Theophylline and theobromine derivatives

Abstract

A novel compound has the following formula: ##STR1## in which R.sub.1 and R.sub.2 are methyl or a group having the formula: ##STR2## provided that one of R.sub.1 and R.sub.2 is methyl and the other is said group, wherein R stands for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR3## in which X.sub.1 and X.sub.2, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a pyridyl group or a group ##STR4## in which Y.sub.1 and Y.sub.2, which may be the same or different stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, X stands for a nitrogen or carbon atom, and n is an integer of from 2 to 10, provided that when R.sub.2 is the group having the formula II, X is not carbon and Z is not pyridyl.

Description

The present invention relates to a theophylline derivative and a theobromine derivative and then processes for manufacturing them. These compounds are novel and have excellent medicinal actions.

More particularly, the theophylline and theobromine derivatives have the following formula. ##STR5## in which R.sub.1 and R.sub.2 are methyl or a group having the formula: ##STR6## provided that one of R.sub.1 and R.sub.2 is methyl and the other is said group, wherein R stands for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR7## in which X.sub.1 and X.sub.2, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a pyridyl group or a group ##STR8## in which Y.sub.1 and Y.sub.2, which may be the same or different stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, X stands for a nitrogen or carbon atom, and n is an integer of from 2 to 10, provided that when R.sub.2 is the group having the formula II, X is not carbon and Z is not pyridyl.

The invention includes an acid addition salt of the derivatives defined as above as well.

Among the compounds according to the invention, the theophylline derivatives have the following formula III. ##STR9## wherein R stand for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR10## in which X.sub.1 and X.sub.2, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a pyridyl group or a group ##STR11## in which Y.sub.1 and Y.sub.2, which may be the same or different stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, X stands for a nitrogen or carbon atom, and n is an integer of from 2 to 10.

Then, the theobromine derivatives have the following formula IV. ##STR12## wherein R stands for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR13## in which X.sub.1 and X.sub.2, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a group ##STR14## in which Y.sub.1 and Y.sub.2, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, and n is an integer of from 2 to 10.

In the definitions of R, X.sub.1, X.sub.2, Y.sub.1 and Y.sub.2 of the general formula [I], by the term "lower alkyl group" are meant linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups. By the term "lower alkoxy group" are meant alkoxy groups corresponding to the above-mentioned lower alkyl groups. As the halogen atom, there can be mentioned chlorine, bromine, iodine and fluorine.

Among theobromine derivatives defined as before, those having the formula IV in which Z is ##STR15## or Z is ##STR16## and n is 2,9 or 10 is preferable.

The compound [I] of the present invention can easily be converted to an acid addition salt by reaction with a pharmacologically acceptable inorganic or organic acid. As the inorganic acid, there can be mentioned hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, and as the organic acid, there can be mentioned maleic acid, fumaric acid, succinic acid, acetic acid, malonic acid, citric acid and benzoic acid.

Typical examples of the theophilline derivatives of the invention will now be mentioned, though the scope of the present invention is not limited by these examples.

7-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)]ethyl}-theophylline 7-{3-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-p-methylbenzhydrylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-p-methoxybenzhydrylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{7-[4-o-trifluoromethylbenzhydrylpiperazinyl-(1)]-n-heptyl}-theophylline 7-{8-[4-benzhydrylpiperazinyl-(1)]-n-octyl}-theophylline 7-{9-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-nonyl}-theophylline 7-{10-[4-p-ethoxybenzhydrylpiperazinyl-(1)]-n-decyl}-theophylline 7-{4-[4-(4',4"-dichlorodiphenylmethyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{2-[(4-phenyl)piperazinyl-(1)]ethyl}-theophylline 7-{3-[(4-phenyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{4-[(4-phenyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{5-[(4-phenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[(4-phenyl)piperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-o-methylphenylpiperazinyl-(1)]-ethyl}-theophylline 7-{3-[4-o-methylphenylpiperazinyl-(1)]-n-propyl}-theophylline 7-{5-[4-o-methylphenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{2-[4-m-methylphenylpiperazinyl-(1)]-ethyl}-theophylline 7-{4-[4-m-methylphenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-m-methylphenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-m-methylphenylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-ethyl}-theophylline 7-{2-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-ethyl}-theophylline 7-{2-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theophylline 7-{3-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-ethyl}-theophylline 7-{3-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-o-methoxyphenylpiperazinyl-(1)]-ethyl}-theophylline 7-{3-[4-o-methoxyphenylpiperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-o-methoxyphenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-o-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-o-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-m-methoxyphenylpiperazinyl-(1)]-ethyl}-theophylline 7-{3-[4-m-methoxyphenylpiperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-m-methoxyphenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-m-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-m-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-p-methoxyphenylpiperazinyl-(1)]-ethyl}-theophylline 7-{4-[4-p-methoxyphenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-p-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-p-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-o-chlorophenylpiperazinyl-(1)]-ethyl}-theophylline 7-{4-[4-o-chlorophenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-o-chlorophenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-o-chlorophenylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-m-chlorophenylpiperazinyl-(1)]-ethyl}-theophylline 7-{4-[4-m-chlorophenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{4-[4-m-chlorophenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{2-[4-o-chlorophenylpiperazinyl-(1)]-ethyl}-theophylline 7-{4-[4-o-chlorophenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-o-chlorophenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-o-chlorophenylpiperazinyl-(1)]-n-hexyl}-theophylline 7-{2-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-ethyl}-theophylline 7-{3-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{4-[4-p-fluorophenylpiperazinyl-(1)]-n-propyl}-theophylline 7-{5-[4-p-fluorophenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{3-[4-m-trifluoromethylphenylpiperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-m-trifluoromethylphenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-m-trifluoromethylphenylpiperazinyl-(1)]-n-pentyl}-theophylline 7-{4-[4-o-trifluoromethylphenylpiperazinyl-(1)]-n-butyl}-theophylline 7-{3-[4-p-trifluoromethylphenylpiperazinyl-(1)]-n-propyl}-theophylline 7-{2-[4-(2-pyridyl)piperazinyl-(1)]-ethyl}-theophylline 7-{3-[4-(2-pyridyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{4-[4-(2-pyridyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{5-[4-(2-pyridyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[4-(2-pyridyl)piperazinyl-(1)]-n-hexyl}-theophylline 7-{7-[(3-methyl-4-m-methylphenyl)piperazinyl-(1)]-n-heptyl}-theophylline 7-{2-[(3-methyl-4-phenyl)piperazinyl-(1)]-ethyl}-theophylline 7-{4-[(3-methyl-4-phenyl)piperazinyl-(1)]-n-butyl}-theophylline 7-{5-[(3-methyl-4-phenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{2-[(3-methyl-4-p-methoxyphenyl)piperazinyl-(1)]-ethyl}-theophylline 7-{5-[(3-methyl-4-p-methoxyphenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{6-[(3-ethyl-4-p-methoxyphenyl)piperazinyl-(1)]-n-hexyl-theophylline 7-{7-[4-m-chlorophenylpiperazinyl-(1)]-n-heptyl}-theophylline 7-{8-[4-(3,4-dimethylphenyl)piperazinyl-(1)]-n-octyl}-theophylline 7-{9-[4-(2,3-diethylphenyl)piperazinyl-(1)]-n-nonyl}-theophylline 7-{10-[4-m-ethoxyphenylpiperazinyl-(1)]-n-decyl}-theophylline 7-{7-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-heptyl}-theophylline 7-{7-[4-(2-methyl-3-ethylphenyl)piperazinyl-(1)]-n-heptyl}-theophylline 7-{3-[4-(2-methyl-3-n-propylphenyl)piperazinyl-(1)]-n-propyl}-theophylline 7-{2-[(4-phenyl)piperidinyl]-ethyl}-theophylline 7-{3-[(4-phenyl)piperidinyl]-n-propyl}-theophylline 7-{4-[(4-phenyl)piperidinyl]-n-butyl}-theophylline 7-{5-[(4-p-chlorophenyl)piperidinyl]-n-pentyl}-theophylline 7-{5-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-pentyl}-theophylline 7-{7-[4-(2-methyl-5-chlorophenyl)piperazinyl-(1)]-n-heptyl}-theophylline 7-{1-[(4-o-methoxyphenyl)piperazinyl-(1)]-n-decyl}-theophylline 7-{10-[4-(2-methyl-5-chlorophenyl)piperazinyl-(1)]-n-decyl}-theophylline 7-{10-[3-methyl-4-m-methylphenylpiperazinyl-(1)]-n-decyl}-theophylline 7-{10-[4-(3,4-dimethylphenyl)piperazinyl-(1)]-n-decyl}-theophylline

