JP3412887B2 - Heterocyclic compounds having angiotensin II antagonistic activity and uses thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel heterocyclic compound having an excellent pharmacological action and its use. More specifically, the present invention has a potent angiotensin II antagonistic action and hypotensive action, and is associated with hypertension, heart disease (heart hypertrophy,
General formula useful as a drug for treating cardiovascular diseases such as heart failure, myocardial infarction, etc.), nephritis and stroke, and as a cerebral function improving drug

[Chemical 8] [In the formula, ring A represents an aromatic heterocyclic group having 5 to 10 ring-constituting atoms which may further have a substituent in addition to R ¹ and R ² , and R ¹ is bonded through a hetero atom. May be
R ² represents a hydrocarbon residue which may be substituted, R ² represents a group capable of releasing a proton in vivo, or a group capable of being converted into this, and R ³ represents a carbonyl group, a thiocarbonyl group, or a group which is oxidized as a ring-constituting group. Optionally represents a 5- to 7-membered heterocyclic residue having a sulfur atom or a ring-constituting group that can be converted to them, and X is a spacer in which the ring Y and the ring W are directly or have an atom chain of 2 or less. And the ring W and the ring Y each represent an optionally substituted aromatic hydrocarbon or aromatic heterocyclic residue, and n represents an integer of 1 to 3. ] It is related with the compound or its salt represented by these, and the angiotensin II antagonist containing these. Furthermore, the compound represented by the above general formula or a salt thereof and a preparation thereof are also expected to be used as a diagnostic agent for the above-mentioned diseases.

[0002]

2. Description of the Related Art The renin-angiotensin system, together with the aldosterone system, is involved in homeostatic control functions such as systemic blood pressure, body fluid volume, and electrolyte balance. The relationship between the renin-angiotensin system and hypertension has been clarified by the development of an angiotensin II (AII) converting enzyme inhibitor (ACE inhibitor) that produces angiotensin II having a strong vasoconstrictor action. Angiotensin
II contracts blood vessels via the angiotensin II receptor on the cell membrane and raises blood pressure, so its antagonist is ACE.
It can be used to treat hypertension caused by angiotensin II as well as inhibitors. Many angiotensins so far
It has been reported that II analogues such as salaracin and [Sar ¹ , Ile ⁸ ] AII have a strong angiotensin II antagonistic action. However, peptidic antagonists have been reported to have a short duration of action when administered parenterally and are ineffective when given orally [MA Ondetti and DW Cushman,
Annual Reports in Medicinal Chemistry, 1
3, 82-91 (1978)]. On the other hand, in order to solve the problems of these peptidic angiotensin II antagonists, studies on non-peptidic angiotensin II antagonists have been conducted. That is, the imidazole derivative having an angiotensin II antagonistic action, which was the forerunner, was disclosed in JP-A-56-71073, 56-71074 and 57-57.
-98270, 58-157768, USP.
4,355,040 and USP 4,340,598. After that, EP-0253310, E
P-0291969, EP-0324377, EP-4
03158, WO-9100277, JP-A-63-23.
In 868 and JP-A-1-117876, improved imidazole derivatives are also disclosed in EP-0409.
332, EP-04606062 and WO-911154
79 is a pyrazole derivative, EP-0323841 and JP-A-1-287071 are pyrrole and triazole derivatives, and USP 4,880,80.
4, EP-0392317, EP-0399732, E
P-0400835 and JP-A-3-63264 disclose benzimidazole derivatives in EP-039973.
1, an azaindene derivative, EP-0407342 a pyrimidone derivative, WO-9115209 a pyrimidine derivative, EP-0475206 and EP-0.
499415 has a pyridine derivative, and EP-04
In 11766, a quinazolinone derivative is EP-0507.
In 94, quinoline derivatives are disclosed as angiotensin II antagonists.

However, in order for an angiotensin II antagonist to be put into practical use as a pharmaceutical, it is necessary to have a potent and persistent angiotensin II antagonistic effect by oral administration. Further, as shown in the publicly known literature so far, a preferable chemical structural feature as a potent angiotensin II antagonist is to have an acidic group such as a tetrazole group or a carboxyl group on the biphenyl side chain, Of these, the tetrazole group is the most preferred and clinical trials as an antihypertensive agent are ongoing [Y. Chri
sten, B. Waeber, J. Nussberger, RJ Lee, PB
MWM Timmermans, and HR Brunner, American Journal of Hypertension (Am. J. Hyp
ertens.), 4,350S (1991)]. However, a compound having a tetrazole ring or an azide compound used when synthesizing the tetrazole ring has hitherto been known as a compound having an explosive risk, which poses a serious problem in mass synthesis or industrialization.

[0004]

DISCLOSURE OF THE INVENTION The present invention is a compound having a strong angiotensin II antagonistic action and a blood pressure lowering action, which can be sufficiently put into practical use as a pharmaceutical, and which has a strong acidic group such as tetrazole group or carboxyl group. It is to provide a novel cyclic compound having a heterocyclic residue that can be substituted.

[0005]

The present inventors have found that renin-
To act as angiotensin system regulator and to be a clinically useful drug for treating cardiovascular diseases such as hypertension, heart disease (cardiac hypertrophy, heart failure, myocardial infarction, etc.) and stroke, and as a brain function improving drug. Conducted extensive research based on the idea that the compound must have angiotensin II receptor antagonism and a potent and persistent angiotensin II antagonism and antihypertensive effect by oral administration. Came. As a result, it was found that the novel cyclic compound (I) has a strong angiotensin II receptor antagonistic action, and also has a continuous and strong AII antagonistic action and antihypertensive action by oral administration, and further research was conducted to complete the present invention.

That is, the present invention is based on the equation (1)

[Chemical 9] [In the formula, ring A represents an aromatic heterocyclic group having 5 to 10 ring-constituting atoms which may further have a substituent in addition to R ¹ and R ² , and R ¹ is bonded through a hetero atom. May be
R ² represents a hydrocarbon residue which may be substituted, R ² represents a group capable of releasing a proton in vivo, or a group capable of being converted into this, and R ³ represents a carbonyl group, a thiocarbonyl group, or a group which is oxidized as a ring-constituting group. Optionally represents a 5- to 7-membered heterocyclic residue having a sulfur atom or a ring-constituting group that can be converted to them, and X is a spacer in which the ring Y and the ring W are directly or have an atom chain of 2 or less. And the ring W and the ring Y each represent an optionally substituted aromatic hydrocarbon or aromatic heterocyclic residue, and n represents an integer of 1 to 3. ] It is an angiotensin II antagonist containing the compound or its salt represented by this, and (2) the compound of Formula (I) or its salt.

In the above general formula (I), ring A has 5 to 10 ring-constituting atoms having at least one unsaturated bond.
(Preferably 5, 6, 8, 9 or 10) aromatic heterocycles, which may be monocyclic or condensed rings. Also,
The bonding positions of the substituents R ¹ and R ^{2 on} the ring A include the ring A
There neither of R ¹ and R ² are a monocyclic - (CH _{2) n} - is preferably located next to the carbon atom to which the group represented bind with, the ring A is for R ¹ is a fused ring - (CH ₂ ) The position next to the carbon atom to which the group represented by _n − is bonded is preferably the peri position of the carbon atom for R ² , but the position is not particularly limited thereto. As the representative heterocyclic group and preferable bonding positions of R ¹ and R ² for each,

[Chemical 10] [In the formula, R ¹ and R ² have the same meanings as described above. ] And the like, but it goes without saying that the present invention is not limited to these.

Examples of the hydrocarbon residue as R ¹ include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group and an aralkyl group. Among them, an alkyl group, an alkenyl group and a cycloalkyl group are particularly preferable. Is preferred. The hydrocarbon residue may be attached to ring A via a heteroatom. The alkyl group as R ¹ is a lower alkyl group having about 1 to 8 carbon atoms, which may be linear or branched, and is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl. , Pentyl, i-pentyl, hexyl,
Examples include heptyl and octyl. The alkenyl group as R ¹ is a lower alkenyl group having about 2 to 8 carbon atoms and may be linear or branched, and examples thereof include vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl and 2-octenyl. And so on. The alkynyl group as R ¹ is a lower alkynyl group having about 2 to 8 carbon atoms and may be linear or branched, and is, for example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octynyl. And so on. Examples of the cycloalkyl group as R ¹ include lower cycloalkyl having about 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The above-mentioned alkyl group, alkenyl group, alkynyl group or cycloalkyl group is a hydroxyl group or an optionally substituted amino group (eg, amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) Alkylamino etc.), halogen, lower (C _1-4 ) alkoxy group, lower (C _1-4 ) alkylthio group and the like.
The aralkyl group as R ¹ is, for example, phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl, and the aryl group as R ¹ is, for example, phenyl.

