RU2168510C2 - Heterocyclic compound, pharmaceutical composition, method of antagonism of angiotensin-ii - Google Patents

Abstract

FIELD: chemistry of heterocyclic compounds, medicine. SUBSTANCE: invention relates to heterocyclic compound of the formula (I)

where R¹ means alkyl that is bound optionally through group of the formula -O-; group of the formula (II)

means group taken among groups (IIa)

, (IIb)

, (IIc)

, (IId)

, (IIe)

, (IIf)

where R¹ has values indicated above. Compound of the above given formula and their salts also are antagonists of angiotensin-II, they show hypotensive effect and activity with respect to central nervous system and can be used as drugs for treatment of patients with circulatory diseases, for example, hypertension diseases and heart diseases (for example, heart hypertrophy, cardiac insufficiency, heart infarctum), attacks, cerebral apoplexy, nephritis, atherosclerosis, Alzheimer's disease, senile feeblemindedness. EFFECT: valuable medicinal properties of compounds. 9 cl, 1 tbl, 12 ex

Description

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

где R₁ является необязательно замещенным остатком углеводорода, возможно связанным через гетероатом; R₂ является необязательно замещенным 5-7-членным гетероциклическим остатком, содержащим в качестве группы, способной образовывать кольцо, карбонильную группу, тиокарбонильную группу, необязательно окисленный атом серы или группу, способную в них превращаться; X - прямая связь или разделяющая группа, содержащая два или менее атомов между циклами Y и W; W и Y независимо представляют необязательно замещенный ароматический углеводородный остаток, необязательно содержащий гетероатом или необязательно замещенный гетероциклический остаток; n = 1-2; а и b, входящие в состав гетероциклического остатка, независимо представляют собой один или два необязательно замещенных атома углерода или гетероатома, с - необязательно замещенный атом углерода или гетероатом; и когда a представляет собой необязательно замещенный атом углерода, R¹ и а могут необязательно быть связаны друг с другом, образуя группу формулы

образующую 5-8-членное кольцо.In particular, this invention relates to compounds of the general formula

where R ₁ is an optionally substituted hydrocarbon residue, optionally linked via a heteroatom; R ₂ is an optionally substituted 5-7 membered heterocyclic residue containing, as a group capable of forming a ring, a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom or a group capable of converting thereto; X is a direct bond or a separating group containing two or less atoms between the cycles Y and W; W and Y independently represent an optionally substituted aromatic hydrocarbon residue optionally containing a heteroatom or optionally substituted heterocyclic residue; n is 1-2; a and b, which are part of the heterocyclic radical, independently represent one or two optionally substituted carbon atoms or heteroatoms, c is an optionally substituted carbon atom or heteroatom; and when a is an optionally substituted carbon atom, R ¹ and a may optionally be linked together to form a group of the formula

forming a 5-8 membered ring.

The renin-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 renin-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 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 of the opposite activity of angiotensin II. However, it is also known that peptide antagonists that are not administered orally do not have a prolonged effect, and when administered orally, they are ineffective [MA Ondetti and DWCushman, 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 possessing activity as angiotensin II antagonists have been described in Japanese applications S56 (1981) - 71073, S56 (1981) - 71074, S57 (1982) - 98270 and S58 (1983) - 157768, US patent 4355040 and 4340598 and etc. More recently, improved imidazole derivatives have been described in EP 0253310, EP 0291969, EP 0324377, EP 403158, WO 9100277, Japanese application S63 (1988) 23868 and Japanese application H1 (1989) 117876; derivatives of pyrrole, pyrazole and triazole are described in EP 0323841, EP 0409332 and Japanese application H1 (1989) 287071; benzimidazole derivatives - in US patent 4880804, EP-0392317, EP-0399732, EP-0400835 and Japanese application H3 (1991) - 632264; azainden derivatives - in EP-0399731; pyrimidone derivatives in EP-0407342; quinazolinone derivatives - in EP-0441766; as antagonists of angiotensin II.

 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 the literature, strong antagonists have an acid group, for example, a tetrazole or carboxy group on the side of the biphenyl chain, a tetrazole group is particularly preferred, and a clinical test of compounds having a tetrazole group was carried out as antihypertensive agents [Y. Christen, B. Waeber, J. Nussberqer, R.J. Lee, P.B.M.W.M. Timmermans, and H. R. Brunner, Am. J. Hypertens., 4, 350S (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.

 This invention aims to produce a new compound containing a heterocyclic residue, which can be substituted on a tetrazole or carboxyl group, which has 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 authors of this invention believe that compounds that block the action of the renin-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, antagonistic angiotensin II, etc. otivohypertonic effect with oral administration. They conducted intensive studies of these compounds with an antagonistic effect of angiotensin II for a long time.

 As a result, the inventors of the present invention 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 effect when administered orally.

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 represented by R ₁ may be a straight or branched lower alkyl group containing from 1 to 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 represented by R ₁ may be a straight or branched lower alkenyl group containing from 2 to 8 carbon atoms, for example vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.

The alkynyl group depicted as R ₁ may be a straight or branched lower alkynyl group containing from 2 to 8 carbon atoms, for example ethynyl, 2-propynyl, 2-butynyl, 2-pentinyl or 2-octynyl.

The cycloalkyl group represented by R ₁ may be a lower cycloalkyl group containing from 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

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

 The aforementioned aralkyl or aryl group may optionally have in its benzene ring at an arbitrary position, for example, a halogen (e.g., F, Cl or Br), a nitro, optionally substituted amino group [e.g., amino, N-lower (1-4C) alkyl amino, or N, N-di-lower (1-4C) alkylamino], lower (1-4C) alkoxy (eg methoxy or ethoxy), lower (1-4C) alkylthio (eg methylthio or ethylthio) or lower (1 -4C) alkyl (e.g. methyl or ethyl).

