CA1053242A - Heterocyclic guanidine derivatives - Google Patents

Heterocyclic guanidine derivatives

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Publication number
CA1053242A
CA1053242A CA177,944A CA177944A CA1053242A CA 1053242 A CA1053242 A CA 1053242A CA 177944 A CA177944 A CA 177944A CA 1053242 A CA1053242 A CA 1053242A
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Prior art keywords
methyl
formula
lower alkyl
amino
guanidine
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CA177,944A
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CA177944S (en
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Charon R. Ganellin
John C. Emmett
Graham J. Durant
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Smith Kline and French Laboratories Ltd
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Smith Kline and French Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

Pharmacologically active guanidines are disclosed having the structural formula wherein R1 is hydrogen or lower alkyl; R2 is a grouping of the formula Het - (CH2)mZ (CH2)n -wherein Het is an imidazole ring which is optionally substituted by lower alkyl, trifluoromethyl, hydroxy, halogen or amino; Z is sulphur, oxygen, NH or a methylene group: m and n are integers from 0 to 4 such that their sum is from 2 to 4; X is COR3, CSR3, SO2R4, N=CHR5 or when Z is methylene, nitro; R3 is lower alkyl, lower alkoxy, or amino;
R4 is lower alkyl, phenyl substituted by lower alkyl, halogen or amino, phenyl, trifluoromethyl or amino; and R5 is phenyl.
These compounds have utility in inhibiting certain actions of histamine which are not inhibited by other antihistamines such as mepyramine as well as being useful as inhibitors of certain actions of gastrin.

Description

This invention relates to pharmacologically active compounds, in particular to pharmacologically active guanidines, to pharmaceutical compositions comprising these compounds and to processes for their preparation. The compounds of the invention can exist as the addition salt but, for convenience~ reference will be made through-out this specification to the parent compounds.

It haæ long been postulated that many of th~ physiologically active substance~ within the animal body, in the ¢ours~ ~ their activity, combine with certain specific sites known a8 receptors.
Histamine i8 a campound which i6 believed to act in 6uch a ~a~ butt since the actions of histamine fall into more than one type, it i8 believed that there i8 more than one type of histamine r~ceptor.
The type of action of histamine which is blocked by drug~ commonly called "antihistamine~" (of which mepyramine is a typical example) is ~elieved to involve a receptor which has been desi~nsted as H-l A further group of substances has recently been described by Black et. al. (Nature 1972, 236, 385) which are distinguished by the fact that they act at histamine receptors other than the H-l receptor and these other receptors have been deæignated a& H-2 receptors. This latter group of substances, to certain of which the present invention relates, are thus of utility in inhibiting certain actions of histamine which are not inhibited by the above-mentioned "antihistamines". The substances of this invention may also be of utility as inhibitors o~ certain aotions f &astrin.

.
Throughout the present specification and claim~, by the term "lower alkyl" we mean an alkyl group containing from 1 to 4 carbon atom~.
2 -. ~ , . . , . : - . , :

` ~OS3;~:~Z
The guanidines with which the present invention is concerned may be represented by the following general formula:
~ N - X
R2NH ~ C
NHR

wherein Rl is hydrogen or lower alkyl such as methyl; R2 is a grouping of the structure shown in Formula II:

Het - (CH2)m Z (CH2)n FOR~ULA II
wherein Het is an imidazole ring which is optionally sub-stituted by lower alkyl, trifluoromethyl, hydroxyl, halogen or amino; Z is sulphur, oxygen, NH or a methylene group: m and n are integers from O - 4 such that their sum is from 2 to 4; ~ is COR3, CSR3, S02R4, N=CHR5 or, when Z is methylene, nitro; R3 is lower alkyl, lower alkoxy or amino; R4 is lower alkyl, phenyl substituted by lower alkyl, halogen or amino, phenyl, trifluoromethyl or amino; and R5 is phenyl.

It will be understood that the structure illustrated in Formula I

E
,.

.. . ..... ... . . .. ..... . .. .. ... . . . . .. .. .. .

. ... . . . . .. . . . . . ..
~ ~ : . :
.. . . .. . .

- ~ . . ~ .. . ... .. .
.
.

is only one of several representations and that other tautomeric forms are al6o covered by the present invention.

In a preferred group of compounds Rl i8 methyl~ Rz i6 preferably Xet - CH2S (CH2)2 and i6 partic~larly preferably such that Het i6 an imidazolyl, thiazolyl, isothiazolyl or pyridyl `
ring, which ring is optionally substituted by methyl, hydroxyl, .
halogen or amino. U~eful compounds are also obtained when X i8 phenyl6ulphonyl, aminosulphonyl or aminocarbonyl.

The compounds of the present invention may be produced fron an amine of the formul~ R2N ~ , wherein R2 has the 6ame significance as in Fo~mula I by reaction thereo~ with a compound Or Formula III.

