IE902979A1 - Substituted heterocyclic five-membered ring derivatives - Google Patents

Abstract

Disclosed are compounds of formula (I) in which M, U, T, V and W are N or C, B is -CH=CH-, O or NR16, Q, Q', Q'' and Q''' are a simple bond or C1-C3 alkylenes residue, R1 is an optionally substituted aromatic or heterocyclic residue and R3 is an optionally substituted mononuclear or polynuclear aromatic isocyclic or N-heterocyclic, which can be prepared by ordinary methods and used as active principles in drugs. [DE3927483A1]

Description

The present invention relates to novel substituted heterocyclic five-membered ring derivatives, the preparation thereof and their use as active substances in pharmaceutical compositions.

The new compounds correspond to the formula M____U I ' II Q-X-Y-Q*-R3 wherein M and U both represent N, N-lower alkyl, CH or C-lower alkyl; T, V and W each represent N or C; or if either V or M represent an N-atom, M or V 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, V and W, which provide single or double bonds, preferably double bonds wherever possible; B represents a one- or two-membered ring component of a mono- aromatic or heteroaromatic ring system, particularly one in which B represents CH=CH, S, 0, NR16; Q, Q', Q and Q· each represent a single bond or a Cb3 alkylene group; R1 represents a group selected from: (II) c E· R (HI) and (IV) ; wherein R4 and Rj each represent H, halogen, R1V OR.,,, aryl, Oaryl, aralkyl, O-aralkyl, N(R11)2; or R4 and Rj together represent an optionally substituted fused C5.7 cycloalkene ring or a fused benzene ring or one of the groups -N=CH-NH-, -N=CH-CH=CH-, -O-CH2-CH2-, -O-CH2-CH2-CH2-, -O-(CH2) ^3-0-, -NH-CO-NH-, -N=CH-CH=N-, -hn-co-(r16)2-o-, -HN-CO-O-, -nh-co-ch2, -HN-CO-CH=CH-HN-CO-CH2-CH2- bound to adjacent carbon atoms of the benzene ring; R6 represents H, halogen, R1V ORn or aryl; R7 represents H, halogen, Rn, OR,,, aryl or aralkyl; and R8 represents H, halogen, R,,, OR,,, aryl, aralkyl or N(Rn)2; or R? and R8 together represent an optionally substituted fused Cs_7-cycloalkene or fused benzene ring; R? and R10 each represent H, halogen, R,,, OR,,, N(R,,)2, aryl, 0-aryl, aralkyl, O-aralkyl; or R? and R10 together represent an optionally substituted fused C5.7-cycloalkene or fused benzene ring; D represents S, 0 or NR16; I > Ε, Ε’, Ε, E”’ each represents CH or N, whilst in the case of the group III not more than two of the symbols E to E' represent N whilst in the case of the group IV not more than three of the symbols E to E' represent N; R^ represents H, a C2.6-alkenyl or alkynyl group, or a Cv12-alkyl which is optionally interrupted by oxygen or substituted by up to 5 halogen atoms, N(R16)2, aryl, Oaryl, a C3.7-cycloaliphatic group or an N-heterocyclic group bound to the alkyl group via the cyclic nitrogen atom and capable of containing O, S or NR16 as a further hetero ring member; R2 represents H, a saturated or unsaturated aliphatic group with up to 8 carbon atoms which may be interrupted by 0, S or NR16 and may be substituted by up to five halogen atoms, 0Η, 0-acyl, oxo, aryl or 0-aryl and may be bonded to the 5-membered heterocyclic group via oxygen; a saturated or unsaturated C3.7-cycloaliphatic ring, optionally substituted by R16, OH, oxo, N(R16)2, optionally bound to the 5-membered heterocyclic group via oxygen or a Cv4-alkylene group; or a group (CH2)n25 NRaRfa (n ~ °f 1f 2 or 3) t which Ra and Rb represent H, or a saturated or unsaturated, optionally oxygeninterrupted aliphatic group having up to 6 carbon atoms which may also be substituted by OH or N(R16)2; Ra may also represent a C3.7-cycloaliphatic group; the entire group NRaRb may also represent a 5 to 7-membered ring which may contain 0, S or NR16 as an additional ring member; R3 represents a mono- or polynuclear, optionally substituted, preferably aromatic, carbocyclic or nitrogen-containing heterocyclic group, the latter being capable of being bound to -Q”»-Y- via a nitrogen or - 4 12 carbon atom, more particularly a group selected from: (V) (V') ,N R-, o Ζ Z 12 r16-n l (V) (VI) L' R R16-N(V”) (VII) (X··) (X·) - 5 wherein (· G represents S, 0, CH, CH=CH, N=CH, CH=N, N=N or NR16; L and L' each represent N or CR,6; R12 represents H, (0)(C,„4-alkyl), aryl, O-aryl, aralkyl, halogen or OH, and 10 R13 represents H, halogen, a C2.6-alkenyl or -alkynyl group, or (0)0.,-(C1.4-alkyl) , wherein the alkyl chain is optionally OH- substituted or substituted by up to five halogen atoms; or R12 and R13 together represent an optionally substituted fused benzene ringing represents H, halogen, CN, OH, (Ο)θ.,-(CV4-alkyl) (wherein the alkyl chain may be substituted by up to 5 halogen atoms), N(R16)2, a C2.6-alkenyl or alkynyl group, CO-(C1.4-alkyl) , CO-ary 1, aralkyl, aryl, 0-aryl, or a group of formula III or IV, and R15 represents H, halogen, OH, (Ο) θ.,-(C,.4-alkyl) optionally substituted by OH or up to 5 halogen atoms; or R14 and R15 together represent an optionally substituted homocyclic or heterocyclic fused five- to seven-membered ring, whilst up to two ring members may 0 be selected from the group N, NR16, O and S; R16 represents H or C,.4 alkyl; R17 represents H, (0),,.,-(^ alkyl or halogen; X-Y represents a single bond, a double-bonding bridging group of the formula CONR,6,CSNR,6,C(NH)NR16, NR,6CO, - 6 so2nr16, nr16so2, conr16nr16, nr16conr16, NR16C(NR16)NR16, NR16CONR16NR16, CO(CH2) ,.^ΝΗ, NH (CH2) V3CO, SO2 (CH2) ν3ΝΗ, NH(CH2) .,_3SO2, and, if the group R3 is linked to Q' via a carbon atom and at least one of the groups Q and Q”’ represents a single bond, X-Y additionally represents CO or O, with the proviso that the group Q-X-Y-Q' does not represent -O-(C^-alkylene) - if R3 denotes an optionally substituted pyridyl, pyridazyl, pyrimidyl or pyrazinyl group and B is CH=CH? and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof.