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

The aforementioned R ₁ group may optionally be linked via a heteroatom [for example, nitrogen [N (R ₉ ), (R ₉ ) means hydrogen or lower (1-4C) alkyl], oxygen or sulfur [-S (O) _m - (m = 0 - 2)], etc.], among them, substituted alkyl or alkenyl may be 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, iso butenyloxy, pentoxy, isopentoxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, allylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, 2-butenylthio, 3-butenylthio, isobutenylthio, pentylthio, pentylthio, pentylthio .) are 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 atoms e.g. pyridyl, pyrimidinyl, pyradazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, benzofuranyl, isobenzofuranyl, indolisinyl, isoindolyl, 3H-indolyl, indolyl, 1 olil, 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 необязательно связана с возможно замещенным ароматическим углеводородным или гетероциклическим 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 represented by R ₂ , examples of which are a possibly substituted 5- and 7-membered (preferably 5- and 6-membered) monocyclic heterocyclic residue 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. The groups represented by R ₂ are shown below.

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

в эту группу входят следующие представители:

Другие примеры групп R₂, связанных через атом азота, являются

В вышеприведенных формулах q = -CH₂-, -NR₉-, атом О или

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 R ₂ is a group of the formula

This group includes the following representatives:

Other examples of R ₂ groups bonded through a nitrogen atom are

In the above formulas, q = —CH ₂ -, —NR ₉ -, an O atom, or

respectively, represent a carbonyl, thiocarbonyl group or possibly an oxidized sulfur atom (e.g., 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 hydrogen atom or possibly substituted lower alkyl).

где i = -О- или -S-, j-> = O, > = S или >S(O)_m, а m имеет тоже самое значение, что и в формуле обозначенной выше. В том случае, когда Y, например, фенил, R₂ может иметь заместители в орто-, мета- или пара-положении, орто-положение предпочтительно.As R ₂ , groups such as an oxadiazole or thiadiazole ring containing an —NH or —OH group as a proton donor and a carbonyl group, a thiocarbonyl 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 group of the formula is preferred

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.

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 ′

heterocyclic residue represented by the formula

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

And the aforementioned heterocyclic radical R ₂ may be optionally substituted with an R ₁₀ group, as shown below.

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, изобутил, 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 возможная 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 возможна 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, циклопентилокси, циклогексилокси или циклогептилокси), 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 алкениллоксигруппа, 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 нафтокси) 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, пропионилоксиметил, H-бутирилоксиметил, изобутирилоксиметил, 1-(этоксикарбонилокси) этил, 1-(ацетилокси) этил, 1-(изобутирилокси) этил, циклогексилкарбонилоксиметил, бензоилоксиметил, цианнамил и циклопентилкарбонилоксиметил). Такие группы могут включать 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).

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 (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or neopentyl), a C _2-6 straight or branched lower alkenyl group or a C _3-8 cycloalkenyl group (e.g. cyclopentyl, cyclohexyl or cycloheptyl); R ₅ is C _1-6 straight or branched lower alkyl group (e.g. 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 (e.g. cyclopentyl, cyclohexyl or cycloheptyl), C _1-3 lower alkyl group substituted by C _3-8 cycloalkyl group (e.g. cyclopentyl, cyclohexyl or cycloheptyl) or a possible substituted aryl group such as phenyl (e.g. benzyl, para-chlorobenzene, phenethyl, cyclopentyl etil or cyclohexylmethyl), C _2-3 lower alkenyl group, a substituted cycloalkyl C _3-8, or an 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 possibly substituted aryl group such as phenyl (e.g. phenyl, para-tolyl or naphthyl), C _1-6 straight or branched lower alkoxy groups (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy or neope tiloksi), C _2-8 straight or branched lower alkenyloxy (e.g., allyloxy, or isobutenyloxy), C _3-8 cycloalkyloxy group (e.g. cyclopentyloxy, cyclohexyloxy or cycloheptyloxy), C _1-3 lower alkoxy group, a substituted cycloalkyl C _3-8 ( for example cyclopentyl, cyclohexyl or cycloheptyl) or a 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} a lower alkenyloxy group substituted with C _3-8 cycloalkyl (e.g. cyclopentyl, cyclohexyl or cycloheptyl) or optionally substituted aryl such as phenyl (e.g. a group having an alkenyloxy residue such as vinyloxy (e.g. cinnamyloxy), propenyloxy, allyloxy or isopropenyloxy) , an aryloxy group comprising a possibly substituted phenoxy group (e.g., phenoxy, para-nitrophenoxy or naphthoxy) and optionally substituted alkyl (e.g. lower (C _1-4 ) alkyl) or acyl (e.g. lower (C _2-5 ) alkanoyl or optional substituted benzoyl). 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, propionyloxymethyl, H-butyryloxymethyl, isobutyryloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (acetyloxy) ethyl, 1- (isobutyryloxy) ethyl, cyclohexylcarbonyloxymethyl, benzoyloxymethyl, cyanamyloxymethyl-cyclopentyl. Such groups may include substituents that 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 heterocyclic residues (a ', b' and c ') and a heterocyclic residue (a'',b''andc'') substituted with R ₁₀ are included in heterocyclic residues represented as R ₂ in of the present invention, tautomers and their substituted compounds of various heterocyclic residues described below are actually included in the R ₂ substituent _{of the} present 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 (e.g. methyl, and triphenylmethyl), halogen (e.g. F, Cl and Br), nitro, cyano lower C _1-4 alkoxy, and a substituted amino group (e.g. amino, methylamino and dimethylamino) and others is possible.