Theophylline derivatives provided according to the present invention are novel compounds which have not been introduced in any of literature references. They have very high vasolidating and blood flow-increasing actions and they are effective for improving blood flows in the cerebral and coronary arteries and the capillary vessels. Furthermore, the compounds of the present invention have an action of controlling coagulation of blood platelets. Accordingly, they are suitable as agents for remedy of various diseases caused by troubles in blood flows in capillary vessels, cerebral blood vessel disorders and sequelae thereof, stenocardia and cardiac infraction. Moreover, theophylline derivatives provided according to the present invention are excellent in other various pharmacological actions such as the action to the central nervous system, the anti-histaminic action, the analgesic action, the anti-asthmatic action and the hypotensive action. Accordingly, the compounds of the present invention can effectively be used as psychic energizers, anti-histaminic agents, analgesic agents, anti-asthmatic agents and hypotensive agents.

Compounds [III] of the present invention can be prepared according to various processes. For example, a process represented by the following reaction formula is ordinarily adopted: ##STR17## wherein A stands for a halogen atom or a p-toluene-sulfonyloxy group, and R, X, Z and n are as defined above.

In short, a compound III of the present invention can be obtained by reacting a compound represented by the general formula V with a compound represented by the general formula VI.

This reaction is carried out in the absence of a solvent or in the presence of a solvent not participating in the reaction, which is appropriately selected from lower alcohols such as methanol, ethanol, propanol and isopropanol, benzene type solvents such as benzene, toluene and xylene, and ethers such as ethyl ether and tetrahydrofuran. The reaction can be advanced even at room temperature, but it is preferred that the reaction be carried out at an elevated temperature of up to the boiling point of the solvent. The reaction can be performed more smoothly by adding an acid binder such as triethylamine, an alkali metal bicarbonate, an alkali metal carbonate or pyridine to the reaction mixture.

Typical examples of the theobromine derivatives of the invention will now be mentioned, though the scope of the present invention is not limited by these examples.

1-{7-[4-o-methoxyphenylpiperazinyl-(1)]-n-heptyl}-theobromine 1-{6-[4-o-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{5-[4-m-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-m-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{8-[4-o-methoxyphenylpiperazinyl-(1)]-n-octyl}-theobromine 1-{10-[4-m-methoxyphenylpiperazinyl-(1)]-n-decyl}-theobromine 1-{2-[4-p-methoxyphenylpiperazinyl-(1)]-ethyl}-theobromine 1-{4-[4-o-ethoxyphenylpiperazinyl-(1)]-n-butyl}-theobromine 1-{4-[4-o,m-dimethylphenylpiperazinyl-(1)]-n-butyl}-theobromine 1-{2-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-ethyl}-theobromine 1-{3-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theobromine 1-{2-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-ethyl}-theobromine 1-{3-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theobromine 1-{2-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-ethyl}-theobromine 1-{3-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theobromine 1-{7-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-heptyl}-theobromine 1-{8-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-octyl}-theobromine 1-{9-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-nonyl}-theobromine 1-{10-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-decyl}-theobromine 1-{5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl-theobromine 1-{2-[4-benzhydrylpiperazinyl-(1)]-ethyl}-theobromine 1-{3-[4-benzhydrylpiperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-benzhydrylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)]-ethyl}-theobromine 1-{3-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{10-[4-p-methoxybenzhydrylpiperazinyl-(1)]-n-decyl}-theobromine 1-{4-[4-(4',4"-dichlorophenylmethyl)piperazinyl-(1)]-n-butyl}-theobromine 1-{9-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-nonyl}-theobromine 1-{8-[4-p-methylbenzhydrylpiperazinyl-(1)]-n-octyl}-theobromine 1-{7-[4-p-trifluoromethylbenzhydrylpiperazinyl-(1)]-n-heptyl}-theobromine 1-{6-[4-o-methylphenylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{2-[4-m-methylphenylpiperazinyl-(1)]-ethyl}-theobromine 1-{3-[4-p-methylphenylpiperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-m-methylphenylpiperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-p-methylphenylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{7-[4-p-trifluoromethylpiperazinyl-(1)]-n-heptyl}-theobromine 1-{8-[4-p-ethoxyphenylpiperazinyl-(1)]-n-octyl}-theobromine 1-{2-[4-o-chlorophenylpiperazinyl-(1)]-ethyl}-theobromine 1{3-[4-p-chlorophenylpiperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-o-chlorophenylpiperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-p-chlorophenylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-m-chlorophenylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{7-[4-p-methoxyphenylpiperazinyl-(1)]-n-heptyl}-theobromine 1-{3-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-propyl}-theobromine 1-{4-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-butyl}-theobromine 1-{5-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[4-(2,3-dichlorophenyl)piperazinyl-(1)]-n-hexyl}-theobromine 1-{7-[4-(2,5-dichlorophenyl)piperazinyl-(1)]-n-heptyl}-theobromine 1-{8-[4-(2,6-dichlorophenyl)piperazinyl-(1)]-n-octyl}-theobromine 1-{9-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-nonyl}-theobromine 1-{10-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-decyl}-theobromine 1-{2-[3-methyl-4-phenylpiperazinyl-(1)]-ethyl}-theobromine 1-{3-[3-methyl-4-phenylpiperazinyl-(1)]-n-propyl}-theobromine 1-{4-[3-methyl-4-phenylpiperazinyl-(1)]-n-butyl}-theobromine 1-{5-[3-methyl-4-phenylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{6-[3-methyl-4-phenylpiperazinyl-(1)]-n-hexyl}-theobromine 1-{2-[3-methyl-4-p-methoxyphenylpiperazinyl-(1)]-ethyl}-theobromine 1-{3-[3-methyl-4-p-methoxyphenylpiperazinyl-(1)]-n-propyl}-theobromine 1-{4-[3-methyl-4-o-methoxyphenylpiperazinyl-(1)]-n-butyl}-theobromine 1-{5-[3-methyl-4-m-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theobromine 1-{7-[4-p-fluorophenylpiperazinyl-(1)]-n-heptyl}-theobromine 1-{10-[3-methyl-4-m-methoxyphenylpiperazinyl-(1)]-n-decyl}-theobromine 1-{10-[4-(2,4-dimethylphenylpiperazinyl-(1)]-n-decyl}-theobromine

