GB2152035A - Tetrahydropyrano(3,4-d)imidazole and tetrahydrothiopyrano(3,4-d) derivatives - Google Patents

Abstract

<IMAGE> Compounds I (n=1 to 4; X=0 or S; R1-R3 independently = H or C1-C4alkyl, R1 being on N1 or N3; R4 and R5 independently = H, C1-C10 alkyl, C5-C7 cycloakyl, benzyl or substituted benzyl, or NR4R5=5- or 6-membered heterocyclic ring) have antiulcerogenic activity.

Description

SPECIFICATION Tetrahydropyrano [3,4-d] imidazole and Tetrahydrothiopyrano [3,4-d] imidazole derivatives The invention relates to (1 or 3),4,6,7-tetrahydropyrano [3,4-d] imidazole and (1 or 3),4,6,7tetrahydrothiopyrano [3,4-d] imidazole derivatives. The invention provides compounds of the general formula I

wherein n is an integerfrom 1 to 4, X represents an oxygen or sulphur atom, each of R1, R2 and R3 independently represents a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms, provided that R1 can be either on N1 or N3, and either each of R4 and B5 independently represents a hydrogen atom, a linear or branched alkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms, a benzyl group or a mono- or di-substituted benzyl group, the substituent(s) being selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, nitro or methylenedioxy groups or fluorine, chlorine or bromine atoms, or R4 and B, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring which may contain other heteroatoms selected from oxygen and nitrogen; any hydrogen bearing nitrogen ring atom may optionally be alkylated; C4 may have R, S or RS configurations, and further provides pharmaceutically acceptable acid addition salts thereof.

The compounds according to the invention may be prepared by a process comprising condensing a 4(5)-(2-hydroxyethyl)-imidazole or 4(5)-(2-mercaptoethyl)-imidazole of the general formula ll

wherein R1, R2 and X are as above defined with an aminoketal or aminoacetal of the general formula Ill

wherein R3, R4, B5 and n are as above defined and either each of R7 and BB represents a lower alkyl group or R7, B8 together represent a low aliphatic chain, the condensation being effected in the presence of a strong acid. Suitable acids include methanesulphonic, trifloroacetic and trifluoromethanesulphonic acids. The reaction is preferably conducted at from 30"C to 1 30 C.

The compounds I wherein R1 represents an alkyl group and each of R4 and B5 represents a hydrogen atom may also be prepared from the compounds I wherein R1, R4 and B5 all represent hydrogen atoms, by reaction with benzylchloroformate to protect the primary amino group, alkylation of the resultant compound of the general formula IV

wherein R2, R3, X and n are as above defined, separation of the resultant regioisomers of the general formula V

wherein Rt represents an alkyl group and R2, R3, X and n are as above defined, and deprotection of each of the regioisomers by catalytic hydrogenation.

The protection of the amino group with benzylchloroformate may be effected in the presence of a base, such as potassium carbonate. The alkylation may be carried out by standard procedures, for example using a compound of the formula B1Y or B10-SO2-0B1 wherein R1 represents an alkyl group and Y represents a chlorine or bromine atom as alkylating agent. This gives a mixture of regioisomers V, clearly distinguishable both by thin layer chromatography on silica gel plates and by NMB spectroscopy. The regioisomers may readily be separated on silica gel columns. The catalytic hydrogenation may be effected using palladium-on-carbon as catalyst.

The compounds of the general formula I wherein R, and Rg are different from hydrogen may be obtained from the compounds I (R4=R5=H) by reductive alkylation with the appropriate aldehydes or ketones (see C.F.

Lane, "Synthesis", 1975, 135).

The process above described are within the scope of the invention.

Pharmaceutical compositions comprising a tetrahydropyrano-[3,4-d] imidazole or a tetrahydrothiopyrano [3,4-d] imidazole derivative according to the invention or a pharmaceutically acceptable salt of either thereof in admixture with a pharmaceutically acceptable diluent or carrier are included within the scope of the invention.

The compounds of the invention have proved to be well tolerated after oral or parental administration and to be active on the gastroenterica I system. In particular they are endowed with anti-ulcerogenic activity and are therefore useful in therapy, for example in the prevention and treatment of peptic ulcers such as duodenal, gastric and oesophageal ulcers. The anti-ulcerogenic activity of the compounds of this invention is shown, for example, by the fact that they are active in the test of the inhibition of restraint ulcers in rats, according to the method of Bonfils et al. (Therapie, 1960, 5, 1069; Jap. J. Pharmac., 1968, 18, 9).

