Blood Pressure

Pyridyl carboximidamide compounds useful in treating blood pressure

Blood Pressure Abstract
Novel carboximidamide derivatives represented by the following formula (A) and acid adduct salts thereof are disclosed: ##STR1## wherein all the substituents have the same meanings as defined above. N-cyano-pyridinecarboxyimidate compounds represented by the following formula (II) which are the intermediates for preparing of N-cyano-N'-substituted-pyridinecarboximidamide derivatives wherein the substituent B in the above described formula (A) is pyridine are also disclosed: ##STR2## wherein all the substituents have the same meanings as defined above. The process for preparing the compounds, the pharmaceutical agents comprising the compound having vasodilating effect, and the therapeutic method of dosing the compound on patients for therapy are also disclosed.

Blood Pressure Claims
We claim:

1. A pyridinecarboximidamide derivative represented by the following formula (I) or an acid adduct salt thereof: ##STR97## wherein X is a hydrogen atom or a chlorine atom,

R is --R.sup.1 or ##STR98## wherein R.sup.1 is ##STR99## wherein R.sup.4 is an alkyl group with 1-3 carbon atoms or an alkoxyl group with 1-3 carbon atoms and b is an integer of 0-1,

R.sup.2 is a hydrogen atom and a is an integer of 1-2, ##STR100## wherein R.sup.5 is one or more members selected from the group consisting of an alkyl group with 1-3 carbon atoms, an alkoxyl group with 1-3 carbon atoms, a phenylalkoxyl group with 1-3 carbon atoms in the alkoxyl moiety, a nitro group, an amino group, an alkylamino group with 1-3 carbon atoms, a phenylalkylamino group with 1-3 carbon atoms in the alkyl moiety, an alkylthio group with 1-3 carbon atoms, a perfluoroalkyl group with 1-3 carbon atoms or a halogen atom, c is an integer of 0-2 and when c is 2, two R.sup.5 's may be the same or different members in the aforementioned group.

2. A pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1, wherein X in formula (I) is a hydrogen atom.

3. A pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1, wherein X in formula (I) is a chlorine atom and R in the formula is ##STR101##

4. A pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 2, wherein in R.sup.4, the alkyl group is methyl and the alkoxy group is methoxy;

in R.sup.5, the alkyl group is methyl, the alkoxyl group is methoxy, the alkylamino group is dimethylamino, the phenylalkoxyl group is benzyloxyl, the phenylalkylamino group is benzylamino, the alkylthio group is methylthio, the perfluoroalkyl group is perfluoromethyl and a halogen atom is chlorine.

Blood Pressure Description
TECHNICAL FIELD

The present invention relates to novel carboximidamide derivatives having vasodilating effect, more particularly N-cyano-N'-substituted pyridinecarboximidamide derivatives and N-cyano-N'-substituted carboximidamide derivatives in which N'-position is substituted by an alkyl substituent, or acid adduct salts thereof, intermediates for preparing them and a process for preparing them.

The present invention also relates to potassium channel activating agents, hypotensors, therapeutic agents of ischemic heart disease, ameliorants of peripheral circulation, ameliorants of cerebral circulation, therapeutic agents of thrombosis and antasthmatics which contain as an active ingredient the above-described N-cyano-N'-substituted pyridinecarboximidamide derivative or an acid adduct salt thereof, and hypotensors which contain as an active ingredient the N-cyano-N'-substituted carboximidamide derivative wherein the N'-position is substituted by an alkyl group or an acid adduct salt thereof. The present invention further relates to the therapeutic methods for patients who need the treatments of potassium channel activation, the treatments of hypertension, the treatment of ischemic heart disease, the treatment of peripheral circulatory failure, the treatment of cerebral circulatory failure, the treatment of thrombosis and the asthma using the aforementioned N-cyano-N'-substituted pyridinecarboximidamide derivative or an acid adduct salt thereof, or the therapeutic method for patients who need hypotensive treatment using the N-cyano-N'-substituted carboximidamide derivative in which N'-position is substituted by an alkyl group or an acid adduct salt thereof.

