CA1075240A - 4,5,6,7-tetrahydroimidazo-(4,5-c)-pyridine derivatives - Google Patents
4,5,6,7-tetrahydroimidazo-(4,5-c)-pyridine derivativesInfo
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- CA1075240A CA1075240A CA269,126A CA269126A CA1075240A CA 1075240 A CA1075240 A CA 1075240A CA 269126 A CA269126 A CA 269126A CA 1075240 A CA1075240 A CA 1075240A
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- pyridine
- imidazo
- carbon atoms
- tetrahydro
- hydrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
ABSTRACT OF THE DISCLOSURE
New 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine deriva-tives are disclosed, and more particularly derivatives of Formula I:
I
wherein R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, phenyl, furyl or thienyl group;
R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl and X is O, S or NR4 where R4 is hydrogen, or a cyano group;
or pharmaceutically acceptable acid addition salts thereof.
Also disclosed is a process of preparing these compounds which comprises condensing an appropriate 4,5,6,7-tetrahydroimidazo [4,5-c]-pyridine with an appropriate alkyl isocyanate, alkyl isothiocyanate or substituted S-methyl thiourea, preferably in a solvent such as ethanol, acetonitrile or dioxane, usually under reflux for from 4 to 12 hours. The products can be isolated by crystalization as free bases or as salts of pharmaceutically acceptable acids. The new compounds have proved to be well tolerated and to inhibit both the number of experimental ulcers and the gastric secretion in experimental animals. Thus, they should prove useful in the therapy of gastric and duodenal ulcers in man.
New 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine deriva-tives are disclosed, and more particularly derivatives of Formula I:
I
wherein R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, phenyl, furyl or thienyl group;
R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl and X is O, S or NR4 where R4 is hydrogen, or a cyano group;
or pharmaceutically acceptable acid addition salts thereof.
Also disclosed is a process of preparing these compounds which comprises condensing an appropriate 4,5,6,7-tetrahydroimidazo [4,5-c]-pyridine with an appropriate alkyl isocyanate, alkyl isothiocyanate or substituted S-methyl thiourea, preferably in a solvent such as ethanol, acetonitrile or dioxane, usually under reflux for from 4 to 12 hours. The products can be isolated by crystalization as free bases or as salts of pharmaceutically acceptable acids. The new compounds have proved to be well tolerated and to inhibit both the number of experimental ulcers and the gastric secretion in experimental animals. Thus, they should prove useful in the therapy of gastric and duodenal ulcers in man.
Description
1075;~0 1 ~his invention relates to new 4,5,6,7-tetrahydro-imidazo-l4,5-c]-pridine derivatives.
This invention provides new derivatives of the formula I:
~, 11 ~,N-C-N~R
¦ H R2 - 10 where Rl is hydrogen or an alkyl having from 1 to 4 . carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, phenyl, ~uryl or thienyl group;
~ . .
. R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl; and ,~ X is 0, S or NR4 where R4 is hydrogen, or a ,~- cyano group;
:~ 20 or a pharmaceutically acceptable acid addition salt !', , thereof.
This invention includes a process of preparing these ~5. compounds which comprises condensing an appropriate 4,5,6,7-~ tetrahydroimidazo-~4,5-cl-pyridine with an appropriate alkyl ': isocyanate, al~yl isothiocyanate or substituted S-methyl thiourea, preferably in a solvent such as ethanol, acetonitrile or dioxane, usually under reflux for from 4 to 12 hours. ~he products can be f isolated by crystallization as free bases or as salts of pharma--~ ceutically acceptable acids.
The new compounds of this invention have proved to be ,, -- 1 --, ~," '`.~L 3 1075;~0 1 well tolerated and to inhibit both the number of experimental ulcers and the gastric secretion in experimental animals. Thus, they should prove useful in the therapy of gastric and duodenal ulcers in man.
The activity of these compounds has been assessed in rats in anti-ulcer and anti-secretory tests. Methiamide, which is well known for its antisecretory activity (Wyllie et al.: Gut.1973, 14, 424), and is considered one of the most active substances in this field (S.Dai et al., Eur. J. Pharm., 1975, 33,277), was 10 adopted as the reference standard.
1. Inhibition of restraint ulcer in rats (Bonfils et al., Therapie, 1960, 15 1096). Six Spraque-Dowley male rats (lOQ-200 g) fasted for 24 hours were used for each group.
A square flexible small-mesh wire netting was used for immobilization. After 4 hours immobilization the rats were sacri-ficed, their stomachs were removed, and lesions counted under a dissecting microscope.
The obtained results were reported in Table I, wherein the values are given as ED50.
The compounds were administered subcutaneously (s.c.) (10 mg/kg) immediately before the immobilization or orally (os) (50 mg/kg) one hour before.
This invention provides new derivatives of the formula I:
~, 11 ~,N-C-N~R
¦ H R2 - 10 where Rl is hydrogen or an alkyl having from 1 to 4 . carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, phenyl, ~uryl or thienyl group;
~ . .
. R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl; and ,~ X is 0, S or NR4 where R4 is hydrogen, or a ,~- cyano group;
:~ 20 or a pharmaceutically acceptable acid addition salt !', , thereof.
This invention includes a process of preparing these ~5. compounds which comprises condensing an appropriate 4,5,6,7-~ tetrahydroimidazo-~4,5-cl-pyridine with an appropriate alkyl ': isocyanate, al~yl isothiocyanate or substituted S-methyl thiourea, preferably in a solvent such as ethanol, acetonitrile or dioxane, usually under reflux for from 4 to 12 hours. ~he products can be f isolated by crystallization as free bases or as salts of pharma--~ ceutically acceptable acids.
The new compounds of this invention have proved to be ,, -- 1 --, ~," '`.~L 3 1075;~0 1 well tolerated and to inhibit both the number of experimental ulcers and the gastric secretion in experimental animals. Thus, they should prove useful in the therapy of gastric and duodenal ulcers in man.
The activity of these compounds has been assessed in rats in anti-ulcer and anti-secretory tests. Methiamide, which is well known for its antisecretory activity (Wyllie et al.: Gut.1973, 14, 424), and is considered one of the most active substances in this field (S.Dai et al., Eur. J. Pharm., 1975, 33,277), was 10 adopted as the reference standard.
1. Inhibition of restraint ulcer in rats (Bonfils et al., Therapie, 1960, 15 1096). Six Spraque-Dowley male rats (lOQ-200 g) fasted for 24 hours were used for each group.
