JPH1045716A - 2,3-diheteroarylacryloylguanidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain 2,3-diheteroarylacryloylguanidine derivative excellent in specificity, causing no side action, having activities for inhibiting an Na<+> /H<+> exchanger and useful as a preventing and treating agent for hypertension, arrhythmia, angina pectoris, etc. SOLUTION: This 2,3-diheteroarylacryloylguanidine derivative is represented by formula I [R<1> and R<2> are each a heteroaryl (substituted by a halogen, etc.); R<3> is H, a halogen or an alkyl (substituted by a halogen)], e.g. N-[(E)-3-(4- pyridyl)-2-(3-thienyl)acryloyl]guanidine. The derivative of formula I is obtained by reacting an acrylic acid of formula II (X is a eliminable group easily substituted by a nucleophilic reagent such as H, a halogen, etc.) or its reactive derivative (e.g. an acid halide) with guanidine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament, particularly Na ⁺
The present invention relates to a 2,3-diheteroarylacryloylguanidine derivative or a salt thereof having an inhibitory effect on / H ⁺ exchanger.

[0002]

2. Description of the Related Art Reactions occurring in cells are affected by pH, and an H ⁺ concentration gradient is a driving force of ATP synthesis. Therefore, it is necessary for the intracellular pH to be accurately controlled in order to perform an accurate cell function.
The Na ⁺ / H ⁺ exchanger is one of the mechanisms controlling the intracellular pH, but it has recently been found that it is closely involved in the activation of cells by various physiologically active substances. Furthermore, N
It has been noted that the enhanced activity of the a ⁺ / H ⁺ exchanger is involved in the onset, maintenance or worsening of certain disease states. For example, ischemic reperfusion myocardial injury and reperfusion arrhythmia (Scholtz W. et alBr. J. Pharmacol. 109 , 562 (199)
3)), hypertension (Rosskof D. et al Hypertens. 21 , 607 (1
993)), cardiac hypertrophy (de la Sierra A. et al Circulation
88 , 1628 (1993)), vascular smooth muscle proliferation (Kranzhofer R. et.
al Circ. Res. 73 , 246 (1993)), diabetic complications (Cane
ssa M. et al Hypertens. 11 , 823 (1993)), bronchoconstriction by endothelin (Battistini B. et al Biochem.
Biophys. Res. Commun., 175 , 583 (1991)), glutamate-induced neuronal death (Manev H. et al Neuropharmacol.
29 , 1103 (1990)), bone resorption (Hall TJ et al Bioche
m. Biophs. Res. Commun. 188 , 1097 (1992)) and their association with various disease states and physiological activities.

[0003]

As a Na ⁺ / H ⁺ exchanger inhibitor, amiloride, a kind of K ⁺ -retaining diuretic, has been known for a long time, and it has also been reported that amiloride has an antiarrhythmic effect. Have been. (Mol. Pharmacol.
25 , 131-136 (1984)). However, there is a problem in the specificity of the action, and it has an antiarrhythmic effect and also has an antihypertensive and salinic excretion, which are undesirable side effects of arrhythmia treatment.

Furthermore, it has been reported that amiloride derivatives exhibit Na ⁺ / H ⁺ exchanger inhibitory activity and antiarrhythmic activity (for example, see J. Membrane Biol. 105 , 1-21 (198)
8)). Also, recently, it has been reported that benzoylguanidine derivatives have Na ⁺ / H ⁺ exchanger inhibitory activity and antiarrhythmic activity (see, for example, JP-A-3-10685).
No. 8). In addition, it has been reported that an alkenylcarbonylguanidine derivative substituted with a phenyl group having a perfluoroalkyl group has a Na ⁺ / H ⁺ exchanger inhibitory activity and an antiarrhythmic effect (JP-A-8-27093). On the other hand, Am. J. Physiol., 260, C271 (1991) discloses a 2,3-diphenyl-substituted acryloylguanidine derivative, which has low reactivity with anti-acylolide antibodies and is evaluated as an amiloride epitope. Is reported to be low. In addition, there is no description on the use of the compound as a pharmaceutical, as well as the Na ⁺ / H ⁺ exchanger inhibitory action of the compound. At present, Na ⁺ / H ⁺ exchanger inhibitors having excellent specificity and no side effects have not yet been obtained, and their creation is eagerly awaited.

[0005]

Means for Solving the Problems The present invention relates to a 2,3-diheteroarylacryloylguanidine derivative represented by the following general formula (I) or a salt thereof.

[0006]

Embedded image

(However, the symbols in the formula have the following meanings. R ¹ and R ² may be the same or different and may be substituted with a substituent selected from the following group A, and condensed with a benzene ring A heteroaryl group which may be substituted, Group A: lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxy group, lower alkoxy lower alkoxy group, lower alkoxycarbonyl group which may be substituted with a halogen atom; , Carboxyl group, halogen atom, nitro group, cyano group, amino group, mono- or di-lower alkylamino group, lower alkanoyl group, lower alkanoyl lower alkylamino group, lower alkanoylamino group, lower alkanoyloxy group, hydroxyl group, mercapto group, Lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfo Group, aminosulfonyl group, a mono- or di-lower alkylaminosulfonyl group, a lower alkylsulfonylamino group, a lower alkylsulfonyl mono-lower alkylamino group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group,
Methylenedioxy group, ethylenedioxy group, propylenedioxy group, aryl group and aralkyl group, R ³ : hydrogen atom, halogen atom or lower alkyl group optionally substituted by halogen atom. )

Further, according to the present invention, there is provided a medicine characterized by containing the above-mentioned 2,3-diheteroarylacryloylguanidine derivative or a salt thereof.

Further, according to the present invention, there is provided a Na ⁺ / H ⁺ exchanger inhibitor comprising the 2,3-diheteroarylacryloylguanidine derivative or a salt thereof as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the general formula (I) is further described as follows. As used herein, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Therefore, specific examples of the “lower alkyl group” as a substituent of R ¹ or R ² or a “lower alkyl group optionally substituted with a halogen atom” for R ³ include, for example, a methyl group, an ethyl group, Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-
Methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group , 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-
Dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl Group, 1-ethyl-
Examples include a 2-methylpropyl group.

A "halogen atom" as a substituent of R ¹ or R ² or a "lower alkyl group optionally substituted with a halogen atom" of R ³ , and a substituent of R ¹ or R ² ; Alternatively, the “halogen atom” of R ³ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Accordingly, the “lower alkyl group which may be substituted by a halogen atom” as a substituent of R ¹ or R ² or R ³ is a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a chlorofluoro group. Methyl group, chlorofluorobromomethyl group, bromomethyl group, iodomethyl group,
It includes a 1-fluoro-2-bromoethyl group, a 1,2-dichloroethyl group and the like.