BACKGROUND ART

As the well-known compounds among the N-cyano-pyridinecarboximidamide compounds in relation to the present invention, there are mentioned N-cyano-3-pyridinecarboximidamide [see Journal of Medicinal Chemistry, 23, 690-692 (1980)], N-cyano-4-(2-ethylpyridine)carboximidamide (see Leprosy Review, 23-30, 1983) and N-cyano-4-pyridinecarboximidamide (see Bulletin des Societes Chimiques Belges, 78, 41-46, 1969). However, all of these compounds are the ones which have no substituent in N'-position and are reported only as the intermediates for producing of diuretics or as the agents for the treatment of Hansen's disease. There is no report of other utility. The syntheses of carboximidamides have been investigated from various aspects, and various synthetic methods mainly of benzenecarboximidamide compounds or alkylcarboximidamides are investigated (see, for example, "The Chemistry of amidines and imidates", Edited by Saul Patai, John Wiley and Sons, 1975). For example, in the case of an N-cyano-N'-substituted benzenecarboximidamide, a synthetic method which comprises converting cyanobenzene into an alkyl benzeneimidate, further reacting cyanamide (NH.sub.2 CN) with the alkyl benzeneimidate in pH 6.5-7.0 to form an alkyl N-cyano-benzeneimidate and reacting an amine compound with the aforementioned imidate has been proposed (see Synthesis, 263, 1971; Synthesis, 673-675, 1978; Journal of Organic Chemistry, 44, 1562-1563 (1979); Synthesis, 123-124, 1980; Synthesis, 402-404, 1983).

However, according to the conventional synthetic methods, particularly the synthesis within the above-described pH range, an alkyl N-cyano-pyrdinecarboximidate is not produced, and thus an N-cyano-N'-substituted pyridinecarboximidamide compound could not be produced.

On the other hand, as regards antihypertensive agents, a variety of pharmaceutical agents have been proposed, but, so far as the present inventor knows, none of these agents have satisfactory effects on the pathologies and patients of all kinds of hypertensions such as essential hypertension, secondary hypertension or the like. Also as regards the treatment of angina pectoris, calcium antagonists or .beta.-blockers and the like have hitherto been used, but the attack of angina pectoris is not completely suppressed by the use of these agents. There are reported no therapeutics having satisfactory cardioprotective effect after the reperfusion of coronary vessel when the pathology develops into myocardial infarction. New types of cardiovascular therapeutics with consideration for these points are continuously desired.

For instance, as a cardiovascular therapeutic based on a new function mechanism, a compound having a potassium channel activating effect has recently been proposed.

The potassium channel activating effect is an effect that potassium channel on cell membrane is opened and the permeability of potassium is enhanced so that hyperpolarization is caused and the contraction of smooth muscle or myocardium is suppressed. As compounds having potassium channel activating effect, there are known, for example, nicorandil, pinacidil and chromakalim (see Trends in Pharmacological Sciences, 8, 283, 1987). These exhibit vasodilating effect, antihypertensive effect, coronary blood flow increasing effect, cerebral vasodilative effect and bronchodilatative effect in animal experiments [see European Journal of Pharmacology, 152, 331 (1988); The Journal of Pharmacology and Experimental Therapeutics, 232, 369 (1985); Journal of Cardiovascular Pharmacology, 8, 798 (1986); Japan Heart Journal, 20, 881 (1979); European Journal of Pharmacology, 99, 219 (1984); British Journal of Pharmacology, 95, 763 (1988)]. Furthermore, these agents clinically exhibit utilities as an antihypertensive drug [see Clinical Physiology, 1, 375 (1981); Journal of Hypertension, 4, S166 (1986)] or as an antianginal drug [see RINSHO YAKURI, 13, 311 (1982)].

As the well-known carboximidamide compounds except the N-cyano-pyridinecarboximidamide compounds relating to the present invention, there are mentioned N-cyano-5-nitro-2-furamidine (Japanese Patent Publication No. 20453/68 and British Patent No. 1133950); N-cyano-2-thiophenecarboximidamide and N-cyano-3-thiophenecarboximidamide [Journal of Medicinal Chemistry, 23, 690-692 (1980)]; and N-(N-cyanoimidoyl)-sulfoximides [Chemisch Berichte, 121, 383-386 (1988)]. However, these compounds have been reported only as the intermediates in the production of anti-bacterial agents or diuretics and the intermediates in the production of thiatriazines, respectively, without descriptions of the vasodilating effect and hypotensive effect. Also, no carboximidamide compounds relating to the present invention which have an alkyl substituent in N'-position have hitherto been reported.

SUMMARY OF THE INVENTION

Summary

The present invention has been done for the purpose of providing a new compound having vasodilating effect. The present inventor has discovered that N-cyano-N'-substituted pyridinecarboximidamide derivatives and N-cyano-N'-substituted carboximidamide derivatives in which the N'-position is substituted with an alkyl substituent have the aforementioned effect and find out from these novel carboximidamide derivatives the ones which are effective as a potassium channel activating agent, a hypotensor, a therapeutic for the treatment of ischemic heart disease, a therapeutic for the treatment of peripheral circulatory failure, an ameliorants of cerebral circulation, a therapeutic for the treatment of thrombosis and an antasthmatic. The present invention has been accomplished on the basis of these discoveries.