Compounds according to the present invention which are preferred include compounds of general formula (I) wherein B represents CH=CH, S, NR16 or 0; R, represents a group of formula II wherein R4, Rj and R6 each represent H, cV4-alkyl, CV4-alkoxy or halogen; or if R5 and R6 represent H, R4 additionally represents aryl, aralkyl, aryloxy or N(R16)2, C5.12 alkyl, C5.12 alkoxy; or R4 and Rj together represent a fused C5.7 cycloalkene, -O- (CH2) v3-0- or -N=CH-NH- group (bound to adjacent carbon atoms of the benzene ring); or if R6 represents hydrogen, R4 and together represent a fused benzene ring; or R1 represents a group of formula III, wherein D is as hereinbefore defined and at most only one of the symbols Ε, Ε', E and E' represents N whilst the others represent CH; and - Ί R? and Rg, both represent H, CV4 alkyl, CV4 alkoxy or halogen and, when Rg represents H, R7 additionally represents C5.12-alkyl or C5.12-aryl; or R7 and Rg together represent a fused C5.7-cycloalkene or fused benzene ring; or R1 represents a group of formula IV wherein, of the symbols Ε, Ε’, E” and E”’, not more than two represent N whilst the others represent CH; and R9 and R10 each represent halogen, R16, 0R16 or N(R16)2; R^, additionally represents aryl, 0-aryl, aralkyl; or R? and R10 together represent a fused C5.7-cycloalkene ring or fused benzene ring; R2 represents H, OH, a saturated or unsaturated aliphatic group with up to 8 carbon atoms, a C3.6-cycloalkyl group, or a C^j-alkyl group substituted with up to five halogen atoms or CH3OCH2CH2; R3 represents a group of formula V, V, V, V', VII or IX, wherein X-Y, G, L, L' , R16 and R17 are as defined hereinbefore; r12 represents R16, aryl or halogen, and 25RU represents R16 or an alkenyl group with up to 4 carbon atoms; orR12 and R13 together represent a fused benzene ring;R14 represents R16, halogen, CN, CF3, CO-(CV4 alkyl) or Or16; 30R15 represents R16, halogen or 0R16;R4 has the preferred meaning above;R11 represents R16; and M, U, Τ, V, W, Q, Q', Q and Q' are as hereinbefore 35 defined; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof.

If the compounds.according to the invention include a pyridine ring, particularly in R3, the nitrogen atom may occur in quaternised form. As the quaternary group, the N-atom carries a lower alkyl or aralkyl group. Particular mention should be made of Cv4-alkyl and benzyl.

In formula V, one (and only one) of the dotted lines represents a double bond. If it starts from the nitrogen atom, the group (R^Jq., is absent.

Within the scope of the above definitions, particular mention should be made of the compounds wherein the five-membered heterocyclic group M... U I i ι I I represents one of the groups R-lQN, RTQ-N I R1Q- or RiQ-n^^n, B represents CH=CH or S; Q and Q' represent a single bond or CH2, Q represents C^-alkylene, but is more preferably a single bond; Q’ is a single bond or, if XY represents CO, it may also represent CH2; R1 represents either of the groups II and III, wherein R4, Rg and R6 each have the meanings stated as preferred hereinbefore, as do D, E, E' and E; R7 and Rg each represent H, CV4 alkyl, Cp4 alkoxy; and Rg may additionally represent aryl; or R7 and R8 together represent a fused benzene ring or a fused C5.7-cycloalkene ring; R^ is as hereinbefore defined; represents H, C^j alkyl, cyclopropyl, phenyl, CF3 or allyl; represents one of the groups V, IX, wherein V is preferably V, V, ZS M VII or R12 represents R16, phenyl or halogen, and R13 represents R16; or R12together with R12 represent a fused benzene ring; R17 is H, CH3, OCHj or Cl; and G, L, L , R4, R14, R1S and R16 have the meanings stated as preferred hereinbefore; X-Y-Q’ represents CONR16, CSNR16, NR16CO, SO2NR16, NR16SO2, NR16CONR16, CO(CH2) υ3ΝΗ, COCH2 or O; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof.

The compounds according to the present invention may occur as free bases or as acid addition salts.

Particular mention should be made of the compounds - 10 of formulae Mu 'I V—R, 'W I Q’ Q-XY-R.

(I’) wherein the five-membered heterocyclic group M____-U I if ,Vis R1Q-N -N i N or R1Q-R.

'N- B represents CH=CH or S; Q, Q1 and Q each represent a single bond or CH2; R, represents a group selected from: wherein Rj represents C^-alkyl, Cl, Br or C3.7-cycloalkyl; Rk represents a fused C5_6-cycloalkene or fused benzene ring; Rm, Rn and Ro each represent H, Cl, CH3, C1.4-alkoxy, CF3 or N(R16)2, and in the case where Ro represents H, R^ and Rn may together represent a fused benzene ring or a group -OCH2O- bound to adjacent carbon atoms of the benzene ring; R16 represents H, CV4 alkyl or N(R16)2, particularly N(CH3)2 and N(C2H5)2; R2 represents CH3 or C2H5; XY represents CONH, CSNH, NHCO, SO2NH, NHCONH, COCH2 or CH2O ; R3 represents a group selected from - 12 wherein one of the symbols L, L* and L represents N, whilst the others represent CH; and Rp represents H or CH3.

