CH626084A5 - Process for the preparation of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine derivatives - Google Patents

Description

The present invention relates to the process for the preparation of new 4,5,6,7-tetrahydroimidazo (4,5-c) pyridine derivatives of the formula defined in claim 1

-nhr and their pharmaceutically acceptable acid addition salts.

In a preferred embodiment of the process according to the invention, the condensation reaction is carried out in a solvent such as ethanol, acetonitrile or dioxane, usually under reflux, for 4-12 h. The products can be isolated by crystallization as free bases or as salts of pharmaceutically usable acids.

The new compounds proved to be well tolerated and inhibited both a number of experimental ulcers and gastric secretion in experimental animals. They can therefore be used to treat gastric and intestinal ulcers in humans.

The efficacy of these compounds was determined in antigen swelling and anti-secretion experiments in rats. Methiamide, a substance well known for its anti-secretion activity (Wyllie et al., Gut, 1973, 14, 424), which is considered to be one of the most active substances in this field (S. Dai et al., Eur. J. Pharm., 1975 , 33, 277) was used as the reference standard.

1. Inhibition of ulcers in rats (Bonfils et al., Thérapie, 1960, 15, 1096)

Six male Sprague-Dowley rats weighing 100 to 120 g, which were starved for 24 hours, were used for each group. A rectangular, flexible wire mesh with a small mesh size was used for immobilization. After 4 hours of immobilization, the rats were sacrificed, their stomachs removed and the injuries counted under a dissecting microscope. The results obtained are given in Table I, in which the values are given as ED 50.

The compounds were administered subcutaneously (10 mg / kg) immediately before immobilization or orally (50 mg / kg) one hour before.

2. Inhibition of gastric secretion in rats (Shay, Gastroenterology, 1945, 43, 5).

The gastric antisecretory activity in rats was determined by the pylorus ligation method.

Six male Sprague-Dowley rats weighing 110 to 130 g were used for each group. The rats were given no food 24 hours before the experiment, but water was available.

On the day of the operation, the pylorus was ligated under light ether anesthesia. Four hours later, the rats were sacrificed, gastric secretion collected and at 3500 min for 10 minutes. centrifuged; the volume minus sediment was determined. The amount of free hydrochloric acid in the gastric juice was determined by titration against 0.01 N sodium hydroxide using a potter indicator. Each compound was injected subcutaneously at a dose of 50 mg / kg at the time of ligation.

Table I shows the results obtained, expressed as ED50.

The reference numbers of the compounds are explained in the examples.

Table I

ED50 for anti-ulcer and anti-secretion effects

connection

Anti-ulcer effectiveness

Anti-secretion

effectiveness

subcutaneously orally subcutaneously

Metiamid

14

64

60

386/1087

0.9

3.1

6

1068

0.6

2.4

50

1116

10th

34

23

1184

0.64

11

22

1286

0.85

8.5

34

1287

19th

50

50

1293

6

25th

8th

1359

5

1.8

40

1360

10th

5.6

19th

1361

10th

25th

50

1367

3.3

6

50

1316

0.75

6.6

50

1348

0.1

0.55

18th

1350

6.5

5.6

50

1365

2nd

3.8

50

1366

0.75

3.8

17th

Due to the fact that many anti-ulcer drugs show remarkable anticholinergic activity, some derivatives have also been tested orally for their antagonism against carbomoline-induced cromodacriorrhea (Winburg M. et al., J. Pharm. Exp. Therap., 1949, 95 , 53).

Table II, which shows the relationships between the ED 50 values for the anticholinergic and anti-ulcer activity, shows that some derivatives at doses of 5-

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are up to 25 times lower than those that are anti-cholinergic, anti-ulcer effective.

Such a ratio for atropine and methiamide is about 2.

Table II EDso in rats per os

connection

Anticholinergic effectiveness

Anticholinergic ED50 / anti-ulcer ED50

Atropine

0.8

2nd

Methiamide

85

1.33

386/1286

50

5.88

1359

45.5

25.28

1360

76

13.57

1316

70

10.61

1348

7.8

14.18

1350

100

17.86

1365

21st

5.53

The following examples are intended to explain the present invention in more detail.

example 1

5- (N-methylthiocarbamoyl) -4,5,6,7-tetra-hydroimidazo- [4, -5-c] pyridine (386/1068)

A solution of 1 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (Farmaco, Ed. Sei., 1967, 22, 821) and 0.65 g of methyl isothioeyanate in 20 ml of ethanol was refluxed for 8 hours. The solution was cooled and filtered. 1.15 g of the compound mentioned in the title were obtained, mp 228 ° C.