The tested compounds were administered per os one hour before the immobilization. Six Sprague-Dawley male rats (100-120 g body weight) fasted for 24 hours were used for each experimental group. A square flexible small-mesh wire netting was used for immobilization and 4 hours after immobilization the rats were sacrificed, their stomachs were removed and the lesions counted under a dissecting microscope.

The table shows the approximate ED50 value of the anti-ulcerongenic activity in the rats obtained for some of the compounds of the invention after oral administration.

The approximate acute toxicity (LD50) of the compounds of the invention was determined in the mouse by single oral administration of increasing doses and measured on the seventh day after treatment. Results are reported in the table.

Considering that some anti-ulcer agents display, as does atropine, a remarkable but undesired anti-cholinergic activity, some of the compounds of the invention were also assessed for their antogonism against the syndrome induced by intraperitoneally (i.p.) administered oxotremorine in mice, according to the method described by Leszkovszky G.P. and Tardos L. (Eur. 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 per os. 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 affects induced by oxotremorine.

The results are reported in the Table.

TABLE-Acute toxicity, anti-ulcer activity and anticholinergic activity of selected compounds (see general formula I)

Example X R1 R2 R3 R4 R5 n LD50 mg/kg Anti-ulcer Anti-cholinergic per os activity ED50 activity mg/kg per os (screening dose 100 mg/kg per os) 1 O H H H H H 1 > 800 50 -- 2 O H H H H i-C3H7 1 > 800 50 -- 3 O H H H H CH(CH3)CH2CH(CH3)2 1 > 200 > 400 25 -- 4 O H H H H # 1 > 400 > 800 15 inactive 5 O H H H H # 1 > 100 > 200 15 -- 6 O H H H # # 1 > 400 > 800 20 inactive 7 O H H H # # 1 > 800 9 inactive The following Examples illustrate the invention.

Example 1 4-Aminomethyl- 1(3), 4,6,7-tetrahydropyrano-[3,4-d] imidazole To a solution of 26.9 g (0.24 mole) of 4-(2-hydroxyethyl)-imidazole (W. Bloemhoff and K.E.T. Kerling, Rec.

Trav. Chim. Pays-Bas, 89, 1181, 1970) in 100 ml of trifluoromethanesulphonic acid, 38A ml (0.26 mol) of aminoacetaldehyde diethylacetal was added dropwise under ice-cooling and vigorous stirring. The reaction mixture was heated to 120 C for 15 minutes, and then cooled and poured into iced water. The solution was percolated through a column of an ion exchanger resin (Amberlite IRA 41 O, OH form, Kg). "Amberlite" is a Trade Mark. The aqueous eluant was evaporated to dryness. The oily dark residue (about 33 g) was dissolved in 50 ml of anhydrous ethanol and treated with a solution of 50 g (0.43 mol) of fumaric acid in 1500 ml of an hydros ethanol.The solution was allowed to stand overnight, and the difumarate of the title compound (56 g, m.p. 1900C) was collected (overall yield 60%). This salt was dissolved in 120 ml of water and the solution was percolated through a column of Amberlite IRA 410 (OH- form, 600g). The aqueous eluant was evaporated to dryness.The oily free base (22 g) was obtained. H-NMR (200 MHz) spectrum in CDCl3: 7.263(s, 1H, NH-CH=) 4.47 6 (dd, J =4.0,5.9 Hz, 1 H, CH-4) 4.023 (ddd, J=1 1.3, 5.5, 2.2 Hz, 1 H CH-6eqJ 3.60 3 (ddd, J = 11.3, 10.0,4.0 Hz, 1 H, CH-6ax) 2.95 # (dd, J=13.4, 4.0 Hz CH(H)NH2) 2.843 (dd, J=13.4, 5.9 Hz, C(H)HNH2) 2.70 # (ddd, J=15.5, 10.0, 5.5 Hz, 1H, CH-7ax) 2.42# (ddd, J=15.5, 4.0, 2.0 Hz 1 H, CH-7eq) 3.2 - 5.03 (br s, 2H, CH2NH2) For analytical purposes, the dihydrochloride of the title compound (4 g, m.p.25 C with decomposition) can be obtained by treating 3.06 g of the free base in 50 ml of ethanol with the stoichiometric amount of ethanolic hydrogen chloride.

