Il-5 inhibiting 6-azauracil derivatives Number:6,803,364 from the United States Patent and Trademark Office (PTO) owispatent The present invention is concerned with the compounds of formula (I), a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein p is 0 to 4; q is 0 to 5; X is O, S, NR.sup.3 or a direct bond; or --X--R.sup.2 is CN; R.sup.1 is H, OH, halo, NH.sub.2, mono- or di(C.sub.1-4 alkyl)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkylO, C.sub.3-7 cycloalkyl, aryl, arylC.sub.1-6 alkyl, NH.sub.2 C.sub.1-4 akyl, mono- or di(C.sub.1-4 alkyl)NH.sub.2 C.sub.1-4 akyl or mono- or di(C.sub.1-4 alkyl)NH.sub.2 C.sub.1-4 alkylNH.sub.2 ; R.sup.2 is aryl, Het.sup.1, optionally substituted C.sub.3-7 cycloalkyl, optionally substituted C.sub.1-6 alkyl; R.sup.3 is H or C.sub.1-4 alkyl; R.sup.4 and R.sup.5 are --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyl, halo, polyhaloC.sub.1-6 alkyl, OH, mercapto, C.sub.1-6 alkylO, C.sub.1-6 alkylthio, C.sub.1-6 alkylC(.dbd.O)O, aryl, cyano, nitro, Het.sup.3, R.sup.6, NR.sup.7 R.sup.8 or C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14, Het.sup.3, R.sup.6 or NR.sup.7 R.sup.8 ; Z is O, S, NH, --CH.sub.2 O or --CH.sub.2 --S--; R.sup.14 is H, C.sub.1-20 acyl, optionally substituted C.sub.1-20 alkyl, optionally substituted C.sub.3-20 alkenyl, C.sub.3-20 alkynyl, C.sub.3-7 cycloalkyl, polyhaloC.sub.1-20 alkyl, Het.sup.5, phenyl; or R.sup.14 is an oxygen containing radical; aryl is optionally substituted phenyl; Het.sup.1, Het.sup.2, Het.sup.3 and Het.sup.5 are optionally substituted heterocycles; Het.sup.4 is a monocyclic heterocycle; provided however that R.sup.2 is other than NH.sub.2 C(.dbd.O), C.sub.1-6 alkylOC(.dbd.O)C.sub.1-6 alkyl; and R.sup.11 is other than COOH, C.sub.1-4 alkylOC(.dbd.O), NH.sub.2 C(.dbd.O), C.sub.1-4 alkylNH.sub.2 C(.dbd.O), OHC.sub.1-4 alkylNH.sub.2 C(.dbd.O), C.sub.1-4 alkylC(.dbd.O)NH.sub.2 C(.dbd.O), C.sub.3-7 cycloalkylNH.sub.2 C(.dbd.O); and R.sup.7, R.sup.8, R. derivatives, inhibiting, Il, 5, inhibiting, 6803364.html, Patent, pto, 6803364

Title: Il-5 inhibiting 6-azauracil derivatives

Abstract: The present invention is concerned with the compounds of formula (I), a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein p is 0 to 4; q is 0 to 5; X is O, S, NR.sup.3 or a direct bond; or --X--R.sup.2 is CN; R.sup.1 is H, OH, halo, NH.sub.2, mono- or di(C.sub.1-4 alkyl)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkylO, C.sub.3-7 cycloalkyl, aryl, arylC.sub.1-6 alkyl, NH.sub.2 C.sub.1-4 akyl, mono- or di(C.sub.1-4 alkyl)NH.sub.2 C.sub.1-4 akyl or mono- or di(C.sub.1-4 alkyl)NH.sub.2 C.sub.1-4 alkylNH.sub.2 ; R.sup.2 is aryl, Het.sup.1, optionally substituted C.sub.3-7 cycloalkyl, optionally substituted C.sub.1-6 alkyl; R.sup.3 is H or C.sub.1-4 alkyl; R.sup.4 and R.sup.5 are --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyl, halo, polyhaloC.sub.1-6 alkyl, OH, mercapto, C.sub.1-6 alkylO, C.sub.1-6 alkylthio, C.sub.1-6 alkylC(.dbd.O)O, aryl, cyano, nitro, Het.sup.3, R.sup.6, NR.sup.7 R.sup.8 or C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14, Het.sup.3, R.sup.6 or NR.sup.7 R.sup.8 ; Z is O, S, NH, --CH.sub.2 O or --CH.sub.2 --S--; R.sup.14 is H, C.sub.1-20 acyl, optionally substituted C.sub.1-20 alkyl, optionally substituted C.sub.3-20 alkenyl, C.sub.3-20 alkynyl, C.sub.3-7 cycloalkyl, polyhaloC.sub.1-20 alkyl, Het.sup.5, phenyl; or R.sup.14 is an oxygen containing radical; aryl is optionally substituted phenyl; Het.sup.1, Het.sup.2, Het.sup.3 and Het.sup.5 are optionally substituted heterocycles; Het.sup.4 is a monocyclic heterocycle; provided however that R.sup.2 is other than NH.sub.2 C(.dbd.O), C.sub.1-6 alkylOC(.dbd.O)C.sub.1-6 alkyl; and R.sup.11 is other than COOH, C.sub.1-4 alkylOC(.dbd.O), NH.sub.2 C(.dbd.O), C.sub.1-4 alkylNH.sub.2 C(.dbd.O), OHC.sub.1-4 alkylNH.sub.2 C(.dbd.O), C.sub.1-4 alkylC(.dbd.O)NH.sub.2 C(.dbd.O), C.sub.3-7 cycloalkylNH.sub.2 C(.dbd.O); and R.sup.7, R.sup.8, R.

