IE902980A1

IE902980A1 - Substituted n-heterocyclic groups, the preparation and use¹thereof

Info

Publication number: IE902980A1
Application number: IE298090A
Authority: IE
Original assignee: Boehringer Ingelheim Int
Priority date: 1989-08-19
Filing date: 1990-08-17
Publication date: 1991-02-27
Also published as: WO1991002731A1; GR900100619A; IL95409A0; AU6157190A; PT95036A

Abstract

Disclosed are compounds of formula (I) in which M, U, T, W and Y are N or C, R1 is a carbocyclic or heterocyclic ring, R2 is H, alkyl, CF3, alkoxy, -CH2-O-alkyl or cycloalkyl, R3 is a (C1-C6 alkylene) heterocycle and V is O or S, which can be prepared by ordinary methods. They are suitable for use as active ingredients for drugs.

Description

The present invention relates to novel compounds which contain N-heterocyclic five-membered rings, the preparation thereof and their use as active substances in pharmaceutical compositions.

The new compounds correspond to the formula wherein M and U both represent N, N-lower alkyl, CH or C-lower alkyl, T, W and Y each represent N or C; or if either Y or M represent an N-atom, M or Y may additionally each represent an S-atom whilst T, U and W each represent carbon atoms; the dotted line represents optional bonds between Μ, T, U, W or Y which provide single or double bonds, preferably double bonds wherever possible; R, represents a group selected from: (II) (III) wherein R4 and Rs each represent H, R1V OR1V halogen, CF3, aryl, N(R11)2; or R4 and Rg together represent a fused C5_710 cycloalkene ring, a fused benzene ring or one of the groups -N=CH-NH-, -N=CH-CH=CH-, -O-CHj-O-, -O-CH2-CH2-O-, -NH-CO-NH- and -N=CH-CH=N- bound to adjacent carbon atoms of the benzene ring; 15R6 represents H,R11'R7 represents H,R11 'R8 represents H,R11 0Rn or aryl; R? and R3 together represent a fused C5.7-cycloalkene or benzene ring; R, and R10 each represent H, R1V OR1V NiR^)^· or R9 and R10 together represent a fused benzene ring; X represents S, 0, NH or N(CV4-alkyl); I X represents CH or N; represents H, C^-alkyl and, if apart from Rn or an R^-containing group, the radicals II, III or IV do not contain any other substituents, R^ additionally represents C5.12-alkyl or C5.12alkoxy; R2 represents H, C1.4-alkyl, CF3, C1.4-alkoxy, CH2-O-(C1.4alkyl) or C3.6-cycloalkyl; R3 represents (C^-alkylene)-Het, wherein Het represents a group selected from: - 3 10 -N \ -R (VIII) (ix) -R R in which Z represents S, N-R12, CH=CH, N=CH or CH=N; R12 represents H, C1.4-alkyl or aryl; and R13 represents H or C1.4-alkyl; or R12 and R13 together may represent a fused benzene ring; R14 represents H, C1.4-alkyl-C1.4-alkoxy or halogen and is optionally present twice; The hydrocarbon chain in the defined groups may be straight-chained or branched. Halogen denotes fluorine, chlorine, bromine or iodine; aryl denotes V represents O or S; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof. - 4 particularly phenyl and, naphthyl. If multiple substitution is possible in the heterocyclic and aromatic groups, the substituents may be identical or different. There may be up to three alkyl or alkoxy groups as substituents, particularly in the case of C,^alkyl or alkoxy, whilst aryl, CF3 or will occur not more than twice but preferably occurs only once.

The group N(Rn)2 occurs at most twice, but preferably only once. The group N(R11)2 may contain identical or different groups. The group VR3 is preferably in the para-position relative to the five-membered heterocyclic ring.

The five-membered heterocyclic ring M------U ; — Τ.. --Ϋ— may be, depending on the definitions of Μ, T, U, W, Y, 20 a triazole ring such as an imidazole ring such as a pyrrole ring such as a thiazole ring such as (R = H or lower alkyl).