The term "heteroaryl group" means a 5- or 6-membered monocyclic aryl group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom,
For example, furyl group, thienyl group, pyrrolyl group, imidazolyl group, virazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, And a pyrazinyl group. A heteroaryl group containing one or two hetero atoms selected from a nitrogen atom and a sulfur atom is preferred.

Accordingly, the term "heteroaryl group optionally condensed with a benzene ring" includes the above-mentioned heteroaryl group and groups in which these groups are condensed with a benzene ring, for example, an indolyl group, an isoindolyl group, an indazolyl group, Quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, benzimidazolyl group, isobenzofuranyl group, benzofuranyl group, 1,2
-Benzoisoxazolyl group, benzoxazolyl group, benzothiazolyl group, benzothienyl group and the like.
The bond to the acryloyl group of these condensed rings may come from an atom on the heteroaryl ring or an atom on the benzene ring.

The "lower alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group. Group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylallyl group, 1-methyl-1-propenyl group, 1-methylallyl group, 1,1-dimethylvinyl group, 1- Pentenyl group, 2
-Pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 2-methyl-
1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group, 1-methyl-1-butenyl group,
1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethylallyl group, 1,2-dimethyl-
1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-
Propenyl group, 1-hexenyl group, 2-hexenyl group,
3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1,1-dimethyl-1-butenyl group, 1,1-dimethyl-2-butenyl group, 1,1-dimethyl-3-butenyl group, 3, 3-dimethyl-1-butenyl group, 1-methyl-1-pentenyl group, 1-methyl-2-pentenyl group,
Examples thereof include a 1-methyl-3-pentenyl group, a 1-methyl-4-pentenyl group, a 4-methyl-1-pentenyl group, a 4-methyl-2-pentenyl group, and a 4-methyl-3-pentenyl group. .

The "lower alkynyl group" has 2 to 6 carbon atoms.
Linear or branched alkynyl groups, each being an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-
2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl group, 1-
Methyl-2-butynyl group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl And the like. The “cycloalkyl group” preferably has 3 to 8 carbon atoms.
And a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

The "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, te
rt-butoxy group, pentyloxy (amyloxy)
Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group,
Examples thereof include a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group, and a hexyloxy group.

The "lower alkoxy lower alkoxy group" refers to a lower alkoxy group having the above "lower alkoxy group" as a substituent, and specific examples thereof include a methoxymethoxy group, an ethoxymethoxy group, a propoxymethoxy group and an isopropoxymethoxy group. Butoxymethoxy group, isobutoxymethoxy group, pentyloxymethoxy group, hexyloxymethoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group and the like.

The "lower alkoxycarbonyl group" includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group,
Butoxycarbonyl, isobutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

"Mono or di-lower alkylamino group"
Is an amino group having a linear or branched alkyl group having 1 to 6 carbon atoms. In the case of "di-lower alkylamino group", the two alkyl groups may be the same or different. Examples of the “mono-lower alkylamino group” include, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, t-
tert-butylamino group, pentylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,2-dimethylpropylamino group,
Hexylamino group, isohexylamino group, 1-methylpentylamino group, 2-methylpentylamino group, 3-
Methylpentylamino group, 1,1-dimethylbutylamino group, 1,2-dimethylbutylamino group, 2,2-dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3-dimethylbutylamino group, 3,3-dimethylbutylamino group, 1-ethylbutylamino group, 2-ethylbutylamino group, 1,1,2-trimethylpropylamino group, 1,2,2-trimethylpropylamino group,
Examples thereof include a 1-ethyl-1-methylpropylamino group and a 1-ethyl-2-methylpropylamino group.

The "di-lower alkylamino group" includes, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di (sec-butyl) amino, di (sec-butyl) amino, (tert-butyl) amino group, dipentylamino group, diisopentylamino group, dineopentylamino group, di (tert-pentyl) amino group and the like. Further, methyl lower amino groups such as methylethylamino group, methylpropylamino group, methylisopropylamino group, methylbutylamino group, methylisobutylamino group, ethylpropylamino group, ethylisopropylamino group, ethylbutylamino group, ethyl Examples thereof include an ethyl lower alkylamino group such as an isobutylamino group and an ethyl sec-butylamino group.

Examples of the "lower alkanoyl group" include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group and the like.

As the "lower alkanoylamino group",
Formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, pivaloylamino group, hexanoylamino group, N-acetyl-N-methylamino group and the like. Can be

The term "lower alkanoyl lower alkylamino group" means a mono- or di-lower alkylamino group substituted with the above-mentioned lower alkanoyl group.

As the "lower alkanoyloxy group",
Examples include a formyloxy group, an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovaleryloxy group, a pivaloyloxy group, and a hexanoyloxy group.

Examples of the "lower alkylthio group" include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, Pentylthio, neopentylthio, tert-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 1,2-dimethylpropylthio, hexylthio, isohexylthio, 1-methylpentylthio Group, 2-methylpentylthio group, 3-methylpentylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-
Dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1, 2-trimethylpropylthio group,
1,2,2-trimethylpropylthio group, 1-ethyl-
Examples thereof include a 1-methylpropylthio group and a 1-ethyl-2-methylpropylthio group.

Examples of the "lower alkylsulfinyl group" include, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, ter-
t-butylsulfinyl group, pentylsulfinyl group,
Isopentylsulfinyl group, neopentylsulfinyl group, tert-pentylsulfinyl group, 1-methylbutylsulfinyl group, 2-methylbutylsulfinyl group, 1,2-dimethylpropylsulfinyl group, hexylsulfinyl group, isohexylsulfinyl group, 1-
Methylpentylsulfinyl group, 2-methylpentylsulfinyl group, 3-methylpentylsulfinyl group,
1,1-dimethylbutylsulfinyl group, 1,2-dimethylbutylsulfinyl group, 2,2-dimethylbutylsulfinyl group, 1,3-dimethylbutylsulfinyl group, 1-ethylbutylsulfinyl group, 2-ethylbutylsulfinyl group, Examples thereof include a 1,1,2-trimethylpropylsulfinyl group, a 1,2,2-trimethylpropylsulfinyl group, a 1-ethyl-1-methylpropylsulfinyl group, and a 1-ethyl-2-methylpropylsulfinyl group.