Patent Number: 6,803,364 Issued on 10/12/2004 to Freyne, et al.

Inventors: Freyne; Eddy Jean Edgard (Rumst, BE); Deroose; Frederik Dirk (Sint Amandsberg, BE); Lacrampe; Jean Fernand Armand (Le Mesnil-Esnard, FR); Embrechts; Werner Constant Johan (Beerse, BE); Fortin; Jerome Michel Claude (Lery, FR)
Assignee: Janssen Pharmaceutica N.V. (Beerse, BE)

Appl. No.: 09/868,384

Filed: August 29, 2001

PCT Filed: December 16, 1999

PCT No.: PCT/EP99/10169

PCT Pub. No.: WO00/37451

PCT Pub. Date: June 29, 2000

Foreign Application Priority Data


Dec 18, 1998 [EP]			98204336

Current U.S. Class: 514/242 ; 544/182

Field of Search: 514/242 544/182

References Cited [Referenced By]

U.S. Patent Documents


3883528	May 1975	Mylan
3912723	October 1975	Miller
4631278	December 1986	Boeckx et al.
4767760	August 1988	Boeckx et al.
4931444	June 1990	Van Wauwe et al.
5256631	October 1993	Lindner et al.

Foreign Patent Documents


2149645	Sep., 1972	DE
0 232 932	Aug., 1987	EP
170 316	May., 1990	EP
476 439	Mar., 1992	EP
737 672	Oct., 1996	EP
0 831 088	Mar., 1998	EP
648 760	Jan., 1999	EP
WO 94/14742	Jul., 1994	WO
WO 94/20446	Sep., 1994	WO
WO 96/31485	Oct., 1996	WO
WO 99 02504	Jan., 1999	WO
WO 99 02505	Jan., 1999	WO

Other References

Carroll et al., "Anticoccidial Derivatives of 6-Azauracil 5. Potentiation by Benzophenone Side Chains," J. Med. Chem. 1983, pp. 96-100, vol. 26. .
Baggiolini et al., "CC Chemokines in Allergic Inflammation." Immunology Today, 1994, pp. 127-133, vol. 15, No. 3. .
Carr et al., "Expression On Porcine .gamma. .delta. lymphocytes Of A Phylogenetically Conserved Surface Antigen Previously Restricted In Expression .gamma. .delta.T Lymphocytes," Immunology, 1994, pp. 36-40, vol. 81. .
Minnicozzi, et al., "The inhibition of interleuken 5 in allergic diseases," Exp. Opin. Ther. Patents, 1999, pp. 147-156, vol. 2, No. 9. .
Mishra et al., "IL-5 Promotes Eosinophil Trafficking to the Esophagus." The Journal of Immunology, 2002, pp. 2464-2469, vol. 168..

Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Lopez; Gabriel Kriegeman; Alana G.

Claims

What is claimed is:

1. A compound selected from the group consisting of: ##STR31## ##STR32##

and an N-oxide, a pharmaceutically acceptable addition salt, or a stereochemically isomeric form thereof.

2. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim 1.

3. A method for treating bronchial asthma in a patient, comprising administering a compound according to claim 1 to said patient.

4. A process of marking a receptor comprising the steps of a) radiolabelling a compound as defined in claim 1; b) administering said radiolabelled compound to biological material, and c) detecting the emissions from the radiolabelled compound.

5. A process of imaging an organ, comprising administering a sufficient amount of a radiolabelled compound of formula (I) as defined by claim 1, and detecting the emissions from the radioactive compound.

Description

The present invention concerns novel IL-5 inhibiting 6-azauracil derivatives useful for treating eosinophil-dependent inflammatory diseases; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.

Eosinophil influx, leading to subsequent tissue damage, is an important pathogenic event in bronchial asthma and allergic diseases. The cytokine interleukin-5 (IL-5), produced mainly by T lymphocytes as a glycoprotein, induces the differentiation of eosinophils in bone marrow and, primes eosinophils for activation in peripheral blood and sustains their survival in tissues. As such, IL-5 plays a critical role in the process of eosinophilic inflammation. Hence, the possibility that inhibitors of IL-5 production would reduce the production, activation and/or survival of eosinophils provides a therapeutic approach to the treatment of bronchial asthma and allergic diseases such as, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and also other eosinophil-dependent inflammatory diseases.

Steroids, which strongly inhibit IL-5 production in vitro, have long been used as the only drugs with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds having the ability to inhibit IL-5 production in human T-cells and which have little or no adverse reactions.

U.S. Pat. No. 4,631,278 discloses .alpha.-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneaceto nitriles and U.S. Pat. No. 4,767,760 discloses 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoal activity, in particular, anti-coccidial activity. EP 831,088 discloses 1,2,4-triazine-3,5-diones as anticoccidial agents.

The present invention provides compounds which have never been described hitherto and which possess a remarkable pharmacological activity as inhibitors of the production of IL-5.

