Cyclic guanidine derivatives, anti-ulceratives and methods of manufacturing the same

Abstract

Derivatives of cyclic guanidine are disclosed, which are represented by the following formula:A--S--Rwherein A is ##STR1## R.sub.1 represent a lower alkyl or substituted phenyl or unsubstituted phenyl group; R.sub.2 is a lower alkyl; R.sub.3 is H or a lower alkyl; R is lower alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, dialkylaminoalkyl, cyanoalkyl, alkoxycarbonylalkyl, carboxylalkenyl, alkoxycarbonyl, alkoxyalkylcarbonyl, dialkylaminocarbonyl, dialkylaminothiocarbonyl, phenoxyalkylcarbonyl, piperidinoalkyl, pyridine carbonyl, substituted or unsubstituted benzoyl, or substituted or unsubstituted benzyl group.The compounds of the present invention are useful as anti-ulcerative agents.

Description

Background of the Invention

This invention relates to new cyclic guanidine derivatives and their acid addition salts, a method of their synthesis and their use as potent anti-ulceratives.

There have heretofore been conventional anti-gastric ulcerative materials which may inhibit the secretion of gastric juice principally by their anti-cholinergic or anti-histaminic activities. Under the prese circumstances, it is desirable to have material which are effective to inhibit the secretion of gastric juice by preventing (H.sup.+, K.sup.+) ATPase in the process of formation of HCl, where Cl.sup.- acts on H.sup.+ secreted by acid (H.sup.+, K.sup.+) ATPase in the gastric membrane.

SUMMARY OF THE INVENTION

The principal object of the present invention is the provision of compounds having (H.sup.+, K.sup.+) ATPase inhibitory activities.

Another object of the present invention is the provision of pharmaceutical compositions useful as anti-peptic ulcerative agents.

Still other objects of the present invention are the provision of cyclic guanidine derivatives and a method for the manufacture thereof.

These and other objects of the invention will become apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to new cyclic guanidine derivatives and their acid-addition salts, and a method of their synthesis and use as potent anti-ulcerative agents.

The compounds of this invention are represented by the general formula (I) :

A--S--R (I) wherein A is pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydro-cycloheptimidazole-13-yl (formula Ia) ; ##STR2## 2-Substituted-cyclohept[d]imidazo[1,2-a]imidazole-3-yl (general formula Ib) ; (R.sub.1 represents a lower alkylor substituted phenyl or unsubstituted phenyl group and R3 is H or a lower alkyl group.) 2-Substituted-9-alkyl-9H-imidazo[1,2-a]benzimidazole-3-yl (general formula Ic) ; ##STR3## (R.sub.1 is same as mentioned above. R.sub.2 is a lower alkyl group.) Or 6-Substituted-1-alkyl-1H-imidazo[1,2-a]imidazole-5-yl (general formula Id) ; ##STR4## (R.sub.1 and R.sub.2 are same as mentioned above.); R is a lower alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, dialkylaminoalkyl, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkenyl, alkoxycarbonyl, alkoxyalkylcarbonyl, dialkylaminocarbonyl, dialkylaminothiocarbonyl, phenoxyalkylcarbonyl, piperidinoalkyl, pyridine carbonyl, substituted or unsubstituted benzoyl or substituted or unsubstituted benzyl group.

In this invention, alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl and alkoxy mean corresponding group of C.sub.1 .about.C.sub.5, respectively. For example, lower alkyl is mentioned such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl etc. And other groups are same as defined in lower alkyl groups.

Consequently, dialkylaminoalkyl group means dimethylaminoethyl, diethylaminoethyl etc. and a substituted phenyl group, for example, means lower-alkylphenyl, alkoxyphenyl or halogenophenyl group.

The compound of general formula (I) can be obtained by reaction of the compound shown by the general formula (II) with a compound of the general formula (III).

[A--S--].sub.2 (II) wherein A is the same as mentioned above. X--R (III) wherein X is a halogen atom and R is the same as mentioned above.

The compounds shown by the general formula (II) are new compounds and can be prepared by reaction of the compounds of general formula (IV) with sulfur monohalide of general formula (V) according to the method of disulfide compound preparation [R. J. Laufer, U.S. pat. no. 3,479,407 (Chem. Abst. 72, 31445g )]

[A--H (IV) wherein A is same as mentioned above. X--S--S--X (V) wherein X is halogen atom.

Among the compounds shown in general formula (IV), in case A is shown in formula (Ia), the compound of the general formula (IV) is corresponding to pyrido[1', 2': 3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydrocycloheptimidazole (IVa), which is a new compound and obtained as follows.