Example 2 4-(isopropylamino-methyl)-1(3),4,6,7-tetrahydropyrano[3,4-d] imidazole To a solution of 1.7 g (0.011 mol) of 4-aminomethyl-1 (3), 4,6,7-tetrahydropyrano [3,4-dl imidazole, prepared as described in Example 1, in 0.9 ml of acetone and 40 ml of methanol, 2.2 ml of 5N methanolic hydrogen chloride and 0.275 g of sodium cyanoborohydride were added. The reaction mixture was vigorously stirred for half an hour. It was then acidified with 6N hydrochloric acid and evaporated in vacuo.

The residue was taken up in water, and the aqueous solution was basified and extracted repeatedly with dichloromethane. The organic phase was dried and evaporated in vacuo. The oily dark residue (about 1.7 g) was dissolved in 10 ml of anhydrous ethanol and treated with a solution of 2 g of fumaric acid in 50 ml of anhydrous ethanol. The solution was allowed to stand overnight, and the difumarate of the title compound (2.8 g, m.p. 157-9 C, yield 59%) was collected.

Example 3 4-[(4-methyl-2-pentylamino)-methyl]-1(3),4,6,7-tetrahydropyrano [3,4-d] imidazole Operating as in Example 2, but using methyl isobutyl ketone instead of acetone, the difumarate of the title compound (m.p. 175 C) was obtained in 65% overall yield.

Example 4 4-(cyclopentylamino-methyl)- 1(3),4,6,7-tetrahydropyrano [3,4-di imidazole Operating as in Example 2, but using cyclopentanone instead of acetone, the difumarate of the title compound (m.p. 1650C) was obtained in 80% overall yield.

Example 5 4-(cyclohexylamino-methyl)-1(3),4,6,7-tetrahydropyrano[3,4-d]imidazole Operating as in Example 2, but using cyclohexanone instead of acetone, the difumarate of the title compound (m.p. 184'C) was obtained in 70% overall yield.

Example 6 4-(dibenzylamino-meth yl)-l (3). 4,6, 7-tetrahydropyrano [3,4dY imidazole Operating as in Example 2, but using benzaldehyde instead of acetone, the title compound (m.p. 140 c) was obtained in 50% overall yield.

Example 7 4-[N,N-di-(4'-chlorobenzyl)-aminomethyl]-1(3),4,6,7-tetrahydropyrano[3,4-d]imidazole Operating as in Example 2, but using p-chlorobenzaldehyde instead of acetone, the difumarate of the title compound (m.p. 177 C) was obtained in 45% overall yield.

Example 8 4-[N,N-di-(3',4'-methylenedioxybenzyl)-aminomethyl]-1(3),4,6,7-tetrahydropyrano[3,4-d]imidazole Operating as in Example 2, but using 3,4-methylenedioxybenzaldehyde instead of acetone, the trifumarate of the title compound (m.p. 162"C) was obtained in 30% overall yield.

Example 9 4-(dimeth ylamino-meth yl)- 1(3), 4,6, 7-tetrahydropyrano i3, 4- di imidazole Operating as in Example 1, but using N,N-dimethylaminoacetaldehyde diethylacetal instead of aminoacetaldehyde diethylacetal, the difumarate of the title compound (m.p. 155-7 C) was obtained in 70% overall yield.

Example 10 4-piperidinomethyl-1(3),4,6,7-tetrahydropyrano[3,4-d]imidazole Operating as in Example 2, but using glutaraldehyde instead of acetone, the title compound (m.p. 155 C, from acetonitrile) was obtained in 70% yield.

Example 11 4-morpholinomethyl-1(3),4,6,7-tetrahydropyrano[3,4-d]imidazole Operating as in Example 2, but using 2,2'-oxydiacetaldehyde instead of acetone, difumarate of the title compound (m.p.155 C) was obtained in 50% yield.

Example 12 4-(benzyloxycarbonylamino-methyl)-1(3),4,6,7-tetrahydropyrano[3,4] imidazole A solution of 10 g (0.0653) mol of 4-aminomethyl-1 (3),4,6,7-tetrahydropyrano [3,4-d] imidazole, prepared as described in Example 1 in 100 ml of dichloromethane was mixed with a solution of 23 g (0.163 mol) of potassium carbonate in 120 ml of water (120 ml) under vigorous stirring. After cooling with an ice-water bath, a solution of 28.8 g (24 ml, 0.163 mol) of benzyl chloroformate in 40 ml of dichloromethane was added dropwise over a period of 6 hours. The cooling bath was removed and the mixture was stirred overnight. The organic layer was separated off, dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue was dissolved in 180 ml of methanol. The solution was cooled with a water bath and 70 ml of 2N aqueous sodium hydroxide was added under stirring. After 1 hour the mixture was neutralized with 70 ml of 2N hydrochloric acid concentrated in vacuo to distill off most of the methanol, and extracted exhaustively with dichloromethane. The organic extracts were dried and evaporated to dryness. The solid residue was crystallized from acetonitrile 14 g (75% yield) of the pure title compound (m.p. 165-167'C) were collected.