Theobromine derivatives provided according to the present invention are novel compounds which have not been introduced in any of literature references. They have very high vasolidating and blood flow-increasing actions and they are effective for improving blood flows in the cerebral and coronary arteries and the capillary vessels. Furthermore, the compounds of the present invention have an action of controlling coagulation of blood platelets. Accordingly, they are suitable as agents for remedy of various diseases caused by troubles in blood flows in capillary vessels, cerebral blood vessel disorders and sequelae thereof, stenocardia and cardiac infraction. Moreover, theobromine derivatives provided according to the present invention are excellent in other various pharmacological actions such as the action to the central vervous system, the anti-histaminic action, the amalgesic action, the anti-asthmatic action and the hypotensive action. Accordingly, the compounds of the present invention can effectively be used as psychic energizers, anti-histaminic agents, analgesic agents, anti-asthmatic agents and hypotensive agents.

Compounds [IV] of the present invention can be prepared according to various processes. For example, a process represented by the following reaction formula is ordinarily adopted: ##STR18## wherein X stands for a halogen atom or a p-toluene-sulfonyloxy group, and R, Z and n are as defined above.

In short, a compond IV of the present invention can be obtained by reacting a compound represented by the general formula VII with a compound represented by the general formula VIII.

This reaction is carried out in the absence of a solvent or in the presence of a solvent not participating in the reaction, which is appropriately selected from lower alcohols such as methanol, ethanol, propanol and isopropanol, benzene type solvents such as benzene, toluene and xylene, and ethers such as ethyl ether and tetrahydrofuran. The reaction can be advanced even at room temperature, but it is preferred that the reaction be carried out at an elevated temperature of up to the boiling point of the solvent. The reaction can be performed more smoothly by adding an acid binder such as triethylamine, an alkali metal bicarbonate, an alkali metal carbonate or pyridine to the reaction mixture.

Excellent physiological actions of the theophylline compound according to the invention will now be described with reference to typical compounds.

Blood Flow-Increasing Action

1. Methods

Male and female mongrel dogs having a body weight of 8 to 20 Kg were used as test animals, and the blood flows in the vertebral and femoral arteries were measured. More specifically, probes of an electromagnetic flow meter (Model MF-27 supplied by Nippon Koden) were attached to one side vertebral artery and one side femoral artery of a dog anesthetized by diethyl barbital (240 mg/kg, hypodermic injection) and sodium pentobarbital (10 mg/Kg, intravenous injection), and the blood flows of both the arteries were simultaneously measured. The test compound was administered by artery puncture at a dose of 0.1, 1 or 10 .mu.g per Kg of the body weight.

2. Results:

The obtained results are shown in Table 2.

The intensity of the increase of the blood flow referred to in Table 2 was determined by using papaverine as a reference sample. The intensity of the sample having a minimum effective dose of 0.1 microgram/kg was designated as A and the intensity of the sample having a minimum effective dose of 1.0 microgram/kg was designated as B. Samples having a minimum effective dose of 10 microgram/kg were divided into two groups, one having an intensity higher than that of papaverine, and the intensity of the former group was designated as C and the intensity of the latter group was designated as D. The intensity of the sample having no activity was designated as E. Data of the increase of the blood flow and the duration of action, obtained with respect to 10 cases by using paraverine, are shown in Table 1.

TABLE 1______________________________________Dose Increase in Duration of(microgram/ Blood Flow Actionkg) (mean .+-. SE) (minutes)______________________________________Vertebral 1 0.3 .+-. 0.2 0.08 .+-. 0.05Artery 10 11.3 .+-. 2.7 0.55 .+-. 0.07Femoral 1 0.4 .+-. 0.3 0.09 .+-. 0.06Artery 10 12.6 .+-. 2.7 0.54 .+-. 0.07______________________________________ TABLE 2__________________________________________________________________________ Increase in Duration Dose Class of Blood Flow of Action (microgram/Compound Activity (ml) (minutes) kg)__________________________________________________________________________ ##STR19## vertebral artery femoral A Aery 101 27 7.8 1.7 0.1 0.1 ##STR20## vertebral artery femoral D Cery 2 16 0.7 0.7 10 10 ##STR21## vertebral artery femoral A Aery 4 22 0.6 1.3 0.1 0.1 ##STR22## vertebral artery femoral B Bery 4 30 0.5 1.0 1 1__________________________________________________________________________

The theobromine derivatives were also examined in the same manner as described before in connection with the theophylline derivatives. Results are shown in Tables 3 and 4. From the results shown in Table 4, it will readily be understood that the compounds of the theobromine type have a very excellent blood flow-increasing action.

TABLE 3______________________________________ Increase inDose Blood Flow Duration of(microgram/ (mean .+-. SE) Actionkg) (ml) (minutes)______________________________________Vertebral 1 0.3 .+-. 0.2 0.08 .+-. 0.05Artery 10 11.3 .+-. 2.7 0.55 .+-. 0.07Femoral 1 0.4 .+-. 0.3 0.09 .+-. 0.06Artery 10 12.6 .+-. 2.7 0.54 .+-. 0.07______________________________________ TABLE 4__________________________________________________________________________ Increase of Duration Dose Class of flood flow of Action (microgram/Compound Activity (ml) (minutes) kg)__________________________________________________________________________ ##STR23## vertebral artery femoral C Cery 65.4 94.1 1.52 1.72 10 10 ##STR24## vertebral artery femoral A Aery 18.7 0.69 0.76 0.1 0.1 ##STR25## vertebral artery femoral B Bery 27.8 84.5 0.68 1.89 1 1 ##STR26## vertebral artery femoral A Aery 15.4 107.9 1.39 2.16 0.1 0.1__________________________________________________________________________

The present invention will now be described in detail with reference to the following Examples that by no means limit the scope of the present invention.

EXAMPLE 1

Synthesis of 7-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)-ethyl}-theopylline hydrochloride

In benzene, 6.3 g of 7-(2-bromoethyl)theophylline, 5.7 g of 1-(p-chlorobenzhydryl)piperazine and 4.0 g of triethylamine are stirred under reflux for 18.5 hours. Triethylamine hydrochloride is removed by filtration and the filtrate is extracted with dilute hydrochloric acid. The extract is made alkaline by dilute sodium hydroxide and is then extracted with chloroform. The chloroform layer is washed with water and dried with anhydrous potassium carbonate. The solvent is removed by distillation and the residual crude crystal is converted to a hydrochloride according to customary procedures. The hydrochloride is recrystallized from methyl cellosolve and water to obtain 4.8 g of intended 7-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)]-ethyl}-theophylline hydrochloride (the yield being 42.5%).

Melting point: 250.degree.-252.degree. C.

