IE47544B1 - N-cyano-n'-alkynyl-s-substituted isothioureas - Google Patents

Description

The present invention relates to certain N-cyano-N’alkynyl-S-substituted isothioureas which are intermediates useful in the preparation of certain N-cyano-N'-[2-[(4methyl-5-imidazolyl)methylthio] -ethyl]-N-alkynylguanidines which are H2 receptor blocking agents, which inhibit gastric acid secretion and which are useful in the treatment of ulcers.

Accordingly, the present invention provides a compound of the formula NCN ϋ 1 R S-CNH — R III wherein R^ is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms and R„ is C. „ alkyl, λ x—y aryl, substituted aryl, aralkyl, CHjCN, -CH^CQGH or -CS^OOGa' wherein R is C, „ lower alkyl. 1-9 j In a preferred embodiment, R of the compound of formula III is -CHCSCR I CH in which R is hydrogen or methyl; in another preferred embodiment R^ is -(CH„) C=CR4 z n in which n is an integer of from 1 to 6 and R is hydrogen or methyl; in another preferred embodiment R^ is CH, I 4 — C-C3SCR I CH, in which R is hydrogen or methyl.

In a more preferred embodiment, R is a propargyl, 2-butyn-l-yl, 3-butyn-l-yl, 2-methyl-3-butyn-2-yl, or 4-pentyn-l-yl group.

The compounds of the present invention are intermediates in the preparation of compounds of the formula ch2 sch2ch2nhcnh-r NCN wherein R is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, or non-toxic pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I are described and claimed in Patent Specification No. 47543.

The compounds of formula I and salts thereof may be prepared by reacting a compound of the formula .CH, Cl CH^CH^NH., II or an acid addition salt thereof, with a compound of the formula NCN I 1 R S—CNH—R III 2 wherein R and R are as above defined, and, if desired, 5 converting the resulting compound of formula I in basic form or an acid addition salt thereof to the corresponding non-toxic pharmaceutically acceptable acid addition salt or free base form.

This process is illustrated by way of example by 10 the following reaction scheme: H CH.

NCN II RS-CNHCH2C=CH N H NCN CH2 SCH2CH2NHCNHCH2C = CH wherein R is as above defined.

The compounds of the present invention may be prepared by the reaction of an appropriately substituted cyanodi15 thioiminocarbonate with an alkynylamine having from 3 to 9 carbon atoms. The general reaction scheme is given below:‘ 47544 - 5 NCN (R2 S)2C=NCN+H2NR1—>R2 S-CNHR1+R2 SH The present invention will be further described with reference to the following Examples.

EXAMPLE 1 N-Cyano-N’-propargyl-S-methylisothiourea A solution of dimethyl cyanodithioiminocarbonate (16.00 g, 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, and then at 25°C for 12 hours. Workup gave the title compound (13.58 g, 81%), mp 16O-164°C.

EXAMPLE 2 N-(2-Butyn-1-yl)-Ν'-cyano-S-methylisothiourea A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.684 mole) and 2-butyn-l-yl-amine (4.73 g, 0.684 mole) in acetonitrile (200 ml) was stirred at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound, mp 180-183°C.

EXAMPLE 3 N-(1,1-Dimethylpropargyl)-N'-cyano-S-methylisothiourea The general procedure of Example 2 is repeated except that the 2-butyn-l-yl-amine utilized therein is replaced by an equimolar amount of 1,1-dimethyIpropargylamine, and the title product is thereby produced.

EXAMPLE 4 N-(1-MethyIpropargyl)-N1 -cyano-S-methylisothiourea The general procedure of Example 2 is repeated except that the 2-butyn-l-yl-amine utilized therein is replaced by an equimolar amount of 1-methylpropargylamine, and the title product is thereby produced. - 6 EXAMPLE 5 N-Cyano-N' -propargyl-S-methylisothiourea A solution of dimethyl cyanodithioiminocarbonate (16.00 g, 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, and then at 25°C for 12 hours. The mixture was cooled and filtered to yield the title compound (13.58 g, 81%), mp 160-164°C.

EXAMPLE 6 N-Cyano-N*-(2-butyn-l-y ^-S-methylisothiourea A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.0684 mole) and 2-butyn-l-yl-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25°C for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound, mp 180-183°C.

EXAMPLE 7 N-Cyano-Ν'-(3-butyn-l-yl)-S-methylisothiourea The general procedure of Example 5 is repeated, except that the propargylamine utilized therein is replaced by an equimolar amount of 3-butyn-l-yl-amine, and the title compound is thereby produced.

EXAMPLE 8 N-Cyano-N'-(4-pentyn-l-yl)-S-methylisothiourea The general procedure of Example 5 is repeated, except that the propargylamine utilized therein is replaced by an equimolar amount of 4-pentyn-l-yl-amine, and the title compound is thereby produced.

EXAMPLE 9 N-Cyano-Ν'-(2-methyl-3-butyn-2-yl)-S-methylisothiourea The general procedure of Example 5 is repeated, 47S44 - 7 except that the propargylamine utilized therein is replaced by an equimolar amount of 1,1-dimethylpropargylamine, and the title compound is thereby produced.

EXAMPLE 10 N-Cyano-N'-(3-butyn-2-yl)-S-methylisothiourea The general procedure of Example 5 is repeated, except that the propargylamine utilized therein is replaced by an equimolar amount of 1-methylpropargylamine, and the title compound is thereby produced.

Claims (7)

1. A compound of the formula NCN 2. Ϋ 1 RS-CNH-R wherein R 1 is a straight or branched chain alkynyl group 2 containing from 3 to 9 carbon atoms, inclusive, and R is C alkyl, aryl, substituted aryl, aralkyl, -CH_CN, X~9 Z -CH„COOH or -CH COOR' where R‘ is C, Q alkyl. Ζ Ζ X—9

2. A compound as claimed in claim 1 in which R 1 is -(CH„) s C R 4 2 n wherein n is an integer of from 1 to 6, inclusive, and R is hydrogen or methyl.

3. A compound as claimed in claim 1 in which R' is -CHC=CR 4 CH, wherein R is hydrogen or methyl.

4. A compound as claimed in claim 1 in which R 1 is CH, C-CSCR CH, wherein R is hydrogen or methyl.

5. A compound as claimed m claim 1 wherein R is a propargyl, 2-butyn-l-yl, 3-butyn-l-yl, 2-methyl-3-butyn2-yl, or 4-pentyn-l-yl group.

6. A process for preparing a compound as claimed in claim 1 substantially as hereinbefore described with reference to any one of the Examples.

7. A compound as claimed in claim 1 whenever 5 prepared by a process as claimed in claim 6.