The above-mentioned aralkyl group or aryl group is at any position on the benzene ring, for example, halogen (eg, F, Cl, Br etc.), nitro, optionally substituted amino group (eg, amino, N). -Lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino etc., lower (C _1-4 ) alkoxy (eg methoxy, ethoxy etc.), lower (C _{1- 4} ) It may have alkylthio (eg, methylthio, ethylthio, etc.), lower (C _1-4 ) alkyl (eg, methyl, ethyl, etc.) and the like.
Among the above, R ¹ is an optionally substituted alkyl, alkenyl group or cycloalkyl group (eg,
Lower (C _1-5 ) alkyl, lower (C _2-5 ) alkenyl or lower (C _3-6 ), which may be substituted with hydroxyl, amino, halogen or lower (C _1-4 ) alkoxy.
Cycloalkyl groups) are preferred. In addition, the above R
¹ is a hetero atom (for example, nitrogen [N (R ⁹ ) (R ⁹ represents hydrogen or lower (C _1-4 ) alkyl)], oxygen, sulfur [-S (O) m- (m is 0 to 2). , Etc.))), etc.), which may be substituted, and which may be substituted, and which is bonded via a hetero atom (eg, methylamino, ethylamino, propylamino, Propenylamino, isopropylamino, allylamino, butylamino, isobutylamino, dimethylamino, methylethylamino, methoxy, ethoxy,
Propoxy, isopropoxy, propenyloxy, allyloxy, butoxy, isobutoxy, sec-butoxy,
t-butoxy, 2-butenyloxy, 3-butenyloxy, isobutenyloxy, pentoxy, isopentoxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, allylthio, butylthio,
Isobutylthio, sec-butylthio, t-butylthio,
2-butenylthio, 3-butenylthio, isobutenylthio, pentylthio, isopentylthio, hexylthio and the like) are preferable.

Examples of the group capable of releasing a proton in vivo as R ² or a group capable of converting into a proton include, for example, an optionally esterified or amidated carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide (--N
HSO ₂ CF ₃ ), phosphoric acid, sulfonic acid and the like,
These groups may be protected by a lower alkyl group which may be substituted or an acyl group, and may be protected under in vivo biological or physiological conditions (for example, oxidation, reduction or hydrolysis by in vivo enzymes, etc.). In vivo reaction)
Any group can be used as long as it can release a proton or can change into a group. Examples of the optionally esterified or amidated carboxyl as R ² include, for example, formula —CO—D [wherein, D is a hydroxyl group and optionally substituted amino (for example, amino, N-lower (C _{1 -4} ) Alkylamino, N, N-dilower (C _1-4 ) alkylamino, etc.) or optionally substituted alkoxy (eg, alkyl group is hydroxyl group, optionally substituted amino (eg, amino, Dimethylamino, diethylamino, piperidino, morpholino, etc.), halogen, lower (C _1-6 ).
Alkoxy, lower (C _1-6 ) alkylthio or optionally substituted dioxolenyl (eg 5-methyl-2
-Oxo-1,3-dioxolen-4-yl etc.) optionally substituted lower (C _1-6 ) alkoxy group, or a formula —O—CH (R ⁴ ) —OCOR ⁵ [wherein R ⁴ Is hydrogen, a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc. ), Carbon number 2-6
Represents a straight-chain or branched lower alkenyl group or a C3-C8 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), and R ⁵ is a straight-chain or branched C1-C6 Lower alkyl groups (eg,
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), carbon number 2
-6 linear or branched lower alkenyl group, C3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), C3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl,
Cyclohexyl) or an optionally substituted aryl group such as phenyl and the like, and has a lower alkyl group having 1 to 3 carbon atoms (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), carbon A lower alkenyl group having 2 to 3 carbon atoms which may be substituted with an aryl group such as cycloalkyl of 3-8 or phenyl which may be substituted (eg, vinyl such as cinnamyl, propenyl, allyl, isopropenyl, etc. Having an alkenyl part of), an optionally substituted aryl group such as phenyl (eg, phenyl,
p-tolyl, naphthyl, etc.), a straight-chain or branched lower alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), a straight-chain or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), A cycloalkyloxy group having 3 to 8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or substituted A lower alkoxy group having 1 to 3 carbon atoms substituted with an aryl group such as phenyl (eg, benzyl, phenethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy and other methoxy, ethoxy, n-propoxy, isopropoxy and other alkoxy moieties) To have Etc.), cycloalkyl having 3 to 8 carbons (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or a lower alkenyloxy group having 2 to 3 carbons substituted with an aryl group such as optionally substituted phenyl (eg, Vinyloxy such as cinnamyloxy,
A group represented by an aryloxy group (eg, phenoxy, p-nitrophenoxy, naphthoxy, etc.) such as phenoxy which may be substituted), etc. which has an alkenyloxy moiety such as propenyloxy, allyloxy, isopropenyloxy, etc. } Is shown], etc. are mentioned. Further, the substituent as R ² is a group capable of releasing a proton in a living body or a group capable of changing to a group, for example,
Tetrazolyl which may be protected by alkyl (eg lower (C _1-4 ) alkyl etc.) or acyl (eg lower (C _2-5 ) alkanoyl, optionally substituted benzoyl etc.), trifluoromethanesulfonic acid It may be amide, phosphoric acid or sulfonic acid. Substituent R
Examples of ² include -COOH and its salts, -COOMe,
-COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-
2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl , 1- (acetyloxy) ethoxycarbonyl, 1-
(Isobutyryloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl,
Cyclopentyl carbonyloxy methoxycarbonyl etc. are mentioned. As such a group, any group can be used as long as it is a group capable of releasing a proton under biological or physiological conditions (for example, an in-vivo reaction such as oxidation, reduction or hydrolysis by an in-vivo enzyme) or a group capable of converting into a proton. May be R ² may be a carboxyl group or a prodrug thereof. R ² may be one which can be biologically or chemically converted into an anion in vivo.

Further, R ² is a group capable of chemically releasing a proton (for example, by oxidation, reduction or hydrolysis) or a group which can be converted into a group (for example, an optionally protected carboxyl group, a tetrazolyl group, a carbo group). Compounds that are aldehyde groups, and hydroxymethyl groups, and cyano groups, etc.) are useful as synthetic intermediates. Among the above, R ² is carboxyl, esterified carboxyl (eg, methyl ester, ethyl ester, or ester in which the group represented by the formula —O—CH (R ⁴ ) —OCOR ⁵ is bonded to carbonyl. ), Optionally protected tetrazolyl, carbaldehyde,
Hydroxymethyl and the like are preferred. Further, ring A is R ¹ ,
In addition to the groups represented by R ² and — (CH ₂ ) _n —, it may further have a substituent Q, and examples of the substituent include halogen (eg, F, Cl, Br, etc.), nitro, cyano. , An optionally substituted amino group [eg, amino, N-
Lower (C _1-4 ) alkylamino (eg, methylamino, etc.), N, N-dilower (C _1-4 ) alkylamino (eg,
Dimethylamino etc.), N-arylamino (eg phenylamino etc.), alicyclic amino (eg morpholino,
Piperidino, piperazino, N-phenylpiperazino and the like)], formula —U—R ⁶ [wherein U is a bond, —O
Represents a —, —S— or —CO—, R ⁶ is hydrogen, an optionally substituted lower alkyl group (eg, hydroxyl group, an optionally substituted amino group (eg, amino etc.), halogen,
Nitro, cyano, lower (C _1-4) alkoxy groups such as optionally substituted lower (C _1-4) optionally substituted with alkyl, etc.), an optionally substituted phenyl group (e.g., hydroxyl, optionally substituted A good amino group (eg, amino, N-lower (C
_1-4 ) Alkylamino (eg, methylamino, etc.), N,
N-di-lower (C _1-4 ) alkylamino (eg, dimethylamino etc.), acylamino (eg, acetylamino etc.)
Etc.), halogen, nitro, cyano, lower (C _1-4 ) alkyl group, lower (C _1-4 ) alkoxy group, lower (C _1-4 ).
An alkylthio group, an acyl group (eg, a phenyl group which may be substituted with an acetyl group, etc.)], and the like. One or two of these substituents may be simultaneously substituted at any position on the ring.

Among the aromatic heterocyclic groups as ring A, pyrazole, pyridine, pyrimidine, quinoline and isoquinoline (particularly pyrazole and pyridine) skeletons are preferable. The optionally substituted aromatic hydrocarbon residue or aromatic heterocyclic residue represented by ring Y and ring W is an aromatic hydrocarbon residue such as a benzene skeleton and pyridine, pyrimidine, pyridazine, pyrazine, thiophene. , Franc,
Pyrrole, imidazole, pyrazole, isothiazole, isoxazole, benzofuran, isobenzofuran, indolizine, isoindoline, 3H-indoline, indoline, 1H-indazoline, purine, 4H-
Quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
A 4- to 7-membered monocyclic or condensed cyclic heterocyclic skeleton containing one or two or more of N, S, and O such as pteridine is mentioned, and a preferable example is a benzene skeleton.

[0013] The ring Y aromatic hydrocarbon residue or aromatic heterocyclic residue represented by has a substituent of the formula R ^3, as R ³ is as described below N, S, O- 5 to 7 members including 1 or 2 or more of them (preferably,
5- to 6-membered) monocyclic optionally substituted heterocyclic residue (preferably nitrogen-containing heterocyclic residue having a protonatable hydrogen atom) or a group that can be changed thereto.
For example,

[Chemical 11] And the bond between the group represented by the formula R ³ and the optionally substituted aromatic hydrocarbon residue or aromatic heterocyclic residue represented by the ring Y is a carbon atom as shown above. In addition to the -carbon bond, when g = -NH- is shown in the above formula, the bond may be bonded via one of a plurality of nitrogen atoms.