Compounds according to the are preferred include compounds 10 wherein the five-membered heterocyclic selected from:present invention which of general formula I M----~u N N- R1 represents either of the groups II and III as hereinbefore described, wherein R4, R5 and R6 each represent H, CV4-alkyl, CV4alkoxy, halogen; if R5 and R6 represent H, R4 0 additionally represents a C5.12-alkyl or -alkoxy group; or if R5 and R6 represent C1.4-alkyl, R4 additionally represents OH; or R4 and Rj together represent a fused C5.7-cycloalkene ring, a methylenedioxy or ethylenedioxy group or, if R6 represents H, additionally a fused benzene ring; X represents S, 0, NH or N(C^-alkyl) ; ι · X' represents N, if X1 represents NH or N-iC,^alkyl), and X' represents CH if X represents S or 0; R? and R8 both represent H, C^-alkyl, phenyl or halogen, and if R8 represents H, R7 additionally represents C5.12-alkyl; or R? and Rg together represent a fused C5.7-cycloalkene or benzene ring; R2 represents H, CH3, C2H5, i-C3H7, cyclopropyl or tbutyl; R3 represents (C14-alkylene)-Het, wherein Het represents the groups V or VI or the group Z-.

A. wherein R12 represents H R13 represents H Z represents S, R14 represents H, CV4-alkyl, C^-alkoxy or halogen; V represents 0 or S; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof. or CH3; or CH3; NH... CH=CH, N=CH or CH-N; .•y— Compounds of the present invention which are particularly preferred include compounds of general formula I wherein M----”U the five-membered heterocyclic ring is denoted by —T. . - 8 10 R, represents a group *4 R. in which R4 and R5 each represent H, C1.4~alkyl, Cl, F or C,.4alkoxy; or R4 and R5 together represent -O-CHZ-O- or -O-CH2-CH2-O-, bound to adjacent carbon atoms of the phenyl ring (in which case R6 represents H) ? Rj represents H, CH3 or OCH3, and if R4 and R5 do not represent H, R6 additionally represents OH; R?, and Rg each represent H, C1.4-alkyl, Cl or Br; or R? and R8 together represent a fused cycloalkene ring with 5 or 6 carbon atoms; R2 represents H, CH3, C2H5, i-C3H7, or cyclopropyl; R3 represents either C2.4-alkylene-Het, if Het represents wherein R12 represents H, CH3, or C6H5; and 10 R13 represents H, or CH3; or C^j-alkylene-Het, if Het represents 0 Ru represents H, CH3, OCH3 or Cl; V represents O or S; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof.

The new compounds may be prepared by a variety of methods analagous to methods known per se. Such methods are described for example in: A. Weinberger and E.C. Taylor, The Chemistry of Heterocyclic compounds John Wiley & Sons, New York 1981 for the triazoles: Vol. 37, p. 34 ff and 66 ff; for the thiazoles: Vol. 34, Part 1, p. 175 ff; or in S. Coffey and M.F. Ansell, Rodd's Chemistry of Carbon Compounds Elsevier Science Publishers, Amsterdam 1986 for the tetrazoles in Vol.