~ N - X
A - Y - C

NHRl FORMULA III

wherein Rl and X have the 6ame significance as in Formula I; Y i8 sulphur or oxygen; and A i~ lower alkyl e.g., methyl~ . .

.
The production of the starting material of formula R2N ~ i8 described in otLr British Specifications Nos. 1,305,547 and 1, 338, 169.

Alternatively, reaction Or the amine of formula R2N ~ with a co~pound of Formula IV: :~

.

~g i . .
. ~ j,.

', ' : , "~ ' ` ' ' ' , ~OS3Z4Z
(A-Y)2 C ~ N - X

RMUlA IV

wherein A, Y and X have the ~ame significance as in Formula III re~ults in the production of an intermediate compound of the following Formula V:

N X

Y - A

V

wherein A, Y, X and R2 have the above significanc~. Reaction of this intermediate with RlNH2 wherein Rl iB hydrogen or lower alkyl yields the requircd compound of Formula I. This reaction scheme i6 particularly suitable for the production of those compounds wherein X i~ S02R4. The compound of Formula IV wherein Y i~ sulphur i6 preferred and may be produced by the reaction of an aminosulphonyi compound of the f~rmula R3So2ri~ under alkaline condition~ with carbon disulphide and an aIkyl halide of formula RlHal wherein Rl i6 lower alkyl and Hal is a halogen such as iodine.
.
Certai~ epecifio methods may also bo used for the production o~ some particular compounds of Formula I. For example to produce those compounds wherein X is aminosulphonyl a guanidine of Formula VI:
NH
: : ~ R NH - C
\
-' NHRl ,~ : FOhlUnA _ 5 _ - -, . .. , . : . :
. . . :.
, . . , .:
, .. . ,: : -wherein Rl and R2 have the same ~ignificance a~ in Formula I may be reacted with~ a diaminosulphonyl c~mpound of Formula VII.

W = N.S02 N~2 FORMULA VII

wherein W is derived from a secondary a~ine of formula W=NH e.g.
piperidine.

A further specific method which may be used to produce those compounds of Formula I wherein X iR aminocarbonyl in~olves mild --acid hydrolysis e.g., with dilute hydrochloric acid at fro~ 20C to 50C of a cyanoguanidine compound of Formula VIII.

~ N - CN
R2N~ - C
~ :' ~ . .

FOR~JULA VIII
~-- .

wherein Rl and R2 have the same significance as in Formula I. The -compounds of Formula I wherein X i~ aminothiocarbonyl may also be prep~red from the cyanoguanidine of Formula VIII by reaction thereof with hydrogen ~ulphide in a ~olvent 6uch a6 pyridine and in the presence of a strong ba~e such a~ triethylamine. The production of the compounds of FormNla VIII are decribed in our British specifications Nos . 1, 305, 547 and 1, 338 ,169 .

':

~ .
.

As stated above, the compoun~ represented by Formula I ha~e been found to have pharmacological activity in the animal body as antagonists to certain actions of histamine which are not block~d by "antihistamines" such as mepyramine. For example, they have been found to inhibit selectively the histamine-stimulated secretion of gastric acid from the perfused stomachs of rats anaesthetised with urethane. Similarly, the action of these compounds may, in many case~ be demonstrated by their antagonism to the effects of histamine on other tissues which, according to the above-mentioned paper of Black et. al., are H-2 receptors. Examples of such tissues are per~used isolated guinea-pig heart, isolated guinea-pig right atrium and i~olated rat uterus. The compounds of the in~ention have also been found to inhibit the secretion of gastric acid stimulated by pentagastrin or by food.

~ he level of activity found for the compositions comprising the compounds of the present invention iB illustrated by the effective dose range in the anaesthetised rat, as mentioned above of from 1 to 256 micromoles per kilogram, given intravenously. Many of the compounds of the pre6ent invention produce a 50% ~nhibition in this test at a dose of from ~ to 15 micromoles per kilogram.

The pharmaceutical carrier employed may be, for example, either a ~olid or liquid. Exemplary of solid carriers are lac~ 8e, terra alba, sucrose~ talc, gelatin, agar9 pectin, acacia, magnesiu~ stearate, stearic acid and the like. Exemplary of liquid carrier6 are syrup~
peanut oil, olive oil, water and the like.

.: . - . - , :

.
, ~: . , : ~ , : , - , , , A wide variety of pharmaceutical forms can be emplo~ed. Thu6 if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effective amount to inhibit histamine activity. The route of administration may be orally or parenterally.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg. to about 250 mg., most preferably from about 100 mg. to about 200 mg.

The active in~redient will preferably be administered in equal doses one to three times per day. The daily dosage regimen w~ll preferably be from about 150 mg. to about 750 mg., most preferably from about 300 mg. to about 600 mg.