H1-NMR spectrum in CDCI3 (200 MHz): 2.4- 2.9# (m, 2H, CH2-CH2-O) 3.4-3.8# (m, 3H, CH2-NH, CH-CH(H)-O) 4.11 # (m, 1H, CH2-C(H)H-O) 4.70 # (m, 1H, CH-CH2NH)

5.49 # (m, 1 H, CH2-NH-COO) 7.39 5 (s, 1 H, H-2) Example 13 (1 or 3)-Ethyl-4-benzyloxycarbonylamino-methyl-(1 or 3), 4,6, 7-tetrahydropyrano [3,4-dy imidazole To a solution of 12 g (0.0418 mol) of 4-(benzyloxycarbonylamino-methyl)-1(3),4,6,7-tetrahydropyrano [3,4-d] imidazole, prepared as described in Example 12, in 170 ml of dichloromethane, cooled with a water bath and vigorously stirred, 25 ml of 18 N aqueous sodium hydroxide, 1.1 of tetrabutylammonium bromide and 4.77 g (3.3 ml, 0.0438 mol) of ethyl bromide were successively added during a period of 2 hours. The mixture was stirred at room temperature for 4 hours. The organic layer was then separated off, washed with water, dried and evaporated to dryness. The oily residue (about 15 g) was chromatographed on a silica gel column (450 g, 230-400 mesh ASTM, ethyl acetate with increasing methanol as eluant) affording the regioisomer A (oil, 10.8 g) as a major product (Rf 0.35 on Merck silica gel 60 F254TLC plates, using ethyl acetate: methanol 9.1 by volume as eluant) and the regioisomer B (oil, 0.8 g) as a minor product (Rf 0.15 Merck silica gel 60 F254 TLC plates, using ethyl acetate: methanol 9.1 by volume as eluant).

H-NMR spectrum (200 MHz, CDCl3) of (Isomer A) 1.39 # (t, J=7.3 Hz, 3H, CH3-CH2-N) 2.4 - 2.9# (m, 2H, CH2-CH2-O) 3.5 - 3.8# (m, 3H, CH2-NH-COO, CH(H)-OCH) 4.20# (m, 1H, CH(H)-OCH) 3.85 # (q, J=7.3Hz, 2H, CH3-CH2-N) 4.68 # (m, 1 H, OCH-CH2NH) 5.09# (s,2H, COOCH2) 5.45# (bt, 1H, NHCOO)

H-NMR spectrum (200 MHz, CDCl3) of (Isomer B) 1.35# (t, J= 7.3 Hz, 3H, CH3-CH2-N) 2.5-2.7# (m, 2H, CH2CH20) 3.3-4.1#(m, 6H, CH2NHCOO, CH2OCH, CH3CH2N) 4.81 5 (dd, J= 1.2, 7.2Hz, 1 1 H, OCH-CH2NH) 5.04# (s,2H, COOCH2) 5.49# (bt, 1H, NHCOO)

Example 14 01 or 3)-Ethyl-4-aminomethyl-( 1 or 3),4, 6, 7-tetrahydropyrano [3,4-d] imidazole (isomer A) To a solution of 10.8 g of (1 or 3)-ethyl-4-(benzyloxycarbonylamino-methyl)-(1 or 3), 4,6,7tetrahydropyrano [3,4-d] imidazole (isomer A, Example 13) in 300 ml of 95% ethanol, 1.3 g of 10% by weight palladium-on-charcoal was added and the mixture was hydrogenated at 1 atmosphere and room temperature for 2 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness affording 5.5 g (90% yield) of the pure title compound as a clear oil.

H'-NMR spectrum (200 MHz, CDCl3) 1.045 (t, 3H, CH3-CH2-N) 1.91 5 (s, 2H, CH2-NH2) 2.1 - 2.9# (m, 4H, CH2-CH2O, CH2-NH2) 3.3 - 4.05 (m, 2H, CH2-CH2O) 3.53 5 (q, 2H, CH3-CH2-N) 4.23 # (m, 1H, CH-CH2NH2) 7.02 5 (s, 1 H, H-2) A crystalline salt (m.p. 173-5 C) of the title compound (ratio free base/fumaric acid 1:1.5) can be prepared for analytical purposes by adding a solution of 2.32 g of fumaric acid in 100 ml of anhydrous ethanol to a solution of 1.81 g of the compound in 20 ml of anhydrous ethanol.

