboxylate .

 To a solution of the compound (517 g) obtained in working example (35a) in methanol (5 ml) was added a 28% solution of sodium methoxide in methanol (579 mg) and the mixture was kept for 1 h at room temperature. To the mixture was added 2 N. HCl, adjusting the pH of the mixture to 3, and then the mixture was concentrated under reduced pressure. The residue was partitioned between water (20 ml) and dichloromethane (50 ml). The organic layer was concentrated to dryness under reduced pressure, and the residue was crystallized from methanol to give the title compound as prisms (308 mg, 68%).

T. pl. 215 - 216 ^o C.

Elemental analysis for C ₂₅ H ₄ O ₅ • 0.1H ₂ O:
Calculated,%: C 65.53; H 4.44; N, 12.23.

 Found,%: C 65.38; H 4.56; N, 12.12.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 3.73 (3H, s), 4.27 (3H, s), 5.63 (2H, s), 7.03 (2H, d) 7.20 - 7.77 (9H, m).

IR (Nujol), cm ^-1 : 1760, 1720, 1560, 1435, 1405, 1285, 1250, 1040, 740.

 35c) 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxybenzimidazole-7-carboxylic acid.

 The compound (228 mg) obtained in working example (35b) was subjected to the reaction described in working example (34f), the product was recrystallized from ethyl acetate and the indicated compound was obtained as colorless prisms (133 mg, 60%).

T. pl. 189 - 190 ^o C.

Elemental analysis for C ₂₄ H ₁₈ N ₄ O ₅ • 0.75H ₂ O:
Calculated,%: C 63.22; H 4.31; N, 12.29.

 Found,% C: 63.50; H 4.28; N, 12.03.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 4.20 (3H, s), 5.73 (2H, s), 7.03 - 7.73 (11H, s), 12.17 ( 1H, broad), 12.93 (1H, broad).

IR (Nujol), cm ^-1 : 1780, 1705, 1560, 1415, 1250, 1040.

 Working Example 36. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propoxybenzimidazole-7-carboxylic acid.

 36a) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propoxybenzimidazole-7-carboxylate .

 A solution of 28% sodium methoxide in methanol (710 mg) was concentrated to dryness under reduced pressure, and the precipitate was dissolved in propanol (10 ml). The compound (517 mg) obtained in working example (35a) was dissolved in the solution, and the solution was kept for 2 hours at room temperature. 2 n. The HCl pH of the solution was adjusted to 3 and concentrated under reduced pressure to dryness. The residue was dissolved in methanol (15 ml) and a 28% solution of sodium metaxide in methanol (710 mg) was added to the solution. The mixture was kept for 15 hours at room temperature, and then the pH of the solution was 2 N. HCl was adjusted to 3 and concentrated under reduced pressure. The residue was partitioned between water (25 ml) and dichloromethane (25 ml). The organic layer was concentrated to dryness under reduced pressure. The resulting dry residue was crystallized from methanol to give the title compound as colorless prisms (310 mg, 64%).

T. pl. 172 - 174 ^o C.

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₅ • 0.2H ₂ O:
Calculated,%: C 66.44; H 5.04; N, 11.48.

 Found,%: C 66.57; H 5.01; N, 11.55.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.00 (3H, t), 1.60 - 2.00 (2H, m), 3.63 (3H, s), 4.23 (2H, t), 5.60 (2H, s), 6.80 - 7.93 (11H, m).

IR (Nujol), cm ^-1 : 1780, 1720, 1550, 1440, 1280, 755.

 36b) 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propoxybenzimidazole-7-carboxylic acid .

 The compound (194 mg) obtained in working example (36a) was subjected to the reaction described in working example (34f), and the product was recrystallized from ethyl acetate, whereby the title compound was obtained as colorless prisms (132 mg, 70%).

T. pl. 170 - 172 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₅ H ₂ O:
Calculated,%: C 63.93; H 4.95; N, 11.47.

 Found,%: C 63.82; H 4.65; N, 11.41.

¹ H-NMR (90 MHz, CDCl ₃ -CD ₃ OD) δ: 1.00 (3H, t), 1.67 - 1.07 (2H, m), 4.50 (2H, t), 5, 67 (2H, m), 7.00 - 7.80 (11H, m).

IR (Nujol), cm ^-1 : 1765, 1725, 1550, 1430.

 Working Example 37. 2-Ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazol-7 -carboxylic acid.

 37a) Methyl-2-ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazol-7- carboxylate.

 To a solution of the compound (517 mg) obtained in working example (35a) in methanol (3 ml) was added triethylamine (404 mg) and ethyl mercaptan (186 mg). The mixture was held at room temperature for 60 hours, and then concentrated to dryness in vacuo. After adding water to the residue, the mixture was brought 2 N HCl to pH 3. The solution was extracted with ethyl acetate (60 ml). The top layer was washed with water (10 ml x 3) and then concentrated to dryness in vacuo. The residue was crystallized from ethyl acetate to give the title compound as colorless prisms (370 mg, 76%).

T. pl. 210 - 211 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₄ S:
Calculated,%: C 64.18; H 4.56; N, 11.52.

 Found,%: C 64.06; H 4.58; N, 11.40.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.40 (3H, t), 3.27 (2H, s), 3.70 (3H, s), 5.70 (3H, s), 6 87-7.87 (11H, m).

IR (Nujol), cm ^-1 : 1760, 11720, 1280, 1260.

 37b) 2-ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid .

 The compound (260 mg) obtained in working example (37a) was subjected to the same reaction as described in example (34f), the product was recrystallized from methanol-water, and the obtained compound was obtained as colorless needle crystals (160 g, 63%) .

T. pl. 146 - 148 ^o C.

Elemental analysis for C ₂₅ H ₂₀ N ₄ O ₄ S:
Calculated,%: C 63.55; H 4.27; N, 11.86.

 Found,%: C 63.28; H 4.37; N, 11.59.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.43 (3H, t), 3.40 (2H, q), 5.70 (2H, q), 5.70 (2H, s), 6 90 - 7.87 (11H, m).

IR (Nujol), cm ^-1 : 1785, 1765, 1700, 1350, 760.

 Working Example 38. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4] methyl] -2-methylthiobenzimidazole-7-carboxylic acid.

 38a) Methyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylthiobenzimidazole-7-carboxylate .

 The compound (690 mg) obtained in working example (35a) was subjected to the same reaction as described in working example (37a), the product was recrystallized from methanol and the indicated compound was obtained as colorless prisms (460 mg, 73%).

T. pl. 231 - 232 ^o C.

Elemental analysis for C ₂₅ H ₂₀ N ₄ O ₄ S:
Calculated,%: C 63.55; H 4.27; N, 11.86.

 Found,%: C 63.36; H 4.33; N, 11.76.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 2.77 (3H, s), 3.73 (3H, s), 5.73 (2H, s), 7.00 - 7.93 ( 11H, m), 12.33 (1H, broad).

IR (Nujol), cm ^-1 : 1760, 1710, 1430, 1270, 1250, 760.

 38b) 1 - [[2- (2,5- (dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylthiobenzimidazole-7-carboxylic acid .

 The compound (360 mg) obtained in working example (38a) was subjected to the same reaction as in example (34f), the product was recrystallized from methanol and the indicated compound was obtained as colorless prisms (270 mg, 77%).

T. pl. 222 - 223 ^o C.

Elemental analysis for C ₂₄ H ₁₈ N ₄ S • 0.8H ₂ O:
Calculated,%: C 60.95; H 4.18; N, 11.85.

 Found,%: C 60.83; H 4.40; N, 11.58.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 2.77 (3H, s), 5.83 (2H, s), 7.00 - 7.77 (11H, m), 12.60 ( 2H, broad).

IR (Nujol), cm ^-1 : 1760, 1270, 760.

 Working Example 39. Two-potassium salt of 2-ethoxy-1 - [[2 '- (oxide-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

Solution of 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 0.2 n. KOH (10 ml) was concentrated to dryness under reduced pressure. Acetone (30 ml) was added to the residue, and the mixture was stirred for three days at room temperature. The precipitated crystals were filtered and dried (120 ^° C., 1.5 hours) to obtain the title compound as colorless needle crystals (470 mg, 89%).

T. pl. 245 - 247 ^o C.

Elemental analysis for C ₂₅ H ₁₈ N ₄ O ₅ K ₂ • 3 / 2H ₂ O:
Calculated,%: C 53.65; H 3.78; N, 10.01.

 Found,%: C 53.77; H 3.63; N, 9.93.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 1.40 (3H, t), 4.53 (2H, q), 5.83 (2H, s), 6.90-7.70 ( 11H, m).

IR (Nujol), cm ^-1 : 3370, 1660, 1570, 1540, 1385.

 Working Example 40. Disodium salt of 2-ethoxy-1 - [[2 '- (5-oxide-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

A solution of sodium methoxide (28%) in methanol (43.7 g) was dissolved in ethanol (500 ml) and then the solution was concentrated to dryness under reduced pressure. Ethanol (500 ml) and 2-ethoxy-1 - [[2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 were added to the residue β-carboxylic acid and the mixture was dissolved. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in ethanol (250 ml) with heating, and then the solution was kept for 40 hours at room temperature. The precipitated crystals were filtered off, washed with ethanol (30 ml), dried (140 ^° C, 2 hours) to obtain colorless prisms (35.5 g), which were then left to stand in air for three days at room temperature and as a result the indicated compound was obtained. as colorless prisms (42.34 g, 61%).

T. pl. 294-297 ^o C.

Elemental analysis for C ₂₅ H ₁₈ N ₄ O ₅ Na ₂ • 5.5H ₂ O:
Calculated,%: C 50.09; H 4.88; N, 9.35.

 Found,%: C 50.32; H 4.71; N, 9.21.

¹ H-NMR (90 MHz, DMCO-d ₆ ) δ: 1.43 (3H, t), 4.57 (2H, q), 5.80 (2H, s), 6.87-7.63 ( 11H, m).

IR (Nujol), cm ^-1 : 3375, 1655, 1615, 1410, 1350, 1280, 1040, 770.

 Working Example 41. Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4 methylthieno [3,4-d] imidazole-6-carboxylate.

 41a) Methyl-1,3-dihydro-4-methyl-2-oxo-thieno [3,4-d] imidazole-6-carboxylate.

 Methyl 3,4-diamino-5-methylthiophene-2-carboxylate (3.0 g) was dissolved in a mixture of N, N-dimethylformamide (5 ml) and dichloromethane (15 ml). Triphosgene (2.4 g) was added portionwise to the solution. The mixture was stirred for two days at room temperature, the precipitate was filtered off, washed with dichloromethane and dried. The resulting white powder (2.4 g) was suspended in N, N-dimethylformamide (25 ml). Sodium hydride (60% in oil, 0.55 g) was added to the suspension, and the mixture was stirred for three days at room temperature. The solvent was evaporated under reduced pressure. 2N was added to the precipitate. HCl. The resulting precipitate was filtered off, washed successively with water, ether and methanol, and then dried to obtain the title compound as a pale brown powder.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.32 (3H, s), 3.73 (3H, s), 10.71 (1H, br.s.), 11.06 (1H , sh.s.).

IR (KBr), cm ^-1 : 3300, 1735, 1675, 1585, 1440.

 41b) Methyl 2-ethoxy-4-methylene [3,4-d] imidazole-6-carboxylate.

 The compound (1.0 g) obtained in working example (41a) was suspended in a mixture of dioxane (10 ml) and dichloromethane (20 ml). Excess triethyloxoniumtetrafluoroborate was added to the suspension at room temperature under a nitrogen atmosphere, and then the mixture was stirred for 19 hours. The reaction mixture was poured into ice water and then extracted four times with a mixture of chloroform and ethanol. The organic layers were combined dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (945 mg, 75%) as a pale yellow powder.

T. pl. 209-210 ^o C.

Elemental analysis for C ₁₀ H ₁₂ N ₂ O ₃ S • 0.02H ₂ O:
Calculated,%: C 49.25; H 5.12; N, 11.49.

 Found,%: C 49.42; H 4.95; N, 11.29.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (3H, s), 2.57 (3H, s), 3.87 (3H, s), 4.54 (2H, q), 9 03 (1H, brs).

IR (KBr), cm ^-1 : 3250, 1670, 1580, 1540.

 41c) Methyl-2-ethoxy-1 - [[2'-5 (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4- d] imidazole-6-carboxylate.

 The compound (100 mg) obtained in working example (41b) and 4-bromomethyl-2- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl (193 mg) was dissolved in N, N- dimethylformamide (3.5 ml). Sodium hydride (60% in oil, 18 mg) was added to the ice-cooled solution under nitrogen. The mixture was stirred for 15 minutes while cooling with ice, and then for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with diluted hydrochloric acid, water and aqueous saline, and then dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (121 mg, 55%) as a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: (3H, t), 2.55 (3H, s), 3.79 (3H, s), 4.52 (2H, q), 5.57 (2H, s), 7.15 (2H, d), 7.23 (2H, d), 7.86 (1H, d).

IR (Neat), cm ^-1 : 1690, 1615, 1570, 1535.

 41d) Methyl 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylate.

 The compound (120 mg) obtained in the working example (41c) was dissolved in a mixture of dioxane (4 ml) and water (1 ml). 1N was added to the ice-cooled solution. NaOH (0.26 ml) and the mixture was stirred for 50 minutes at the same temperature. The reaction mixture was acidified with 2 N. HCl and was extracted with ethyl acetate. The extract was washed with water, dried, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow oil. The product was crystallized from a mixture of ether and hexane to give the title compound (81 mg, 77%) as pale yellow crystals.

T. pl. 208-210 ^o C.

Elemental analysis for C ₂₅ H ₂₂ N ₄ O ₅ S:
Calculated,%: C 61.21; H 4.52; N, 11.42.

 Found,%: C 60.98; H 4.55; N, 11.27.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.42 (3H, s), 3.74 (3H, s), 4.42 (2H, q), 5 58 (2H, s), 7.2-7.7 (7H, m), 7.82 (1H, dd), 7.68 (1H, brs).

IR (KBr), cm ^-1 : 1760, 1700, 1620, 1580, 1535.

 Working Example 42. Disodium Salt 1 - [[2 '- (2,5-dihydro-5-oxo-1,2.4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxy-4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 The compound (0.5 g) obtained in working example 9 was suspended in methanol (10 ml). An aqueous solution (5 ml) of sodium hydroxide (90 mg) was added to the suspension, and the mixture was stirred for 10 minutes at room temperature. The reaction solution was concentrated to dryness to form crude crystals. Recrystallization from ethanol-ether gave the title compound as pale yellow crystals (0.28 g, 49%).

T. pl. 263-266 ^o C (decomposition).

Elemental analysis for C ₂₃ H ₁₆ N ₄ O ₅ SNa ₂ • 1.0H ₂ O (mol. M. 524.46):
Calculated,%: C 52.67; H 3.46; N, 10.68.

 Found,%: C 52.88; H 3.43; N, 10.45.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.37 (2H, s), 4.00 (3H, s), 5.80 (2H, s), 7.16-7.50 ( 8H, m).

IR (KBr), cm ^-1 : 1680, 1620, 1575, 1545, 1460, 1395, 1360.

 Working Example 43. 2-ethyl-1 - [[3 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 43a) 4'-methyl-3-cyanobiphenyl.

 This compound was synthesized in accordance with a known procedure (E. Hamana, S. Furushima & t. Hiiyama, Chem. Lett. 1989, 1711).

T. pl. 71-73 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 7.28 (2H, d), 7.46 (2H, d), 7.51 (1H, t), 7 60 (1H, td); 7.79 (1H, td); 7.84 (1H, t).

IR (KBr), cm ^-1 : 2230, 1475, 825, 800.

 43b) 4'-methylbipinyl-3-carboxamidoxime.

 To a solution of hydroxylamine hydrochloride (2.61 g) in DMCO (20 ml) was added a solution of 20% NaOMe in methanol (7.25 g) and the mixture was stirred for 10 min at room temperature. To the reaction mixture was added a solution of the compound (1.45 g) obtained in working example (43a) in DMCO (10 ml). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and colorless crystals (1.30 g, 76.6%) were obtained.

T. pl. 134-136 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 4.93 (2H, bs), 7.25 (2H, d), 7.41-7.66 (5H, m), 7.85 (1H, t).

IR (KBr), cm ^-1 : 3495, 3385, 1660, 1585.1440, 1375, 940, 925, 900, 795.

 43c) 5-trichloromethyl-3- (4'-methylbipinyl-3-yl) 1,2,4-oxadiazole.

Trichloroacetic anhydride (2.13 g) was added to a suspension of the compound (1.30 g) obtained in working example (43b) in toluene (30 ml). The mixture was stirred for 30 minutes at 80 ^° C. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to give a colorless oil (2.09, quantitatively).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 7.28 (2H, d), 7.55 (2H, d), 7.56 (1H, t), 7 76 (1H, td), 8.07 (1H, td), 8.32 (1H, t).

IR (Neat), cm ^-1 : 1570, 1515, 1460, 1355, 1335, 850, 825, 800, 745, 690.

 43d) 3- (4'-bromomethylbiphenyl-3-yl) -5-trichloromethyl-1,2,4-oxadiazole.

