GB1565647A - Pharmacologically active compounds 4-substituted-imidazole-5-methanols - Google Patents

Pharmacologically active compounds 4-substituted-imidazole-5-methanols Download PDF

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GB1565647A
GB1565647A GB31968/75A GB3196875A GB1565647A GB 1565647 A GB1565647 A GB 1565647A GB 31968/75 A GB31968/75 A GB 31968/75A GB 3196875 A GB3196875 A GB 3196875A GB 1565647 A GB1565647 A GB 1565647A
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ethyl
formula
methylthio
imidazolyl
hydroxymethyl
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Smith Kline and French Laboratories Ltd
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Smith Kline and French Laboratories Ltd
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Priority to GB31968/75A priority Critical patent/GB1565647A/en
Priority to ZA763686A priority patent/ZA763686B/en
Priority to BE168682A priority patent/BE843840A/en
Priority to IL50006A priority patent/IL50006A0/en
Priority to PH18667A priority patent/PH13417A/en
Priority to DK316376A priority patent/DK316376A/en
Priority to PT65377A priority patent/PT65377B/en
Priority to FR7622069A priority patent/FR2319341A1/en
Priority to CS764839A priority patent/CS203054B2/en
Priority to CA257,589A priority patent/CA1075702A/en
Priority to ZM96/76A priority patent/ZM9676A1/en
Priority to SE7608478A priority patent/SE7608478L/en
Priority to GR51356A priority patent/GR61114B/en
Priority to AT552376A priority patent/AT356668B/en
Priority to LU75495A priority patent/LU75495A1/xx
Priority to AU16447/76A priority patent/AU508262B2/en
Priority to FI762191A priority patent/FI762191A/fi
Priority to ES450309A priority patent/ES450309A1/en
Priority to DE19762634430 priority patent/DE2634430A1/en
Priority to AR264157A priority patent/AR213100A1/en
Priority to DD194154A priority patent/DD125205A5/xx
Priority to JP51092242A priority patent/JPS5219663A/en
Priority to HU76SI1532A priority patent/HU174068B/en
Priority to NL7608505A priority patent/NL7608505A/en
Priority to NO762659A priority patent/NO762659L/no
Priority to SU762386215A priority patent/SU655310A3/en
Priority to RO87167A priority patent/RO72312B/en
Priority to OA55903A priority patent/OA05405A/en
Publication of GB1565647A publication Critical patent/GB1565647A/en
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    • 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
    • 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
    • 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
    • C07D233/66—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 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Description

(54) PHARMACOLOGICALLY ACTIVE COMPOUNDS 4-SUBSTITUTED-IMIDAZOLE-5-METHANOLS (71) We, SMITH KLINE & FRENCH LABORATORIES LIMITED of Mundells, Welwyn Garden City, Hertfordshire, England, a British company do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement : - This invention relates to pharmacologically active compounds, to methods for preparing these compounds and to pharmaceutical compositions containing these compounds. The invention also includes acid addition salts of these compounds and where reference is made to the free bases throughout this specification, it is intended to include these salts.
Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors. Histamine is such 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 H1-receptors (Ash & Schild, Brit. 7. Phannw. Chenrorher, 27 427, (1966)).
However, other of the biological actions of histamine are not inhibited by "antihist amines" and actions of this types which are inhibited by a compound described by Black et at (Nature, 236, 385 (1972)) and called burimamide are mediated through receptors which are defined by Black et at, as histamine H2-receptors. Thus histamine H2-receptors are defined as those histamine receptors which are not blocked by inepyramine but are blocked by burimamide. Compounds which block histamine H=receptors are referred to as histamine H2-receptor antagonists.
Blockade of histamine H2-receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2,-receptor antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents, and as agents which act on the cardiovascular 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 H1- and H2 receptor antagonists is useful. The compounds of this invention are histamine H,-receptor antagonists. These compounds are represented by the following formula:
FORMULA I wherein n is 2 or 3; Z is sulphur or methylene; X is sulphur, CHNO2 or N. CN; Y is hydrogen, lower alkyl or HetCH,Z'(CH,).; Z' is sulphur or methylene; n' is 2 or 3; and Het is 5-hydroxymethylXimidazolyl, an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring.