2-hydroxy cycloheptimidazole (VI) was hydrogenated to a compound (VII) and a compound (VII) was chlorinated to a compound (VIII). By reacting the compound (VIII) with 2-picolyl chloride hydrochlolide, a compound (IX) was obtained. The compound (IX) was cyclized in ethanol-HCl, and obtained was the objective compound (IVa). ##STR5##

The compounds shown by the formula (IVa) and the general formula (II) for starting material are new compounds and some of them are exemplified as follows.

(1) Pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydro

cycloheptimidazole.

(2) Bis 13,13'-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydro

cycloheptimidazole disulfide.

(3) Bis 3,3'-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole disulfide. (4) Bis 3,3'-2-(4-methoxyphenyl)-cyclohept[d]imidazo[1,2-a]imidazol disulfide. (5) Bis 3,3'-2-(4-fluorophenyl)-cyclohept[d]imidazo[1,2-a]imidazol disulfide. (6) Bis 3,3'-2-(4-chlorophenyl)-cyclohept[d]imidazo[1,2-a]imidazol disulfide. (7) Bis 3,3'-2-phenyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazol disulfide (8) Bis 3,3'-2-(4-fluorophenyl)-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazol disulfide. (9) Bis 3,3'-2-methyl1-cyclohept[d]imidazo[1,2-a]imidazole disulfide. (10) Bis 3,3'-2-methyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazol disulfide (11) Bis 3,3'-2,9-dimethyl-9H-imidazo[1,2-a]benzimidazole disulfide. (12) Bis 3,3'-2-phenyl-9-methyl-9H-imidazo[1,2-a]benzimidazole disulfide. (13) Bis 5,5'-1,6-dimethyl-1H-imidazo[1,2-a]imidazole disulfide. (14) Bis 5,5'-1-methyl-6-phenyl-1H-imidazo[1,2-a]imidazole disulfide.

The above-mentioned compounds numbered from (1), (2), to (14) will be referred to hereinafter, as compound (1), compound (2), compound (14) respectively.

In the general formula (IV), in case A is shown in the formula (Ib) as 2-substituted-cyclohept[d]imidazo[1,2-a]imidmazole, this compound can be obtained according to the method of N. Abe et al. [Bull.Chem.Soc.Japan, 56, 3703-14, (1983)].

In this method, a compound which has a substituted phenyl group as R.sub.1 in the general formula(IV), from which compound (4), (5) or (6) is derived, is obtained by using a .alpha.-bromoacetophenone derivative having said substituted phenyl group.

A 2-methyl substituted compound of the general formula(IV)--a starting material for compound (9)--is prepared by using a chloroacetone instead of said .alpha.-bromoacetophenone.

A starting material for compound (7),(8) or (10) is obtained by using a substituted 2-amino-cycloheptimidazol.

In the general formula (VI): A-H, in case A is shown in the formula (Ic) as 2-substituted-9-alkyl-9H-imidazo[1,2-a]benzimidazole, this compound can be prepared according to the procedure of A. M. Simonov et al. [Khim. Geterotsikl. Soedin. 1970, 838-41 ( Chem. Abst. 73, 109739f )]

Furthermore in general formula (IV), in case A is shown in formula (Ia) as 6-substituted-1-alkyl-1H-imidazo[1,2-a]imidazole, this compound is obtained by the method of L. F. Miller et al.[J. Med. Chem. 15, 415, (1972)]

The reaction of compounds of general formula (II) with the compound of general formula (111) can be carried out in the presence of hydrogenating agents. As the hydrogenating agents used in this reactions, NaBH is preferable but other hydride compounds can be applied. As the solvent used in this reactions, alcohols and tetrahydrofuran are mentioned. Furthermore inert solvents in this reaction can be available. The reaction proceeds at ambient or elevated temperature.

The reaction products are refined in the usual manner such as recrystalization or column chromatography.

The compounds related to the general formula (I) are exemplified as follows.