Example 2

5- (N-ethylthiocarbamoyl) -4,5,6,7-tetra-hydroimidazo- [4,5-c] pyridine (386/1293)

A solution of 1.85 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 2 g of ethyl isothiocyanate in 15 ml of acetonitrile was refluxed for 7 hours. The solution was cooled and filtered. 2.5 g of the compounds mentioned in the title were obtained, mp. 185 ° C.

Example 3

5- (N-n-Propylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo - [- 4,5-c] pyridine (386/1361)

The procedure was as in Example 1, but using propyl isothioeyanate. The compound mentioned in the title was obtained in 81% yield, mp. 151 ° C.

Example 4

5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo- [4,5-c] pyridine (386/1087)

A solution of 2 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine hydrochloride and 2.5 g of isopropyl isothiocyanate in 20 ml of acetonitrile and 5 ml of ethanol was refluxed for 8 hours. Evaporation of the solvent left a residue which was treated with 1 equivalent of ethanolic hydrogen chloride. When the solvent was evaporated, a residue remained which, when crystallized from acetone, gave 2.5 g of the hydrochloride of the compound mentioned in the title, mp. 170 ° C.

Example 5

5- (N-n-Butylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo- [4, -5-c] pyridine (386/1331)

The procedure was as in Example 1, but butyl

isothioeyanate was used. The compound mentioned in the title was obtained in 75% yield, mp. 130 ° C.

Example 6

5- (N-Cyclohexylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo- [4,5-c] pyridine (386/1294)

The procedure was as in Example 2, but using cyclohexyl isothiocyanate. The compound mentioned in the title was obtained in 82% yield, mp. 183 ° C.

Example 7

4-ethyl-5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydroimi-dazo [4,5-c] pyridine (386/1214)

A solution of 2.9 g of 4-ethyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (Farmaco, Ed. Sci. 1967, 22, 821) and 3 g of methyl isothiocyanate in 32 ml Acetonitrile and 8 ml of ethanol were refluxed for 8 hours. The solution was evaporated in vacuo and the residue was crystallized from diethyl ether, giving 3 g of the compound mentioned in the title, mp. 230 ° C.

Example 8

5- (N-allylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo- [4,5-c] pyridine (386/1185)

The procedure was as in Example 2, but using allyl isothioeyanate. The compound mentioned in the title was obtained in 71% yield, mp. 172 ° C.

Example 9

4-ethyl-5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1184)

The procedure was as in Example 7, but using isopropyl isothiocyanate. The compound mentioned in the title was obtained in 79% yield, mp. 215 ° C.

Example 10

4-ethyl-5- (N-allylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1216)

The procedure was as in Example 7, but using allyl isothioeyanate. The compound mentioned in the title was obtained in 70% yield, mp. 205 ° C.

Example 11

4-ethyl-5- (N-butylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1215)

The procedure was as in Example 7, but using butyl isothioeyanate. The compound mentioned in the title was obtained in 75% yield, mp. 180 ° C.

Example 12

4-phenyl-5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1254)

A solution of 3.5 g of 4-phenyl-4,5,6,7-tetrahydro-imi-dazo [4,5-c] pyridine (Farmaco, Ed. Sei., 1967, 22,821) and 3.5 g of methyl isothiocyanate in 55 ml of dioxane was refluxed for 4 hours. The solution was cooled and filtered; 3.6 g of the compound mentioned in the title were obtained, mp 228 ° C.

Example 13

4-phenyl-5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1253)

The procedure was as in Example 12, but using isopropyl isothiocyanate. The compound mentioned in the title was obtained in 80% yield, mp. 198 ° C.

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Example 14

4-isopropyl-5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydrohnidazo [4,5-c] pyridine (386/1257)

To a solution of 20 g of histamine dihydrochloride in 54 ml of water and 440 ml of methanol was added 19.6 g of sodium hydroxide dissolved in 54 ml of water and 25 ml of isobutyraldehyde, and the solution was refluxed for 24 hours. Then the solution was concentrated with 200 ml. Acidified hydrochloric acid and evaporated in vacuo. The residue was taken up in methanol. The methanolic extract was evaporated in vacuo to give 23 g of 4-isopropyl-4,5,6,7-tetrahy-droimidazo [4,5-c] pyridine dihydrochloride, mp. 238 ° C., from which the free base, mp 112 ° C., was obtained by ion exchange on “Amberlite” IRA 410 (brand name). A solution of 1.3 g of the base in 10 ml of dioxane was treated with 1.3 g of methyl isothiocyanate and refluxed for 4 hours. The solution was cooled and filtered. 1.4 g of the compound mentioned in the title were obtained, mp. 240 ° C.