As the "lower alkylsulfonyl group",
Specifically, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, s
ec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, tert-pentylsulfonyl group, 1-methylbutylsulfonyl group, 2-methylbutylsulfonyl group, 1,2- Dimethylpropylsulfonyl, hexylsulfonyl, isohexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutyl Sulfonyl group, 2,2-dimethylbutylsulfonyl group, 1,3-dimethylbutylsulfonyl group, 1
-Ethylbutylsulfonyl group, 2-ethylbutylsulfonyl group, 1,1,2-trimethylpropylsulfonyl group, 1,2,2-trimethylpropylsulfonyl group, 1
-Ethyl-1-methylpropylsulfonyl group, 1-ethyl-2-methylpropylsulfonyl group and the like.

[0029] The term "mono- or di-lower alkylaminosulfonyl group" means a one or two hydrogen atoms have been substituted with a lower alkyl group having an aminosulfonyl group, represented by the general formula -SO ₂ -NRR ' (R is a lower alkyl group, and R ′ is a hydrogen atom or a lower alkyl group). In the case of a di-lower alkylaminosulfonyl group, the two alkyl groups may be the same or different. As the “mono-lower alkylaminosulfonyl group”, specifically, for example, an N-methylaminosulfonyl group,
N-ethylaminosulfonyl group, N-propylaminosulfonyl group, N-isopropylaminosulfonyl group, N
-Butylaminosulfonyl group, N-isobutylaminosulfonyl group, N-sec-butylaminosulfonyl group,
Examples include an N-tert-butylaminosulfonyl group, an N-pentylaminosulfonyl group, an N-hexylaminosulfonyl group, and the like.

Examples of the "di-lower alkylaminosulfonyl group" include, for example, N, N-dimethylaminosulfonyl group, N, N-diethylaminosulfonyl group, N, N-dipropylaminosulfonyl group, N, N-diisopropylaminosulfonyl Group, N, N-dibutylaminosulfonyl group, N, N-diisobutylaminosulfonyl group, N, N
N-dipentylaminosulfonyl group, N, N-diisopentylaminosulfonyl group, N, N-dineopentylaminosulfonyl group, N, N-di (tert-pentyl)
And an aminosulfonyl group. Further, N-methyl such as N-methyl-N-ethylaminosulfonyl group, N-methyl-N-propylaminosulfonyl group, N-methyl-N-isopropylaminosulfonyl group, N-methyl-N-butylaminosulfonyl group, etc. N-ethyl-N-lower such as -N-lower alkylaminosulfonyl, N-ethyl-N-propylaminosulfonyl, N-ethyl-N-isopropylaminosulfonyl, N-ethyl-N-butylaminosulfonyl, etc. And an alkylaminosulfonyl group.

The “lower alkylsulfonylamino group” is
Means one of the hydrogen atoms have been substituted with lower alkylsulfonyl group for the amino group, represented by the general formula -NH-SO ₂ -R (R represents a lower alkyl group.). Specifically, for example, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, isopropylsulfonylamino group, butylsulfonylamino group, isobutylsulfonylamino group, sec-butylsulfonylamino group, pentylsulfonylamino group, hexylsulfonylamino And the like.

The "lower alkylsulfonyl mono-lower alkylamino group" means two groups, the hydrogen atoms are substituted with each lower alkylsulfonyl group and a lower alkyl group of the amino group, the general formula -NR-SO ₂ - R ′ (R and R ′ are the same or different and represent a lower alkyl group). As the "lower alkylsulfonylmono-lower alkylamino group", specifically, for example, N-methylsulfonyl-N-methylamino group, N-ethylsulfonyl-N-methylamino group, N-propylsulfonyl-N-
Methylamino group, N-isopropylsulfonyl-N-methylamino group, N-butylsulfonyl-N-methylamino group, N-isobutylsulfonyl-N-methylamino group, N-sec-butylsulfonyl-N-methylamino group, N-tert-butylsulfonyl-N-methylamino group, N-pentylsulfonyl-N-methylamino group,
N- such as N-hexylsulfonyl-N-methylamino group
N-lower alkylsulfonyl- such as lower alkylsulfonyl-N-methylamino group, N-methylsulfonyl-N-ethylamino group, N-ethylsulfonyl-N-ethylamino group and N-propylsulfonyl-N-ethylamino group Examples include an N-ethylamino group, an N-methylsulfonyl-N-propylamino group, an N-methylsulfonyl-N-isopropylamino group, an N-methylsulfonyl-N-butylamino group, and the like.

"Mono-lower alkylaminocarbonyl group"
Is a group represented by the general formula -C (= O) NHR, wherein (R
Represents a lower alkyl group. ), Specifically, N-methylaminocarbonyl group, N-ethylaminocarbonyl group, N-propylaminocarbonyl group, N-isopropylaminocarbonyl group, N-butylaminocarbonyl group, N-isobutylaminocarbonyl group and the like. No.

"Di-lower alkylaminocarbonyl group"
Is a group represented by the general formula -C (= O) NRR '(R and R' are the same or different and represent a lower alkyl group), and specifically, an N, N-dimethylaminocarbonyl group , N, N-diethylaminocarbonyl group, N-methyl-N-ethylaminocarbonyl group, N, N-dipropylaminocarbonyl group and the like.

As the "aryl group", C6-C1
Four aryl groups are preferred, and specific examples include phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl, and phenanthryl groups.

The "aralkyl group" is preferably a group in which an arbitrary hydrogen atom of the above-mentioned "lower alkyl group" is substituted with an "aryl group". Specifically, a benzyl group, a phenethyl group, a 1-phenylethyl group , 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 1-methyl-2-phenylethyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 1-phenyl Butyl group, 2-methyl-3-phenylpropyl group, 2-methyl-2-phenylpropyl group, 2
-Methyl-1-phenylpropyl group, 1-methyl-3-
Phenylpropyl group, 1-methyl-2-phenylpropyl group, 1-methyl-1-phenylpropyl group, 1-ethyl-2-phenylethyl group, 1,1-dimethyl-2-phenylethyl group, 5-phenylpentyl Group, 4-phenylpentyl group, 3-phenylpentyl group, 2-phenylpentyl group, 1-phenylpentyl group, 3-methyl-4
-Phenylbutyl group, 3-methyl-3-phenylbutyl group, 3-methyl-2-phenylbutyl group, 3-methyl-
1-phenylbutyl group, 6-phenylhexyl group, 5-
Phenylhexyl group, 4-phenylhexyl group, 3-phenylhexyl group, 2-phenylhexyl group, 1-phenylhexyl group, 4-methyl-5-phenylpentyl group, 4-methyl-4-phenylpentyl group, 4- Methyl-3-phenylpentyl group, 4-methyl-2-phenylpentyl group, 4-methyl-1-phenylpentyl group, 1
-Naphthylmethyl group, 2-naphthylmethyl group, 2- (1
-Naphthyl) ethyl group, 2- (2-naphthyl) ethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, 3- (1-naphthyl) propyl group, 3-
(2-naphthyl) propyl group, 2- (1-naphthyl) propyl group, 2- (2-naphthyl) propyl group, 1- (1
-Naphthyl) propyl group, 1- (2-naphthyl) propyl group, 1-methyl-2- (1-naphthyl) ethyl group, 1
-Methyl-2- (2-naphthyl) ethyl group, 4- (1-
Naphthyl) butyl group, 4- (2-naphthyl) butyl group,
3- (1-naphthyl) butyl group, 3- (2-naphthyl)
Butyl group, 2- (1-naphthyl) butyl group, 2- (2-
A naphthyl) butyl group, a 1- (1-naphthyl) butyl group,
1- (2-naphthyl) butyl group, 2-methyl-3- (1
-Naphthyl) propyl group, 2-methyl-2- (1-naphthyl) propyl group, 2-methyl-2- (2-naphthyl)
Propyl group, 2-methyl-1- (1-naphthyl) propyl group, 2-methyl-1- (2-naphthyl) propyl group,
5- (1-naphthyl) pentyl group, 5- (2-naphthyl) pentyl group, 4- (1-naphthyl) pentyl group, 4
-(2-naphthyl) pentyl group, 3-methyl-4- (1
-Naphthyl) butyl group, 3-methyl-4- (2-naphthyl) butyl group, 6- (1-naphthyl) hexyl group, 6-
(2-naphthyl) hexyl group, 5- (1-naphthyl) hexyl group, 5- (2-naphthyl) hexyl group, 4-methyl-5- (1-naphthyl) pentyl group, 4-methyl-5
-(2-naphthyl) pentyl group, diphenylmethyl group (benzhydryl group), trityl group and the like.