Elementary Analysis Values as C.sub.26 H.sub.29 O.sub.2 N.sub.6 CH.2HCl: Calculated: C=55.16%, H=5.53%, N=14.85%. Found: C=55.19%, H=5.38%, N=14.87%.

EXAMPLE 2

Synthesis of 7-{4-[4-o-methoxyphenylpiperazinyl-(1)]-n-butyl}-thoephylline

In benzene, 6.9 g of 7-(4-bromo-n-butyl)theophylline, 3.8 g of o-methoxyphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 18 hours. The subsequent treatments are carried out in the same manner as described in Example 1. The obtained crude crystal is recrystallized from ethanol to obtain 3.8 g of intended 7-{4-[4-o-methoxyphenylpiperzinyl-(1)]n-butyl}-theophylline (the yield being 37.6%).

Melting Point: 117.degree.-118.degree. C.

Elementary Analysis Values as C.sub.22 H.sub.30 O.sub.3 N.sub.6 : Calculated: C=61.94%, H=7.10%, N=19.71%. Found: C=62.10%, H=7.21%, N=19.86%.

EXAMPLE 3

Synthesis of 7-{5-[4-o,m-dimethylphenylpiperazinyl-(1)-n-heptyl}-theophylline

In toluene, 9.9 g of 1-(5-bromo-n-heptyl)theophylline, 3.8 g of o,m-dimethylphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 11.5 hours, and the subsequent treatments are carried out in the same manner as described in Example 1. The obtained crude crystal is recrystallized from ethanol to obtain 4.3 g of intended 7-{5-[4-o,m-dimethylphenylpiperazinyl-(1)]-n-heptyl}-theophylline.

Meltint Point: 115.degree.-117.degree. C.

Elementary Analysis Values as C.sub.24 H.sub.34 O.sub.2 N.sub.6 : Calculated: C=65.71%, H=7.38%, N=19.16%. Found: C=65.42%, H=7.92%, N=19.31%.

EXAMPLE 4

Synthesis of 7-{7-[(3-methyl-4-m-methylphenyl)-piperazinyl-(1)]-n-heptyl}-theophylline hydrochloride

In toluene, 7.8 g of 7-(7-bromo-n-heptyl)theophylline, 3.8 g of N-(m-methylphenyl)-2-methyl-N-piperazine and 4.0 g of triethylamine are stirred under reflux for 11 hours. The subsequent treatments are carried out in the same manner as described in Example 1 to obtain 10 g of a crude crystal. The obtained crude crystal is purified by silica gel chromatography and converted to a hydrochloride according to customary procedures to obtain 5.3 g of intended 7-{7-[3-methyl(4-m-methylphenyl)piperazinyl-(1)-n-heptyl}-theophylline hydrochloride.

Melting point: 222.degree.-265.degree. C.

Elementary Analysis Values as C.sub.26 H.sub.39 O.sub.2 N.sub.6 Cl.sub.2.1/2H.sub.2 O Calculated: C=57.02%, H=7.38%, N=15.35%. Found: C=57.00%, H=7.88%, N=15.20%.

EXAMPLES 5 THROUGH 95

Compounds shown in Table 3 are prepared according to the method described in Example 1.