Example 15

4-isopropyl-5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1258)

The procedure was as in Example 14, but using isopropyl isothiocyanate. The compound mentioned in the title was obtained in 80% yield, mp. 203 ° C.

Example 16

3-methyl-5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1276)

A solution of 1 g of 3-methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 1 g of methyl isothiocyanate in 10 ml of acetonitrile was refluxed for 4 hours. The solution was cooled and filtered. 0.9 g of the compound mentioned in the title were obtained, mp. 235 ° C.

Example 17

3-methyl-5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1286)

The procedure was as in Example 16, but using isopropyl isothiocyanate. The compound mentioned in the title was obtained in 66% yield, mp. 205 ° C.

Example 18

5- (N-phenylthiocarbamoyl) -4,5,6,7-tetra-hydroimidazo- [4,5-c] pyridine (386/1116)

The procedure was as in Example 2, but using phenyl isothiocyanate. The compound mentioned in the title was obtained in 82% yield, mp. 205 ° C.

Example 19

5- (N-Cyano-N / -methylguanyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridine (386/1347)

A solution of 1.23 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 1.29 g of N ^ -dimethyl-N'-cyanoisothiourea

(CH3-NH-C = N-CN)

I.

S-CH3

in 15 ml of acetonitrile was refluxed for 21 hours. After evaporation to dryness, chromatography on silica gel (ethyl acetate-ethanol as eluent) of the residue gave 630 mg of the pure compound mentioned in the title, mp 240 ° C.

Example 20 5-Guanyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1289)

A solution of 1.23 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 0.9 g of S-methylisothiourea in 15 ml of acetonitrile was refluxed for 8 hours. After evaporating to dryness, the residue was treated with 1 equivalent of ethanolic hydrogen chloride. After cooling, 1.4 g of the monohydrochloride of the compound mentioned in the title were obtained, mp. 310 ° C.

Example 21 4-Ethyl-5-guanyl-4,5,6,7-tetrahydro-imidazo [4,5-c] pyridine (386/1284)

The procedure was as in Example 20, 1.5 g of monohydrochloride of the compound mentioned in the title, mp. 300 ° C. (dec.), From 1.51 g of 4-ethyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine were obtained.

Example 22 4-Ethyl-5- (N-ethylguanyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1336)

A solution of 1.51 g of 4-ethyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 1.18 g of N-ethyl-S-methylisothiourea in 15 ml of acetonitrile was added for 8 hours held at reflux. After evaporation to dryness, the residue was treated with 1 equivalent of ethanolic hydrogen bromide. After cooling, 1.5 g of the monohydrobromide of the compound mentioned in the title were obtained, mp. 275 ° C.

Example 23

4-ethyl-5- (N-isopropylguanyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1337)

The procedure was as in Example 22, but using N-isopropyl-S-methylisothiourea. 1.6 g of the monohydrobromide of the compound mentioned in the title were obtained, mp. 280 ° C. (dec.).

Example 24

5- (N-ethylguanyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine

The procedure was as in Example 22. The monohydrobromide of the compound mentioned in the title was obtained in 50% yield from 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine.

Example 25 5- (N-Isorpopylguanl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine

The procedure was as in Example 23. The monohydrobromide of the compound mentioned in the title was obtained in 55% yield from 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine.

Example 26

4-phenyl-5- (N-methylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1261)

A solution of 3 g of 4-phenyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 3.42 g of methyl isocyanate in 40 ml of dry dioxane was refluxed for 1½ hours. Evaporation to dryness gave 4.72 g of a solid which was washed with ethyl acetate, dissolved in 60 ml of methanol and treated with 15 ml of 2N sodium hydroxide at room temperature for 2 hours. After neutralization, the solution was extracted with chloroform. When the solvent was evaporated, a residue remained which was taken up in ethyl acetate; 2.5 g of the compound mentioned in the title were obtained, mp. 180 ° C.

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Example 27

4-phenyl-5- (N-isorpopylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1351)

The procedure was as in Example 26, but using isopropyl isocyanate. 3.11 g of the compound mentioned in the title were obtained, mp. 245 ° C.

