GB2152052A

GB2152052A - Hexahydroazepino(3,4-d)imidazole derivatives

Info

Publication number: GB2152052A
Application number: GB08503218A
Authority: GB
Inventors: Ugo Scarponi; Luigi Bernardi; Giuliana Arcari; Roberto Ceserani
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1984-02-17
Filing date: 1985-02-08
Publication date: 1985-07-31
Also published as: JPS60184082A; DE3504711A1; GB8503218D0; GB2152052B; GB8404241D0; BE901727A

Abstract

1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivatives of the formula R4=H, C1-C4 acyclic hydrocarbon, C3-C6 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl R1 (on N<1> or N<3>) = H, C1-C4 acyclic hydrocarbon, benzyl, substituted benzyl, R2 and R3 independently = H, C1-C4 acyclic hydrocarbon, phenyl, substituted phenyl, X = O, S, NH, N-CN, N-SO2C6H4CH3, N-COR6, CH-NO2, CH-SO2R5 R5 = C1-C4 acyclic hydrocarbon, phenyl substituted phenyl R6 = C1-C4 acyclic hydrocarbon, C3-C6 cycloalkyl, phenyl, substituted phenyl are anti-ulcer agents. p

Description

SPECIFICATION Hexahydroazepino[3,4-d]imidazole derivatives The invention relates to 1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivatives, to process for their preparation and to pharmaceutical compositions containing them.

The invention provides 1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivatives having the general formula I

wherein R4 represents a hydrogen atom, a saturated or unsaturated acyclic hydrocarbon group having from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, a benzyl or phenyl group, or a mono- or disubstituted benzyl orphenyl group, the substituent(s) being selected from alkoxy groups having from 1 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, chlorine atoms, bromine atoms, nitro groups and a methylenedioxy group, R1, which may be on N' or N3, represents a hydrogen atom, an acyclic hydrocarbon group as defined for R4, a benzyl group or a substituted benzyl group as defined for R4, each of R2 and R3 independently represents a hydrogen atom, an acyclic hydrocarbon group as defined for R4, a phenyl group or a substituted phenyl group as defined for R4, and X represents an oxygen or sulphur atom, an imino, cyano-imino,p-toluenesulphonyl-imino or nitromethylene group or a group of the formula CH-SO2R5 or N -COR6 wherein B5 represents any of the groups which R2 may represent except a hydrogen atom and B6 represents a cycloalkyl group having from 3 to 6 carbon atoms or any of the groups which B5 may represent.

The compounds according to the invention may be prepared starting from a 1 (3),4,5,6,7,8-hexahydro[3,4- d]imidazole derivative having the general formula II

wherein R2 and B3 are as above defined. These compounds II may themselves be prepared by reacting a 4-( s-aminopropyl)-imidazole of the general formula Ill

wherein R2 is as above defined with an aldehyde R3CHO wherein R3 is as above defined. This reaction may be carried out in a solvent, particularly an alcoholic solvent such as methanol, ethanol, n-butanol or 2-methoxyethanol, in the presence of an aqueous alkali solution, suitably under reflux. The compound II need not be isolated before proceeding with the preparation of the compounds I.

The compounds I wherein X represents an oxygen or sulphur atom or an imino group and R1 represents a hydrogen atom are prepared by reacting the compound II with an isocyanate R4-NCO, an isothiocyanate R,;-NCS or a cyanamide R4-NH-CN respectively, R4 being as above defined, in a solvent which may be acetonitrile or dimethylformamide.The compounds I, wherein X represents a cyano-imino,p- toluenesulphonyl-imino or nitromethylene group or a group of the formula CH-SO2R5 or N -COR6 wherein R5 and R6 are as above defined and R1 represents a hydrogen atom, are prepared by reacting the compound II with a compound of the general formula IV

wherein Xis as defined in this sentence and reacting the resultant compound with an amine of the general formula R4NH2 wherein R4 is as above defined. It is not necessary to isolate the product of reaction of compounds Ill and IV.Finally, the compounds I wherein R1 represents any of the groups above defined for it other than a hydrogen atom are prepared from the compounds I wherein R1 represents a hydrogen atom by reaction thereof with a compound of the general formula R1Y or R1-O-S02-O -R1 wherein R1 is as defined in this sentence and Y represents a chlorine or bromine atom in a catalytic two-phase system (see, e.g., J.