The compound of the present invention is cis-trans (or (E) -form or (Z) -form) based on a double bond of an acryloyl group.
There are geometric isomers of The present invention includes those separated ((E) -form or (Z) -form) or mixtures thereof. Among the compounds of the present invention, those in which R ¹ and R ² have a cis configuration are particularly preferred. Further, the compounds of the present invention exist as tautomers based on the presence of a guanidinocarbonyl group, and the present invention includes separated ones or mixtures thereof. In addition to the above, depending on the type of substituent, there may be geometric isomers and tautomers,
The present invention includes a separated form or a mixture of these isomers. The compound of the present invention may have an asymmetric carbon atom, and may have an (R) form based on the asymmetric carbon atom;
The (S) -form optical isomer may exist. The present invention includes mixtures and isolated forms of these optical isomers.

The compound of the present invention may form an acid addition salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloric acid, hydrobromic acid,
Inorganic acids such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid,
Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,
Examples thereof include acid addition salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid.

The present invention further includes various hydrates, solvates and polymorphs of the compound (I) of the present invention and salts thereof.

(Production Method) The compounds of the present invention and salts thereof can be produced by applying various synthetic methods, utilizing the characteristics based on the basic skeleton or the types of substituents.

[0041]

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(Wherein R ¹ , R ² and R ³ have the above-mentioned meanings. X is an elimination which can be easily substituted by a nucleophile such as a hydroxyl group, a halogen atom, a lower alkoxy group, an aralkyloxy group, etc.) The compound (I) of the present invention can be produced by reacting acrylic acid represented by the general formula (II) or a reactive derivative thereof with guanidine. When the acrylic acid derivative (II) has a functional group active in a reaction such as a hydroxyl group or an amino group, these functional groups are protected with a protecting group in advance, and after performing this reaction, the protecting group is removed. As a result, the compound (I) of the present invention can be obtained.

Examples of the reactive derivative of acrylic acid include acid halides, acid anhydrides, active esters, lower alkyl esters, acid azides and the like. Examples of the acid halide include acid chloride and acid bromide.

As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate. Mixed acid anhydride with aralkyl chlorocarbonate such as benzyl chlorocarbonate, mixed anhydride with aryl chlorocarbonate such as phenyl chlorocarbonate, mixed with alkanoic acid such as isovaleric acid and pivalic acid Acid anhydride and the like.

As the active ester, p-nitrophenyl ester, N-hydroxysuccinimide ester,
Pentafluorophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,
N-hydroxy-5-norbornene-2,3-dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy-4,5-dichlorophenyl ester, 2-hydroxypyridine ester,
2-pyridyl thiol ester, 1-benzotriazolyl ester and the like can be mentioned.

Such a reactive derivative of acrylic acid is
It can be easily obtained from the corresponding acrylic acid according to the usual methods commonly used.

When reacting with an acid halide or an acid anhydride, the reaction can be carried out in a solvent under cooling to room temperature in the presence of a base or an excess of guanidine. As the base, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Alternatively, organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and 4-dimethylaminopyridine are exemplified.

Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and 1,4-dioxane, and halogenated carbon solvents such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrogen-based solvent, dimethylformamide,
Examples include amide solvents such as dimethylacetamide, and basic solvents such as pyridine. These solvents are used alone or in combination of two or more. The solvent should be appropriately selected according to the type of the starting compound and the like.

When reacting with an ester derivative, the reaction can be carried out in a solvent in the presence of an equimolar or excess guanidine under cooling or at room temperature or under heating. In some cases, after the solvent is distilled off, heating may be performed at about 130 ° C. for a short time. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane, and amide solvents such as dimethylformamide and dimethylacetamide. These solvents are used alone or in combination of two or more. In the case of other esters, for example, alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; amide solvents such as dimethylformamide and dimethylacetamide And the like.
These solvents are used alone or in combination of two or more.

When X is a hydroxyl group, the reaction is preferably carried out in the presence of a condensing agent. As the condensing agent, for example,
Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide (WS
C), benzotriazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphoride (BOP), diphenylphosphonyl azide (DPP)
A), 1,1′-carbonylbis-1H-imidazole (CDI) and the like. In some cases, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4
An additive such as -oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) may be added.

Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene and xylene; ether solvents such as tetrahydrofuran and 1,4-dioxane; halogenated carbon solvents such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrogen-based solvent, dimethylformamide,
Examples include amide solvents such as dimethylacetamide, and basic solvents such as pyridine. These solvents are used alone or in combination of two or more.

(Production method of raw material compound) Acrylic acid or its reactive derivative (II) to be a raw material compound in the above production method
Can be synthesized by a known method. For example, it can be manufactured by the following manufacturing method.