(15) 13-Cyanomethylthio-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11pentahydro-cycloheptimidazole. (16) 13-(2-Propenyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11pentahydro-cycloheptimidazole. (17)13-((E,Z)-2-Butenyl)thio-pyrido[1',2':3,4]imidazo[1,2-a](7,8,9,10,11-pentahydro-cycloheptimidazole. (18) 13-(2-Propenyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11pentahydro-cycloheptimidazole. (19) 13-(2-Butynyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11pentahydro-cycloheptimidazole. (20) 13-(Acetyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydro-cycloheptimidazole fumarate. (21) 13-(Propionyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11pentahydro-cycloheptimidazole fumarate. (22) 13-(2-Dimetylaminoethyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]7,8,9,10,11-pentahydro-cycloheptimidazole. (23) 13-[2-(1-Piperidino)ethyl]thio-pyrido[1',2':3,4]imidazo[1,2-a]7,8,9,10,11-pentahydro-cycloheptimidazole. (24) 13-(Methoxycarbonylmethyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]7,8,9,10,11-pentahydro-cycloheptimidazole. (25) 13-(Dimethylaminocarbonyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]7,8,9,10,11-pentahydro-cycloheptimidazole. (26) 13-(Dimethylaminothiocarbonyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]7,8,9,10,11-pentahydro-cycloheptimidazole. (27) 13-(2-(N-Propionylamino)benzyl)thio-pyrido[1',2':3,4]imidazo[1,2-a]7,8,9,10,11-pentahydro-cycloheptimidazole. (28) 3-(Methyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (29) 3-(Propyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (30) 3-(2-Propenyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (31) 3-((E,Z)-2-Butenyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (32) 3-(2-Propynyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (33) 3-(2-Butynyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (34) 3-(Acetyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (35) 3-(Propionyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (36) 3-(Pivaloyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (37) 3-(Acryloyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (38) 3-(Crotonoyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (39) 3-(2-Dimethylaminoethyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (40) 3-(2-(1-Piperidino)ethyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (41) 3-Cyanomethyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (42) 3-(Methoxycarbonylmethyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (43) 3-(Methoxyacetyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (44) 3-(3-Methoxypropionyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (45) 3-(Dimethylaminocarbonyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (46) 3-(Dimethylaminothiocarbonyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (47) 3-(Ethoxycarbonyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (48) 3-(Picolinoyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (49) 3-(Benzoyl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (50) 3-(2-(N-Propionylamino)benzyl)thio-2-phenyl-cyclohept[d]imidazo [1,2-a]imidazole. (51) 3-(butyryl)thio-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole. (52) 3-(propionyl)thio-2-phenyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazole. (53) 3-(valeryl)thio-2-phenyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazole. (54) 3-(propionyl)thio-2-(4-methoxyphenyl)-cyclohept[d]imidazo[1,2-a]imidazole. (55) 3-(acetyl)thio-(4-fluorophenyl)-cyclohept[d]imidazo[1,2-a]imidazole. (56) 3-(propionyl)thio-2-(4-fluorophenyl)-cyclohept[d]imidazo[1,2-a]imidazole. (57) 3-(acetyl)thio-2-(4-chlorophenyl)-cyclohept[d]imidazo[1,2-a]imidazole. (58) 3-(propionyl)thio-2-(4-chlorophenyl)-cyclohept[d]imidazo[1,2-a]imidazole. (59) 3-(propionyl)thio-2-(4-fluorophenyl)-7-isopropyl-cyclohept[d]imidazo [1,2-a]imidazole. (60) 3-((E)-2-Carboxy-2-ethenyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (61) 3-(2-Propenyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (62) 3-((E,Z)-2-Butenyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (63) 3-(Propinyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (64) 3-(Butynyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (65) 3-(Acetyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (66) 3-(Propionyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (67) 3-(Butyryl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (68) 3-(Pivaloyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (69) 3-(Crotonoyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (70) 3-(Dimethylaminoethyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (71) 3-(2-(1-Piperidino)ethyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (72) 3-(Methoxyacetyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (73) 3-(Dimethylaminocarbonyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (74) 3-(Dimethylaminothiocarbonyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (75) 3-(3-MethoxyPropionyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (76) 3-(Picolinoyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (77) 3-(Benzoyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (78) 3-(2-(N-Propionylamino)benzyl)thio-2-methyl-cyclohept[d]imidazo [1,2-a]imidazole. (79) 3-(Cyanomethyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (80) 3-(Methoxycarbonylmethyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (81) 3-(isobutyryl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (82) 3-(valeryl)thio-2-methyl-cyclohept [d]imidazo[1,2-a]imidazole. (83) 3-(4-methoxybenzoyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (84) 3-(4-fluorobenzoyl)thio-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole. (85) 3-(4-chlorobenzoyl)thio-2-methyl-7-isopropyl-cyclohept[d]imidazo [1,2-a]imidazole. (86) 3-(benzoyl)thio-2-methyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazole. (87) 3-(Propionyl)thio-2-phenyl-9-methyl-9H-imidazo[1,2-a]benzimidazole. (88) 3-(Propionyl)thio-2,9-dimethyl-9H-imidazo[1,2-a]benzimidazole. (89) 3-(Methoxyacetyl)thio-2-phenyl-9-methyl-9H-imidazo[1,2-a]benzimidazole. (90) 5-(Propionyl)thio-6-phenyl-1-methyl-1H-imidazo[1,2-a]imidazole. (91) 5-(Propionyl)thio-1,6-dimethyl-1H-imidazo[1,2-a]imidazole. (92) 5-(Phenoxyacetyl)thio-6-phenyl-1-methyl-1H-imidazo[1,2-a]imidazole.