TABLE 5__________________________________________________________________________ ##STR27## Elementary Analysis Values (upper values: Recrystal- Melting calculated values,Example lization Point Molecular lower values: found values)No. n X R Z Solvent (.degree.C.) Formula C (%) H (%) N(%)__________________________________________________________________________5 2 N H ##STR28## ethanol 228-234 (decompo- sition) C.sub.19 H.sub.24 O.sub.2 N.sub.6. HCl 51.70 51.53 9.45 9.16 19.04 18.706 3 N H ##STR29## methanol 143-145 C.sub.20 H.sub.26 O.sub.2 N.sub.6 62.79 62.66 6.87 6.90 21.98 22.017 4 N H ##STR30## ethanol 114-115 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.60 63.61 7.13 7.25 21.20 21.348 5 N H ##STR31## ethanol/ isopropyl ether 112-113 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.35 64.44 7.38 7.49 20.47 20.439 6 N H ##STR32## ethanol/ isopropyl ether 200-203 (decompo- sition) C.sub.23 H.sub.32 O.sub.2 N.sub.6. HCl 55.52 55.26 6.90 6.71 16.90 16.5910 2 N H ##STR33## ethanol 149-150 C.sub.20 H.sub.20 O.sub.2 N.sub.6 62.80 62.52 6.85 6.85 21.98 21.8111 3 N H ##STR34## ethanol 114-116 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.60 63.26 7.13 7.21 21.20 20.7512 5 N H ##STR35## ethanol/ isopropyl ether 113-114 C.sub.22 H.sub.32 O.sub.2 N.sub.6 65.05 65.08 7.61 7.80 19.80 19.7513 2 N H ##STR36## ethanol 121-122 C.sub.20 H.sub.26 O.sub.2 N.sub.6 62.80 62.98 6.85 6.83 21.98 21.9714 4 N H ##STR37## ethanol 237-239 (decom- position) C.sub.22 H.sub.30 O.sub.2 N.sub.6. HCl 54.66 54.57 6.67 6.69 17.39 17.4715 5 N H ##STR38## ethanol 239-241 (decom- position) C.sub.23 H.sub.32 O.sub.2 N.sub.6. HCl 55.30 55.32 6.87 6.90 16.83 16.9816 6 N H ##STR39## ethanol 224-226 (decom- position) C.sub.24 H.sub.34 O.sub.2 N.sub.6. HCl 56.35 56.05 7.09 7.10 16.43 16.4217 2 N H ##STR40## ethanol/ isopropyl ether 103-106 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.61 63.64 7.12 7.03 21.20 21.0518 3 N H ##STR41## ethanol 116-118 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.35 64.31 7.38 7.48 20.47 20.5219 4 N H ##STR42## ethanol 275-276 (decom- position) C.sub.23 H.sub.32 N.sub.6 O.sub.2.H Cl 59.92 59.54 7.21 7.26 18.23 18.0520 5 N H ##STR43## ethanol 136-138 C.sub.24 H.sub.34 O.sub.2 N.sub.6 65.71 66.00 7.83 7.94 19.16 19.1321 6 N H ##STR44## ethanol/ isopropyl ether 167-170 (decom- position) C.sub.25 H.sub.30 O.sub.2 N.sub.6. HCl 57.14 56.75 7.30 7.50 15.99 16.4422 2 N H ##STR45## ethanol 151-152 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.61 63.93 7.12 7.17 21.20 21.2623 3 N H ##STR46## ethanol 153-155 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.36 64.08 7.38 7.46 20.48 20.1024 4 N H ##STR47## ethanol 114-116 C.sub.23 H.sub.32 O.sub.2 N.sub.6 65.05 64.63 7.61 7.53 19.80 19.7925 5 N H ##STR48## ethanol 115-117 C.sub.24 H.sub.34 O.sub.2 N.sub.6 65.71 65.42 7.38 7.97 19.16 19.3126 2 N H ##STR49## ethanol 140-141 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.61 63.46 7.12 6.96 21.20 21.1227 3 N H ##STR50## ethanol 128-129 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.36 63.71 7.37 7.43 20.47 20.3428 4 N H ##STR51## ethanol 251-252 (decom- position) C.sub.23 H.sub.34 O.sub.2 N.sub.6. Cl 59.92 59.99 7.21 7.33 18.23 18.3329 5 N H ##STR52## ethanol/ isopropyl ether 80-83 C.sub.24 H.sub.34 O.sub.2 N.sub.6. 1/2H.sub.2 O 64.39 64.63 7.90 7.92 18.78 19.2630 2 N H ##STR53## methyl cellosolve 272-273 (decom- position) C.sub.20 H.sub.20 O.sub.3 N.sub.6. HCl 50.95 50.76 6.00 5.68 17.83 17.5231 3 N H ##STR54## methanol 240-243 (decom- position) C.sub.21 H.sub.28 O.sub.3 N.sub.6. HCl 51.95 51.76 6.24 6.15 17.31 16.9832 4 N H ##STR55## ethanol 117-118 C.sub.22 H.sub.30 O.sub.3 N.sub.6 61.94 62.10 7.10 7.21 19.71 19.8633 5 N H ##STR56## ethanol 120-121 C.sub.23 H.sub. 32 O.sub.3 N.sub.6.H.sub.2 O 60.23 60.50 7.49 7.20 18.33 18.3734 6 N H ##STR57## ethanol/ isopropyl ether 213-215 (decom- position) C.sub.24 H.sub.34 O.sub.3 N.sub.6. HCl 54.63 54.61 6.89 6.58 15.93 15.4935 2 N H ##STR58## methyl cellosolve 170-171 C.sub.20 H.sub.26 O.sub.3 N.sub.6 60.28 60.58 6.58 6.63 21.09 21.1436 3 N H ##STR59## methyl cellosolve 161-163 C.sub.21 H.sub.28 O.sub.3 N.sub.6 61.13 61.12 6.85 6.85 20.38 20.5837 4 N H ##STR60## methanol 211-212 (decom- position) C.sub.22 H.sub.30 O.sub.3 N.sub.6. Cl 57.07 56.99 6.75 6.64 18.15 18.0538 5 N H ##STR61## ethanol 120-121 C.sub.23 H.sub.32 O.sub.3 N.sub.6. .sub.2 O 60.23 60.50 7.49 7.20 18.33 18.3739 6 N H ##STR62## ethanol 208-210 (decom- position) C.sub.24 H.sub.34 O.sub.3 N.sub.6 HCl 54.64 54.51 6.88 6.91 15.93 15.9940 2 N H ##STR63## ethanol 155-156 C.sub.20 H.sub.26 O.sub.3 N.sub.6 60.28 60.12 6.58 6.59 21.09 21.0541 3 N H ##STR64## methyl cellosolve 165-167 C.sub.21 H.sub.28 O.sub.3 N.sub.6 61.13 61.18 6.85 6.92 20.38 20.2642 4 N H ##STR65## ethanol 115-116 C.sub.22 H.sub.30 O.sub.3 N.sub.6 61.94 61.77 7.10 19.71 19.4643 5 N H ##STR66## ethanol 127-129 C.sub.23 H.sub.32 O.sub.3 N.sub.6 62.69 62.36 7.33 7.33 19.08 19.4144 4 N H ##STR67## ethanol/ methyl cellosolve 161-162 C.sub.19 H.sub.23 O.sub.2 N.sub.6 Cl 56.64 56.79 5.77 5.60 20.86 20.9345 3 N H ##STR68## ethanol 121-122 C.sub.20 H.sub.25 O.sub.2 N.sub.6 Cl 57.61 57.64 6.06 5.96 20.16 20.2346 2 N H ##STR69## acetone 117-119 C.sub.22 H.sub.29 O.sub.2 N.sub.6 Cl 59.37 59.53 6.58 6.80 18.89 19.1147 2 N H ##STR70## methyl cellosolve 134-136 C.sub.19 H.sub.23 O.sub.2 N.sub.6 Cl 56.63 56.86 5.77 5.93 20.86 20.6348 3 N H ##STR71## ethanol 109-111 C.sub.20 H.sub.25 O.sub.2 N.sub.6 Cl 57.61 57.55 6.06 6.35 20.16 19.0049 4 N H ##STR72## isopropanol/ isopropyl ether 96-98 C.sub.21 H.sub.27 O.sub.2 N.sub.6 Cl 58.52 58.82 6.33 6.41 