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

X shows that the adjacent ring W (for example, a phenylene group) is bonded to the ring Y (for example, a phenyl group) directly or through a “spacer” containing two or less atoms (a direct bond is preferred). The spacer can be any divalent chain in which one or two atoms form a straight chain, 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 формулы

где R означает группу формулы

приведены ниже

где h и n' 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.Among the compounds designated by R ₂ , W, X, Y, and n described above, preferred are those given in the following formulas:
among

preferred compounds depicted by the following formulas, for example:

Typical examples of heterocyclic compounds of the formula

where R is a group of the formula

are given below

where h and n '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 above.

The heterocyclic compound represented by the above formula may be substituted, in addition to the group R, by the group R ₃ , which may form an anion or a group that can be converted into it.

Examples of the R ₃ group capable of forming an anion, or a group that can be converted into it, are possibly esterified 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, [wherein D is a carboxyl group, a possibly substituted amino group (eg, amino, N-lower (1-4C) alkylamino and N, N-di- lower (1-4C) alkylamino) or possibly substituted alkoxy {e.g., lower (1-6C) alkoxy group in which the alkyl residue is optionally substituted by a hydroxyl group, possibly substituted by amino (e.g. amino, dimethylamino, diethylamino, piperidino and morpholino) , halogen, lower (1-6C) alkoxy, lower (1-6C) a Kilty dioksolenilnaya or optionally substituted (e.g., 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 (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl), C _2-6 straight or branched lower an alkenyl group or a C _3-8 cycloalkyl group (e.g. cyclopentyl, cyclohexyl and cycloheptyl); R ₅ is a straight or branched lower C _1-6 alkyl group (e.g. 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 (e.g. cyclopentyl, cyclohexyl and cycloheptyl), C _1-3 lower alkyl group substituted with C _3-8 cycloalkyl (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or optionally substituted an aryl group such as phenyl (e.g. benzyl, para-chlorobenzene, phenethyl, cyclopentylmethyl, cyclohexylmethyl), C _2-3 a lower alkenyl group optionally substituted with C _3-8 cycloalkyl, or a possibly substituted aryl group such as phenyl (e.g. cinnamyl etc. having an alkenyl radical such as vinyl, propenyl, allyl and isopropenyl), an aryl group, such as possibly substituted phenyl (e.g., phenyl, para-tolyl and naphthyl), C _1-6 straight or branched lower alkoxy (e.g., methoxy, ethoxy n-propoxy, isopropoxy, n-butoxy, isopropoxy, sec-butoxy, n- pentyloxy, isopentyloxy and neopentoxy), C _2-8 straight or branched lower alkenyl a xi group (e.g., allyloxy and isobutenyloxy), a C _3-8 cycloallyloxy group (e.g., cyclopentyloxy, cyclohexyloxy and cycloheptyloxy), a C _1-3 lower alkoxy group substituted with C _3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl and cycloheptyl) or an aryl group such as possibly substituted phenyl (e.g. benzyloxy, phenethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy having an alkoxy radical such as methoxy, ethoxy, n-propoxy and isopropoxy), a C _2-3 lower alkenyloxy group substituted with a C _3-8 cycloalkyl ( e.g. cyclopentyl, cyclohexyl and cycloheptyl) or an aryl group such as optionally 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 (e.g. phenoxy, p-nitrophenoxy and naphthoxy)]}]. An example of an R ₃ group may also be a group that can form an anion or a group that can be converted into it (e.g. tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid, possibly protected by alkyl (e.g. lower C _1-4 alkyl) or acyl (e.g. lower C _2-5 with alkanoyl and optionally substituted 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- ilmetoksokarbonil, atsetoksimetilloksikarbonil, propioniloksimetoksikarbonil, n-butirilmetoksikarbonil, izobutiriloksimetoksikarbonil, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutyryloxy) ethoxycarbonyl, tsiklogeksilkarboniloksimetoksikarbonil, benzoiloksimetoksikarbonil, and tsinnamiloksikarbonil tsiklopentilkarboniloksimetoksikarbonil. As such groups, you can use any group 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.

A compound 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, tetrazolyl group, carboaldehyde group, hydroxymethyl group; cyano group) chemically (for example, by oxidation, reduction or hydrolysis ) are useful as intermediates.

Among the R ₃ groups, a carboxyl esterified carboxyl ester (e.g. methyl ester, ethyl ester 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.