For therapeutic use, the pharmacologically active compounds of the present invention will normally be administered as a ,. ... . . . .
:: .: , -.: . .

~OS;~ 2 pharmaceutical compo~ition comprising as the ~ an essential active ingredient at least one such compound in the basic form or in the form of an addition salt with a ph~rmaceutically acceptable acid and in association with a ph~rmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric, picric and maleic acids.

Other pharmacologically active compounds may in certain cases be included in the composition. Advantageously the compositions will be made up in a dosage unit form appropriate to the desired mode of administration, for example as a tablet, capsule, injectable solution or as a cream for topical administration.

The invention i8 illustrated but in no way limited by the following ex~mple :-N-[3-(4-Imidazol~ ro~ N'-nitro ~ nidine.

A solution of 4(5)-(3-aminopropyl)imidazole (2.7 g.) and S-methyl-N-nitroisothiourea (2.9g.) in methanol (50 ml.) was heated at 50L65 for 4-5 hours. Concentration, followed by recrystallisation of the rosidue from methanol yielded N-~3-(4-imidazolyl)propyl]-N'-nitro~uanidine, m.p. 156-158.
(Found: C, 39.7; ~, 5.8; N, 39.4. C ~ N602 requires: C, 39.6; 1~, 5.7; ~, 39.6) , : ., - - .: . .

. .: .. , : , -.. , . - . .
-. : : . .. .
- : . ' .:
.

EXAMPLE 2.

N-Benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]
~uanidine.

A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.93g.) and N-benzenesulphonyl-S-methylisothiourea (8.og.) in acetonitrile (100 ml.) was heated under reflux for 24 h~urs. Concentration, followed by chromatographic purification on a column of ~llica gel with benzene - methanol (10:1) and recrystallisation from aqueous ethanol and th~ acetonitrile afforded N-benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanid~ne (2.5 g.) m.p.
149-150.
(Found: C, 47.8; H, 5.6; N, 19.9; S, 18.1. C14H19N52S2 requires: C, 47.6; ~, 5.4; N, 19.8; S~ 18.1.) EXAMP$E 3 -Methyl-N'-~2-((4-methyl-5-imidazolyl)methylthio)ethyl-N"-::: L=~
(a) A mixture of trifl~oromethyl ulphonamide (4.2 g.) and bis-S-methylthio~N-methylformimine, (7.6 g.) wa~ heated at 120 ~or 4~hours, Cooling, followed by the addition of hexane afforded N, S-dimethyl-N'-trifluoromethane~ulphonyli50thiourea (5.0g.) .p. 88-89.~ ~
(To~nd: C~ 20.3j~, 3.o; n, 1l.9; s, 27.2. C4H7F3N22S2 requires: C~ 20.3~ N~ 3.0; N~ 11,9; S~ 27,2~
(b) ;~A solution of~4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.54~g.) and N,;S-dimethyl-N'-trifluoromethanesulphonylisothiourea (4.90~ ) ln ethanol (50 ml.) was heated under reflux for 24 hours-: :- ::

.

~05;~24'~
Concentration, followed by chromatographic purification on a column of silica eel with~thyl acetate-ethanol (4sl) a~ eluant yielded N-methyl-N'-[2_((4_methyl_5-imidazolyl)methylthio)ethyl~-N'l-trifluoromethanesulphonylguanidine as a glass (2,8 g.) (Found: C, 33.5; H, 4.7; S, 17.5. CloH16F3N502S2 requires: C, 33.4; H, 4.5; S, 17.8.) N-(4-Chlorbenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-
3~aL~---thylthio)ethyl-E~ 3~

(a) A mixture of 4-chlorobenzenesulphonamide (6.0 g.) and bis-S-methylthio-N-methylformi~ine (8~ ~ ~as heated at 12o-l25o for
4 hours to give N-(4-chlorobenzenesulphonyl)-N',S-dimethylisothiourea (5.8 g.), m.p. 1?l-l23o tfrom ethanol-hexane).
(Fotmd: C, 38.5; H, 4.1; N, 9.9; Cl, 12.7; S, 22.8. C9HllCl N202S2 requiree: C, 38.8; H, 4.0; N, 10.1; C1, 12.7; S, 2~.0) (b) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.33 g.) and N-(4-chlorobenzene6ulphonyl)-N',S-dimethylisothiourea (5.40 ~.) in acetonitrile was heat~d under reflux ~or 24 hour6.
Concentration, followed by recrystallisation from aqueous ethanol a~forded N-~4-chloroben enesulphonyl)-N'-methyl-N"-~2-((4-methyl-
5-imida~olyl)methylthio)ethyl]guanidine (4.6 g.), ~.p. 153-154.
(Found: C, 44.9; H, 5.1; N~ 17.1; Cl, 8.8; S, 15.7 C15~20N502S2 requires: C, 44.8; H~ 5.0; N, 17.4; Cl, 8.8; S, 16Ø

EXAMPLE ~

N-(3,4-Dichlorobenzenesulphonyl)-N'-methyl-N''-[2-((4-methyl-5-(a) A mixture o~ ~,4-dichlorobenzenesulphonamida (6.5 g.) and bi6-S-methylthio-N-methylformim$ne ~8.o g.) was heated at 120 for ~ 11 ~

,,, - , , - . . - ~ - - . - . : . -.