In other words, the carboximidamide derivatives according to the present invention are represented by the following formula (A): ##STR3## wherein

when B is ##STR4## wherein X represents a hydrogen atom or a chlorine atom, R'" represents --R.sup.1 or ##STR5## wherein

R.sup.1 represents an alkyl group, ##STR6## an alkyl group having a nitroxyl group,

wherein R.sup.4 represents an alkyl group or an alkoxyl group and b denotes an integer of 0 or 1, and R.sup.2 represents one or more members selected from the group consisting of an alkyl group, an aryl group, a nitroxyl group, an arylalkoxyl group, a hydroxyl group and a hydrogen atom and a denotes an integer of 1-3, provided that when a is an integer of 2 or more, two or more R.sup.2 's may be the same or different members in the aforementioned group, and

R.sup.3 represents ##STR7## wherein R.sup.5 represents one or more members selected from the group consisting of an alkyl group, an alkoxyl group, an arylalkoxyl group, a nitro group, an amino group, an alkylamino group, an arylalkylamino group, an alkylthio group, a perfluoroalkyl group or a halogen atom, and c denotes an integer of 0-5, provided that when c denotes an integer of 2 or more, two or more R.sup.5 's may be the same or different members in the aforementioned group; and

when B is ##STR8##

The present invention also relates to acid adduct salts thereof.

The compound according to the present invention includes the compound which has pyridine as the substituent B in the formula (A) and the compound having no pyridine.

The compound having pyridine as the substituent B is the pyridinecarboxyimidamide derivative represented by the following formula (I): ##STR9## wherein

X represents a hydrogen atom or a chlorine atom;

R represents --R.sup.1 or ##STR10## wherein

R.sup.1 represents an alkyl group, ##STR11## or an alkyl group having a nitroxyl group, wherein R.sup.4 represents an alkyl group or an alkoxyl group and b denotes an integer of 0-1,

R.sup.2 represents one or more members selected from the group consisting of an alkyl group, an aryl group, a nitroxyl group, an arylalkoxyl group, a hydroxyl group and a hydrogen atom, and a denotes an integer of 1-3, provided that when a is an integer of 2 or more, two or more R.sup.2 's may be the same or different members in the aforementioned group,

R.sup.3 represents ##STR12## wherein R.sup.5 represents one or more members selected from the group consisting of an alkyl group, an alkoxyl group, an arylalkoxyl group, a nitro group, an amino group, an alkylamino group, an arylalkylamino group, an alkylthio group, a perfluoroalkyl group or a halogen atom, c denotes an integer of 0-5, provided that when c denotes an integer of 2 or more, two or more R.sup.5 's may be the same or different members in the aforementioned group;

or an acid adduct salt thereof.

The compound according to the present invention which has no pyridine as the substituent B is the carboximidamide derivative represented by the following formula (I'): ##STR13## wherein X" represents ##STR14##

The present invention also relates to the intermediate obtained in the course of the production of the compound represented by the formula (I). The N-cyano-pyridinecarboxyimidate compound which is the intermediate obtained in the course of the production of the compound of the present invention is represented by the following formula (II): ##STR15## wherein X represents a hydrogen atom or a chlorine atom, and R' represents an alkyl group.

Furthermore, the present invention relates to the process for producing the compound represented by the formula (I).

That is to say, the process for producing the pyridinecarboximidamide derivative represented by the formula (I) set forth above is characterized in that a cyanopyridine compound represented by the following formula (III) is reacted with an alcohol and sodium hydride or a sodium alkoxide to form a compound represented by the following formula (IV), which is reacted with cyanamide in a buffer solution having a pH in the range of 5.0-6.0 to form an N-cyano-pyridinecarboximidate compound represented by the above-described formula (II), which is further reacted with an amine compound represented by the formula NH.sub.2 -R, wherein R has the same meaning as defined above: ##STR16## wherein X represents a hydrogen atom or a chlorine atom, and R' represents an alkyl group.

The present invention also relates to the use of the carboximidamide derivatives represented by the above-described formula (A). In other words, the present invention relates to potassium channel activating agents, hypotensor, therapeutic agents of ischemic heart disease, therapeutic agents of peripheral circulatory failure, ameliorants of cerebral circulation, therapeutic agents of thrombosis and antasthmatics which contain the pyridinecarboximidamide derivative represented by the formula (I) or an acid adduct salt thereof as an effective ingredient, and hypotensors which contain as an active ingredient the N-cyano-N'-substituted carboximidamide derivative wherein the N'-position is substituted by an alkyl group or an acid adduct salt thereof, and relates to the therapeutic methods for patients who need the treatments of potassium channel activation, the treatment of hypertension, the treatment of ischemic heart disease, the treatment of peripheral circulatory failure, the treatment of cerebral circulatory failure, the treatment of thrombosis and the asthma using the aforementioned N-cyano-N'-substituted pyridinecarboximidamide derivative or an acid adduct salt thereof, and the therapeutic method for patients who need hypotensive treatment using the N-cyano-N'-substituted carboximidamide derivative in which N'-position is substituted by an alkyl group or an acid adduct salts thereof.