19.51 19.2650 5 N H ##STR73## ethanol/ methanol 151-154 C.sub.22 H.sub.31 O.sub.2 N.sub.6 Cl.sub.3.1/2 H.sub.2 O 50.04 50.02 6.13 6.17 16.23 15.9351 2 N H ##STR74## methyl cellosolve 167-169 C.sub.19 H.sub.23 O.sub.2 N.sub.6 Cl 56.63 56.66 5.77 5.81 20.86 20.9152 3 N H ##STR75## methyl cellosolve 241-244 (decom- position) C.sub.20 H.sub.25 O.sub.2 N.sub.6 Cl. 2HCl 49.03 48.66 5.57 5.20 17.16 16.8453 4 N H ##STR76## ethanol 107-109 C.sub.21 H.sub.27 O.sub.2 N.sub.6 Cl 58.52 58.77 6.33 6.38 19.50 19.4454 5 N H ##STR77## isopropanol/ ether 127-130 C.sub.22 H.sub.29 O.sub.2 N.sub.6 Cl. 2HCl 51.01 50.49 6.05 6.20 16.23 16.0255 6 N H ##STR78## methanol 110-111 C.sub.23 H.sub.31 O.sub.2 N.sub.6 Cl 60.17 60.20 6.82 6.96 18.31 18.6856 2 N H ##STR79## methyl cellosolve 146-147 C.sub.19 H.sub.22 O.sub.2 N.sub.6 Cl.sub.2 52.18 52.23 5.07 4.95 19.22 19.3957 3 N H ##STR80## methyl cellosolve 124-126 C.sub.20 H.sub.24 O.sub.2 N.sub.6 Cl.sub.2 53.21 53.50 5.37 5.32 18.62 18.5258 4 N H ##STR81## methanol 130-132 C.sub.21 H.sub.26 O.sub.2 N.sub.6 Cl.sub.2 54.19 54.44 5.64 5.73 18.06 18.2159 3 N H ##STR82## methanol 128-129 C.sub.20 H.sub.25 O.sub.2 N.sub.6 F 59.97 59.94 6.30 6.31 20.99 21.1260 4 N H ##STR83## methanol 223-226 (decom- position) C.sub.21 H.sub.27 O.sub.2 N.sub.6 F. 2HCl 51.74 51.65 6.00 5.84 17.25 16.9461 5 N H ##STR84## ethanol/ methanol 140-141 C.sub.22 H.sub.29 O.sub.2 N.sub.6 F 61.65 61.32 6.83 6.77 19.61 19.6762 3 N H ##STR85## methanol 115-116 C.sub.21 H.sub.25 O.sub.2 N.sub.6 F.sub.3 55.98 56.46 5.60 5.71 18.66 19.2663 4 N H ##STR86## ethanol/ isopropyl ether 215-218 C.sub.22 H.sub.26 O.sub.2 N.sub.6 F.sub.3. 2HCl 49.16 49.25 5.26 5.42 15.64 16.2164 5 N H ##STR87## ethanol/ isopropyl ether 114-115 C.sub.23 H.sub.29 O.sub.2 N.sub.6 F.sub.3 57.72 57.55 6.12 6.13 17.56 17.7165 2 N H ##STR88## methanol 153-155 C.sub.18 H.sub.23 O.sub.2 N.sub.7 58.51 58.48 6.29 6.38 26.54 26.2266 3 N H ##STR89## ethanol 139-140 C.sub.19 H.sub.25 O.sub.2 N.sub.7 59.50 59.52 6.58 6.65 25.57 25.8067 4 N H ##STR90## ethanol 120-121 C.sub.20 H.sub.27 O.sub.2 N.sub.7 60.42 60.14 6.86 6.90 24.67 24.4068 5 N H ##STR91## ethanol/ isopropyl ether 102-104 C.sub.21 H.sub.29 O.sub.2 N.sub.7 61.28 61.26 7.12 7.11 23.83 23.6669 6 N H ##STR92## ethanol 96-97 C.sub.22 H.sub.31 O.sub.2 N.sub.7 62.08 62.01 7.36 7.46 23.04 23.3570 3 N H ##STR93## methyl cellosolve 252-254 C.sub.27 H.sub.32 O.sub.2 N.sub.6. HCl 59.44 59.28 6.29 6.42 15.41 15.5971 4 N H ##STR94## ethanol/ methanol 238-240 C.sub.23 H.sub.34 O.sub. 2 N.sub.6. 2HCl 60.09 59.14 6.50 6.48 15.02 14.9372 5 N H ##STR95## methyl cellosolve 115-117 (decom- position) C.sub.29 H.sub.36 O.sub.2 N.sub.6 69.56 69.87 7.26 7.39 16.79 16.7073 6 N H ##STR96## ethanol 212-214 C.sub.30 H.sub.38 O.sub.2 N.sub.6. HCl 61.30 61.27 6.87 7.04 14.30 14.5174 2 N H ##STR97## methyl cellosolve 250-252 C.sub.26 H.sub.29 O.sub.2 N.sub.6 Cl. 2HCl 55.16 55.19 5.53 5.38 14.85 14.8775 3 N H ##STR98## methyl cellosolve 222 (decom- position) C.sub.27 H.sub.31 O.sub. 2 N.sub.6 Cl. 2HCl.H.sub.2 O 54.22 53.64 5.91 5.92 14.06 14.0976 4 N H ##STR99## methanol 208-210 C.sub.28 H.sub.33 O.sub.2 N.sub.6 Cl. 2HCl 56.61 55.97 5.95 6.04 14.15 13.9277 5 N H ##STR100## ethanol/ isopropyl ether 117-119 C.sub.29 H.sub.35 O.sub.2 N.sub.6 Cl 65.08 65.23 6.60 6.64 15.70 16.0278 6 N H ##STR101## ethanol 201-203 C.sub.30 H.sub.37 O.sub.2 N.sub.6 Cl. 2HCl.1/2H.sub.2 O 57.09 57.00 6.40 6.54 13.32 13.9079 2 N CH.sub.3 ##STR102## ethanol 128-130 C.sub.20 H.sub.26 O.sub.2 N.sub.6 62.80 62.73 6.85 6.87 21.98 21.9180 4 N CH.sub.3 ##STR103## isopropanol 99-100 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.36 64.51 7.37 7.47 20.47 20.8781 5 N CH.sub.3 ##STR104## acetone/ isopropyl ether 111-113 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.28 63.74 7.09 7.12 21.09 21.3582 2 N CH.sub.3 ##STR105## ethanol 117-118 C.sub.21 H.sub.28 N.sub.6 O.sub.3 61.14 61.00 6.84 6.94 20.38 20.2383 5 N CH.sub.3 ##STR106## isopropanol 85-87 C.sub.24 H.sub.31 O.sub.3 N.sub.6 63.82 63.56 6.93 7.69 18.61 18.6384 2 C H ##STR107## methanol 155-156 C.sub.20 H.sub.25 O.sub.2 N.sub.5 65.36 65.69 6.87 6.80 19.06 19.1785 3 C H ##STR108## methyl cellosolve 157-159 C.sub.21 H.sub.27 O.sub.2 N.sub.5 66.10 66.05 7.15 7.16 18.36 18.5586 4 C H ##STR109## ethanol 117-118 C.sub.22 H.sub.29 O.sub.2 N.sub.5 66.80 67.01 7.40 7.51 17.71 17.7087 7 N CH.sub.3 ##STR110## ethanol/ isopropyl ether 200-204 C.sub.25 H.sub.35 O.sub.2 N.sub.6 Cl. HCl.H.sub.2 O 55.44 55.36 7.09 6.88 15.52 15.9288 7 N H ##STR111## hydrous ethanol 239-241 C.sub.26 H.sub.37 O.sub.2 N.sub.6. HCl.1/2H.sub.2 O 57.02 57.46 7.38 7.45 15.35 15.7789 8 N H ##STR112## hydrous ethanol 181-183 C.sub.27 H.sub.40 N.sub.6 O.sub.2. HCl 58.79 58.71 7.68 7.58 15.24 15.2290 5 N H ##STR113## ethanol/ isopropyl ether 112-114 C.sub.22 H.sub.26 O.sub.2 N.sub.6. Cl 55.11 55.09 5.90 5.93 17.53 17.3191 7 N H ##STR114## hydrous methanol 223-226 (decom- position) C.sub.25 H.sub.35 O.sub.2 N.sub.6 Cl. 2HCl 53.90 53.49 6.17 6.60 15.09 15.5092 10 N H ##STR115## ethanol 207-209 (decom- position) C.sub.28 H.sub.41 O.sub.3 N.sub.6. HCl 57.71 57.76 7.45 7.91 14.43 14.1193 10 N H ##STR116## ethanol 211-213 (decom- position) C.sub.28 H.sub.41 O.sub.2 N.sub.6 Cl. HCl 59.45 59.31 7.50 14.80 14.6994 10 N CH.sub.3 ##STR117## methanol/ isopropyl ether 211-214 (decom- position) C.sub.29 H.sub.46 O.sub.2 N.sub.6. HCl.2H.sub.2 O 56.38 56.12 8.17 7.76 13.60 13.4695 10 N H ##STR118## methanol/ isopropyl ether 187-190 (decom- position) C.sub.29 H.sub.44 O.sub.2 N.sub.6. HCl 59.87 59.42 7.99 7.96 14.45 14.09__________________________________________________________________________