: : ' . ' ; : ' - ' : : ' ' ~ . .: -: : .' , ,: :. , . . , . ~ :

~os;~z~z 4 hours to ~ive N-(3,4-dichlorobenzenesulphonyl)-N',S-dimethylisothiourea (7.3 g.) m.p. 158-15g (from methanol).
(Found: C, 34.4; H, 3.1; N, 8.9; Cl, 22.9; S, 20~4. C9HloC12N202S2 requires: C~ 34.5; ~, 3.2; N, 8.9; Cl, 22.6; S~ 20.2) (b) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.49 g.~ and N-(3.4-dichlorobenzenesulphonyl)-N', S-dimethylisothiourea (6.20 g.) in acetonitrile (250 ml.) wa~ heated under re~lux for 48 hours. Concentration, followed by chromatograph~c purification on a column of alumina with se~uential eluti~n by benze~e-ethylacetate (1:4) and benzene-ethanol (1:4) afforded N-(3,4-dichlorobenzene-sulphonyl)-N'-methyl-N"-[2-((4-methyl-5^imidazolyl)methylthio)ethyl]
guanidine as a glass (1.7 g.) (Found: C, 41.7; H, 4.8; N, 15.9; Cl, 16.~; S, 14.4 C15~19N5C1202S2 requires: C, 41.3; H, 4.4; N, 16~1; Gl, 16.3; S, 14.7.) EYA~PiE 6 N-Benzenesulphonyl-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)-eth~l]RNanidine A solution of N-benzenesulphonyliminodithiocarbonic acid dimethyl ester (13.0 g.) and 4-methyl-5-((2-aminoethyl)thiomethyl~imidazole (8.5 g.) in ethanol (100 ml.~ was stirred at room temperature for 4 hours. Excess ethanolic methyla~ine was added and stirring was continued for 2 hours at room temperature. Following concentration, the residue was dissol~ed in ethanol-ether (1:1) and chilled af~ording N-benzenesulphonyl-N'-methyl-N"-~2-t(4-methyl-5-imidazolyl~methylthio) ethyl]guanidine (15.0 g.), m.p. 156.5 - 157.5 (from water) (Found: 5, 49.0; ~, 5.8; N, 19.0; S~ 17.~. C15H21N502S2 requires: C, 49.0; ~, 5~8; N, 19~1; S, 17.5.

.
- - ~: . .

- ., : , .,' ~':
. : . .

~053Z4~

, N-Methanesulphonyl-N'_methyl_N"-[2-((4_methyl_5-imidazolyl)methylthio) ethyl]~uanidine A solution of N-m~thanesulphonyliminodithiocarbonic acid dim~thyl ester (10.0 g.) and 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (8.5 g.) in ethanol (100 ml.) was stirred at room temperature ~or 3 hours. Exce~s ethanolic methylamine was added and stirring continued for 3 hours at room temperature. Concentration and trituration with ice-water afforded N-methanesulphonyl-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (12.7 g.), m.p. 133-134 (from water) (Found: C, 39.2; H, 6.4; N, 22.6; S, 20.7 C10~19N52S2 requires: C, 39.3; H, 6.3; N, 22.9; S, 21Ø) EX~MPLE 8 N-Ethanesulphonyl-N'-methyl-N"-~2-(t4-methyl-5-imidazolyl)methylthio) ethyl]~uanidine To a solution of ethanesulphonamide (12.0 g.) in dimethylformamide (75 ~ at 4, was added a solution of sodium hydroxide (4.45 g.) in water (6 ml.) and oarbon disulp~lide (3.6 ml.) After stirring for lO minutes at 5 sodium hydroxide (2.2 g.) in water (3 ml.) and carbon disulphate (1.5 ml) was added and after a further 10 minutes similar quantities o~ sodium hydroxide and carbon disulphide were again added. After stirring for 10 minutes at 5, methyl iodide (42.6 g.) was added without external cooling ~1d stirring was continued for 2 hours and the reaction mixture added to water (750 ml.) Extraction with ether and concentration yielded crude N-ethaneRulphonyl-imin ~ arbonic acid dimethyl ester (h. 4 g.) This ~aB reacted directly with 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.0 g.) and methylamine in ethanol by the method described in Example 7. The ~ _ 13 _ , , . . . . . - - - . . . .- - -. . ...... . .
.:.