IV, Part D, p. 211 ff; for the pyrazoles or imidazoles -loin Vol. IV, Part C, ρ. 1 ff or 120 ff, for imidazoles in Vol. IV, Part C, ρ. ΐχθ ff, Elsevier Science Publishers, Amsterdam, 1986. 1 According to a further feature of the present 5 invention, we provide processes for the preparation of a compound of formula I as defined above which comprises either wherein R1, R3, V and R14 are as defined above, reacting an imide chloride of formula XI or XII respectively wherein R1, R3, R14 and V have the above meanings, with a metal azide in an aprotic solvent such as dimethylformamide at e.g. temperatures of from 60 to 120’C; or b) for the preparation of a triazole of formula Ic: reacting an imide chloride of formula XI with an acylhydrazide of formula OC(R)-NH-NH2 (wherein R represents H, or lower alkyl) in an aprotic solvent such as toluene; or wherein R,, R2, R3, V and R14 are as defined above i) for Id, reacting a 1,4-diketone of formula XIII 30 with an amine of formula XIV (xiii) - 12 10 wherein Rv R2, meanings, R3, V and R14 have the above reacting a 1,4-ketoaldehyde of formula ii) for Ie, wherein R2, R3, R14 and V are as defined above, an amine of formula XV with R^NHj (XV) wherein R1 is as defined above, each reaction being carried out in the presence of an acid such as toluenesulphonic acid with cleaving of water; or d) for the preparation of a pyrazole of formula If or lg: - 13 10 wherein R,, R2, R3, Ru and V are as defined above, reacting a 1,3-ketoaldehyde of formula XVII or a 1,3-diketone of formula XVIII respectively (XVII) R R14 and V are as defined above, with a hydrazine of formula NH2-NH2 and NH2-NHR2 respectively in an aprotic solvent such as ethanol; or e) for the preparation of a thiazole of formulae lh or Ii: wherein Rv R3, R14 and V are as defined above, reacting an α-haloketone of formula XIX or XX respectively (XX) and V are as defined above, with thioformamide in an aprotic solvent such as acetonitrile at 0 to 25°C; or f) For the preparation of an imidazole of formulae Ik or II: R.

(Ik) (II) - 15 wherein Rv Rz, Rj> R14 and V are as defined above, reacting a substituted amide of formula XXIIa or XXIIb respectively ( XXIIb) wherein R1 and Rz are as defined above, with an aniline of formula XXI (xxi) wherein R3, V and R14 are as defined above, in the presence of PC13 with heating? or g) for the preparation of a compound of formula I wherein in R3, Het represents one of the groups V VI, VII or VIII: reacting a compound of formula XXIII Μ-----U R1—Tv -'Y-R2 V-iCj^-Cg-Alkylenj-G (XXIII) - 16 wherein G represents a leaving group, preferably halogen or a sulphonic acid ester group, and M , U, Τ, Y, W, R,, R2, R(^ ^nd V are as defined above, with either of the heterocyclic groups corresponding to V, VI, VII or VIII in a polar solvent; or h) for the preparation of a compound of formula I as defined above: reacting a compound of the formula XXIV (XXIV) (wherein Me represents alkali metal and M, U, Τ, Y, W, R,, R2, Ru and V are as defined above) with a compound of formula G - R3 (wherein G represents a leaving group and R3 is as defined above) in a polar solvent such as ethanol, DMF, DMSO, preferably at 25 to 80 °C; or i) for the preparation of a compound of formula I wherein R3 contains as a heterocyclic group a 4H1,2,4-triazole ring linked by the 4-position: reacting an amine of formula XXV M-----U (XXV) V-(C-j-Cg-Alkylen) -NH2 - 17 wherein M, U, T, Y, W, Rv R2, Ru and V are as defined above, with a compound of formula XXVI (XXVI) wherein R12 and R13 are as defined above, in a cyclisation reaction.

If desired, bases initially obtained by processes a) to i) above may be converted into acid addition salts or quaternised in the usual way, whilst salts obtained initially may be converted into free bases. The starting materials for processes a) to i) above may be prepared by known methods.

The novel compounds according to the present invention have valuable pharmacological properties; of particular note is their PAF-antagonistic activity. As is well known, PAF (platelet activating factor) is the phospholipid acetyl-glyceryl-ether-phosphoryl-cholein (AGEPC) which is known as a potent lipid mediator released by animal and human proinflammatory cells.

These cells include primarily basophilic and neutrophilic granulocytes, macrophages (from blood and tissue) and thrombocytes which are involved in inflammatory reactions.

The compounds of the present invention are therefore therapeutically useful in the treatment of pathological conditions and diseases in which PAF is implicated.

In pharmacological trials, PAF is seen to cause bronchoconstriction, a lowering of blood pressure, the - 18 triggering of thrombocyte aggregation and a proinflammatory activity. These experimentally demonstrable effects of PAF1 indicate, directly or indirectly, possible functions of this mediator in anaphylaxis, in the pathophysiology of bronchial asthma and in inflammations in general.

