CA1068715A - Process for preparing substituted guanidines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Pharmacologically active compounds of the formula:

Description

` 10687:15 This invention relates to a process for preparing pharmacologically active compounds which block histamine H2-receptors. The compounds prepared by the invention can exist as acid addition salts but, for convenience, reference will be made througllout this specification to the free bases.

Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors.
Histamine is SUC]I a substance and it has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine is a typical example, and diphenhydramine and chlorpheniramine are other examples, are mediated through histamine Hl-receptors (Ash and Schild, Brit. J. Pharmac.
Chemother, 27, 427, (1966)). However, other biological actions of histamine are not inhibited by "antihistamines" and actions of this type which are inhibited by a compound described by Black et al. ~Nature, 236, 385 (1972) and called burimamide are mediated through receptors which are defined by Black et al. as histamine H2-receptors. Thus histamine H2-receptors may be defined as those histamine receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine ll2-receptors are referred to as histamine H2-antagonists.

Blockade of histamine H2-receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2-antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardio-vascular system, for example as inhibitors of the effects of histamine on blood pressure. In the treatment of certain conditions, for example inflammation and in inhibiting the actions of histamine on blood pressure, a combination of histamine 1~ and H2-antagonists is useful.

The compounds prepared by this invention are histamine H2-antagonists. These compounds are represented by the following formula:

N~l Rl - S - C~

wherein Rl represents a grouping of the structure shown in Formula 2:

}let - CH2S(C~12)2 wherein Het is imidazole optionally substituted by (Cl 4) alkyl, preferably methyl and R2 is hydrogen, (Cl 4) alkyl, preferably methyl.

1~ will be understood that the structure illustrated in ~`ormula 1 is only one of several possible representations and that other tautomeric forms are also covered by the present invention. Ilydrates, pharmaceutically acceptable salts, and hydrated pharmaceutically acceptable salts of compounds of Formula 1 are also covered by the present invention.

687ll5 Preferably }-let is a 4-imidazolyl ring optionally substituted by (Cl 4) alkyl. Particularly preferably, Het is a 5-methyl-4-imidazolyl ring.

An example of a specific compound which can be prepared by the present invention is S-[2-(S-methyl-4-imidazolyl-methylthio)ethyl]isothiourea.

Compounds of Formula 1 are prepared in accordance with the invention by reacting a compound of Formula 3:

/ N~2 S = C
\ NHR2 wherein R2 is as defined for Formula 1, with a compound of formula RlY where Rl is as defined for Formula 1 and Y is chlorine or bromine. The compounds of formula RlY can be prepared from the corresponding alcohols of formula R10H
by standard techniques, e.g., the chlorides can be prepared from the corresponding alcohols by reaction with thionyl chloride.

The alcohols of formula R101-1 can be prepared by the reaction of mercaptoethanol with a compound of formula HetCH2Y, in which Het has the same significance as in Formula 2 and Y
represents chlorine or bromine. Preferably this reaction is carried out in a solvent in the presence of a base, such as with sodium ethoxide in dry ethanol.

1~:)68715 The compounds of Formula 1 block histamine H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by "antihistamines" such as mepyramine but are inhibited by burimamide. For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kilogram intravenously. This procedure is referred to in the above mentioned paper of Ash and Schild. The activity of these compounds as histamine H2-antagonists is also demonstrated by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine Hl-receptors. For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.

The compounds prepared by the process of this invention inllibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.

In addition, the compounds prepared by this invention show anti-inflammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume is reduced by subcutaneous injection of doses of a compound of Formula 1. In a conventional test, such as the measurement of blood pressure in the anaesthetised cat, the action of the compounds of this invention in inhibiting the vasodilator action of histamine can also be demonstrated. The level of activity of the compounds is 1068'7~5 illustrated by the effective dose producing 50~ inhibition of gastric acid secretion in the anaesthetized rat and the dose producing 50~ inhibition of histamine-induced tachycardia in the isolated guinea pig atrium.

For therapeutic use, the pharmacologically active compounds will normally be administered as a pharmaceutical composltion comprising as the or an essential active ingredient at least one such compound in basic form or in the form of a pharmaceutically acceptable acid addition salt and associated with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and they can conveniently be formed from the corresponding bases of Formula 1 by standard procedures, for example by treating the base with an acid in a lower alkanol or by the use of ion exchange resins to form the required salt, either directly from the base or from a different addition salt.