A square flexible small-mesh wire netting was used for immobilization. After 4 hours immobilization the rats were sacri-ficed, their stomachs were removed, and lesions counted under a dissecting microscope.
The obtained results were reported in Table I, wherein the values are given as ED50.
The compounds were administered subcutaneously (s.c.) (10 mg/kg) immediately before the immobilization or orally (os) (50 mg/kg) one hour before.
2. Inhibition of gastric secretion in rats (Shay, Gastroenterolo~y, 1945, 43, 5). Gastric antisecretory activity was evaluated in rats by the pylorus ligature technique.
Six Sprague-Dowley male rats (110-130 g) were used for each group. Twenty-four hours before the test, the rats were deprived of food but their water supply was maintained.
On the day of the operation, the pylorus was ligated 30 under light ether anesthesia. Four hours after the ligature, the 1~75~40 1 rats were sacrificed, the stomach secretion was collected and centrifuged at 3500 r.p.m. for 10 minutes, and the volume, less sediment, was determined. The amount of the free hydrochloric acid in the gastric juice was determined by titration against 0.01 N sodium h~droxide, using Topfer's Indicator. Each compound, at a dose of 50 mg/kg, was injected subcutaneously at the time of ligature.
Table Ishows the results obtained expressed as ED50.
The compound reference numbers are explained in the Examples below.
TABLE I
lO ED50's for anti-ulcer and anti-secretory acitivities ~ lAnti-ulcer Anti-secretory . ~ ,_ Compound 1 s.c. p.o.s.c.
Methiamide 14 64 60 386/1087 0.9 3.1 6 1068 0.6 2.4 50 1184 0.64 11 22 1286 0.85 8.5 34 1287 i9 50 50 135g 5 1.8 40 1360 10 5.6 19 1367 3.3 6 50 1316 0.75 6.6 50 1348 0.1 O.SS 18 1350 6.5 5.6 50 1365 2 3.8 50 136~ 0.75 3.8 _ 17 Considering that many anti-ulcer agents display a remarkable anti-cholinergic activity, some derivatives have been ~75'~40 1 also orally assessed for their antagonism against cromodacrior-rhea induced by carbacholine in rats (Winburg M. et al.:
J.Pharm.Exp. Therap., 1949, 95, 53).
As appears from Table II, showing the ratios between the ED50,s for the anti-cholinergic and anti-ulcer activity, some derivatives display an anti-ulcer activity at doses 5 to 25 times lower than those active as anti-cholinergic.
For both atropine and methiamide such a ratio is about 2.
TABLE II - ED50 in rats per os Compound Anti-cholinergic Anti-cholinergic ED50/
/Anti-ulcer ED50 Atropine 0.8 2 ; Methiamide 85 1.33 386/1286 50 5.88 /1359 45.5 25.28 /1360 76 13.57 /1316 70 10.61 f1348 7.8 14.18 /1350 100 17.86 /1365 21 5.53 In the therapeutic field, the products of the present invention may be administered by the oral or the parenteral route.
The therapeutic compositions normally employed include one or more compounds of the present 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 steri-lized are employed for the parenteral administration. Conventional
Six Sprague-Dowley male rats (110-130 g) were used for each group. Twenty-four hours before the test, the rats were deprived of food but their water supply was maintained.
On the day of the operation, the pylorus was ligated 30 under light ether anesthesia. Four hours after the ligature, the 1~75~40 1 rats were sacrificed, the stomach secretion was collected and centrifuged at 3500 r.p.m. for 10 minutes, and the volume, less sediment, was determined. The amount of the free hydrochloric acid in the gastric juice was determined by titration against 0.01 N sodium h~droxide, using Topfer's Indicator. Each compound, at a dose of 50 mg/kg, was injected subcutaneously at the time of ligature.
Table Ishows the results obtained expressed as ED50.
The compound reference numbers are explained in the Examples below.
TABLE I
lO ED50's for anti-ulcer and anti-secretory acitivities ~ lAnti-ulcer Anti-secretory . ~ ,_ Compound 1 s.c. p.o.s.c.
Methiamide 14 64 60 386/1087 0.9 3.1 6 1068 0.6 2.4 50 1184 0.64 11 22 1286 0.85 8.5 34 1287 i9 50 50 135g 5 1.8 40 1360 10 5.6 19 1367 3.3 6 50 1316 0.75 6.6 50 1348 0.1 O.SS 18 1350 6.5 5.6 50 1365 2 3.8 50 136~ 0.75 3.8 _ 17 Considering that many anti-ulcer agents display a remarkable anti-cholinergic activity, some derivatives have been ~75'~40 1 also orally assessed for their antagonism against cromodacrior-rhea induced by carbacholine in rats (Winburg M. et al.:
J.Pharm.Exp. Therap., 1949, 95, 53).
As appears from Table II, showing the ratios between the ED50,s for the anti-cholinergic and anti-ulcer activity, some derivatives display an anti-ulcer activity at doses 5 to 25 times lower than those active as anti-cholinergic.
For both atropine and methiamide such a ratio is about 2.
TABLE II - ED50 in rats per os Compound Anti-cholinergic Anti-cholinergic ED50/
/Anti-ulcer ED50 Atropine 0.8 2 ; Methiamide 85 1.33 386/1286 50 5.88 /1359 45.5 25.28 /1360 76 13.57 /1316 70 10.61 f1348 7.8 14.18 /1350 100 17.86 /1365 21 5.53 In the therapeutic field, the products of the present invention may be administered by the oral or the parenteral route.
The therapeutic compositions normally employed include one or more compounds of the present 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 steri-lized are employed for the parenteral administration. Conventional
3~
excipients may be employed, among which the most common are starch, 1C~75Z40 1 lactose, talc, magnesium stearate, and the like.
This invention is illustrated by the following Examplesin which all temperatures are in degrees Celsius (C).
Exam~le 1 -5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine (386/1068).
A solution of 1 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed.Sci., 1967, 22, 821) and 0.65 g of methyl isothiocyanate in 20 ml of ethanol are refluxed for 8 h.
The solution is cooled and filtered: 1.15 g of 5-(N-methyl-thio-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 228, are collected.
Example 2 5-(N-ethyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine ~386/1293).
A solution of 1.85 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2 g of ethyl isothiocyanate in 15 ml of ace-tonitrile are refluxed for 7 h. The solution is cooled and filtered:
2.5 g of 5-[N-ethyl-thiocarbamoyl]-4,5,6,7-tetrahydroimidazo-E4,5-c]-pyridine, m.p. 185, are collected.
Example 3 5-(N-n-propyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1361).