PAF antagonists are needed on the one hand in order to clarify any additional pathophysiological functions of this mediator in animals and humans, and on the other hand in order to treat pathological conditions and diseases in which PAF is implicated, particularly inflammatory and allergic processes. Examples of indications for a PAF antagonist compound of the present invention include inflammatory processes of the tracheobronchial tree (acute and chronic bronchitis, bronchial asthma) or of the kidneys (glomerulonephritis), the joints (rheumatic complaints), anaphylactic conditions, allergies and inflammation in the mucous membranes (rhinitis, conjunctivitis) and the skin (e.g. psoriasis) and shock caused by sepsis, endotoxins or burns.

Other important indications for a PAF antagonist compound of the present invention include lesions and inflammation in the gastric and intestinal linings, such as shock ulcers, ulcerative colitis, Crohn's disease, stress ulcers and peptic ulcers in general, but particularly ventricular and duodenal ulcers; obstructive lung diseases such as bronchial hyperreactivity, inflammatory diseases of the pulmonary passages, such as chronic bronchitis; cardiac/circulatory diseases such as polytrauma, anaphylaxis, arteriosclerosis, inflammatory intestinal diseases, EPH gestosis (edema-proteinuria hypertension), diseases of extracorporeal circulation, e.g. heart insufficiency, cardiac infarct, organ damage caused by high blood pressure, ischaemic diseases, inflammatory and immunological diseases, immune modulation in the - 19 transplanting of foreign tissues, e.g. the rejection of kidney, liver and oth^r transplants, immune modulation in leukaemia; propagation of metastasis, e.g. in bronchial neoplasia, diseases of the CNS, such as migraine, multiple sclerosis, endogenic depression, agarophobia (panic disorder), and the compounds according to the invention have also proved effective cyto- and organoprotective agents, e.g. for neuroprotection, e.g. in cirrhosis of the liver, DIC (disseminated intravascular coagulation); side effects of drug therapy, e.g. anaphylactoid circulatory reactions, incidents caused by contrast media, side effects in tumour therapy; incompatibilities in blood transfusions; fulminant liver failure (CC14 intoxication); amanita phalloides intoxication (mushroom poisoning); symptoms of parasitic diseases (e.g. worms); autoimmune diseases (e.g. Werlhof's disease); autoimmune haemolytic anaemia, autoimmunologically induced glomerulonephritis, thyroids Hashimoto, primary myxoedema, pernicious anaemia, autoimmune atrophic gastritis, Addison's disease, juvenile diabetes, Goodpasture syndrome, idiopathic leucopenia, primary biliary cirrhosis, active or chronically aggressive hepatitis (HBsAg-neg.), ulcerative colitis and systemic lupus erythematodes (SLE), ideopathic thrombocytopenic purpura (ITP).

Also, the compounds of the present invention find use in the treatment of the immune function in Aids, diabetes, juvenile diabetes, diabetic retinopathy, polytraumatic shock, haemorrhagic shock; PAF-associated interaction with tissue hormones (autocoid hormones), lymphokines and other mediators, the suppression of undesirable angiogenesis. They may also be used in combinations, particularly for those indications for which PAF-antagonists are suitable. Accordingly, the PAF-antagonists may be combined, for example, with βIE 902980 - 20 adrenergics, parasympatholytics, corticosteroids, antiallergic agents, secretolytics and antibiotics.

When they are combined with TNF (tumour necrosis factor) the TNF is better tolerated (disturbing side effects are eliminated); the TNF can therefore, if desired, be used in higher dosages than when it is administered on its own. (The term combination here also includes administration of the two active substances in separate preparations and at a certain time interval). When the compounds according to the invention are administered together with /?-adrenergics, a synergistic effect can be achieved, e.g. in broncholysis. It is also very advantageous to combine the PAF-antagonists with immunosuppressants, e.g. the various cyclosporins.