The heterocyclic compound represented by formula I may also have substituents such as halogen (e.g., F, Cl and Br), nitro, cyano, a possibly substituted amino group [eg, amino, N-lower (1-4C) alkylamino (eg, methylamino ), N, N-di-lower (1-4C) alkylamino (eg, dimethylamino), N-arylamino (eg, phenylamino), alicyclic amino (eg, morpholino, piperidino, piperazino and N-phenylpiperazino)], groups represented by by the formula UR ₆ , [where U is a —O—, —S— or —CO— bond, and R ₆ is hydrogen, optionally substituted lower alkyl groups (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 ', [where D' is hydrogen, a hydroxyl group, a possibly substituted amino group (eg, amino, N-lower (1-4C) alkylamino and N, N-di-lower (1-4C) alkylamino) or possibly substituted alkoxy group (e.g. lower (1-6C) alkoxy group, the alkyl residue of which is possibly substituted by a hydroxyl group, possibly substituted by an amino (e.g. amino, dimethyl amino, diethylamino, piperidino and morpholino), halogen, lower (1-6C) alkoxy, lower (1-6C) alkylthio or optionally substituted dioxolenyl (e.g. 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 (eg 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 (e.g. methyl, ethyl, n-propyl, isopropyl , 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 (e.g. cyclopentyl, cyclohexyl and cycloheptyl), a 1-3C lower alkyl group substituted with a 5-7C cycloalkyl group (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or an aryl group such as phenyl (e.g. benzyl, para-chlorobenzene, phenethyl, cyclopentylmethyl and cyclohexylmethyl), 2-3C lower alkenyl group substituted by cycloalkyl 5-7C (e.g., cycle pentyl, cyclohexyl and cycloheptyl) or an aryl group such as phenyl (e.g. cinnamyl having an alkenyl radical such as vinyl, propenyl, allyl or isopropenyl), a possibly substituted aryl group such as phenyl (e.g. phenyl, para-tolyl and naphthyl), 1-6C straight or branched lower alkoxy groups (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 (e.g. allyloxy and isobutene oxy), 5-7C cycloalkyloxy group (e.g. cyclopentyloxy, cyclohexyloxy and cycloheptyloxy), 1-3C lower alkoxy group substituted with 5-7C cycloalkyl (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or an aryl group such as possibly substituted phenyl (e.g. , benzyloxy, phenethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy having an alkoxy radical such as methoxy, ethoxy, n-propoxy and isopropoxy), a 2-3C alkenyloxy group substituted with 5-7C cycloalkyl (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or optionally substituted an aryl group such as phenyl (eg, cinnamyloxy having an alkenyloxy residue such as vinyloxy, propenyloxy, allyloxy and isopropenyloxy) and an aryloxy group such as possibly substituted phenyloxy (eg phenoxy, paranitrile phenoxy and naphthoxy), and l is 0 or 1] or tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid, each possibly protected by alkyl (e.g. lower (1-4C) alkyl) or acyl (e.g. lower (2-5C) alkanoyl and optionally substituted benzoyl).

где R₁ обозначает возможно замещенный низший (1-5C) алкил, который может быть связан через гетероатом (например, О, N(Н) и S) (предпочтителен низший (2-4C) алкил), R₂ обозначает оксадиазол или тиадиазол, имеющие карбонильную группу, тиокарбонильную группу, необязательно окисленный атом серы или группу, способную превращаться в них, и необязательно защищенные необязательно замещенным низшим (1-4C) алкилом (например, алкил, трифенилметил, метоксиметил, ацетоксиметил, метоксикарбонилоксиметил, этоксикарбонилоксиметил, циклогексилоксикарбонилоксиэтил и пивалоилоксиметил) или ацилом (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) алкокси группу, алкильный остаток которой возможно замещен гидроксилом, аминогруппой, галогеном, низшей (2-6C)алканоилокси группой (например, ацетилокси и пивалоилокси), 1- низший(1-6C) алкоксикарбонилокси (например, метоксикарбонилокси, этоксикарбонилокси и циклогексилоксикарбонилокси) или низшей (1-4C) алкокси группой] или тетразолил возможно защищенный низшей (1-4C)алкил или ацильной группой (например, низший (2-5C)алканоил или бензоил), и изображает гетероциклическое кольцо формулы

Способ получения
Соединения вышеприведенных формул (1) и (1а) могут быть получены, например, методами, приведенными ниже.Among the compounds indicated by the above formula (1a), preferred are compounds of the formula

where R ₁ denotes a possibly substituted lower (1-5C) alkyl, which may be bonded via a heteroatom (e.g. O, N (H) and S) (lower (2-4C) alkyl is preferred), R ₂ is oxadiazole or thiadiazole, having a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom or a group capable of being converted thereto, and optionally protected by an optionally substituted lower (1-4C) alkyl (e.g. alkyl, triphenylmethyl, methoxymethyl, acetoxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, cyclohexyl and pivaloyloxymethyl) or an acyl (e.g. lower (2-5C) alkanoyl or benzoyl), R ₃ represents a group of formula; -CO-D ″ [where D ″ is a hydroxyl group, an amino group, an N-lower (1-4C) alkylamino, N, N-di-lower (1-4C) alkylamino or a lower (1-4C) alkoxy group, the alkyl residue of which is optionally substituted by hydroxyl, amino, halogen, lower (2-6C) alkanoyloxy group (e.g. acetyloxy and pivaloyloxy), 1-lower (1-6C) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy and cyclohexyloxycarbonyloxy) or lower (1- 4C) alkoxy group] or tetrazolyl possibly protected by lower (1-4C) alkyl or acyl group (eg lower (2-5C) alkanoyl and benzoyl), and represents a heterocyclic ring of the formula

Production method
Compounds of the above formulas (1) and (1a) can be obtained, for example, by the methods described below.

где R₁, R₂, W, X, Y, а, b, с и n имеют тот же смысл, что и в формулах приведенных, а 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, and L denotes 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 moles of each of the bases and an alkylating agent per mole 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, halides (e.g. chlorides, bromides and iodides) and substituted sulfonic acid esters (e.g. para-toluene sulfonic acid ester) can be used, for example, substituted.

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 column chromatography).

где R₁, W, X, Y, а, 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 above reaction (b) consists in preparing the oxadiazole compound (1c) by converting the cyano compound (1a) to amidoxime (1b) followed by ring closure.

 The reaction for preparing compound (1b) is carried out using about 2-10 moles of hydroxylamine per 1 mol of compound (1a), usually in an organic solvent.

 Examples of such solvents are amides (e.g. dimethylformamide and dimethylacetamide), sulfoxides (e.g. dimethyl sulfoxide), alcohols (e.g. methanol and ethanol), esters (e.g. dioxane and tetrahydrofuran) and halogenated hydrocarbons (e.g. methylene chloride and chloroform).