[0053]

Embedded image

(Wherein, R ¹ , R ² , R ³ and X have the above-mentioned meanings. Y is a lower alkanoyl group, mesyl group, tosyl group, trifluoromethanesulfonyl group which may be substituted by a halogen atom) And Z represents a halogen atom.) The acetic acid ester derivative represented by the general formula (III) is cooled with lithium diisopropylamide (LDA) in an inert solvent such as tetrahydrofuran, preferably -60 to -8.
The reaction is carried out at 0 ° C., and then the reaction is carried out by reacting with a carbonyl derivative represented by the general formula (IV) in an inert solvent. By appropriately setting the conditions, the intermediate represented by the general formula (II) can be obtained in this coupling reaction without isolating the intermediate.
In some cases, the acrylic acid derivatives represented by a) and (IIb) can be obtained directly as a single compound or as a mixture of (IIa) and (IIb). Alternatively, the coupling reaction may give a propionate derivative represented by the general formula (V). In this case, the propionic acid ester derivative (V) is further reacted with an acid halide represented by the general formula (VI) or an acid anhydride represented by the general formula (VII) in the presence of a base to esterify a hydroxyl group. To convert to the compound represented by the general formula (VIII). Here, acetic anhydride, trifluoroacetic anhydride and the like can be used as the acid anhydride, and acetic chloride, trifluoroacetic chloride, methanesulfonyl chloride, tosyl chloride or trifluoromethanesulfonyl chloride can be used as the acid halide. An acid (YOH) or the like is eliminated from the compound represented by the general formula (VIII) in the presence of a base at room temperature or with heating to give a compound of the general formula (II)
The acrylic acid derivatives represented by a) and (IIb) are each obtained as a single compound or as a mixture. Further, the ester compound represented by the general formula (VIII) is subjected to the next step without isolation, and is isolated from the general formulas (IIa) and (II).
The compounds of b) can each be obtained as single compounds or as mixtures.

By hydrolyzing the acrylic acid derivatives represented by the general formulas (IIa) and (IIb), acrylic acid represented by the general formulas (IIc) and (IId) can be obtained.

[0056]

Embedded image

(Wherein R ¹ , R ² and R ³ have the same meanings as above). The carbonyl derivative (IV) and the acetic acid derivative (IX) are heated to reflux in acetic anhydride in the presence of a base such as triethylamine. Also, the starting compounds (IIc) and (II
d) can be produced (Reference: Org. Synth.
Coll. Vol IV: 730-731 (1963), Org. Synth. Coll. Vo
l IV: 777-779 (1963)).

The reaction product obtained by each of the above production methods is
It is isolated and purified as various solvates such as a free compound, a salt or a hydrate thereof. The salt can be produced by subjecting the salt to a usual salt formation reaction. Isolation, purification, extraction, concentration,
It is performed by applying ordinary chemical operations such as distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, optical isomers can be separated by a general racemic resolution method, for example, fractional crystallization or chromatography. Optical isomers can also be synthesized from appropriate optically active starting compounds.

[0059]

The compound of the present invention is useful as an active ingredient of a pharmaceutical preparation. In particular, since it has an activity inhibiting effect on the cellular sodium-proton alternating transport mechanism (Na ⁺ / H ⁺ exchanger), it prevents or prevents diseases related to various physiological activities and pathological conditions involving the Na ⁺ / H ⁺ exchanger. Useful for treatment.

Specifically, diseases caused by enhancement of the cellular sodium-proton alternating transport mechanism (Na ⁺ / H ⁺ exchanger), such as hypertension (eg, essential hypertension or renal failure, primary aldosteronism) , Adrenal oxygen deficiency, Lid
dle syndrome, Gordon syndrome, renal tubular acidosis (RTA) type IV, hyporenin hypoaldosteronism,
Secondary hypertension associated with primary disease such as bilateral renal vascular hypertension), arrhythmia, angina, cardiac hypertrophy, organ damage due to ischemia reperfusion (eg, injury during cardiac ischemia reperfusion, surgical treatment (eg, Disorders due to organ transplantation or PTCA), disorders due to decreased blood flow at the time of organ transplantation, myocardial infarction, prevention of myocardial infarction recurrence (eg, prevention of secondary myocardial infarction, prevention of cardiac accident recurrence), protection of organs during ischemia and suppression of symptoms Improvement (eg, heart, brain, kidney, gastrointestinal,
Disorders associated with ischemia of the lungs, liver, and skeletal muscles, especially those associated with cerebral infarction, sequelae after stroke, disorders associated with cerebral edema), cell proliferative disorders, arteriosclerosis, diabetic complications (eg, retina) Disease, nephropathy), cancer, intimal thickening (eg, atherosclerotic disease, arteritis, vascular restenosis after PTCA operation, vascular stenosis at the time of vascular transplantation), hypertrophy / thickening of tissues / organs (eg, heart , Kidney, prostate, hypertrophy and thickening of smooth muscle tissue, etc.), cardiac fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, renal glomerulosclerosis, protection of transplanted organs, edema, cerebral edema, chronic heart disease (Eg, heart failure), cardiomyopathy, pulmonary embolism, acute and chronic kidney disease (eg, renal failure), cerebral infarction, chronic cerebral circulation disorder (eg, stroke), cranial nerve disorder (eg, dementia, AIDS), disorder due to hyperglycemia ( For example, diabetic neuropathy, hyperlipidemia, etc.), It is useful as a prophylactic / therapeutic agent for disorders associated with insulin resistance, shock (eg, allergic, cardiac, hypovolemic and bacterial shock), inflammatory diseases, lung and bronchial disorders, osteoporosis, acid-base disorders. .

The compound of the present invention can also be used as a diagnostic agent for hypertension, diabetes, arteriosclerosis, etc. involving the sodium-proton alternating transport mechanism (Na ⁺ / H ⁺ exchanger).

The action of the compound of the present invention was confirmed by the following pharmacological tests. Inhibition test of platelet swelling reaction in rabbits [Principle] When an acid is loaded on platelets, Na ⁺ / H ⁺ exchanger is activated because H ⁺ ions are excreted outside the cells. In this case, when Na ⁺ ions are present in the external solution, activation of the Na ⁺ / H ⁺ exchanger will simultaneously take up Na ⁺ ions into cells. The influx of Na ⁺ ions into cells draws in water molecules due to the osmotic pressure gradient, resulting in swelling of platelets.

[Platelet rich plasma (PRP: platelet rich pl
Preparation of asma)] Rabbits were pentobarbital (30 mg)
/ Kg, intraauricular vein injection), fixate in dorsal position, incision of cervical skin to expose carotid artery, anticoagulation in advance using polyethylene cannula (venous catheter (5Fr), Atom) ACD-A solution (acid-c
Blood is collected in a plastic centrifuge tube containing 1/10 volume. About 100 ml of blood is obtained from a rabbit of about 2 kg. After mixing well, centrifuge at 1400 rpm (350 × g) for 10 minutes at room temperature. This supernatant is PRP, and about 20 to 40 ml is obtained from 100 ml of blood.