Throughout the present specification, by the term "lower alkyl" we mean an alkyl group containing from 1 to 4 carbon atoms.
A useful group of compounds according to our invention are those wherein Y is lower alkyl, e.g., methyl. Another useful group is that wherein Z is sulphur, and n is 2.
Z' is preferably sulphur, n' is preferably 2 and Het is preferably 5-methyl-4imidazolyl, 5-brornoirnidazolyl, 3 - hydroxy - 2 - pyridyl, 3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-thiazolyl or 3-isothiazolyl. Specific com- pounds within the scope of the present invention include: N-methyl-N' [2-((S4iydroxymethyi4irnidazolyi)methyithio)ethyl and N - methyl - N' - cyano - N" - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methyl- thio)ethyl]guanidine The compounds of the present invention can be produced from the amine of Formula II:
FORMULA II wherein n and Z have the above significance by reactions such as those disclosed in our British specification Nos. 1,338,169, 1,397,436, 1,421,792 and 1,431,589 the particular reaction used depending of course on the nature of X and Y in Formula I.
For example, the compounds wherein X is sulphur and Y is lower alkyl can be pro- duced by reaction of the amine of Formula II with a lower alkyl isothiocyanate of Formula HI: Y'-N=C= S FORMULA III wherein Y' is lower alkyl. A similar reaction using benzoyl isothiocyanate yields an N-benzoyl thiourea which, on acid hydrolysis to remove the benzoyl group yields a compound of Formula I wherein X is sulphur and Y is hydrogen. The compounds wherein X is sulphur and Y is HetCH2Z'(CH2)n, can be prepared by first reacting an amine of Formula II with carbon disulphide to give a dithiocarbamic acid of Formula IV:
FORMULA IV wherein Z and n have the above significance and R is hydrogen, which compound is then reacted with a methyl halide to give the corresponding methyl ester (Formula IV, R=methyl), and finally reacting this ester with an amine of formula HetCH'(CH2),NH, to yield the required compound.
The compounds wherein X is CHNO2 or N . CN can be produced by reaction of an amine of Formula II with a compound of formula Va:
FORMULA Va wherein Q is lower alkyl and X' is CHNO2 or N . CN or, when X' is CHNO2, the corresponding monosulphoxide compound of Formula Vb:
FORMULA Vb to give a compound V1:
FORMULA VI followed by reaction of this latter compound with an amine of formula Y NH2 to give the required compound of Formula I. Acid addition salts of the compounds of Formula I can be prepared by known methods.
The amine of Formula II wherein Z is sulphur is conveniently prepared by reduction of the corresponding carboxylic acid of Formula VII:
FORMULA VII This reduction is conveniently carried out by electrolytic means, or alternatively by chemical reduction of the corresponding ester with lithium aluminium hydride.
The synthesis of the compound of Formula VII can commence from ethyl ethoxyacetoacetate which is first converted with nitrous acid into the known compound of formula VIII:
FORMULA VIII Reduction of this compound with stannous chloride gives the corresponding amine which, without isolation, is reacted with ammonium thiocyanate to give the imidazole2-thione of Formula IX:
FORMULA IX Desulphurisation of this compound gives the imidazole derivative of Formula X:
FORMULA X When this compound is subjected to a series of reactions which can be effected without isolation of any intermediate and which comprise (a) hydrolysis of the ethyl ester to the acid (b) cleavage of the ethyl ether to the hydroxy compound and (c) reaction of the resultant, 4-hydroxymethyl-5-carboxy compound with an aminothiol of the formula HS(CH2)aNH2, the required compound of Formula VII is produced.