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

 The amidoxime (1b) thus obtained is then treated with chloroformate (e.g. methyl ether and ethyl ether) in a common organic solvent (e.g. chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile and pyridine) in the presence of a base (e.g. triethylamine, pyridine, sodium carbonate) and potassium carbonate) to form the - o - acyl compound.

Advantageously, the reaction is carried out at a ratio of ethyl formate amidoxime (1b) of 2-5 mol / 1 mol in the presence of 2-5 moles of triethylamine in tetrahydrofuran at 0 ^° C. to room temperature for 1-5 hours.

 Upon heating the obtained o-acyl amidoxime in a conventional organic solvent, a cyclized compound (1c) is formed.

 Examples of solvents are aromatic hydrocarbons (e.g., benzene, toluene and xylene), ethers (e.g., dioxane and tetrahydrofuran) and halogenated hydrocarbons (e.g., dichloroethane and chloroform). Preferably, oxadiazole is obtained by heating the o-acyl amidoxime under reflux for 1-3 hours in boiling xylene.

Реакция (с) состоит в получении оксадиазолона (1d) при гидролизе соединения (Y), являющегося продуктом алкилирования соединения (III) алкилирующим агентом, полученным по реакции (e).Reaction (s)

Reaction (c) consists in the preparation of oxadiazolone (1d) by hydrolysis of compound (Y), which is a product of the alkylation of compound (III) with an alkylating agent obtained by reaction (e).

 Examples of organic solvents are esters (e.g., dioxane and tetrahydrofuran) and alcohols (e.g., methanol and ethanol).

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

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

Реакция (d) состоит в получении соединения спирта (1e) при восстановлении альдегида (1f).Reaction (d)

Reaction (d) consists in obtaining the alcohol compound (1e) by reducing the aldehyde (1f).

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

 Complexes of metal hydrides, such as sodium borohydride, can be used as a reducing agent.

Preferably, the reaction is carried out by adding a reducing agent to a solution of compound (1e) in methanol at a temperature of 0 ^° C. — room temperature, followed by stirring for 0.5 to 2 hours.

 The reaction products obtained from reactions (a) to (d), 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 of the salts with organic acids such as acetic acid, nitric acid, succinic acid and maleic acid, alkali metal salts, 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 (e)

where L has the same meaning as before.

 Compound (IVd) is obtained by reaction (e) by the conversion of compound (IVa) containing a cyano group to an 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) by reacting from 1 to 10 moles of trichloroacetic anhydride or hexachloroacetone with 1 mole of aldoxime (IVb) in accordance with the method described in the literature [F. Eloy, et al., Helv. Chim. Acta, 49, 1430 (1966)], with the formation of oxadiazole (IVc), then (IVc) halogenated with an agent such as N-bromosuccinimide or N-bromoacetamide (molar ratio from 1/1 to 1 / 1,5) in halogenated hydrocarbon (for example, carbon tetrachloride) at a temperature of from 50 ^o C to a boiling point of the solvent from 1 to 3 hours, in the presence of a catalytic amount of initiator (for example, benzoyl peroxide and azobisisobutyronitrile). This reaction can be carried out when exposed to light.

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

where R ^{13 is} an optionally substituted alkyl group shown by the aforementioned R ¹⁰ (e.g. triphenylmethyl, methoxymethyl and cyanoethyl) or a tert-butyldimethylsilyl group and L has the same meaning as before.

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

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

In the reaction for the production of iminothiocarbonate (IVg) from compound (IVf), it is preferable to react compound (IVf) with methyl iodide (molar ratio = 1: 1 to 2) in an organic solvent (e.g. methanol, ethanol, dimethylformamide (DMF) and acetonitrile) , in the presence of 1 to 2 moles, with respect to one mole (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 the preparation of oxadiazole (IVh) from compound (IVg), it is preferable to react (IVg) with hydroxylamine (molar ratio = 1: about 1 to 2) in alcohol (e.g. methanol or ethanol) at a temperature of from room temperature to 50 ^o C for about 10-20 hours, followed by heating the reaction mixture in an organic solvent (e.g., toluene and benzene) in the presence of an approximately catalytic amount of acid (e.g., p-toluenesulfonic acid) at a temperature of from 50 ^° C. to the boiling point used solvent 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 (IVi), 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 to 2 in an organic solvent (for example, chloroform, methylene chloride) , dioxane, tetrahydrofuran and pyridine) in the presence of 1 to 2 moles of base (e.g. potassium carbonate, sodium carbonate, triethylamine and pyridine) at a temperature of from 0 ^o C to room temperature for 1 to 3 hours.

 The reaction for the preparation of compound (IVk) by halogenation of the compound (IVj) can be carried out in the same manner as the reaction for the preparation of compound (IVd) from compound (IVc) according to reaction (e).

где R¹³ и L имеют то же самое значение, что и раньше.Reaction (g)

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

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

In a reaction to produce hydrazide (IVl) from a carboxylic acid (IVe) (IVe), it reacts with approximately 2-5 moles of a halogenating agent (e.g., oxalyl chloride and thionyl chloride) in an organic solvent, e.g. tetrahydrofuran, chloroform and methylene chloride, at room temperature to boiling point solvent used for 1 to 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 moles of hydrazine hydrate in an organic solvent (e.g. 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 moles of isocyanate (e.g., sodium or potassium salt) in an aqueous solution in the presence of an acid (e.g., hydrochloric or sulfuric acid) in an amount equivalent to the amount of isocyanate used at a temperature of from 0 ^o C to room temperature for 1-5 hours.