A further feature of the present invention comprises a method of treatment of diseases or disorders in a subject in which PAF is implicated which comprises administering to said subject an effective amount of a compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I, as hereinbefore defined, in the form of a single enantiomer or diastereoisomer or mixtures thereof and/or a physiologically acceptable acid addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.

The new compounds may be administered topically, orally, transdermally, parenterally or by inhalation.

The compounds may occur as active ingredients in conventional preparations, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, such as plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, aerosols for inhalation, ointments, emulsions, syrups and - 21 suppositories.

The therapeutic and prophylactic dose depends on the nature and gravity of the disease.

An effective dose of the compounds according to the 5 invention is between 1 and 100, preferably between 10 and 80 mg/dose for oral administration and, for intravenous or intramuscular administration, between 0.001 and 50, preferably between 0.1 and 30 mg/dose.

For inhalation, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% active substance, should be used, as well as powders and suspensions in liquefied propellant gases.

Pharmacological characteristics The following data have been assembled for a representative group of compounds according to the invention, relating to the inhibition of PAF-induced thrombocyte aggregation IC50 mol/1 (A) and the 3H PAF20 receptor binding test (B) (cf. EP-A 0254245, pages 20 to 21) : Compound A (IC50xlO'6) B (Ki[M]xlO'9) 25 Example 1 4.4 36 Example 2 3.8 4.8 - 22 The following Examples serve to illustrate the present invention wittiout, however, limiting it.

I Example 1 5 1- Γ4-flmidazol-l-vl)-ethoxyphenvll-5-methyl-2-phenvlimidazole 3.7 g of 1-(4-methoxyphenyl)-5-methyl-2-phenyl10 imidazole (prepared from N-(4-methoxyphenyl)-N’chlorobenzamidine and 1-trimethylsilyloxypropene) are stirred in 50 ml of chloroform with 45 ml of 1 molar boron tribromide in methylene chloride for 24 hours at 20°C. The mixture is then decomposed with 135 ml of IN sodium hydroxide solution, extracted three times with 100 ml of chloroform, dried and distilled off. 1.95 g of hydroxy compound are heated to 90°C for 6 hours with 1.2 g of potassium carbonate and 1.95 g of 1chloromethyl-p-toluenesulphonic acid ester in 50 ml of dimethylformamide. The mixture is then diluted with water and the product is extracted with chloroform, dried and distilled off.

The residue is heated in 50 ml of dimethylformamide with 0.7 g of imidazole sodium for 3 hours to 100°C, then diluted with ice water, extracted with chloroform and purified over a silica gel column (eluant: chloroform/ethanol 4:1). The title compound is obtained in a yield of 0.9 g (18.7% of theory) M.p. 132-135°C (from ether).

Example 2 2- (3,5-Dimethoxvphenvl)-5-methyl-l-Γ4-(3-pvridvlmethoxy)-phenyl)pyrrole 2.0 g of 4-(3-pyridylmethoxy)aniline (prepared by reacting p-nitrophenol with 3-picolyl-o-chloride and - 23 subsequent reduction of the nitro group), 2.6 g of 1(3,5-dimethoxyphenyl)-yl, 4-pentandione are dissolved in 50 ml of toluene and refluxed in the presence of a catalytic amount of toluenesulphonic acid using a water separator (90 minutes). After the toluene has been evaporated off the residue is dissolved in 100 ml of chloroform, washed with water, acetic acid, water again and dilute sodium hydroxide solution and concentrated by evaporation. The residue is dissolved in ether and cooled. The crystals precipitated are suction filtered and washed with ether. 2.8 g (70% of theory) of the title compound are obtained, m.p. 105-108°C.

According to the invention the compounds listed in the following Tables may also be obtained.