Preparation of the amines of Formula II wherein Z is methylene can commence from a compound of Formula XI: E=N(CH2)n+2COCl FORMULA XI wherein n has the same significance as in Formula I and E=N is a suitably protected amine group e.g., phthalimido. Reaction of a compound of Formula XI with acetylene in a suitable solvent and in the presence of a Lewis acid, e.g., AICla gives a compound of Formula XII: E=N(CH2)11+,COCH=CHCl FORMULA XII which, on treatment with triphenyl phosphine gives a compound of Formula XIfl: E =N(CH2)COCH =CHPPh3 cie FORMULA XIII When this compound is reacted with S-methylisothiourea the product is an imidazole derivative of Formula XIV:
FORMULA XIV and when this is reacted with sodium methoxide cf. the process described and claimed in British Application 44439/76, the product is the compound of Formula XV:
FORMULA XV Desulphurisatiorl of the compound of Formula XV with Raney nickel to remove the 2-rnethylthio group and treatment with concentrated hydrochloric acid to convert the methoxymethyl to a hydroxymethyl group and to remove the amine protecting group yields an amine of Formula II wherein Z is methylene.
The compounds of Formula I 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 Hrreceptor 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 H,-receptors. For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compounds of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.
In addition, the compounds of 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 I. 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 of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secretion in the anaesthetized rat and the dose producing 50% inhibition of histamiasinduced tachycardia in the isolated guinea pig atrium.
For therapeutic use, the pharmacologically active compounds of the present invention will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in the basic form or in the form of a pharmaceutically acceptable addition salt with an acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and can conveniently be formed from the corresponding bases of Formula I by standard procedures, for example by treating the base with an acid in a (C1~ 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 invention therefore provides pharmaceutical compositions comprising a pharmaceutically acceptable diluent or carrier and a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. The pharmaceutical carrier employed can be, solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
Exemplary of liquid carriers are syrup, peanut oil, olive oil and water.
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 fonn, or be in the form of a troche or lozenge. The amount of solid carrier can be varied widely but preferably will be from 25 mg to 1 g. If a liquid carrier is used, the preparation 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 nonaqueous 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 form of presentation.
The active ingredient will be present in the composition in an effective amount to block histamine H2-receptors. The route of administration can be oral or parenteral.
Advantageously the composition 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.
Preferably, each dosage unit will contain the active ingredient in an amount of from 50 mg to 250 ing.
The active ingredient will preferably be administered one to six times per day.
The daily dosage regimen will preferably be from 150 mg to 1500 mg.
The Examples are given by way of illustration. All temperatures are in degrees Centigrade: EXAMPLE 1 N-Methyl-N'- [2(5-hyd roxymethvlimolyi) methylthio)-ethyl] thiourea (i) Ethyl eoximino oxotethoxybutyrate (24.8 g) was added slowly in 30 minutes to cooled (15), well stirred solution/suspension of stannous chioride dihydrate (58.5 g) in concentrated hydrochloric acid (97 ml) and then powdered tin (1.2 g) was added. After 2 hours the mixture was diluted with water (300 ml), cooled to 0 C and hydrogen sulphide passed into the solution which was then filtered. The pli of the solution was adjusted to about 1.0 with sodium hydroxide and an aqueous solution of ammonium thiocyanate (10.3 g) added together with further sodium hydroxide to adjust the pH to about 2.0. After warming with stirring to 95" for 15 minutes the reaction mixture was cooled to 0 and, on standing, a sandy coloured precipitate was obtained which on recrystallisation from water yielded 4ethoxycarbonyl-5-ethoxy- methyl-2-mercaptoimidazole, (11.9 g), mp. 162.5--163".
(Found: C, 47.14; H, 6.04; N, 11.97; S, 13.68% C,H1N2O3S requires: C, 46.94; H, 6.13; N, 12.17; S, 13.92%).
(ii) To a stirred soution at 40 of 4-ethoxycarbonyl-5-ethoxymethyl-2-mercapto- imidazole (11.9 g) in ethanol (700 ml) was added Raney nickel (55 g) and the mixture heated under reflux for 2.5 hours. After cooling, filtration and evaporation of the filtrate the residue was recrystallised from water to give 4-ethoxycarbonyl-5-ethoxy- methylimidazole (6.1 g) m.p. 1431440.
(Found: C, 54.71; H, 7.05; N, 14.00% C9H14N2O3 requires: C, 54.53; H, 7.12; N, 14.13%).