For example,

[Chemical 12] > = Z,> = Z ′ and> = Z ″ are each a carbonyl group, a thiocarbonyl group or an optionally oxidized sulfur atom (eg, S, S (O), S (O) _2, etc.), preferably Represents a carbonyl or thiocarbonyl group, more preferably a carbonyl group, m represents 0, 1 or 2, and R
⁹ represents a hydrogen atom or an optionally substituted lower alkyl group. ] As R ³ , for example, 2,5-dihydro-5-oxo-
1,2,4-oxadiazole ring residue, 2,5-dihydro-5-thioxo-1,2,4-oxadiazole ring residue or 2,5-dihydro-5-oxo-1,2, -NH as a proton donor such as 4-thiadiazole ring residue
A group having simultaneously an —OH group and a carbonyl group, a thiocarbonyl group or a sulfinyl group as a proton acceptor is preferable. Further, the heterocyclic residue represented by R ³ may have a substituent on the ring bonded to form a condensed ring, and R ³ is a 5- or 6-membered heterocyclic ring. Residues are preferred. R ³ is especially a formula

[Chemical 13] [In formula, i shows -O- or -S-, j is> C =
0,> C = S or> S (O) _m , where m is as defined above. ] A group represented by (in particular, 2,5-dihydro-5
-Oxo-1,2,4-oxadiazol-3-yl,
2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-
1,2,4-thiadiazol-3-yl) is preferred. R
The substitution position of ³ may be any position of ortho, meta and para, for example, when the ring Y is phenyl, but the ortho position is preferable.

Further, the above heterocyclic residue (R ³ ) has tautomers as shown below. For example,

[Chemical 14] There are three tautomers of a, b and c such as

[Chemical 15] The heterocyclic residue represented by includes all of the above a, b and c. Further, the heterocyclic residue (R ³ ) may be substituted with a group represented by R ¹⁰ as shown below.

[0016]

[Chemical 16] The group represented by R ¹⁰ is represented by the formula —CH (R ⁴ ) —
OCOR ⁵ [In the formula, R ⁴ is hydrogen, and a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
t-butyl, n-pentyl, isopentyl, neopentyl, etc.), a straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) R ⁵ is a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), a linear or branched lower alkenyl group having 2 to 6 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cyclo). Heptyl etc.), cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or lower alkyl group having 1 to 3 carbon atoms substituted with an aryl group such as optionally substituted phenyl (eg, , Benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), cycloalkyl having 3 to 8 carbon atoms, or 2-3 carbon atoms which may be substituted with an aryl group such as optionally substituted phenyl.
Lower alkenyl groups (eg, those having an alkenyl moiety such as vinyl, propenyl, allyl, isopropenyl such as cinnamyl) and optionally substituted aryl groups such as phenyl (eg, phenyl, p-tolyl, naphthyl, etc.) ), A linear or branched lower alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy). , Isopentyloxy, neopentyloxy, etc.), carbon number 2-8
A straight or branched lower alkenoxy group (eg, allyloxy, isobutenyloxy, etc.), a cycloalkyloxy group having 3-8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), 3-8 carbon atoms A cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or a lower alkoxy group having 1 to 3 carbon atoms substituted with an optionally substituted aryl group such as phenyl (eg, benzyloxy, phenethyloxy, cyclopentylmethyloxy, Cyclohexylmethyloxy and other methoxy, ethoxy, n-propoxy, isopropoxy and other alkoxy moieties), C3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or even if substituted C2-C3 lower alkenyloxy group substituted with an aryl group such as phenyl (eg, vinyloxy such as cinnamyloxy, and alkenyloxy moieties such as propenyloxy, aryloxy, isopropenyloxy, etc.), which may be substituted A group represented by aryloxy group such as phenoxy (eg, phenoxy, p-nitrophenoxy, naphthoxy, etc.), optionally substituted alkyl (eg, lower (C _1-4 ) alkyl) or acyl ( Examples include lower (C _2-5 ) alkanoyl, optionally substituted benzoyl and the like. Examples of the substituent R ¹⁰ include methyl, ethyl, propyl, t-butyl, methoxymethyl, triphenylmethyl, cyanoethyl, acetyl, propionyl, pivaloyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 5- Methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, ylbutyryloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (acetyloxy) Examples thereof include ethyl, 1- (isobutyryloxy) ethyl, cyclohexylcarbonyloxymethyl, benzoyloxymethyl, cinnamyl, cyclopentylcarbonyloxymethyl and the like. Such groups include biologically or under physiological conditions (eg,
In vivo reactions such as oxidation, reduction or hydrolysis by in-vivo enzymes) or chemically original formula

[0017]

[Chemical 17] Any substituent may be used as long as it is a substituent (so-called prodrug) that can be converted to a heterocyclic residue represented by. Tautomers (a, b and c) of the above heterocyclic residues and R ¹⁰
The same applies to the above-mentioned various heterocyclic residues such that the heterocyclic residues (a ′, b ′ and c ′) substituted with are included in the heterocyclic residue as the substituent R ³ in the present invention. In addition, the tautomer and the substituent thereof are naturally included in the substituent R ³ in the present invention. Further, the substituent R ³ may have a substituent other than the group represented by the above formula R ¹⁰ , for example, an optionally substituted alkyl group (eg, methyl, triphenylmethyl, etc.), halogen (Eg, F, C
l, Br, etc.), nitro, cyano, lower (C _1-4) alkoxy, an amino group which may be substituted (e.g., amino,
And methylamino, dimethylamino, etc.). Examples of the ring W include an optionally substituted aromatic hydrocarbon residue and a heterocyclic residue which may contain one or more N, O, S atoms, and specifically, benzene and pyridine. , Pyrazine, pyridazine, thiophene, furan, pyrrole, imidazole, pyrazole, isothiazole, isoxazole skeleton (preferably benzene skeleton) and the like. The aromatic hydrocarbon residue and aromatic heterocyclic residue represented by ring Y and ring W may have a substituent, and examples of the substituent include halogen (eg, F, Cl, Br). Etc.), nitro, cyano, lower (C _1-4 ) alkoxy, an optionally substituted amino group (eg, amino, methylamino, dimethylamino, etc.) and the like.

X represents that an adjacent ring W (eg, phenylene group, etc.) and ring Y (eg, phenyl group, etc.) are bonded to each other directly or via a spacer having an atomic chain of 2 or less (preferably direct bonding). The spacer having an atomic chain of 2 or less has 2 atoms having 1 or 2 atoms constituting the straight chain portion.
Any valent chain may be used, and it may have a side chain. Specifically, lower (C _1-4 ) alkylene, -CO-,
-O-, -S-, -NH-, -CO-NH-, -OC
_{H 2 -, - S-CH} 2 -, - CH = CH- , and the like. n represents an integer of 1 or 2 (preferably 1). The above formulas represented by R ³ , W, X, Y and n

[Chemical 18] Indicated by, for example,

[Chemical 19] Are preferred.

Among the compounds represented by the above formula (I), the formula

[Chemical 20] [In the formula, examples of the aromatic heterocyclic group represented by ring A include

[Chemical 21] R ¹ may be bonded via a heteroatom (eg, O, N (H), S, etc.) and may be substituted lower (C _1-6 ) alkyl (preferably lower) (C _2-4 )
Alkyl) and R ² is of the formula —CO—D ″ [wherein D ″
Is a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino or an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy. (Eg acetyloxy,
Pivaloyloxy etc.), lower (C _4-7 ) cycloalkanoyloxy, 1-lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy etc.), 1-lower (C _3-7 ) cyclo Alkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy etc.) or lower (C _1-4 ) alkoxy optionally substituted with lower (C _1-4 ) alkoxy], and R ³ is Optionally substituted lower (C _1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, acetyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, cyclohexyloxycarbonyloxyethyl, pivaloyl) oxymethyl, etc.) or an acyl group (e.g., lower (C _2-5) A Kanoiru, benzoyl, etc.)
May be protected by the formula

[Chemical formula 22] [In formula, i shows -O- or -S-, j is> C =
Compounds represented by O,> C = S or> S (O) m, wherein m represents a group represented by the above meaning] are preferable. In the above formula (I ′), R ² is N-hydroxycarbamimidoyl (-C (= N-OH) -NH
_The compound which is ₂ ) is useful as a synthetic intermediate for a compound in which R ² is oxadiazole or thiadiazole.

Production Method The compound of the above general formula (I) can be produced, for example, by the following method. Reaction (a)

[Chemical formula 23] [In the formula, A, R ¹ , R ² , W, X, Y and n have the same meanings as described above. In the reaction (a), the cyano compound (Ia) is converted to the amidoxime compound (Ia).
After b), the ring is closed to give an oxadiazole compound.
(Ic) is obtained. The reaction for obtaining the compound (Ib) is carried out by adding 2 to 1 mol of the compound (Ia) to hydroxylamine.
It is carried out in an ordinary organic solvent using about 10 mol. Such solvents include amides (eg, dimethylformamide, dimethylacetamide, etc.), sulfoxides (eg, dimethylsulfoxide, etc.), alcohols (eg, methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), Halogenated hydrocarbons (eg methylene chloride, chloroform, etc.) are used.