Example 15 (1 or 3)-Ethyl-4-aminomethyl-(1 or 3),4,6,7-tetrahydropyrano [3,4-dJ imidazole (Isomer B) To a solution of 0.8 g of (1 or 3)-ethyl-4-(benzyloxycarbonylamino-methyl)-(1 or 3), 4,6,7-tetrahydropyrano [3,4-d] imidazole (isomer B, Example 13) in 30 ml of 95% ethanol, 100 mg of 10% by weight palladium-on-charcoal was added and the mixture was hydrogenated at 1 atmosphere and room temperature for 2 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness affording 400 mg of the pure title compound as a clear oil.

H'-NMR spectrum (200 MHz, CDCl3) 1.39 5 (t, 3H, CH3-CH2) 2.6-2.9# (m, 2H, CH2-CH2-O 3.01# (d, 2H, CH-CH2-NH2) 3.765 (m, 1 H, CH2-CH(H)-O) 3.87 5 (q, 2H, CH3-CH2-N) 4.105 (m, 1H, CH2-C(H)H-O) 4.725 (m, 1H, CH-CH2NH2) 7.40 5 (s, 1 H, H-2) Example 16 (1 or 3)-Ethyl-4-(cyclopentylamino-methyl)-(1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole (isomer A) To a solution of 1.3 g of (1 or 3)-ethyl-4-aminomethyl-(1 or 3),4,6,7-tetrahydropyrano [3,4-d] imidazole (isomer A, Example 14) in 20 ml of methanol 1.44 ml of 5N hydrogen chloride in methanol, 0.7 ml of cyclopentanone and 180 mg of sodium cyanoborohydride were successively added.The mixture was stirred at room temperature for 1 hour, and was then acidified with 6N hydrochloric acid and evaporated to dryness.

The solid residue was taken up in 40 ml of water. The solution was washed with diethyl ether, basified with 2N aqueous sodium hydroxide solution and exhaustively extracted with dichloromethane. The extracts were dried and evaporated to dryness affording the pure title compound (900 mg) as a clear oil.

H'-NMR spectrum (60 MHz, CDCI3)

3.87 5 (q, 2H, CH3-CH2-N) 3.5 - 4.5# (m, 2H, CH2-CH2-O) 4.73 # (m, 1H, CH-CH2NH) 7.33 8 (s, 1 H, H-2) For analytical purposes the dihydrochloride of the title compound (m.p. 235 C with decomposition) can be prepared by treating 1.25 g of the free base in 10 ml of methanol with the stoichiometric amount of methanolic hydrogen chloride.

Example 17 (1 or 3)-Ethyl-4-(cyclopentylamino-methyl-(1 or 3),4,6, 7-tetrahydropyrano [3,4-dy imidazole (Isomer B) Operating as in Example 16, but starting from 420 mg of (1 or 3)-ethyl-4-aminomethyl-(1 or 3),4,6,7-tetrahydropyrano [3,4-d] imidazole (isomer B, Example 15), the title compound (350 mg) was obtained in a colourless oil.

H'-NMR spectrum (60 MHz, CoCI3)

3.9 # (q, 2H, CH3-CH2-N) 3.5 - 4.3 # (m, 2H, CH2-CH2-O) 4.88 # (m, 1H, CH-CH2-NH) 7.37 5 (s, 1 H, H-2)

Claims (29)

1. (1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole or a (1 or 3), 4,6,7-tetrahydrothiopyrano[3,4-d]- imidazole derivative of the general formula I

wherein n is an integer from 1 to 4, X represents an oxygen or sulphur atom, each of B1, R2 and Rg independently represents a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms, provided that R1 can be either on N1 or N2, and either each of R4 and B5 independently represents a hydrogen atom, a linear or branched alkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms, a benzyl group or a mono or di-substituted benzyl group, the substituent(s) being selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, nitro or methylenedioxy groups or fluorine, chlorine or bromine atoms, or R4 and R5, together with the nitrogen atom to which they are attached, form a 5-or 6-membered heterocyclic ring which may contain other heteroatoms selected from oxygen and nitrogen; any hydrogen bearing nitrogen ring atom may optionally be alkylated; C4 may have R, S or RS configurations, or a pharmaceutically acceptable acid addition salt thereof.