Particular emphasis should be placed on the following compounds of formulae: wherein the five-membered heterocyclic group —T. V— is a group R1 N -N or a group selected from: represents naphthyl wherein RL represents C1.4-alkyl, Cl or Br; R'k represents a fused cyclopentene or fused - 13 cyclohexene ring; R'm represents H> Cl, C^-alkoxy, Cl, CF3 or CH3, and R'n represents H, C,.4-alkoxy, Cl or CH3; °r R'm and R'n together represent a group -OCH2Obound to adjacent carbon atoms of the benzene ring; R'o represents H, CH3O or CH3; X-Y represents CONH, CSNH.

In the above definitions the following should be borne in mind: Where symbols occur several times in one formula they may have identical or different meanings.

Unless otherwise stated, the hydrocarbon chains may be either unbranched or branched. The word ’'halogen indicates fluorine, chlorine, bromine or iodine; halogen atoms in aliphatic groups are predominantly fluorine and chlorine. The corresponding groups are, for example, CF3, OCF3, CF2CF3, CC1F2. The word aryl preferably denotes phenyl or naphthyl. The term heteroaryl also indicates those groups which are made up of aromatic and heteroaromatic rings, e.g. quinoline or quinazoline.

The term aralkyl is used to denote aryl or heteroaryl groups which are bound via a straight-chained or branched alkylene bridge.

The aromatic or heteroaromatic groups may be monoor polysubstituted and may each contain identical or different substituents. Substituents include halogen, C1-4-alkyl, CV4-alkoxy (which may also be halogen substituted), N(R,6)2, NO2, lower alkenyl or alkynyl groups, CN, aryl, C3.7-cycloalkyl, COOR16, CON(R16)2, SO2N(R16)2, 0-aryl, O-aralkyl, NHSO2-(Cv4-alkyl) , OH, NR16COR18 (wherein R18 represents H, N(R16)2 or an aliphatic or cycloaliphatic group with up to 7 carbon atoms). The term lower denotes groups with up to 6, preferably up to 4 carbon atoms.

Whereas halogen, alkyl or alkoxy may occur up to three times in a ring as substituents (in exceptional cases four or five substituents are possible on the phenyl ring), the other substituents generally only occur once or twice. The total number of substituents is generally not more than three per ring.

In the case of halogen atoms, optionally present with alkyl or alkoxy groups, up to 5 substituents may be present in one ring. It will be understood that the possibilities of substitution may be reduced by heteroatoms in the ring. If for example the group IV is only one substituent (i.e. R?) can be present.

Examples of substituents in accordance with the above remarks include in particular: F, Cl, Br, CH3, benzyl, cyclopropyl, phenyl, allyl, propargyl, COOCH3, or phenoxy.

Alkenyl and alkynyl groups are generally bound via a saturated carbon atom.

If R16 appears in the groups given for X-Y, it preferably represents H.

If R^ occurs as a substituent in the groups II, III and IV in addition to other substituents, the chain length is preferably restricted to up to 4 members. If R^ includes a heterocyclic group, this is preferably a five- to seven-membered ring, preferably not aromatic, e.g. pyrrolidine, piperidine, piperazine or morpholine, and these rings may, for example, be substituted by lower alkyl.

Examples of typical groups II to IV include: phenyl, benzyl, 3-methoxy-, dimethylamino- or 3chlorophenyl; 3,5-dimethoxy-, 3,5-dimethyl-, 3-methoxy5-trifluoromethyl-, trimethoxy- or 3,5-dichlorophenyl; thien-2-yl, 5-lower alkyl-, 5-phenyl-, 4-cyclopentyl-, - 15 5-cyclohexyl-, 5-chloro-, 5-bromo- or 5-allylthien-2-yl; or the groups wherein these ring systems may optionally also contain additional substituents, particularly halogen atoms, lower alkyl and alkoxy groups, and N(R16)2. Groups representative of R2 are lower alkyl and alkoxy groups, C3.6~cycloalkyl groups, halogen substituted alkyl and alkoxy groups such as CF3, OCF3, C2F5, OC2F5 and also CH2N(R16)2 as well as methoxyethyl, ethoxyethoxy, allyl and propargyl.

The group R3 may be selected from a large number of possibilities. Some simple ring systems which R3 may represent will now be mentioned by way of example: pyrrole, pyrazole, N-methylpyrrole, imidazole, thiazole, triazole, tetrazole, 1,2,4- and 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine and pyrazole, and these rings may also be substituted, e.g. by lower alkyl groups or halogen atoms.

The following should also be mentioned as possible groups for R3: phenyl, phenylphenyl, phenoxyphenyl, whilst these groups may also be substituted, for example, by lower alkyl, - 16 lower alkoxy, N(R16)2, CF3 or halogen; groups derived from fused systems, such ag«theophylline, benzimidazole, or the groups The fused systems may also contain additional substituents such as OH, CH3, OCH3 or Cl.

If the groups II to X' represent fused ring systems, they may be bound via the fused ring.

The five-membered heterocyclic group M____--U may be, depending on the definitions of Μ, T, U, V, W, a triazole ring such as N - N -N a tetrazole ring such as an imidazole ring such as R-N a thiazole ring such as lower alkyl) be prepared by a variety of (wherein R represents H or The new compounds may methods analogous 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 in Vol. IV, Part C, ρ. 1 ff or 120 ff).

According to a further feature of the present invention, we provide processes for the preparation of a compound of formula I as defined above which comprises either a) for the preparation of a tetrazole of formula Ia or lb: N ......—N N--N R1Q-N _N (la) R1QQ’ Nx I Q' (lb) Q-X-Y-Q 1 -R.