Example 28

4-ethyl-5- (N-methylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1295)

A solution of 1.51 g of 4-ethyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 2.28 g of methyl isocyanate in 20 ml of dry dioxane was refluxed for 1½ hours. The solution was cooled and filtered. The collected solid was dissolved in 30 ml of methanol and treated with 7 ml of 2N sodium hydroxide for 2 hours at room temperature. After neutralization, the solution was extracted with chloroform. Evaporation of the solvent left a residue which was taken up in ethyl acetate. 1.05 g of the compound mentioned in the title were obtained, mp. 240 ° C.

Example 29

4-ethyl-5- (N-isopropylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1316)

The procedure was as in Example 28, but using isopropyl isocyanate. The compound mentioned in the title was obtained in 70% yield, mp. 170 ° C.

Example 30

5- (N-methylcarbamoyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridine (386/1350)

The procedure was as in Example 28, 1.8 g of the compound mentioned in the title, mp. 213 ° C., being obtained from 2.46 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine were.

Example 31 5- (N-isopropylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1348)

A solution of 2.46 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 6.8 g of isopropyl isocyanate in 50 ml of dry dioxane was refluxed for 2 hours. After evaporating to dryness, the residue was dissolved in 25 ml of methanol and treated with 12.5 ml of 2N sodium hydroxide for 2 hours at room temperature. After neutralization, the solution was extracted with chloroform. Evaporation of the solvent gave 2.21 g of a residue in the form of an oil which was treated with 1 equivalent of hydrogen chloride in isopropanol. After cooling, 1.7 g of the hydrochloride of the compound mentioned in the title were obtained, mp. 190 ° C.

Example 32 5- (N-Cyclopropylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1365)

A solution of 3.69 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 7.47 g of cyclopropyl isocyanate in 20 ml of dry dioxane was refluxed for 1½ hours. After evaporating to dryness, the residue was dissolved in 44 ml of methanol and treated with 11 ml of 2N sodium hydroxide for 1 hour at room temperature. After neutralization, the solution was extracted with chloroform. When the solvent was evaporated, a residue remained which was taken up in acetonitrile; 2.12 g of the compound mentioned in the title were obtained, mp. 215 ° C.

Example 33 5- (N-Cyclopentylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1366)

The procedure was as in Example 32, but using cyclopentyl isocyanate. 3.46 g of the compound mentioned in the title were obtained, mp. 225 ° C.

Example 34

5- (N-Cyclopentylthiocarbamoyl) -4,5,6,7-tetra-hydroimidazo- [4,5rc] pyridine (386/1360)

The procedure was as in Example 2, but using cyclopentyl isothiocyanate. The compound mentioned in the title was obtained in 60% yield, mp. 185 ° C.

Example 35

5- (N-cyclopropylthiocarbamoyl) -4,5,6,7-tetra-hydroimidazo- [4,5-c] pyridine (386/1359)

A solution of 2.462 g of 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 2.97 g of cyclopropyl isothiocyanate in 20 ml of acetonitrile was refluxed for 7 hours. After evaporation to dryness, the residue was chromatographed on silica gel (ethyl acetate-ethanol as eluent), giving 1.42 g of the pure compound mentioned in the title, mp. 185 ° C.

Example 36

4-cyclohexyl-5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1368)

The procedure was as in Example 14, 15.5 g of 4-cyclohexyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine, mp. 150 ° C., from 18.4 g of histamine dihydrochloride and 24.4 ml of hexahydrobenzaldehyde were obtained. A solution of 2.05 g of 4-cyclohexyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 1.1 g of methyl isothiocyanate in 30 ml of acetonitrile was refluxed for 5 hours. The solution was cooled and filtered. 2.5 g of the compounds mentioned in the title were obtained, mp 232 ° C.

Example 37

4-cyclohexyl-5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1367)

The procedure was as in Example 36, with 2.53 g of the compound mentioned in the title, mp. 218 ° C., from 2.05 g of 4-cyclohexyl-4,5,6,7-tetrahydroimidazo [4.5 -c] pyridine and 1.52 g of isopropyl isothiocyanate were obtained.