The above-mentioned compounds numbered from 15 to 92 will be referred to hereinafter, as compound 15 compound 92 respectively.

The compounds of general formula (I) of this invention have excellent (H.sup.+, K.sup.+)ATPase inhibition effects as shown later and the compounds of general formula (I) can be applied as anti-ulceratives in the form of their free bases or their pharmaceutically acceptable acid-addition salts, for instance, mineral acids such as hydrochloric acid, sulfuric acid or organic acid such as succinic acids or fumaric acid.

Concerning dosage forms, the compounds of the present invention can be administered perorally or parenterally. Doses to be administered to particular patients are various, depending on the patient's condition, patient's response or age. Usually dosage of the compound is from 10 mg to 500 mg for an adult a day.

The following examples illustrate a few antiulceractive dosage unit compositions comprising the compound of the present invention.

______________________________________(Dosage example 1) Granules______________________________________Compound 18 50 mgLactose 40 mgCornstarch 57 mgMethyl cellulose 3 mgTotal 150 mg______________________________________ The mixture of these compositions is granulated in a conventional manner. ______________________________________(Dosage example 2) Tablet______________________________________Compound 48 30 mgLactose 30 mgCornstarch 45 mgMagnesium stearate 2 mgTotal 110 mg______________________________________ The mixture of these compositions is compressed into 110 mg tablet in a conventional manner.

The following examples show pharmacological activity of the compounds of this invention and their preparation.

PHARMACOLOGICAL DATA 1

Inhibitory activities of gastric-acid secretion in the acute fistula rat.

Determination of gastric-acid secretion is performed by the method of Y. Goto et al.(Expenentia 32, 946, (1976)). Male Wistar rats are anesthetized with urethane (1.2 g/kg, i.p.) 2 hours after the oral administration of compounds. A dual polyethylene cannula is introduced into the gastric lumen after ligation of the pylorus and the esophagus. The stomach is rinsed with 5 ml of saline through the gastric cannula at 15 min interval. The acid output during 15 minutes period is titrated with 0.01N NaOH. Histamine.2HCl (10 mg/kg, s.c.) is administered as a secretory agent 4 hours after the administration of compounds.

The inhibitory percent of compounds on histamine-stimulated acid secretion is calculated and the results are shown in table I.

TABLE 1______________________________________Compd.NO. Dose(mg/Kg) Total acid inhibition______________________________________21 50 64.934 50 76.635 50 54.037 50 51.538 50 63.443 50 53.844 50 80.753 50 73.765 50 68.866 50 63.768 50 73.969 50 83.576 50 83.777 50 82.581 50 79.882 50 81.287 50 53.892 50 65.6______________________________________

PHARMACOLOGICAL DATA 2

Inhibition of (H.sup.+, K.sup.+)ATPase activities. Inhibition of (H.sup.+, K.sup.+)ATPase activities is determined by the method of F. Fellenius et al., [Nature 290, 159-61, (1981)]. (H.sup.+, K.sup.30 )ATPase is prepared from the pig gastric mucosa and the test compound is incubated with 2 mM of ATPase, 40 mM of tris-buffer (pH 7.4), 2 mM of MgCl.sub.2 and 10 mM of KCl at 37.degree. C. Inorganic phosphate occurring by stimulation of ATPase is determined. The results are shown in Table 2.

Table 2______________________________________ (H.sup.+,K.sup.+)ATPaseCompd.No. IC.sub.50 (M)______________________________________16 16.518 3.0619 47.321 18.123 91.334 2.4735 10.537 2.2038 13.343 2.2344 8.7548 2.7253 1.9555 1.4057 0.7966 17.569 22.772 5.975 55.181 2.7987 25.892 16.0______________________________________ IC.sub.50 :Concentration of 50% inhibition

EXAMPLE 1

Pyridio[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydro-cyclohept imidazole (Compd. 1)

(1) 1,4,5,6,7,8-hexahydro-2-hydroxy-cycloheptimidazole ##STR6##

A solution of 2-Hydroxy-cycloheptimidazole (16.0 g) in methanol was stirred vigorously with platinum oxide (0.2 g) in the hydrogen stream. An off-white suspended solution obtained after 16 hrs, was refluxed and filtered. The insoluble material was extracted again with hot methanol (200 ml) and filtered. The combined filtrate was concentrated in reduced pressure. Obtained yellow powder was washed with ethanol (50 ml) and filtered. 14.6 g of the desired compound was obtained. m.p. 272 .degree. C./dec.