When using an inorganic acid salt (eg, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.) or an organic acid salt (eg, oxalic acid hydroxylamine, etc.), such a hydroxylamine is a suitable base (eg, potassium carbonate,
Sodium carbonate, sodium hydroxide, triethylamine, sodium methanolate, sodium ethanolate, sodium hydride, etc.) are allowed to coexist in the same amount to carry out the reaction. The reaction conditions vary depending on the reagent and solvent used at that time, but it is preferable to treat hydroxyamine hydrochloride with sodium methoxide or triethylamine in dimethylsulfoxide and then to react at about 50 to 100 ° C. for about 2 to 24 hours. The amidoxime derivative (Ib) thus obtained is treated with a chlorocarbonic acid ester (eg, methyl ester, ethyl ester, etc.) and in the presence of a base (eg, triethylamine, pyridine, potassium carbonate, sodium carbonate, etc.) in an ordinary organic solvent. (Eg, chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile, pyridine, etc.) to obtain an o-acyl derivative. The reaction conditions will differ depending on the reagent and solvent used at that time, but are usually 2 per 1 mol of the amidoxime compound (Ib).
In the presence of ~ 5 mol of ethyl chlorocarbonate and about 2-5 mol of triethylamine in tetrahydrofuran at 0 ° C ~
It is preferable to react at room temperature for about 1 to 5 hours. In the reaction for obtaining the ring-closed compound (Ic) from the o-acyl amidoxime compound thus obtained, the desired compound can be easily obtained by heating in an ordinary organic solvent. Examples of such a solvent include aromatic hydrocarbons (eg, benzene, toluene,
Xylene etc.), ethers (eg dioxane, tetrahydrofuran etc.) and halogenated hydrocarbons (eg dichloroethane, chloroform etc.) are used. The reaction conditions are preferably such that the o-acyl amidoxime compound is heated under reflux in xylene for about 1 to 3 hours.

Reaction (b)

[Chemical formula 24] [In the formula, A, R ¹ , R ² , W, X, Y and n have the same meanings as described above. In the reaction (b), the amidoxime compound (Ib) obtained in the reaction (a) is ring-closed to obtain an oxathiadiazole compound (Id). The amidoxime compound (Ib) is reacted with thionyl chloride in a usual organic solvent (eg, dichloromethane, chloroform, dioxane, tetrahydrofuran, etc.) and in the presence of a base (eg, pyridine, triethylamine, etc.) to obtain the compound (Id). The reaction conditions vary depending on the reagent and solvent used at that time, but in the presence of about 1 to 3 mol of pyridine with respect to 1 mol of the amidoxime compound (Ib), dichloromethane is used as a solvent, and 0 ° C to -3.
It is preferable to add about 2 to 10 mol of thionyl chloride while cooling to about 0 ° C. and react for about 30 minutes to 1 hour.

Reaction (c)

[Chemical 25] [In the formula, A, R ¹ , R ² , W, X, Y and n have the same meanings as described above. In the reaction (c), the amidoxime compound (Ib) obtained in the reaction (a) is ring-closed to obtain a thiadiazole compound (Ie). In the reaction for obtaining the compound (Ie), about 1 to 2 mol of 1,1′-thiocarbonyldiimidazole is used per 1 mol of the compound (Ib), and 1 to 10 equivalents of a Lewis acid (eg, trifluoride) is used. It is carried out in the presence of a boron-diethyl ether complex, stannous chloride, stannic chloride, zinc chloride, cuprous chloride, silica gel, etc.) in an ordinary organic solvent. As such a solvent, ethers (eg, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.) and the like are used. Alternatively, the compound (Ib) is dissolved in methanol and chloroform, and 1,1′-thiocarbonyldiimidazole is added while stirring with silica gel at 0 ° C. to room temperature, and then reacted at room temperature for about 30 minutes to 2 hours. It is better to let them do it.

Reaction (d)

[Chemical formula 26] [In the formula, A, R ¹ , R ² , W, X, Y and n have the same meanings as described above. The above reaction (d) is carried out by ring-closing the amidoxime compound (Ib) obtained in the above reaction (a).
f) is obtained. In the reaction for obtaining the compound (If), about 1 to 10 mol of 1,1′-thiocarbonyldiimidazole is used with respect to 1 mol of the compound (Ib), and the reaction is carried out in a usual solvent in the presence of a base. Such solvents include ethers (eg, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (eg, methylene chloride,
Chloroform, etc.), acetonitrile, acetone, etc. are used. As the base, amines (eg, triethylamine, pyridine, 2,6-dimethylpyridine, 1,
5-diazabicyclo [4.3.0] non-5-ene, 1,
8-diazabicyclo [5.4.0] -7-undecene etc.) and the like. The reaction conditions vary depending on the reagent and solvent used at that time, but it is preferable to dissolve the compound (Ib) in acetonitrile and carry out the reaction at 0 ° C. to room temperature for about 10 minutes to 24 hours.

The above reaction (d) can also be carried out under the following reaction conditions. Compound (I
b) About 1 to 10 mol of acetic anhydride is used per 1 mol, and the reaction is carried out in a usual solvent in the presence of a base. As such a solvent, halogenated hydrocarbons (eg methylene chloride, chloroform etc.), ethers (eg dioxane, tetrahydrofuran etc.) etc. are used. In addition, examples of the base include amines (eg, triethylamine, pyridine, etc.). As a reaction condition, it is preferable that the compound (Ib) is dissolved in methylene chloride and the reaction is performed at 0 ° C. to room temperature for about 1 to 5 hours. 1 mol of the O-acetylamidoxime thus obtained was reacted with about 3 to 10 mol of carbon disulfide in the presence of a base in an organic solvent to give a thioketone (If).
Is what you get. As such a solvent, amides (eg, N, N-dimethylformamide, dimethylacetamide, etc.), dimethyl sulfoxide, etc. are used. Examples of the base include sodium hydride and potassium t-butoxy. As the reaction conditions, it is preferable to add O-acetylamidoxime and carbon disulfide in dimethylformamide at room temperature with stirring while adding sodium hydride little by little and to react for about 1 to 3 hours.

Reaction (e)

[Chemical 27] [In the formula, A, R ¹ , R ² , W, X, Y and n have the same meanings as described above. R ¹² represents a lower (C _1-8 ) alkyl group. In the above formula (e), the amide compound (Ig) is converted into halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.),
The imino ether compound (Ih) can be obtained in good yield by reacting with 1 to 2 times the molar amount of triethyloxonium tetrafluoroborate at 0 ° C. to room temperature for about 30 minutes to 2 hours. Next, the imino ether compound (Ih) is added to a normal organic solvent (eg, benzene, toluene, methylene chloride, chloroform, dioxane, pyridine, etc.) in an amount of 1 to 2 moles of chloroformic acid ester (eg, chloromethyl formate). , Chloroethyl formate, etc.) of 1 to 2 times the molar amount of a base (eg,
The reaction is carried out in the presence of 2,4,6-trimethylpyridine, triethylamine, dimethylpyridine, methylpyridine, diethylaniline, etc. The reaction conditions may vary depending on the reagent and solvent used at that time, but in toluene 10 to 10
When the reaction is carried out at about 0 ° C. for about 1 to 3 hours, the N-alkoxycarbonyl compound (Ii) can be obtained in good yield. The obtained N-alkoxycarbonyl compound (Ii) is used in an alcohol (eg, methanol, ethanol, etc.) to prepare a 2-fold molar amount of hydroxylamine hydrochloride and a base (eg, sodium methoxide, sodium ethoxide, potassium carbonate). Etc.) to cause ring closure. As reaction conditions, it is preferable to carry out the reaction at 50 ° C. to about the boiling point of the solvent for about 3 to 10 hours.

Reaction (f)

[Chemical 28] [In the formula, A, R ¹ , R ² , R ⁹ , W, X, Y and n have the same meanings as described above. In the reaction (f), a carboxylic acid (Ik) is obtained by alkaline hydrolysis of the ester (Ij). About 1 to 3 mol of alkali is used with respect to 1 mol of compound (Ij), and the reaction is usually performed in a solvent such as alcohols containing water (eg, methanol, ethanol, methyl cellosolve, etc.). Examples of such alkali include lithium hydroxide,
Sodium hydroxide and potassium hydroxide are used. The reaction conditions include room temperature to 100 ° C. and 1 to 10
It is carried out for about 3 hours, but preferably about 3 to about the boiling point of the solvent.
It is recommended to react for about 5 hours.

Reaction (g)

[Chemical 29] [In the formula, A, R ¹ , R ³ , R ¹⁰ , W, X, Y and n have the same meanings as described above. In the reaction (g), an alkylating agent is allowed to act in the presence of a base to carry out alkylation. 1-3 mol of a base and 1 to 3 mol of a compound (Ig) and an alkylating agent 1-3
It is used in a molar amount and is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone or ethylmethylketone. As such a base, sodium hydride, potassium t-butoxy, potassium carbonate, sodium carbonate or the like is used. As such an alkylating agent, substituted halides (eg, chloride, bromide, iodide, etc.), substituted sulfonic acid esters (eg, p-toluene sulfonic acid ester, etc.) and the like are used. The reaction condition varies depending on the combination of the base used and the alkylating agent, but is usually 0
It is preferable to carry out the treatment at about room temperature to about room temperature for about 1 to 10 hours. When chloride or bromide is used as the alkylating agent, potassium iodide or sodium iodide is preferably added to accelerate the reaction.