. : .. . : . - :

lOS32~Z
product was chromatographed on a column of silica gel with ethyl acetate-ethanol (2:1) as eluant to yield N-ethanesulphonyl-N'-methyl-N''-t2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine as a glass (4.0 g.) (Eolmd: C, 41.2; H, 7~4; N, 21.0; S, 19.1. Clll~lN52s2(+3% C2H50H) requires: S, 41.7; H, 7.5; N, 21.3; S, 19.5, EXA~`~LE 9 N-Methyl-N'-[2-(~4-methyl~-imidazolyl)methylthio)ethyl]-N"-n-~ro~anesul~honyl~uanidine (a) Reaction of n-propanesulphonamide with sodium hydroxidç, carbon disulphide and methyliodide by the method described in Example 8 dithio afforded N-n-propanesulphonylimin ~ arbonic acid dimethyl e6ter, m.p. 73-74 (from ethanol-hex~ne).
(Found: C~ 31.7; H, 5.7; N, 6.2; S, 42,0. C6 ~3N02S3 requires: C, 31.7; H, 5.8; N, 6.2; S, 42.3) dithio (b) Ths reaction of N-n-propane~ulphonylimin ~ arbonic acid (4.7 g.) dimethyl e~ter with 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.5 g.) and methylamine by the method described in Example 7 followed by chromatographic purification on a column of silica ~el with ethyl acetate-ethanol ~4:1) as eluant afforded N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-n-prop~nesulphonylguanidine as a glass (5.0 g.).
(Found: N, 20.1; S, 18.4; C12H23N50252 (+5% C2H5 require6: N, 20.0; S, 18.3.) N-Methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl-N"-toluenesul~honYl~uanidine The reaction of N-p toluenesulphonylim~noditbiocarbonic acid dimethyl ester (10~0 g.) with 4-methyl-5-~(2-aminoethyl)thiomethyl)imidazole (6.2 g.) and methylamine by the method described ln Example 6 _ 14 _ - ~ -, , , . , :
- . : ,. . .
, I , . , : .,: .

afforded N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-~-toluenesulphonylguanidine (5~5 g.), m.p. 137.5-138~5 (from ethanol-ether ) (Found: C, 50.4; H, 6.2; N, 18.3; S, 17.0 C16H23N502S2 requires: C, 50.4; H, 6.1; N, 18.4; S, 16.8) AMPL~ 11 anidine (a) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imi&azole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[ (4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate tl3.0 g.) m.p. 230-235 (from aqueous methanol)r (b) The guanidine sulphate (10.0 g.j was added to a solution of sodium (1.53 g.) in ethanol (100 ml.) F~ltration and concentration gave the guanidine base which was disisolved in dimethylsulphoxide (20 ml.) and added gradually to a solution of N-piperidyl6ulphamid~
(5.3 g.) in dimethylsulphoxide (10 ml.) The mixture was heated on the steam bath for 2 hours and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel with ethylacetate-ethanol (3:2) as eluant yielding a product (2.38 g.) which was recrystallised from water and then methanol-ether to give N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-sulphamylguanidin~, m.p. 130-133~.
(Found: C~ 3Z.5; H, 5.6; N, 28.3; S, 21.6. 8H16N62S2 requires: C~ 32.8; H, 5.8; N, 28.7; S, 21.9) _ 15_ . ~ :: ~ - , . - : .
- . . -:
~ ;
- ~ - .

EXA~L~ lOS324Z
N-Methyl-N'-[2_((4_methyl-5-imida~olyl)methy~thio)ethyl~-N"-6ulphamylguanidine (a) A solution of N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine (2.0 g.) in hydrochloric acid (25 ml.) was heated on the steam bath for 2 hours. Concentration followed by recrystallisation of the product from ethanol-ether afforded N-methyl-N"-t2-((4-methyl-5-imidazolyl)methylthio~ethyl]~uanidine dihydrochloride (1.44 g.) m.p. 204-206.
(Found: C, 35.8; H~ 6.5; S, 10.8; Cl, 23.7. 9 1~5 requires: C~ 36.0; H, 6.4; S, lQ.7; Cl, 2~.6) (b) The guanidine dihydrochloride (3.0 ~was added to a solution of sodium (o.46 g.) in ethanol (50 ml.) and following warming with stirring for 0.5 hours, the mixture was cooled ~nd filtered~ N-Piperidylsulphamide (1.64 g.) was added to the filtrate which was heated under reflux for 24 hours. Following concentration the residue was chromatographed firstly on silica gel with ethyl acetate-ethanol~(4:1) as eluant and then on alumina with a similar eluant, to yield N-methyl-NI-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-sulphamylguanidine as a glass (1.05 g.) (Found C~ 36-1; H~ 6-1; N~ 26-1; S, 19-8- C9H18N602S2 (+3% C2H50H) requires: C, 35.8; H, 6.1; N, 26.6; S, 20.3) EXA~LE 13 N-(4-Am~nobenzenesulphonyl~-N'-m~thyl-N"-[2-(4-methyl-5-imida~olyl) methylthio)ethYl]~uanidine (a) The reaction of 4-aminobenzenesulphonamide (17.2.g.) with sodium . .
hydroxide, carbon disulphide and methyl iodide by the method described in Example 8~afforded N-(4-aminobenzenesulphonyl)iminodithiocarbonic acid dimethyl ester (9.4 g.), m.p. 202-204 (from ethanol).