(iii) 4 - Ethoxycarbonyl - 5 - ethoxymethylimidazole (6.0 g) was dissolved in 48% aqueous hydrobromic acid (650 ml) and refluxed together with cysteamine hydrochloride (3.4 g) for 17 hours. Evaporation of the reaction mixture to dryness- and recrystallisation from butanol diethyl ether (15:85) gave 4-carboxy-5-[2-aminoethyl thio]methylimidazole dihydrobromide (10.9 g), m.p. 219-220 .
(Found: C, 23.11; H, 3.64; N, 11.58; Br, 44,41% C,H,lN302S.2HBr requires: C, 23.16; H, 3.61; N, 11.57; Br, 44.02%).
(iv) A solution of 4-carboxy-5-[2-aminoethylthio]methylimidazole dlhydro- bromide (1.0 g) in 10% by volume sulphuric acid (24 ml) was electrolysed for 3 hours at constant current (1.0 amp) and 8-10 volts over a stirred mercury cathode and platinum anode separated by a porous disc.
Adjustment of the pH to 9-10 with potassium carbonate (8.3 g) and evaporation to dryness yielded a residue which was extracted with hot isopropanol and this extract evaporated to give 5-hydroxymethyl4-[2aminoethylthiol -rethylimidazole (0.4 g).
(v) An aqueous ethanolic (1:5, 6 ml) solution of the 5-hydroxy:nethyi[2- aminoethylthiolmethylimidazole (0.4 g) was refluxed with methyl isothiocyanate (0.2 g) for 0.5 hours. After cooling a precipitate separated on standing and the supernatant liquid evaporated to yield an oil which was recrystallised from acetonitrile give, as a white solid, N-methyl-N'-[2-((5-hydroxymethyl)methylthio)ethyl]- thiourea (0.1 g), rnbp. 138.5-139.5 .
(Found: C, 41.59; H, 6.37; N, 21.38% C9H16N4OS2 requires: C, 41.51; H, 6.19; N, 21.52%).
EXAMPLE 2 N-Methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-imidazolyl)- methylthio)ethyij guanidine To a solution of 5-hydroxymethyl-4-(2-aminoethylthio)methylimidazole (0,4 g) in ethanol (3 ml) was added an ethanolic solution of dimethyl cyanodithioimidocarbonate (0.3 g) and stirred at 15C for 2 hours. Evaporation of the solvent yielded, as an oil, S - methyl - N - cyano - N' - [2 - ((5 - hydroxymethyi - 4 - imidazolylmethylthio)- ethyl]isothiourea to which was added excess of an ethanolic solution of methylamine (7 g). After stirring for 70 hours, the reaction mixture was purified by preparative thin layer chromatography to yield the tittle product, as an oil (0.1 g). The structure of the product was confirmed by the n.m.r. spectrum in D2O which showed the following resonances: imidazole-2-fl Singlet at 8 8.69 integral 0.7 protons calculated 1.0 protons imidazole-CH2-O singlet at 8 4.72 integral obscured by HDO.
in:1dazoleCH2-S singIet at a 3.92 integral 1.9 protons calculated 2.0 protons -CH2-N triplet at # 3.34 integral 1.9 protons calculated 2.0 protons CH3-ND singlet at # 2.78 # integral 5.0 protons S-cW,CH, triplet at s 2.71 J calculated 5.0 protons EXAMPLE 3 When 5-hydroxymethyl-4-(2-aminomethylthio)methyl imidazole is reacted with 1 nitro-2,2-bis-methylthioethylene the product is 1-nitro-2-methylthio-2-[2-((5-hydroxy- methyl-4-imidazolyl)methylthio)ethylamino] ethylene.