[Measurement of Na ⁺ / H ⁺ exchanger activity by platelet swelling reaction] The platelet swelling reaction was measured by a spectrophotometer (U-type) equipped with a personal computer (Vectra 286/12, Yokogawa-Hewlett-Packard Company). 3,000 (Hitachi, Ltd.). That is, a plastic cuvette containing a propionic acid solution (970 μl) as an acid load was attached, and PRP (14
0 μl) is added and the absorbance is measured immediately. The measurement wavelength is 680 nm. The absorbance change appears as an exponential decrease reaching a plateau in 3-4 minutes. The test drug is D
After dissolving to 10 mM with MSO, the solution is diluted with a propionic acid solution to an optimum concentration and used as a propionic acid solution containing a test drug. The swelling reaction is suppressed by a decrease in the concentration of the external Na ⁺ ion or by an increase in the concentration of the test drug having an Na ⁺ / H ⁺ exchanger inhibitory action. The composition of the propionic acid solution is as follows. Sodium propionate, 14
0 mM; N- (2-hydroxyethyl) piperazine-
N'-2-ethanesulfonic acid (HEPES), 20 m
M; glucose, 10 mM; potassium chloride, 5 mM; magnesium chloride, 1 mM; calcium chloride, 1 mM;
H6.7.

In order to qualitatively evaluate the Na ⁺ / H ⁺ exchanger inhibitory activity of the test drug, the amount of change per unit time is calculated from the obtained change in absorbance and expressed in logarithm. From the initial gradient of this graph, the rate constant of the swelling reaction is determined. It has been confirmed that this rate constant does not depend on the platelet count.
Finally, a drug-specific inhibition constant (K _i value) is calculated by performing a Dickson plot (X-axis: drug concentration, Y-axis: reciprocal of the rate constant) of the rate constant at each concentration of the test drug. [Results] The compounds of the present invention exhibited good K _i values and had excellent Na ⁺ / H ⁺ exchanger inhibitory activity.

A pharmaceutical composition containing one or more of the compound represented by the general formula (I) or a salt thereof as an active ingredient contains a carrier, an excipient, and other additives which are usually used for formulation. It is prepared using

A drug containing the compound (I) of the present invention or a salt thereof as a main component can be prepared by a generally used method using a drug carrier, an excipient and the like usually used in the art. Can be. Dosing tablets, pills,
Any form of oral administration such as capsules, granules, powders, and liquid preparations, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermals may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
Such compositions may further comprise preservatives, wetting agents, emulsifiers,
Adjuvants such as dispersants, stabilizers (eg, lactose), solubilizers (eg, glutamic acid, aspartic acid) may be included. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These also produce sterile solid compositions,
Before use, it can also be used by dissolving it in sterile water or a sterile solvent for injection.

The daily dose is about 0.001 per body weight.
To 10 mg / kg is appropriate, but once a day to 4 mg / kg.
It is preferable to administer about 0.01 to 1 mg / kg per time. The dose is appropriately determined depending on the individual case in consideration of the symptoms, age of the administration subject, sex and the like.

[0072]

The present invention will be described below in more detail with reference to examples. The method for producing the starting compounds used in the examples will be described as reference examples.

Reference Example 1 Pyridine-4-aldehyde 4.53
g, thiophene-3-acetic acid 5.01 g, triethylamine 5 ml, and acetic anhydride 10 ml were stirred in a 100 ° C. oil bath for 5 hours and 25 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was recrystallized from methanol to give (E) -3- (4-pyridyl) -2- (3-thienyl).
2.408 g of acrylic acid were obtained. Mass analysis (m / z): 232 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
6.92 (1H, dd), 7.04 (2H, d), 7.37 (1H, dd), 7.57
(1H, dd), 7.69 (1H, s), 8.45 (2H, d), 13.04 (1H, b
rs)

(Reference Example 2) (E)-
3- (3-Pyridyl) -2- (3-thienyl) acrylic acid was obtained. Mass spectrometry value (m / z): 232 (FAB, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
6.92-6.93 (1H, m), 7.26 (1H, dd), 7.37-7.40 (2H,
m), 7.59 (1H, dd), 7.75 (1H, s), 8.35 (1H, d), 8.4
1-8.42 (1H, m), 12.88 (1H, brs)

(Reference Example 3) (E)-
2- (3-Pyridyl) -3- (2-thienyl) acrylic acid was obtained. Mass spectrometry value (m / z): 232 (FAB, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
7.06 (1H, dd), 7.47-7.51 (2H, m), 7.57 (1H, d), 7.
68 (1H, dt), 8.11 (1H, s), 8.41 (1H, d), 8.64 (1H,
dd), 12.76 (1H, brs)

(Reference Example 4) (E)-
2- (3-Pyridyl) -3- (3-thienyl) acrylic acid was obtained. Mass spectrometry (m / z): 232 (FAB, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
6.32-6.33 (1H, m), 7.40-7.42 (1H, m), 7.47 (1H, dd
d), 7.61 (1H, d), 7.67 (1H, dt), 7.92 (1H, s), 8.3
8 (1H, d), 8.60 (1H, dd), 12.79 (1H, brs)

(Reference Example 5) (E)-
2- (3-Pyridyl) -3- (4-pyridyl) acrylic acid was obtained. Mass analysis (m / z): 227 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
7.00 (2H, d), 7.43 (1H, dd), 7.67 (1H, dt), 7.86
(1H, s), 8.33 (1H, d), 8.45 (2H, d), 8.56 (1H, d
d), 13.26 (1H, brs)

(Reference Example 6) In the same manner as in Reference Example 1, (E)-
3- (2-Thiazolyl) -2- (3-pyridyl) acrylic acid was obtained. Mass spectrometry (m / z): 233 (FAB, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
7.54 (1H, dd), 7.75-7.77 (2H, m), 7.94 (1H, d), 8.
00 (1H, s), 8.48 (1H, d), 8.68 (1H, dd), 13.24 (1H,
brs)

(Reference Example 7) In the same manner as in Reference Example 1, (E)-
3- (4-Methyl-2-phenyl-5-thiazolyl) -2- (3-pyridyl) acrylic acid was obtained. Mass analysis (m / z): 323 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
2.59 (3H, s), 7.40-7.78 (7H, m), 8.05 (1H, s), 8.4
4 (1H, m), 8.70 (1H, dd)

(Reference Example 8) (E)-
3- (2-Phenyl-4-thiazolyl) -2- (3-pyridyl) acrylic acid was obtained. Mass spectrometry (m / z): 309 (FAB, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
7.37-7.75 (7H, m), 7.83 (1H, s), 7.92 (1H, s), 8.4
3 (1H, m), 8.58 (1H, dd)