(b) The reaction of N-(4-aminobenzenqsulphonyl)iminodithiocarbonic acid dimethyl ester (8.9 g.) with 4-methyl-5-((2-aminoethyl)thiomethyl)imidazol9 5.5 g.)`and methylamine by the method deseribed in Example 7~ followed by ohrom~atographic purification on a column of alumina with ethyl acetate ethanol ~4:1) as eI~ant afforded (N-(4-aminobenzenesulphonyl)-N'-methyl-Nn-~2-((4-~ethyl-5-imidazolyl)methylthio)ethyl]guanidine as a glass.
(Found: S~ 1~.7~ 15N22N602S2 requires: S~ 16.8%) , - - : : . -.. , EXAMPL~ 14 lQS3Z4Z

N-Acet~l~N~-[2-((4-methyl-5-imidazolyl)methylthio)eth~l]~uanidine N-Acetyl-S-methylisothiouronium iodide (5, 20 g.) was di8solVed in acetonitrile (100 ml.), excess solid potassium c~rbonate added and the suspension stirred at room temperature for 0.5 hour~. Followi~g filtration, 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.42 g.) was added and stirring was continugd at room temperature for 48 hours.
The white solid formed ~luring the reaction was collected and recry~tallised from acetonitrile to give ~-acetyl-N~-~2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine9 m.p. 163-1~4.
(Found: C~ 47.0; H, 6.9; N, 27.4; S,12.4; 10 17 5 requires: C, 47.0, H, 6.7; N, 27.4; S, 12.6) _ A1~PLE 15 N-Carbethox~-N'-~2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine A solution of N-carbethoxy-0-methyli~ourea (1.46 g.) and 4-methyl-5-((2-aminoeth~-l)thi ethyl)imidazole (1.71 g.) in methanol (25 ml) was stirred at room temperature for 7 days. The white solid formed during the reaction was collected and recrystallised from methanol to givè N-carbethoxy-N~-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine~m.p. 196-197.

(Found: C~ 46.5; H, 6,9; N, 24.8; S, 11,5. 511X19N52S

requires: C, 46.3; ~ 6~7; N~ 24.5; S~ 11.2) - :. . : .. : :. . . - ; . . : :.

~OS3Z4Z
EXA~PLE 16 N-Carbamyl-N'-methyl-N"-~2-((4-metllyl-5-imidazolyl)methylthio~
ethyl]~uanidine dihydrochloride A solution of N-cynno_N'-methyl-~ 2-((4-methyl-5-imidazolyl)-methylthio)ethyl~guanidine (1.25 g.) in N hydrochloric acid (15 ml.) was kept at room temperature for 60 hours, and then heated at 40-45 for 20 hours. Follo~ing concentration and ba6ification with sodium ethoxide in eth~nol, the product was chromatographed on silica gel with isopropyl alcohol as eluant. Acidification with ethanolic hydrogen chloride ~nd final recrystallisation ~rom isopropyl alcohol afforded N-carbamyl-N'-methyl-N'I-[2-((4-meth~l-5-imidazolyl)methylthio)ethyl]guanidine dihydrochloride (o.60 g.) m.p. 186-187.
(Found: C~ 35.1; H, 6.1; N~ 23.9; Cl, 20.6. ClOH18N6S- 2 HCl require6: C~ 35.0; H, 5.9; N, 24.5; Cl, 20.7.

N-Methyl-M'-C2-((4-methyl-5-imidazolyl)methylthio)ethyl]-M"-thiocorba-rlRuanidine Ga6eous hydrogen sulphide was pas6ed through a solution of N-cyano-N'-methy}-N -~2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (5.0~g.) ~n~pyridine (45~ml.)containing triethylamine (9 ml.) at room te~perature for 24 hours and at 50- for a similar period.
Concentration, followed by chromatographic purification on a column of~silica~;gel with ethylacetate-isopropyl alcohol (5:1) as eluant and~aoidifioation~with~ethanolic hydrogen chloride afforded N-methyl- -N'-E2_((4-methyl-5-imi:dazolyl)methylthio)ethyl~-N"-thiocarbamyl-guanidin-~(2.4 g.), m.p. 170-171 (from isopropyl alcohol) ~053Z4'~

~Found: C, 33-4; I~, 5.7; r~, 23.0; S, 17.6; Cl, 1~-5- Clo~8N6S2~2HCl requires: C, 33.4; ~I, 5~6; N, 23.4; S, 17.9; Cl, 19.7.