The present invention is concerned with the compounds of formula ##STR2##

the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein p represents an integer being 0, 1, 2, 3 or 4; q represents an integer being 0, 1, 2, 3, 4 or 5; X represents O, S, NR.sup.3 or a direct bond; or --X--R.sup.2 taken together may represent cyano; R.sup.1 represents hydrogen, hydroxy, halo, amino, mono- or di(C.sub.1-4 alkyl)amino, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.3-7 cycloalkyl, aryl, arylC.sub.1-6 alkyl, aminoC.sub.1-4 alkyl, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl or mono- or di(C.sub.1-4 alkyl)amino-C.sub.1-4 alkylamino; R.sup.2 represents aryl, Het.sup.1, C.sub.3-7 cycloalkyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C.sub.1-4 alkyl)amino, --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyloxy optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkylsulfonyloxy, C.sub.3-7 cycloalkyl optionally substituted with --C.dbd.O)--Z--R.sup.14, aryl, aryloxy, arylthio, Het.sup.1, Het.sup.1 oxy and Het.sup.1 thio; and if X is O, S or NR.sup.3, then R.sup.2 may also represent --C(.dbd.O)--Z--R.sup.14, aminothiocarbonyl, C.sub.1-4 alkylcarbonyl optionally substituted with --C(.dbd.Q)--Z--R.sup.14, C.sub.1-4 alkylthiocarbonyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, arylcarbonyl, arylthiocarbonyl, Het.sup.1 carbonyl or Het.sup.1 thiocarbonyl; R.sup.3 represents hydrogen or C.sub.1-4 alkyl; each R.sup.4 independently represents --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyl, halo, polyhaloC.sub.1-6 alkyl, hydroxy, mercapto, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylcarbonyloxy, aryl, cyano, nitro, Het.sup.3, R.sup.6, NR.sup.7 R.sup.8 or C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14, Het.sup.3, R.sup.6 or NR.sup.7 R.sup.8 ; each R.sup.5 independently represents --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyl, halo, polyhaloC.sub.1-6 alkyl, hydroxy, mercapto, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylcarbonyloxy, aryl, cyano, nitro, Het.sup.3, R.sup.6, NR.sup.7 R.sup.8 or C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14, Het.sup.3, R.sup.6 or NR.sup.7 R.sup.8 ; each R.sup.6 independently represents C.sub.1-6 alkylsulfonyl, aminosulfonyl, mono- or di-(C.sub.1-4 alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC.sub.1-6 alkyl-sulfonyl, C.sub.1-6 alkylsulfonyl, phenylC.sub.1-4 alkylsulfonyl, piperazinylsulfonyl, piperidinyl-sulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C.sub.1-4 alkyl-N-piperidinylaminosulfonyl or mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkylsulfonyl; each R.sup.7 and each R.sup.8 are independently selected from hydrogen, C.sub.14 alkyl, hydroxy-C.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, aryl, arylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, arylcarbonyl, Het.sup.3 carbonyl, --C(.dbd.O)--Z--R.sup.14, mono- or di(C.sub.1-4 alkyl)amino-C).sub.4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het.sup.3 aminocarbonyl, Het.sup.3 amino-thiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl, C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, Het.sup.3 and R.sup.6 ; or R.sup.7 and R.sup.8 taken together with the nitrogen atom to which they are attached form a radical of formula ##STR3## R.sup.9 and R.sup.10 are each independently selected from hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, phenyl, phenylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, phenylcarbonyl, Het.sup.3 carbonyl, --C(.dbd.O)--Z--R.sup.14, mono- or di(C.sub.1-4 alkyl)amino-C.sub.1-4 alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het.sup.3 aminocarbonyl, Het.sup.3 aminothiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl, C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, Het.sup.3 and R.sup.6 ; or R.sup.9 and R.sup.10 taken together with the nitrogen atom to which they are attached form a radical of formula ##STR4## each R.sup.11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, --C(.dbd.O)--Z--R.sup.14, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, trihalomethyl, C.sub.1-4 alkyloxy optionally substituted with --C(.dbd.O)--Z--R.sup.14, formyl, trihaloC.sub.1-4 alkylsulfonyloxy, R.sup.6, NR.sup.7 R.sup.8, C(.dbd.O)NR.sup.15 R.sup.16, aryl, aryloxy, arylcarbonyl, C.sub.3-7 cycloalkyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.3-7 cycloalkyloxy optionally substituted with --C(.dbd.O)--Z--R.sup.14, phthalimide-2-yl, Het.sup.3, Het.sup.4 and C(.dbd.O)Het.sup.3 ; R.sup.12 and R.sup.13 are each independently selected from hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, phenyl, phenylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, phenylcarbonyl, --C(.dbd.O)--Z--R.sup.14, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl, C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14 and R.sup.6 ; or R.sup.9 and R.sup.10 taken together with the nitrogen atom to which they are attached form a radical of formula ##STR5## each Z independently represents O, S, NH, --CH.sub.2 --O-- --CH.sub.2 --S-- whereby --CH.sub.2 -- is attached to the carbonyl group; each R.sup.14 independently represents hydrogen, C.sub.1-20 acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms), C.sub.1-20 alkyl, C.sub.3-20 alkenyl optionally substituted with phenyl, C.sub.3-20 alkynyl, C.sub.3-7 cycloalkyl, polyhaloC.sub.1-20 alkyl, Het.sup.5, phenyl or C.sub.1-20 alkyl substituted with one or more substituents selected from hydroxy, NR.sup.17, R.sup.18, phenyl, mono- or di(C.sub.1-4 alkyl)amino, cyano, Het.sup.5, C.sub.1-4 alkyloxycarbonyl, phenylC.sub.1-4 alkyloxycarbonyl and C.sub.3-7 cycloalkyl; or R.sup.14 represents a radical of formula ##STR6## ##STR7## wherein n is 0 to 5; m is 1 to 4; s is zero to 4; r is 0 to 2; R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e and R.sup.f are each independently hydrogen, or C.sub.1-6 alkyl; phenyl or C.sub.3-7 cycloalkyl; or R.sup.e and R.sup.f taken together may form --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 ----CH.sub.2 --CH.sub.2 --; R.sup.g, R.sup.h and R.sup.k are each independently hydrogen or C.sub.1-4 alkyl; each R.sup.j independently is C.sub.1-4 alkyl; R.sup.i is --O--R.sup.6, C.sub.1-6 alkyl, phenyl or C.sub.3-7 cycloalkyl optionally substituted with C.sub.1-4 alkyloxy; R.sup.n is hydrogen, C.sub.1-4 alkyl, phenyl, phenylC.sub.1-4 alkyl or C.sub.3-7 cycloalkyl; R.sup.m is hydrogen or C.sub.1-4 alkyloxy; or --Z--R.sup.14 taken together form a radical of formula ##STR8## R.sup.15 and R.sup.16 are each independently selected from hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, aryl, arylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, --C(.dbd.O)Z--R.sup.14, arylcarbonyl, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, arylaminocarbonyl, arylamino-10 thiocarbonyl, aminocarbonylmethylene, mono- or di(C.sub.1-4 alkyl)aminocarbonyl-methylene, Het.sup.3 aminocarbonyl, Het.sup.3 aminothiocarbonyl, pyridinylC.sub.1-4 alkyl, Het.sup.3 or R.sup.6 ; or R.sup.15 and R.sup.16 taken together with the nitrogen atom to which they are attached form a radical of formula ##STR9## R.sup.17 and R.sup.18 are each independently selected from hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, dihydroxyC.sub.1-4 akyl, phenyl, phenylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, phenylcarbonyl, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, phenylamino-carbonyl, phenylaminothiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl, C.sub.1-4 alkanediyl-C(.dbd.O)--Z--C.sub.1-6 alkyl, --C(.dbd.O)--Z--C.sub.1-6 alkyl, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--C.sub.1-6 alkyl and R.sup.6 ; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkyloxy, formyl, polyhaloC.sub.1-4 alkyl, NR.sup.9 R.sup.10, --C(.dbd.O)NR.sup.9 R.sup.10, --C(.dbd.O)--Z--R.sup.14, R.sup.6, --O--R.sup.6 ; phenyl, Het.sup.3, C(.dbd.O)Het.sup.3, and C.sub.1-4 alkyl substituted with one or more substituents each independently selected from halo, hydroxy, C.sub.1-4 alkyloxy, --C(.dbd.O)--Z--R.sup.14, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, Het.sup.3 or NR.sup.9 R.sup.10 ; Het.sup.1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het.sup.2, R.sup.11 and C.sub.1-4 alkyl optionally substituted with one or two substituents independently selected from Het.sup.2 and R.sup.11 ; Het.sup.2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R.sup.11 and C.sub.1-4 alkyl optionally substituted with one or two substituents each independently selected from R.sup.11 ; Het.sup.3 represents a monocyclic heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, --C(.dbd.O)--Z--R.sup.14, C.sub.1-4 alkylcarbonyl, phenylC.sub.1-4 alkyl, piperidinyl, NR.sup.12 R.sup.13, R.sup.6 and C.sub.1-4 alkyl substituted with one or two substituents each independently selected from hydroxy, C.sub.1-4 alkyloxy, phenyl, --Y--C.sub.1-4 alkanediyl-C(.dbd.O)--Z--R.sup.14, --C(.dbd.O)--Z--R.sup.4, R.sup.6 or NR.sup.12 R.sup.13 ; Het.sup.4 represents a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl; Het.sup.5 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzo-thienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimida-zolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two, three or four substituents each independently selected from hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, C.sub.1-4 alkylcarbonyl, piperidinyl, NR.sup.17 R.sup.18, C(.dbd.O)--Z--C.sub.1-6 alkyl, R.sup.6, sulfonamido and C.sub.1-4 alkyl substituted with one or two substituents independently selected from hydroxy, C.sub.1-4 alkyloxy, phenyl, C(.dbd.O)--Z--C.sub.1-6 alkyl, --Y--C.sub.1-6 alkanediyl--C(.dbd.O)--Z--C.sub.1-6 alkyl, R.sup.6 and NR.sup.17 R.sup.18 ; provided however that R.sup.2 is other than aminocarbonyl, C.sub.1-6 alkyloxycarbonylC.sub.1-6 alkyl; and R.sup.11 is other than carboxyl, C.sub.1-4 alkyloxycarbonyl, aminocarbonyl, C.sub.1-4 alkylaminocarbonyl, hydroxyC.sub.1-4 alkylaminocarbonyl, C.sub.1-4 alkylcarbonylaminocarbonyl, C.sub.3-7 cycloalkylaminocarbonyl; and R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.15 and R.sup.16 are other than C.sub.1-4 alkylcarbonyloxyC.sub.1-4 alkylcarbonyl, hydroxyC.sub.1-4 alkylcarbonyl; and Het.sup.3 is other than a monocyclic heterocycle substituted with carboxyl or C.sub.1-4 alkyloxycarbonyl; and the compounds of formula (I) contain at least one --C(.dbd.O)--Z--R.sup.14 moiety.