Reaction (h)

[Chemical 30] [In the formula, A, R ¹ , R ² , W, X, Y and n have the same meanings as described above. In the above reaction (h), the trichloromethyloxadiazole compound (Im) is hydrolyzed by using an alkali in an organic solvent or an organic solvent containing water to give oxadiazolone (Ic).
Is what you get. Examples of such organic solvents include ethers (eg, dioxane, tetrahydrofuran, etc.) and alcohols (eg, methanol, ethanol, etc.).
Examples of such alkali include sodium hydroxide, potassium hydroxide and lithium hydroxide. The reaction conditions include the compound (Im) in dioxane of 2 to 10
It is preferable to add a 0.5 to 1 N sodium hydroxide aqueous solution in a molar amount and to carry out the reaction at 0 ° C. to room temperature for about 30 minutes to 2 hours. After completion of the reaction, the reaction products obtained in the reactions (a) to (h) as described above can be easily isolated by usual isolation and purification methods such as column chromatography and recrystallization. I can. In addition, these compounds (I) are salts with physiologically acceptable acids or bases by a conventional method, for example, salts with inorganic acids such as hydrochlorides, sulfates and nitrates, and depending on the compound, acetates and oxalates. , A salt with an organic acid such as a succinate or a maleate, a salt with an alkali metal such as a sodium salt or a potassium salt, or a salt with an alkaline earth metal such as a calcium salt.
The starting compound can be synthesized, for example, by the method shown below.

Reaction (i)

[Chemical 31] [In the formula, L represents a halogen atom or a substituted sulfonic acid ester. In the above reaction (i), the cyano compound (IIa) is converted into the above reaction (a).
The compound (IId) is obtained by using the same reaction conditions as the amidoxime compound (IIb), ring-closing the compound to form an oxadiazole compound (IIc), and further halogenation.
The amidoxime derivative (IIb) obtained from the compound (IIa) was described in the literature in the same manner as the reaction (a) [F. Eloy et al., Helv. Chim. Acta, 49 ,
1430 (1966)], amidoxime (IIb)
The compound (IIc) thus obtained is reacted with 1-10 mol of trichloroacetic acid anhydride or hexachloroacetone to 1 mol thereof to obtain an oxadiazole compound (IIc). ), The compound (II
c) About 1 to 1.5 mol of a halogenating agent (eg, N-bromosuccinimide, N-bromoacetamide, etc.) and a catalytic amount of a reaction initiator (eg, benzoyl peroxide, azo) relative to 1 mol. 50) in the presence of (bisisobutyronitrile, etc.)
It is advisable to carry out the heating reaction at a temperature of about ℃ to the boiling point of the solvent for about 1 to 3 hours. At this time, it can also be performed under light irradiation.

Reaction (j)

[Chemical 32] [In the formula, L is as defined above. In the reaction (j), a carboxylic acid (IIe) is converted into an amide (IIf) by a conventional method, and then a halogen compound (IIg) is obtained. Carboxylic acid (IIe) in an organic solvent (eg, tetrahydrofuran, chloroform, methylene chloride, etc.) and 2 to 5 mol of a halogenating agent (eg, oxalyl chloride, thionyl chloride, etc.) at room temperature to about the boiling point of the solvent. React for about 20 hours. At this time, it is preferable to add a catalytic amount of dimethylformamide to accelerate the reaction. The obtained acid halide is preferably reacted with an excess of aqueous ammonia in an organic solvent (eg, tetrahydrofuran, dioxane, etc.) at 0 ° C. to room temperature for about 1 to 10 hours. In this way, the amide compound (IIf) can be obtained in good yield. The reaction for obtaining the halogenated compound (IIg) from the amide compound (IIf) thus obtained is preferably carried out by the same method as shown in the reaction (i).

Reaction (k)

[Chemical 33] [In the formula, R ¹³ represents an optionally substituted alkyl group represented by R ¹⁰ (eg, triphenylmethyl, methoxymethyl, cyanoethyl, etc.) or a t-butyldimethylsilyl group. L has the same meaning as above. In the reaction (k), a carboxylic acid (IIe) was converted to an acyl isothiocyanate by a conventional method, and reacted with an alcohol to obtain a carbonylthiocarbamate (IIh), which was then methylated to give a carbonyl (IIi). Furthermore, the compound (IIi)
Is reacted with hydroxylamine and then thermally closed to give an oxadiazole compound (IIj). In the reaction for obtaining carbonylthiocarbamate (IIh) from carboxylic acid (IIe), (IIe) is contained in halogenated hydrocarbons (eg, chloroform, methylene chloride, etc.) in an amount of 2 to 5 mol per 1 mol of (IIe). An acid chloride is obtained by heating and reacting the same with a halogenating agent (eg, thionyl chloride) at about 50 ° C. to about the boiling point of the solvent for about 1 to 5 hours. The obtained acid chloride was treated with ether (eg, dioxane, tetrahydrofuran, etc.) in 2
˜5 mol of thiocyanate (eg, sodium, potassium salt, etc.) is heated to react at 50 ° C. to boiling point of solvent for 1 to 3 hours to give isothiocyanate. The resulting isothiocyanate is preferably heated and reacted with about 2 to 10 mol of alcohol (eg, methanol, ethanol, etc.) at 50 ° C. to about the boiling point of the solvent for about 15 minutes to 1 hour.

In the reaction for obtaining the iminomonothiocarbonate (IIi) from the compound (IIh), about 1 to 2 mol of a base (eg, NaOMe, Na ₂ C) per 1 mol of (IIh).
In the presence of O ₃ , K ₂ CO _3, etc., an organic solvent (eg, methanol, ethanol, dimethylformamide (DMF),
It is preferable to react with about 1-2 mol of methyl iodide in acetonitrile or the like) at room temperature to about 50 ° C. for about 10 to 24 hours. From compound (IIi) to oxadiazole (II
In the reaction for obtaining j), about 1 to 2 mol of hydroxylamine in an alcohol (eg, methanol, ethanol, etc.) and 10 to 10 mol at room temperature to 50 ° C. per 1 mol of (IIi).
After reacting for about 20 hours, a catalytic amount of acid (eg, p-
In the presence of toluenesulfonic acid and the like), it is preferable to carry out a heating reaction in an organic solvent (eg, toluene, benzene and the like) at 50 ° C. to the boiling point of the solvent for about 1 to 3 hours. In the reaction for obtaining the demethylated product (IIk) from the compound (IIj), it is preferable that an excess of pyridine hydrochloride and (IIj) are melt-reacted under a nitrogen stream at about 150 to 160 ° C. for about 30 minutes to 1 hour. In the reaction for obtaining the compound (IIl) from the compound (IIk), about 1 to 2 mol of an alkylating agent (eg, triphenylmethyl chloride, methoxymethyl chloride, cyanoethyl chloride, etc.) is used with respect to 1 mol of the compound (IIk). Organic solvent (eg,
Chloroform, methylene chloride, dioxane, tetrahydrofuran, pyridine, etc.) in the presence of about 1 to 2 mol of a base (eg, potassium carbonate, sodium carbonate, triethylamine, pyridine, etc.) at 0 ° C. to room temperature for about 1 to 3 hours. Is preferred. The reaction of halogenating the compound (IIl) to obtain the compound (IIm) can be carried out in the same manner as the reaction of the compound (IIc) to the compound (IId) in the above reaction (i).

Reaction (l)

[Chemical 34] [In the formula, L is as defined above. In the reaction (l), a carboxylic acid (IIe) is converted into a hydrazide (IIn) and then a semicarbazide (IIo) by a conventional method, and further dehydration ring closure is performed to an oxadiazolone (IIp) to obtain a halogeno compound (IIq). is there. In the reaction for obtaining hydrazide (IIn) from carboxylic acid (IIe), (IIe) is added to an organic solvent (eg, tetrahydrofuran, chloroform, methylene chloride, etc.) in an amount of about 2 to 5 mol of a halogenating agent (eg, oxalyl chloride, (Thionyl chloride etc.) at room temperature to about the boiling point of the solvent for about 1 to 20 hours. At this time, it is preferable to add a catalytic amount of dimethylformamide to accelerate the reaction. The acid chloride thus obtained was added to an organic solvent (eg, tetrahydrofuran, dioxane, etc.) in an amount of 2
~ 5 mol of saturated hydrazine and room temperature ~ 50 ° C,
The compound (IIn) is obtained by reacting for about 1 to 10 hours.

In the reaction for obtaining the semicarbazide (IIo) from the hydrazide (IIn) thus obtained, (IIn) and 2
~ 5 mol of isocyanate (eg, sodium or potassium salt) in an aqueous solution in the presence of the same amount of acid (eg, hydrochloric acid, sulfuric acid, etc.) as the isocyanate used, at 0 ° C to room temperature, It is preferable to react for about 5 hours. In the reaction for obtaining oxadiazolone (IIp) from thus obtained semicarbazide (IIo), (IIo) is mixed with an organic solvent (eg,
5 to 20 depending on the boiling point of the solvent in benzene, xylene, etc.)
It is preferable to heat the reaction for about a time. The reaction for obtaining the halogeno compound (IIq) from the oxadiazolone (IIp) thus obtained is preferably carried out by the same method as shown in the above reaction (i).