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

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

Реакция (h) получения амида (IVg) проводится по существу тем же способом, что и при проведении реакции (g).Reaction (h)

The amide (IVg) reaction (h) is carried out essentially in the same manner as in the reaction (g).

Carboxylic acid (IVe) is reacted with about 2-5 moles of a halogenating agent (e.g. oxalyl chloride or thionyl chloride) in an organic solvent (e.g. tetrahydrofuran, chloroform or methylene chloride) at room temperature to the boiling point of the solvent used for about 1- 20 hours It is preferable 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 (e.g. 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 (IVg) from the obtained amide derivative (IVq) is preferably carried out essentially in the same manner as in the case of reaction (e) or (f).

 Compounds (I) and their salts are less toxic, are more effective inhibitors against vasoconstriction and the hypertensive effect of angiotensin II, contributes to the hypotensive effect in animals, especially in warm-blooded animals, such as humans, dogs, rabbits and rats, and therefore they are useful as therapeutic not only in case of hypertension, but also in the case of diseases of the circulatory system, such as impaired cardiac activity (heart hypertrophy, heart failure, heart attack or similar disorders va), brain 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 its pure form, or in a mixture with pharmaceutically acceptable carriers, adjuvants, excipients and / or and diluents.

 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, can be prepared by a method known in the art using a suitable dispersant, wetting or dispersing agent. Injections may be in the form of, for example, a solution or suspension, which can be prepared with a non-toxic diluent taken orally, for example, in the form of an aqueous solution, or with a solvent suitable for a sterile injection. Examples of excipients or acceptable solvents used include water, Ringer's solution and isotonic aqueous saline. Further, a sterile, non-volatile oil can usually be used as a solvent or suspending agent. Any fixed oil or fatty acid can 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-irritant carrier, for example coconut oil and polyethylene glycol, which is in the solid state at normal 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, methods of administration, rate of elimination, combinations of drugs and the course of the diseases that they treat and other factors that need to 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 from 1 to 50 mg for oral administration or from 1 to 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
By 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 cannot be considered as limitations of the invention.

 When the compound (1) of the present 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 formulations.

1. Capsules
(1) 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 10 mg
(2) lactose 90 mg
(3) microcrystalline cellulose 70 mg
(4) magnesium stearate 10 mg
one capsule 180 mg
(1), (2), (3) and half (4) are mixed and granulated. The residue (4) is added to the granules and all this is placed in gelatin capsules.

2. Pills
(1) 2-ethoxy-1- [[2'-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 10 mg
(2) lactose 35 mg
(3) wheat starch 150 mg
(4) microcrystalline cellulose 30 mg
(5) magnesium stearate 5 mg
one tablet 230 mg
(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 resulting mixture under pressure.

3. Injection
1) 2-ethoxy-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl benzimidazole-7-carboxylic acid disodium salt 10 mg
2) inositol 100 mg
3) benzyl alcohol 20 mg
one capsule 130 mg
(1), (2) and (3) are dissolved in distilled water for injection, until a full volume of 2 ml is obtained with which the ampoule is filled. All operations are carried out under sterile conditions.

4. Capsules
(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 mg
(2) lactose 90 mg
(3) microcrystalline cellulose 70 mg
(4) magnesium stearate 10 mg
one capsule 180 mg
(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. Pills
(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 mg
(2) lactose 35 mg
(3) wheat starch 150 mg
(4) microcrystalline cellulose 30 mg
(5) magnesium stearate 5 mg
one tablet 230 mg
(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
(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 mg
(2) Inositol 100 mg
(3) benzyl alcohol 20 mg
one ampoule 130 mg
(1), (2) and (3) are dissolved in distilled water for injection, to obtain a total volume of 2 ml, which is poured into an ampoule. All operations are carried out under sterile conditions.

 7.

Capsules (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 mg
(2) lactose 90 mg
(3) microcrystalline cellulose 70 mg
4) magnesium stearate 10 mg
one capsule 180 mg
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. Pills
(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 mg
(2) lactose 35 mg
(3) wheat starch 150 mg
(4) microcrystalline cellulose 30 mg
(5) magnesium stearate 5 mg
one tablet 230 mg
(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
1) 2-ethoxy-1 - [(2 '- (2,5-dihydro-5-oxo-1,2, 4-thiadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carbon disodium acid 10 mg
(2) Inositol 100 mg
(3) benzyl alcohol 20 mg
one capsule 130 mg
(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
Ethyl 2-ethyl-4,7-dihydro-7 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] - 4- oxothieno [2,3-b] pyridine-5-carboxylate
1a) Ethyl 7 - [[2 '- (5-trischloromethyl-1,2,4-oxodiazol-3-yl) biphenyl-4-yl] methyl] -2-ethyl-4,7-dihydro-4-oxo-thieno [ 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-dimethylformamide (DMF) (7 ml) was added sodium hydride in 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 (3c) (0.6 g) in N, N-dimethylformamide (4 ml), and the mixture was stirred for two 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, q) 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.

1b) 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
To an ice-cooled solution of the compound (0.49 g) obtained in Working Example (1a) in a mixture of dioxane (8 ml), tetrahydrofuran THF (8 ml) and water (4 ml) was added 1 N NaOH (0.9 ml). After stirring for 40 minutes under ice cooling, 1 N NaOH (0.4 ml) was added to the mixture, and the mixture was stirred for 20 minutes under ice cooling. To the reaction mixture was added 1 N-HCl (2.0 ml) and water, 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%), mp. 243-235 ^o C.