EXAMPLE 4 When, S - methyi - N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl) methyithio)ethyl j isothiourea is refluxed in pyridine for 7 hours with the following compounds: 5-hydroxyrnethyl4(2-aminoethylthio)methylimidazole} 5-methyl-4-(2-aminoethylthio)methylimidazole, 5-bromo-4-(2-aminoethylthio)methylimidazole, 3-hydroxy-2-(2-aminoethylthio)methylpyridine, 3-methoxy-2-(2-aminoethylthio)methylpyridine, 3-chloro-2-(2-aminoethylthio)methylpyridine, 3-bromo-2-(2-aminoethylthio)methylpyridine, 2-(2-amin oethylthio)methylthiazole, 3-(2-aminoethylthio)methylisothiazole and 4-(4aminobutyl)imidazole the products are, respectively: N - cyano - N,N' - bis - [2 - ((5 - hydroxymethyl - 4 - imidazolyl) - methylthio) ethyl] guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyi - 4 - imidazolyi)methylthio)ethyl] N" - [2 - ((5 - methyl - 4 - imidazolyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [2 - ((5 - bromo - 4 - imidazolyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [2 - ((3 - hydroxy - 2 - pyridyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyi)methylthio)ethyl] N" - [2 - ((3 - methoxy - 2 - pyridyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - irnidazolyl)methylthio)ethyl] N" - [2 - ((3 - chloro - 2 - pyridyl)methyithio)ethyl] guanidine N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [2 - ((3 - bromo - 2 - pyridyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyi - 4 - imidazolyl)mRthylthio)ethyl] N" - [2 - (2 - thiazolylmethylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyi)methyithio)ethyl] N" - [2 - (3 - isothiazolylmethylthio)ethyl] guanidine and N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [4 - (4 - imidazolylbutyl)jguanidine.
EXAMPLE 5 Reaction of 5-hydroxymethyl-4-[(2-aminoethyithio)methyl]-imidazole with benzoylisothiocyanate and acid hydrolysis of the product to remove the N-benzoyl group yields N- [2-((5-hydroxymethy1imidazolyl)methyithio)ethylj thiourea.
EXAMPLE 6 when in the process of Example 1, 3-mercaptopropylamine hydrochloride is used in place of cysteamine hydrochloride (see Ex. 1 (iii)), the resultant product is Nmethyl-N'- [3-((5-hydroxymethyl-imidazolyl)methylthio)propyl] thiourea.
EXAMPLE 7 Reaction of 5-hydroxymethyl-4-(4-aminobutyl)imidazole with dimethyl cyanodi thioimidocarbonate and subsequently with methylamine according to the process of Example 2 yields N-methyl-N'-cyano-N''-[4-(5-hydroxymethyl-4-imidazolyl)butyl]- guanidine.
WHAT WE CLAIM IS: 1. A compound of the formula:
wherein n is 2 or 3; Z is sulphur or methylene; X is sulphur, CHNO2 or N . CN; Y is hydrogen, lower alkyl or HetCH2Z'(CH2), ; Z' is sulphur or methylene; n' is 2 or 3;
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (12)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    nitro-2,2-bis-methylthioethylene the product is 1-nitro-2-methylthio-2-[2-((5-hydroxy- methyl-4-imidazolyl)methylthio)ethylamino] ethylene.
    EXAMPLE 4 When, S - methyi - N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl) methyithio)ethyl j isothiourea is refluxed in pyridine for 7 hours with the following compounds: 5-hydroxyrnethyl4(2-aminoethylthio)methylimidazole}
    5-methyl-4-(2-aminoethylthio)methylimidazole,
    5-bromo-4-(2-aminoethylthio)methylimidazole,
    3-hydroxy-2-(2-aminoethylthio)methylpyridine,
    3-methoxy-2-(2-aminoethylthio)methylpyridine,
    3-chloro-2-(2-aminoethylthio)methylpyridine,
    3-bromo-2-(2-aminoethylthio)methylpyridine, 2-(2-amin oethylthio)methylthiazole, 3-(2-aminoethylthio)methylisothiazole and 4-(4aminobutyl)imidazole the products are, respectively: N - cyano - N,N' - bis - [2 - ((5 - hydroxymethyl - 4 - imidazolyl) - methylthio) ethyl] guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyi - 4 - imidazolyi)methylthio)ethyl] N" - [2 - ((5 - methyl - 4 - imidazolyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [2 - ((5 - bromo - 4 - imidazolyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [2 - ((3 - hydroxy - 2 - pyridyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyi)methylthio)ethyl] N" - [2 - ((3 - methoxy - 2 - pyridyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - irnidazolyl)methylthio)ethyl] N" - [2 - ((3 - chloro - 2 - pyridyl)methyithio)ethyl] guanidine N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [2 - ((3 - bromo - 2 - pyridyl)methylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyi - 4 - imidazolyl)mRthylthio)ethyl] N" - [2 - (2 - thiazolylmethylthio)ethyl]guanidine, N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyi)methyithio)ethyl] N" - [2 - (3 - isothiazolylmethylthio)ethyl] guanidine and N - cyano - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methylthio)ethyl] N" - [4 - (4 - imidazolylbutyl)jguanidine.