Dockx, Synthesis, 1973,441). The compounds I are usually obtained as a mixture of two regioisomers (R1 in position 1 and R1 in position 3), clearly distinguishable both by thin layer chromatography on silica gel plates and by NMR spectrometry, and easily separated on silica gel columns.

The compounds of the invention have proved to be active on the gastroenterical system. They have been found to inhibit both the number of experimental ulcers and the gastric secretion in experimental animals.

They should thus prove useful in therapy, for example in the prevention and treatment of peptic ulcers, e.g.

duodenal gastric and oesophageal ulcers. The activity of these compounds was assessed in rats in anti-ulcer and anti-secretory tests.

The anti- ulcerogenic activity of the compounds of the invention is shown by the fact that they are active in the test of the inhibition of stress ulcers in rats (restraint in water at 23"C for 4 hours), according to the method of M. Usardi et al. (Prostaglandins, 8,43, 1974). The tested compounds were administered per os (p.o.) one hour before the stress. Six Charles River male rat (140+ 10 g body weight) fasted for 16 hours were used for each experimental group. At the end of the stress, the rats were killed and the gastric ulcers evaluated by counting them. The inhibition of gastric ulcerations, evaluated as percentage inhibition of ulcer index (number of ulcers), was expressed as ED50 (dose which reduces gastric ulcerations by 50% in comparison with control rats).

TABLE 1 Inhibition of stress ulcers in rats Compound prepared in Example ED50 {mg/Kg p. o.) 3(Isomer) 10 3 (Isomer B) 1 4 (IsomerA) 1.5 The gastric anti-secretory activity of the compounds of the invention was evaluated in rats by the pylorus ligature technique (H. Shay et al., Gastroenterology 5,43, 1945). Six Sprague-Dawley male rats (110-130 g) body weight for each group were used. Twenty four hours before the test, the rats were deprived of food while water was maintained. On the day of operation, the pylorus was ligated under light ether anaesthesia.

Four hours after the ligature the rats were sacrificed, the stomach secretion collected, centrifuged at 3500 r.p.m. for 10 minutes and the volume, less sediment, was determined. The amount of free hydrochloric acid in the gastric juice was determined by titration against 0.1 N sodium hydroxide to an end point of pH 7.

For example, the compound prepared in Example 4 (Isomer A) shows an ED50 of 10 mg/Kg in this biological test. Considering that some anti-ulcer agents display, as does atropine, a remarkable but undesired anti-cholinergic activity, some of the compounds of this invention were also assessed for their antagonism against the syndrome induced by intraperitoneally (i.p.) administered oxotremorine in mice, according to the method described by G. P. Leszkovsky and L. Tardos (Europ. J. Pharmac, 1971, 15,310).

The tested compounds were administered to groups of 5 male mice, 20-25 g body weight, at the screening dose of 100 mg/kg p.o. The degree of peripheral cholinergic activation induced by oxotremorine was measured by salivation and lachrymation, and the degree of central cholinergic activation by the severity of tremors and hypothermia. Atropine sulphate suppressed both peripheral and central effects induced by oxotremorine. For example, the compound prepared in Example 4 (Isomer A) was found inactive as an anticholinergic agent.

In the therapeutic field, the products of the invention may be administered by the oral or the parenteral route. The therapeutic compositions normally employed should include one or more compounds of the invention with a conventional quantity of a solid or a liquid vehicle. The compositions may be prepared as tablets, powders, pills or other forms pharmaceutically suitable for oral or parenteral administration. Liquid diluents duly sterilized may be employed for the parenteral administration. Conventional excipients may be employed, among which the most common are starch, lactose, magnesium stearate, and the like. The preferred oral dosage range in humans should be about 50-400 mg daily.

The invention is illustrated by the following Examples.