To a solution of the compound (29.09 g) obtained in the working example (43c) in CCl ₄ (50 ml) was added NBS (1.10 g) and BPO (0.20 g). The mixture was irradiated with light. The reaction mixture was cooled to room temperature and insoluble materials were filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (Merk. Art. 9385 (1980), AcOEt: n-hex. = 1:10) to obtain a colorless syrup (2.40 g, 60%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.57 (2H, s), 7.49-7.68 (5H, m), 7.75-7.79 (1H, m), 8, 09-8.17 (1H, m), 8.33 (1H, m).

 43e) Methyl-2-ethyl-1 - [[3 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl] methyl] -4-methylene [3,4-d ] imidazole-6-carboxylate.

To a solution of methyl 2-ethylthio-4-methyl-1H-thieno [3,4-d] imidazole-6-carboxylate (0.80 g) in DMF (10 ml) was added sodium hydride (60% in oil, while cooling with ice). 0.14 g). The mixture was stirred for 10 minutes, and then, under ice cooling, a solution of the compound (1.53 g) obtained in working example (43d) in DMF (10 ml) was added. The mixture was stirred for 1 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, saturated brine and dried. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain colorless crystals. To a solution of crystals in a mixture of chloroform (10 ml) - methanol (10 ml) was added 1 N. NaOH (3 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated and 1 N. HCl adjusted the pH of the mixture to 3-4. The mixture was partitioned between CHCl ₃ and water. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness with the release of crude crystals. Recrystallization from methanol-ethyl acetate gave colorless crystals (0.74 g, 84%).

 T. pl. 248-251 (decomposition).

Elemental analysis for C ₂₅ H ₂₂ N ₄ O ₄ S ₂ • 0.5 H ₂ :
Calculated,%: C 58.24; H 4.50; N, 10.87.

 Found,%: C 58.24; H 4.38; N, 10.77.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t), 2.63 (3H, s), 3.30 (2H, s), 3.78 (3H, s), 5 75 (2H, s), 7.27 (2H, d), 7.51-7.60 (3H, m), 7.69-7.78 (2H, m), 7.98 (1H, t )

IR (KBr), cm ^-1 : 1780, 1755, 1690, 1460, 1320, 1170, 1090, 760.

 43f) 2-ethylthio-1 - [[3 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

The compound (0.60 g) obtained in working example (43e) was suspended in a mixture of tetrahydrofuran (20 ml) - H ₂ O (20 ml). Lithium hydride (0.25 g, 5.96 mmol) was added to the suspension, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated, the aqueous residue was added with 1N. HCl was adjusted to pH 3. Precipitated crystals were filtered and dried. The crystals were recrystallized and colorless crystals were isolated (0.33 g, 56.7%).

T. pl. 177-179 ^° C (decomp.).

Elemental analysis for C ₂₄ H ₂₀ N ₄ O ₄ S ₂ • 0.5H ₂ O:
Calculated,%: C 57.47; H 4.22; N, 11.17.

 Found,%: C 57.63; H 4.04; N, 11.17.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.35 (3H, t), 2.56 (3H, s), 3.26 (2H, s), 5.73 (2H, s) 7.26 (2H, d), 7.65 (1H, t), 7.69 (2H, d), 7.81 (1H, td), 7.90 (1H, td), 8.08 ( 1H, t).

IR (KBr), cm ^-1 : 1770, 1755, 1650, 1530, 1460, 1165, 765.

 Working Example 44. 2-Ethylthio-1 - [[4 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4- methylthieno [3,4-d] imidazole-6-carboxylic acid.

 44a) 4'-Methyl-4-cyanobiphenyl.

 This compound was synthesized in a manner analogous to the procedure described in working example (43a).

T. pl. 108-109 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.42 (3H, s), 7.29 (2H, d), 7.50 (2H, d), 7.64-7.75 (4H, m).

IR (KBr), cm ^-1 : 2225, 1495, 815.

 44b) 4'-Methylbiphenyl-4-carboxamidoxime.

 This compound was synthesized according to a procedure similar to that described in working example (43b).

 44c) 3- (4'-methylbiphenyl-4-yl) -5-trichloromethyl-1,2,4-oxadiazole.

 This compound was synthesized according to a procedure similar to that described in working example (43c).

T. pl. 126-127 ^o C. Yield 75%.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.42 (3H, s), 7.29 (2H, d), 7.55 (2H, d), 7.72 (2H, d), 8 17 (2H, d).

IR (KBr), cm ^-1 : 1610, 1585, 1540, 1470, 1420, 1345, 905, 855, 845, 825, 810, 755, 725.

 44d) 3- (4'-bromomethylbiphenyl-4-yl) trichloromethyl-1,2,4-oxadiazole.

 The specified compound was obtained in the form of colorless needle crystals (71%) from the compound obtained in working example (44c), according to the method described in working example (43d).

T. pl. 113-116 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.56 (2H, s), 7.51 (2H, d), 7.64 (2H, d), 7.73 (2H, d), 8 20 (2H, d).

IR (KBr), cm ^-1 : 1475, 1400, 1350, 845, 830, 800, 760, 755.

 44e) Methyl 2-ethylthio-1 - [[4 '- (2,5-dinidro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] -4-methylthieno [3, 4-d] imidazole-6-carboxylate.

 The specified compound was obtained in the form of pale yellow crystals (0.4 g, 25%) from the compound (1.53 g) obtained in working example (44d), in a manner analogous to that described in working example (43e).

T. pl. 251-255 ^o C (decomposition).

Elemental analysis for C ₂₅ H ₂₂ N ₄ O ₄ S ₂ :
Calculated,%: C 55.85; H 4.43; N, 10.98.

 Found,%: C 58.89; H 4.35; N, 10.81.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.36 (3H, t), 2.57 (3H, s), 3.27 (2H, s), 3.70 (3H, s) 5.70 (2H, s), 7.22 (2H, d), 7.72 (2H, d), 7.87 (4H, s).

IR (KBr), cm ^-1 : 1760, 1690, 1460, 1320, 1305, 1255, 1240, 1160, 1090, 760.

 44f) 2-Ethylthio-1 - [[4 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3 , 4-d] imidazole-6-carboxylic acid.

 The specified compound was obtained in the form of colorless crystals (0.29 g, 90%) from the compound (0.33 g) obtained in working example (44e), according to a method similar to that described in working example (43f).

T. pl. 202-204 ^o C (decomposition).

Elemental analysis for C ₂₄ H ₂₀ N ₄ O ₄ S ₂ :
Calculated,%: C 57.68; H 4.19; N, 11.21.

 Found,%: C 57.83; H 4.48; N, 11.39.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.35 (3H, t), 2.56 (3H, s), 3.26 (2H, s), 5.72 (2H, s) 7.24 (2H, d), 7.72 (2H, d), 7.87 (4H, s),
IR (KBr), cm ^-1 : 1760, 1640, 1610, 1600, 1535, 1460, 1165, 770.

 Working Example 45. 2-Ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) methyl-biphenyl-4-yl] methyl] -4 -methylthieno [3,4-d] imidazole-6-carboxylic acid.

 45a) 4'-Methyl-2-hydroxymethylbiphenyl.

 To an ice-cooled suspension of lithium aluminum hydride (1.79 g) in tetrahydrofuran (50 ml) was added dropwise a solution of 4-methylbiphenyl-2-carboxylic acid (5.0 g) in tetrahydrofuran (30 ml). The mixture was stirred for 17 hours at room temperature. Ethyl acetate (10 ml) and water (50 ml) were added to the reaction mixture, and then insoluble materials were filtered through celite. The filtrate was concentrated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous sodium bicarbonate solution and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as a colorless syrup (3.95 g, 84%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 4.62 (2H, s), 7.20-7.41 (7H, m), 7.51-7, 56 (1H, m).

IR (Neat), cm ^-1 : 3350, 3020, 2920, 1480, 1440, 1030, 1000, 820, 755.

 45b) 4'-Methyl-2-chloromethylbiphenyl.

 Thionyl chloride (3.56 g) was added dropwise to an ice-cooled solution of the compound (3.95 g) obtained in the working example (45a) in chloroform (50 ml). One drop of dimethylformamide was then added to the mixture and the mixture was boiled under reflux for 1 hour. The reaction mixture was concentrated to dryness and the residue was suspended in a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried, the solvent was evaporated under reduced pressure to obtain the title compound as a pale yellow oil (4.15 g, 96%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 4.53 (2H, s), 7.23-7.41 (7H, m), 7.50-7, 56 (1H, m).

IR (Neat), cm ^-1 : 1480, 1440, 1260, 1480, 1000, 825, 820, 755, 690, 655.

 45c) 4'-Methyl-2-cyanomethylbiphenyl.

 To a solution of the compound (4.15 g) obtained in working example (45b) in acetonitrile (50 ml) was added potassium cyanide (2.5 g) and 18-crown-6 (0.5 g). The mixture was boiled for 10 hours under reflux. Insoluble materials were filtered off, and the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil (3.71 g, 93%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 3.62 (2H, s), 7.14-7.39 (7H, m), 7.50-7, 55 (1H, m).

IR (Neat), cm ^-1 : 2240, 1480, 820, 760.

 45d) 4'-Methylbiphenyl-2-acetamidoxime.

To a solution of hydroxylamine hydrochloride (1.68 g) in dimethyl sulfoxide (10 ml) was added a solution of a 28% solution of sodium methoxide in methanol (4.65 g), and the mixture was stirred for 20 min at room temperature. To the mixture was added a solution of the compound obtained in working example (45c) in dimethyl sulfoxide (3 ml), and the mixture was stirred for 1.5 hours at 100 ^° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as colorless crystals (0.92 g, 79%).

T. pl. 127-128 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.40 (3H, s), 3.46 (2H, s), 4.33 (2H, s s), 7.18-7.43 (8H , m).

IR (KBr), cm ^-1 : 3450, 3350, 1670, 1590, 1480, 1380, 940, 820, 760.

 45e) 3- (4'-methylbiphenyl-2-yl) methyl-5-trichloromethyl-1,2,4-oxadiazole.

The compound obtained in working example (45d) (0.92 g) was suspended in toluene (20 ml). Trichloroacetic anhydride (1.42 g) was added to the suspension, and the mixture was stirred at 80-90 ^° C for 1 h. The reaction mixture was concentrated to dryness, the residue was dissolved in ethyl acetate, washed with water and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.25 g, 88%).

¹ H-NMR (200 MHz, CDCl ₃ ), δ: 2.40 (3H, s), 4.11 (2H, s), 7.19-7.42 (8H, m).

IR (Neat), cm ^-1 : 1580, 1490, 1355, 1050, 860, 800, 760, 735, 705.

 45f) 3- (4'-bromethylbiphenyl-2-yl) methyl-5-trichloromethyl-1,2,4-oxadiazole.

 To a solution of the compound (1.25 g) obtained in working example (45e) in carbon tetrachloride (20 ml) was added N-bromosuccinimide (0.67 g) and α, α-azo-bisisobutyronitrile (0.1 g) and the mixture was boiled for 1 h under reflux. Insoluble materials were filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give a pale yellow syrup (0.91 g, 60%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.10 (2H, s), 4.55 (2H, s), 7.23-7.41 (8H, m).

 45g) Methyl-2-ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) methylbiphenyl-4-yl] methyl] thieno [3, 4-d]] imidazole-4-methyl-6-carboxylate.

 To an ice-cooled solution of methyl 2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylate (0.75 g) in dimethylframamide (5 ml) was added sodium hydride (60% in oil, 0.13 g) and the mixture was stirred for 10 minutes. To the ice-cooled mixture was added dropwise a solution of the compound (0.91 g) obtained in working example (45f) in dimethylformamide (5 ml) and then stirred for 1 h at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous brine and dried. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain a pale yellow syrup. The syrup was dissolved in a mixture of chloroform (5 ml) - methanol (10 ml), then 1N was added to the solution. NaOH (2 ml) and moved 30 min at room temperature. The reaction mixture was concentrated to dryness and the residue was diluted with water. pH of an aqueous solution of 1 N. HCl was adjusted to 3 and extracted with chloroform. The extract was washed with water, dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The crude crystals thus obtained were recrystallized from ethyl acetate-methanol to give the title compound as pale yellow needle crystals (0.31 g, 20%).

T. pl. 172-173 ^o C (decomposition).

Elemental analysis for C ₂₆ H ₂₄ N ₄ O ₄ S ₂ (mol. M. 520, 63):
Calculated,%: C 59.98; H 4.65; N, 10.76.

 Found,%: C 59.78; H 4.55; N, 10.41.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t), 2.61 (3H, s), 3.28 (2H, s), 3.76 (3H, s), 3.83 (2H, s), 7.16-7.39 (8H, m), 8.68 (1H, br s).

IR (KBr), cm ^-1 : 1765, 1695, 1685, 1600, 1540, 1460, 1430, 1320, 1240, 1170, 1090, 760.

 45h) 2-Ethylthio-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) methylbiphenyl-4-yl] methyl] thieno [3,4 -d] imidazole-4-methyl-6-carboxylic acid.

 To a solution of the compound (0.25 g) obtained in the working example (45 g) in a mixture of tetrahydrofuran (10 ml) - water (5 ml) was added lithium hydroxide monohydrate (0.10 g) and the mixture was boiled for 30 hours under reflux, 1 n HCl brought the pH of the mixture to 3 and was extracted with chloroform. The extract was washed with water, dried, and the solvent was evaporated under reduced pressure and crude crystals were isolated. Recrystallization from ethyl acetate-hexane provided the title compound as pale yellow needle crystals (0.18 g, 74%).

 T. pl. 184-186 (decomposition).

Elemental analysis for C ₂₅ H ₂₂ N ₄ O ₄ S ₂ (mol. M. 506, 61):
Calculated,%: C 59.27; H 4.38; N, 11.06.

 Found,%: C 59.10; H 4.22; N, 10.91.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.35 (3h, t), 3.26 (2H, q) 3.80 (2H, s), 5.73 (2H, s), 7.20-7.40 (8H, m).

IR (KBr), cm ^-1 : 1810, 1790, 1650, 1535, 1460, 1326, 1170, 760.

 Working Example 46. 2-Ethylthio-1 - [[2 '- (1,4-dihydro-3-trifluoromethyl-5-oxo-1,2,4-triazolyl-4-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-methyl-6-carboxylic acid.

 46a) 4- (4'-Methylbiphenyl-2-yl) semicarboside.

To a ice-cooled solution of (4'-methylbiphenyl-2-yl) carboxylic acid (3.0 g) and triethylamine (2.2 ml) in N, N-dimethylformamide (10 ml) in a nitrogen atmosphere was added DPA (1.4, ml) and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The resulting solution was added dropwise to benzene heated to 80 ^° C (150 ml). The mixture was then stirred for 20 minutes at the same temperature. The isocyanate solution thus obtained was added dropwise to a solution of hydrazine (2.0 ml) in benzene (50 ml), heated to 70 ^° C. for 90 minutes. The powdery product obtained by evaporating the solvent under reduced pressure was washed with ethyl acetate and dried, thereby obtaining the title compound as a white powder (2.9 g, 85%).

T. pl. 148-151 ^o C.

Elemental analysis for C ₁₄ H ₁₅ N ₃ O • 0.5H ₂ O:
Calculated,%: C 68.66; H 6.33; N, 17.16.

 Found,%: C 68.80; H 6.34; N, 17.18.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.40 (3H, s), 3.55 (2H, ss), 6.11 (1H, s s), 7.0-7.4 (7H, m), 8.21 (1H, d), 8.32 (1H, br s).

IR (KBr), cm ^-1 : 1690, 1615, 1580, 1520.

 46b) 3-Trifluoromethyl-4- (4'-methylbiphenyl-2-yl) -1,2,4-thiazol-5-one.

To an ice-cooled solution of the compound (700 mg) obtained in working example (46a) in dichloromethane (10 ml) under nitrogen atmosphere was added trifluoroacetic anhydride (0.43 ml) and pyridine (0.32 ml). The mixture was stirred for 1 hour while cooling with ice, and then another 20 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The residue was dissolved in benzene (8 ml) and phosphorus oxychloride (1.5 ml) was added to the solution. The mixture was stirred for 4 hours at 80 ^° C. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with water and aqueous saline, and then the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a pale brown oil (620 mg, 66%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.42 (3H, s), 7.1-7.5 (7H, m), 8.17 (1H, d).

IR (KBr), cm ^-1 : 1620, 1520, 1510.

 46c) 4- (4'-Methylbiphenyl-2-yl) -3-methoxymethoxy-5-trifluoromethyl-1,2,4-triazole.

 To an ice-cooled solution of the compound (600 mg) obtained in working example (46b) and triethylamine (0.34 ml) in dichloromethane (12 ml) under a nitrogen atmosphere was added chloromethyl ether (0.17 ml). The mixture was stirred for 9 hours and then triethylamine (0.15 ml) and chloromethyl ether (0.17 ml) were added. The mixture was stirred for 13 hours under ice-cooling. The solvent was evaporated under reduced pressure. Diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give a pale yellow oil (395 mg, 57%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.34 (3H, s), 3.40 (3H, s), 9.91 (2H, s), 7.0-7.5 (8H, m).

IR (neat), cm ^-1 : 1620, 1600, 1580, 1520.

 46d) 4- (4'-bromomethylbiphenyl-2-yl) -3-methoxymethoxy-5-trifluoromethyl-1,2,4-triazole.