    EXAMPLE 5 Reaction of 5-hydroxymethyl-4-[(2-aminoethyithio)methyl]-imidazole with benzoylisothiocyanate and acid hydrolysis of the product to remove the N-benzoyl group yields N- [2-((5-hydroxymethy1imidazolyl)methyithio)ethylj thiourea.
    EXAMPLE 6 when in the process of Example 1, 3-mercaptopropylamine hydrochloride is used in place of cysteamine hydrochloride (see Ex. 1 (iii)), the resultant product is Nmethyl-N'- [3-((5-hydroxymethyl-imidazolyl)methylthio)propyl] thiourea.
    EXAMPLE 7 Reaction of 5-hydroxymethyl-4-(4-aminobutyl)imidazole with dimethyl cyanodi thioimidocarbonate and subsequently with methylamine according to the process of Example 2 yields N-methyl-N'-cyano-N''-[4-(5-hydroxymethyl-4-imidazolyl)butyl]- guanidine.
    WHAT WE CLAIM IS: 1. A compound of the formula:
    wherein n is 2 or 3; Z is sulphur or methylene; X is sulphur, CHNO2 or N . CN; Y is hydrogen, lower alkyl or HetCH2Z'(CH2), ; Z' is sulphur or methylene; n' is 2 or 3;
    and Het is 5-hydroxymethyl4-imidazoly2 an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring; or a pharmaceutically acceptable acid addition salt thereof.
  2. 2. A compound according to claim 1, wherein Y is hydrogen, lower alkyl or HetCH3Z'(CH2)n; and Het is 5-hydroxymethyl4-imidazolyl, an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, chloro or bromo, a thiazole ring or an isothiazole ring.
  3. 3. A compound according to claim 1 or claim 2, wherein Z is sulphur.
  4. 4. A compound according to any one of claims 1 to 3, wherein n is 2.
  5. 5. A compound according to any one of claims 1 to 4, wherein Y is lower alkyl.
  6. 6. A compound according to claim 1, wherein Y is HetCH2S(CH, and Het is 5-methyl4-imidazolyl, 5-bromo-4-imidazolyl, 3-hydroxy-2-pyridyl, 3-methoxy-2 pyiidyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-thi olyl or 3-isothiazolyl.
  7. 7. N - Methyl - N' - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)methyithio)ethylj- thiourea
  8. 8. N - Methyl - N' - cyano - N" - [2 - ((5 - hydroxymethyl - 4 - imidazolyl)- methylthio)ethyl] guanidine.
  9. 9. A compound according to claim 1, as hereinbefore described in any one of Examples 1, 2 and-4 to 7.
  10. 10. A process for the production of a compound according to claim 1 which comprises reacting an amine of the formula:
    wherein Z and n have the same significance as in claim I (a) (to prepare compounds of formula I where X is sulphur and Y is lower alkyl or hydrogen) with an isothiocyanate of formula Y'NCS wherein Y' is lower alkyl or benzoyl and when Y' is benzoyl subjecting the product of the reaction to acid hydrolysis; (b) (to prepare compounds of formula I where X is sulphur and Y is HetCH2Z'(CH2)n) with carbon disulphide to give a dithiocarbonic acid which is then esterified with a methyl halide to give an ester of formula
    and reacting the compound of formula IV with an amine of formula HetCH'(CH,NH2; or (c) (to prepare compounds of formula I where X is CHNO2 or N . CN) with a compound of formula:
    wbrrein X' is CHNO2 or N.CN; X" is CHNO2, and Q is lower alkyl to give a compound of the formula:
    and then reacting the compound of formula VI with an amine of formula YNH2; and if desired converting the compound of formula I produced into an acid addition salt thereof.