A special group of compounds are those compounds of formula (I) wherein R represents aryl, Het.sup.1, C.sub.3-7 cycloalkyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C.sub.1-4 alkyl)amino, --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkyloxy optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkylsulfonyloxy, C.sub.3-7 cycloalkyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, aryl, aryloxy, arylthio, Het.sup.1, Het.sup.1 oxy and Het.sup.1 thio; and if X is O, S or NR.sup.3, then R.sup.2 may also represent --C(.dbd.O)--Z--R.sup.14, aminothiocarbonyl, C.sub.1-4 alkylcarbonyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.1-4 alkylthiocarbonyl optionally: substituted with --C(.dbd.O)--Z--R.sup.14, arylcarbonyl, arylthiocarbonyl; each R.sup.6 independently represents C.sub.1-6 alkylsulfonyl, aminosulfonyl, mono- or di(C.sub.1-4 alkyl)aminosulfonyl, mono or di(benzyl)aminosulfonyl, polyhaloC.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfonyl, phenylC.sub.1-4 alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C.sub.1-4 alkyl-N-piperidinylaminosulfonyl; each R.sup.7 and each R.sup.8 are independently selected from hydrogen, C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, aryl, arylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, arylcarbonyl, --C(.dbd.O)--Z--R.sup.14, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het.sup.3 aminocarbonyl, Het.sup.3 aminothiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl, Het.sup.3 and R.sup.6 ; R.sup.9 and R.sup.10 are each independently selected from hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, phenyl, phenylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, phenylcarbonyl, --C(.dbd.O)--Z--R.sup.14, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het.sup.3 aminocarbonyl, Het.sup.3 aminothiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl, Het.sup.3 and R.sup.6 ; each R.sup.11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, --C(.dbd.O)--Z--R.sup.14, trihalomethyl, C.sub.1-4 alkyloxy optionally substituted with --C(.dbd.O)--Z--R.sup.14, formyl, trihaloC.sub.1-4 alkylsulfonyloxy, R.sup.6, NR.sup.7 R.sup.8, C(.dbd.O)NR.sup.15 R.sup.16, aryl, aryloxy, arylcarbonyl, C.sub.3-7 cycloalkyl optionally substituted with --C(.dbd.O)--Z--R.sup.14, C.sub.3-7 cycloalkyloxy optionally substituted with --C(.dbd.O)--Z--R.sup.14, phthalimide-2-yl, Het.sup.3 and C(.dbd.O)Het.sup.3 ; R.sup.12 and R.sup.13 are each independently selected from hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, dihydroxyC.sub.1-4 alkyl, phenyl, phenylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, phenylcarbonyl, --C(.dbd.O)--Z--R.sup.14, mono- or di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C.sub.3-7 cycloalkyl, pyridinylC.sub.1-4 alkyl and R.sup.6 ; each R.sup.14 independently represents hydrogen, C.sub.1-20 acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms), C.sub.1-20 alkyl, C.sub.3-7 cycloalkyl, polyhaloC.sub.1-20 alkyl; or R.sup.14 represents a radical of formula ##STR10## R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e and R.sup.f are each independently hydrogen, C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; or R.sup.e and R.sup.f taken together may form --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --; R.sup.15 and R.sup.16 are each independently selected from dihydroxyC.sub.1-4 alkyl, aryl, arylC.sub.1-4 alkyl, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, --C(.dbd.O)--Z--R.sup.14, arylcarbonyl, mono- or di(C.sub.1-4 alkyl)-aminoC.sub.1-4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het.sup.3 aminocarbonyl, Het.sup.3 aminothiocarbonyl, pyridinylC.sub.1-4 alkyl, Het.sup.3 or R.sup.6 ; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, polyhaloC.sub.1-4 alkyl, NR.sup.9 R.sup.10, --C(.dbd.O)--Z--R.sup.14, R.sup.6, phenyl, Het.sup.3, and C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14 or NR.sup.9 R.sup.10 ; Het.sup.1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyrdazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het.sup.2, R.sup.11 and C.sub.1-4 alkyl optionally substituted with Het.sup.2 and R.sup.11 ; Het.sup.2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl,dithianyl, trithianyl, triazinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R.sup.11 and C.sub.1-4 alkyl optionally substituted with R.sup.11 ; Het.sup.3 represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, substituents each independently selected from C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, --C(.dbd.O)--Z--R.sup.14, C.sub.1-4 alkylcarbonyl, phenylC.sub.1-4 alkyl, piperidinyl, NR.sup.12 R.sup.13, R.sup.6 and C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14, R.sup.6 or NR.sup.12 R.sup.13.