Elemental analysis of C ₂₇ H ₂₃ N ₃ O ₅ :
Calculated,%: C 64.66; H 4.62; N, 8.38;
Found,%: C 64.70; H 4.70; N, 8.33.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.22 (3H, t), 1.29 (3H, t), 2.79 (2H, dc), 4.23 (2H, j), 5.50 (2H, s), 7.10 (1H, t), 7.31-7.40 (4H, m), 7.50-7.73 (4H, m), 8.77 (1H, s), 12.37 (1H, br.s)
IR (KBr) cm ^-1 : 3430, 2980, 1782, 1727, 1602, 1542, 1500.

Working example 2
3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-propyl-4 (3H) -quinazolinone
2a) 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-dimethylformamide (8 ml), sodium hydride (60% in oil; 60 mg) was added 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 the working example (3 s) 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 (0.5 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, s), 7.16 (2H, d), 7.22 (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.

2b) 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 (2a) with a mixture of dioxane (6 ml) and water (1.5 ml) was added 1N-NaOH (1.0 ml) under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling. 1N HCl (2.0 ml) and water were added to the reaction mixture, 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%), mp. 251-253 ^o C.

Elemental analysis for C ₂₆ H ₂₂ N ₄ O ₃ :
Calculated%: C 71.22; H 5.06; N, 2.78.

 Found,%: C 70.93; N, 5.04; N, 12.72.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.91 (3H, t), 1.63-1.82 (2H, m), 2.74 (2H, t), 5.45 ( 2H, s), 7.24 (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, w, s).

IR (KBr) cm ^-1 : 3120, 2970, 1768, 1638, 1605, 1590.

Working example 3
2-butyl-4-chlorop-5-formyl-1 - [[2'- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] imidazole
3a) 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 methylate 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 to obtain the title compound as an amorphous product (11.2 g, 96%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 4.42 (2H, s 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.

3b) 5-trichloromethyl-3- (4'-methylbiphenyl-2-yl) -1,2,4-oxadiazole
Trichloroacetic anhydride was added dropwise to a solution of the compound (10 g) obtained according to working example (3a) 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 ) δ: 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.

3c) 3- (4'-bromomethylbiphenyl-2-yl) -5-trichloromethyl-1,2,4-oxadiazole
To a solution of the compound (24.8 g) obtained in working example (3c) in carbon tetrachloride (300 ml) was added N-bromosuccinimide (12.5 g) and α, α ′ -azobisisobutyronitrile (1.15 g) and a mixture boiled for 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 recrystallized from an ether-hexane mixture to give the title compound as colorless crystals (23.0 g, 76%), mp. 77-79 ^o C.

Elemental analysis for C ₁₆ H ₁₀ N ₂ OBrCl 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), 7.38 (2H, d), 7.44-7.65 (3H, m), 7.91-7.95 (1H, m).

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

(3d) 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 (25 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 hour 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 (3c) 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.

3e) 2-butyl-4-chlorop-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 (3d) 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 under ice-cooling. 1N-HCl (1 ml) and water were added to the reaction mixture, 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 recrystallized from ether-hexane to give the title compound as white crystals (0.225 g, 87%), mp. 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, w), 9.68 (1H, s).

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

Working example 4
2-butyl-4-chlorop-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -5- hydroxymethylimidazole
To a solution of the compound (0.15 g) obtained in working example (3c) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added sodium hydroxide (16 mg) and the mixture was stirred at room temperature for 1 hour. 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%), mp. 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, DMSO-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, w), 5.29 (2H, s), 7.14 (2H, d) 7.30 (2H, d), 7.48-7.72 (4H, m).

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

Working example 5
5-butyl-3-ethoxycarbonyl-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] pyrazole
5a) 5-butyl-3-ethoxycarbonyl-1 - [[2 '- (5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] pyrazole
To an ice-cooled solution of 3-butyl-5-ethoxycarbonyl-pyrazole (0.3 g) and the compound (0.95 g) obtained in working example (3c) in anhydrous tetrahydrofuran (10 ml) in a nitrogen atmosphere was added sodium hydride ( 60%, 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, t), 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.

5b) 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 (5a) in a mixture of dioxane (4 ml) and water (1 ml) was added 1N-NaOH (0.6 ml) under ice-cooling. The mixture was stirred for 20 minutes under ice-cooling. 1N-HCl (0.9 ml) and water were added to the reaction mixture, 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%), mp. 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: 0.91 (3H, t), 1.28-1.46 (2H, m), 1.37 (3H, t), 1.53-1, 68 (2H, m), 2.56 (2H, t), 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, w).

IR (KBr) cm ^-1 : 2960, 1777, 1725, 1600, 1485.

Working example 6
2-butyl-4-chloro-1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] imidazol-5- carboxylic acid
To a solution of the compound (0.27 g) obtained in working example (3e) in pyridine (5 ml) was added an aqueous solution (2.5 ml) of potassium permanganate (0.147 g). The mixture was stirred for three hours at room temperature. The reaction mixture was then 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%), mp. 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, DMSO-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 7
2-butyl-4-chlorop-1 - [[2 '- (2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl] methyl] imidazol-5- carbaldehyde
To an ice-cooled solution of 2-butyl-4-chlorimidazole-5-carbaldehyde (0.19 g) in N, N-dimethylformamide (1 ml) was added sodium hydride (60% in oil; 44 mg) and the mixture was stirred for 10 minutes. 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%), mp. 178-179 ^o C.

Elemental analysis for C ₂₃ H ₂₁ N ₄ ClO ₃ :
Calculated,%: C 63.23; H 4.84; N, 12.82.