Example 38

4- (2-thienyl) -5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1369)

The procedure was as in Example 14, 15 g of 4- (2-thienyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine, mp. 170 ° C., from 18.4 g Histamine dihydrochloride and 18.4 ml of 2-thiophenaldehyde were obtained. A solution of 2.05 g of 4- (2-thienyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine and 1.52 g of isopropyl isothiocyanate in 30 ml of acetonitrile was added for 5 hours held at reflux. The solution was cooled and filtered. 2.18 g of the compound mentioned in the title were obtained, mp. 205 ° C.

Example 39

4- (2-thienyl) -5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo- [4,5-c] pyridine (386/1383)

The procedure was as in Example 38, the compound mentioned in the title being obtained in 66% yield, mp. 215 ° C.

Example 40

4- (2-furyl) -5- (N-methylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1372)

The procedure was as in Example 14, with 12 g of 4- (2-furyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (oil)

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6

18.4 g of histamine dihydrochloride and 16.6 ml of furfural were obtained. A solution of 1.89 g of 4- (3-furyl) -4,5,6,7-tetrahy-droimidazo [4,5-c] pyridine and 1.1 g of methyl isothiocyanate in 20 ml of acetonitrile was added for 5 hours held at reflux. The solution was cooled and filtered. 1.54 g of the compound mentioned in the title were obtained, mp. 200 ° C.

Example 41

4- (2-furyl) -5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1373).

The procedure was as in Example 40, with 1.61 g of the compound mentioned in the title, mp. 195 ° C., from 1.89 g of 4- (2-furyl) -4,5,6,7-tetrahydroimidazo- [4 , 5-c] pyridine and 1.52 g of isopropyl isothiocyanate were obtained.

Example 42

4-Cyclohexyl-5- (N-methylcarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1374).

The procedure was as in Example 28, 3.1 g of the compound mentioned in the title, mp. 250 ° C., from 4.1 g of 4-cyclo-hexyl-4,5,6,7-tetrahydroimidazo- (4,5- c] pyridine were obtained.

Example 43

4-cyclohexyl-5- (N-isopropylcarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1375)

The procedure was as in Example 29, 3.45 g of the compound mentioned in the title after crystallization from ethanol, mp 254 ° C., from 4.1 g of 4-cyclohexyl-4,5,6,7-tetrahydroimidazo [4.5 -c] pyridine were obtained.

Example 44

4- (2-thienyl) -5- (N-isopropylcarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1376)

The procedure was as in Example 26, but using isopropyl isocyanate. 2.3 g of the compound mentioned in the title, after crystallization from ethanol, mp. 223 ° C. (dec.), From 3.5 g of 4- (2-thienyl) -4,5,6,7-tetrahydro-imidazo - [4,5-c] pyridine obtained.

Example 45 4-isopropyl-5- (N-isopropylcarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1377)

The procedure was as in Example 26, but using isopropyl isocyanate. 2.8 g of the compound mentioned in the title were crystallized from acetonitrile, mp. 202 ° C., from 2.48 g of 4-isopropyl-4,5,6,7-tetrahydroimi-dazo- [4,5-c] -pyridine received.

Example 46

4- (2-thienyl) -5- (N-methylcarbamoyl) -4,5,6,7-tetrahydroimidazo- [4,5-c] pyridine (386/1378)

The procedure was as in Example 26, with 1.14 g of the compound mentioned in the title after crystallization from acetonitrile, mp. 230 ° C., from 3.5 g of 4- (2-thienyl) -4,5,6,7- tetrahydroimi-dazo- [4,5-c] pyridine were obtained.

Example 47

4- (2-furyl) -5- (N-methylcarbamoyl) -4,5,6,7-tetra-hydroimidazo [4,5-c] pyridine (386/1379)

The procedure was as in Example 26, with 1.55 g of the compound mentioned in the title after crystallization from acetonitrile, mp. 205 ° C., from 1.89 g of 4- (2-furyl) -4,5,6,7- tetrahydroimi-dazo- [4,5-c] pyridine were obtained.

Example 48

4- (2-furyl) -5- (N-isopropylcarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1382)

The procedure was as in Example 26, but using isopropyl

pyl isocyanate was used. After crystallization from acetonitrile, 2.23 g of the compound mentioned in the title, mp. 237 ° C. (dec.), From 2.84 g of 4- (2-furyl) -4,5,6,7-tetrahydroimidazo - [4,5-c] pyridine obtained.

Example 49

3-methyl-4-ethyl-5- (N-isopropylthiocarbamoyl) -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine (386/1391)

The procedure was as in Example 17, the compound mentioned in the title being obtained after crystallization from ethanol in 50% yield, mp. 196 ° C.