2. 4-Aminomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]-imidazole.

3. 4-lsopropylaminomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

4. 4-(4-Methyl-2-pentylaminomethyl )-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

5. 4-Cyclopentylaminomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

6. 4-Cyclohexylaminomethyl-1 (3),4,6,7-tetrahydropyrano [3,4-d]imidazole.

7. 4-Dibenzylaminomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

8. 4-[N,N-di-(4'-chlorobenzyl)-aminomethyl]-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

9. 4-[N,N-di(3',4'-methylenedioxybenzyl )-aminomethyl]-1 (3),4,6,7-tetra hydropyrano [3,4-d]imidazole.

10. 4-Dimethylaminomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

11. 4-Piperidinomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

12. 4-Morpholinomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

13. 4-Benzyloxycarbonylaminomethyl-1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

14. Either of the isomers (1 or 3)-Ethyl-4-benzyloxycarbonylaminomethyl-(1 or 3),4,6,7-tetrahydropyrano [3,4-d]imidazole.

15. Either of the isomers (1 or 3)-Ethyl-4-aminomethyl-(1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

16. Either of the isomers (1 or 3)-Ethyl-4-cyclopentylaminomethyl)-(1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole.

17. A process for the preparation of a (1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole or a (1 or 3),4,6,7-tetrahydrothiopyrano[3,4-d]imidazole according to claim 1, the process comprising condensing a 4(5)-(2-hydroxyethyl)-imidazole or a 4(5)-(2-mercaptoethyl)-imidazole of the general formula II as herein defined with an aminoketal or aminoacetal of the general formula Ill as herein defined, the condensation being effected in the presence of a strong acid.

18. A process according to claim 17 in which the strong acid is methanesulphonic acid, trifluoroacetic acid or trifluoromethanesulphonic acid.

19. A process according to claim 17 or claim 18 in which the condensation is carried out at from 300Cto 130"C.

20. A process for the preparation of a (1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole or a (1 or 3),4,6,7-tetrahydrothiopyrano[3,4-d]imidazole of the general formula I wherein R1 represents an alkyl group, each of R4 and B5 represents a hydrogen atom and X, n, R2 and B3 are as defined in claim 1, the process comprising reacting a 1 (3),4,6,7-tetrahydropyrano[3,4-d]imidazole or a 1 (3),4,6,7-tetrahydrothiopyrano[3,4-d]imidazole of the general formula I wherein each of R1, R4 and B5 represents a hydrogen atom and X, n, R2 and Rg are as defined in claim 1 with benzylchloroformate to protect the primary amine group, alkylating the resultant compound of the general formula IV as herein defined, separating the resultant regioisomers of the general formula \ > as herein defined, and deprotecting each of the regioisomers by catalytic hydrogenation.

21. A process according to claim 20 in which the reaction with benzylchloroformate is effected in the presence of a base.

22. A process according to claim 21 in which the base is potassium carbonate.

23. A process according to any of claims 20 to 22 in which the regioisomers are separated by chromatography on silica gel using an ethyl acetate: methanol mixture with an increasing proportion of methanol as eluent.

24. A process according to any of claims 20 to 23 in which the catalyst hydrogenation is effected using a palladium-pn-carbon catalyst at ambient temperature and atmospheric pressure.

25. A process for the preparation of a (1 or 3),4,6,7-tetrahydropyrano[3,4-d]imidazole or a (1 or 3),4,6,7-tetrahydrothiopyrano[3,4-d]imidazole wherein R1 represents an alkyl group and X, n, R2, R3, R4 and B5 are as defined in claim 1 with the proviso that R4 and B5 do not simultaneously represent hydrogen atoms, the process comprising reductively alkylating a compound prepared according to any of claims 20 to 24 with sodium cyanoborohydride and an appropriate aldehyde or ketone.

26. A process according to claim 17, the process being substantially as described herein with reference to Example 1.

27. A process according to claim 20, the process being substantially as described herein with reference to Examples 12to 15.

28. A process according to claim 25, the process being substantially as described herein with reference to any of Examples 1 to 11, 16 or17.

29. A pharmaceutical composition comprising a (1 or 3),-4,6,7-tetrahydropyrano[3,4-d]imidazole or a (1 or 3),-4,6,7-tetrahydrothiopyrano[3,4-d]imidazole according to any of claims 1 to 16 or a pharmaceutically acceptable salt of any such compound in admixture with a pharmaceutically acceptable diluent or carrier.