Reference Example 9 a) A solution of 3.10 g of diisopropylamine in 60 ml of tetrahydrofuran at -70 ° C. to -60 ° C. under an argon atmosphere at 1.68 g.
18.2 ml of a solution of n-butyllithium M in n-hexane was added dropwise and stirred for 30 minutes. Pyridine-3- at −70 ° C.
A solution of 5.06 g of acetic acid ethyl ester in 20 ml of tetrahydrofuran was added dropwise, and after stirring for 30 minutes, a solution of 4.88 g of 1-methylindole-3-carboxaldehyde in 20 ml of tetrahydrofuran was added dropwise.After stirring for 90 minutes, the temperature was gradually raised to room temperature. Stirred overnight. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give (E) -3- (1-methyl-3-indolyl) -2- (3-
2.23 g of ethyl pyridyl) acrylate was obtained. Mass spectrometry value (m / z): 306 (EI, M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.3
0 (3H, t), 3.59 (3H, s), 4.27 (2H, q), 6.18 (1H,
s), 7.20-7.41 (4H, m), 7.66 (1H, dt), 7.76 (1H, d),
8.31 (1H, s), 8.57 (1H, d), 8.66 (1H, dd)

B) (E) -3- (1-methyl-3-indolyl) -2- (3
To a solution of 2.12 g of ethyl (pyridyl) acrylic acid in 100 ml of ethanol was added 20 ml of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 23 hours. After neutralization with 1 N hydrochloric acid, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with ethanol to give (E) -3- (1-methyl-3-indolyl)-
1.69 g of 2- (3-pyridyl) acrylic acid was obtained. Mass analysis (m / z): 279 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
3.64 (3H, s), 6.50 (1H, s), 7.09-7.71 (6H, m), 8.1
4 (1H, s), 8.43 (1H, brs), 8.60 (1H, brd), 12.43 (1
H, brs)

Example 1 A mixture of 1.500 g of (E) -3- (4-pyridyl) -2- (3-thienyl) acrylic acid, 1.470 g of 1,1'-carbonyldiimidazole, and 20 ml of dimethylformamide was prepared. Stirred at room temperature for 35 minutes. A suspension containing 1860 mg of guanidine hydrochloride and 779 mg of 60% sodium hydride in 30 ml of dimethylformamide was added dropwise to this solution under ice-cooling. After stirring for 1 hour and 50 minutes under ice-cooling, water was added to the reaction solution, and acetic acid was added. Extracted with ethyl. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate.
533 mg of [(E) -3- (4-pyridyl) -2- (3-thienyl) acryloyl] guanidine was obtained. Mp one hundred eighty-four to one hundred eighty-seven ° C. Mass spectrometry value (m / z): 273 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
6.87 (1H, dd), 6.91-6.93 (2H, m), 7.24 (1H, dd),
7.49 (1H, dd), 7.60 (1H, s), 8.37-8.39 (2H, m)

(Embodiment 2) In the same manner as in Embodiment 1, (E)-
From 3- (3-pyridyl) -2- (3-thienyl) acrylic acid, N-
[(E) -3- (3-Pyridyl) -2- (3-thienyl) acryloyl] guanidine was obtained. Mass analysis (m / z): 273 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
6.86 (1H, dd), 7.19-7.23 (2H, m), 7.28 (1H, dt),
7.49 (1H, dd), 7.70 (1H, s), 8.23 (1H, d), 8.34 (1
H, dd)

(Embodiment 3) In the same manner as in Embodiment 1, (E)-
From 2- (3-pyridyl) -3- (2-thienyl) acrylic acid, N-
[(E) -2- (3-Pyridyl) -3- (2-thienyl) acryloyl] guanidine was obtained. Mass analysis (m / z): 273 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
6.99 (1H, dd), 7.20 (1H, d), 7.42-7.45 (2H, m), 7.
54-7.57 (1H, m), 8.13 (1H, s), 8.30 (1H, d), 8.56
(1H, dd)

(Embodiment 4) In the same manner as in Embodiment 1, (E)-
From 2- (3-pyridyl) -3- (4-pyridyl) acrylic acid, N-
[(E) -2- (3-Pyridyl) -3- (4-pyridyl) acryloyl] guanidine was obtained. Mass spectrometry value (m / z): 268 (CI, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
6.88 (2H, d), 7.34-7.37 (1H, m), 7.54-7.57 (1H, m),
7.80 (1H, s), 8.23 (1H, d), 8.37 (2H, d), 8.48 (1H, d
d)

(Example 5) In the same manner as in Example 1, (E)-
From 3- (2-thiazolyl) -2- (3-pyridyl) acrylic acid, N-
[(E) -3- (2-thiazolyl) -2- (3-pyridyl) acryloyl]
Guanidine was obtained. Mass analysis (m / z): 274 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
7.48 (1H, dd), 7.61-7.63 (2H, m), 7.85 (1H, d), 8.
14 (1H, s), 8.35 (1H, d), 8.60-8.61 (1H, m)

Example 6 N-[(E) -3- (4-pyridyl) -2- (3
-Thienyl) acryloyl] guanidine 310mg methanol
To a 10 ml solution was added 113 mg of methanesulfonic acid diluted with 10 ml of methanol at room temperature. The methanol was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give N-[(E) -3- (4-pyridyl)-
2- (3-thienyl) acryloyl] guanidine methanesulfonate (311 mg) was obtained. 178-182 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
2.39 (3H, s), 6.95 (1H, dd), 7.06 (2H, d), 7.59 (1
H, s), 7.60 (1H, dd), 7.68 (1H, dd), 8.40-8.51 (6H,
m), 10.75 (1H, brs)

(Example 7) In the same manner as in Example 6, N-
From [(E) -3- (3-pyridyl) -2- (3-thienyl) acryloyl] guanidine, N-[(E) -3- (3-pyridyl) -2- (3-thienyl)
[Acryloyl] guanidine methanesulfonate was obtained. 195-198 ° C Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
2.35 (3H, s), 6.98 (1H, dd), 7.30-7.33 (1H, m), 7.
37-7.40 (1H, m), 7.63 (1H, m), 7.70 (1H, s), 7.72
(1H, dd), 8.37-8.39 (5H, m), 8.48 (1H, d), 10.47 (1
H, brs)

(Example 8) In the same manner as in Example 6, N-
From [(E) -2- (3-pyridyl) -3- (4-pyridyl) acryloyl] guanidine, N-[(E) -2- (3-pyridyl) -3- (4-pyridyl)
[Acryloyl] guanidine methanesulfonate was obtained. Melting point 171-173 ° C. nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
2.30 (3H, s), 7.00 (2H, d), 7.49 (1H, dd), 7.74-7.
76 (2H, m), 8.24 (4H, brs), 8.40 (1H, s), 8.50 (2H,
d), 8.64 (1H, d), 10.79 (1H, brs)