Q-X-Y-Q ' -R, wherein Rv Q, Q', B, Q, X, Y, Q' and R3 are as defined above, reacting an imide chloride of formula XI or XII respectively R1Q-N Cl z I Q’ Γ—4- \ B _-=E7- s' Q-X-Y-Q' (xi) Cl R,Q-C Ni Q’ (xn) B Q-X-Y-Q'10 wherein all the symbols have the above meanings, with metal azide in a solvent such as dimethylformamide at temperatures from 60 to 120°C; or b) for the preparation of a triazole of formula Ic B / Q-X-Y-Q’-R3 wherein R,, Q', Q, Q', X-Y, B, and R3 are as defined above, reacting an imide chloride of formula XI as defined above with an acyl hydrazide of formula OC(R)NH-NH2 in an aprotic solvent such as toluene; or c) for the preparation of a pyrrole of formula Id or Ie; - 20 10 Q' (Id) -X B Q_X_Y_Q1-R^ wherein Rv Q, Q', Q, defined above, Q' (Ie) ι B Q—X-Y-Q1-R3 Q ·, X-Y, B, and R3 are as i) for Id, reacting a 1,4-diketone of formula XIII with an amine of formula XIV, (XIII) R1Q ii) R, NH_ I 2 Q’ z B :z/ (xiv) Q-X-Y-Q'-R3 wherein all the symbols have the above meanings, and for Ie, reacting a 1,4-ketoaldehyde of formula XVI with an amine of formula XV (XV) I Q’ (XVI) Q-X-Y-Q'-R3 wherein all the symbols have the above meanings - 21 each reaction being carried out in the presence of an acid such as toluenesvuLphonic acid with cleaving of water; or d) for the preparation of pyrazoles of formula If or lg: N - -NH 1 -R, R-.Q- and B (If) N Q-X-Y-Q1-R. (lg) Q-X-Y-Q’-R, wherein, Rv R2, Q, Q', Q, Q' , B, X-Y and R3 are as defined above, reacting a ketoaldehyde of formula XVII or XVIII respectively R, Λ RjQ HCO J.

(XVIII) Β (XVII) ./ Q-XY-Q’-R, Q-XY-Q’-R. '3 * *** ~ *3 wherein all the symbols have the above meanings, with hydrazine in an aprotic solvent such as ethanol with heating; or e) for the preparation of a thiazole of formula lh or Ii: NRjQR-lQΓ Q' (lh) N Q' (Ii) \ -J Q-XY-Q'-R.

Q-XY-Q'-R, wherein R,, Q, Q', Q, Q' , B, X-Y and R3 are as defined above, reacting a α-haloketone of formula XIX or XX respectively R-jQBr Q· (XIX) or (XX) '\ ./ Q-XY-Q”’-R3 ./ Q-XY-Q'-R3 wherein all the symbols have the above meanings, with thioformaraide in an aprotic solvent such as acetonitrile at 0 to 25 *C; or f) for the preparation of a compound of formula I wherein X-Y represents CONR16, CSNR16, CO (CH2) ,.3NR16, C(NH)R16, SO2NR16 or SO2 (CH2) ,.3NR16; and M, U, Τ, V, R,, Q, R2, W, R16, Q', B, Q, Q' and R3 are as 626206 31 - 23 defined above, reacting a compound of formula XXI M———U 1 ' i i ' < ι I RlQ-T^ /VR2 w i Q· (XXI) rfl B Q-X’-Z (wherein Z represents OH, halogen, lower alkoxy, lower acyloxy; and X' represents CO, CS, COiCH^pj,, C(NH) , S02, SO2(CH2)1.3 and the remaining symbols have the above meanings) with an amine of formula XXII R16HN-Q'-R3 (XXII) or a hydrazine of formula XXIIa R16NH-NR16-Q!-R3 (XXIIa) wherein Q' , R16 and R3 have the above meanings, under standard conditions, e.g. as described in Houben-Weyl VIII, 653 ff and E5, 941 ff; or g) for the preparation of compounds of formula I wherein X-Y represents NR16CO, NR16CONH, NR16SO2, NR,6(CH2) t.jCO, or NR16(CH2) ^jSOj; and M, U, T, V, R1, Q, R2, W, Q', B, Q, Q' , R16 and R3 are as defined above, - 24 reacting an amine of formula XXIII M_____-U \ (XXIII) ./ Q-NHR16 wherein M, U, T, V, R,, Q, R^ W, Q', B, Q, Q' , R and R3 are as defined above, '16 either with a carboxylic or sulphonic acid or acid derivative of formula XXIV Z-X-Q'-R3 (XXIV) or with an isocyanate of formula XXV OCN-Q'-R3 (XXV) wherein Z represents OH, halogen, lower alkoxy, or 2 5 lower acyloxy, X represents (CH^.jSO.,, (CH^.jCO, SO2 or CO and Q ' and R3 have the above meanings, using conventional methods; or h) for the preparation of compounds of formula I wherein X-Y represents NR16CONR16, NR16C (NR16) NR16 or NR16CONR16NR16; and M, U, T, V, R, Q, R2, W, Q', B, Q, Q' , R16 and R3 are as defined above, reacting a compound of formula XXIa - 24a 10 i (XXIa) QM-NR1X - -Z wherein X' represents CO or C(NR16), Z has the meanings indicated in process f) above, and the remaining symbols are as defined above, with an amine of formula XXII or a hydrazine of formula XXIIa as defined in process f) above; or for the preparation of compounds of formula I wherein Q represents a C^j-alkylene group; and either X-Y represents a single bond, and M, U, T, V, R1, Q, Q' , Q' , R2, W, B and R3 are as defined above; or X-Y represents an oxygen atom, and Q' represents a C^j-alkylene group, and Μ, V, Τ, V, R, Q, R2, W, B, Q'and R3 are as defined above, reacting a compound of formula XXVI M___U I < f ' I I I V-R_ // 2 (XXVI) Q“- X-Y- Q G wherein G represents a leaving group, preferably halogen or a sulphonic acid ester group, and all the remaining symbols have the above meanings, with either of the heterocyclic groups as defined above for R3 in a polar solvent; or - 24b j) for the preparation of compounds of formula I wherein X-Y represents an oxygen atom, Q and Q' both represent a single bond, and Μ, V, Τ, V, Q, Q' , Rv R2, W, B and R3 are as defined above, reacting a compound of formula XXVII MU RjQ-T V-R, (XXVII) Q' OMe (wherein Me represents an alkali metal, and all the remaining symbols 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.