Example 50

4-phenyl-5-guanyl-4,5,6,7-tetrahydro-imidazo [4,5-c] pyridine (386/1401)

The procedure was as in Example 20, the monohydrochloride of the compound mentioned in the title being obtained in recrystallization from ethanol in 80% yield, mp. 288 ° C. (dec.).

Example 51

4-cyclohexyl-5-guanyl-4,5,6,7-tetrahydro-imidazo [4,5-c] pyridine (386/1405)

The procedure was as in Example 20, the monohydrochloride of the compound mentioned in the title being obtained after crystallization from ethanol in 60% yield, mp. 305 ° C. (dec.).

The characteristic substituents of the compounds of formula I produced according to the above examples are summarized in the following Table III:

Table III

Example No.

ri r *

r3

r4

X

1

H

H

CH3

S

2nd

H

H

c2h5

S

3rd

H

H

c3h7

S

4th

H

H

ì-c3h7

S

5

H

H

n-qh9

s

6

H

H

Cyclohexyl

s

7

H

C2H5

CHs

s

8th

H

H

Allyl

s

9

H

C2H5

ì-c3h7

s

10th

H

C2H5

Allyl

s

11

H

C2H5

n — c4h9

s

12

H

Phenyl ch3

s

13

H

Phenyl

ì-c3h7

s

14

H

ì-c3h7

CH3

s

15

H

1-c3h7

ì-c3h7

s

16

CH3

H

CHs

s

17th

CH3

H

ì-c3h7

s

18th

H

H

Phenyl

s

19th

H

H

CHs

CN

NR4

20th

H

H

H

H

no4

21st

H

C2H5

H

H

NR4

22

H

C2H5

C2H5

c2h5

no4

23

H

C2H5

Ì-C3H7

ì-c3h7

no4

24th

H

H

C2H5

c2h5

NR4

25th

H

H

ì-c3h7

ì-c3h7

no4

26

H

Phenyl

CHs

0

27

H

Phenyl

Ì-C3H7

0

28

H

C2H5

CHs

0

29

H

C2H5

ì-c3h7

0

30th

H

H

ch3

0

31

H

H

Ì-C3H7

0

32

H

H

Cyclopropyl

0

33

H

H

Cyclopentyl

0

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

7

Table III (continued)

626084

Example No.

ri ra r3

r4

X

34

H

H

Cyclopentyl

S

35

H

H

Cyclopropyl

S

36

H

Cyclohexyl

CHs

S

37

H

Cyclohexyl

Ì-c3h7

S

38

H

Thienyl

Ì-C3H7

S

39

H

Thienyl

CHs

s

40

H

Furyl

CHs

s

41

H

Furyl

1-C3H7

s

42

H

Cyclohexyl

CHs

0

43

H

Cyclohexyl

Ì-c3h7

0

44

H

Thienyl

Ì-c3h7

0

45

H

Ì-c3h7

Ì-c3h7

0

46

H

Thienyl

CHs

0

47

H

Furyl

CH3

0

48

H

Furyl

Ì-C3H7

0

49

CHs c2h5

Ì-c3h7

s

50

H

Phenyl

H

H

no4

51

H

Cyclohexyl

H

H

no4

Claims (3)

626084 2. The method according to claim 1, characterized in that condensed in a solvent from the group of ethanol, acetonitrile and dioxane for 4-12 hours at reflux. 2nd PATENT CLAIMS 1. Process for the preparation of new 4,5,6,7-tetrahy-droimidazo- (4,5-c) -pyridine derivatives of the formula N C-NHR wherein Ri is hydrogen or alkyl with 1-4 C atoms, R2 is hydrogen, alkyl with 1-4 C atoms, cycloalkyl with 3-6 C atoms, phenyl or a heterocyclic hydrocarbon radical, R3 is hydrogen, straight or branched chain alkyl or alkenyl with 1-6 C atoms or cycloalkyl with 3-6 C atoms or a phenyl group, and X is oxygen, sulfur or NR4, where R4 is hydrogen, alkyl with 1-4 C atoms, amino, cyano, nitro or acylamino stands, and of their pharmaceutically usable acid addition salts, characterized in that a 4,5,6,7-tetrahy-droimidazo (4,5-c) pyridine with an alkyl isocyanate or isothiocyanate or with a substituted S- Methylthiourea condensed. 3. Compounds of the formula I prepared by the process according to claim 1