Operating as in Example 1, but employing propyl isothiocyanate, the product is obtained in 81~ yield, m.p. 151.
xample 4 5-(N-i propyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine ~386/1087).
; A solution of 2 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride and 2.5 g of isopropyl isothiocyanate in ' 1 20 ml of acetonitrile and 5 ml of ethanol is refluxed 8 h. Evapo-ration of the solvent leaves a residue that is treated with one equivalent of ethanolic hydrogen chloride. Evaporation of the solvent leaves a residue which is crystallized from acetone to give 2.5 g of 5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 170.
Example 5 5-(N-n-butyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1331).
Operating as in Example 1, but employing butyl isothio-cyanate the product is obtained in 75% yield, m.p. 130.
Example 6 5-(N-cyclohexyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1294).
Operating as in Example 2, but employing cyclohexyl isothiocyanate the product, m.p. 183, is obtained in 82% yield.
Example 7
excipients may be employed, among which the most common are starch, 1C~75Z40 1 lactose, talc, magnesium stearate, and the like.
This invention is illustrated by the following Examplesin which all temperatures are in degrees Celsius (C).
Exam~le 1 -5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine (386/1068).
A solution of 1 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed.Sci., 1967, 22, 821) and 0.65 g of methyl isothiocyanate in 20 ml of ethanol are refluxed for 8 h.
The solution is cooled and filtered: 1.15 g of 5-(N-methyl-thio-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 228, are collected.
Example 2 5-(N-ethyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine ~386/1293).
A solution of 1.85 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2 g of ethyl isothiocyanate in 15 ml of ace-tonitrile are refluxed for 7 h. The solution is cooled and filtered:
2.5 g of 5-[N-ethyl-thiocarbamoyl]-4,5,6,7-tetrahydroimidazo-E4,5-c]-pyridine, m.p. 185, are collected.
Example 3 5-(N-n-propyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1361).
Operating as in Example 1, but employing propyl isothiocyanate, the product is obtained in 81~ yield, m.p. 151.
xample 4 5-(N-i propyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine ~386/1087).
; A solution of 2 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride and 2.5 g of isopropyl isothiocyanate in ' 1 20 ml of acetonitrile and 5 ml of ethanol is refluxed 8 h. Evapo-ration of the solvent leaves a residue that is treated with one equivalent of ethanolic hydrogen chloride. Evaporation of the solvent leaves a residue which is crystallized from acetone to give 2.5 g of 5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 170.
Example 5 5-(N-n-butyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1331).
Operating as in Example 1, but employing butyl isothio-cyanate the product is obtained in 75% yield, m.p. 130.
Example 6 5-(N-cyclohexyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1294).
Operating as in Example 2, but employing cyclohexyl isothiocyanate the product, m.p. 183, is obtained in 82% yield.
Example 7
4-Ethyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-t4,5-c]-pyridine (386/1214).
A solution of 2.9 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Framaco, Ed.Sci. 1967, 22, 821) and 3 g of methyl isothiocyanate in 32 ml of acetonitrile and 8 ml of ethanol is refluxed for 8 h. The solution is evaporated in vacuo, and the residue crystallized from diethyl ether to give 3 g of 4-ethyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine, m.p. 230.
Example 8
A solution of 2.9 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Framaco, Ed.Sci. 1967, 22, 821) and 3 g of methyl isothiocyanate in 32 ml of acetonitrile and 8 ml of ethanol is refluxed for 8 h. The solution is evaporated in vacuo, and the residue crystallized from diethyl ether to give 3 g of 4-ethyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine, m.p. 230.
Example 8
5-(N-allyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/ll85)~
Operating as in Example 2, but employing allylisothio-, p.
~ ., 107~Z~0 1 cyanate, the p~od~lct, m.p. 172/ is obtained in 71~ yield.
Example 9 4-Ethyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine (386/1184).
Operating as in Example 7, but employing isopropyl iso-thiocyanate, the product, m.p. 215, is obtained in 79% yield.
Example 10 4-Ethyl-5-(N-allyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine (386/1216).
Operating as in Example 7, but employing allyl isothio-cyanate, the product, m.p. 205, is obtained in 70% yield.
Example 11 4-Ethyl-5-(N-butyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine (386/1215).
Operating as in Example 7, but employing butyl isothio-cyanate, the product, m.p. 180, is obtained in 75% yield.
Example 12 4-Phenyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1254).
A solution of 3.5 g of 4-phenyl-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine (Farmaco, Ed.Sci., 1967, 22, 821) and 3.5 g of methyl isothiocyanate in 55 ml of dioxane is refluxed for 4 h. The solution is cooled and filtered: 3.6 g of 4-phenyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c~-pyri-dine, m.p. 228, are collected.
Example 13 !'' 4-Phenyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine (386/l253).
;~ Operating as in Example 12, but employing isopropyl iso-thiocyanate, the product, m.p. 198, is obtained in 80% yield.
752~0 E~ample 14 4-iso-propyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[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, 19.6 g of sodium hydroxide dissolved in 54 ml of water and 25 ml of isobutyraldehyde are added and the solution refluxed for 24 h. The solution is then acidified with 200 ml of conc. hydrochloric acid and evaporated in vacuo. The residue is taken up in methanol. The methanolic ex-tract is evaporated in vacuo to give 23 g of 4-isopropyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine dihydrochloride, m.p. 238, from which the free base, m.p. 112, is obtained by ion-exchange on Amberlite (Trade Mark) IRA 410. A solution of 1.3 g of the base in 10 ml of dioxane is treated with 1.3 g of methyl isothiocyanate and refluxed or 4 h. The solution is cooled and filtered; 1.4 g of 4-isopropyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 240, are collected.
Example 15 4-iso-propyl-5-(N-iso~ropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1258).
Operating as in Example 14, but employing isopropyl isothiocyanate, the product, m.p. 203, is obtained in 80% yield.
Example 16 3-Methyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine ~86/1276).
A solution of 1 g of 3-methyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and l g of methyl isothiocyanate in 10 ml of acetonitrile is refluxed for 4 h. The solution is cooled and filtered: 0.9 g of 3-methyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 235, are collected.
.
1 _xample :l7 3-Methyl-5-(N-isopropyl-thiocarbamoyl-4,5,6,7-tetra-hydro-imidazo-l4,5-c]-pyridine ~386/1286).
Operating as in Example 16, but employing isopropyl iso-thiocyanate, the product, m.p. 205, is obtained in 66% yield.
Example 18 5-(N-Phenyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c3-pyridine (386/1116).