As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C.sub.3-7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C.sub.1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C.sub.1-6 alkyl is meant to include C.sub.1-4 alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like C.sub.1-20 alkyl is meant to include C.sub.1-6 alkyl and the higher homologues thereof having 7 to 20 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl, nonadecyl, eicosyl and the like C.sub.5-20 alkyl is meant to include C.sub.1-20 alkyl except for C.sub.1-4 alkyl; polyhaloC.sub.1-4 alkyl is defined as polyhalosubstituted C.sub.1-4 alkyl, in particular C.sub.1-4 alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; polyhaloC.sub.1-6 alkyl is defined as polyhalosubstituted C.sub.1-6 alkyl; polyhaloC.sub.1-20 alkyl is defined as polyhalosubstituted C.sub.1-20 alkyl. The term C.sub.1-4 alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C.sub.2-6 alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 2 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term C.sub.3-20 alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 20 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; and the carbon of said C.sub.3-20 alkenyl connected to the remainder of the molecule preferably is saturated; and the term C.sub.3-20 alkynyl defines straight and branched chain hydrocarbon radicals containing one triple bond and having from 3 to 20 carbon atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl and the like; and the carbon of said C.sub.3-20 alkynyl connected to the remainder of the molecule preferably is saturated.

Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4 and Het.sup.5 are meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4 or Het.sup.5, for instance, pyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.

The heterocycles represented by Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4 and Het.sup.5 may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl.