Reaction (m)

[Chemical 35] [In the formula, R ¹ , R ² , W, X, Y, Q and n have the same meanings as described above, and R ⁷ is a substituent represented by R ³ or a cyano group, a carboxyl group, a carbamoyl group, a lower ( C _1-4 ) alkylcarbamoyl group, lower (C _1-6 ) alkoxycarbonyl group, nitro group, formyl group, hydroxymethyl group and lower (C _1-4 ) alkyl group are shown. ] In the reaction (m), a diketone (IV
The alkylating agent (II) acts on a) to carry out alkylation. Using 1 to 3 mol of a base and 1 to 3 mol of an alkylating agent with respect to 1 mol of the compound (IVa), usually dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethylketone, tetrahydrofuran, dioxane, Alternatively, it is performed in a solvent such as a hydrocarbon such as toluene or benzene. As such a base, sodium hydride, potassium t-butoxy, potassium carbonate, sodium carbonate, sodium methoxide or the like is used, and the amount is 0 to 150.
The alkylated product (IVb) can be obtained in good yield by reacting at about C for about 1 to 50 hours. Next, the compound (IVb) is added to an ordinary solvent (eg, hydrous alcohol, ethanol, ether, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-methoxyethanol, acetic acid, etc.) in an amount of 0 to 10
Pyrazole (In) can be obtained in good yield by reacting with 1 to 10 times mol of substituted or unsubstituted hydrazine at about 0 ° C. for about 1 to 60 hours.

Reaction (n)

[Chemical 36] [In the formula, R ¹ , R ² , R ⁷ , W, X, Y, Z and n have the same meanings as described above, and R ⁸ represents a lower (C _1-4 ) alkyl group or a benzyl group. ] In the formula (n), the diketone body (IVa) has 1 to 20
A double mole of o-alkyl or benzylhydroxyamine is usually added to alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, 2
Imide (IVc) can be obtained in good yield by reacting in a solvent such as methoxyethanol at about 0 to 100 ° C. for about 1 to 24 hours. Next, the reaction for reacting the imide derivative (IVc) with the alkylating agent (II) to obtain the alkylated derivative (IVd) is preferably carried out by the same method as shown in the reaction (m).
Further, the reaction for obtaining the pyrazole (In) from the alkylated product (IVd) is preferably carried out by the same method as shown in the reaction (m).

Reaction (o)

[Chemical 37] [In the formula, R ¹ , R ² , R ⁷ , W, X, Y, Q and n have the same meanings as described above. ] The above reaction (o) includes diketone (IVa) and amidine, guanidine, o-alkyl or arylisourea, s-
Pyrimidine (Io) is obtained by dehydration condensation with alkyl or aryl isothiourea and the like.

Reaction (p)

[Chemical 38] [In the formula, R ¹ , R ⁷ , L, W, X, Y, Q, and n have the same meanings as described above. In the reaction (p), the ketoester (IVe) is alkylated with the alkylating agent (II) in the same manner as in the reaction (m) to hydrolyze and decarboxylate the resulting compound (IVf). , A ketone body (IVg) is obtained. Next, the ketone body (IVg) is added to isatin and a base such as sodium hydroxide or potassium hydroxide for 5 to 10 days, 50 to 15
Reaction at 0 ° C. in a solvent (eg, alcohol, 2-methoxyethanol, dioxane, water, etc.) to give quinoline (I
p) is obtained.

Reaction (q)

[Chemical Formula 39] [Wherein R ¹ , R ² , R ⁷ , L, W, X, Y and n have the same meanings as described above, and M represents a metal (eg, lithium, magnesium, activated zinc, cadmium, etc.). Show. ] In the reaction (q), 1 to the compound (II) is used.
After reacting a 3-fold molar amount of metal to form the organometallic compound (IIr), the aromatic heterocyclic compound (III) is -100 to 100.
In the presence of a catalyst (tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) nickel chloride, etc.) at about ℃, usually in an organic solvent such as ethers (tetrahydrofuran, diethyl ether, dioxane, etc.) or toluene. For 1 to 24 hours to obtain an alkylated product (In).

Reaction (r)

[Chemical 40] [Wherein R ¹ , R ² , R ⁷ , L, M, W, X, Y and n
Has the same meaning as above. In the reaction (r), the compound (III) is mixed with 0.8 to 1.2 times mol of butyl lithium or tertiary butyl lithium by -1.
After reacting in an organic solvent such as ethers (diethyl ether, tetrahydrofuran, dioxane, etc.) or toluene at about 00 to 50 ° C. for about 10 minutes to 3 hours to give an organometallic compound (IIIa), an alkylating agent (II) Is reacted in the same solvent at -100 to 50 ° C for 10 minutes to 24 hours to obtain an alkylated product (In).

The compound (I) and its salt thus produced have low toxicity and strongly suppress the vasoconstriction and blood pressure increasing action of angiotensin II, and are particularly effective in animals, particularly mammals (eg, humans, dogs, rabbits, rats, etc.). It is effective not only as a therapeutic agent for hypertension but also as a therapeutic agent for cardiovascular diseases such as heart disease (heart hypertrophy, heart failure, myocardial infarction, etc.), stroke, kidney disease, arteriosclerosis, etc. is there. In addition, the compound (I) is useful as a brain function improving agent for Alzheimer's disease and senile dementia due to its central action, and further has anxiolytic action and antidepressant action. The preparation of the present invention using the compound (I) or a salt thereof as such a drug is orally or parenterally, or by an inhalation method, or by rectal injection,
Alternatively, it can be used by topical injection, and can be used as a pharmaceutical composition or preparation (eg, powder, granule, tablet, pill, capsule, injection, suppository, syrup, emulsion, elixir, suspension, solution). Etc.) and they use at least one compound of the invention alone or in admixture with pharmaceutically acceptable carriers, adjuvants, excipients, excipients and / or diluents. be able to.

The preparation of the present invention can be prepared according to a usual method. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also
It may be a solution or suspension in a non-toxic parenterally-available diluent such as an aqueous solution or a solvent that can be used for sterile injection. Examples of the vehicle or solvent that can be used include water, Ringer's solution, isotonic saline solution, and the like. Further, aseptic non-volatile oil may be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. A suppository for rectal administration is a drug and a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at the temperature of the intestinal tract and melt in the rectum. It can be manufactured by mixing with a substance that emits.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like described above. In such dosage forms, the active ingredient compound is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectin. , Tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms also
As usual, further additives may be included, eg inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbic acid, antioxidants such as ascorbic acid, α-tocopherol, cysteine. Examples include agents, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, perfume agents and the like. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which contain an inert diluent commonly used in the art, such as water. You may stay. The dosage for a particular patient depends on the age, weight, general health, sex, diet, time of administration, mode of administration, excretion rate, drug combination, and the extent of the condition being treated by the patient at the time. , And these or other factors. The dose varies depending on the target disease, symptom, administration subject, administration method, etc., but when administered as a therapeutic agent for essential hypertension in adults, the daily dose is 1 to 100 mg (preferably 1 to 50 mg) by oral administration, intravenous injection. Then, the daily dose of 0.01 to 50 mg (preferably 0.1 to 30 mg) is preferably administered once or divided into 2 to 3 times.

[0045]

EXAMPLES The present invention will be described in more detail below with reference to formulation examples, reference examples, examples and experimental examples, but it goes without saying that these do not limit the present invention. Formulation Example The compound (I) of the present invention can be used, for example, in hypertension, heart disease,
When used as a therapeutic agent for cardiovascular diseases such as stroke and nephritis, it can be used, for example, by the following prescription. 1. Capsule (1) 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methylpyrazole- 5-Carboxylic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2), (3) and 1/2 amount of (4) were mixed. Then, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5 -Carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1), (2), (3), 2/3 amount of (4 ) And 1/2 amount of (5) are mixed and then granulated. The rest of (4) and (5) are added to the granules and pressed into tablets.

3. Injection (1) 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] Methylpyrazole-5-carboxylic acid disodium salt 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2) and (3) are dissolved in water for injection to a total volume of 2 ml and ampoule is prepared. Enclose in. All steps are performed aseptically. 4. Capsule (1) Methyl 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methylpyrazole -5-carboxylate 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2), (3) and 1/2 amount of (4) are mixed. Then, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 5. Tablet (1) Methyl 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methylpyrazol- 5-carboxylate 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1), (2), (3), 2/3 amount of ( After mixing 4) and 1/2 amount of (5), granulate. The rest of (4) and (5) are added to the granules and pressed into tablets.

6. Injection (1) Methyl 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] Methylpyrazol-5-carboxylate sodium salt 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) dissolved in water for injection to a total volume of 2 ml, ampoule Enclose in. All steps are performed aseptically. 7. Capsule (1) 3-butyl-1- (2-chlorophenyl) -4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl ) Biphenyl-4-yl] methylpyrazole-5-carboxylic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2), (3) and 1 Mix 2 volumes of (4) and granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 8. Tablet (1) 3-Butyl-1- (2-chlorophenyl) -4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) Biphenyl-4-yl] methylpyrazole-5-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1), (2), ( 3), 2/3 amount of (4) and 1/2 amount of (5) are mixed and then granulated. The rest of (4) and (5) are added to the granules and pressed into tablets.