Operating as in Example 2, but employing phenyl isothio-cyanate, the product, m.p. 205, is obtained in 82% yield.
Example 19 5-~N-cyano-N'-methyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1347).
A solution of 1.23 g of 4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine and 1.29 g of N,S-dimethyl-N'-cyano-isothiourea (CH3-NH-C=N-CN) in 15 ml of acetonitrile is refluxed for 21 h.
, S-CH3 G
After evaporation to dryness, chromatography on silica ~el (ethyl acetaté-ethanol as eluant) of the residue gives 630 mg of the pure 20 title compound, m.p. 240.
~ Example 20 r 5-Guanyl-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine ,. ..
(386/1285~.
' A solution of 1.23 q of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 0.9 g of S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness, the residue is treated with one equivalent of ethanolic hydrogen chloride. After cooling, 1.4 g of 5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydrochloride, m.p. 310, are 30 collected.
.
_ g _ ,~' 1075'Z~0 1 Example 21 4-Ethyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1284).
Operating as in Example 20, 1.5 g of 4-ethyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine monohydrochloride, m.p. 300 (dec.), are obtained from 1.51 g of 4-ethyl-4,5,6,7,-tetrahydro-imidazo-[4,5-c]-pyridine.
Example 22 4-Ethyl-5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c3-pyridine (386/1336).
A solution of 1.5 g of 4-ethyl-4,5,6,7-tetrahydro-imi-dazo-[4,5-c]-pyridine and 1.18 g of N-ethyl-S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness the residue is treated with one equivalent of ethanolic hydrogen bromide. After cooling, 1.5 g of 4-ethyl-5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydro-l bromide, m.p. 275, are collected.
Example 23 4-Ethyl-5-(N-isopropyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1337).
Operating as in Example 22, but employing N-isopropyl-S-methyl-isothiourea, 1.6 g of 4-ethyl-5-(N-isopropyl-g~anyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine monohydrobromide (m.p. 280 (dec.)) are obtained.
Example 24 .
5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-14,5-cl-pyridine.
Operating as in Example 22, the monohydrobromide of the :-:
title compound is obtained in 50% yield from 4,5,6,7-tetrahydro-imidazol4,5-c]-pyridine.
1~7S240 ~;xamplc 2r~
5~ isopropyl-guanyl)-4,5,6,7-tetrahydro-imidaza-[4,5-c]-pyridine.
Operating as in Example 23, the monohydrobromide of the title compound is obtained in 55% yield from 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
E~ample 26 4-Phenyl-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine ~386/1261).
A solution of 3 g of 4-phenyl-4,5,6,7-tetrahydro-imidazo-~4,5-c3-pyridine and 3.42 g of methyl isocyanate in 40 ml of dry dioxane is refluxed for 1.5 h. Evaporation to dryness gives a ~, solid (4.72 g) that is washed with someethyl acetate, dissolved in 60 ml of methanol and treated with 15 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in ethyl acetate to give 2.5 g of the title compound, m.p. 180.
Example 27 4-Phenyl-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1351).
Operating as in Example 26, but employing isopropyl iso-cyanate, 3.11 g of the title compound, m.p. 245, are obtained.
Example 28 4-Ethyl-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c3-pyridine (386~1295).
A solution of 1.51 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine and 2.28 g of methyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. The solution is cooled and 30 filtered. The solid collected is dissolved in 30 ml of methanol 1~7S'~40 1 and treated with 7 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization the solution is ex~racted with chloroform. Evaporation of the solvent leaves a residue that is taken up in ethyl acetate. 1.05 g of the title compound, m.p. 240, are collected.
E~ample 29 4-Ethyl-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-~4,5-c~-pyridine (386/1316).
Operating as in Example 28, employing isopropyl iso-lO cyanate, the title compound, m.p. 170, is obtained in 70% yield.
Example 30 5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine (386/1350).
Operating as in Example 28, 1.8 g of the title compound, m.p. 213, are obtained from 2.46 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
Example 31 5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine (386/1348).
A solution of 2.46 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 6.8 g of isopropyl isocyanate in 50 ml of dry dioxane is refluxed for 2 h. After evaporation to dryness, the residue is dissolved in 25 ml of methanol and treated with 12.5 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization, the solution is extracted with chloroform. Evapo-ration of the solvent leaves a residue ~2.21 g, oil) that is treated with one equivalent of hydrogen chloride in isopropanol.
A~ter cooling, 1.7 g of 5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 190, are collected.
1~7~Z~O
E~mole 32 5-(N-cyclopropyl-carbamoyl)-~,5,6,7-tetrahydro-imidazo-~4,5-c]-pyridine (386/1365).
A solution of 3.69 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.47 g of cyclopropyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. After evaporation to dryness, the residue is dissolved in 44 ml of methanol and treated with 11 ml of 2N sodium hydroxide for l.S h at room temperature. After neutralization, the solution is extracted with chloroform. Evapora-tion of the solvent leaves a residue that is taken up in acetoni-trile to give 2.12 g of the title compound, m.p. 215.
Example 33 5-(N-cyclopentyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1366).
Operating as in Example 32, but employing cyclopentyl isocyanate, 3.46 g of the title compound, m.p. 225, are obtained.
Example 34 5-~cyclopentyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-~4,5-c]-pyridine (386/1360).
Operating as in Example 2, but employing cyclopentyl isothiocyanate, the title compound, m.p. 185, is obtained in 60%
- yield.
Example 35 5-(N-cyclopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-r4,S-c3-pyridine (386~1359).
A solution of 2.462 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c3-pyridine and 2.97 g of cyclopropyl isothiocyanate in 20 n~l of acetonitrile is refluxed for 7 h. After evaporation to dryness, the residue is chromatographed on silica gel (ethyl acetate-30 ethanol as eluant) to give 1.42 g of the pure title compound, m.p.1~5.
)75Z40 1 Example 36 4-Cyclohexyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c3-pyridine (386/l368)~
Operating as in Example 14, 15.5 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 150, are obtained from 18.4 g of histamine dihydrochloride and 24.4 ml of hexahydrobenzaldehyde. A solution of 2.05 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo[4,5-c~-pyridine and 1.1 g of methyl isothiocyanate in 30 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered, and 2.50 g of the title compound, m.p. 232, are collected.