To a solution of the compound (390 mg) obtained in the working example (46c) in carbon tetrachloride (15 ml) was added N-bromosuccimide (230 mg) and α, α-azobisisobutyronitrile (20 mg). The mixture was stirred for 4.5 hours at 80 ^° C. The reaction mixture was diluted with chloroform, the solution was washed with aqueous sodium bicarbonate and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (380 mg, 80%) as a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.39 (3H, s), 4.48 (2H, s), 4.94 (2H, s), 7.2-7.6 (8H, m).

IR (neat), cm ^-1 : 1615, 1600, 1575.

 46e) Methoxymethyl-2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylate.

A mixture of methyl 2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylate (2.15 g) with 1 N. LiOH (8 ml) and methanol (25 ml) were stirred for 60 hours at 70 ^° C. The methanol was evaporated under reduced pressure. To the residue was added 1 N. HCl. The resulting precipitate was filtered off, washed with chloroform and dried. The brown powder thus obtained (560 mg) was suspended in dichloromethane (10 ml). Triethylamine (0.35 ml) and chloromethyl ether (0.19 ml) were added to the suspension. The mixture was stirred for 2 hours. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried and concentrated by dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (445 mg, 19%) as a white powder.

T. pl. 128-130 ^o C.

Elemental analysis for C ₁₁ H ₁₄ N ₂ O ₃ S ₂ :
Calculated,%: C 46.14; H 4.93; N, 9.78.

 Found,%: C 45.90; H 4.93; N, 9.56.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45 (2H, t), 2.64 (3H, s), 3.31 (2H, s), 3.53 (3H, s), 9 29 (1H, brs).

IR (KBr), cm ^-1 : 1640, 1620, 1540.

 46f) 2-Ethylthio-1 - [[2 '- (1,4-dihydro-3-trifluoromethyl-5-oxo-1,1,4-triazol-4-yl) biphenyl] methyl] thieno [3,4- d] imidazole-4-methyl-methyl-6-carboxylic acid.

 The compound (280 mg) obtained in working example (46e) and the compound obtained in working example (46d) were dissolved in 912 ml N, N-dimethylformamide). Sodium hydride (60% in oil, 47 mg) was added to the ice-cooled solution under nitrogen.

The mixture was stirred for 2 hours at the same temperature. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and aqueous brine, and then dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow oil (464 g). The oil was dissolved in a mixture of trifluoroacetic acid (4 ml) and chloroform (5 ml). The solution was stirred for 5 hours at 70 ^° C. The reaction mixture was diluted with chloroform, washed with water, dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (60 mg, 10%) as a pale brown powder.

T. pl. 178-180 ^o C (decomposition).

Elemental analysis for C ₂₅ H ₂₀ N ₅ O ₃ S ₂ F ₃ • 0.5H ₂ O:
Calculated,%: C 52.81; H 3.72; N, 12.32.

 Found,%: C 52.83; H 3.54; N, 12.30.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t), 2.60 (3H, s), 3.30 (2H, s), 5.67 (2H, s), 7 0-7.5 (7H, m); 8.06 (1H, d).

IR (KBr), cm ^-1 : 1655, 1620, 1595, 1580, 1530.

 Working Example 47. Methyl 2-ethylthio-1 - [[2 '- [1,4-dihydro-3-methyl-5-oxo-1,2,4-triazol-4-yl] biphenyl-4-yl] methyl ] thieno [3,4-d] imidazole-4-methyl-6-carboxylate.

 47a) 1-Acetyl-4- (4'-metholbiphenyl-2-yl) semicarboside.

 To a solution of the compound (300 mg) obtained in working example (31a) in dichloromethane (5 ml) was added acetic anhydride (0.12 ml) and pyridine (0.10 ml). The mixture was stirred for 15 hours at room temperature. The reaction mixture was poured into a mixture of ice water and was extracted with a mixture of chloroform and ethanol. The extract was washed with water, dried and the solvent was evaporated under reduced pressure, followed by isolation of the title compound (320 mg, 90%) as a white powder.

T. pl. 203-205 ^o C.

Elemental analysis for C ₁₆ H ₁₇ N ₃ O ₂ :
Calculated,%: C 67.83; H 6.05; N, 14.83.

 Found,%: C 67.53; H 5.90; N, 14.84.

¹ H-NMR (200 MHz, DMCO-D ₆ ) δ: 1.75 (3H, s), 2.37 (3H, s), 7.0-7.4 (7H, m), 7.55 ( 1H, s), 7.94 (1H, s), 8.33 (1H, s), 9.59 (1H, s).

IR (KBr) cm ^-1 : 1660, 1595, 1540.

 47b) 3-Methyl-4- (4'-methylbiphenyl-2-yl) -1,2,4-triazol-5- (4H) -one.

To a solution of the compound (950 mg) obtained in working example (31a) in benzene (920 ml) was added phosphorus oxychloride (1.2 ml) and the mixture was stirred for 20 hours at 90 ^° C. The solvent was evaporated under reduced pressure and the residue diluted with ethyl acetate and then washed with water and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (460 mg, 51%) as a white powder.

T. pl. 102-104 ^o C.

Elemental analysis for C ₁₆ H _{15 3} O:
Calculated,%: C 72.43; H 5.70; N, 15.84.

 Found,% C: 72.37; H 5.68; N, 15.96.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.40 (3H, s), 6.83 (1H, br s), 7.0-7.5 (7H, m), 8.20 ( 1H, d).

IR (KBr) cm ^-1 : 1640, 1575, 1530.

 47c) 3-Methyl-4- (4'-methylbiphenyl-2-yl) -1-methoxymethyl-1,2,4-triazol-5 (H) -one.

 To the ice-cooled compound (250 ml) obtained in working example (31b), in dichloromethane (8 ml) in a nitrogen atmosphere was added chloromethyl ether (0.18 ml) and triethylamine (0.20 ml). The mixture was stirred for 23 hours at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (75 mg, 25%) as a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.09 (3H, s), 2.34 (3H, s), 3.28 (3H, s), 4.95 (2H, s), 7 0-7.4 (8H, m).

IR (Neat), cm ^-1 : 1715, 1640, 1590, 1570, 1515.

 47d) Methyl-2-ethylthio-1 - [[2 '[1,4-dihydro-1-methoxymethyl-3-methyl-5-oxo-1,2,4-triazol-4-yl] biphenyl-4-yl ] methyl] thieno [3,4-d] imidazole-4-methyl-6-carboxylate.

To a solution of the compound obtained in working example (31c) in carbon tetrachloride (5 ml) was added N-bromosuccinimide (48 mg) and α, α-azobisisobutyronitrile (95 ml). The mixture was stirred for 5 hours at 80 ^° C. The reaction mixture was poured into an aqueous solution of sodium bicarbonate and was extracted with chloroform. The extract was dried and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give a pale yellow oil (34 mg). This oil (34 mg) and methyl 2-ethithio-4-methylthieno [3,4-d] imidazole-6-carboxylate (30 mg) were dissolved in N, N-dimethylformamide (4 ml). Sodium hydride (60% in oil, 5 mg) was added to the ice-cooled solution under nitrogen. The mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The residue was partitioned with ethyl acetate, the solution was washed with water, aqueous brine and then dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the indicated compound (42 mg, 85%) was rested as a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, t), 2.05 (3H, d), 2.62 (3H, s), 3.18 (3H, s), 3 30 (2H, q), 3.77 (3H, s), 4.91 (2H, d), 5.69 (2H, s), 7.0-7.4 (8H, m).

IR (Neat), cm ^-1 : 1720, 1695, 1645, 1605, 1540.

 47e) Methyl-2-ethylthio-1 - [[2 '- (1,4-dihydro-3-methyl-5-oxo-1,2,4-triazol-4-yl] methyl] thieno [3,4- d] imidazole-4-methyl-6-carboxylate.

The compound (42 mg) obtained in working example (31d) was dissolved in a mixture of trifluoroacetic acid (1 ml) and chloroform (1.5 ml) and the solution was stirred for 12 hours at 60 ^° C. The reaction mixture was diluted with chloroform, washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give a pale yellow oil. After crystallization from a chloroform-ether mixture, the title compound (34 mg, 87%) was obtained as pale yellow crystals.

T. pl. 204 - 206 ^o C.

Elemental composition for C ₂₆ H ₂₅ N ₅ O ₃ S ₂ • 0.4 CHCl ₃ :
Calculated,%: C 55.88; H 4.51; N, 12.34.

 Found,%: C 55.73; H 4.49; N, 12.57.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (3H, s), 2.41 (3H, s), 2.63 (3H, s), 3.33 (2H, q), 3 80 (3H, s), 5.77 (2H, s), 6.83 (1H, br), 7.0-7.6 (7H, m), 8.18 (1H t).

IR (KBr), cm ^-1 : 1685, 1630, 1600, 1570, 1535, 1520.

 Working Example 48. 1 [[2 '- (2,4-dihydro-4-methyl-3-oxo-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] -2-ethylthio -4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 48a) 4-Methyl-1- [24 (4-phenyl) benzoyl] semicarboside.

 To a solution of 4'-methylbiphenyl-2-carbonylhydrazide (2.3 g) in chloroform (20 ml) was added methyl isocyanate (10 ml) and the mixture was stirred for 1 h at room temperature. The resulting crystalline precipitate was filtered off and purified on a silica gel column chromatography. The crude crystals thus obtained were recrystallized from chloroform-methanol to give colorless needle crystals (0.86 g, 31%).

T. pl. 181-182 ^o C.

Elemental analysis for C ₁₆ H ₁₇ N ₃ O ₂ :
Calculated,%: C 67.83; H 6.05; N, 14.83.

 Found,%: C 67.65; H 6.90; N, 14.85.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.34 (3H, s), 3.30 (3H, d), 5.55 (1H, d), 7.21 (2H, d) 7.32-7.56 (6H, m); 7.85 (1H, s); 9.79 (1H, s).

IR (KBr), cm ^-1 : 3380, 3250, 3220, 1690, 1645, 1540, 820, 760.

 48b) 2,4-dihydro-5- (4'-methylbiphenyl-2-yl) -4-methyl-1,2,4-triazol-3-one.

 The compound (0.86 g) obtained in working example (48a) was dissolved in 1N. NaOH (8 ml) and the solution were boiled under reflux for 15 h, 1 N The HCl pH of the solution was adjusted to 3-4 and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude crystals. Recrystallization from ethyl acetate-hexane gave the title compound as colorless needle crystals (0.60 g, 74%).

T. pl. 181-182 ^o C.

Elemental analysis for C ₁₆ H ₁₅ N ₃ O:
Calculated,%: C 72.43; H 5.70; N, 15.84.

 Found,%: C 72.54; H 5.74; N, 15.95.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 2.55 (3H, s), 7.16 (2H, d), 7.22 (2H, d), 7 42-7.65 (4H, m); 9.72 (1H, s).

IR (KBr), cm ^-1 : 3180, 3060, 1700, 1490, 1465, 1330, 1080, 1040, 960, 820, 800, 780, 760, 750, 700, 650.

 48c) 2,4-dihydro-2-methoxymethyl-5- (4'-methylbiphenyl-2-yl) -4-methyl-1,2,4-triazol-3-one.

Sodium hydride (60% in oil, 72 mg) was added to a ice-cooled solution of the compound (0.40 g) obtained in working example (48b) in DMF (1 ml). The mixture was stirred for 30 minutes, and then chloromethyl ether (0.14 g) was added. The reaction mixture was stirred at 0 ^° for 1.5 hours, and then diluted with water and extracted with acetic acid. The extract was washed with water and dried. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.40 g, 87%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.35 (3H, s), 2.55 (3H, s), 3.43 (3H, s), 5.20 (2H, s), 7 14 (2H, d); 7.21 (2H, d); 7.40-7.64 (4H, m).

IR (Neat), cm ^-1 : 1720, 1490, 1460, 1440, 1395, 1380, 1330, 1295, 1175, 1095, 1040, 920, 820, 785, 760.

 48d) 5- (4'-bromomethylbiphenyl-2-yl) -4,5-dihydro-1-methoxymethyl-4-methyl-1,2,4-triazol-3-one.

 The compound (0.40 g) obtained in working example (48c), NBS (0.23 g) and benzoyl peroxide (17 mg) was added to carbon tetrachloride (10 ml). The mixture was refluxed and irradiated with light for one hour. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude crystals. Recrystallization from ethyl acetate-hexane gave the title compound as colorless prisms (0.38 g, 73%).

T. bale. 137-138 ^o C.

Elemental analysis for C ₁₈ H ₁₈ N ₃ BrO ₂ • 0.5 H ₂ O:
Calculated,%: C 54.42; H 4.82; N, 10.58.

 Found,%: C 54.50; H 4.66; N, 10.51.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.60 (3H, s), 3.41 (3H, s), 4.49 (2H, s), 5.19 (2H, s), 7 29 (2H, d), 7.38 (2H, d), 7.45-7.67 (4H, m).

IR (KBr), cm ^-1 : 1710, 1490, 1470, 1455, 1440, 1375, 1380, 1295, 1235, 1180, 1090, 915, 860, 855, 790, 765, 755, 610.

 48e) Methyl-1 - [[2 '- (2,4-dihydro-2-methoxymethyl-4-methyl-3-oxo-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] 2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylate.

 To an ice-cooled solution of methyl 2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylate (0.26 g) in DMF (1 ml) was added sodium hydride (60% in oil, 48 mg ) The mixture was stirred for 20 minutes. The compound (0.38 g) obtained in working example (36d) was added to the reaction mixture, and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract solution was washed with water and dried. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.30 g, 55%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.55 (3H, s), 2.63 (3H, s), 3.30 (2H, q), 33 , 37 (3H, s), 3.77 (3H, s), 5.18 (2H, s), 5.71 (2H, s), 7.19 (2H, d), 7.25 (2H, d) 7.42-7.64 (4H, m).

IR (Neat), cm ^-1 : 1705, 1605, 1540, 1460, 1440, 1320, 1240, 1170, 1095, 755.

 48f) Methyl-2-ethylthio-1 - [[2 '(2,4-dihydro-4-methyl-3-oxo-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] - 4-methylthieno [3,4-d] imidazole-6-carboxylate.

The compound (0.30 g) obtained in working example (48e) was dissolved in a mixture of trifluoroacetic acid (2 ml) and chloroform (2 ml). The solution was stirred for 5.5 days at 60 ^° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.27 g, 96%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, t), 2.53 (3H, s), 2.63 (3H, s), 3.30 (2H, q), 3 77 (3H, s), 5.71 (2H, s), 7.15 (2H, d), 7.23 (2H, d), 7.42-7.65 (4H, m).

IR (Neat), cm ^-1 : 1700, 1600, 1540, 1460, 1435, 1320, 1240, 1195, 1170, 1095, 750.

48g) 2-Ethylthio-1 - [[2 '- (2,4-dihydro-4-methyl-3-oxo-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] -4 methylthieno [3,4-d] imidazole-6-carboxylic acid
The compound (0.27) obtained in working example (48f) and lithium hydroxide monohydrate (0.11 g) were dissolved in a mixture of THF (2 ml) and water (2 ml) and the solution was stirred for 8 hours at 60-70 ^o C The reaction mixture was diluted with water, insoluble materials were filtered and 1 N. HCl adjusted the pH of the filtrate to 3-4. The crystalline precipitate was filtered off and purified on a silica gel column chromatography to isolate crude crystals. Recrystallization from a chloroform-methanol mixture gave the title compound as pale yellow prisms (70 mg, 27%).

T. pl. 228-229 ^o C (decomposition).

Elemental analysis for C ₂₅ H ₂₃ N ₅ O ₃ S ₂ • 5 H ₂ O:
Calculated,%: C 58.35; H 4.70; N, 13.61.

 Found,%: C 58.64; H 4.59; N, 13.71.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (3H, s), 2.44 (3H, s), 2.63 (3H, s), 3.35 (2H, q), 5 61 (2H, s), 7.10 (2H, d), 7.20 (2H, d), 7.46-7.64 (4H, m).

IR (KBr), cm ^-1 : 1690, 1605, 1540, 1490, 1460, 1415, 1315, 1240, 1200, 1170, 1100, 940, 805, 780, 760.

 Working Example 49. 2-Ethylthio-1 - [[2 '- (5-hydroxy-2-1,2,4-triazol-3-yl) biphenyl-4-yl-methyl] -4-methylthieno [3,4 -d] imidazole-6-carboxylic acid.

 1-Methyl-1- (4'-methylbiphenyl-2-carbonyl) hydrazide.

 To a solution of 4'-methylbiphenyl-2-carboxylic acid (3.2 g) and DMF (one drop) in THF (35 ml) was added dropwise oxalyl chloride (2.9 g) and the mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. pressure. The residue was added dropwise to a solution of monoethyl hydrazine (6.9 g) in THF (80 ml). The reaction mixture was stirred for one hour at room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (3.6 g, 100%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 2.62 (3H, s), 4.39 (2H / s), 7-, 19-7.47 (8H , m).

IR (Neat), cm ^-1 : 3300, 3200, 1630.

 49b) 1-Methyl-1- [2- (4-methylphenyl) benzoyl] semicarboside.

 To a solution of the compound (3.6 g) obtained in working example (49a), in 1 N. HCl (37 ml) was added dropwise an aqueous solution (30 ml) of sodium isocyanate (2.6 g) and the mixture was stirred for 3 hours at room temperature. The crystalline precipitate was filtered off and recrystallized from a methanol-ethyl acetate mixture and the title compound was isolated as colorless prisms (3.1 g, 74%).