EXAMPLE 1 4-Ethyl-5-(N-isopropyl-thiocarbamoyl)- 1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole [I:R1=R2=H; R3=C2H5, X=S, R4=CH(CH3)2] A solution of 1.25 g of 4-(-aminoprnpyI)-imidazole in 12.5 ml of n-butanol was added dropwise under stirring over a period of one hour to a refluxing solution of 581 mg (0.72 ml) of propionaldehyde in 5 ml of n-butanol. Further propionaldehyde (0.36 ml x 2) was added to the reaction mixture until no more starting material could be detected by thin layer chromatography (MERCK silica gel 60 F254 TLC plates, using toluene:ethanol:33% aqueous methylamine 6:3:1 by volume as eluant system and the Pauly's spray reagent forspotvisualisation on chromatograms).

The reaction mixture was then evaporated to dryness. The oily residue was redissolved in 20 ml of acetonitrile, treated with 1 ml of isopropyl isothiocyanate and refluxed for 5 hours. The reaction mixture was then evaporated to dryness and the residue was chromatographed on a silica gel column (80 g, 230-400 mesh ASTM, ethyl acetate with increasing methanol as eluant) affording 356 mg of the pure title compound (m.p.150 C) as a white solid.

H-NMR spectrum (200 MHz, DMSO-d6): 0.81 3 (t, J=7.5Hz,3H,4-CH2CH3)

1.5-1.9 8 (m, 4H, 4-CH2-CH3, 7-CH2) 2.553 (m, 2H, 8-CH2) 3.203 (m, 1H, 6-CH(H)) 4.15#(bm, 1H, 6-C(H)H) 4.623 (m, 1 H, NHCH) 6.40#(bm, 1H, 4-CH) 6.953 (bd, J=7Hz, 1 H, NHCH) 7.34 3 (s, 1 H, H-2) 11.72 3 (bs, 1 H, NH- 1(3)) EXAMPLE 2 4-Ethyl-5-(N-methyl-thiocarbamoyl)-1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole {I:: R = R2 H, R3=C2H X=S, R4=CH3) Operating as in Example 1, but using methyl isothiocyanate instead of isopropyl isothiocyanate, the title compound (m.p.200-2 C) was obtained in 30% overall yield.

EXAMPLE 3 1(3),4-Diethyl-5-(N-isopropyl-thiocarbamoyl)-1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole (IA and IS: R1=R3=C2H5, R2=H, X=S, R4=CH(CH3)2) To a solution of 1.33 g of 4-ethyl-5-(N-isopropyl-thiocarbamoyl)-1 (3),4,5,6,7,8-hexahydroazepino[3,4- d]imidazole, prepared as described in Example 1, in 20 ml of methylene dichloride there were successively added under vigorous stirring 3 ml of 18N sodium hydroxide solution, 130 mg of tetrabutylammonium bromide and a solution of 545 mg of ethyl bromide in 1 ml of methylene dichloride.Stirring was maintained till no more starting material could be detected by thin layer chromatography (MERCK silica gel 60 F254 TLC plates, using toluene:ethanol:33% aqueous methylamine 22:7:1 by volume as eluant system and the Pauly's spray reagent for spot visualisation on chromatograms). The organic layer was then separated off, washed with water, dried over sodium sulphate, and evaporated to dryness. The oily residue (about 1.5 g) in thin layer chromatography (MERCK silica gel 60 F254TLC plates, using methylene dichloride:methanol 9:1 by volume as eluant system and the 254 nm UV light for spot visualisation on chromatograms) appears mainly constituted by two products largely separated on the plate.It is chromatographed on a silica gel column (45g, 230-400 mesh ASTM, methylene dichloride with increasing methanol as eluant) affording the regioisomer (IA) (oil, 600 mg) corresponding to the forerunning spot on the chromatograms; H1-NMR spectrum (200 MHz, CDCI3):: 0.81# (t,J= 7.3Hz,3H,4-CH2-CH3)

1.7-1.9 8 (m, 2H, 7-CH2) 1.9-2.1 5 (m,2H,4-CH2CH3) 2.51 5 (t, J=6.4Hz,2H,8-CH2) 3.35# (ddd, J=4,9,16Hz,1H,6-CH(H)) 3.71# (q, J=7.3Hz, 2H, N-CH2CH3)