The C.sub.1-20 acyl is derived from

acetic acid CH.sub.3 COOH tridecanoic acid C.sub.12 H.sub.25 COOH propionic acid C.sub.2 H.sub.5 COOH myristic acid C.sub.13 H.sub.27 COOH butyric acid C.sub.3 H.sub.7 COOH pentadecanoic acid C.sub.14 H.sub.29 COOH valeric acid C.sub.4 H.sub.9 COOH palmitic acid C.sub.15 H.sub.31 COOH hexanoic acid C.sub.5 H.sub.11 COOH heptadecanoic acid C.sub.16 H.sub.33 COOH heptanoic acid C.sub.6 H.sub.13 COOH stearic acid C.sub.17 H.sub.35 COOH octanoic acid C.sub.7 H.sub.15 COOH oleic acid C.sub.17 H.sub.33 COOH nonanoic acid C.sub.8 H.sub.17 COOH linolic acid C.sub.17 H.sub.31 COOH decanoic acid C.sub.9 H.sub.19 COOH linolenic acid C.sub.17 H.sub.29 COOH undecanoic acid C.sub.10 H.sub.21 COOH nonadecanoic acid C.sub.18 H.sub.37 COOH lauric acid C.sub.11 H.sub.23 COOH icosanoic acid C.sub.19 H.sub.39 COOH

The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulphonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, choline and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. For example, one or more nitrogen atoms of any of the heterocycles in the definition of Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4 and Het.sup.5 may be N-oxidised.

Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, a hydroxy substituted triazine moiety may also exist as the corresponding triazinone moiety; a hydroxy substituted pyrimidine moiety may also exist as the corresponding pyrimidinone moiety.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible stereoisomeric forms in which the compounds of formula (I) can exist. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centres may have the R- or S-configuration, used herein in accordance with Chemical Abstracts nomenclature. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

The compounds of formula (I) and some of the intermediates in the present invention contain one or more asymmetric carbon atoms. The pure and mixed stereochemically isomeric forms of the comppounds of formula (I) are intended to be embraced within the scope of the present invention.

Whenever used hereinafter, the term "compounds of formula (I)" is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, quaternary amines and their stereochemically isomeric forms.

The numbering of the phenyl ring bearing substituent R.sup.4 is given hereinbelow and is used herein as such when indicating the position of the R.sup.4 substituents on said phenyl ring, unless otherwise indicated. ##STR11##

The carbon atom bearing the two phenyl rings and the R.sup.1 and --X--R.sup.2 substituents will be referred herein as the central carbon atom.

An interesting group of compounds are those compounds of formula (I) wherein the 6-azauracil moiety is connected to the phenyl ring in the para or meta position relative to the central carbon atom; preferably in the para position.

Another interesting group contains those compounds of formula (I) wherein one or more of the following restrictions apply: p is 0, 1 or 2; X is S, NR.sup.3, or a direct bond; more in particular NH or a direct bond; each R.sup.5 independently is halo, polyhaloC.sub.1-6 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy or aryl, preferably, chloro or trifluoromethyl, more preferably chloro; the at least one --C(.dbd.O)--Z--R.sup.14 moiety contained by the compound of formula (I) is born by R.sup.2 ; R.sup.2 is Het.sup.1 or C.sub.1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C.sub.1-4 alkyl)amino, C(.dbd.O)--Z--R.sup.14 C.sub.1-6 alkyloxy optionally substituted with C(.dbd.O)--Z--R.sup.14, C.sub.1-6 alkylsulfonyloxy, C.sub.3-7 cycloalkyl optionally substituted with C(.dbd.O)--Z--R.sup.14, aryl, aryloxy, arylthio, Het.sup.1, Het.sup.1 oxy and Het.sup.1 thio; and if X is O, S or NR , then R.sup.2 may also represent aminothiocarbonyl, C.sub.1-4 alkylcarbonyl optionally substituted with C(.dbd.O)--Z--R.sup.14, C.sub.1-4 alkylthiocarbonyl optionally substituted with C(.dbd.O)--Z--R.sup.14, arylcarbonyl, arylthiocarbonyl, Het.sup.1 carbonyl or Het.sup.1 thiocarbonyl; particularly R.sup.2 is Het.sup.1 or in the event X is NH, R.sup.2 may also be aminothiocarbonyl or Het.sup.1 carbonyl; R.sup.1 is hydrogen or methyl; preferably, methyl; R.sup.6 is C.sub.1-6 alkylsulfonyl or aminosulfonyl; R.sup.7 and R.sup.8 are each independently hydrogen, C.sub.1-4 alkyl, Het.sup.3 or R.sup.6 ; R.sup.9 and R.sup.10 are each independently hydrogen, C.sub.1-4 alkyloxyC.sub.1-4 alkyl, C.sub.1-4 alkylcarbonyl, aminocarbonyl, Het.sup.3 carbonyl, Het.sup.3 or R.sup.6 ; R.sup.11 is cyano, nitro halo, C.sub.1-4 alkyloxy, formyl, NR.sup.7 R.sup.8, C(.dbd.O)NR.sup.15 R.sup.16, --C(.dbd.O)--Z--R.sup.14, aryl, arylcarbonyl, Het.sup.3, Het.sup.4 or C(.dbd.O)Het.sup.3 ; more preferably R.sup.11 is phenyl, --C(.dbd.O)--O--R.sup.14, --C(.dbd.O)--S--R.sup.14, or, --C(.dbd.O)--NH--R.sup.14 ; R.sup.14 is dihydrofuranyl, C.sub.5-20 alkyl, C.sub.3-20 alkenyl, polyhaloC.sub.1-6 alkyl, Het.sup.5 or C.sub.1-20 alkyl substituted with one or more substituents selected from phenyl, C.sub.1-4 alkylamino, cyano, Het.sup.1, hydroxy and C.sub.3-7 cycloalkyl; R.sup.17 and R.sup.18 are each independently hydrogen or phenyl; aryl is phenyl optionally substituted with one, two or three substituents each independently selected from nitro, cyano, halo, hydroxy, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkyloxy, formyl, polyhaloC.sub.1-4 alkyl, NR.sup.9 R.sup.10, C(.dbd.O)NR.sup.9 R.sup.10, C(.dbd.O)--O--R.sup.14, --O--R.sup.6, phenyl, C(.dbd.O)Het.sup.3 and C.sub.1-4 alkyl substituted with one or more substituents each independently selected from halo, hydroxy, C.sub.1-4 alkyloxy, C(.dbd.O)--Z--R.sup.14, Het.sup.3 or NR.sup.9 R.sup.10 ; Het.sup.1 is a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, in particular imidazolyl, oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het.sup.2, R.sup.11 and C.sub.1-4 akyl optionally substituted with Het.sup.2 or R.sup.11 ; preferably Het.sup.1 is imidazolyl, oxadiazolyl, thiazolyl or pyridinyl each independently and optionally substituted with one, or where possible, two or three substituents each independently selected from Het.sup.2, R.sup.11 and C.sub.1-4 alkyl optionally substituted with Het.sup.2 or R.sup.11 ; Het.sup.2 is an aromatic heterocycle; more in particular furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R.sup.11 and C.sub.1-4 alkyl; : Het.sup.3 is azetidinyl, piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkylcarbonyl, piperidinyl and C.sub.1-4 alkyl substituted with one or two substituents independently selected from hydroxy, C.sub.1-4 alkyloxy and phenyl; Het.sup.4 is thienyl; Het.sup.5 is piperidinyl or piperazinyl optionally substituted with C.sub.1-4 alkyl or sulfonamido.