T. pl. 217-218 ^o C.

Elemental analysis for C ₁₆ H ₁₇ N ₃ O ₂ :
Calculated,%: C 67.83; H 6.05; N, 14.83.

 Found,%: C 67.99; H 6.02; N, 15.03.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.34 (3H, s), 3.00 (3H, s), 6.08 (1H, s), 7.19 (2H, d) 7.24-7.50 (6H, m); 8.15 (1H, s).

IR (KBr), cm ^-1 : 3470, 3330, 1680, 1645, 1610, 1520, 1460, 1390, 1340, 825, 755.

 49c) 1-Methyl-5- (4'-methylbiphenyl-2-yl) -3-hydroxy-1,2,4-triazole.

 In accordance with the procedure described in working example (48b), the compound was obtained as colorless prisms (2.7 g, 93%) from the compound (3.1 g) obtained in working example (49b).

T. pl. 271-272 ^o C.

Elemental analysis for C ₁₆ H ₁₅ N ₃ O:
Calculated,%: C 72.43; H 5.70; N, 15.84.

 Found,%: C 72.30; H 5.74; N, 15.79.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.31 (3H, s), 2.95 (3H, s), 7.06 (2H, d), 7.18 (2H, d) 7.51-7.68 (4H, m); 10.84 (1H, s).

IR (KBr), cm ^-1 : 1580, 1510, 1490, 1440, 1325, 1275, 890, 880, 840, 820, 760, 620.

 49d) 3-Ethoxycarbonyloxy-1-methyl-5- (4'-methylbiphenyl-2-yl) -1,2,4-triazole.

 Ethyl chloroformate (0.31 g) was added to a suspension of the compound (0.65 g) obtained in working example (49c) and triethylamine (0.29 g) in methylene chloride (10 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with water and dried. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.55 g, 68%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.40 (3H, t), 2.34 (3H, s), 3.02 (3H, s) 4.37 (2H, q), 7, 09 (2H, d), 7.41-7.64 (4H, m).

IR (Neat), cm ^-1 : 1780, 1505, 1360, 1230.

 49e) 5- (4-bromomethylphenyl-2-yl-3-ethoxycarbonyloxy-1-methyl-1,2,4-triazole.

 According to the procedure described in working example (48d), said compound was obtained as a colorless oil (0.63 g, 94%) from a compound (0.55 g) obtained in working example (49d).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t), 3.05 (3H, s), 4.37 (2H, s), 4.48 (2H, s), 7 19 (2H, d); 7.54-7.66 (4H, m).

IR (Neat), cm ^-1 : 1770, 1500, 1470, 1435, 1400, 1360, 1230, 760.

 49f) Methyl 1 - [[2 '- (3-ethoxycarbonyloxy-1-methyl-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] -2-ethylthio-4-methylthieno [3 , 4-d] imidazole-6-carboxylate.

 In accordance with the procedure described in working example (48e), the compound was obtained as a colorless oil (0.22 g, 25%) from the compound (0.63 g) obtained in working example (49e).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.40 (3H, t), 1.41 (3H, t), 2.63 (2H, s), 2.97 (3H, s), 3 , 29 (2H, q), 3.76 (3H, s), 4.36 (2H, q), 5.69 (2H, s), 7.14 (4H, s), 7.42-77, 64 (4H, m).

IR (Neat), cm ^-1 : 1780, 1690, 1605, 1540, 1510, 1460, 1440, 1365, 1320, 1240, 1170, 1090, 760.

 49g) 2-ethylthio-1 - [[2 '- (3-hydroxy-1-methyl-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4 -d] imidazal-6-carboxylic acid.

 In accordance with the procedure described in the working example (48g), the compound was obtained as colorless prisms from the compound (0.22 g) obtained in the working example (49e).

T. pl. 236-237 ^o C.

Elemental analysis for C ₂₅ H ₂₃ N ₅ O ₃ S ₂ • 0.2 H ₂ O:
Calculated,%: C 59.97; H 4.63; N 13.75.

 Found,%: C 59.00; H 4.76; N, 13.68.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.33 (3H, t), 2.55 (3H, s), 2.92 (3H, s), 3.24 (2H, q) 5.69 (2H, s); 7.12 (4H, s-like); 7.50-7.68 (4H, m).

IR (KBr), cm ^-1 : 1690, 1640, 1600, 1585, 1540, 1460, 1415, 1370, 1305, 1270, 1235, 1200, 1170, 1095, 935, 775, 765.

 Working Example 50. 1 - [[2 '- (2,4-dihydro-3-oxo-1,2,4-triazol-5-yl) biphenyl-4-yl] methyl] -2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 50a) 2,5-dihydro-5- (4'methylbiphenyl-2-yl) -1,2,4-thiazol-3-one.

 1- (4-methylphenyl) benzoyl] semicarboside (4.6 g) and phosphorus oxychloride (10.3 g) were suspended in benzene (100 ml), and then the suspension was boiled under reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and the precipitated crystals were filtered. Recrystallization from methanol gave the title compound as colorless needle crystals (3.4 g, 79%).

T. pl. 245-246 ^o C (decomposition).

Elemental analysis for C ₁₅ H ₁₃ N ₃ O:
Calculated,%: C 71.70; H 5.21; N, 16.72.

 Found,%: C 71.37; H 5.42; N, 16.72.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 4.84 (2H, s), 7.17 (4H, s) 7.39-7.58 (3H , m), 7.85-7.89 (1H, m).

IR (KBr), cm ^-1 : 3260, 3080, 1670, 1655, 1605, 1580, 1025, 820, 765, 750.

 50b) 1,2 - (& (2,4-dihydro-1,2 - (& (2,4-) bis (methoxymethyl) -3- (4-methylbiphenyl-2-yl) 1,2,4-triazole -3-he.

 In accordance with the procedure described in working example (48c), a mixture of isomers (1: 2) of the indicated compound was obtained as a colorless oil (1.6 g, 73%) from the compound (1.6 g) obtained in the working example (50a).

¹ H-NMR (200 MHz, CDCl ₃ ), δ: 2.38 (3H, s), 3.09 (3H, s), 3.30 (1H, s) 3.40 (2H, s), 4 30 (2H, s), 4.56 (2H, s) 7.20-7.30 (4H, m), 7.39-7.54 (4H, m).

IR (Neat), cm ^-1 : 2220, 1685, 1480, 1440, 1360, 1290, 1240, 1190, 1090, 915, 820, 760.

 50c) 3- (4'-Bromomethylbiphenyl-2-yl) -1,2 - (& 2,4-dihydro-1,2 - (& 2,4) -bis (methoxymethyl) -1,2,4-triazole -3-he.

 According to the procedure described in working example (48d), a mixture of the isomers (1: 2) of the indicated compound was obtained as a colorless oil (2.0 g, 100%) from the compound obtained in working example (50b).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.10 (3H, s), 3.23 (1H, s), 3.41 (2H, s), 4.31 (2H, s), 4 54 (2H, s), 7.35-7.65 (8H, m).

IR (Neat), cm ^-1 : 2210, 1680, 1440, 1360, 1285, 1240, 1230, 1190, 915, 760.

 50d) Methyl-2-ethylthio-1 - [[2 '- (1,2- & 2,4) -dihydro-1,2 - (& 2,4) -bis-methoxymethyl) -5-oxo-1, 2,4-triazol-3-yl] methyl] -4-methylthio- [3,4-d] imidazole-6-carboxylate.

 In accordance with the procedure described in working example (48e), a mixture of the isomers of the indicated compound was obtained as a pale yellow oil (0.65 g, 43%) from the compound (1.0 g) obtained in the working example (50 s )

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (3H, s), 2.62 (3H, s), 3.05 (3H, s), 3.26 (1H, s), 3 30 (2H, s), 3.36 (2 / 3H, s), 3.77 (3H, s), 4.22 (2H, s), 4.22 (2H, s), 4.42 ( 2H, s), 5.72 (2H, s), 7.21-7.57 (8H, m).

IR, cm ^-1 : 2220, 1690, 1600, 1540, 1460, 1430, 1360, 1320, 1285, 1240, 1195, 1165, 1090, 755.

 50f) Methyl-2-ethylthio-1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-triazol-3-yl) biphenyl-4-yl] methyl] -4- methylthieno [3,4-d] imidazole-6-carboxylate.

 According to the procedure described in working example (48f), said compound was obtained as yellow prisms (0.28 g, 50%) from the compound (0.65 g) obtained in working example (50d).

T. pl. 272-273 ^o C (decomposition).

Elemental analysis for C ₂₅ H ₂₃ N ₅ O ₃ S ₂ :
Calculated,%: C 59.39; H 4.58; N, 13.85.

 Found,%: C 59.17; H 4.74; N, 13.81.

¹ H-NMR (200 MHz-d ₆ ) δ: 1.36 (3H, s), 2.56 (3H, s), 3.26 (2H, s), 3.70 (3H, s), 5 66 (2H, s), 6.96 (2H, br s), 7.12 (2H, d), 7.22 (2H, d), 7.41-7.63 (3H, m), 7.69 (1H, dd).

IR (KBr), cm ^-1 : 3275, 3100, 1680, 1660, 1535, 1450, 1430, 1320, 1235, 1160, 1090, 755.

 50f) 2-Ethylthio-1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-triazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3 , 4-d] imidazole-6-carboxylic acid.

 In accordance with the procedure described in the working example (48g), the compound was obtained as colorless needle crystals (0.17 g, 65%) from the compound (0.27 g) obtained in the working example (50e).

T. pl. 205-207 ^o (decomposition).

Elemental analysis for C ₂₄ H ₂₁ N ₅ O ₃ S ₂ :
Calculated,%: C 58.64; H 4.31; N, 14.25.

 Found,%: C 58.30; H 4.16; N, 14.12.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.35 (3H, t), 2.54 (3H, s), 3.24 (2H, s), 5.70 (2H, s) 6.95 (2H, s), 7.15 (2H, d), 7.22 (2H, d), 7.41-7.63 (3H, m), 7.69 (1H, dd).

IR (KBr), cm ^-1 : 1660, 1650, 1595, 1535, 1450, 1305, 1240, 1160.

 Working Example 51. Methyl 2-n-butyl-1 - [[2 '- (2,4-dioxoimidazolidin-1-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

 51a) Methyl-2-n-butyl-1 - [[2 '- (t-butoxycarbonylamino) biphenyl) -4-yl] methyl] benzimidazole-7-carboxylate.

Methyl-2-butyl-1 - [[2 '- (t-butoxycarbonyl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (600 mg) and triethylamine (0.2 ml) were dissolved in N, N- dimethylformamide (3 ml). Diphenylphosphorylazide (DPPA) (0.32 ml) was added dropwise to a solution of ice-cooled under nitrogen atmosphere. The mixture was stirred for 4.5 hours at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with water three times and dried. The solution thus obtained was concentrated under reduced pressure to a volume of 20 ml. The concentrate was added dropwise with stirring at 80 ^° C. to toluene (25 ml). The mixture was stirred at the same temperature for 20 minutes. T-butanol (15 ml) was added to the reaction mixture, and the mixture was stirred for 17 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (510 mg, 73%) as a pale yellow oil.

 51b) Methyl 2-n-butyl-1 - [(2'-aminobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate.

The compound (510 mg) obtained in the working example (51 a) was dissolved in concentrated HCl (0.8 ml) and methanol (10 ml), and then the solution was stirred for 70 minutes at 70 ^° C. The solvent was removed under reduced pressure. An aqueous bicarbonate solution was added to the precipitate, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give a pale yellow oil, which crystallized from ether to give the title compound (370 mg, 90%) as white crystals.

T. pl. 97-99 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₃ O ₂ :
Calculated,%: C 75.52; H 6.58; N, 10.16.

 Found,%: C 75.27; H 6.81; N, 9.99.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95 (3H, t), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 2.92 ( 2H, t), 3.65 (2H, br s), 3.73 (3H, s), 5.79 (2H, s), 6.7-7.5-) 9H, m), 7.64 (1H, dd), 7.95 (1H, dd).

IR (KBr), cm ^-1 : 1720, 1630, 1600, 1575, 1520.

 51c) Methyl 2-n-butyl-1 - [[2 '- (ethoxycarbonylmethylamino) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

 The compound (408 mg) was dissolved in N, N-dimethylformamide (12 ml), and potassium carbonate (150 mg) was added to the solution at room temperature. The mixture was stirred for 63 hours at room temperature, and then the solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was dried, concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, and the indicated compound (139 mg, 28%) was obtained as a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96 (3H, t), 1.24 (3H, t), 1.4-1.6 (2H, m), 1.8-2, 0 (2H, m), 2.93 (2H, t), 3.73 (3H, s), 3.85 (2H, d), 4.17 (2 H, q), 4.51 (1H, t), 5.79 (2H, s), 6.55 (IH, d), 6.7-7.5 (8H, m), 7.64 (IH, dd), 7.95 (1H, dd )

IR (Neat), cm ^-1 : 1745, 1720, 1600, 1580, 1520, 1505.

 51d) Methyl 2-n-butyl-1 - [[2 '- [(N-chloroacetylcarbamoyl) - (N-ethoxycarbonylmethyl) amino] biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

 To an ice-cooled solution of the compound (260 mg) obtained in working example (51c) in dichloromethane (10 ml) under a nitrogen atmosphere was added dropwise chloroacetyl isocyanate (80 μl). The mixture was stirred for 2 hours at the same temperature and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the title compound (193 mg, 60%) as a white powder.

T. pl. 149-151 ^o C.

Elemental analysis for C ₃₃ H ₃₅ N ₄ O ₆ Cl • O • 2H ₂ O:
Calculated,%: C 63.65; H 5.73; N, 9.00.

 Found,%: C 63.46; H 5.65; N, 8.72.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.98 (3H, t), 1.25 (3H, t), 1.3-1.6 (2H, m), 1.7-2, 0 (2H, m), 2.91 (2H, t), 3.32 (1H, d), 4.58 (1H, d), 5.79 (2H, s), 6.91 (2H, d) ), 7.11 (2H, d), 7.2-7.7 (6H, m), 7.95 (1H, d).

IR (KBr), cm ^-1 : 1750, 1720, 1690, 1520.

 51e) Methyl-2-n-butyl-1 - [[2 '- (2,4-dioxoimidazolidin-1-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

 The compound (180 g) obtained in working example (51d) was dissolved in a mixture of methanol (10 ml) and chloroform (3 ml). Sodium N-methyldithiocarbonate was added to the solution in a nitrogen atmosphere at room temperature. The mixture was stirred for 5 hours at room temperature, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give a colorless oil (137 mg). Sodium hydride (60% in oil, 13 mg) was added to a solution of oil in N, N-dimethylformamide (3 ml) under ice-cooling under nitrogen atmosphere. The mixture was stirred for 2 hours while cooling with ice, and then another 4 hours at room temperature. After evaporation of the solvent, the residue was diluted with chloroform, then washed with diluted hydrochloric acid and dried. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow oil. This product was crystallized from chloroform to give the title compound (40 mg, 32%) as a pale yellow powder.

T. pl. 175-178 ^o C.

Elemental analysis for C ₂₉ H ₂₇ N ₄ O ₄ • 0.3H ₂ O:
Calculated,%: C 69.39; H 5.74; N, 11.16.

 Found,%: C 69.47; H 5.83; N, 10.98.

¹ H-NMR (200 MHz, CLCl ₃ ) δ: 0.95 (3H, t), 1.3-1.6 (2H, m), 2.95 (2H, t), 3.68 (2H, s), 3.71 (3H, s), 5.79 (2H, s), 6.89 (2H, d), 7.1-7.5 (7H, m), 7.63 (1H, d) ), 7.97 (1H, dd), 8.14 (1H, br s).

IR (KBr), cm ^-1 : 3450, 2960, 2740, 1170, 1730, 1610, 1525.

 Working Example 52. Methyl 2-butyl-1 - [[2 '- (2,4-dioxo-3H-thiazolidin-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

 52a) Methyl-2- [N- (2'-butoxycarbonylbiphenyl-4-yl) methyl-N-valeryl] amino-3-nitrobenzoate.

Sodium hydride (60% in oil, 0.40 g) was added to a solution of methyl 3-nitro-2-valerylaminobenzoate (2.79 g) in DMF (20 ml) with stirring and ice-cooling. After stirring for 5 minutes, 2-tert-butoxycarbonylbiphenylmethyl bromide (4.51 g, 13 mmol) was added to the mixture. The reaction mixture was stirred for 2 hours at 70 ^° C. and extracted with ethyl acetate. The extract was washed with water and dried (MgS) ₄ , and then the solvent was evaporated in vacuo. The residue was purified by column chromatography to give crude crystals. Recrystallization from isopropyl ether gave the title compound (4.41 g, 81%) as colorless crystals.

T. pl. 127-128 ^o C.

Elemental analysis for C ₃₁ H ₃₄ N ₂ O ₇ :
Calculated,%: C 68.12; H 6.27; N, 5.12.

 Found,%: C 68.27; H 6.27; N, 4.85.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.80 (3H, t), 1.20 (2H, m), 1.23 (9H, s), 1.53 (2H, m), 2 05 (2H, t), 3.62 (3H, s), 4.56 and 4.77 (2H, each d), 7.05 (2H, d), 7.13 (2H, d), 7 27-7.83 (5H, m), 8.12 (1H, dd), 8.23 (1H, dd).

IR (Nujol), cm ^-1 : 1740, 1710, 1675, 1600.