4.71# (bd, J=16Hz,1H,6-C(H)H)(visible only when spectrum is taken at 50 C) 5.12#(bs,1H,CH-4) 5.52# (bd, J=7Hz, 1H, NHCH) 7.145(s, (s,1H,H-2) and the regioisomer (IB) (100 mg) corresponding to the lower spot on the chromatograms; H1-NMR spectrum (200 MHz, CDCl3):: 0.90 # (t,J=7.5Hz,3H,4-CH2-CH3)

1.48 # (t,J=7.3Hz,3H,N-CH2CH3) 1.6-1.8 # (m, 2H,7-CH2) 1.8-2.0 # (m, 2H,4-CH2-CH3) 2.7-2.9 5 (m, 2H, 8-CH2) 3.50 # (dd, J=1 1,15Hz, 1H, 6-CH(H)) 3.86 # (dd, J =4,15Hz, 1 H, 6- C(H)H) 4.05 # (q,J=7.3Hz,2H,N-CH2CH3) 4.62 # (m, 1H, NH-CH) 5.38 # (bd,J=7Hz,1H,NHCH) 6.82 # (dd,J =6,10Hz,1H,4-CH) 7.21 5 (s, 1 H, H2) EXAMPLE 4 1(3)Ethyl-5-(N-isopropyl-thiocarbamoyl)-1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole (IA) and (IB): (RI= C2H5; R2=R2--H, X= S; R4= CH{CH3)2) Operating as in Example 1 and 3, but using formaldehyde instead of propionaldehyde, the title compounds were obtained in 20% overall yield.

H1-NMR spectrum (60 MHz, CDC13 and DMSO-d6) of the major isomer (IA) (m.p.170-2 C):

7.67 3 (s, 1 H, H-2)

Claims

1. Al (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivative having the general formula I as herein defined.

2. 4-Ethyl-5-(N-isopropyl-thiocarbomyl)-1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole.

3. 4-Ethyl-5-(N-methyl-thiocarbomyl)-1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole.

4. Either isomer of 1 (3),4-diethyl-5-(N-isopropylthiocarbomyl)-1 (3),4,5,6,7,8-hexahydroazepino[3,4d]imidazole.

5. Either isomer of 1 (3)-ethyl-5-(N-isopropyl-thiocarbamoyl)-1 (3),4,5,6,7,8-hexahydroazepino[3,4- d]imidazole.

6. A method for the preparation of a 1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivative having the general formula I wherein R1 represents a hydrogen atom, R2, R3 and R4 are as defined herein and X represents an oxygen or sulphur atom or an imino group, the method comprising reacting a compound of the general formula II as defined herein with an isocyanate R4-NCO, an isothiocyanate R4-NCS or a cyanamide R4-NH-CN respectively, R4 being as defined herein, in a solvent.

7. A method according to claim 6 wherein the solvent is acetonitrile or dimethylformamide.

8. A method for the preparation of a 1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivative having the general formula I wherein R1 represents a hydrogen atom, R2, B3 and R4 are as defined herein and X represents a cyano-imino, p-toluenesulphonyl-imino or nitromethylene group or a group of the formula CH - S02R5 or N -COR6 wherein B5 and B6 are as defined herein, the method comprising reacting a compound of the general formula Il as defined herein with a compound of the general formula IV

wherein Xis as defined in this claim and reacting the resultant compound with an amine of the general formula R4NH2 wherein R4 is as defined herein.

9. A method for the preparation of a 1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivative having the general formula I wherein R2, R3, R4 and X are as defined herein and R1 represents any of the groups defined herein for it other than a hydrogen atom, the process comprising reacting a compound of the general formula I prepared by a process according to any of claims 6 to 8 with a compound of the general formula R1Y or R1-O-S02-O-R1 wherein R1 is as defined in this claim and Y represents a chlorine or bromine atom in a catalytic two-phase system.

10. A method for the preparation of a 1 (3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivative according to claim 1, the method being substantially as described herein with reference to any of the Examples.

11. A pharmaceutical composition comprising a 1(3),4,5,6,7,8-hexahydroazepino[3,4-d]imidazole derivative according to claim 1 in admixture with a pharmaceutically acceptable diluent or carrier.