; EXAMPLE 18 N-Benzylideneamino-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl~Fuanidine - ?
A solution of benzaldehyde-4-methylthio6emicarbazone(3.9 e. ) &nd methyliodide (11. 2.g.) in absolute ethanol (40 ml.)was heated under reflux for 16 hour~. Concentration and recry~talli~ation from ethanol afforded the S-methylisothi~uronium iodide (5.3 g.) m.p. ~ -194-196, which was basi~ied with aqueou~ sodium carbonate and extract~d with ethyl acetate to afford the base (Z.5 ~.) This was di~olved in ethanol containing 4-methyl-5-((2-aminoethyl)-thiomethyl)imidazole ~2.0 g.)and the solution heated under reflux for ~ days. Concentration followed by purification on a column of silica ~el with eth~ol as eluant afforded N-benzylidenamino-N~-[2_((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine a~ a low melting solid.
(Found: C, 58.1j H, 7.0; S, 9.7; C16~2N6S
requires: C, 58.2; H, 6.7; Sg 9.7.
~`" .

E)~A~`IPL~ lg ,, Sequential reaction of N-benzenesulphonyliminodithiocarbonic acid dimethyl ester accordin~ to a process similar to that described in Example 6 with any of th~ following substances:
~a) 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole (b) 4-[4-aminobutyllimidazole ~c~ 4-trifluoromethyl-5~1(2-aminoethyl)thiomethyl]imidazole (d) 4-1(2-aminoethoxy)methyl]imidazole (e) 4-methyl-5-[(3-aminopropyl)thiomethyl]imidazole (f) 4-[(2-aminoethyl)aminomethyl]imidazole , ~'1' , .

105;~
and then with excess methylamine result6 respecti~ely in the product~on of the following compound6:

(a) N-benzenesulphonyl-N'-methyl-N"--[2_((4~bromo-5-imidazolyl) methylthio)ethyl~uanidine (b) N-benzenesulphonyl-N~_methyl-N"-r4-(4-imddazol71butyl]guanidine (c) N-ben~enesulphonyl-N~-methyl-N'!-t2-(t4-tri nuoro~ethyl-5- :
imid~zolyl)methylthio)ethyl]guanid~ne (d) N-benzenesulphonyl-N'-methyl-N"-~2-((4-imidazolyl)methox~) ethyl]&uanidine (e) N-benzenesulphonyl-N'-methyl-N"-~3-((4-methyl-5-imidazolyl) methylthio)propyl]guanidine (f) N-benzenesulphonyl-N'-methyl-N"-t2-((4-imidazolyl)methylamino) ethyl]guanidine INGREDIENTS A~OUNTS

N-henzenesulphonyl-N'-methyl-N"-C2-((4-methyl-5~i~idazolyl) methylthio)ethyl]guanidine 15Q mg.
sucros~ . 75 mg-starch 25 mg.
talc 5 mg.
stear1c acid 2 mg.

The ingredlents ar~ ucreened, mix~d and fill~d into a hard gelatin cap6ulQ.

D~ ~

- , ~

Claims (17)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for the production of a guanidine deri-vative of the formula:

I

wherein R1 is hydrogen or lower alkyl; R2 is a grouping of the formula Het - (CH2)mZ (CH2)n- II
wherein Het is an imidazole ring which may be unsubstituted or substituted by lower alkyl, trifluoromethyl, hydroxy, halogen or amino; Z is sulphur, oxygen, NH or a methylene group; m and n are integers from 0 to 4 such that their sum is from 2 to 4; X is COR3, CSR3, SO2R4, N=CHR5 or, when Z is methylene, nitro; R3 is lower alkyl, lower alkoxy or amino;
R4 is lower alkyl, phenyl substituted by lower alkyl, halogen or amino, phenyl, trifluoromethyl or amino; and R5 is phenyl, said process comprising:
(a) reacting an amine of the formula wherein R2 has the above significance with a compound of the formula wherein R1 and X have the above significance; Y is sulphur or oxygen; and A is lower alkyl, (b) reacting an amine of the formula R2NH2 wherein R2 has the above significance first with a compound of the formula (A-Y)2 C = N - X
wherein X has the above significance; Y is sulphur or oxygen;