EXAMPLE 96

Synthesis of 1-{4-[4-o,m-dimethylphenylpiperazinyl-(1)-n-butyl}-theobromine

In toluene, 9.5 g of 1-(4-bromo-n-butyl)theobromine, 3.8 g of o,m-dimethylphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 13 hours. Triethylamine hydrochloride is removed by filtration and the filtrate is extracted with dilute hydrochloric acid. The extract is made alkaline by dilute sodium hydroxide and is then extracted with chloroform. The chloroform layer is washed with water and dried with anhydrous potassium carbonate. The solvent is removed by distillation and the residual crude crystal is recrystallized from methyl cellosolve to obtain 3.7 g of intended 1-{4-[4-o,m-dimethylphenylpiperazinyl-(1)]-n-butyl}-theobromine (the yield being 43.64%).

Melting Point: 134.degree.-135.degree. C.

Elementary Analysis Values as C.sub.23 H.sub.32 O.sub.2 N.sub.6 : Calculated: C=65.05%, H=7.61%, N=19.80%. Found: C=65.11%, H=7.72%, N=19.46%.

EXAMPLE 97

Synthesis of 1-{5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine hydrochloride

In toluene, 7.9 g of 1-(5-bromo-n-pentyl)theobromine, 5.0 g of N-benzyhydrylpiperazine and 4 g of triethylamine are stirred under reflux for 30 hours. The subsequent treatments are carried out in the same manner as described in Example 96. The obtained crude crystal is converted to a hydrochloride according to customary procedures to obtain 4.7 g of intended 1-}5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine hydrochloride (the yield being 40.9%).

Melting Point: 262.degree.-264.degree. C. (decomposition).

Elementary Analysis Values as C.sub.29 H.sub.36 O.sub.2 N.sub.6.2HCl: Calculated: C=60.93%, H=6.71%, N=14.71%. Found: C=60.57%, H=7.15%, N=14.65%.

EXAMPLE 98

Synthesis of 1-{7-[4-o-methoxyphenylpiperazinyl-(1)]-n-heptyl}-theobromine

In toluene, 7.5 g of 1-(7-bromo-n-heptyl)theobromine, 3.8 g of N-o-methoxyphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 11.5 hours, and the subsequent treatments are carried out in the same manner as described in Example 96. The obtained crude crystal is purified by silica gel chromatography to obtain 4.6 g of intended 1-7-[4-o-methoxyphenylpiperazinyl(1)-n-heptyl-theobromine (the yield being 49.1%).

Melting Point: 97.degree.-98.degree. C.

Elementary Analysis Values as C.sub.25 H.sub.36 O.sub.3 N.sub.6 : Caculated: C=64.08%, H=7.74%, N=17.94%. Found: C=63.90%, H=7.67%, N=18.01%.

EXAMPLES 99 THROUGH 148

Compounds shown in Table 6 are prepared according to the method described in Example 96.

TABLE 6__________________________________________________________________________ ##STR119## Elementary Analysis ValuesEx- Recrystal- Melting (upper values: calculated values,ample lization Point Molecular lower values: found values)No. n R Z Solvent (.degree.C.) Formula C (%) H (%) N__________________________________________________________________________ (%) 99 6 H ##STR120## ethanol 197-198 (decom- position) C.sub.24 H.sub.34 N.sub.6 O.sub.2.2HCl. 2H.sub.2 O 52.65 52.64 7.01 7.10 15.35 15.28100 2 H ##STR121## ethanol 251 (decom- position) C.sub.20 H.sub.26 O.sub.2 N.sub.6.2HCl 52.75 52.41 6.21 6.11 18.46 18.31101 5 H ##STR122## ethanol 133-135 C.sub.23 H.sub.32 O.sub.2 N.sub.6 65.05 65.03 7.61 7.62 19.80 19.82102 6 H ##STR123## ethanol 206-208 (decom- position) C.sub.24 H.sub.34 O.sub.2 N.sub.6.2HCl. 2H.sub.2 O 52.65 53.10 7.01 6.91 15.35 15.44103 2 H ##STR124## ethanol 151-153 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.60 63.60 7.13 7.05 21.20 21.28104 3 H ##STR125## ethanol 154-156 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.36 64.13 7.37 7.49 20.47 20.32105 4 H ##STR126## ethanol 124-126 C.sub.23 H.sub.32 O.sub.2 N.sub.6 65.05 65.03 7.61 7.61 19.80 19.82106 5 H ##STR127## ethanol 121-123 C.sub.24 H.sub.34 O.sub.2 N.sub.6 65.71 65.68 7.38 7.73 19.16 19.36107 2 H ##STR128## ethanol 161-162 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.60 63.67 7.13 7.07 21.20 21.16108 3 H ##STR129## ethanol 124-126 C.sub.23 H.sub.30 O.sub.2 N.sub.6 64.36 63.65 7.37 7.20 20.47 20.32109 4 H ##STR130## methyl cellosolve 134-135 C.sub.23 H.sub.32 O.sub.2 N.sub.6 65.05 65.11 7.61 7.72 19.80 19.46110 5 H ##STR131## ethanol/ isopropyl ether 118-120 C.sub.24 H.sub.34 O.sub.2 N.sub.6 65.71 65.65 7.38 7.95 19.16 18.94111 6 H ##STR132## isopropanol/ isopropyl ether 91-93 C.sub.25 H.sub.36 O.sub.2 N.sub.6 66.34 65.84 8.02 8.31 18.57 18.50112 2 H ##STR133## ethanol 139-141 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.61 63.73 7.12 7.30 21.20 21.21113 3 H ##STR134## ethanol 137-139 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.36 64.19 7.37 7.44 20.47 20.36114 4 H ##STR135## ethanol 148-150 C.sub.23 H.sub.32 O.sub.2 N.sub.6 65.05 64.44 7.61 7.52 19.80 19.70115 5 H ##STR136## isopro- panol 99-101 C.sub.24 H.sub.34 O.sub.2 N.sub.6 65.71 65.33 7.38 7.79 19.16 19.12116 6 H ##STR137## ethanol/ isopropyl ether 89-90 C.sub.25 H.sub.36 O.sub.2 N.sub.6 66.33 66.26 8.03 8.21 18.57 18.24117 5 H ##STR138## ethanol 165-166 (decom- position) C.sub.23 H.sub.32 O.sub.3 N.sub.6.HCl 57.91 57.81 6.97 7.19 17.62 17.21118 6 H ##STR139## ethanol/ methanol 79-81 C.sub.24 H.sub.34 O.sub.3 N.sub.6 63.40 63.35 7.55 7.70 18.49 18.69119 2 H ##STR140## ethanol 122-124 C.sub.19 H.sub.23 O.sub.2 N.sub.6 56.63 56.67 5.77 5.67 20.86 21.19120 4 H ##STR141## isopropanol/ isopropyl ether 111-113 C.sub.21 H.sub.27 O.sub.2 N.sub.6 Cl.1/22H.sub.2 O 57.33 57.53 6.65 6.29 19.10 19.14121 6 H ##STR142## isopropanol/ methanol 106-107 C.sub.23 H.sub.31 O.sub.2 N.sub.6 60.17 60.21 6.82 6.97 18.31 18.63122 2 CH.sub.3 ##STR143## methyl cellosolve 176-178 C.sub.20 H.sub.26 O.sub.2 N.sub.6 62.79 63.19 6.87 6.89 21.98 22.03123 3 CH.sub.3 ##STR144## ethanol 126-128 C.sub.21 H.sub.28 O.sub.2 N.sub.6 63.61 63.56 7.12 7.28 21.20 21.54124 4 CH.sub.3 ##STR145## ethanol 120-122 C.sub.22 H.sub.30 O.sub.2 N.sub.6 64.35 64.81 7.38 7.47 20.47 20.37125 5 CH.sub.3 ##STR146## ethanol/ isopropyl ether 102-104 C.sub.23 H.sub.32 O.sub.2 N.sub.6 65.07 65.10 7.60 7.77 19.80 19.82126 6 CH.sub.3 ##STR147## ethanol 101-103 C.sub.24 H.sub.34 O.sub.2 N.sub.6 65.71 65.64 7.38 7.95 19.16 19.19127 2 CH.sub.3 ##STR148## isopropanol 118-119 C.sub.21 H.sub.25 O.sub.3 N.sub.6.1/22H .sub.2 O 60.27 60.73 6.28 6.81 20.09 20.15128 3 CH.sub.3 ##STR149## methanol 142-143 C.sub.22 H.sub.30 O.sub.3 N.sub.6 61.95 61.95 7.09 7.13 19.71 19.91129 4 CH.sub.3 ##STR150## ethanol 108-110 C.sub.23 H.sub. 32 O.sub.3 N.sub.6 62.70 62.84 7.32 7.39 19.08 19.24130 3 H ##STR151## methyl cellosolve 162-163 C.sub.20 H.sub.24 O.sub.2 N.sub.6 Cl.sub.2 53.21 53.11 5.37 5.41 18.62 18.62131 4 H ##STR152## methyl cellosolve 140-142 C.sub.21 H.sub.26 O.sub.2 N.sub.6 Cl.sub.2 54.19 54.24 5.64 5.71 18.06 17.91132 5 H ##STR153## methyl cellosolve 132-134 C.sub.22 H.sub.28 O.sub.2 N.sub.6 Cl.sub.2 55.11 55.03 5.90 5.86 17.53 17.65133 6 H ##STR154## ethanol 144-145 C.sub.23 H.sub.30 O.sub.2 N.sub.6 Cl.sub.2 55.57 56.04 6.14 6.32 17.03 17.09134 2 H ##STR155## ethanol 175-176 C.sub.26 H.sub.30 O.sub.2 N 68.10 68.20 6.59 6.57 18.33 18.50135 3 H ##STR156## ethanol 150-151 C.sub.27 H.sub.32 O.sub.2 N.sub.6 68.62 68.66 6.83 6.87 17.79 17.85136 4 H ##STR157## methyl cellosolve 163-165 C.sub.28 H.sub.34 O.sub.2 N.sub.6 69.10 68.96 7.06 7.00 17.27 17.22137 5 H ##STR158## isopropanol 262-264 C.sub.29 H.sub.36 O.sub.2 N.sub.6.2HCl 60.93 60.57 6.71 7.15 14.71 14.65138 2 H ##STR159## methanol 228-230 (decom- position) C.sub.26 H.sub.29 O.sub.2 N.sub.6.2HCl. H.sub.2 O 53.48 54.05 5.70 5.45 14.40 14.35139 3 H ##STR160## methyl cellosolve 194-195 (decom- position) C.sub.27 H.sub.31 O.sub.2 N.sub.6.2HCl. 2H.sub.2 O 52.64 53.21 5.74 5.95 13.64 13.74140 4 H ##STR161## ethanol/ isopropyl ether 142-144 C.sub.28 H.sub.33 O.sub.2 N.sub.6 64.53 64.76 6.40 6.52 16.13 16.16141 5 H ##STR162## methanol/ ethanol 85-87 C.sub.29 H.sub.35 O.sub.2 N.sub.6 Cl.2HCl 57.47 56.96 6.17 6.68 13.87 13.73142 6 H ##STR163## ethanol/ isopropyl ether 85-88 C.sub.30 H.sub.37 O.sub.2 N.sub.6 Cl.2HCl 57.92 57.56 6.33 6.69 13.51 13.14143 7 H ##STR164## acetone/ isopropyl ether 81-83 C.sub.24 H.sub.33 O.sub.2 N.sub.6 63.12 62.69 7.30 7.33 18.41 18.33144 7 H ##STR165## purified by column chro- matography (silica 90-91 C.sub.25 H.sub.36 O.sub.2 N.sub.6 66.34 66.24 8.02 8.03 18.57 18.54145 8 H ##STR166## hydrous ethanol 173-177 C.sub.26 H.sub.38 N.sub.6 O.sub.3.2HCl. H.sub.2 O 54.44 54.19 7.38 7.37 14.65 14.67146 8 H ##STR167## hydrous ethanol 228-230 C.sub.27 H.sub.40 N.sub.6 O.sub.2.HCl 62.95 62.91 8.62 8.04 16.32 16.41147 10 H ##STR168## hydrous ethanol 147-150 C.sub.29 H.sub.44 N.sub.6 O.sub.2.2HCl. H.sub.2 O 58.08 58.28 8.07 8.08 14.02 13.94148 10 CH.sub.3 ##STR169## ethanol 154-157 C.sub.29 H.sub.44 N.sub.6 O.sub.3.2HCl. 1/2H.sub.2 O 57.44 57.32 7.81 7.92 13.86 13.84__________________________________________________________________________