Suitably, Het.sup.1 represents a heterocycle selected from imidazolyl, triazolyl, furanyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, benzothiazolyl, benzoxazolyl, purinyl, 1H-pyrazolo-[3,4-d]pyrimidinyl, benzimidazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazo-[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het.sup.2, R.sup.11 and C.sub.1-4 alkyl optionally substituted with Het.sup.2 or R.sup.11. Suitably, Het.sup.2 represents furanyl, thienyl or pyridinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with C.sub.1-4 alkyl. Suitably, Het.sup.3 represents pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two or three substituents each independently selected from C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, --C(.dbd.O)--Z--R.sup.14, C.sub.1-4 alkylcarbonyl, phenylC.sub.1-4 alkyl, piperidinyl, NR.sup.12 R.sup.13 and C.sub.1-4 alkyl substituted with --C(.dbd.O)--Z--R.sup.14 or NR.sup.12 R.sup.13.

Particular compounds are those compounds of formula (I) wherein R.sup.4 and R.sup.5 each independently are --C(.dbd.O)--Z--R.sup.14, halo, polyhaloC.sub.1-6 alkyl, C.sub.1-6 alkyl optionally substituted with --C(.dbd.O)--Z.sub.7 R.sup.14, C.sub.1-6 alkyloxy or aryl, more in particular, chloro or trifluoromethyl.

Other particular compounds are those compounds of formula (I) wherein R.sup.2 represents aryl, Het.sup.1, C.sub.3-7 cycloalkyl optionally substituted with --C(.dbd.O)--Z--R.sup.14 or C.sub.1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C.sub.1-4 alkyl)amino, C.sub.1-6 alkyloxy, C.sub.1-6 alkylsulfonyloxy, C.sub.1-6 alkyloxycarbonyl, C.sub.3-7 cycloalkyl, aryl, aryloxy, arylthio, Het.sup.1, Het.sup.1 oxy and Het.sup.1 thio; and if X is O, S or NR.sup.3, then R.sup.2 may also represent --C(.dbd.O)--Z--R.sup.14, aminothiocarbonyl, CC.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylthiocarbonyl, arylcarbonyl or arylthiocarbonyl; more in particular R.sup.2 is oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het.sup.2, R.sup.11 and C.sub.1-4 alkyl optionally substituted with Het.sup.2 or R.sup.11.

Yet other particular compounds are those compounds of formula (I) wherein X is O, S, NH or a direct bond, more preferably S or a direct bond, most preferably a direct bond.

Preferred compounds are those compounds of formula (I) wherein q is 1 or 2 and one R.sup.4 substituent, preferably chloro, is in the 4 position.

Other preferred compounds are those compounds of formula (I) wherein p is 1 or 2 and the one or two R.sup.5 substituents, preferably chloro, are in the ortho position relative to the central carbon atom.

In order to simplify the structural representation of the compounds of formula (I), the group ##STR12##

will hereinafter be represented by the symbol D.

Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (I) wherein W.sup.1 is a suitable leaving group such as, for example, a halogen atom, with an appropriate reagent of formula (III). ##STR13##

Said reaction may be performed in a reaction-inert solvent such as, for example, acetonitrile, N,N-dimethylformamide, acetic acid, tetrahydrofuran, ethanol or a mixture thereof. Alternatively, in case the reagent of formula (III) acts as a solvent, no additional reaction-inert solvent is required. The reaction is optionally carried out in the presence of a base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium bicarbonate, sodiumethanolate and the like. Convenient reaction temperatures range between -70.degree. C. and reflux temperature.