If desired, bases obtained initially by methods a) to j) 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 j) 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 - 25 phospholipid acetyl-glyceryl-ether-phosphoryl-cholein (AGEPC) which is known’aq 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 triggering of thrombocyte aggregation and a proinflammatory activity. These experimentally demonstrable effects of PAF 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 - 26 as shock ulcers, ulcerative colitis, Crohn's disease, stress ulcers and peptiq ulcers in general, but particularly ventricular and duodenal ulcers; obstructive lung diseases such as bronchial hyper5 reactivity, 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 transplanting of foreign tissues, e.g. the rejection of kidney, liver and other 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 - 27 or chronically aggressive hepatitis (HBsAg-neg.), ulcerative colitis and1 systemic lupus erythematodes (SLE), ideopathic thrombocytopenic purpura (ITP).

Also, the compounds of the present invention find 5 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 βadrenergics, 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 /3-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 is 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 IE $02979 - 28 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 suppositories.

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

An effective dose of the compounds according to the 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 are data for a representative group of compounds according to the invention, giving the inhibition of the PAF-induced thrombocyte aggregation IC5Q mol/1 (A) and the 3H PAF-receptor binding test (B) (cf. EP-A 0254245, p. 20 to 21): - 29 Compound A(IC50xlO'6) B (Ki[M]xlO'9) I Tab. 1/1 3.2 1.6 Tab. II/l 0.11 0.25 Tab. II/2 0.12 0.19 Tab. III/4 0.36 5.1 Tab. V/2 0.63 2.8 - 30 The following Examples serve to illustrate the present invention without, however, limiting it.

Example 1 5 4-Γ 2-(3,5-Dichloroohenvl)-4-methvl-3H-imidazol-3-vl1-N(3-ovridvl)-benzamide 2.0 g of 1-(4-carbethoxyphenyl)-5-methyl-2-(3,510 dichlorophenyl)-imidazole (prepared from 3,5-dichloro-aacetamidoacetophenone, m.p. 95-98’C, by reacting with ethyl 4-aminobenzoate) are saponified in 50 ml of ethanol and 20 ml of 10% sodium hydroxide solution to form the acid. The acid is then refluxed for 2 hours in 50 ml of chloroform and 2 ml of thionyl chloride, the chloroform is distilled off and the acid chloride is mixed with 50 ml of dioxan. The solution is heated to 80°C for 30 minutes, then diluted with 200 ml of ice water. The product is extracted with chloroform, dried and distilled off.

The title compound is recrystallised from ethanol; m.p. 94-98°C.

Example 2 4-Γ 5—(3,5-Dimethoxvphenvl)-lH-tetrazol-l-vl1-N-(3pyridvl)-benzamide 3,5-dimethoxybenzoic acid is converted into the acid chloride using thionyl chloride in chloroform at reflux temperature and the acid chloride is reacted with ethyl 4-aminobenzoate in the presence of triethylamine under heating to form the amide. The amide is refluxed in toluene with phosphorus pentachloride. After removal of the solvent the imide chloride is cyclised in dimethylformamide with sodium azide at ambient temperature to obtain ethyl 4-[5-(3,5-dimethoxyphenyl)IE 902979 - 31 ΙΗ-tetrazol-l-yl]-benzoate. The ester obtained is refluxed for 60 minutes in methanol with 20% aqueous sodium hydroxide solution. The solution is acidified, the acid is isolated and recrystallised from methanol; m.p. 220-222’C. 6.5 g of the acid obtained are refluxed in 150 ml of chloroform and 6 ml of thionyl chloride for 2 hours, the chloroform is distilled off and the acid chloride is heated to 80°C in 100 ml of dioxan with 4.6 g of 310 aminopyridine for 30 minutes. It is then diluted with ice water, the precipitate formed is suction filtered and recrystallised from ethanol.

The title compound is obtained in a yield of 4 g (49.8% of theory), m.p. 217-219’C.

The examples in the following Tables may also be obtained by methods analogous to the above Examples. - 32 Table I No.R1r2R3 M.p. [°CJ 1 Phenyl Methyl 3-Pyridyl 2 5-Methyl- Methyl 3-Pyridyl 20 3 thien-2-yl 3,5-Dimethoxyphenyl Methyl 3-Pyridyl 179-81 4 3,5-Di-t-butyl- 4-hydroxy- Methyl 3-Pyridyl 25 5 phenyl 3-Methoxyphenyl Methyl 3-Pyridyl 6 3,5-Dichloro- phenyl Isopropyl 3-Pyridyl 7 3,5-Dichloro- Methyl 3-Pyridyl 94-8 30 phenyl - 33 Table II I ' Compounds of formula No.R1 r2R3 M.p. [ 1 3,5-Dimethoxy- phenyl Methyl 3-Pyridyl 179-81 20 2 3,5-Dichlorophenyl Methyl 3-Pyridyl 187-90 3 2-Thienyl Methyl 3-Pyridyl 4 3,5-Di-t-butyl4-hydroxyphenyl Methyl 3-Pyridyl 25 5 3-Dimethylaminophenyl Methyl 4-Pyridyl 6 3-Chlorophenyl Methyl 4-Pyridyl - 34 Table III I ' Compounds of formula N-N No.R!R3 M.p. [*' 1 2-Naphthyl 3-Pyridyl 203-4 2 2-Thienyl 3-Pyridyl 195-200 20 3 2-Chlorophenyl 3-Pyridyl 4 3,5-Dimethoxyphenyl 3-Pyridyl 217-9 5 3,5-Di-t-butyl4-hydroxyphenyl 3-Pyridyl 6 3-Methoxy-5-methyl- 4-Pyridyl 25 7 phenyl 3-Trifluoromethylphenyl 3-Pyridyl 8 3-Chlorophenyl 3-Pyridyl 217-20 9 Phenyl 3-Pyridyl 176 - 35 Table IV I > Compounds of formula M.p. f 3,5-Dimethoxyphenyl 2-Thienyl 3 3,5-Di-t-butyl4-hydroxyphenyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 232-6 IE 902973 - 36 Table V Compounds of formula 2-Thienyl Methyl 3-Pyridyl 164-6 3,5-Dimethoxy- Methyl 3-Pyridyl 185-7 phenyl 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 IE 902978 - 38 Monofluorotrichloromethane and Difluorodichloromethane (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 (13)