Example 37 4-Cyclohexyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-- tetrahydro-imidazo-[4,5-c]-pyridine (386/1367) Operating as in Example 36, 2.53 g of the title compound, m.p. 218 are obtained from 2.05 g of 4-cyclohexyl-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine and 1.52 g of isopropyl isothio-cyanate.
i Example 38 "
;- 20 4-(2-thienyl)-5-N-isopropyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pridine (386/1369) Operating as in Example 14,15 g of 4-(2-thienyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 170, are obtained from 18.4 g of histamine dihydrochloride and 18.4 ml of 2-thiophenaldehyde. A solution of 2.05 g of 4-(2-thienyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.52 g-of isopropyl i isothiocyanate in 30 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered: 2.18 g of the title compound, m.p. 205, are collected .
.
Example 39 4-(2-thienyl)-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-:
- 107~240 1 hydro-imidazo-[4,S-c~-pyridine (386/1383).
Operatiny as in Example 38, the title compound is obtained in 56% yield, m.p. 215.
Examplc 40 4-(2-furyl)-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c3-pyridine (336/1372).
Operating as in Example 14, 12 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (oil) are obtained from 18.4 g of histamine dihydrochloride and 16.6 ml of furfural.
A solution of 1.89 g o~ 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine a.nd 1.1 g of methyl isothiocyanate in 20 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered: 1.54 g of the title compound, m.p. 200, are collected.
Example 41 4-(2--furyl)-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine t386/1373).
' Operating as in Example 40, 1.61 g of the title compound, m.p. 195, are obtained from 1.89 g of 4-(2-furyl)-4,5,6,7-tetra-hydro-imidazo-~4,5-c]-pyridine and 1.52 g of isopropyl isothio-~ cyanate.
Example 42 4-Cyclohexyl-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1374).
Operating as in Example 28, 3.1 g of the title compound, m.p. 250, are obtained from 4.1 g of 4-cyclohexyl-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine.
Example 43 -:
4-Cyclohexyl-S-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-t4,5-c]-pyridine (386/1375).
Operating as in Example 29, 3.45 g of the title compound, ;;
~075240 1 crystallized from ethanol and melting at 254, are obtained from 4.1 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
E~ample 44 4-(2-thienyl)-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine (386/1376).
Operating as in Example 26, but employing isopropyl iso-cyanate, 2.3 g of the title compound, crystallized from ethanol and melting at 223 (dec.), are obtained from 3.S g of 4-(2-thienyl) 4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine.
Example 45 4-Isopropyl-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-14,5-c]-pyridine (386/1377).
Operating as in Example 26, but employing isopropyl iso-cyanate, 2.8 g of the title compound, crystallized from acetoni-trile and melting at 202, are obtained from 2.48 g of 4-isopropyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine. -~
Example 46 4-(2-thienyl)-5-~N-methyl-car~amoyl)-4,5,6,7-tetrahydro-j imidazo-[4,5-c]-pyridine (386/1378).
Operating as in Example 26, 1.14 g of the title com-pound, crystallized from acetonitrile and melting at 230, are obtained from 3.5 g of 4-(2-thienyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
Example 47 4-(2-furyl)-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1379).
Operating as in Example 26, 1.55 g of the title com-pound, crystallized from acetonitrile and melting at 205, are ~- o~tained from 1.89 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
., 10~524~0 1 E~~mple ~8 4-(2-furyl)-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine (386/1382).
Operating as in Example 26, but employing isopropyl iso-cyanate, 2.23 g of the title compound, crystallized from acetoni-trile and melting at 237 (dec.), are obtained from 2.84 of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-~4,5-c]-pyridine.
Example 49 3-Methyl-4-ethyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386~1391).
Operating as in Example 17, the title compound crystal-lized from ethanol and melting at 196, is obtained in 50~ yield.
Example 50 4-Phenyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1401).
Operating as in Example 20, the monohydrochloride of the title compound, crystallized from ethanol and melting at 288 (dec.), is obtained in 80~ yield.
Example 51 4-Cyclohexyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-14,5-c~-pyridine (386/1405).
Operating as in Example 20, the monohydrochloride of the title compound, crystallized from ethanol and melting at 305 (dec.), is obtained in 60% yield.
For the convenience of those concerned, ~able III below gives the identification of the various subs~ituents in formula I
!~ .
for the compounds of the working examples:
, ~
.
' 30 , - 17 -,, .
'~ ' ,:
-Example No. Rl R2 R3 R4 X
.
3 H c3 7 S
4 H H i-C H S
H H n-C H S
Operating as in Example 2, but employing allylisothio-, p.
~ ., 107~Z~0 1 cyanate, the p~od~lct, m.p. 172/ is obtained in 71~ yield.
Example 9 4-Ethyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine (386/1184).
Operating as in Example 7, but employing isopropyl iso-thiocyanate, the product, m.p. 215, is obtained in 79% yield.
Example 10 4-Ethyl-5-(N-allyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine (386/1216).
Operating as in Example 7, but employing allyl isothio-cyanate, the product, m.p. 205, is obtained in 70% yield.
Example 11 4-Ethyl-5-(N-butyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine (386/1215).
Operating as in Example 7, but employing butyl isothio-cyanate, the product, m.p. 180, is obtained in 75% yield.
Example 12 4-Phenyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1254).
A solution of 3.5 g of 4-phenyl-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine (Farmaco, Ed.Sci., 1967, 22, 821) and 3.5 g of methyl isothiocyanate in 55 ml of dioxane is refluxed for 4 h. The solution is cooled and filtered: 3.6 g of 4-phenyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c~-pyri-dine, m.p. 228, are collected.
Example 13 !'' 4-Phenyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine (386/l253).
;~ Operating as in Example 12, but employing isopropyl iso-thiocyanate, the product, m.p. 198, is obtained in 80% yield.
752~0 E~ample 14 4-iso-propyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[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, 19.6 g of sodium hydroxide dissolved in 54 ml of water and 25 ml of isobutyraldehyde are added and the solution refluxed for 24 h. The solution is then acidified with 200 ml of conc. hydrochloric acid and evaporated in vacuo. The residue is taken up in methanol. The methanolic ex-tract is evaporated in vacuo to give 23 g of 4-isopropyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine dihydrochloride, m.p. 238, from which the free base, m.p. 112, is obtained by ion-exchange on Amberlite (Trade Mark) IRA 410. A solution of 1.3 g of the base in 10 ml of dioxane is treated with 1.3 g of methyl isothiocyanate and refluxed or 4 h. The solution is cooled and filtered; 1.4 g of 4-isopropyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 240, are collected.
Example 15 4-iso-propyl-5-(N-iso~ropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1258).
Operating as in Example 14, but employing isopropyl isothiocyanate, the product, m.p. 203, is obtained in 80% yield.