 Found,%: C 63.07; H 4.87; N, 12.69.

¹ H-NMR (200 MHz, CDCl 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, w), 9.76 (1H, s).

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

 Working example 8.

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 7 in methanol (5 ml) was added sodium borohydride (4 mg) and the mixture was stirred for one hour at 0 ^° C. The solvent was evaporated under reduced pressure and the residue was adjusted to pH 3- 4 1N - HCl. The crystalline precipitate was filtered off and recrystallized from ethyl acetate-hexane to give the title compound as colorless prisms (47 mg, 94%) b.p. 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, w).

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

Working example 9
2-butyl-5-ethoxycarbonyl-3 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -4 (3H ) -pyrimidinone
9a) 2-butyl-5-ethoxycarbonyl-3 - [[2 '- (5-trichloromethyl-1,2,4-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 minutes at room temperature. To the reaction mixture was added a solution of the compound (1.02 g) obtained in the working example (3 s) in anhydrous tetrahydrofuran (5 ml), and the mixture was refluxed for b hours. The reaction mixture was then 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 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.

9b) 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 (9a) was dissolved in a mixture of dioxane (4 ml) and water (1 ml). 1N-NaOH (0.4 ml) was added to the ice-cooled solution, and the reaction mixture was stirred for 30 minutes under ice-cooling. After adding 1N - 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%), mp. 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 10
1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] - 6-propoxy-3-propyluracil
10a) 6-chlorop-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 a 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 (3c) 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 (2H, 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.

10b) 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 (10a) in a mixture of dioxane (4 ml) and water (1 ml) was added ice-cold 1N-NaOH. The mixture was stirred for 30 minutes under ice-cooling, and then 1N-HCl (1.5 ml) and water were added to the reaction mixture and 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) was 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 at 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%), mp. 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), 1.56-1.73 (2H, m), 1.74-1, 93 (2H, m), 3.85 (2H, t), 3.98 (2H, t), 5.11 (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.

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 present invention (10 ^-6 M or 10 ^-7 M) and ¹²⁵ I-angiotensin II ( ¹²⁵ I-AII) (1.85 kBq / 50 microliters) were added to the fraction of receptor-containing membranes, and the resulting mixture was incubated for 1 hour at room temperature. Receptor-bound and unbound ¹²⁵ I-AII was separated using a filter (Whatman GF / B filter), and the radioactivity of ¹²⁵ I-AII bound to the receptor was measured.

 The test results are presented in the table.

Experimental Example 2
Inhibition of the vasopressor action of AII by the compounds of the present invention.

Methodology
Jcl: SD rats (9-week-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 for control, the vasopressor effect of A-II was determined by administering it intravenously (100 ng / g). Drugs were administered orally; then, at each predetermined point in time, A-II was administered intravenously 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.

Claims (9)

1. A heterocyclic compound of the formula

where R ¹ represents alkyl, which is optionally attached via a group of the formula -O-;
R ² represents a group selected from:

where q is —O—;

independently represents a carbonyl group;
group of formula

represents a group selected from

wherein R ¹ is as defined above, said group being optionally substituted in addition to R ^{1 with} halogen, hydroxymethyl, C _1-4 alkyl, carbaldehyde group or R ³ group, which is an optionally esterified or amidated carboxyl,
or its salt. 2. The compound according to claim 1, in which R ² represents a 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group. 3. The compound or its salt according to claim 1, in which R ¹ represents lower (C _1-8 ) alkyl, which is optionally attached via a group of the formula -O-. 4. The compound or its salt according to claim 1, in which R ¹ represents lower (C _1-5 ) alkyl, which is optionally attached via a group of the formula -O-. 5. The compound according to claim 1, in which the group of the formula

optionally substituted in addition to the group R ^{1 with an} optionally esterified or amidated carboxyl. 6. The compound according to claim 1, in which the group of the formula

optionally substituted in addition to the R ¹ group with an optionally esterified carboxyl. 7. The compound according to claim 1, in which the group of the formula

optionally substituted in addition to the group R ^{1 with an} optionally esterified carboxyl of the formula —CO — D, where D is hydroxy, lower (C _1-6 ) alkoxy, the alkyl moiety of which may be substituted with hydroxy, optionally substituted amino, halogen, lower (C _{1- 6} ) alkoxy, lower (C _1-6 ) alkylthio or optionally substituted dioxolenyl, or a group of the formula —O — CH (R ⁴ ) —OCOR ⁵ , where R ⁴ is hydrogen, lower (C _1-6 ) alkyl, lower (C _2-6 ) alkenyl or lower (C _3-8 ) cycloalkyl; R ⁵ represents lower (C _1-6 ) alkyl, lower (C _2-6 ) alkenyl, lower (C _3-8 ) cycloalkyl, lower (C _1-3 ) alkyl substituted with lower (C _3-8 ) cycloalkyl or aryl lower (C _2-3 ) alkenyl optionally substituted with lower (C _3-8 ) cycloalkyl or aryl, aryl, lower (C _1-6 ) alkoxy, lower (C _2-8 ) alkenyloxy, lower (C _3-8 ) cycloalkyloxy, lower (C _1-3 ) alkoxy substituted with lower (C _3-8 ) cycloalkyl or aryl, lower (C _2-3 ) alkenyloxy substituted with lower (C _3-8 ) cycloalkyl or aryl, or aryloxy.  8. A pharmaceutical composition exhibiting the property of an angiotensin II antagonist, characterized in that it contains a therapeutically effective amount according to claim 1 or a pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable carrier, excipient or diluent.  9. A method for antagonizing angiotensin II in mammals, characterized in that a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered to a mammal.

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