9. Injection (1) 3-butyl-1- (2-chlorophenyl) -4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole- 3-yl) biphenyl-4-yl] methylpyrazole-5-carboxylic acid disodium salt 10 mg (2) inosit 100 mg (3) benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) to a total volume of 2 ml. Dissolve it in water for injection and seal it in an ampoule. All steps are performed aseptically. 10. Capsule (1) 3-Butyl-1- (2-chlorophenyl) -4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4 -Yl] methylpyrazole-5-carboxylic acid 10 mg (2) lactose 90 mg (3) microcrystalline cellulose 70 mg (4) magnesium stearate 10 mg 1 capsule 180 mg (1), (2), (3) and half amount After mixing (4), granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

11. Tablets (1) 3-butyl-1- (2-chlorophenyl) -4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4- Ilyl] methylpyrazole-5-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1), (2), (3), 2 Mix 3 parts (4) and 1/2 parts (5) and granulate. The rest of (4) and (5) are added to the granules and pressed into tablets. 12. Injection (1) 3-Butyl-1- (2-chlorophenyl) -4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4 -Ill] methylpyrazole-5-carboxylic acid disodium salt 10 mg (2) inosit 100 mg (3) benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) in water for injection to a total volume of 2 ml Melt and seal in ampoules. All steps are performed aseptically.

Reference Example 1 4-Methylbiphenyl-2'-carboxamido oxime hydroxylamine hydrochloride (17.9 g) in dimethyl sulfoxide (120 ml) was dissolved in sodium metal (5.
92 g) and a methanol solution of sodium methoxide prepared from anhydrous methanol (50 ml) were added. 1 at room temperature
After stirring for 0 minutes, 2'-cyano-4-methylbiphenyl (10 g) was added, and the reaction solution was stirred at 100 ° C for 5 hours. After cooling, the reaction solution was partitioned with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. Wash the organic layers together and dry,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white amorphous substance (11.2 g, 96%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 4.42 (2
H, br s), 7.22 (2H, d), 7.31-7.50 (5H, m), 7.56-7.60 (1
H, m). IR (KBr) cm ^-1 : 3490, 3380, 1642, 1575, 1568.

Reference Example 2 5-Trichloromethyl-3- (4'-methylbiphenyl-2-yl) -1,2,4-oxadiazole The compound (10 g) obtained in Reference Example 1 in benzene (100 m
l) Trichloroacetic anhydride (16.4 g) was added dropwise to the solution, and the reaction solution was heated under reflux for 2 hours. After cooling, the reaction solution was concentrated to dryness, and the residue was partitioned with ether and water. The aqueous layer was extracted with ether, the organic layers were combined, washed with water, dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 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 (4
H, s), 7.44-7.64 (3H, m), 7.88-7.93 (1H, m). IR (neat) cm ^-1 : 3025, 1600, 1580, 1561, 1508.

Reference Example 3 5-Trichloromethyl-3- (4'-bromomethylbiphenyl-2-yl) -1,2,4-oxadiazole Tetrachloride of the compound (24.8 g) obtained in Reference Example 2 Carbon (3
(00 ml) solution with N-bromosuccinimide (12.5 g)
And α, α′-azobisisobutyronitrile (1.1
5 g) was added and the mixture was heated under reflux for 2 hours. After cooling, the white insoluble matter was removed by filtration, and the filtrate was diluted with dichloromethane. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ether-hexane to give the title compound as colorless crystals (23.0 g, 76%). Melting point 77-79 ° C. Elemental analysis value C ₁₆ H ₁₀ N ₂ OBrCl ₃ .0.5H ₂ O ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.52 (2H, s), 7.23 (2
H, 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.

Reference Example 4 4'-Bromomethylbiphenyl-2-carboxamide 4'-Methylbiphenyl-2-carboxamide (2.1
g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrate (AIBN; 82 mg) were added to benzene (20 ml), and the mixture was stirred at 60-70 ° C for 20 hr. The precipitated crystals were collected by filtration, washed with isopropyl ether, suspended in water, and stirred for 30 minutes. The insoluble matter was collected by filtration and dried. The crude crystals were recrystallized from ethyl acetate-methanol to give colorless needle crystals (1.6 g, 55%). Melting point 220-221 ° C. (d) Elemental analysis value as C ₁₄ H ₁₂ BrNO ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 4.75 (2H, s), 7.31-
7.69 (10H, m). IR (KBr) cm ^-1 : 3150, 3000, 1570, 1540, 1520, 1
500, 1300, 665.

Example 1 Methyl 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methylpyrazole -5-carboxylate a) Ethyl 2-methoxyimino-4-oxooctanoate Ethyl 2,4-dioxooctanoate (20g)
(K.Seki et al., Chem.Pharm.Bull., 32,1568 (1984)) in ethanol (100 ml) solution was added with methoxyamine hydrochloride (8.4 g) under ice cooling and stirred for 1 hour. Stir at room temperature for an additional 15 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ether. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound as a colorless oil (16.6).
g, 72%). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.91 (3H, t), 1.23-1.41 (2H,
m), 1.50-1.64 (2H, m), 2.47 (2H, t), 3.70 (2H, s), 4.06 (3H,
s), 4.36 (2H, q) .IR (neat) cm ^-1 : 2960,2935,1720,1340,1125,1045.b) ethyl 3- (2'-cyanobiphenyl-4-yl) methyl-2- Methoxyimino-4-oxooctanoate Compound (10.8 g) obtained in Example 1a), 4-bromomethyl-2′-cyanobiphenyl (12.2 g), anhydrous potassium carbonate (13.8 g) and dimethylformamide ( 100 ml) and mixed at room temperature for 20 hours. Water (1.5 l) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound as a colorless oil (10.7 g, 5
7%). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.89 (3H, t), 1.20-1.36 (5H,
m), 1.49-1.63 (2H, m), 2.34 (2H, t), 3.00 (1H, dd), 3.46 (1H,
dd), 3.97 (3H, s), 4.19-4.33 (3H, m), 7.25 (2H, d), 7.37-7.5
0 (4H, m), 7.62 (1H, m), 7.74 (1H, d). IR (neat) cm ^-1 : 2955,2940,2220,1720,1480,1245,1045,7
65.

C) Ethyl 3-butyl-4- (2'-
Cyanobiphenyl-4-yl) methylpyrazole-5-
Carboxylate Compound obtained in Example 1b) (2.8 g), hydrazine
Monohydrate (1 g), acetic acid (30 ml) and 2-methoxyethanol (15 ml) were mixed and stirred at 105 ° C. for 60 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ether. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound as a pale yellow powder (1.4 g, 55%). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.23-1.40 (5H,
m), 1.50-1.63 (2H, m), 2.61 (2H, t), 4.19 (2H, s), 4.35 (2H,
q), 7.26 (2H, d), 7.38-7.50 (4H, m), 7.63 (1H, dd), 7.74 (1H,
d). IR (nujol) cm ⁻¹ : 3400,3230,2225,1700,1445,1145.d) Ethyl 3-butyl-4- (2′-hydroxycarbamimidoylbiphenyl-4-yl) methylpyrazole-5 -Carboxylate The compound obtained in Example 1c) (1.4 g), hydroxylamine hydrochloride (2.5 g), triethylamine (3.3 g).
g) and dimethylsulfoxide (35 ml) were mixed to give 7
Stir at 0 ° C. for 90 hours. Water (300 ml) in the reaction solution
Was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow powder (1.4 g, 91%). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.85 (3H, t), 1.20-1.37 (5H,
m), 1.44-1.68 (2H, m), 2.56 (2H, t), 4.14 (2H, s), 4.34 (2H,
q), 4.41 (2H, brs), 7.15-7.59 (7H, m), 7.78 (1H, d) .IR (nujol) cm ^-1 : 3180, 1710, 1655, 16
50, 1045. e) Methyl 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-
3-yl) biphenyl-4-yl] methylpyrazole-
5-Carboxylate A solution of the compound (0.65 g) obtained in Example 1d) and triethylamine (0.11 g) in dichloromethane (15 ml) was added dropwise with a solution of methyl chlorocarbonate (0.11 g) in dichloromethane (2 ml) under ice cooling. did. After stirring for another 30 minutes, the reaction solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to give a pale yellow powder (0.47 g).
Got This pale yellow powder (0.47 g) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.46 g)
g) was added to ethyl acetate (7 ml), and the mixture was heated under reflux for 2 hours. The reaction solution was washed with diluted hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was stirred with 28% sodium methoxide methanol solution (0.30 g) in methanol (40 ml) at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound as colorless needle crystals (0.33 g, 50%). . Melting point 194-195 ℃ Elemental analysis value As C ₂₄ H ₂₄ N ₄ O ₄ ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.20-1.40 (2H,
m), 1.44-1.60 (2H, m), 2.55 (2H, t), 3.74 (3H, s), 4.12 (2H,
s), 7.16 (2H, d), 7.21 (2H, d), 7.40-7.65 (3H, m), 7.85 (1H,
d) .IR (nujol) cm ^-1 : 3250,1755,1710,1455.

Example 2 3-Butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methylpyrazole- 5-Carboxylic acid A solution of the compound obtained in Example 1e) (0.23 g) and 1N sodium hydroxide (1 ml) in methanol (2 ml) was added 5 times.
Stir at 0 ° C. for 20 hours. The reaction solution was concentrated under reduced pressure,
Water (10 ml) and 2N hydrochloric acid (1 ml) were added to the residue and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound as colorless columnar crystals (0.16 g, 72
%). As mp 213-214 ° C. Elemental analysis C ₂₃ H ₂₂ N ₄ O ₄ ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.22-1.40 (2H,
m), 1.46-1.63 (2H, m), 2.58 (2H, t), 4.16 (2H, s), 7.24 (4H,
s), 7.40-7.68 (4H, m) .IR (nujol) cm ^-1 : 3175,1800,1690.