Example 16 3-Methyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine ~86/1276).
A solution of 1 g of 3-methyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and l g of methyl isothiocyanate in 10 ml of acetonitrile is refluxed for 4 h. The solution is cooled and filtered: 0.9 g of 3-methyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 235, are collected.
.
1 _xample :l7 3-Methyl-5-(N-isopropyl-thiocarbamoyl-4,5,6,7-tetra-hydro-imidazo-l4,5-c]-pyridine ~386/1286).
Operating as in Example 16, but employing isopropyl iso-thiocyanate, the product, m.p. 205, is obtained in 66% yield.
Example 18 5-(N-Phenyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c3-pyridine (386/1116).
Operating as in Example 2, but employing phenyl isothio-cyanate, the product, m.p. 205, is obtained in 82% yield.
Example 19 5-~N-cyano-N'-methyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1347).
A solution of 1.23 g of 4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine and 1.29 g of N,S-dimethyl-N'-cyano-isothiourea (CH3-NH-C=N-CN) in 15 ml of acetonitrile is refluxed for 21 h.
, S-CH3 G
After evaporation to dryness, chromatography on silica ~el (ethyl acetaté-ethanol as eluant) of the residue gives 630 mg of the pure 20 title compound, m.p. 240.
~ Example 20 r 5-Guanyl-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine ,. ..
(386/1285~.
' A solution of 1.23 q of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 0.9 g of S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness, the residue is treated with one equivalent of ethanolic hydrogen chloride. After cooling, 1.4 g of 5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydrochloride, m.p. 310, are 30 collected.
.
_ g _ ,~' 1075'Z~0 1 Example 21 4-Ethyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1284).
Operating as in Example 20, 1.5 g of 4-ethyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine monohydrochloride, m.p. 300 (dec.), are obtained from 1.51 g of 4-ethyl-4,5,6,7,-tetrahydro-imidazo-[4,5-c]-pyridine.
Example 22 4-Ethyl-5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c3-pyridine (386/1336).
A solution of 1.5 g of 4-ethyl-4,5,6,7-tetrahydro-imi-dazo-[4,5-c]-pyridine and 1.18 g of N-ethyl-S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness the residue is treated with one equivalent of ethanolic hydrogen bromide. After cooling, 1.5 g of 4-ethyl-5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydro-l bromide, m.p. 275, are collected.
Example 23 4-Ethyl-5-(N-isopropyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1337).
Operating as in Example 22, but employing N-isopropyl-S-methyl-isothiourea, 1.6 g of 4-ethyl-5-(N-isopropyl-g~anyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine monohydrobromide (m.p. 280 (dec.)) are obtained.
Example 24 .
5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-14,5-cl-pyridine.
Operating as in Example 22, the monohydrobromide of the :-:
title compound is obtained in 50% yield from 4,5,6,7-tetrahydro-imidazol4,5-c]-pyridine.
1~7S240 ~;xamplc 2r~
5~ isopropyl-guanyl)-4,5,6,7-tetrahydro-imidaza-[4,5-c]-pyridine.
Operating as in Example 23, the monohydrobromide of the title compound is obtained in 55% yield from 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
E~ample 26 4-Phenyl-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine ~386/1261).
A solution of 3 g of 4-phenyl-4,5,6,7-tetrahydro-imidazo-~4,5-c3-pyridine and 3.42 g of methyl isocyanate in 40 ml of dry dioxane is refluxed for 1.5 h. Evaporation to dryness gives a ~, solid (4.72 g) that is washed with someethyl acetate, dissolved in 60 ml of methanol and treated with 15 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in ethyl acetate to give 2.5 g of the title compound, m.p. 180.
Example 27 4-Phenyl-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1351).
Operating as in Example 26, but employing isopropyl iso-cyanate, 3.11 g of the title compound, m.p. 245, are obtained.
Example 28 4-Ethyl-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c3-pyridine (386~1295).
A solution of 1.51 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine and 2.28 g of methyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. The solution is cooled and 30 filtered. The solid collected is dissolved in 30 ml of methanol 1~7S'~40 1 and treated with 7 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization the solution is ex~racted with chloroform. Evaporation of the solvent leaves a residue that is taken up in ethyl acetate. 1.05 g of the title compound, m.p. 240, are collected.
E~ample 29 4-Ethyl-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-~4,5-c~-pyridine (386/1316).
Operating as in Example 28, employing isopropyl iso-lO cyanate, the title compound, m.p. 170, is obtained in 70% yield.
Example 30 5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine (386/1350).
Operating as in Example 28, 1.8 g of the title compound, m.p. 213, are obtained from 2.46 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
Example 31 5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-14,5-c]-pyridine (386/1348).
A solution of 2.46 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 6.8 g of isopropyl isocyanate in 50 ml of dry dioxane is refluxed for 2 h. After evaporation to dryness, the residue is dissolved in 25 ml of methanol and treated with 12.5 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization, the solution is extracted with chloroform. Evapo-ration of the solvent leaves a residue ~2.21 g, oil) that is treated with one equivalent of hydrogen chloride in isopropanol.
A~ter cooling, 1.7 g of 5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 190, are collected.
1~7~Z~O
E~mole 32 5-(N-cyclopropyl-carbamoyl)-~,5,6,7-tetrahydro-imidazo-~4,5-c]-pyridine (386/1365).
A solution of 3.69 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.47 g of cyclopropyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. After evaporation to dryness, the residue is dissolved in 44 ml of methanol and treated with 11 ml of 2N sodium hydroxide for l.S h at room temperature. After neutralization, the solution is extracted with chloroform. Evapora-tion of the solvent leaves a residue that is taken up in acetoni-trile to give 2.12 g of the title compound, m.p. 215.
Example 33 5-(N-cyclopentyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1366).
Operating as in Example 32, but employing cyclopentyl isocyanate, 3.46 g of the title compound, m.p. 225, are obtained.
Example 34 5-~cyclopentyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-~4,5-c]-pyridine (386/1360).
Operating as in Example 2, but employing cyclopentyl isothiocyanate, the title compound, m.p. 185, is obtained in 60%
- yield.
Example 35 5-(N-cyclopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-r4,S-c3-pyridine (386~1359).
A solution of 2.462 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c3-pyridine and 2.97 g of cyclopropyl isothiocyanate in 20 n~l of acetonitrile is refluxed for 7 h. After evaporation to dryness, the residue is chromatographed on silica gel (ethyl acetate-30 ethanol as eluant) to give 1.42 g of the pure title compound, m.p.1~5.