Claims
1. Compounds of general formula I wherein
2. Q-X-Y-Q'-R.
3. (I), 15 M and U both represent N, N-lower alkyl, CH or C-lower alkyl;
4. T, V and W each represent N or C; or if either V or M represent an N-atom, M or V may additionally each 20 represent an S-atom whilst T, U and W each represent carbon atoms; the dotted line represents optional bonds between Μ, T, U, V and W, which provide single or double bonds; 25 B represents a one- or two-membered ring component of a mono- aromatic or heteroaromatic ring system, particularly one in which B represents CH=CH, S, 0, NR 16 ; 30 Q, Q', Q and Q' each represent a single bond or a C V3 alkylene group;
5. R 1 represents a group selected from:
6. (II) (III) (IV); - 40 wherein
7. R 4 and Rj each represent H, halogen, R n , OR 1V aryl, 0aryl, aralkyl, O-aralkyl, N(R 11 ) 2 ; or
8. R 4 and Rj together represent an optionally substituted fused Cj. 7 cycloalkene ring or a fused benzene ring or one of the groups
9. -N=CH-NH-, —N=CH—CH=CH—, -O-CH 2 -CH 2 -, -O-CH 2 -CH 2 -CH 2 -,
10. 10 -O-(CH 2 ),. 3 -O-, -NH-CO-NH-, -N=CH-CH=N-, -hn-co-(r 16 ) 2 -o-, -HN-CO-O-, -nh-co-ch 2 , -HN-CO-CH=CH-HN-CO-CH 2 -CH 2 - bound to adjacent carbon atoms of the benzene ring; 15 R 6 represents H, halogen, R 11 ’ OR n or aryl; R 7 represents H, halogen, R 11' 0R n , aryl or aralkyl; and R 8 represents H, halogen, R 11 · OR 1V aryl, aralkyl or 20 N(R 11 ) 2 ; or R ? and R 8 together represent an optionally substituted fused Cj. 7 -cycloalkene or fused benzene ring; 25 R 9 and R 10 each represent H, halogen, R 1V 0R n , N(R 11 ) 2 , aryl, 0-aryl, aralkyl, O-aralkyl; or R? and R 10 together represent an optionally substituted fused Cj. 7 -cycloalkene or fused benzene ring; D represents S, 0 or NR 16 ; Ε, Ε', Ε, E' each represents CH or N, whilst in the case of the group III not more than two of the symbols 35 E to E' represent N whilst in the case of the group IV not more than three of the symbols E to E' represent N; - 41 R n represents H, a C 2 . 6 -alkenyl or alkynyl group, or a Cj.^-alkyl which is optionally interrupted by oxygen or substituted by up to 5 halogen atoms, N(R 16 ) 2 , aryl, 0aryl, a C 3 . 7 -cycloaliphatic group or an N-heterocyclic 5 group bound to the alkyl group via the cyclic nitrogen atom and capable of containing O, S or NR 16 as a further hetero ring member; R z represents H, a saturated or unsaturated aliphatic 10 group with up to 8 carbon atoms which may be interrupted by O, S or NR 16 and may be substituted by up to five halogen atoms, OH, 0-acyl, oxo, aryl or 0-aryl and may be bonded to the 5-membered heterocyclic group via oxygen; a saturated or unsaturated C 3 . 7 -cycloaliphatic 15 ring, optionally substituted by R 16 , OH, oxo, N(R 16 ) 2 , optionally bound to the 5-membered heterocyclic group via oxygen or a C V4 -alkylene group; or a group (CH 2 ) n NR a R b (n = 0, 1, 2 or 3) , in which R a and R b represent H, or a saturated or unsaturated, optionally oxygen20 interrupted aliphatic group having up to 6 carbon atoms which may also be substituted by OH or N(R 16 ) 2 ; R a may also represent a C 3 . 7 -cycloaliphatic group; the entire group NR fl R b may also represent a 5 to 7-membered ring which may contain 0, S or NR 16 as an additional ring 2. 5 member; R 3 represents a mono- or polynuclear, optionally substituted, preferably aromatic, carbocyclic or nitrogen-containing heterocyclic group, the latter being capable of being bound to via a nitrogen or carbon atom, more particularly a group selected from: ^16^0-1 Ί2 L' -R (V) R 16- N (V) R 16- N (V) -N - 42 10 N F'L I 1 I N z % R - “T R 13 L. R 12 -N R 12 ! 4 (V··) (VI) (VII) (Χ·) (χ··) wherein G represents S, O, CH, CH=CH, N=CH, CH=N, N=N or NR 16 ; 35 L and L' each represent N or CR 16 ; R 12 represents H, (0)(C^-alkyl), aryl, O-aryl, - 43 aralkyl, halogen or OH, and I > R 13 represents H, halogen, a C 2 . 6 -alkenyl or -alkynyl group, or (Ο)θ.,-(C^-alkyl) , wherein the alkyl chain is 5 optionally OH- substituted or substituted by up to five halogen atoms; or R 12 and R 13 together represent an optionally substituted fused benzene ring; R u represents H, halogen, CN, OH, (O) 0 . 1 -(C 1 . 4 -alkyl) (wherein the alkyl chain may be substituted by up to 5 halogen atoms), N(R 16 ) 2 , a C 2 . 6 -alkenyl or -alkynyl group, CO-(C 1 . 4 -alkyl) , CO-aryl, aralkyl, aryl, O-aryl, or a 15 group of formula III or IV, and R 15 represents H, halogen, OH, (O) 0 _ 1 — (C 1 . 4 -alkyl) optionally substituted by OH or up to 5 halogen atoms; 2 0 or R 14 and R 15 together represent an optionally substituted homocyclic or heterocyclic fused five- to seven-membered ring, whilst up to two ring members may be selected from the group N, NR 16 , O and S; 25 R 16 represents H or C V4 alkyl; R 17 represents H, (O) 0 . 1 -C 1 . 4 alkyl or halogen; X-Y represents a single bond, a double-bonding bridging 3. 