Table I Compounds of the formula No. R3' -N M.p.[’] -ch2-n \— N .N 3 CH -CH ch3 - 25 Table II ι Compounds of the formula ' No. R, R3' M.p.f c<ch3)3 - 26 086206 31 -£j/-1)(ctl3>2 O-n-C.HQ 4 9 -CH2-N N ......-N 0-n-C.Ho 4 9 OCH_ I 777 f OCH3 Compound of the formula - 27 Table III M.p.[° Cl No. R1 M.p.[° — N - 29 Table IV V I ' Compounds of the formula No. R, M.p.[°C] Cl -ch2-n The following preparation Examples serve to further illustrate the present invention without, however, limiting it: Formulation Examples 1. Tablets Composition: Active substance according to the invention Stearic acid Glucose parts by weight 6 parts by weight 564 parts by weight The constituents are processed in the usual way to form tablets weighing 600 mg. If desired the content of active substance may be increased or reduced and the quantity of glucose reduced or increased accordingly. 2. Suppositories Composition: Active substance according to the invention 80 parts by weight Powdered lactose 45 parts by weight Cocoa butter 1575 parts by weight The ingredients are combined in the usual way to form suppositories weighing 1.7 g. 3. Powder for inhalation Micronised powdered active substance in a quantity of 0.02 mg, (for a compound of formula I; particle size about 0.5 to 7 Mm) is combined with 10 mg of micronised lactose and optionally suitable amounts of other active substances and packed into hard gelatine capsules. The powder is inhaled using conventional inhalers, e.g. according to DE-A 3345 722. 4. Metering aerosol Active substance according to the invention 0.5% by weight Sorbitan trioleate 0.5% by weight - 32 Monofluorotrichloromethane and Difluorodichloromethaiie (2:3) 99.0% by weight The mixture is packed into metering aerosols of the 5 conventional kind. The metering device is designed, for example, to deliver 0.05 ml of the preparation on each actuation.

Claims

Claims I ·

1. Compounds of formula 1 15 wherein M and U both represent N, N-lower alkyl, CH or C-lower alkyl, T, W and Y each represent N or C; or if either Y or M represent an N-atom, M or Y additionally each represent 20 an S-atom whilst T, U and W each represent carbon atoms; the dotted line represents optional bonds between Μ, T, U, W or Y which provide single or double bonds; - 34 wherein R 4 and R s each represent H, R n , OR,,, halogen, CF 3 aryl, N(R 11 ) 2 ; or R 4 and Rj together represent a fused C s . 7 ~ cycloalkene ring, a fused benzene ring or one of the groups -N=CH-NH-,' -N=CH-CH=CH-, -O-CH 2 -O-, -O-CH 2 -CH 2 -O-, -NH-CO-NH- and -N=CH-CH=N- bound to adjacent carbon atoms of the benzene ring; R 6 represents Η, Rjj 0R n or aryl? R 7 represents H, R 11Z halogen or aryl, and R 3 represents H, R n or halogen; or R 7 and R 3 together represent a fused C 5 . 7 -cycloalke: or benzene ring; R, and R. o each represent H, R.,, ORj., N(R,j) 2 ; or R? and R. o together represent a fused benzene ring, X represents S, 0, NH or N(C..,-alkyl) ; X'represents CH or N? R,, represents H, C,. 4 -alkyl and, if apart from R., an Rj.-containing group, the radicals II, III or IV do not contain any other substituents, Rj, additionally represents C 5 ., 2 -alkyl or C 5 . 12 -aikoxy; R 2 represents H, C,. 4 -alkyl, CF 3 , C,. 4 -alkoxy, CH Z -O-(C, alkyl) or C 3 . 0 ~cycloalkyl; R 3 represents (C,. 0 -alkylene)-Het, wherein Het represents a group selected from: -N /L—'*12 ‘13 (VI) -N R,„ lo (V) (VII) - 35 10 -N N: lN (VIII) (IX) k 13 in which Z represents S, N-R 12 , CH=CH, N=CH or CH=N; R 12 represents H, C^-alkyl or aryl; and R 13 represents H or C,. 4 -alkyl; or R 12 and R 13 together may represent a fused benzene ring; R 14 represents H, C l . 4 -alkyl-C 1 . 4 -alkoxy or halogen and is optionally present twice; V represents O or S; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof.