  11. 11. A compound according to claim 1 whenever produced by a process according to claim 10.
  12. 12. A pharmaceutical composition comprising as the or an essential active ingredient a compound according to any one of claims 1 to 9 and 11 in association with a pharmaceutically acceptable diluent or carrier.
GB31968/75A 1975-07-31 1975-07-31 Pharmacologically active compounds 4-substituted-imidazole-5-methanols Expired GB1565647A (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
GB31968/75A GB1565647A (en) 1975-07-31 1975-07-31 Pharmacologically active compounds 4-substituted-imidazole-5-methanols
ZA763686A ZA763686B (en) 1975-07-31 1976-06-21 Pharmacologically active compounds
BE168682A BE843840A (en) 1975-07-31 1976-07-06 NEW GUANIDINES AND THIOUREES, THEIR PREPARATION PROCESS AND THEIR USES
IL50006A IL50006A0 (en) 1975-07-31 1976-07-09 Heterocyclic substituted guanidine analogs
PH18667A PH13417A (en) 1975-07-31 1976-07-09 Thiourea and guanidine derivative having actively as hestamine h2 receptor antagonists and pharmaceuas histamine h2 receptor artagonists and pharmaceutical composition
DK316376A DK316376A (en) 1975-07-31 1976-07-13 HISTAMIN H2 ANTAGONISTS
PT65377A PT65377B (en) 1975-07-31 1976-07-16 Pharmacologically active compounds
FR7622069A FR2319341A1 (en) 1975-07-31 1976-07-20 NEW GUANIDINES OR THIOUREES, THEIR PREPARATION PROCESS AND THEIR APPLICATION
CS764839A CS203054B2 (en) 1975-07-31 1976-07-21 Method of preparing imidazolyl compounds
CA257,589A CA1075702A (en) 1975-07-31 1976-07-22 Process for the preparation of substituted guanidine compounds
ZM96/76A ZM9676A1 (en) 1975-07-31 1976-07-23 Pharmacologically active compounds
SE7608478A SE7608478L (en) 1975-07-31 1976-07-27 PHARMACEUTICAL
GR51356A GR61114B (en) 1975-07-31 1976-07-27 Process for the production of pharmacologically active compounds
AT552376A AT356668B (en) 1975-07-31 1976-07-27 METHOD FOR PRODUCING IMIDAZOLYL GUANIDINES
LU75495A LU75495A1 (en) 1975-07-31 1976-07-29
AU16447/76A AU508262B2 (en) 1975-07-31 1976-07-30 Imidazoles
FI762191A FI762191A (en) 1975-07-31 1976-07-30
ES450309A ES450309A1 (en) 1975-07-31 1976-07-30 Pharmacologically active compounds 4-substituted-imidazole-5-methanols
DE19762634430 DE2634430A1 (en) 1975-07-31 1976-07-30 UREA DERIVATIVES, THEIR SALT WITH ACIDS, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
AR264157A AR213100A1 (en) 1975-07-31 1976-07-30 PROCEDURE FOR THE PREPARATION OF COMPOUNDS DERIVED FROM N- (2-HYDROXIMETHYL-N-IMIDAZOLIL) -GUANIDINE
DD194154A DD125205A5 (en) 1975-07-31 1976-07-30
JP51092242A JPS5219663A (en) 1975-07-31 1976-07-30 Heterocyclic compound
HU76SI1532A HU174068B (en) 1975-07-31 1976-07-30 Process for preparing pharmacologically active imidazole
NL7608505A NL7608505A (en) 1975-07-31 1976-07-30 PROCESS FOR PREPARING PHARMACOLOGICALLY ACTIVE MATERIALS.