0 group of the formula CONR 16 ,CSNR 16 ,C(NH)NR 16 , NR 1& CO, so 2 nr 16 , nr 16 so 2 , conr 16 nr 16 , nr 16 conr 16 , nr 16 c(nr 16 )nr 16 , NR 16 CONR 16 NR 16 , CO (CH 2 ) t.jNH, NH (CH 2 ) V3 CO, SO 2 (CH 2 ) ,^ΝΗ, NH(CH 2 ) V3 SO 2 , and, if the group R 3 is linked to Q 1 via a carbon atom and at least one of the groups Q and Q' 35 represents a single bond, X-Y additionally represents CO or 0, with the proviso that the group qm-x-y-q»· does not represent -O-iC^j-alkylene)- if R 3 denotes an - 44 optionally substituted pyridyl, pyridazyl, pyrimidyl or pyrazinyl group and B (is CH=CH; and all diastereoisomeric, enantiomeric and racemic 5 forms thereof or mixtures thereof and/or acid-addition salts thereof. 2. Compounds as claimed in claim 1, wherein 10 B represents CH=CH, S, NR 16 or O; R 1 represents a group of formula II wherein R 4 , Rj and R 6 each represent H, C 1 . 4 -alkyl, C^-alkoxy or halogen? or if Rj and R 6 represent H, R 4 additionally 15 represents aryl, aralkyl, aryloxy or N(R 16 ) 2 , C 5 . 12 alkyl, C 5 . 12 alkoxy; or R 4 and Rj together represent a fused C 5 . 7 cycloalkene, -O-(CH 2 ) ,_ 3 -O- or -N=CH-NH- group (bound to adjacent carbon atoms of the benzene ring); or if R 6 represents hydrogen, R 4 and Rj together represent a fused 20 benzene ring; or R, represents a group of formula III, wherein D is as hereinbefore defined and at most only one of the 25 symbols Ε, Ε’, E and E' represents N whilst the others represent CH; and R 7 and R 8 , both represent H, C,_ 4 alkyl, C,. 4 alkoxy or halogen and, when R fl represents H, R ? additionally 30 represents C 5 . 12 -alkyl or C 5 . 12 -aryl; or R 7 and Rg together represent a fused C 5 . 7 -cycloalkene or fused benzene ring; or R, represents a group of formula IV wherein, of the 35 symbols Ε, Ε', E and E', not more than two represent N whilst the others represent CH; and - 45 R? and R lo each represent halogen, R 16 , OR 16 or N(R 16 ) 2 ; R? additionally represents aryl, O-aryl, aralkyl; or R? and R 10 together represent a fused C 5 . 7 -cycloalkene ring or fused benzene ring; R 2 represents H, OH, a saturated or unsaturated aliphatic group with up to 8 carbon atoms, a C 3 . 6 -cycloalkyl group, or a C V3 -alkyl group substituted with up to five halogen atoms or CH 3 OCH 2 CH 2 ; R 3 represents a group of formula V, V, V, V', VII or IX, wherein X-Y, G, L, L', R 16 and R 17 are as defined hereinbefore; R 12 represents R 16 , aryl or halogen, and 15 R U represents R 16 or an alkenyl group with up to 4 carbon atoms; or R 12 and R 13 together represent a fused benzene ring; R 14 represents R 16 , halogen, CN, CF 3 , CO-(C 1 . 4 alkyl) ° R 1 6 ; 20 R 15 represents R 16 , halogen or 0R 16 ; R 4 is as defined in claim 1; R n represents R 16 ; and M, U, Τ, V, W, Q, Q', Q and Q' are as defined in 25 claim 1; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof and/or acid-addition salts thereof. 30 3. Compounds as claimed in claim 1 as herein specifically disclosed in any of the Examples. 4. A process for the preparation of a compound of formula I as defined in claim 1 which comprises either a) for the preparation of a tetrazole of formula Ia or lb: - 46 10 (la) R-jQ•N x I Q* (lb) Q-X-Y-Q*-R 3 Q-X—Y-Q'-Rwherein R v Q, Q 1 , B, Q, X, Y, Q' and R 3 are as defined in claim 1, reacting an imide chloride of formula XI or XII respectively R 1 Q-N / ' C I Q' Cl Cl I R X Q-C^ N I Q’ ./ (XI) Q-X-Y-Q'-R 3 (XII) Q-X-Y-Q’-R 3 wherein all the symbols have the above meanings, with a metal azide in a solvent such as dimethylformamide at 25 temperatures from 60 to 120’C; or b) for the preparation of a triazole of formula Ic (IC) ./ Q-X-Y-Q · -R, - 47 wherein R,, Q' , Q”, Q 1 , X-Y, B, and R 3 are as defined in claim l, reacting an |mide chloride of formula XI as defined above with an acyl hydrazide of formula OC(R)NH-NH 2 in an aprotic solvent such as toluene; or c) for the preparation of a pyrrole of formula Id or Ie: RjQ-N (Ie) Q* (Id) B Q-X-Y-Q , -R 3 Q-X-Y-Q'-R 3 wherein R,, Q, Q', Q, Q' , X-Y, B, and R 3 are as defined in claim 1, i) for Id, reacting a XIII with an amine 1,4-diketone of formula of formula XIV, (XIII) V H 2 Q' B (XIV) Q-X-Y-Q'-R 3 wherein all the symbols have the above meanings, ii) and for Ie, reacting a 1,4-ketoaldehyde of formula XVI with an amine of formula XV (XV) — — - x B Q-X-Y-Q‘-R 3 wherein all the symbols have the above meanings, each reaction being carried out in the presence of an acid such as toluenesulphonic acid with cleaving of 15 water; or d) for the preparation of pyrazoles of formula If or lg; Q' and \ H / (If) Q-X-Y-Q'-R 3 q* (ig) B :==^/ Q-X-Y-Q’-R 3 wherein, R v R 2 , Q, Q', Q, Q', as defined in claim 1, B, X-Y and R 3 are reacting a ketoaldehyde of formula XVII or XVIII respectively - 49 10 θ) Λ Q-XY-Q“·-Rg Β (XVII) or (XVIII) Q-XY-Q’ —R, wherein all the symbols have the above meanings, with hydrazine in an aprotic solvent such as ethanol with heating; or for the preparation of a thiazole of formula lh or Ii; NR 1 QΓ Q' (lh) Q' (Ii) -J ... / Q-XY-Q'-R, Q-XY-Q'-R, wherein R v Q, Q’, Q, Q', B, X-Y and R 3 are as defined in claim 1, reacting