Claims

1. A compound having the formula ##STR170## in which one of R.sub.1 and R.sub.2 is methyl and the other of R.sub.1 and R.sub.2 has the formula ##STR171## wherein R is hydrogen or lower alkyl; Z is pyridyl and or ##STR172## in which Y.sub.1 and Y.sub.2, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is C; and n is an integer of from 2 to 10; with the proviso that when R.sub.1 is methyl, R.sub.2 is not ##STR173## or a pharmaceutically acceptable salt thereof.

2. A compound having the formula ##STR174## wherein R is hydrogen or lower alkyl; Z is selected from the group consisting of (a) ##STR175## in which X.sub.1 and X.sub.2, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen, (b) pyridyl and (c) ##STR176## in which Y.sub.1 and Y.sub.2, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is C; and n is an integer of from 2 to 10; or a pharmaceutically acceptable salt thereof.

3. A compound having the formula ##STR177## in which X.sub.1 and X.sub.2, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; and n is an integer of from 2 to 10; or a pharmaceutically acceptable salt thereof.

4. A compound as claimed in claim 3 in which n is 4, X.sub.1 is m-methoxy and X.sub.2 is hydrogen.

5. A composition as claimed in claim 3 in which n is 4, X.sub.1 is p-chloro and X.sub.2 is hydrogen.

6. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 1, for vasodilating purposes, in combination with a pharmacologically acceptable carrier.

7. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 1, for analgesic purposes, in combination with a pharmacologically acceptable carrier.

8. A method for treating a subject suffering from blood circulatory insufficiency which comprises administering to the subject a pharmaceutical composition as defined in claim 6.

9. A method for treating a subject suffering from a pain which comprises administering to the subject a pharmaceutical composition as defined in claim 7.

10. A compound of the formula ##STR178## wherein R is hydrogen or lower alkyl, and Y.sub.1 and Y.sub.2, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is C; and n is an integer of from 2 to 10; or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 2, for vasodilating purposes, in combination with a pharmacologically acceptable carrier.

12. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 2, for analgesic purposes, in combination with a pharmacologically acceptable carrier.

13. A method for treating a subject suffering from blood circulatory insufficiency which comprises administering to the subject a pharmaceutical composition as defined in claim 11.

14. A method for treating a subject suffering from a pain which comprises administering to the subject a pharmaceutical composition as defined in claim 12.