Pyridyl carboximidamide compounds useful in treating blood pressure

• US 5,223,508 A
• Filed: 02/28/1992
• Issued: 06/29/1993
• Est. Priority Date: 12/27/1988
• Status: Expired due to Term

• Current Assignee: Kirin Pharma KK
• Original Assignee: Kirin Beer Kabushiki Kaisha
• Inventors: Ogawa, Nobuyuki, Izawa, Toshio, Kashiwabara, Tomoko, Nakajima, Shohachi
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US07/843,847
• Time in Patent Office: 487 Days
• Field of Search: 546/284, 546/330, 514/336, 514/357
• US Class Current: 514/336
• CPC Class Codes: C07C 257/18 having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 335/32 having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
• CPC Class Codes: C07D 213/78 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 241/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

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.

Claims

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 --R¹ or ##STR98## wherein R¹ is ##STR99## wherein R⁴ 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,

R² is a hydrogen atom and a is an integer of 1-2, ##STR100## wherein R⁵ 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 R⁵ '"'"'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 R⁴, the alkyl group is methyl and the alkoxy group is methoxy;

in R⁵, 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.

5. A pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1, which is selected from the group consisting of the following compounds or an acid adduct salt thereof:

N-cyano-N'"'"'-phenyl-2-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-methoxyphenyl)-2-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-methylbenzyl-2-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-chlorobenzyl)-2-pyridinecarboximidamide;

N-cyano-N'"'"'-[4-(trifluoromethyl)benzyl)-2-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(4-methylphenyl)ethyl]-2-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(4-chlorophenyl)ethyl]-2-pyridinecarboximidamide;

N-cyano-N'"'"'-(2-thienylmethyl)-2-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-methylphenyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-benzyl -3-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-methylbenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-methoxybenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-dimethylaminobenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[4-(trifluoromethyl)benzyl[-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-chlorobenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-nitrobenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(3,4-dichlorobenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[3,5-bis(trifluoromethyl)benzyl]-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(3-benzyloxybenzyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(2-phenylethyl)-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(2-methoxyphenyl)ethyl]-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(4-chlorophenyl)ethyl]-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(4-benzylaminophenyl)ethyl]-3-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide;

N-cyano-N'"'"'-phenyl-4-pyridinecarboximidamide;

N-cyano-N'"'"'-(3,4-dichlorobenzyl)-4-pyridinecarboximidamide;

N-cyano-N'"'"'-(4-methylthiobenzyl)-4-pyridinecarboximidamide;

N-cyano-N'"'"'-(3-benzyloxybenzyl)-4-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(4-chlorophenyl)ethyl]-4-pyridinecarboximidamide;

N-cyano-N'"'"'-[2-(2-methoxyphenyl)ethyl]-4-pyridinecarboximidamide;

N-cyano-N'"'"'-(2-phenylthioethyl)-4-pyridinecarboximidamide; and

N-cyano-N'"'"'-(2-phenylethyl)-3-(6-chloropyridine)carboximidamide.

6. A pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1, which is selected from the group consisting of the following compounds or an acid adduct salt thereof:

N-cyano-N'"'"'-benzyl-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(2-phenylethyl)-3-pyridinecarboximidamide; and

N-cyano-N'"'"'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.

7. A hypotensor comprising as an effective ingredient a pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1 and a carrier or diluent, wherein the pyridinecarboximidamide derivative is selected from the group consisting of the following compounds:

N-cyano-N'"'"'-benzyl-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(2-phenylethyl)-3-pyridinecarboximidamide; and

N-cyano-N'"'"'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.

8. A hypotensor comprising as an effective ingredient a pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1 and a carrier or diluent, wherein the pyridinecarboximidamide derivative is the following compound or an acid adduct salt thereof:

N-cyano-N'"'"'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.

9. A method for decrease in blood pressure, characterized in that the effective amount of a pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1 and a carrier or diluent, wherein the pyridinecarboximidamide derivative is selected from the group consisting of the following compound are administered to a patient who needs decrease in blood pressure or an acid adduct salt thereof:

N-cyano-N'"'"'-benzyl-3-pyridinecarboximidamide;

N-cyano-N'"'"'-(2-phenylethyl)-3-pyridinecarboximidamide; and

N-cyano-N'"'"'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.

10. A method for decrease in blood pressure, characterized in that the effective amount of a pyridinecarboximidamide derivative or an acid adduct salt thereof according to claim 1 and a carrier or diluent wherein the pyridinecarboximidamide derivative is the following compound or an acid adduct salt thereof are administered to a patient who needs decrease in blood pressure:

N-cyano-N'"'"'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.