2. Compounds as claimed in claim 1, wherein the fivemembered heterocyclic ring -u T. is selected from: R, represents either of the groups II and III as defined in claim 1, wherein R 4 , R 5 and R 6 each represent H, C^-alkyl, C V4 15 alkoxy, halogen; if R 5 and R 6 represent H, R 4 additionally represents a C 5 . 12 -alkyl or -alkoxy group; or if R s and R 6 represent C^-alkyl, R 4 additionally represents OH; or 20 R 4 and R s together represent a fused C 5 . 7 -cycloalkene ring, a methylenedioxy or ethylenedioxy group or, if R 6 represents H, additionally a fused benzene ring ; 25 X represents S, O, NH or N(C.,_ 4 -alkyl) ; X' represents N, if X represents NH or N-(C,,_ 4 alkyl), and X' represents CH if X represents S or 0; R 7 and R e both represent H, C 1 . 4 -alkyl, phenyl or halogen, and if R 8 represents H, R 7 additionally represents C 5 . 12 -alkyl; or R ? and Rg together represent a fused C 5 . 7 -cycloalkene 35 or benzene ring; represents H, CH 3 , C 2 H 5 , i-C 3 H 7 , cyclopropyl or tIE 902980 - 37 10 butyl; represents (C V4 -alkylene)-Het, wherein Het represents the groups V or VI as defined in claim 1 or the group Z--R. / S' 12 wherein R 12 represents H or CH 3 ; R 13 represents H or CH 3 ; Z represents S, NH 12 , CH=CH, N=CH or CH-N, 15 R 14 represents H, C^-alkyl, C V4 -alkoxy or halogen; V represents O or S; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition 20 salts thereof.

3. Compounds as claimed in claim 1 wherein the five-membered heterocyclic ring is denoted by or claim 2, M----·'U - 38 R, represents a group or R r R, R 4 and R 5 each represent H, C^-alkyl, Cl, F or C V4 alkoxy; or R 4 and Rg together represent -O-CH 2 -O- or -O-CH 2 -CH 2 -O-, bound to adjacent carbon atoms of the phenyl ring (in which case R 6 represents H) ; R 6 represents H, CH 3 or OCH 3 , and if R 4 and Rg do not represent H, R 6 additionally represents OH; R ? , and R 8 each represent H, C 1 . 4 -alkyl, Cl or Br; or R 7 and R 8 together represent a fused cycloalkene ring with 5 or 6 carbon atoms; R 2 represents H, CH 3 , C 2 H 5 , i-C 3 H 7 , or cyclopropyl; R 3 represents either C 2 _ 4 -alkylene-Het, if Het represents -N \ R 12 ° r -N :N wherein R 12 represents H, CH 3 , or C 6 H 5 ; and R 13 represents H, or CH 3 ; or C 1 . 2 -alkylene-Het, if Het represents / R 14 represents H, CH 3 , OCH 3 or Cl; V represents 0 or S; 10 and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof.