The pharmaceutical carrier employed can be solid or liquid.
Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and thc like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the compositions 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 can be varied widely but preferably will be from about 1~:)68715 25 mg to about 1 g. If a liquid carrier is used, the compositions can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions can be 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 block histamine ll2-receptors. The route of administration can be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg to about 250 mg. The active ingredient will preferably be administered one to six times per day. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg. Advantageously the compositions will be made up in a dosage form appropriate to the desired mode of administration, for example as a tablet, capsule, injectable solution or as a cream or ointment for topical application.

The invention is illustrated and in no way limited by the follawing Example wllerein all temperatures are given in degrees Centigrade:

1~68715 LXAMI'LE

S-[2-(5-Methyl-4-imidazolylmethylthio)ethyl~isothiouronium sulphate.

a) Sodium (3.0 g) was added, with stirring under nitrogen, to dry ethanol (75 ml). After the sodium had dissolved mercaptoethanol (9.0 ml) was introduced and to this mixture was added 4-methyl-5-chloromethylimidazole hydrochloride (10 g), as a solid, over a period of 1.5 hours at room temperature.
The mixture was then stirred for a further 1 hour at room temperature. After this time the reaction was warmed and the ethanol distilled off at reduced pressure. The residue was taken up in water, acidified with concentrated hydrochloric acid, and continuously extracted with ether to remove the excess mercaptoethanol. The aqueous fraction was then basified using solid sodium carbonate and continuously extracted with ethyl acetate. To the extract was added a further volume of ethyl acetate and the whole warmed to re-dissolve the crude product which had deposited. After drying (MgS04) and reducing the volume, crystallisation from this solution below 40 and cooling to -15 afforded 2-(5-methyl-4-imidazolylmethylthio) ethanol, m.p. 7 4- 7 6 .
(Found: C, 49.1; H~ 6.8; N, 16.2; C7H12N20 S
requires: C, 48.8; H, 7.0; N, 16.3~o).

b) 2-(5-Methyl-4-imidazolylmethylthio)ethanol (O. 34 g,

2 mmol) and thionyl chloride (0.238 g, 2 mmol) were heated together, with stirring, at reflux temperature in chloro-form (10 ml) for one hour, giving a grey solution and a green oil. A second equivalent of thionyl chloride (0.238 g) was added at reflux temperature and immediately the oil went into solution and a solid started to crystallise. After a further 15 minutes at reflux temperature the mixture was cooled and the solid collected (0.395 g). Recrystallisation from acetonitrile gave l-chloro-Z-(5-methyl-4-imidazolyl-methylthio) ethane hydrochloride, m.p. 163-165, (0.29 g).
(Pound: C, 37.1; Il, 5.2; N, 12.6; S, 14.1; Cl, 31.2;
C7HllCl N2S requires: C, 37.0; H, 5.3; N, 12.3; S, 14.1;
Cl, 31. 2%) .

c) l-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane hydrochloride (3.9 g, 17 mmol) and thiourea (1.30 g, 17 mmol) were heated together at reflux temperature for 48 hours in ethanol (50 ml). After cooling the ethanol was evaporated and the residual oil converted to the sulphate salt by dissolution in water (220 ml) and passage down an ion-exchange column. The water was evaporated and the residual oil triturated with boiling methanol to give a white solid (4~33 g).
Crystallisation of this solid from aqueous methanol gave S~ [ 2- ( 5-methyl ~4 -imidazolylmethylthio)-ethyl]isothiouronium sulphate, ( 3~70 g) ~ m.p. 217~220.
~ound: C, 29.4; H, 5.1; N, 17.1; S~ 29.0; C8H14N4S2.H2S04 requires: C, 29.3; Il~ 4.9; N, 17.1; S~ 29.3~o).

Claims (4)

WHAT IS CLAIMED IS

1. A process for preparing a compound of the formula:

wherein R1 represents a grouping of the structure Het - CH2S(CH2)2 -wherein Het is optionally substituted by (C1-4) alkyl, and R2 is hydrogen or (C1-4) alkyl which comprises reacting a thiourea of formula NH2 CS NHR2 with a compound of formula R1 Y, Y being chlorine or bromine and if desired obtaining a hydrate or pharmaceutically acid addition salt or hydrated salt thereof.

2. The process according to Claim 1 for preparing S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]isothiourea which comprises reading 1-chloro-2-(5-methyl-4-imidazolylmethylthio) ethane with thiourea.

3. A compound of the formula wherein R1 represents a grouping of the structure Het - CH2S(CH2)2 --1?-wherein Het is imidazole optionally substituted by (C1-4) alkyl, and R2 is hydrogen or (C1-4)alkyl, or a hydrate or pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

4. S-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]isothiourea when prepared or produced by the process of claim 2 or an obvious chemical equivalent thereof.