and A is lower alkyl to give an intermediate compound of the formula VI

and then said intermediate is reacted with an amine of the formula R1NH2 wherein R1 is hydrogen or lower alkyl.
2. The process for the production of a guanidine derivative according to claim 1 wherein an amine of the formula wherein R2 has the same significance as in the formula set out in claim 1 is first reacted with a compound of the formula (A-Y)2C=N - X
wherein X has the same significance as in the formula set out in claim 1; Y is sulphur or oxygen; and A is lower alkyl to give an intermediate compound of the formula and then said intermediate is reacted with an amine of the formula R1NH2 wherein R1 is hydrogen or lower alkyl,
3. A guanidine derivative of the formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein R1, R2 and X are as in claim 1 whenever produced by a method according to claim 1 or 2 or an obvious chemical equivalent thereof.
4. The process as claimed in claim 1 wherein X is COR3, SO2R4 or, when Z is methylene, nitro; R3 is lower alkyl, lower alkoxy or amino; and R4 is lower alkyl, trifluoromethyl, or amino.
5. A guanidine derivative of formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein R1 and R2 are as in claim 1, X is COR3, SO2R4 or when Z is methylene, nitro, R3 is lower alkyl, lower alkoxy or amino; and R4 is lower alkyl, trifluoromethyl, or amino whenever produced by a method according to claim 4 or an obvious chemical equivalent thereof.
6. A process as claimed in claim 1 wherein R1 is methyl, and R2 and X are as in claim 1.
7. A guanidine derivative of formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein R1 is methyl and R2 and X are as in claim 1, whenever produced by a method according to claim 6 or an obvious chemical eqivalent thereof.
8. A process as claimed in claim 1 wherein R2 is such that Z is sulphur, m is 1, n is 2, and R1 and X are as in claim 1.
9. A guanidine derivative of formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein Het, X and R1 are as in claim 1, Z is sulphur, m is 1 and n is 2 whenever produced by a method according to claim 8 or an obvious chemical equivalent thereof.
10. A process as claimed in claim 1 wherein the imidazole ring is optionally substituted by methyl, hydroxyl, halogen or amino.
11. A guanidine derivative of formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein the imidazole ring is optionally substituted by methyl, hydroxyl, halogen or amino and m, n, Z, X and R1, are as in claim 1, whenever produced by a method according to claim 10 or an obvious chemical equivalent thereof.
12. A process as claimed in claim 1 wherein X is phenylsulphonyl, aminosulphonyl or aminocarbonyl.
13. A guanidine derivative of formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein X is phenylsulphonyl, aminosulphonyl or aminocarbonyl and R1 and R2 are as in claim 1, whenever produced by a method according to claim 12 or an obvious chemical equivalent thereof.
14. A process for the production of N-benzenesulphonyl-N'-[2-(4-methyl-5-imidazolyl)methylthio)ethyl]guanidine in which 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole is reacted with N-benzenesulphonyl-S-methylisothiourea.
15. A process for the production of N-benzenesulphonyl-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine in which 4-methyl-5-((2-aminoethyl)thiomethyl)-imidazole is reacted with N-benzenesulphonyliminodithiocarbonic acid dimethyl ester to give, as intermediate, N-benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methyl-isothiourea which is then reacted with methylamine.
16. N-benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine whenever prepared or produced by the process of claim 14 or an obvious chemical equivalent thereof.
17. N-benzenesulphonyl-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine whenever prepared or produced by the process of claim 15 or an obvious chemical equivalent thereof.
CA177,944A 1972-09-05 1973-08-01 Heterocyclic guanidine derivatives Expired CA1053242A (en)

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GB1554153A (en) * 1975-05-15 1979-10-17 Smith Kline French Lab Process for making 2-amino-2-alkylthionitroethylenes
US4165378A (en) 1977-04-20 1979-08-21 Ici Americas Inc. Guanidine derivatives of imidazoles and thiazoles
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NO781300L (en) 1977-04-20 1978-10-23 Ici Ltd PROCEDURE FOR PREPARATION OF PHYSIOLOGICALLY ACTIVE GUANIDINE DERIVATIVES
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JPS4975575A (en) 1974-07-20
DE2344833A1 (en) 1974-03-14
FR2199466B2 (en) 1977-01-28
IE38123B1 (en) 1978-01-04
GB1398426A (en) 1975-06-18
BE804145A (en) 1974-02-28
IL42879A (en) 1976-10-31
FR2199466A2 (en) 1974-04-12
IL42879A0 (en) 1973-11-28
DE2344833C2 (en) 1981-10-29
AU5890673A (en) 1975-02-06
AU473158B2 (en) 1976-06-17
IE38123L (en) 1974-03-05
HU166637B (en) 1975-04-28
JPS5732062B2 (en) 1982-07-08
NL7310836A (en) 1974-03-07

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