)75Z40 1 Example 36 4-Cyclohexyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c3-pyridine (386/l368)~
Operating as in Example 14, 15.5 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 150, are obtained from 18.4 g of histamine dihydrochloride and 24.4 ml of hexahydrobenzaldehyde. A solution of 2.05 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo[4,5-c~-pyridine and 1.1 g of methyl isothiocyanate in 30 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered, and 2.50 g of the title compound, m.p. 232, are collected.
Example 37 4-Cyclohexyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-- tetrahydro-imidazo-[4,5-c]-pyridine (386/1367) Operating as in Example 36, 2.53 g of the title compound, m.p. 218 are obtained from 2.05 g of 4-cyclohexyl-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine and 1.52 g of isopropyl isothio-cyanate.
i Example 38 "
;- 20 4-(2-thienyl)-5-N-isopropyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pridine (386/1369) Operating as in Example 14,15 g of 4-(2-thienyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 170, are obtained from 18.4 g of histamine dihydrochloride and 18.4 ml of 2-thiophenaldehyde. A solution of 2.05 g of 4-(2-thienyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.52 g-of isopropyl i isothiocyanate in 30 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered: 2.18 g of the title compound, m.p. 205, are collected .
.
Example 39 4-(2-thienyl)-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-:
- 107~240 1 hydro-imidazo-[4,S-c~-pyridine (386/1383).
Operatiny as in Example 38, the title compound is obtained in 56% yield, m.p. 215.
Examplc 40 4-(2-furyl)-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c3-pyridine (336/1372).
Operating as in Example 14, 12 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (oil) are obtained from 18.4 g of histamine dihydrochloride and 16.6 ml of furfural.
A solution of 1.89 g o~ 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine a.nd 1.1 g of methyl isothiocyanate in 20 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered: 1.54 g of the title compound, m.p. 200, are collected.
Example 41 4-(2--furyl)-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine t386/1373).
' Operating as in Example 40, 1.61 g of the title compound, m.p. 195, are obtained from 1.89 g of 4-(2-furyl)-4,5,6,7-tetra-hydro-imidazo-~4,5-c]-pyridine and 1.52 g of isopropyl isothio-~ cyanate.
Example 42 4-Cyclohexyl-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1374).
Operating as in Example 28, 3.1 g of the title compound, m.p. 250, are obtained from 4.1 g of 4-cyclohexyl-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine.
Example 43 -:
4-Cyclohexyl-S-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-t4,5-c]-pyridine (386/1375).
Operating as in Example 29, 3.45 g of the title compound, ;;
~075240 1 crystallized from ethanol and melting at 254, are obtained from 4.1 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
E~ample 44 4-(2-thienyl)-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine (386/1376).
Operating as in Example 26, but employing isopropyl iso-cyanate, 2.3 g of the title compound, crystallized from ethanol and melting at 223 (dec.), are obtained from 3.S g of 4-(2-thienyl) 4,5,6,7-tetrahydro-imidazo-[4,5-c~-pyridine.
Example 45 4-Isopropyl-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-14,5-c]-pyridine (386/1377).
Operating as in Example 26, but employing isopropyl iso-cyanate, 2.8 g of the title compound, crystallized from acetoni-trile and melting at 202, are obtained from 2.48 g of 4-isopropyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine. -~
Example 46 4-(2-thienyl)-5-~N-methyl-car~amoyl)-4,5,6,7-tetrahydro-j imidazo-[4,5-c]-pyridine (386/1378).
Operating as in Example 26, 1.14 g of the title com-pound, crystallized from acetonitrile and melting at 230, are obtained from 3.5 g of 4-(2-thienyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
Example 47 4-(2-furyl)-5-(N-methyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1379).
Operating as in Example 26, 1.55 g of the title com-pound, crystallized from acetonitrile and melting at 205, are ~- o~tained from 1.89 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine.
., 10~524~0 1 E~~mple ~8 4-(2-furyl)-5-(N-isopropyl-carbamoyl)-4,5,6,7-tetra-hydro-imidazo-[4,5-c]-pyridine (386/1382).
Operating as in Example 26, but employing isopropyl iso-cyanate, 2.23 g of the title compound, crystallized from acetoni-trile and melting at 237 (dec.), are obtained from 2.84 of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-~4,5-c]-pyridine.
Example 49 3-Methyl-4-ethyl-5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386~1391).
Operating as in Example 17, the title compound crystal-lized from ethanol and melting at 196, is obtained in 50~ yield.
Example 50 4-Phenyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (386/1401).
Operating as in Example 20, the monohydrochloride of the title compound, crystallized from ethanol and melting at 288 (dec.), is obtained in 80~ yield.
Example 51 4-Cyclohexyl-5-guanyl-4,5,6,7-tetrahydro-imidazo-14,5-c~-pyridine (386/1405).
Operating as in Example 20, the monohydrochloride of the title compound, crystallized from ethanol and melting at 305 (dec.), is obtained in 60% yield.
For the convenience of those concerned, ~able III below gives the identification of the various subs~ituents in formula I
!~ .
for the compounds of the working examples:
, ~
.
' 30 , - 17 -,, .
'~ ' ,:
-Example No. Rl R2 R3 R4 X
.