an α-haloketone of formula XIX or XX respectively - 50 10 Q· (XIX) Q”-XY-Q'-R 3 \ wherein all the symbols have the above meanings, with thioformamide in an aprotic solvent such as 15 acetonitrile at 0 to 25’C; or f) for the preparation of a compound of formula I wherein X-Y represents CONR 10 , CSNR 16 , CO (CH 2 ) V3 NR 16 , C(NH)R 16 , SO 2 NR 16 or SO 2 (CH 2 ) v3 NR 16 ; and M, U, T, V, 20 R 1 , Q, R 2 , W, R 16 , Q', B, Q, Q ' and R 3 are as defined in claim 1, reacting a compound of formula XXI Q* (XXI) B A Q M -X'-Z (wherein Z represents OH, halogen, lower alkoxy, lower acyloxy; and X' represents CO, CS, COfCH^.j,, C(NH), S0 2 , SOjfCHj^.j and the remaining symbols have - 51 the above meanings) with an amine of formula XXII R 16 HN-Q’-R 3 (XXII) or a hydrazine of formula XXIIa R 16 NH-NR 16 -Q 'Rj (XXIIa) 10 wherein Q ' , R 16 and R 3 have the above meanings, under standard conditions; or g) for the preparation of compounds of formula I wherein X-Y represents NR 16 CO, NR 16 CONH, NR 16 SO 2 , 15 NR 16 (CH 2 ) ^jCO, or NR 16 (CH 2 ) ^SOj? and M, U, Τ, V, R,, Q, R 2 , W, Q', B, Q, Q' , R 16 and R 3 are as defined above, reacting an amine of formula XXIII M----~ U 20 : : R-jQ-T. -' v_R 2 I Q’ ----1 \ (XXIII) 25 B U=/ Q-NHR 16 wherein M, U, Τ, V, R v Q, R 2 , W, Q’, B, Q, Q'” , R 30 and R 3 are as defined above, either with a carboxylic or sulphonic acid or acid derivative of formula XXIV 3 5 Z-X-Q'»'-R 3 (XXIV) or with an isocyanate of formula XXV - 52 OCN-Q” ’ -R 3 (XXV) wherein Z represents OH, halogen, lower alkoxy, or lower acyloxy, X” represents (CH^.jSO^ (CH 2 ) V3 CO, 5. SO 2 or CO and Q ' and R 3 have the above meanings, using conventional methods; or h) for the preparation of compounds of formula I wherein X-Y represents NR 16 CONR 16 , NR 16 C (NR 16 ) NR 10 or 10 NR 16 CONR 16 NR 16 ; and M, U, T, V, R, Q, Rj, W, Q', B, Q, Q ' , R 16 and R 3 are as defined in claim 1, reacting a compound of formula XXIa 20 Q . ' (XXIa) B Uzk/ Q-NR ir - X ... -2 wherein X' represents CO or C(NR 16 ), Z has the meanings indicated in process f) above; and the remaining symbols are as defined above, with an amine of formula XXII or a hydrazine of 30 formula XXIIa as defined in process f) above; or i) for the preparation of compounds of formula I wherein Q represents a C V3 -alkylene group; and either X-Y represents a single bond, and M, U, T, 35 V, R v Q, Q', Q' , R 2 , W, B and R 3 are as defined in claim 1; or X-Y represents an oxygen atom, and Q 1 represents a C.,_ 3 -alkylene group, and Μ, V, T, V, R, - 53 Q, R 2 , W, B, Q' and R 3 are as defined in claim 1, reacting a compound of formula XXVI M—.y.-rU I. « * I • f Q“- X-Y-Q G wherein G represents a leaving group, preferably halogen or a sulphonic acid ester group, and all the remaining symbols have the above meanings, 15 with either of the heterocyclic groups as defined in claim 1 for R 3 in a polar solvent; or j) for the preparation of compounds of formula I wherein X-Y represents an oxygen atom, Q and Q' 20 both represent a single bond, and Μ, V, Τ, V, Q, Q', R,, R 2 , W, B and R 3 are as defined in claim 1, reacting a compound of formula XXVII M .-——U I, tl (XXVII) OMe (wherein Me represents an alkali metal, and all the remaining symbols are as defined above) 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; - 54 and, if desired, subsequently converting any bases obtained into acid addition salts, and/or subsequently converting racemates obtained into the individual enantiomers or into forms with a predominance of one 5 enantiomer, and/or subsequently converting compounds obtained carrying a tertiary nitrogen in the group R 3 into a quaternised derivative with suitable lower alkyl derivatives. 10 5. A process as claimed in claim 4 substantially as hereinbefore described and with reference to any of the Examples . 6. Compounds as claimed in claim 1 whenever prepared 15 by a process as claimed in claim 4 or claim 5. 7. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I, as defined in claim 1, in the form of a single enantiomer 20 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. 25 8. Compositions as claimed in claim 7 substantially as herein described. 9. Compounds of general formula I as claimed in claim 1 and physiologically acceptable acid addition salts 30 thereof for use in therapy. 10. The use of a compound as claimed in any one of claims 1 to 3 and 6 or a physiologically acceptable acid-addition salt thereof for the preparation of a 35 medicament for use in the treatment of diseases in which PAF is implicated.
11. 11. The use as claimed in claim 10 for the treatment of inflammatory and allergic conditions or autoimmune diseases. 5
12. 12. 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 in claim 1 or a physiologically acceptable acid addition salt thereof.
13. 13. Each and every novel compound, process, method, composition and use herein disclosed. Dated this 17th day of August 1990. BY TOMKINS & CO., Applicants' Agents, SIGNED