 52b) Methyl-2-butyl-1- [2'-tert. -butoxycarbonylbiphenyl-4-yl] methyl-benzimidazole-7-carboxylate.

 To a mixture of the compound (3.20 g) obtained in working example (52a), concentrated HCl (0.5 ml) and methanol (30 ml), iron powder (1.35 g) was added. The mixture was boiled under reflux for 1.5 hours. Insoluble materials were filtered through celite. The filtrate was concentrated to dryness and concentrated HCl (0.5 ml) and methanol (50 ml) were added to the residue. The mixture was boiled under reflux for 1.5 hours, and then concentrated to dryness. The residue was partitioned between water and chloroform. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the title compound (2.38 g, 82%) as an oil.

Elemental analysis for C ₃₁ H ₃₄ N ₂ O ₄ • 1 / 2H ₂ O:
Calculated,%: C 73.35; H 6.95; N, 5.52.

 Found,%: C 73.42; H 6.98; N, 5.45.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.97 (3H, t), 1.19 (9H, s), 1.48 (2H, m), 2.93 (2H, t), 3 76 (3H, s), 5.83 (2H, s), 6.87 (2H, d), 7.16-7.51 (6H, m), 7.64-7.77 (2H, m ), 7.95 (1H, dd).

IR (Neat), cm ^-1 : 1715, 1700, 1595.

 52c) Methyl-2-butyl-1- [2'-carboxylbiphenyl-4-yl] methylbenzimidazole-7-carboxylate.

To a solution of the compound (2.35 g) obtained in working example (52b) in dichloromethane (8 ml) was added trifluoroacetic acid (10 ml). The mixture was boiled for 1 h at room temperature, diluted with water and extracted with chloroform. The extract was washed with water, dried (MgSO ₄ ), and the solvent was evaporated in vacuo. The residue was purified on a chromatographic column with isolation of crystals. Recrystallization from diethyl ether gave the title compound as colorless prisms (2.04 g, 98%).

T. pl. 192-194 ^o C.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.90 (3H, t), 1.40 (2H, m), 1.78 (2H, m), 2.94 (2H, t) 3.65 (3H, s), 3.84 (1H, s), 5.73 (2H, s), 6.87 (2H, d), 7.22-7.57 (7H, m), 7.70 (1H, dd); 7.88 (1H, dd).

IR (Nujol), cm ^-1 : 3420, 1725, 1690, 1600.

 52d) Methyl-2-butyl-1- [2'-hydroxymethylbiphenyl-4-yl] methylbenzimidazole-7-carboxylate.

A mixture of methyl 2-butyl-1- [2'-carboxybiphenyl-4-yl] methylbenzimidazole-7-carboxylate (0.44 g) and thionyl chloride (0.15 ml) in chloroform (4 ml) was boiled with constant stirring with the reverse refrigerator for 30 minutes The reaction mixture was concentrated and the resulting product was used in the subsequent reaction without purification. A mixed solution of the indicated product in tetrahydrofuran (6 ml) was added dropwise under ice-cooling to a suspension of aluminum lithium hydride (40 mg) in tetrahydrofuran (6 ml). The reaction mixture was stirred for 1 min at the same temperature, 2N was added to the mixture. HCl, then water and was extracted with chloroform. The extract was washed with water and dried (MgSO ₄ ), and then purified on a silica gel chromatography column to isolate oil. Crystallization of this product from isopropyl ether gave colorless prisms (0.13 g, 31%).

T. pl. 126-127 ^o C.

Elemental analysis for C ₂₇ H ₂₈ N ₂ O ₃ :
Calculated,%: C 75.68; H 6.59; N, 6.54.

 Found,%: C 75.20; H 6.66; N, 6.55.

 52e) Methyl 2-butyl-1- [2'-formylbiphenyl-4-yl] methylbenzimidazole-7-carboxylate.

 A mixture of the compound (0.73 g) obtained in working example (52d), pyridinium dichromate (0.75) and dichloromethane (20 ml) was stirred for 15 hours at room temperature. Insoluble materials were filtered through celite and concentrated to dryness. The residue was purified by silica gel column chromatography to isolate crude crystals. Recrystallization from ethyl acetate-diethyl ether gave colorless prisms (0.62 g, 85%).

T. pl. 103-104 ^o C.

Elemental analysis of C ₂₇ H ₂₆ N ₂ O ₃ :
Calculated,%: C 76.03; H 6.1; N, 6.57.

 Found,%: C 75.95; H 6.07; N, 6.56.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96 (3H, t), 1.48 (2H, m), 2.93 (2H, t), 3.74 (3H, s), 5 84 (2H, s), 6.96 (2H, d), 7.22-7.72 (7H, m), 7.94-8.06 (2H, m), 9.91 (1H, s )

IR (Nujol), cm ^-1 : 1720, 1695, 1595.

 52f) Methyl-2-butyl-1- [2'-cyanohydroxymethylbiphenyl-4-yl] methyl-benzimidazole-7-carboxylate.

To a solution of the compound (0.61 g) obtained in working example (52e) in ethyl acetate (6 ml) was added an aqueous solution (1.5 ml) of sodium hydrogen sulfate (0.74 g) and an aqueous solution (1.5 ml) potassium cyanide (0.47 g). The reaction mixture was stirred for 2 hours at room temperature and then for another 1 hour at 60 ^° C. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the title compound (0.61 g, 94%) as a syrup.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.87 (3H, t), 1.36 (2H, m), 1.71 (2H, m), 2.80 (2H, t), 3 74 (3H, s), 5.47 (2H, s), 5.75 (2H, s), 6.85 (2H, d), 7.16-7.93 (9H, m).

IR (Neat), cm ^-1 : 3420.2360, 1720, 1605.

 52g) Methyl-2-butyl-1- [2 '- (2,4-dioxothiazolidin-5-yl) biphenyl-4-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxylate.

 Thionyl chloride (0.15 ml, 2.1 mmol) was added to a solution of the compound (0.60 g) obtained in working example (52f) in chloroform. The solution was boiled for 1 hour under reflux. The reaction mixture was concentrated and the residue was used in the subsequent reaction without purification.

A mixture of the compound obtained above and thiourea (0.11 g) in methanol (10 ml) was refluxed for 1 hour. Then 2N was added. HCl (13 ml) and the reaction mixture were refluxed for another 12 hours. The extract was washed with water, dried (MgSO ₄ ) and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to isolate crystals. Recrystallization from a dichloromethane-ethyl acetate mixture gave the title compound (0.40 g, 59%) as colorless prisms.

T. pl. 141-142 ^o C.

Elemental analysis for C ₂₉ H ₂₇ N ₃ O ₄ S:
Calculated,%: C 67.82; H 5.30; N, 8.18.

 Found,%: C 67.71; H 5.62; N, 8.14.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.89 (3H, t), 1.40 (2H, m), 1.78 (2H, m), 2.91 (2H, t) 3.69 (3H, s), 5.46 (1H, s), 5.76 (2H, s), 6.93 (2H, d), 7.15-7.61 (8H, m), 7.87 (1H, d); 12.28 (1H, w).

IR (Nujol), cm ^-1 : 1745, 1725, 1700, 1605.

 Working example 53. 2-Ethylthio-1 - [[3 '- (2,5-dihydro-5-oxo-1,2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] thieno [3, 4-d] imidazole-4-methyl-6-carboxylic acid.

 53a) Methyl 4'-methylbiphenyl-3-carboxylate.

Copper powder was gradually added to a mixture of methyl 3-iodobenzoate (26.1 g) in 4-iodotoluene (21.9 g) at 180-190 ^° C. The mixture was then stirred for 6 hours at 200-210 ^° C. The reaction mixture was cooled to room temperature and toluene was added thereto. Insoluble materials were filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give a colorless oil (6.61 g, 29%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.40 (3H, s), 3.94 (3H, s), 7.26 (2H, d), 7.49 (1H, t), 7 52 (2H, d), 7.77 (1H, m), 7.99 (1H, td), 8.26 (1H, t).

 53b) 4'-Methylbiphenyl-3-carboxylic acid.

 To a solution of the compound (2.36 g) obtained in working example (53a) in lithium tetrahydrofuran (20 ml) - aqueous (10 ml) mixture was added lithium hydroxide monohydrate (1.31 g). The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated, diluted with water and washed with ethyl acetate. Water layer using 1 N. HCl was adjusted to pH 3. The crystalline precipitate was filtered off, dried, and the title compound was obtained as colorless needle crystals (1.73 g, 78%).

T. pl. 182-187 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 7.28 (2H, d), 7.54 (1H, t), 7.54 (2H, d), 7 83 (1H, m), 8.08 (IH, td), 8.35 (1H, t).

IR (KBr), cm ^-1 : 1700, 1450, 1415, 1310, 1300, 1270, 1260, 810, 755, 720.

 53c) 4'-Methylbiphenyl-3-carboxamide.

 Thionyl chloride (1.94 g) and dimethylformamide (two drops) were added to a suspension of the compound (1.73 g) obtained in working example (53b) in chloroform (25 ml). The mixture was refluxed for 4 hours. The reaction mixture was concentrated to dryness and toluene was added to the residue. The mixture was again concentrated to dryness. This procedure was repeated four times and a pale yellow oil was isolated, which was added dropwise under ice-cooling to 25% aqueous ammonia (20 ml). The mixture was stirred for 30 minutes at room temperature. The resulting crystalline precipitate was filtered off, dried, and the title compound was obtained as colorless crystals (1.73 g, quantitatively).

T. pl. 200-205 ^o C.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.36 (3H, s), 7.30 (2H, d), 7.41 (1H, s s), 7.51 (1H, t ), 7.63 (2H, d), 7.76-7.86 (2H, m), 810 (1H, br s), 8.14 (1H, t).

IR (KBr), cm ^-1 : 3300, 3150, 1670, 1630, 1605, 1580, 1450, 1410, 1390, 1125, 800, 685.

 53d) 4'-Methyl-3-cyanobiphenyl.

 A mixture of the compound (1.70 g) obtained in the working example (53c) and thionyl chloride (10 ml) was refluxed for 4.5 hours. The reaction mixture was concentrated by dryness and toluene was added to the residue. The mixture was again concentrated to dryness. The procedure was repeated three times, and then the residue was purified by silica gel column chromatography to obtain the title compound as colorless crystals (1.50 g, 96%).

T. pl. 71-73 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 7.28 (2H, d), 7.46 (2H, d), 7.51 (1H, t), 7 60 (1H, td); 7.79 (1H, td); 7.84 (1H, t).

IR (KBr), cm ^-1 : 2230, 1475, 825, 800.

 53e) 4'-Methylbiphenyl-3-carboxyamidoxime.

To a solution of hydroxylamine hydrochloride (2.61 g) in diethyl sulfoxide (20 ml) was added a solution of 28% sodium metaxide in methanol (7.25 g). The mixture was then stirred for 10 min at room temperature, and then a solution of the compound (1.45 g) obtained in working example (53d) in dimethyl sulfoxide (10 ml) was added. The mixture was stirred for one hour at 100 ^° C, and then water was added to the mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo to dryness, dried and concentrated in vacuo by dryness. The residue was purified by silica gel column chromatography to obtain the title compound as colorless crystals (1.30 g, 76%).

T. pl. 134-136 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 4.93 (2H, br s), 7.25 (2H, d), 7.41-7.66 ( 5H, m), 7.85 (1H, t).

IR (KBr), cm ^-1 : 3495, 3385, 1660, 1585, 1440, 1375, 940, 925,900, 795.

 53f) 3-4'-Methylbiphenyl-3-yl) -5-trichloromethyl-1,3,4-oxadiazole.

Trichloroacetic anhydride (2.13 g) was added to a suspension of the compound (1.30 g) obtained in working example (53e) in toluene (30 ml) and the mixture was stirred for 30 minutes at 80 ^° C. The reaction mixture was concentrated to dryness and dissolved in ethyl acetate. The solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography to obtain the title compound as an oil (2.09 g, quantitatively).

¹ H-NMR (200 MHz, CDCL ₃ ) δ: 2.41 (3H, s), 7.28 (2H, d), 7.55 (2H, d), 7.56 (1H, t), 7 76 (1H, td), 8.07 (1H, td), 8.32 (1H, t).

 53g) 3-4'-Bromomethylbiphenyl-3-yl) -5-trichloromethyl-1,2,4-oxadiazole.

 To a solution of the compound (2.09 g) obtained in working example (53f) in carbon tetrachloride (50 ml) was added N-bromosuccinimide (NBS) (1.10 g) and benzoyl peroxide (BPO) (0.20 g). The mixture was refluxed and light irradiated for 1 h. The reaction mixture was cooled to room temperature and insoluble materials were filtered off. The filter was concentrated, the materials were filtered. The filter was concentrated to dryness, and the residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (2.40 g, 59%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.57 (2H, s), 7.49-7.68 (5H, m), 7.75-7.79 (1H, m), 8, 09-8.17 (1H, m), 8.33 (1H, m).

 53h) Methyl-2-ethylthio-1 - [[3 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] thieno [3, 4-d] imidazole-4-methyl-6-carboxylate.

 To a ice-cooled solution of methyl 2-ethylthio-4-methylthieno [3,4-d] imidazole-6-carboxylate (0.80 g) in dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.14 d). After stirring for 10 minutes, a solution of the compound (1.53 g) obtained in working example (53g) in dimethylformamide (10 ml) was added to an ice-cooled mixture, and then stirred for another hour at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated aqueous brine, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give a colorless crystalline product. To a solution of crystals in a mixture of chloroform (10 ml) - methanol (10 ml) was added 1 N. NaOH (3 ml) and the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated and 1 N. HCl adjusted the pH to 3-4. The aqueous mixture was partitioned between chloroform and water. The organic layer was dried, the solvent was removed in vacuo and crude crystals were obtained. After recrystallization from the methanol-ethyl acetate mixture, the title compound was isolated as colorless needle crystals (0.74 g, 83%).

T. pl. 248-251 ^o C (decomposition).

Elemental analysis for C ₂₅ H ₂₂ N ₄ S ₂ • H ₂ O:
Calculated,%: C 58.24; H 4.50; N, 10.87.

 Found,%: C 58.24; H 4.33; N, 10.77.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t), 2, 63 (3H, s), 3.30 (2H, s), 3.78 (3H, s), 5 75 (2H, s), 7.27 (2H, d), 7.51-7.60 (3H, m), 7.69-7.78 (2H, m), 7.98 (1H, t )

IR (KBr), cm ^-1 : 1780, 1755, 1690, 1460, 1320, 1170, 1090, 760.

 53i) 2-Ethylthio-1 [[3 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] thieno [3,4- d] imidazole-4-methyl-6-carboxylic acid.

 To a suspension of the compound (0.60 g) obtained in the working example (53h) in a mixture of tetrahydrofuran (20 ml) - water (10 ml) was added lithium hydroxide monohydrate (0.25 g). The mixture was refluxed for 15 hours. The reaction mixture was concentrated and the aqueous residue was 1N. HCl was adjusted to pH 3. A crystalline precipitate was recrystallized to give colorless needle crystals (0.33 g, 56%).

T. pl. 177-179 ^o C (decomposition).

Elemental analysis for C ₂₄ H ₂₀ N ₄ O ₄ S ₂ • 0 • 5H ₂ O:
Calculated,%: C 57.47; H 4.22; N, 11.17.

 Found,%: C 57.63; H 4.04; N, 11.17.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.35 (3H, t), 2.56 (3H, s), 3.26 (2H, s), 5.73 (2H, s), 7 26 (2H, d), 7.65 (1H, t), 7.69 (2H, d), 7.81 (1H, td), 8.08 (1H, t).

KB (KBr), cm ^-1 : 1770, 1755, 1650, 1530, 1460, 1165, 765.

 Working Example 54. 2-Ethoxy-1 - [[2 '- (2, 5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 54a) 4'-bromomethylbiphenyl-2-carboxamide.

A mixture of 4'-methylbiphenyl-2-carboxamide (2.1 g), N-bromo-succinimide (2.5 g) and azobisisobutyronitrate (AIBN; 82 mg) in benzene (20 ml) was stirred for 20 hours at a temperature of 60-70 ^o C. The resulting crystalline precipitate was filtered off, washed with isopropyl ether and suspended in water. The suspension was stirred for 30 minutes, insoluble products were filtered off, dried and crude crystals were isolated. Recrystallization from ethyl acetate-methanol mixture gave colorless needle crystals (1.6 g), 55%).

T. pl. 220-221 ^o C (decomposition).

Elemental analysis for C ₁₄ H ₁₂ B ₂ NO:
Calculated,%: C 57.95; H 4.17; N, 4.83.

 Found,%: C 57.85; H 4.16; N, 4.77.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 4.75 (2H, s), 7.31-7.69 (10H, m).

IR (KBr), cm ^-1 : 3150, 3000, 1570, 1520, 1500, 1300, 665.

 54b) Methyl-2- [N-tert-butoxycarbonyl-N- (2'-carbamoylbiphenyl-4-yl) methylamino] -3-nitrobenzoate.

A mixture of methyl 2- (N-tert-butoxycarbonylamino) -3-nitrobenzoate (1.8 g), 4'-bromomethylbiphenyl-2-carboxamide (1.8 g) and K ₂ CO ₃ (0.86 g) in acetonitral (25 ml) was refluxed for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO ₄ . The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography to give a yellow syrup (2.3 g, 90%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 3.83 (3H, s), 4.48 (1H, d), 4.92 (1H, d), 5 29 (1H, br s), 7.13-7.54 (8H, m), 7.80-7.91 (2H, m), 8.06 (1H, dd).