NO762659A NO762659L (en) 1975-07-31 1976-07-30
SU762386215A SU655310A3 (en) 1975-07-31 1976-07-30 Method of obtaining imidazole derivatives
RO87167A RO72312B (en) 1975-07-31 1976-07-31 Process for obtaining a thiourea derivative
OA55903A OA05405A (en) 1975-07-31 1976-07-31 Process for the preparation of pharmacologically active compounds.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB31968/75A GB1565647A (en) 1975-07-31 1975-07-31 Pharmacologically active compounds 4-substituted-imidazole-5-methanols

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AR (1) AR213100A1 (en)
AT (1) AT356668B (en)
AU (1) AU508262B2 (en)
BE (1) BE843840A (en)
CA (1) CA1075702A (en)
CS (1) CS203054B2 (en)
DD (1) DD125205A5 (en)
DE (1) DE2634430A1 (en)
DK (1) DK316376A (en)
ES (1) ES450309A1 (en)
FI (1) FI762191A (en)
FR (1) FR2319341A1 (en)
GB (1) GB1565647A (en)
GR (1) GR61114B (en)
HU (1) HU174068B (en)
IL (1) IL50006A0 (en)
LU (1) LU75495A1 (en)
NL (1) NL7608505A (en)
NO (1) NO762659L (en)
OA (1) OA05405A (en)
PH (1) PH13417A (en)
PT (1) PT65377B (en)
RO (1) RO72312B (en)
SE (1) SE7608478L (en)
SU (1) SU655310A3 (en)
ZA (1) ZA763686B (en)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288742A (en) * 2013-06-04 2013-09-11 四川百利药业有限责任公司 Preparation method for high-purity ingavirin raw material
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Families Citing this family (8)

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Publication number Priority date Publication date Assignee Title
US4165378A (en) 1977-04-20 1979-08-21 Ici Americas Inc. Guanidine derivatives of imidazoles and thiazoles
IE47044B1 (en) 1977-04-20 1983-12-14 Ici Ltd Guanidine derivatives
US4112234A (en) 1977-08-22 1978-09-05 Bristol-Myers Company Imidazolylmethylthioethyl alkynyl guanidines
USRE31588E (en) * 1977-06-03 1984-05-22 Bristol-Myers Company Imidazolylmethylthioethyl alkynyl guanidines
US4233302A (en) 1977-12-23 1980-11-11 Glaxo Group Limited Amine derivatives and pharmaceutical compositions containing them
EP0008596A1 (en) * 1978-09-04 1980-03-19 DEVINTER Europe S.A. Société anonyme dite: Preparation of 4-hydroxymethyl-imidazole derivatives from the corresponding 4-imidazole carboxylic acid esters
US4200760A (en) * 1978-09-26 1980-04-29 Bristol-Myers Company Imidazolylalkylthioalkylamino-ethylene derivatives
JPS5914460B2 (en) * 1978-12-27 1984-04-04 相互薬工株式会社 Production method of cimetidine, an anti-H↓2 receptor

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CA938556A (en) * 1970-06-25 1973-12-18 Smith Kline And French Laboratories Limited Pharmaceutical compositions containing thiourea derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288742A (en) * 2013-06-04 2013-09-11 四川百利药业有限责任公司 Preparation method for high-purity ingavirin raw material
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

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RO72312B (en) 1984-03-31
FR2319341A1 (en) 1977-02-25
AU1644776A (en) 1978-02-02
SU655310A3 (en) 1979-03-30
ES450309A1 (en) 1977-12-01
CS203054B2 (en) 1981-02-27
ZM9676A1 (en) 1977-07-21
AU508262B2 (en) 1980-03-13
AT356668B (en) 1980-05-12
NL7608505A (en) 1977-02-02
DE2634430A1 (en) 1977-02-10
LU75495A1 (en) 1977-03-03
BE843840A (en) 1977-01-06
ATA552376A (en) 1979-10-15
GR61114B (en) 1978-09-13
ZA763686B (en) 1977-05-25
PH13417A (en) 1980-03-30
FI762191A (en) 1977-02-01
PT65377B (en) 1978-01-19
JPS5219663A (en) 1977-02-15
DK316376A (en) 1977-02-01
RO72312A (en) 1984-03-15
OA05405A (en) 1981-02-28
SE7608478L (en) 1977-02-01
FR2319341B1 (en) 1979-01-12
PT65377A (en) 1976-08-01
HU174068B (en) 1979-10-28
CA1075702A (en) 1980-04-15
IL50006A0 (en) 1976-09-30
DD125205A5 (en) 1977-04-06
AR213100A1 (en) 1978-12-15
NO762659L (en) 1977-02-01

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