4. Compounds as claimed in claim 1 as herein specifically disclosed in any of the Examples.

5. A process for the preparation of a compound of formula I as defined in claim 1 which comprises either wherein R,, R 3 , V and R u are as defined in claim 1, reacting an imide chloride of formula XI or XII 35 respectively Cl ] (XI) VR Rj^-C^N' VR (xii) wherein R v R 3 , R 14 and V have the above meanings, with a metal azide in an aprotic solvent such as dimethylformamide at e.g. temperatures of from 60 to 120°C; or b) for the preparation of a triazole of formula Ic: wherein R 1 , R 14 , V and R 3 are as defined in claim 1, reacting an imide chloride of formula XI with an acylhydrazide of formula OC(R)-NH-NH 2 (wherein R represents H, or lower alkyl) in an aprotic solvent such as toluene; or c) for the preparation of a pyrrole of general formula Id or Ie: - 41 10 i) for Id, reacting a 1,4-diketone of formula XIII with an amine of formula XIV wherein R,, meanings, V and R u have the above ii) for Ie, reacting a 1,4-ketoaldehyde of formula XVI wherein R z , R 3 , R 14 and V are as defined above, with an amine of formula XV R,-NH 2 (XV) 15 wherein R, is as defined above, each reaction being carried out in the presence of an acid such as toluenesulphonic acid with cleaving of water; or wherein R,, R z , R 3 , R 14 and V are as defined in claim 1, reacting a 1,3-ketoaldehyde of formula XVII or a 1,3-diketone of formula XVIII respectively (XVII) '14 R and V are as defined above, with a hydrazine of formulae NH 2 -NH 2 or NH 2 -NHR 2 respectively in an aprotic solvent such as ethanol; or wherein R 1 , R 3 , R 14 and V are as defined in claim 1, reacting an α-haloketone of formula XIX or XX respectively - 44 with thioformamide in an aprotic solvent such as acetonitrile at 0> to 25’C; or f) For the preparation of an imidazole of formulae Ik or II: wherein R 1 , R 2 , R 3 , R 14 and V are as defined in claim 1, reacting a substituted amide of formula XXIIa or XXIIb respectively (XXIIb) wherein R 1 and R 2 are as defined above, with an aniline of formula XXI wherein R 3 , V and R 14 are as defined above, in the 10 presence of PC1 3 with heating; or g) for the preparation of a compound of formula I wherein in R 3 , Het represents one of the groups V, VI, VII or VIII as defined in claim 1: 15 reacting a compound of formula XXIII MT-rv—U R -Τ. Y-R (XXIII) -Alkylen) -G wherein G represents a leaving group, preferably halogen or a sulphonic acid ester group, and M, U, Τ, Y, W, R,, R 2 , R u and V are as defined above, with either of the heterocyclic groups corresponding to V, VI, VII or VIII in a polar solvent; or h) for the preparation of a compound of formula I as defined in claim 1: reacting a compound of the formula XXIV (wherein Me represents alkali metal and M, U, T, Y, W, R,, R z , R 14 and V are as defined in claim 1) with a compound of formula G - R 3 (wherein G represents a leaving group and R 3 is as defined in claim 1) in a polar solvent such as ethanol, DMF, DMSO, preferably at 25 to 80°C; or i) for the preparation of a compound of formula I as claimed in claim 1 wherein R 3 contains as a heterocyclic group a 4H-1,2,4-triazole ring linked by the 4-position: reacting an amine of formula XXV Mu R (XXV) V-(C-,-C,-Alkylen)-NH_ 1 O z wherein M, U, T, Y, W, R,, R 2 , R 14 and V are as defined in claim 1, with a compound of formula XXVI RO NH (XXVI) wherein R 12 and R 13 are as defined above in a cyclisation reaction; and if desired, subsequently converting bases initially 15 obtained into acid addition salts and/or, if desired, subsequently converting the derivatives obtained into quaternised derivatives in the usual way, and, if desired, subsequently converting acid addition salts obtained initially into the free bases.

6. A process as claimed in claim 5 substantially as hereinbefore described and with reference to any of the Examples. 25

7. Compounds as claimed in claim 1 whenever prepared by a process as claimed in claim 5 or claim 6.

8. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I, as 30 defined in claim 1, in the form of a single enantiomer or diastereoisomer or mixtures thereof and/or a physiologically acceptable acid addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Compositions as claimed in claim 8 substantially as herein described.

10. Compounds of general formula I as claimed in claim 1 and physiologically(acceptable acid addition salts thereof for use in therapyj 5

11. The use of a compound as claimed in any one of claims 1 to 4 and 7 or a physiologically acceptable acid-addition salt thereof for the preparation of a medicament for use in the treatment of diseases in which PAF is implicated.

12. The use as claimed in claim 11 for the treatment of inflammatory and allergic conditions and autoimmune diseases. 15

13. The use as claimed in claim 11 or claim 12 for the treatment of inflammatory conditions of the tracheobronchial tree.

14. A method of treatment of diseases or disorders in a 20 subject in which PAF is implicated which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof. 25

15. Each and every novel compound, process, method, composition and use herein disclosed.