IR (Neat), cm ^-1 : 1740-1660, 1600, 1535, 1480, 1450, 1160, 1130, 860, 830, 760.

 54c) Methyl-2- (2'-carbamoylbiphenyl-4-yl) methylamino-3-nitrobenzoate.

A mixture of the compound (2.8 g) obtained in example (54b) in methanol (15 ml) and 1 N. HCl (6 ml) was refluxed for 2 hours. After removing the solvent, the residue was made basic with an aqueous solution of NaHCO ₃ and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography, the product was recrystallized from ethyl acetate-hexane mixture, and yellow needle crystals (1.6 g, 73%) were obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.90 (3H, s), 4.25 (2H, s), 5.20 (1H, s s), 5.46 (1H, s s) 6.73 (1H, d), 7, 32-7.54 (7H, m), 7.78 (1H, dd), 7.97 (1H, dd), 8.12 (1H, dd).

IR (KBr), cm ^-1 : 3470, 3330, 1695, 1670, 1605, 1580, 1530, 1500, 1450, 1350, 1260, 1120, 1110, 765, 745.

 54d) Methyl-3-amino-2- (2'-carbamoylbiphenyl-4-yl) methyl-aminobenzoate.

To a suspension of nickel chloride (4 mg) in methanol (20 ml) was added a small amount of NaBH ₄ and the compound (1.2 g) obtained in Example (54c). To the ice-cooled reaction mixture, NaBH ₄ (0.45 g) was added portionwise over 30 minutes. After stirring for 30 minutes, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and dried over MgSO ₄ . The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give a colorless syrup (0.84 g, 76%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.80 (3H, s), 4.25 (2H, s), 5.12 (1H, s s), 5.42 (1H, s s) 688-6.94 (2H, m), 7.20-7.56 (8H, m), 7.78-7.83 (1H, m).

IR (Neat), cm ^-1 : 3450, 3350, 3180, 1700-1660, 1610, 1470 1380, 1290, 1200, 760.

 54e) Methyl-1 [(2'-carbamoylbiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate.

To dioxane (2 ml) was added the compound (0.84 g) obtained in Example (54d), tetraethoxymethane (0.63 g) and acetic acid (0.13 g), and the mixture was stirred for 6 hours at 80-90 ^° C. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography. Recrystallization from ethyl acetate-hexane mixture gave colorless needle crystals (0.61 g, 64%).

T. pl. 198-199 ^o C.

Elemental analysis for C ₂₅ H ₂₃ N ₃ O ₄ :
Calculated,%: C 69.92; H 5.40; N, 9.78.

 Found,%: C 69.96; H 5.68; N, 9.81.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.52 (3H, t), 3.78 (3H, s), 4.73 (2H, q), 5.14 (1H, b s), 5.39 (1H, br s), 5.66 (2H, s), 7.03 (2H, d), 7.20 (1H, t), 7.30-7.56 (6H, m), 7.73-7.81 (2H, m).

 54f) Methyl-2-ethoxy-1 [(2 '- (ethoxycarboimidoyl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylad.

To methylene chloride (50 ml) was added the compound (4.3 g) obtained in Example (54e) and triethylenetetrafluororate (2.8 g). The mixture was stirred for one hour at room temperature. The reaction mixture was washed with saturated aqueous NaHCO ₃ and dried over MgSO ₄ . The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography. Recrystallization from isopropyl ether gave colorless prismatic crystals (3.6 g, 78%).

T. pl. 105-106 ^o C.

Elemental analysis for C ₂₇ H ₂₇ N ₃ O ₄ :
Calculated,%: C 70.88; H 5.95; N, 9.18.

 Found,%: C 70.66; H 5.96; N, 9.16.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t), 1.50 (3H, t), 3.79 (3H, s), 4.01 (2H, q), 4 67 (2H, q), 5.66 (2H, s), 7.02 (2H, d), 7.13-7.58 (8H, m), 7.73 (1H, dd).

IR (KBr), cm ^-1 : 3310, 1715, 1640, 1620, 1550, 1480, 1460, 1430, 1390, 1375, 1350, 1330, 1280, 1250, 1220, 1170, 1130, 1110, 1080, 1040, 1005 , 870, 760, 750, 740.

 54g) Methyl-2-ethoxy-1 - [[2 '- [(N-methoxycarbonyl) ethoxycarboimidoyl] biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

To toluene (10 ml) was added the compound (1.5 g) obtained in Example (54f), ethyl chloroformate (0.41 g) and 2,6-dimethylpyridine (0.46 g) and the mixture was stirred for 3 hours at 80-90 ^o C. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃ and dried over MgSO ₄ . The solvent was removed in vacuo and the residue was recrystallized from ethyl acetate to obtain colorless prisms (1.5 g, 88%).

T. pl. 157-158 ^o C.

Elemental analysis for C ₂₉ H ₂₉ N ₃ O ₆ :
Calculated,%: C 67.56; H 5.67; N, 8.15.

 Found,%: C 67.43; H 5.70; N, 8.10.

¹ H-NMR (200 MHz, CDCl ₃ ) delta: 0.68 (3H, t), 1.50 (3H, t), 3.57 (3H, s), 3.81 (3H, s), 3 87 (2H, q), 4.67 (2H, q), 5.67 (2H, s), 7.04 (2H, d), 7.15 (1H, t), 7.23-7, 50 (6H, m), 7.55 (1H, dd), 7.72 (1H, dd).

IR (KBr), cm ^-1 : 1710, 1650, 1615, 1550, 1475, 1455, 1445, 1430, 1410, 1390, 1375, 1350, 1320, 1270, 1240, 1220, 1140, 1010, 800, 765, 755 .

 54h) Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate.

 To methanol (15 ml) was added the compound (1.0 g) obtained in Example (54g), hydroxylamine hydrochloride (0.28 g) and MeONa (0.22 g). The mixture was refluxed for 6 hours. Water was added to the reaction mixture. The resulting crystalline precipitate was filtered off and, after recrystallization from ethyl acetate-hexane mixture, colorless prisms (0.7 g, 77%) were obtained.

T. pl. 186-187 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.43 (3H, t), 3.46 (3H, s), 4.39 (2H, s), 5.62 (2H, s), 6 88-7.01 (4H, m), 7.09 (2H, d), 7.26-7.30 (1H, m), 7.45 (1H, dd), 7.54-7.60 (2H, m), 7.85-7.89 (1H, m), 10.25 (1H, br s).

IR (KBr), cm ^-1 : 1780, 1720, 1610, 1550, 1490, 1470, 1435, 1410, 1390, 1350, 1280, 1220, 1130, 1040, 755.

 54i) Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate.

A mixture of the compound (0.23 g) obtained in Example (54g), methyl chloroformate (66 mg) and 2,4,6-trimethylpyridine (85 mg) in toluene (1 ml) was stirred for 16 hours at 80-90 ^° C. Precipitate filtered, the solvent was removed in vacuo. The residue was added to a mixture of hydroxylamine hydrochloride (42 mg) and NaOMe (32 mg) in methanol (2 ml). The mixture was refluxed for 5.5 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and dried over MgSO ₄ . The solvent was evaporated in vacuo, and the residue was crystallized from ethyl acetate-methanol to give colorless prisms (0.13 g, 55%).

 54j) 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid .

The estimate of the compound (0.47 g) obtained in example (54h) and 1 N. NaOH (3 ml) in methanol (3 ml) was refluxed for 30 minutes. The reaction mixture was brought 1 N. HCl to pH 3-4. The resulting crystals were filtered and recrystallized from ethyl acetate-hexane mixture. The crystals were suspended in water (2 ml) and the suspension was stirred for 2 hours at 60 ^° C. Insoluble materials were filtered off, dried, and colorless crystals were obtained (0.25 g, 54%). This product corresponded to the product obtained in example 1.

¹ H-NMR (20-0 MHz, DMCO-d ₆ ) δ: 1.38 (3H, t), 4.58 (2H, q), 5.68 (2H, s), 7.04 (2H, d), 7.13-7.25 (3H, m), 7.45-7.69 (6H, m).

 Example 55. 2-Ethyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5,7- dimethylimidazo [4,5-d] pyridine.

 To a solution of 5,7-dimethyl-2-ethylimidazo [4,5-d] pyridine (0.7 g) synthesized in accordance with European Patent EP 0400974 A2 in dimethylformamide (10 ml) was added hydride (60%) under ice-cooling. in oil, 0.18 g) and the mixture was stirred for 10 minutes. To the ice-cooled reaction mixture was added the compound (2.10 g) obtained in Example (22c), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain a brown syrup. To a solution of the product in methanol (10 ml) was added an aqueous solution of 1 N. NaOH and the solution was stirred for 30 minutes at room temperature. The reaction mixture is 1 N. HCl was adjusted to pH 3-4 and extracted with chloroform. The extract was dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography. The crude crystals thus obtained were recrystallized from ethyl acetate-hexane to give the title compound as colorless crystals (0.35 g, 20%).

T. pl. 149-152 ^o C.

Elemental analysis for C ₂₅ H ₂₃ N ₅ O ₂ • 0.1H ₂ O (427.29).

 Calculated,%: C 70.27; H 5.47; N, 16.39.

 Found,%: C 70.24; H 5.42; N, 16.40.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.24 (3H, s), 2.42 (3H, s), 2.51 (3H, s), 2.64 (2H, q), 5 39 (2H, s), 6.83 (1H, s), 7.05 (2H, d), 7.17 (2H, d), 7.29-7.34 (1H, m), 7, 48 (1H, dt), 7.57 (1H, dt), 7.75-7.80 (1H, m).

IR (KBr), cm ^-1 : 1780, 1610, 1595, 1505, 1495, 1465, 1455, 1425, 1390, 765.

 Example 56. 2-Ethyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -7-methylimidazo [ 4,5-b] pyridine-5-carboxylic acid.

 56a) 4-Methyl-2-nitraminopyridine.

2-amino-4-methylpyridine (25 g) was added gradually under ice-cooling to concentrated sulfuric acid (150 ml). A pre-ice-cold mixture of concentrated nitric (26 ml) and concentrated sulfuric (19 ml) acids was added dropwise to the mixture, while maintaining the temperature of the mixture at 0 ^° C. The mixture was then stirred for 2.5 hours. The reaction mixture was poured into 300 g of ice and the mixture neutralized under cooling with ice with aqueous ammonia. Insoluble materials were filtered off and the filtrate was concentrated. The resulting crystalline precipitate was filtered off, dried, and the title compound was obtained as yellow needle crystals (26.3 g, 74%).

T. pl. 185-187 ^o C.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.40 (3H, s), 7.02 (1H, dd), 7.47 (1H, s), 8.05 (1H, d) .

IR (KBr), cm ^-1 : 1625, 1600, 1520, 1415, 1375, 1365, 1320, 1295, 1260, 1215, 1165.

 56b) 2-amino-4-methyl-3 (and 5) nitropyridine.

4-Methyl-2-nitraminopyridine (34.1 g) was added to concentrated sulfuric acid (170 ml), while maintaining 0 ^° C. The mixture was stirred for 24 hours at room temperature and poured into ice (500 g), and then with cooling ice was neutralized with aqueous ammonium hydroxide. The reaction mixture was cooled until crystalline products were isolated. The crystals were filtered off, dried and a mixture of 3-nitro and 5-nitro derivatives was obtained as yellow crystals (23.5 g, 3-nitro derivatives: 5-nitro derivative 1: 1.7).

3-Nitro derivative: ¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.36 (3H, s), 6.60 (1H, d), 7.09 (2H, br s), 8 07 (1H, d).

5-Nitro derivative: ¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 2.46 (3H, s), 6.32 (1H, s), 7.30 (2H, s s), 8 76 (1H, s).

 56c) 2-Ethyl-7-methylimidoso [4,5-b] pyridine.

 A suspension of the compound (23.4 g) obtained in Example (56b) and 5% Pd-C (13 g) in methanol (500 ml) was stirred under a nitrogen atmosphere. Insoluble materials were filtered off, the filtrate was concentrated to dryness and brown syrup was obtained. The syrup was mixed with polyphosphoric acid (240 g) and propionic acid (40 g) and the mixture was stirred for 20 minutes at room temperature. The reaction mixture was poured into an ice-water mixture and neutralized with aqueous ammonium hydroxide. The resulting crystalline precipitate was filtered and recrystallized from chloroform. The resulting crystalline precipitate (by-product) was filtered. The filtrate and mother liquor were combined and concentrated, and then the resulting crystalline precipitate was filtered and washed with chloroform. The filtrates were combined and concentrated to dryness, and then purified on a silica gel column chromatography. The crude crystals thus obtained were recrystallized from an ethyl acetate-hexane mixture to give the title compound as pale yellow crystals (4.55 g).

T. pl. 117-119 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.56 (3H, t), 2.70 (3H, s), 3.11 (2H, q), 7.05 (1H, d), 8 19 (1H, d).

IR (KBr), cm ^-1 : 1630, 1540, 1445, 1375, 1365, 890, 820.

 56d) 2-Ethyl-7-methylimidazo [4,5-b] pyridin-4N-oxide.

 To chlorine-cooled solution of the compound (2.0 g) obtained in Example (56c) in chloroform (30 ml) was added m-chlorobenzoic acid (2.78 g). The mixture was stirred for 10 minutes and then boiled under reflux for one hour. The reaction mixture was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate-methanol mixture gave the title compound as colorless needle crystals (1.92 g, 85%).

T. pl. 189-191 ^o C.

Elemental analysis for C ₉ H ₁₁ N ₃ O • 0.2H ₂ O (180.81):
Calculated,%: C 59.79; H 6.36; N, 23.24.

 Found,%: C 59.94; H 6.61; N, 23.23.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.33 (3H, t), 2.46 (3H, s), 2.86 (2H, q), 6.96 (1H, d), 8 00 (1H, d).

IR (KBr), cm ^-1 : 1480, 1420, 1280, 1250, 1230, 1170, 765.

 56e) 5-cyano-2-ethyl-7-methylimidazo [4,5-b] pyridine.

 To a suspension of the compound (2.0 g) obtained in Example (56d) in acetonitrile (30 ml) was added trimethylsilyl cyanide (4.5 g) and triethylamine (1.15 g), and the mixture was refluxed for 16 hours. Reaction mixture concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from ethyl acetate to give the title compound as pale yellow needle crystals (1.40 g, 66%).

T. pl. 216-218 ^o C (decomposition).

Elemental analysis for C ₁₀ H ₁₀ N ₄ (186.22):
Calculated,%: C 64.50; H 5.41; N, 30.09.

 Found,%: C 64.26; H 5.45; N, 29.87.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.54 (3H, t), 2.75 (3H, s), 3.22 (2H, s), 7.50 (1H, s).

IR (KBr), cm ^-1 : 2225, 1615, 1600, 1515, 1415, 1395, 1375, 1295, 1270, 785.

 56f) Methyl 2-ethyl-7-methylimidazo [4,5-b] pyridine-5-carboxylate.

 The compound (1.3 g) obtained in Example (56e) was suspended in a 9N solution. hydrogen chloride in methanol. The suspension was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 5 with saturated aqueous sodium bicarbonate and then extracted with chloroform. The extract was dried and the solvent was removed under reduced pressure to give crude crystals. Recrystallization from ethyl acetate-methanol mixture gave the title compound as colorless prisms (1.33 g, 86%).

T. pl. 208-210 ^o C.

Elemental analysis for C ₁₁ H ₁₃ N ₃ O ₃ (219.24):
Calculated,%: C 60.26; H 5.98; N, 19.17.

 Found,%: C 60.14; H 5.99; N, 19.07.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t), 2.74 (3H, s), 3.14 (2H, s), 4.03 (3H, s), 7 92 (1H, s).

IR (KBr), cm ^-1 : 3240, 1730, 1615, 1510, 1435, 1405, 1385, 1300, 1250, 1200, 750.

 56g) Methyl-2-ethyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -7-methylimidazo [4,5-b] pyridine-5-carboxylate.

 To a solution of the compound (1.0 g) obtained in Example (56f) in dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.21 g) at room temperature. The mixture was stirred for 5 minutes, the compound (2.27 g) obtained in Example (22c) was added, and then stirred at room temperature for another 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with aqueous brine and dried. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to obtain colorless crystals. The crystals were dissolved in chloroform (7.5 ml) -methanol (15 ml) mixture. To the solution was added an aqueous solution of 1 N. sodium hydroxide and the mixture was stirred for 20 minutes at room temperature. 1N was added to the reaction mixture. HCl until a pH of 3-4 is reached, and then extracted with chloroform. The extract was dried, the solvent was removed under reduced pressure, and crude crystals were obtained. Recrystallization from ethyl acetate-methanol mixture gave the title compound as colorless prisms (1.07 g, 58%).

T. pl. 246-248 ^o C (decomposition).

Elemental analysis for C ₂₆ H ₂₃ N ₅ O ₄ (469.50):
Calculated,%: C 66.51; H 5.94; N, 14.92.

 Found,%: C 66.37; H 4.97; N, 14.84.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.31 (3H, t), 2.63 (3H, s), 2.80 (2H, s), 3.93 (3H, s), 5 52 (2H, s), 7.14 (2H, d), 7.23 (2H, d), 7.35 (1H, dd), 7.43-7.63 (2H, m), 7, 76 (1H, dd), 7.92 (1H, s), 9.15 (1H, brs),
IR (KBr), cm ^-1 : 1780, 1705, 1485, 1465, 1435, 1275, 1220, 760.