(2) 2-Chloro-l,4,5,6,7,8-hexahydro-cycloheptimidazole. ##STR7##

The compound (3.8 g) obtained from above mentioned Procedure (1), was reacted with phosphorus oxychloride (49.7 g) and dimethylaniline (4.03 g) at 80 C overnight. The reacted solution was concentrated by reduced pressure and the residue was poured on the ice water. After neutralized with NaHCO.sub.3, the solution was extracted with chloroform. The solvent was evaporated, then the residue was purified with silica gel chromatography [eluent; AcOEt (ethyl acetate) ] 1.15 g of the desired compound was obtained as white needle.

m.p. 214.0-215.3 .degree. C.

(3) 1-Picolyl-2-chloro-4,5,6,7,8-pentahydro-cycloheptimidazole ##STR8##

The compound (3.5 g) obtained from above mentioned procedure (2), was dissolved in DMF (30 ml), NaH (55 %, 2.5 g) was added to this solution and stirred for 10 min. at room temperature. 2-Picolylchloride hydrochloride (3.4 g) was added to the above solution and reacted for 1.5 hrs at room temperature. The reaction mixture was poured onto the saturated NaCI solution (150 ml) and extracted with AcOEt (200 ml). After it was washed with water, dried (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The residue was purified with silica gel chromatography [eluent; AcOEt:Hexane(1:1) ] and 4.7 g of colorless oil was obtained.

M.S.(m/e): 261(M.sup.+), 226(B.P.), 208, 169, 143, 118, 93, 78, 65, 51.

IR(cm.sup.-1): 2914, 2842, 1590, 1467, 1434, 1395, 1347, 750, 681.

(4) Pyrido[1',2':3,4]imidazo[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydrocycloheptimidazole ##STR9##

A mixture of the compound (8.6 g) obtained from above me*cIoned procedure (3) and a solution of 12 % HCl-EtOH (60 ml) in sealed tube was reacted for 0.5 hr at room temperature then 17 hrs. at 80 .degree. C. After cooling, the reaction mixture was concentrated at reduced pressure. Water (100 ml) was added to the residue and made alkaline with Na.sub.2 CO.sub.3, then extracted with ether (200 ml). After removed the solvent, it was purified with silica gel chromatography (eluent; AcOEt). 6.7 g of the desired compound (greenish yellow powder) was obtained.

m.p. 113.5-114.degree. C.

M.S.(m/e): 225(M.sup.+, B.P.), 196, 171, 132, 105, 91, 78, 65.

IR(KBr, cm.sup.-1): 3094, 2904, 2836, 1629, 1596, 1443, 1314, 726.

EXAMPLE 2

Bis 13,13'-pyrido[1',2':3,4]imidazo[1,2-a]-7,8,9,10,11-pentahydrocycloheptimidazole disulfide (Compd. 2) ##STR10##

Sulfur monochloride (0.077 g) was dropwise added to the dissolved compd. 1 (0.32 g) in THF (20 ml) under water cooling. Then, the mixture was stirred for 2 hrs. at room temperature and allowed to stand overnight. The obtained precipitates were purified with silica gel column chromatography by eluted CHCl.sub.3 : MeOH (20:1). 0.268 g of the desired compound was obtained (74 %).

m.p. 174-176 .degree. C./dec.

M.S.(m/e): 256(M.sup.+ /2), 223, 122(B.P.), 105, 91, 78.

IR(cm.sup.-1): 2914, 1575, 1212, 750, 666.

The following compounds were obtained as same manner as Example 2.

EXAMPLE 3

3,3'-2-phenyl-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR11##

EXAMPLE 4

Bis 3,3'-2-(4-methoxyphenyl)-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR12##

EXAMPLE 5

Bis 3,3'-2-(4-fluorophenyl)-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR13##

EXAMPLE 6

Bis 3,3'-2-(4-chlorophenyl)-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR14##

EXAMPLE 7

Bis 3,3'-2-phenyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR15##

EXAMPLE 8

Bis 3,3'-2-(4-fluorophenyl)-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR16##

EXAMPLE 9

Bis 3,3'-2-methyl-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR17##

EXAMPLE 7

Bis 3,3'-2-methyl-7-isopropyl-cyclohept[d]imidazo[1,2-a]imidazole disulfide ##STR18##