Example 3 Methyl 3-butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5 -Carboxylate A solution of the compound (0.80 g) obtained in Example 1d) in dichloromethane (15 ml) was mixed with 1,1'-dithiocarbonyldiimidazole (0.24 g) in dichloromethane (5 m).
l) The solution was added dropwise to the solution under ice-cooling and stirred for 1 hour. Silica gel (Merck, Art7734, 6 g), chloroform (80 ml) and methanol (20 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The silica gel was filtered off, washed with a mixed solvent of chloroform-methanol (5: 1), and the filtrate was concentrated under reduced pressure. The residue was mixed with methanol (25%) together with 28% sodium methoxide methanol solution (0.30 g).
ml) at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from isopropyl ether to give the title compound as colorless columnar crystals (0.28 g, 33%). Got as. Melting point 171-172 ℃ Elemental analysis value C ₂₄ H ₂₄ N ₄ O ₃ S ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.87 (3H, t), 1.20-1.40 (2H,
m), 1.43-1.58 (2H, m), 2.48 (2H, t), 3.70 (3H, s), 4.10 (2H,
s), 7.13 (2H, d), 7.16 (2H, d), 7.38-7.62 (3H, m), 7.87 (1H,
d), 9.90 (1H, brs). IR (nujol) cm ^-1 : 3260,1715,1705,1670.

Example 4 3-Butyl-4- [2 '-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methylpyrazol-5- Carboxylic acid From the compound (0.23 g) obtained in Example 3, the title compound was converted into colorless columnar crystals (0.19 g, 85) in the same manner as in Example 2.
%). Melting point 202-203 ℃ (Ethyl acetate) Elemental analysis value as C ₂₃ H ₂₂ N ₄ O ₃ S ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.87 (3H, t), 1.21-1.40 (2H,
m), 1.45-1.60 (2H, m), 2.55 (2H, t), 4.15 (2H, s), 7.19 (4H,
s), 7.37-7.62 (4H, m), 11.90 (1H, brs) .IR (nujol) cm ^-1 : 3190,3120,3060,1680,1415,1265,1150.

Example 5 Methyl 3-butyl-1- (2-chlorophenyl) -4
-[2 '-(2,5-dihydro-5-oxo-1,2,
4-thiadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5-carboxylate a) ethyl 3-butyl-1- (2-chlorophenyl) -4- (2'-cyanobiphenyl-4-yl) methyl Pyrazole-5-carboxylate The compound obtained in Example 1b) (1.6 g) and 2′-chlorophenylhydrazine hydrochloride (2.2 g) were used in Example 1
The title compound was obtained as an orange oil (1.2 g, 65%) in a similar manner to c). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.87 (3H, t), 1.01 (3H, t), 1.25
-1.43 (2H, m), 1.54-1.68 (2H, m), 2.64 (2H, t), 4.12 (2H, q),
4.25 (2H, s), 7.30 (2H, d), 7.36-7.51 (8H, m), 7.63 (1H, dd),
7.76 (1H, d). IR (neat) cm ⁻¹ : 2950,2925,2220,1720,1490,1235,760.b) Ethyl 3-butyl-1- (2-chlorophenyl) -4- (2′- Hydroxycarbamimidoylbiphenyl-4-yl) methylpyrazole-5-carboxylate From the compound obtained in Example 5a) (1.2 g) to Example 1
The title compound was obtained as an orange oil (0.57 g, 45%) in a similar manner to d). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.87 (3H, t), 1.01 (3H, t), 1.23
-1.43 (2H, m), 1.50-1.65 (2H, m), 2.62 (2H, t), 4.12 (2H, q),
4.23 (2H, s), 4.41 (2H, brs), 7.23 (2H, d), 7.33-7.60 (10H,
m) .IR (nujol) cm ⁻¹ : 3380,1720,1650,1495,1240.c) Methyl 3-butyl-1- (2-chlorophenyl) -4- [2 ′-(2,5-dihydro-5) -Oxo-
1,2,4-Oxadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5-carboxylate The compound obtained in Example 5b) (0.30 g) to Example 1
The title compound was obtained as a yellow oil (0.20) in the same manner as in e).
g, 65%). Elemental analysis value as C ₃₀ H ₂₇ N ₄ ClO ₄ · 0.1AcOEt ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.26-1.45 (2H,
m), 1.52-1.70 (2H, m), 2.63 (2H, t), 3.63 (2H, t), 3.67 (3H,
s), 4.22 (2H, s), 7.27 (4H, s), 7.36-7.62 (7H, m), 7.88 (1H,
d) .IR (neat) cm ^-1 : 2955,1785,1730,1490,1440,1240,760,73
0.

Example 6 3-Butyl-1- (2-chlorophenyl) -4- [2 '
-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5-carboxylic acid The compound obtained in Example 5c) (0. 16 g) and in the same manner as in Example 2) to give the title compound as a yellow powder (0.10).
g, 63%). Elemental analysis value As C ₂₉ H ₂₅ N ₄ ClO ₄ ⅕CH ₂ Cl ₂ ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.92 (3H, t), 1.31-1.50 (2H,
m), 1.60-1.75 (2H, m), 2.72 (2H, t), 4.15 (2H, s), 7.18 (4H,
s), 7.30-7.66 (7H, m), 7.90 (1H, d) .IR (nujol) cm ^-1 : 1765,1720,1490,765.

Example 7 Methyl 3-butyl-1- (2-chlorophenyl) -4
-[2 '-(2,5-dihydro-5-oxo-1,2,
4-Thiadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5-carboxylate From the compound obtained in Example 5b) (0.27 g) to Example 3
In the same manner as in the above, the title compound was obtained as an orange oil (0.1
3 g, 46%). Elemental analysis value as C ₃₀ H ₂₇ N ₄ ClO ₃ S ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.26-1.45 (2H,
m), 1.53-1.70 (2H, m), 2.63 (2H, t), 3.67 (3H, s), 7.25 (4H,
s), 7.36-7.60 (7H, m), 7.90 (1H, d), 8.28 (1H, brs). IR (neat) cm ^-1 : 2955,1725,1700,1670,760.

Example 8 3-Butyl-1- (2-chlorophenyl) -4- [2 '
-(2,5-Dihydro-5-oxo-1,2,4-thiadiazol-3-yl) biphenyl-4-yl] methylpyrazole-5-carboxylic acid From the compound obtained in Example 7 (0.10 g) The title compound was obtained as a pale yellow powder (80 mg, 82) in the same manner as in Example 2.
%). Elemental analysis value as C ₂₉ H ₂₅ N ₄ ClO ₃ S ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.93 (3H, t), 1.32-1.50 (2H,
m), 1.60-1.75 (2H, m), 2.74 (2H, t), 4.19 (3H, s), 7.15 (2H,
d), 7.24 (2H, d), 7.30-7.60 (7H, m), 8.00 (1H, d), 8.38 (1H, b
rs) .IR (nujol) cm ^-1 : 1700,1670,1490,765.

Experimental Example 1 Angiotensin II binding inhibitory effect on angiotensin receptor [Experimental method] Douglas et al. [Endochronology (E
ndocrinology), 102, 685-696 (197)
8)] was modified to perform angiotensin II (A-II) receptor binding inhibition experiment. From the cortex of bovine adrenal gland AI
An I receptor membrane fraction was prepared. The compound of the present invention (10 ⁻⁶ M or 10 ⁻⁷ M) and ¹²⁵ I-angiotensin II (
¹²⁵ I-AII) (2.44 kBq / 50 μl) was added to the receptor membrane fraction and incubated at room temperature for 1 hour.
Filter the bound and free ¹²⁵ I-AII (Whatman GF
/ B filter) and ¹²⁵ I-bound to the receptor
The radioactivity of AII was measured. [Experimental Results] The experimental results concerning the compounds of the present invention are shown in the table.

Experimental Example 2 Inhibitory effect of the compound of the present invention on AII pressor response [Experimental method] Jcl: SD rats (9 weeks old, male) were used. On the day before the experiment, the femoral artery and vein were cannulated under anesthesia with pentobarbital Na, and kept under conditions of fasting and free water intake until just before the experiment. On the day of the experiment, the arterial cannula was connected to a blood pressure transducer and the mean blood pressure was recorded on a polygraph. Control A before drug administration
The pressor response by intravenous administration of -II (100 ng / kg) was determined. The drug was orally administered, and thereafter, A-II was intravenously administered at each measurement point, and the pressor response was similarly determined, and the inhibition rate was determined by comparing the reactions before and after drug administration. [Experimental Results] The experimental results concerning the compounds of the present invention are shown in [Table 1].
Shown in.

[Table 1]

Continuation of the front page (56) Reference JP-A-4-327586 (JP, A) International publication 91/015479 (WO, A1) European patent application publication 501892 (EP, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 413/10 C07D 417/10 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The formula: [In the formula, R ¹ represents C _1-6 alkyl, R ² represents a carboxyl group, a C _1-4 alkoxycarbonyl group or an amide group, and Q represents a hydrogen atom or a phenyl group which may be substituted with a halogen. And R ³ is of the formula (In the formula, i represents a group represented by -O- or -S-)] or a salt thereof. 2. An angiotensin II antagonist containing the compound according to claim 1 or a salt thereof.