 56h) 2-Ethyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -7-methylimidazole [4 5-b] pyridine-5-carboxylic acid.

To a suspension of the compound (0.9 g) obtained in Example (56g) in methanol (20 ml) was added 1N. an aqueous solution of sodium hydroxide (4.5 ml) and the mixture was stirred for 3 hours at 60 ^° C. 1N was added to the reaction mixture. HCl and adjusted the pH of the mixture to 3-4. The precipitated crystalline precipitate was filtered off and dried. The crystals thus obtained were recrystallized from an ethyl acetate-methanol mixture to obtain the title compound as colorless crystals (0.61 g, 69%).

T. pl. 161-164 ^o C (decomposition).

Elemental analysis for C ₂₅ H ₂₁ N ₅ O ₄ (455.47):
Calculated,%: C 65.93; H 4.65; N, 15.38.

 Found,%: C 65.63; H 4.67; N, 15.15.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.25 (3H, t), 2.64 (3H, s), 2.86 (2H, s), 5.62 (2H, s) 7.22 (2H, d), 7.29 (2H, d), 7.48-7.72 (4H, m), 7.88 (1H, s).

IR (KBr), cm ^-1 : 1790, 1695, 1285, 1270.

 Example 57. Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 carboxylate.

 57a) Methyl-3-amino-2 - [[2 '- (ethoxycarbonyloxycarbamimidoyl-4-yl] methylamino] benzoate.

To a suspension of compound (7.1) obtained in Example (1a) in methanol (120 ml) was added hydroxylamine hydrochloride (5.56 g) and triethylamine (6.06 g). The mixture was stirred for 3 days at 70 ^° C. under nitrogen. Methanol was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (50 ml). The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. Triethylamine (2 g) was added to a solution of the residue in tetrahydrofuran (100 ml) under ice-cooling. A solution of ethyl chlorocarbonate (1.4 g) in tetrahydrofuran (20 ml) was added dropwise to the mixture. The reaction mixture was stirred for 1 h at the same temperature and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried and concentrated to dryness with the formation of a pale yellow syrup (8.6 g).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35 (3H, t), 3.80 (3H, s), 4.20 (2H, s) 4.32 (2H, q), 4, 57 (2H, brs), 6.83-6.93 (2H, m), 7.27-7.54 (8H, m), 7.64-7.70 (1H, m).

IR (CHCl ₃ ), cm ^-1 : 3520, 3415, 3350, 1765, 1700, 1635.

 57b) Methyl-2-ethoxy-1 - [[2 '- (ethoxycarbonyloxycarbamimidoyl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

The pale brown syrup (8.58 g) obtained in Example (57a) was dissolved in dioxane (20 ml). Tetraethoxymethane (8.64 g) and acetic acid (1.56 g) were added to the solution. The mixture was stirred for 2 hours at 100 ^° C. The reaction mixture was concentrated to dryness. The residue was crystallized from ethyl acetate (50 ml). The resulting crystalline precipitate was filtered off and the title compound was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.50 (3H, t), 3.77 (3H, s), 4.31 (2H, q), 4.69 (2H, q), 5 64 (2H, s), 7.01 (2H, d), 7.17 (1H, t), 7.26-7.55 (6H, m), 7.72 (1H, d).

IR (CHCl ₃ ), cm ^-1 : 3520, 3410, 1765, 1710, 1635, 1545.

 57c) Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate.

The gray crystals (4.0 g) obtained in Example (57b) were dissolved in ethyl acetate (50 ml). To the solution was added 1,8-diazabicyclo [5.4.0] -andec-7-ene (DBA, 3.2 g) and the mixture was stirred for 2 hours at 80 ^° C. The reaction mixture was partitioned between ethyl acetate (50 ml) and 1N. HCl (20 ml). The organic layer was washed with water, dried and concentrated to dryness. The residue was crystallized from a chloroform-ethyl acetate mixture to obtain the title compound as colorless prisms (2.1 g, 45%), which corresponded to the compound obtained in Example (1d).

 Example 58. Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 carboxylate.

The gray crystals (4.0 g) obtained in Example (57) were dissolved in ethyl acetate (50 ml). Potassium carbonate (3 g) was added to the solution (instead of DBA) and the mixture was stirred for 18 hours at 90 ^° C. The resulting crystalline precipitate was filtered off and suspended in water (30 ml), the pH of the suspension was 2 N. HCl was adjusted to 3-4. The resulting crystals were filtered, dried and the indicated compound was obtained as colorless crystals (1.81 g, 38%), which corresponded to the compound obtained in Example (57).

 Example 59. 2-Ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxydiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

The compound (3.2 g) obtained by the method of example (1d) is suspended in 0.5 N. NaOH (50 ml). This suspension is stirred for 3 hours at 60 ^° C., the pH of the reaction mixture is adjusted to 3-4 by adding 2N. HCl. The resulting crystals are collected by filtration and washed with water. The crystals thus obtained were stirred in ethanol (45 ml) for 1 h to obtain colorless prismatic crystals (2.9 g, 94%).

T. pl. 212-214 ^o C.

Elemental analysis for C ₂₅ H ₂₀ N ₄ O ₄ :
Calculated,%: C 65.78; H 4.42; N, 12.27.

 Found,%: C 65.72; H 4.67; N, 12.28.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.47 (3H, t), 4.67 (2H, q), 5.77 (2H, s), 7.07-7.70 (11H, m) 13.0 (1H, bs)
IR (Nujol), cm ^-1 : 1780, 1700, 1555, 1470, 1440, 1290, 1050, 765.

 Example 60. Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4, -thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- 7-carboxylate.

 To tetrahydrofuran (15 ml), 1,1'-thiocarbonyldiimidazole (0.36 g) was added first with stirring at room temperature, followed by the compound obtained in Example (1c) (0.89 g). After stirring for 30 minutes, the reaction mixture was concentrated to dryness. The concentrate is dissolved in ethyl acetate, the resulting solution is washed with dilute hydrochloric acid and water, and then dried. Silica gel (7 g) was added to a solution of the obtained residue in a mixture of chloroform-methanol (5: 1, 150 ml), and the resulting mixture was stirred at room temperature for 48 hours. Insoluble products are filtered off and the filtrate is concentrated to dryness to give a syrupy product. It is purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate gave colorless prismatic crystals (0.33 g, 34%).

T. pl ^. 212-212 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₄ S:
Calculated,%: C 64.18; H 4.56; N, 11.52; S 6.59.

 Found,%: C 64.44; H 4.56; N, 11.44; S 6.42.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.43 (3H, t), 3.70 (3H, s), 4.57 (2H, q), 5.67 (2H, s) 6, 93-7.60 (10H, m), 7.77-7.90 (1H, m), 9.43 (1H, br).

IR (Nujol), cm ^-1 : 1715, 1665, 1550, 1440, 1430, 1285, 1250, 1040.

 Example 61. 2-Ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate .

The compound obtained in example (60a) (0.68 g) was suspended in 0.2 n. aqueous NaOH solution (10 ml). The suspension is stirred for 20 hours at 60 ^o C, after which its pH is adjusted to 3-4 by adding 1 N. HCl. The resulting crystals were collected by filtration and recrystallized from methanol to obtain colorless prismatic crystals (0.29 g, 44%).

T. pl. 210-211 ^o C.

Elemental analysis for C ₂₅ H ₂₀ N ₄ O ₄ S:
Calculated,%: C 63.55; H 4.27; N, 11.86; S 6.79.

 Found,%: C 63.26; H 4.32; N, 11.84; S 6.59.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.49 (3H, n), 4.64 (2H, q), 5.76 (2H, s), 7.06-7.70 (11H, m), 12.13 (1H, bs)
IR (Nujol), cm ^-1 : 1720, 1670, 1550, 1425, 1425, 1280, 1035.

 Working Example 62. Methyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] benzimidazole -7-carboxylate.

The mixture obtained in working example (1c) of methyl-2-ethoxy-1 [[2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.66 g), thiocarbonyldiimidazole (0.3 g) and 1, 5-diazabicyclo [4.3.0] non-5-ene (0.56 g) in acetonitrile (15 ml) was stirred at room temperature for 20 hours, after evaporation of the solvent, the residue was dissolved in water and the pH of the resulting solution was adjusted to 4-5 and then extracted with ethyl acetate. The extract was dried and concentrated to dryness, the residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-methanol gave colorless crystals (0.2 g, 20%)
¹ H-NMR (200 MHz, DMCO-d) δ: 1.41 (3H, t), 3.68 (3H, s), 4.61 (2H, s), 5.49 (2H, s), 6.89 (2H, d), 7.15 (2H, d), 7.18 (1H, t), 7.25-7.61 (5H, m), 7.68 (1H, dd), 8 81 (1H, s).

 Working Example 63. Methyl-2-butyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- 7-carboxylate.

 63a) Methyl-1 - [[2 '- (N-acetoxycarbamimidoyl) biphenyl-4-yl] methyl] -2-butylbenzimidazole-7-carboxylate.

To a solution of methyl 2-butyl-1 - [[2 '- (hydroxycarbamimidoyl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (1.83 g) in dichloromethane (20 ml) was added triethylamine (0.46 g) and acetic anhydride (0.46 g) and the reaction mixture is stirred for 2 hours at room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water, the organic layer was washed with an aqueous solution of NaHCO ₃ and water. The solution was dried and concentrated to dryness to give a pale yellow solid (1.99 g, quantitative yield).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96 (3H, t), 1.38-1.56 (2H, m), 1.80-1.95 (2H, m), 2, 14 (3H, s), 2.93 (2H, s), 3.74 (3H, s), 4.60 (2H, ss), 5.76 (2H, s), 6.87 (2H, d) ), 7.20-7.50 (6H, m), 7.55-7.65 (2H, m), 7.93 (1H, d).

IR (Nujol), cm ^-1 : 3325, 3170, 1750, 1720, 1630, 1280.

 This compound is used in the next reaction without any further purification.

 63b) Methyl-2-butyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]] methyl] benzimidazole- 7-carboxylate.

To a mixture of methyl 2-butyl-1 - [[2 '- (acetoxycarbamimidol) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (2.0 g) and CS ₂ (1.5 g) in DMF (12 ml) sodium hydride (60% in oil, 0.56 g) is added over 10 minutes and the reaction mixture is stirred for 2 hours at room temperature. The mixture was poured into a mixture of ice and water and the pH of the resulting solution was adjusted to 3. The mixture was extracted with ethyl acetate, the extract was washed with water, dried and concentrated to dryness. The residue was crystallized from chloroform-methanol to give pale yellow prismatic crystals (0.64 g, 32%).

T. pl. 180-181 ^o C.

Elemental analysis for C ₂₈ H ₂₆ N ₄ O ₃ S:
Calculated,%: C 67.45; H 5.26; N, 11.24.

 Found,%: C 67.14; H 5.05; N, 10.97.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.90 (3H, t), 1.30-1.50 (2H, m), 1.69-1.84 (2H, m), 2.90 (2H, t), 3.65 (3H, s), 5.73 (2H, s), 6.89 (2H, d), 7.19 (2H, d), 7.28 (1H , t), 7.44-7.72 (5H, m), 7.87 (2H, d).

IR (Nujol), cm ^-1 : 1720, 1430, 1285, 1265, 755.

 Working Example 64. 2-butyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 -carboxylic acid.

The solution obtained in the working example 63 methyl ether (0.42 g) in an aqueous solution of 0.3 N. NaOH (8.2 ml) was stirred for 1.5 h at 50 ^o C, the pH of the reaction solution was adjusted to 3 by adding 2 N. HCl and the solution is extracted with ethyl acetate (40 ml). The organic layer was washed with water and concentrated to dryness. The resulting crystals were recrystallized from ethanol-ethyl acetate to give colorless prismatic crystals (0.25 g, 63%).

T. pl. 178-180 ^o C.

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₃ S:
Calculated,%: C 66.92; H 4.99; N, 11.56.

 Found,%: C 66.72; H 4.95; N, 11.72.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.88 (3H, t), 1.28-1.47 (2H, m), 1.65-1.80 (2H, m), 2.85 (2H, t), 5.90 (2H, s), 6.90 (2H, d), 7.17 (2H, d), 7.26 (1H, t), 7.42-7 69 (5H, m); 7.85 (1H, d).

IR (Nujol), cm ^-1 : 3400, 1700, 1430, 1410, 1335, 1230.

 Working Example 65. Methyl-2-butyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- 7-carboxylate.

 The target compound (0.22 g) is obtained with a yield of 44% according to the procedure described in working example 60, from the hydroxycarbamimidoyl derivative (0.46 g) obtained in working example 2.

T. pl. 178-179 ^o C.

Elemental analysis for C ₂₈ H ₂₆ N ₄ O ₃ S:
Calculated,%: C 67.45; H 5.26; N, 11.24.

 Found,%: C 67.31; H 5.27; N, 11.25.

¹ H-NMR (200 MHz, CDCl ₃ ), δ: 0.92 (3H, t), 1.30-1.50 (2H, m), 1.60-1.73 (2H, m), 3 62 (3H, s), 5.69 (2H, s), 6.72 (2H, d), 6.98-7.27 (5H, m), 7.53-7.80 (3H, m ), 7.80-7.78 (1H, m), 11.35 (1H, br s).

IR (Nujol), cm ^-1 : 1720, 1700, 1660, 1453, 1290, 1280, 1265, 1125, 760, 750
Working Example 66. 2-butyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 The target compound (0.16 g) was obtained in 82% yield by the procedure of working example 61 from the compound (0.2 g) obtained in working example 65.

T. pl. 238-239 ^o C (decomp.).

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₃ S • 1 / 3H ₂ O:
Calculated,%: C 66.11; H 5.07; N, 11.42.

 Found,%: C 66.29; H 4.98; N, 11.58.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.88 (3H, t), 1.27-1.45 (2H, m), 1.65-1.80 (2H, m), 2.83 (2H, t), 5.88 (2H, s), 6.87 (2H, s), 7.14 (2H, d), 7.24 (1H, t), 7.41-7 64 (5H, m); 7.83 (2H, d).

IR (Nujol), cm ^-1 : 3255, 1675, 1450, 1420, 1240, 1230, 1205, 755.

 Working Example 67. Methyl-2-ethyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- 7-carboxylate.

 The target compound (0.17 g) was obtained in 38% yield according to the procedure of working example 60 from the compound (0.4 g) obtained in working example 31.

T. pl. 203-205 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₃ S • 0.5 H ₂ O:
Calculated,%: C 65.12; H 4.83; N, 11.68.

 Found,%: C 65.30; H 4.54; N, 11.63.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.13 (3H, t) 2.64 (2H, q), 3.53 (3H, s), 5.62 (2H, s), 6, 59 (2H, d), 6.8-7.9 (7H, m),
IR (KBr), cm ^-1 : 1715, 1690, 1600, 1520.

 Working Example 68. 2-ethyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 The target compound (0.4 g) was obtained in 58% yield according to the procedure of working example 61 from the ester (0.7 g) obtained in working example 67.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 1.30 (3H, t), 2.86 (2H, q), 5.89 (2H, s), 6.90 (2H, d) 7.15 (2H, d), 7.27 (1H, t), 7.4-7.7 (5H, m), 7.86 (1H, d)
IR (KBr), cm ^-1 : 1700, 1655, 1570.

 Working Example 69. Methyl-2-ethyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- 7-carboxylate.

 The target compound (0.12 g) was obtained in 22% yield by the procedure of working example 62 from the compound (0.45 g) obtained in working example 31.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23 (3H, t), 2.78 (2H, s), 3.76 (3H, s), 5.52 (2H, s), 6 91 (2H, d), 7.10 (2H, d), 7.1-7.7 (6H, m), 7.93 (1H, d).

 Working Example 70. Methyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylbenzimidazol-7 carboxylate.

 70a) Methyl-1 - [[2 '- (N-acetoxycarbamimidoyl) biphenyl-4-yl] methyl] -2-propylbenzimidazole-7-carboxylate.

 The target compound (0.95 g) was obtained in 86% yield by the procedure of working example 63 from the hydrocarbamimidoyl derivative (1 g) obtained in working example 30.

T. pl. 177-178 ^o C.

Elemental analysis for C ₂₈ H ₂₈ N ₄ O ₄ S • 0.1 H ₂ O (486, 36):
Calculated,%: C 69.15; H 5.84; N, 11.52.

 Found,%: C 68.93; H 5.80; N, 11.54.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.07 (3H, t), 1.84-2.03 (2H, m), 2.15 (3H, t), 2.91 (2H, t), 3.74 (3H, s), 4.57 (2H, s), 5.76 (2H, s), 6.87 (2H, d), 7.21-7.52 (6H, m), 7.59-7.64 (2H, m), 7.94 (1H, dd).

IR (KBr), cm ^-1 : 3495, 3365, 1745, 1720, 1620, 1285, 1275, 1260, 1230, 1205.

 70b) Methyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylbenzimidazole-7-carboxylate .

 The target compound (0.14 g) was obtained in 28% yield by the procedure of working example (63b) from the N-acetoxycarbamimidoyl derivative (0.5 g) obtained in working example (70a).