EXAMPLE 11

Bis 3,3'-2,9-dimethyl-9H-imidazo[1,2-a]benzimidazole disulfide ##STR19##

EXAMPLE 12

Bis 3,3'-2-phenyl-9-methyl-9H-imidazo[1,2-a]benzimidazole disulfide ##STR20##

EXAMPLE 13

Bis 5,5'-1,6-dimethyl-1H-imidazo[1,2-a]imidazole disulfide ##STR21##

EXAMPLE 14

Bis 5,5'-1-methyl-6-phenyl-1H-imidazo[1,2-a]imidazole disulfide ##STR22##

EXAMPLE 15

13-Cyanomethylthio-pyrido[1',2':3,4]imidazo [1,2-a]-7,8,9,10,11- Pentahydro-cycloheptimidazole (Compound. 15)

NaBH.sub.4 was added at room temperature to the dissolved compd. 2 (0.512 g) in THF (9 ml) and MeOH (0.05 ml). After the mixture was stirred for 5 minutes, bromoacetonitrile (0.14 ml) was added and reacted for 30 minutes. To the resultant solution, saturated ammonium chloride solution was added and stirred for 1 hr, then extracted with AcOEt. The AcOEt solution was washed with satd. NaCl, dried (Na.sub.2 SO.sub.4) and evaporated the solvent. The residue was purified with silica gel chromatography eluent; AcOEt:hexane (5:2)]0.33 g (y 55.7 %) of the desired compound was obtained as yellow crystalline.

m.p. 145-147

M.S.(m/e): 296(M.sup.+), 256(B.P.), 223, 196, 122, 78, 51.

IR(KBr, cm.sup.-1): 3256, 2914, 2842, 1590, 1515, 1311, 741.

N.M.R. (8) : 1.6-2.1(6H,m,CH.sub.2 x3), 2.7-3.(2H,m,CH.sub.2), 3.1-3.4(2H,m,CH.sub.2), 3.351(2H,s,SCH.sub.2), 6.3-6.6(1H,t-like), 6.8-7.1(1H,m), 7.4-7.6(1H,d), 7.9-8.2(1H,d-like).

The following compounds in table 3 obtained as the same manner as Example 15.