EFFECT OF THE INVENTION

The carboximidamide derivatives according to the present invention have vasodilating effect and hypotensive effect, and the carboximidamide derivatives having a pyridine substituent have further potassium channel activating effect.

The carboximidamide derivatives according to the present invention have vasodilative effect and hypotensive effect, and the pyridinecarboximidamide derivatives have further potassium channel activating effect as described above. They also have coronary vasodilative effect, cardioprotective effect, peripheral blood vessel resistance decreasing effect, cerebral vasodilative effect, platelet aggregation inhibiting effect and bronchodilatative effect.

It should be extraordinary that the carboximidamide derivative according to the present invention has various physiological effects set forth above.

DETAILED DESCRIPTION OF THE INVENTION

The carboximidamide derivatives according to the present invention are represented by the formula (A) set forth above and include the N-cyano-N'-substituted pyridinecarboximidamide derivatives having pyridine as the substituent B and the N-cyano-N'-substituted carboximidamide derivatives having no pyridine, wherein respective substituents have the same meanings as defined above.

[I] N-cyano-N'-substituted-pyridinecarboximidamide derivatives

The pyridinecarboximidamide derivative according to the present invention is the N-cyano-N'-substituted-pyridinecarboximidamide derivative represented by the formula (I) set forth above (wherein respective substituents have the same meanings as defined above).

In the formula (I), the alkyl group of R.sup.1 has preferably 1-10 carbon atoms, particularly 5-8 carbon atoms. It may be the alkyl group in a straight chain or a branched chain, preferably in a branched chain. The alkyl group having a nitroxyl group of R.sup.1 is preferably the one having 1-5 carbon atoms, particularly 1-3 carbon atoms. In this case, one or more, preferably one or two, nitroxyl groups may be contained. The nitroxyl group may be bonded to either one of primary, secondary or tertiary carbon atoms, and particularly the nitroxyl group is desirably bonded to a primary carbon atom.

The alkyl group of R.sup.2 has preferably 1-5 carbon atoms, particularly 1-3 carbon atoms. The aryl group is preferably a tolyl group, a xylyl group or a phenyl group, more preferably a phenyl group. The arylalkoxyl group is preferably a phenethyloxy group, a 3-phenylpropyloxy group or a benzyloxy group, more preferably a benzyloxy group.

When two or more R.sup.2 's are simultaneously contained, these plural R.sup.2 's may be the same or different members in the aforementioned group consisting of the groups and the atom set forth above. When R.sup.4 is an alkyl group or an alkoxyl group, the alkyl or alkoxyl group preferably contains 1-5 carbon atoms, particularly 1-3 carbon atoms. R.sup.5 represents one or more members selected from the aforementioned group as defined above. When two or more R.sup.5 's are simultaneously contained, the R.sup.5 's may be the same or different members in the group. When R.sup.5 is an alkyl group or an alkoxyl group, the alkyl or alkoxyl group preferably contains 1-5 carbon atoms, particularly 1-3 carbon atoms. When R.sup.5 is an arylalkoxyl group, the arylalkoxyl group is preferably a phenethyloxy group, a 3-phenylpropyloxy group or a benzyloxy group, particularly a benzyloxy group. The alkylamino group preferably contains 1-5 carbon atoms, preferably 1-3 carbon atoms. The arylalkylamino group is preferably a phenethylamino group, a 3-phenylpropylamino group or a benzylamino group, more preferably a benzylamino group. When R.sup.5 is an alkylthio group or a perfluoroalkyl group, each of these groups preferably contains 1-5 carbon atoms, particularly 1-3 carbon atoms.

The halogen atom may be any of halogen atoms, and it is preferably fluorine, chlorine or bromine.

The aforementioned N-cyano-N'-substituted pyridinecarboximidamide derivative according to the present invention has a basic nitrogen atom and thus forms an acid adduct salt. Acids with which an acid adduct salt is formed include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like; or organic acids such as acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid, tartaric acid, fumaric acid, glutamic acid, pantothenic acid, laurylsulfonic acid or the like. It is needless to say that when an acid adduct salt is used as a medicine, the acid must be the one which is pharmaceutically acceptable.