T. pl. 206-209 ^o C (decomp.).

Elemental analysis for C ₂₇ H ₂₄ N ₄ O ₃ S • 0.2 H ₂ O (488.18):
Calculated,%: C 66.43; H 5.04; N, 11.48.

 Found,%: C 66.42; H 5.14; N, 11.51.

¹ H-NMR (200 MHz, DMCO-d ₆ ) δ: 0.98 (3H, t), 1.71-1.90 (2H, m), 2.88 (2H, t), 3.65 ( 3H, s0.5.73 (2H, s), 6.89 (2H, d), 7.21 (2H, d), 7.28 (1H, t), 7.44-7.72 (5, m0, 7.88 (1H, dd).

IR (KBr), cm ^-1 : 1725, 1450. 1435, 1410, 1335, 1325, 1285, 1270, 1210, 1125, 770, 760.

 Working Example 71. Methyl -1- [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylbenzimidazol-7 carboxylate.

 The target compound (0.16 g) was obtained in 25% yield by the procedure of working example 60 from the hydroxycarbamimidoyl derivative (0.58 g) obtained in working example 30.

T. pl. 225-227 ^° C (decomp.).

Elemental analysis for c ₂₇ H ₂₄ N ₄ O ₃ S • 0.2 H ₂ O:
Calculated,%: C 66.43; H 5.04; N, 11.48.

 Found,%: C 66.64; H 5.16; N, 11.26.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.01 (3H, t), 1.60-1.80 (2H, m), 2.70 (3H, t), 3.60 (3H, s), 5.69 (3H, s), 6.71 (2H, d), 6.96-7.05 (4H, m), 7.22-7.26 (1H, m), 7.50 -7.59 (3H, m), 7.83-7.87 (1H, m), 11.40 (1H, br s).

IR (KBr), cm ^-1 : 1720, 1700, 1685, 1460, 1435, 1410, 1290, 1270, 1125, 755.

 The following compounds are prepared according to the procedures described in working examples 1-71.

 Working Example 72. 1 [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxybenzimidazole-7-carboxylic acid.

 Working Example 73. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-propoxybenzimidazol-7- carboxylic acid.

 Working Example 74. 1 - [[2 '- (2,5-dihydro-5-oxo-1,24-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-isopropoxybenzimidazole-7-carboxylic acid .

 Working Example 75. 2-butoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 -carboxylic acid.

 Working Example 76. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylthiobenzimidazol-7- carboxylic acid.

 Working Example 77. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylthiobenzimidazol-7- carboxylic acid.

 Working Example 78. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylthiobenzimidazole-7-carboxylic acid.

 Working Example 79. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-isopropylthiobenzimidazol-7- carboxylic acid.

 Working Example 80. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylaminobenzimidazol-7- carboxylic acid.

 Working Example 81. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylaminobenzimidazol-7- carboxylic acid.

 Working Example 82. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylaminobenzimidazol-7- carboxylic acid.

 Working Example 83. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylbenzimidazol-7- carboxylic acid.

 Working Example 84. 2-cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl] biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 Working Example 85. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2,4-dimethylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 Working Example 86. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) -biphenyl-4-yl] methyl] -2-ethyl-4 -methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 87. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -4-methyl-2- propylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 88. 2-Cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -4- methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 89. 1 - [[2 '- (2,5-dihydro-5-oxo-1,24-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxy-4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 Working Example 90. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-4- methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 91. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -4-ethoxy-2- propoxythieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 92. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -4-ethoxy-2- methylthiotieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 93. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylthio-4- methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 94. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -4-methyl-2- methylaminothieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 95. 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylamino-4- methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 96. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxybenzimidazol-7- carboxylic acid.

 Working Example 97. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propoxybenzimidazole-7-carboxylic acid.

 Working Example 98. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-isopropoxybenzimidazole-7-carboxylic acid.

 Working Example 99. 2-butoxy-1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 Working Example 100. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylthiobenzimidazole-7-carboxylic acid.

 Working Example 101. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylthiobenzimidazole-7-carboxylic acid.

 Working Example 102. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propylthiobenzimidazole-7-carboxylic acid.

 Working Example 103. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-isopropylthiobenzimidazole-7-carboxylic acid.

 Working Example 104. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methylaminobenzimidazole-7-carboxylic acid.

 Working Example 105. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -2-ethylaminobenzimidazole-7-carboxylic acid.

 Working Example 106. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -2-propylaminobenzimidazole-7-carboxylic acid.

 Working Example 107. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -2-methylbenzimidazole-7-carboxylic acid.

 Working example 108. 2-cyclopropyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylic acid.

 Working Example 109. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -2,4-dimethylthieno [3 , 4-d] imidazole-6-carboxylic acid.

 Working Example 110. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -2-ethyl-4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 111. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4-yl] methyl] -4-methyl-2-proopiltieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 112. 2-Cyclopropyl-1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 113. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxy-4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 114. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 115. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methyl-2-propoxythieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 116. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methyl-2-methylthiotieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 117. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylthio-4-methylthiotieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 118. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4-methyl-2-methylaminothieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 119. 1 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylamino-4-methylthieno [3,4-d] imidazole-6-carboxylic acid.

 Working Example 120. 1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxybenzimidazole-7-carboxylic acid .

 Working Example 121. 1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxybenzimidazole-7-carboxylic acid .

 Working Example 122. 2-butyl-1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazo-7-carboxylic acid.

 Working Example 123. 1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylthiobenzimidazole-7-carboxylic acid .

 Working Example 124. 1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxy-4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 Working Example 125. 1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 Working Example 126. 2-butyl-1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 Working Example 127. 1 - [[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethylthio-4-methylthieno [ 3,4-d] imidazole-6-carboxylic acid.

 Working Example 128. 2-ethyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 129. 2-propyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 130. 2-butyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 131. 2-methoxy-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 132. 2-ethoxy-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 133. 2-propoxy-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 134. 2-Cyclopropopyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Working Example 135. 2-ethyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5,7 dimethylimidazo [4,5-b] pyridine.

 Working Example 136. 2-propyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 137. 2-butyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 138. 2-methoxy-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 139. 2-Ethoxy-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 140. 2-propoxy-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 141. 2-cyclopropyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 142. 2-methyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) -biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 143. 2-ethyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 144. 2-cyclopropyl-3 - [[2 '- (2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methyl] -5, 7-dimethylimidazo [4,5-b] pyridine.

 Working Example 145. 2-Ethoxy-3 [[2 '- (2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl) -biphenyl-4-yl] methyl] -5.7 dimethylimidazo [4,5-b] pyridine.

 Experimental example 1. Inhibition of the binding of angiotensin-II to the angiotensin receptor.

 Methodology

 An experiment on the inhibition of the binding of angiotensin-II (A-II) to the corresponding receptor was carried out by modifying the procedure described by Douglas et al. (Endocrinology, 102, 685-696, 1978)). The fraction of membranes containing the A-II receptor was prepared from the cortical layer of bovine adrenal glands.

The compound of the invention (10 ^-6 M or 10 ^-7 M) and ¹²⁵ I-angiotensin II ( ¹²⁵ I-AII) (1.85 kBq / 50 μl) were added to the fraction of receptor-containing membranes and the resulting mixture was incubated for 1 h at room temperature . Receptor bound and unbound ¹²⁵ I-AII was separated by a filter (Whatman GF / B filter) and the radioactivity of ¹²⁵ I-AII bound to the receptor was measured.

 The corresponding results are presented in the table.

 Experimental Example 2

 Inhibition of a Compound of the Invention of a Vasopressor Action AII

 Methodology

 Rats (9 weeks old, males) were used as experimental animals. On the eve of the experiment, the femoral arteries and veins of sodium phenobarbital anesthetized animals were cannulated. The animals were not given food, but were allowed to drink water freely until the start of the experiment. On the day of the experiment, the arterial cannula was connected to a blood pressure sensor and the average blood pressure was recorded using a polygraph. Before administration of the drug, the vasopressor effect of A-II was determined for control by administering it intravenously (100 ng / kg). The drugs were administered orally, then A-II was administered intravenously at each predetermined point in time and the vasopressor effect was determined in a similar manner. The percentage of drug inhibition of A-II-induced vasopressor action was evaluated by comparing its values before and after drug administration.

 The corresponding results are presented in the table.

Claims (28)

1. Heterocyclic compounds of the general formula I

where R is a group of the formula

where R ^{1 is} alkyl or cycloalkyl which may be bonded to the heterocycle through a group of the formula —N (R ⁹ ) -, where R ^{9 is} hydrogen or lower C ₁ C ₄ -alkyl, —O— or —S (O) _m -, where m 0 2, and which may be substituted by a hydroxy group optionally substituted by an amino group, a halogen, a lower C ₁ C ₄ alkoxy group or a lower C ₁ C ₄ alkylthio group;
R ² group selected from

where g is —CH ₂ -, —NR ⁹ , where R ^{9 is} hydrogen or lower C ₁ C ₄ alkyl, —O— or —SO _m , where m 0 2;
groups

independently carbonyl, thiocarbonyl, optionally an oxidized sulfur atom, or a group capable of converting into them;
a and e, forming a heterocyclic residue, independently represent one or two optionally substituted carbon, nitrogen, sulfur or oxygen atoms;
d, forming a heterocyclic residue, is one optionally substituted carbon, nitrogen, sulfur or oxygen atom;
b and c independently represent one optionally substituted carbon or nitrogen atom;
f forming a heterocyclic residue is a carbon atom optionally substituted with an optionally esterified or amidated carboxyl, or nitrogen, sulfur or an oxygen atom
or their salts. 2. The compound according to claim 1, in which the group of the formula

represents a group selected from the following:

where h is

where m 0 2, an integer, —NR ⁹ , where R ^{9 is} hydrogen or a lower C ₁ C ₄ is an alkyl group or —O—, said group being optionally substituted in addition to R and R ¹ . 3. The compound according to claim 1, in which a group of the formula

has a structure selected from the following

where h is

where m 0 2, an integer, —NR ⁹ , where R ^{9 is} hydrogen or a lower C ₁ C ₄ alkyl group, or —O—;
R ³ optionally esterified or amidated carboxyl. 4. The compound or its salt according to claim 1, in which a group of the formula

represents benzimidazole, thienoimidazole or imidazopyridine. 5. The compound or its salt according to claim 3, in which R ³ optionally esterified carboxyl. 6. A compound or salt thereof according to claim 5, wherein group R ³ -CO-D Formula in which D a hydroxy group, a lower C ₁ to C ₆ alkoxy, the alkyl portion of which may be substituted with hydroxy, optionally substituted amino, halogen, lower C ₁ -C ₆ alkoxy, lower C ₁ - C ₆ alkylthio, or optionally substituted dioksolenilom or a group of formula -O-CHR ⁴ -OCOR ⁵ wherein R ⁴ is hydrogen, lower C _{1-C 6} -alkyl, lower C ₂ C ₆ alkenyl or lower C ₃ C ₈ cycloalkyl and R ⁵ lower C ₁ C ₆ alkyl, lower C ₂ C ₆ alkylene, lower C ₃ C ₈ cycloalkyl, lower C ₁ -C ₃ alkyl substituted with lower C ₃ C ₈ -q kloalkilom or aryl lower _C-2
C ₃ alkenyl optionally substituted with lower C ₃ - C ₈ cycloalkyl or aryl, aryl, lower C ₁ C ₆ alkoxy, lower C ₂ C ₈ alkenyloxy, lower C ₃ - C ₈ cycloalkyloxy, lower -C ₁ C ₃ alkoxy substituted with lower C ₃ C ₈ cycloalkyl or aryl; lower C ₂ C ₃ alkenyloxy substituted with lower C ₃ C ₈ cycloalkyl or aryl or aryloxy. 7. The compound or its salt according to claim 1, in which R ¹ lower-C ₁ C ₈ -alkyl, which may be bonded by a group of the formula -NR ⁹ in which R ^{9 is} hydrogen or lower-C ₁ -C ₄ -alkyl , —SO— or —SO _m -, where m 0 2, is an integer, and which may be substituted by hydroxy, amino-N-lower-C ₁ C ₄ -alkylamino, N, N-lowering-C ₁ C ₄ -alkylamino , halogen, lower C ₁ -C ₄ alkoxy or lower C ₁ C ₄ -alkylthio. 8. The compound or its salt according to claim 1, in which R ¹ lower-C ₁ C ₅ -alkyl, which may be bound by a group of the formula -NR ⁹ -, in which R ^{9 is} hydrogen or lower-C ₁ - C ₄ - alkyl, —O— or —SO _m -, where m 0 2, and which may be substituted with hydroxy, amino, halogen or lower C ₁ C ₄ alkoxy. 9. The compound or its salt according to claim 1, in which R ^{2 a} group of the formula

in which i —O— or —S—;
j carbonyl group, thiocarbonyl group, optionally oxidized sulfur atom or a group converted to it. 10. The compound or its salt according to claim 1, in which R ² is a 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group. 11. The compound or its salt according to claim 1, in which R ² is a 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl group. 12. The compound or its salt according to claim 1, in which R ² is a 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl group. 13. Heterocyclic compound or its salt

in which R ¹ lower-C ₁ C ₅ -alkyl, which may be bonded via -O-, -NH- or -S- and which may be substituted by hydroxy, amino, N-lower-C ₁ C ₄ -alkylamino, N , N-lowering-C ₁ -C ₄ -alkylamino, halogen, lower-C ₁ -C ₄ -alkoxy or lower-C ₁ -C ₄ -alkylthio;
R ² group of the formula

in which i —O— or —S—;
j carbonyl group, thiocarbonyl group, optionally oxidized sulfur atom or a group converted to it;
R ³ optionally esterified or amidated carboxyl and a group of the formula

has a structure selected from the group consisting of

14. The compound or its salt according to item 13, in which R ¹ is lower-C ₂ C ₄ -alkyl, which may be bonded through -O-, -NH- or -S-. 15. The compound or its salt according to item 13, in which R ^{3 a} group of formulas -CO-D, in which D hydroxy, amino, N-lower-C ₁ - C ₄ -alkylamino, N, N-lowering-C ₁ C _4- alkylamino, lower-C ₁ C ₆ -alkoxy, lower-C ₁ C ₆ -alkylthio or optionally substituted dioxolenyl, or a group of the formula —O — CHR ⁴ —OCOR ⁵ in which R ^{4 is} hydrogen, lower — C ₁ —C ₆ -alkyl, lower-C ₂ C ₆ alkenyl or lower-C ₃ - C ₈ cycloalkyl;
R ⁵ lower C ₁ -C ₆ alkyl, lower C ₂ -C ₆ alkenyl, lower C ₃ C ₈ -cycloalkyl, lower C ₁ -C ₆ -alkyl substituted with lower C ₃ C ₈ -cycloalkyl or aryl, lower C ₂ C ₃ alkenyl optionally substituted with lower C ₃ C ₈ cycloalkyl or aryl, aryl, lower C ₁ —C ₆ alkoxy, lower C ₂ C ₈ alkenyloxy, lower C ₃ C _8- cycloalkyloxy, lower-C ₁ -C ₃ -alkoxy substituted with lower-C ₃ C ₈ -cycloalkyl or aryl, lower-C ₂ -C ₃ -alkenyloxy substituted with lower-C ₃ C ₈ -cycloalkyl or aryl, or aryloxy. 16. The compound or its salt according to item 13, in which R ³ group of the formula -CO-D ″, in which D ″ hydroxy, amino, N-lower-C ₁ - C ₄ -alkylamino, N, N-lower -C ₁ C ₄ -alkylamino or lower-C ₁ C ₄ -alkoxy, the alkyl part of which may be substituted with hydroxy, amino, holoid, lower-C ₂ C ₆ -alkanoyloxy, 1-lower-C ₁ C ₆ -alkoxycarbonyl or lower -C ₁ - C ₄ alkoxy. 17. The compound or its salt according to item 13, in which R ³ optionally esterified carboxyl. 18. The compound or its salt according to item 13, in which the group of the formula

has the structure of benzimidazole, thienoimidazole or imidazopyridine. 19. The compound according to item 13, in which R ^{2 a} group selected from the group consisting of 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5- oxo-1,2,4-thiadiazol-3-yl and 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl.  20. The compound according to claim 1, which is 1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazole-3- il) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.  21. The compound according to claim 1, which is 1- [2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl-4 - methyl-2-propoxythieno [3,4-d] imidazole-6-carboxylic acid.  22. The compound according to claim 1, which is 2-ethyl - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.  23. The compound according to claim 1, which is 2-ethoxy-1 - [[2'- (2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl-biphenyl-4-yl ] methyl] benzimidazole-7) -carboxylic acid.  24. The compound according to claim 1, which is 2-ethyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4- yl] - methyl] -5,7-dimethylimidazo [4,5-b] pyridine.  25. The compound according to claim 1, which is 2-methoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4- yl] methyl] -4-methylthieno [3,4-d] imidazole-6-carboxylic acid.  26. The compound according to claim 1, which is 2-cyclopropyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4- yl] methyl] benzimidazole-7-carboxylic acid.  27. A pharmaceutical composition exhibiting the activity of an angiotensin II antagonist comprising an active component and a pharmaceutically acceptable carrier, excipient or diluent, characterized in that it contains a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.  28. The compound according to claim 1, which is 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4- yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof.  29. A method for antagonizing angiotensin II in mammals by administering an active substance to a mammal, characterized in that a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered to the mammal as an active substance.

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