TABLE 3__________________________________________________________________________Compds. No. m.p. (.degree.C.) M.S. (m/e)__________________________________________________________________________ ##STR23## R16 CH.sub.2CHCH.sub.2 59-60 297 (M.sup.+)17 CH.sub.2 CHCHCH.sub.3 107.5-109 311 (M.sup.+)18 CH.sub.2CCH 85-86.5 295 (M.sup.+)19 CH.sub.2CCCH.sub.3 79-79.5 309 (M.sup.+)20 COCH.sub.3.fumarate 163 (dec.) 299 (M.sup.+ fumaric acid)21 COC.sub.2 H.sub.5.fumarate 164 (dec.) 313 (M.sup.+ fumaric acid)22 CH.sub.2CH.sub.2N(CH.sub.3).sub.2 105-107 328 (M.sup.+)23 ##STR24## 110.5-112 368 (M.sup.+)24 CH.sub.2 COOCH.sub.3 110.5-112.5 329 (M.sup.+)25 CON(CH.sub.3).sub.2 141 (dec.) 328 (M.sup.+)26 CSN(CH.sub.3).sub.2 107-109 344 (M.sup.+)27 ##STR25## 161 (dec.) 418 (M.sup.+) ##STR26## R R.sub.1 R.sub.328 CH.sub.3 C.sub.6 H.sub.5 H 219-220 326 (M.sup.+)29 CH.sub.2CH.sub.2CH.sub.3 C.sub.6 H.sub.5 H 158-159 319 (M.sup.+)30 CH.sub.2CHCH.sub.2 C.sub.6 H.sub.5 H 126-128 317 (M.sup.+)31 CH.sub.2 CHCHCH.sub.3 C.sub.6 H.sub.5 H 150-15 331 (M.sup.+)32 CH.sub.2CCH C.sub.6 H.sub.5 H 139 (dec.) 315 (M.sup.+)33 CH.sub.2CCCH.sub.3 C.sub.6 H.sub.5 H 184-185 329 (M.sup.+)34 COCH.sub.3 C.sub.6 H.sub.5 H 189-191 319 (M.sup.+)35 COC.sub.2 H.sub.5 C.sub.6 H.sub.5 H 179-181 333 (M.sup.+)36 COC(CH.sub.3).sub.3 C.sub.6 H.sub.5 H 209-211 361 (M.sup.+)37 COCHCH.sub.2 C.sub.6 H.sub.5 H 199-201 331 (M.sup.+)38 ##STR27## C.sub.6 H.sub.5 H 181-182 345 (M.sup.+)39 CH.sub.2CH.sub.2N(CH.sub.3).sub.2 C.sub.6 H.sub.5 H 142-143.5 348 (M.sup.+)40 ##STR28## C.sub.6 H.sub.5 H 163-164 388 (M.sup.+)41 CH.sub.2 CN C.sub.6 H.sub.5 H 189-190 316 (M.sup.+)42 CH.sub.2COOCH.sub.3 C.sub.6 H.sub.5 H 155-156 349 (M.sup.+)43 COCH.sub.2OCH.sub.3 C.sub.6 H.sub.5 H 178-179 349 (M.sup.+)44 COCH.sub.2CH.sub.2OCH.sub.3 C.sub.6 H.sub.5 H 165-166 363 (M.sup.+)45 CON(CH.sub.3).sub.2 C.sub.6 H.sub.5 H 174-175.5 348 (M.sup.+)46 CSN(CH.sub.3).sub.2 C.sub.6 H.sub.5 H 202-203 364 (M.sup.+)47 COOC.sub.2 H.sub.5 C.sub.6 H.sub.5 H 183-184.5 349 (M.sup.+)48 ##STR29## C.sub.6 H.sub.5 H 213-214 382 (M.sup.+)49 ##STR30## C.sub.6 H.sub.5 H 193 381 (M.sup.+)50 ##STR31## C.sub.6 H.sub.5 H 151-152 438 (M.sup.+)51 COC.sub.3 H.sub.7 C.sub.6 H.sub.5 H 190-191 347 (M.sup.+)52 ##STR32## C.sub.6 H.sub.5 ##STR33## 144-145 375 (M.sup.+)53 ##STR34## C.sub.6 H.sub.5 ##STR35## 93-94 403 (M.sup.+)54 ##STR36## ##STR37## H 205-207 309 (M.sup.+)55 ##STR38## ##STR39## H 199-200 337 (M.sup.+)56 ##STR40## ##STR41## H 211 351 (M.sup.+)57 ##STR42## ##STR43## H 202-203 353 (M.sup.+)58 ##STR44## ##STR45## H 211 367 (M.sup.+)59 ##STR46## ##STR47## ##STR48## 186-188 393 (M.sup.+)60 ##STR49## CH.sub.3 H 285 (dec.) 285 (M.sup.+)61 CH.sub.2CHCH.sub.2 CH.sub.3 H 136-138 255 (M.sup.+)62 CH.sub.2 CHCHCH.sub.3 CH.sub.3 H 145-146 269 (M.sup.+)63 CH.sub.2CCH CH.sub.3 H 131 (dec.) 253 (M.sup.+)64 CH.sub.2CCCH.sub.3 CH.sub.3 H 149-150 267 (M.sup.+)65 COCH.sub.3 CH.sub.3 H 172 (dec.) 257 (M.sup.+)66 COC.sub.2 H.sub.5 CH.sub.3 H 171 (dec.) 271 (M.sup.+)67 COC.sub.3 H.sub.7 CH.sub.3 H 158-159 285 (M.sup.+)68 COC(CH.sub.3).sub.3 CH.sub.3 H 191-192 299 (M.sup.+)69 ##STR50## CH.sub.3 H 132-133 283 (M.sup.+)70 CH.sub.2CH.sub.2N(CH.sub.3).sub.2 CH.sub.3 H 142-143.5 286 (M.sup.+ )71 ##STR51## CH.sub.3 H 138-139 326 (M.sup.+)72 COCH.sub.2OCH.sub.3 CH.sub.3 H 160-161 287 (M.sup.+)73 CON(CH.sub.3).sub.2 CH.sub.3 H 165 (dec.) 286 (M.sup.+)74 CSN(CH.sub.3).sub.2 CH.sub.3 H 183 (dec.) 302 (M.sup.+)75 COCH.sub.2CH.sub.2OCH.sub.3 CH.sub.3 H 152-153 301 (M.sup.+)76 ##STR52## CH.sub.3 H 201 (dec.) 320 (M.sup.+)77 ##STR53## CH.sub.3 H 190-192 319 (M.sup.+)78 ##STR54## CH.sub.3 H 204-205 376 (M.sup.+)79 CH.sub.2 CN CH.sub.3 H 206-207 254 (M.sup.+)80 CH.sub.2COOCH.sub.3 CH.sub.3 H 137-138 287 (M.sup. +)81 ##STR55## CH.sub.3 H 182-183 285 (M.sup.+)82 ##STR56## CH.sub.3 H 158 299 (M.sup.+)83 ##STR57## CH.sub.3 H 182-183 285 (M.sup.+)84 ##STR58## CH.sub.3 H 192-193 337 (M.sup.+)85 ##STR59## CH.sub.3 H 189-191 353 (M.sup.+)86 ##STR60## CH.sub.3 ##STR61## 141-142 361 (M.sup.+) ##STR62## R R.sub.1 R.sub.287 COC.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.3 223-224 335 (M.sup.+)88 COC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 102-104 273 (M.sup.+)89 COCH.sub.2OCH.sub.3 C.sub.6 H.sub.5 CH.sub.3 119-121 351 (M.sup.+) ##STR63## R R.sub.1 R.sub.290 COC.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.3 118-119 285 (M.sup.+)91 COC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 Oil 223 (M.sup.+)92 ##STR64## C.sub.6 H.sub.5 CH.sub.3 112-113 363 (M.sup.+)__________________________________________________________________________