3 H c3 7 S
4 H H i-C H S
H H n-C H S
6 H H cyclohexyl S
8 H H allyl S
g H C2H5 1-C3H7 S
C2H5 allyl S
11 2 5 n-C4Hg S
12 H phenyl CH3 S
! 13 H phenyl l-C3H7 S
~ 14 H i_C H CH3 S
.; 15 H i-C H l-C3H7 S
2017 CH3 H ~-C3H7 S
18 H H phenyl S
22 C2 5 2 5 ~ NR4 24 ~ C2 5 H NR4 25 H H l-C3H7 H NR4 : 26 H phenyl CH3 0 30 27 H phenyl l-C3H7 ~28 C2 5 CH3 o ,.
L~, 1~75Z40 1 TABLE III continued Example No. Rl R2 R3 R4 X
H H CEl3 0 31 H H l-C3H7 32 H H cyclopropyl 0 33 H H cyclopentyl 0 34 H H cyclopentyl S
1035 H H cyclopropyl S
36 H cyclohexyl CH3 S
37 H cyclohexyl l-C3H7 S
38 H thienyl i-C H S
: - 3 7 39 H thienyl CH3 S
H furyl CH3 S
: 41 H furyl l-C3H7 S
42 H cyclohexyl CH3 0 43 H cyclohexyl l-C3H7 44 H thienyl 1_C3H7 2045 H i-C3H7 1-C3H7 46 H thienyl CH3 0 47 H furyl CH3 0 48 H furyl i_C3H7 0 H phenyl H H NR4 51 H cyclohexyl H H NR4 '' ,.:
8 H H allyl S
g H C2H5 1-C3H7 S
C2H5 allyl S
11 2 5 n-C4Hg S
12 H phenyl CH3 S
! 13 H phenyl l-C3H7 S
~ 14 H i_C H CH3 S
.; 15 H i-C H l-C3H7 S
2017 CH3 H ~-C3H7 S
18 H H phenyl S
22 C2 5 2 5 ~ NR4 24 ~ C2 5 H NR4 25 H H l-C3H7 H NR4 : 26 H phenyl CH3 0 30 27 H phenyl l-C3H7 ~28 C2 5 CH3 o ,.
L~, 1~75Z40 1 TABLE III continued Example No. Rl R2 R3 R4 X
H H CEl3 0 31 H H l-C3H7 32 H H cyclopropyl 0 33 H H cyclopentyl 0 34 H H cyclopentyl S
1035 H H cyclopropyl S
36 H cyclohexyl CH3 S
37 H cyclohexyl l-C3H7 S
38 H thienyl i-C H S
: - 3 7 39 H thienyl CH3 S
H furyl CH3 S
: 41 H furyl l-C3H7 S
42 H cyclohexyl CH3 0 43 H cyclohexyl l-C3H7 44 H thienyl 1_C3H7 2045 H i-C3H7 1-C3H7 46 H thienyl CH3 0 47 H furyl CH3 0 48 H furyl i_C3H7 0 H phenyl H H NR4 51 H cyclohexyl H H NR4 '' ,.:
Claims (2)
1. A process for preparing a compound of the formula I:
I
where R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, a phenyl, thienyl or furyl group;
R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl; and X is O, S or NR4 where R4 is hydrogen, or a cyano group;
which comprises condensing an appropriate 4,5,6,7-.
tetrahydroimidazo-[4,5-c]-pyridine with an alkyl isocyanate, isothiocyanate or substituted S-methyl thiourea in a solvent selected from the group consisting of ethanol, acetonitrile and dioxane under reflux from 4 to 12 hours.
2. A compound of the formula I:
I
I
where R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, a phenyl, thienyl or furyl group;
R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl; and X is O, S or NR4 where R4 is hydrogen, or a cyano group;
which comprises condensing an appropriate 4,5,6,7-.
tetrahydroimidazo-[4,5-c]-pyridine with an alkyl isocyanate, isothiocyanate or substituted S-methyl thiourea in a solvent selected from the group consisting of ethanol, acetonitrile and dioxane under reflux from 4 to 12 hours.
2. A compound of the formula I:
I
Claim 2 continued:
where R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, a thienyl or furyl group;
R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl; and X is O, S or NR4 where R4 is hydrogen, or a cyano group;
or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
where R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms;
R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, a thienyl or furyl group;
R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or phenyl; and X is O, S or NR4 where R4 is hydrogen, or a cyano group;
or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB573/76A GB1524481A (en) | 1976-01-07 | 1976-01-07 | Tetrahydo - imidazopyridine derivatives |
| GB2707176 | 1976-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1075240A true CA1075240A (en) | 1980-04-08 |
Family
ID=26236032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA269,126A Expired CA1075240A (en) | 1976-01-07 | 1977-01-04 | 4,5,6,7-tetrahydroimidazo-(4,5-c)-pyridine derivatives |
Country Status (9)
| Country | Link |
|---|---|
| AT (1) | AT356653B (en) |
| CA (1) | CA1075240A (en) |
| CH (1) | CH626084A5 (en) |
| DE (1) | DE2700012A1 (en) |
| DK (1) | DK146655C (en) |
| FR (1) | FR2337726A1 (en) |
| NL (1) | NL7614577A (en) |
| SE (1) | SE422062B (en) |
| SU (1) | SU667136A3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018078363A1 (en) * | 2016-10-25 | 2018-05-03 | Proximagen Limited | Process for the preparation of (3s,4s)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3h-imidazo[4,5-c]pyridine-5(4h)-carboxylate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1098015B (en) * | 1978-08-07 | 1985-08-31 | Farmaceutici Italia | NEW 4,5,6,7, -TETRAIDROIMIDAZO-OPEN SQUARE PAR 4,5-C CLOSED SQUARE PAR-PIRIDIN-DERIVATIVES |
| US6908926B1 (en) | 1999-04-16 | 2005-06-21 | Novo Nordisk A/S | Substituted imidazoles, their preparation and use |
-
1976
- 1976-12-30 NL NL7614577A patent/NL7614577A/en not_active Application Discontinuation
-
1977
- 1977-01-03 DK DK177A patent/DK146655C/en not_active IP Right Cessation
- 1977-01-03 SE SE7700041A patent/SE422062B/en not_active IP Right Cessation
- 1977-01-03 DE DE19772700012 patent/DE2700012A1/en not_active Withdrawn
- 1977-01-04 CA CA269,126A patent/CA1075240A/en not_active Expired
- 1977-01-04 AT AT1877A patent/AT356653B/en not_active IP Right Cessation
- 1977-01-05 FR FR7700162A patent/FR2337726A1/en active Granted
- 1977-01-06 SU SU772435956A patent/SU667136A3/en active
- 1977-01-06 CH CH15377A patent/CH626084A5/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018078363A1 (en) * | 2016-10-25 | 2018-05-03 | Proximagen Limited | Process for the preparation of (3s,4s)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3h-imidazo[4,5-c]pyridine-5(4h)-carboxylate |
| US10988473B2 (en) | 2016-10-25 | 2021-04-27 | Benevolental Cambridge Limited | Process for the preparation of (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-C]pyridine-5(4H)-carboxylate |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2337726A1 (en) | 1977-08-05 |
| ATA1877A (en) | 1979-10-15 |
| DK177A (en) | 1977-07-08 |
| NL7614577A (en) | 1977-07-11 |
| AT356653B (en) | 1980-05-12 |
| SE7700041L (en) | 1977-07-08 |
| CH626084A5 (en) | 1981-10-30 |
| DK146655C (en) | 1984-05-07 |
| FR2337726B1 (en) | 1980-03-14 |
| DK146655B (en) | 1983-11-28 |
| SE422062B (en) | 1982-02-15 |
| SU667136A3 (en) | 1979-06-05 |
| DE2700012A1 (en) | 1977-07-21 |
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