(Example 9) In the same manner as in Example 6, N-
[(E) -3- (2-thiazolyl) -2- (3-pyridyl) acryloyl]
N-[(E) -3- (2-thiazolyl) -2- (3-pyridyl) acryloyl] guanidine methanesulfonate was obtained from guanidine. Mass analysis (m / z): 274 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
2.34 (3H, s), 7.63 (1H, dd), 7.85-7.86 (2H, m), 8.
01 (1H, d), 8.07 (1H, s), 8.30 (4H, brs), 8.57 (1H,
m), 8.78 (1H, m), 10.75 (1H, brs)

Example 10 In the same manner as in Examples 1 and 6, (E) -2- (3-pyridyl) -3- (3-thienyl) acrylic acid was converted to N-[(E) -2- (3-Pyridyl) -3- (3-thienyl) acryloyl] guanidine methanesulfonate was obtained. Mass analysis (m / z): 273 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) [delta]:
2.36 (3H, s), 6.25 (1H, d), 7.46 (1H, dd), 7.57 (1
H, dd), 7.69 (1H, d), 7.77-7.79 (1H, m), 7.90 (1H,
s), 8.33 (4H, brs), 8.48 (1H, s), 8.71 (1H, m), 1
0.48 (1H, brs)

(Example 11) In the same manner as in Examples 1 and 6, (E) -3- (4-methyl-2-phenyl-5-thiazolyl) -2-
From (3-pyridyl) acrylic acid, N-[(E) -3- (4-methyl-2-
Phenyl-5-thiazolyl) -2- (3-pyridyl) acryloyl]
Guanidine 1.3 methanesulfonate was obtained. Mass analysis (m / z): 364 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) [delta]:
2.36 (3.9H, s), 2.67 (3H, s), 7.44-7.73 (6H, m),
7.92 (1H, m), 8.10 (1H, s), 8.36 (4H, brs), 8.61
(1H, brs), 8.85 (1H, brs)

Example 12 In the same manner as in Examples 1 and 6, (E) -3- (2-phenyl-4-thiazolyl) -2- (3-pyridyl) acrylic acid was converted to N-[(E ) -3- (2-Phenyl-4-thiazolyl) -2- (3-pyridyl) acryloyl] guanidine 1.3 methanesulfonate. Mass analysis (m / z): 350 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) [delta]:
2.39 (3.9H, s), 7.41-7.55 (5H, m), 7.68 (1H, dd),
7.93 (1H, s), 7.97 (1H, m), 8.02 (1H, s), 8.41 (4H,
brd), 8.65 (1H, brs), 8.78 (1H, brd)

(Example 13) In the same manner as in Examples 1 and 6, (E) -3- (1-methyl-3-indolyl) -2- (3-pyridyl)
N-[(E) -3- (1-methyl-3-indolyl) -2 from acrylic acid
-(3-Pyridyl) acryloyl] guanidine 1.4 methanesulfonate was obtained. Mass analysis (m / z): 320 ( FAB, M + +1) Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) [delta]:
2.38 (4.2H, s), 3.68 (3H, s), 6.64 (1H, s), 7.21
(1H, t), 7.28 (1H, t), 7.50 (1H, d), 7.79 (1H, d),
7.91 (1H, m), 8.22 (1H, brd), 8.35 (1H, s), 8.42
(4H, brs), 8.78 (1H, brs), 8.90 (1H, brs)

Table 1 below shows the chemical structural formulas of the compounds obtained in Examples 1 to 13. In the table, Py is a pyridyl group, Th is a thienyl group, Tz is a thiazolyl group,
Sul represents a methanesulfonate, respectively.

[0097]

[Table 1]

The compounds having the following chemical structural formulas can be easily prepared in substantially the same manner as described in the above Examples or Production Methods, or by applying some modifications obvious to those skilled in the art. Can be manufactured. In the table, Pyr
Represents a pyrrolyl group, Im represents an imidazolyl group, Bn represents a benzyl group, Me represents a methyl group, and Ph represents a phenyl group.

[0099]

[Table 2]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/38 AED A61K 31/38 AED 31/40 ABN 31/40 ABN 31/425 ABS 31/425 ABS 31/44 31/44 ABQ ABQ C07D 213/61 C07D 213/61 333/24 333/24 401/06 209 401/06 209 233 233 409/06 207 409/06 207 213 213 417/06 213 417/06 213 333 333 521/00 521/00 (71) Applicant 591032596 Frankfurter Str. 250, D-64293 Darmstadt, Federal Republic of Germany (72) Inventor Toshio Okazaki 8-6-5 Nagayama, Ryugasaki-shi, Ibaraki Pref. (72) Inventor Kei Toyoshima 3-13-1 Ninomiya, Tsukuba-shi, Ibaraki Noya 326 (72) Inventor Kazumi Kikuchi 1-29-1-701 Senju, Adachi-ku, Tokyo (72) Inventor Masahiro Takanashi 1204-55 Matsugasaki, Kashiwa-shi, Chiba

Claims (3)

[Claims] 1. A 2,3-diheteroarylacryloylguanidine derivative represented by the following general formula (I) or a salt thereof. Embedded image (However, the symbols in the formula have the following meanings. R ¹ and R ² may be the same or different and may be substituted with a substituent selected from the following group A, and may be condensed with a benzene ring. Group A: lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxy group, lower alkoxy lower alkoxy group, lower alkoxycarbonyl group, carboxyl group which may be substituted with a halogen atom , Halogen atom, nitro group, cyano group, amino group, mono- or di-lower alkylamino group, lower alkanoyl group, lower alkanoyl lower alkylamino group, lower alkanoylamino group, lower alkanoyloxy group, hydroxyl group, mercapto group, lower alkylthio group , Lower alkylsulfinyl group, lower alkylsulfonyl group, A sulfonyl group, a mono- or di-lower alkylaminosulfonyl group, a lower alkylsulfonylamino group, a lower alkylsulfonyl mono-lower alkylamino group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group,
Methylenedioxy group, ethylenedioxy group, propylenedioxy group, aryl group and aralkyl group, R ³ : hydrogen atom, halogen atom or lower alkyl group optionally substituted by halogen atom. ) 2. A medicament comprising the 2,3-diheteroarylacryloylguanidine derivative or a salt thereof according to claim 1. 3. A Na ⁺ / H ⁺ exchanger inhibitor comprising the 2,3-diheteroarylacryloylguanidine derivative according to claim 1 or a salt thereof as an active ingredient.