Claims

1. A compound of the formula:

A--S--R

wherein:

A is ##STR65## wherein: R.sub.1 represents a lower alkyl or phenyl group, said phenyl group being optionally substituted by a lower alkyl, alkoxy or halogeno group;

R.sub.3 is a hydrogen atom or a lower alkyl group, and

R represents a lower alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, dialkylaminoalkyl, cyanoalkyl, alkoxycarbonylalkyl, carboxy alkenyl, alkoxycarbonyl, alkoxyalkylcarbonyl, dialkylamino carbonyl, dialkylaminothiocarbonyl, phenoxyallkylcarbonyl, piperidinoalkyl, pyridine carbonyl, substituted or unsubstituted benzoyl, or substituted or unsubstituted benzyl group and pharmaceutically acceptable acid addition salts thereof.

2. A compound of the formula:

A--S--R

wherein:

A is ##STR66## wherein: R.sub.1 represents a lower alkyl or phenyl group, said phenyl group being optionally substituted by a lower alkyl, alkoxy or halogeno group;

R.sub.2 represents a lower alkyl group, and

R represents a lower alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, dialkylaminoalkyl, cyanoalkyl, alkoxycarbonylalkyl, carboxy alkenyl, alkoxycarbonyl, alkoxyalkylcarbonyl, dialkylamino carbonyl, dialkylaminothiocarbonyl, phenoxyallkylcarbonyl, piperidinoalkyl, pyridine carbonyl, substituted or unsubstituted benzoyl, or substituted or unsubstituted benzyl group and pharmaceutically acceptable acid addition salts thereof.

3. An anti-gastric ulcerative agent comprising a pharmaceutically acceptable carrier and as an active ingredient a compound defined in claim 1.

4. An anti-gastric ulcerative agent comprising a pharmaceutically acceptable carrier and as an active ingredient a compound defined in claim 2.

5. A compound according to claim 2 wherein:

A is ##STR67## wherein R.sub.1 represents a lower alkyl or phenyl group which is optionally substituted by a lower alkyl, alkoxy or halogeno group and R.sub.2 represents a lower alkyl; R is an alkanoyl or alkoxyalkylcarbonyl group, and pharmaceutically acceptable acid addition salts thereof.

6. A compound according to claim 1 wherein:

A is ##STR68## and R represents a methyl, propyl, propenyl, butenyl, propynyl, butynyl, acetyl, propionyl, pivaloyl, acryloyl, crotonoyl, dimetylaminoethyl, piperidino, cyanomethyl, methoxycarbonylmethyl, methoxyacetyl, methoxypropionyl, dimethylaminocarbonyl, dimethylaminothiocarbonyl, ethyoxycalbonyl, picolinoyl, benzoyl, N-propionylamino or butyryl group,

7. A compound according to claim 1 wherein:

A is ##STR69## wherein R.sub.1 represents a phenyl, methoxy phenyl, fluorophenyl or chlorophenyl group; r.sub.3 is H or an isopropyl group and

R represents a propionyl, valeryl, or acetyl group.

8. A compound according to claim 1 wherein:

A is ##STR70## wherein R.sub.1 is a lower alkyl, group and R.sub.3 is H or a lower alkyl group and

R represents a pivaloyl, dimethylaminoethyl, piperidino, methoxyacetyl, dimethylaminocarbonyl, dimethylaminothiocarbonyl, methoxypropionyl, picolinoyl, N-propionylamino, cyanomethyl, methoxycarbonylmethyl, isobutyryl, valeryl, methoxybenzoyl, fluorobenzoyl, chlorobenzoyl or benzoyl group.

9. A compound according to claim 2 wherein

A is ##STR71## R.sub.1 is a lower alkyl or phenyl group; R represents a propionyl or methoxyacetyl group.