In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallisation, distillation, trituration and chromatography.

Alternatively, compounds of formula (I) may generally be prepared by cyclising an intermediate of formula (IV) wherein L is a suitable leaving group such as, for example, C.sub.1-6 alkyloxy or halo, and E represents an appropriate electron attracting group such as, for example, an ester, an amide, a cyanide, C.sub.1-6 alkylsulfonyloxy and the like groups; and eliminating the group E of the thus obtained triazinedione of formula (V). Said reaction procedure is analogous to the one described in EP-A-0,170,316. ##STR14##

Some of the compounds and intermediates of the present invention can be prepared according to or analogous to the procedures described in EP-A-0,170,316 and EP-A-0,232,932.

For instance, scheme 1 depicts a reaction pathway for the preparation of compounds of formula (I) wherein R.sup.1 is hydrogen and X is a direct bond, said compounds being represented by formula (I-a-1). A ketone of formula (VI) can be reacted with a reagent of formula (VII) wherein W.sup.2 is a suitable leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, tetrahydrofuran, diethylether, and in the presence of a suitable base such as, for example, butyl lithium, thus forming an intermediate of formula (VIII). The hydroxy group of the intermediates of formula (VIII) may be eliminated by using a suitable reagent such as for example, formamide in acetic acid or triethylsilane in trifluoroacetic acid, thus obtaining an intermediate of formula (IX) of which the nitro group may subsequently be reduced to an amino group which in turn may then be converted to the 6-azauracil group as described in EP-A-0,170,316, thus obtaining compounds of formula (I-a-1). ##STR15##

In addition to the reaction procedure shown in scheme 1, other compounds of formula (I) wherein X is a direct bond may be prepared starting from a ketone of formula (X) (Scheme 2). Reacting said ketone of formula (X) with an intermediate of formula (III) wherein X is a direct bond, said intermediates being represented by formula (III-a), results in a compound of formula (I) wherein R.sup.1 is hydroxy and X is a direct bond, said compounds being represented by formula (I-a-2). Said reaction may be performed in a reaction-inert solvent such as, for example, tetrahydrofuran, diethylether, diisopropyl-acetamide or a mixture thereof, in the presence of a base such as, for example, butyl lithium. Alternatively, intermediate of formula (III-a) may first be transformed into a Grignard reagent, which may then be reacted with the ketone of formula (X). Said compounds of formula (I-a-2) may further be converted to compounds of formula (I) wherein R.sup.1 is a C.sub.1-6 alkyloxy group represented by formula (I-a-3) using art-known group transformation reactions. The compounds of formula (I-a-2) may also be converted to compounds of formula (I) wherein R.sup.1 is halo, said compounds being represented by formula (I-a-4). A convenient procedure is converting the hydroxy group to a chlorine atom using a suitable reagent such as, for example, thionyl chloride. Said compounds of formula (I-a4) may further be converted to compounds of formula (I) wherein R.sup.1 is amino, said compounds being represented by formula (I-a-5), using ammonia or a functional derivative thereof, in a reaction-inert solvent such as, for example, tetrahydrofuran; or may be converted to compounds of formula (I-a-3) using art-known group transformation reactions.

Reducing the ketone of formula (X) to its corresponding hydroxy derivative of formula (XI) using a suitable reducing agent such as, for example, sodiumborohydride in a reaction-inert solvent such as for example, water, an alcohol, tetrahydrofuran or a mixture thereof; subsequently converting said hydroxy group to a suitable leaving group W.sup.4 being for example a halogen, thus obtaining an intermediate of formula (XII), and finally reacting said intermediate of formula (XII) with an intermediate of formula (III) in a suitable solvent such as, for example, tetrahydrofuran, N,N-dimethyl-formamide, acetonitrile, acetic acid, ethanol or a mixture thereof, and optionally in the presence of a suitable base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene or sodiumbicarbonate, will result in a compound of formula (I) wherein R.sup.1 is hydrogen, said compounds being represented by formula (I-b).

Alternatively, intermediates of formula (XI) can be directly transformed to compounds of formula (I-b) wherein X is S, said compounds being represented by formula (I-b-1), using a suitable mercapto containing reagent of formula R.sup.2 --SH in a suitable reaction solvent such as, for example, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or the like.

Also starting from a ketone of formula (X), compounds of formula (I) may be prepared wherein R.sup.1 is hydrogen and --X--R.sup.2 is --NH--C(.dbd.O)-(aryl or C.sub.1-6 alkyl), said compounds being represented by formula (I-c). To that effect, a ketone of formula (X) is reacted with formamide in formic acid or a functional derivative thereof, at elevated temperatures. The resulting intermediate of formula (XII) is hydrolysed to the corresponding amine of formula (XIV), which may then be further reacted with an intermediate of formula (XV) wherein W.sup.3 is a suitable leaving group, in the presence of a suitable base, such as, for example pyridine, optionally in the presence of a reaction-inert solvent such as, for example, dichloromethane. ##STR16##

Compounds of formula (I) wherein X is a direct bond and R.sup.2 is a heterocycle, said compounds being generally represented by formula (I-d), can conveniently be prepared by cyclisation of the appropriate intermediate. Intramolecular cyclisation procedures are feasible and scheme 3 lists several examples.

Starting point is the conversion of the cyano group of a compound of formula (I) wherein --X--R.sup.2 is cyano, said compounds being represented by formula (I-e), to a carboxyl group thus forming intermediates of formula (XVII) using art-known techniques such as, for example, using a combination of sulphuric and acetic acid in water, which in turn may be further reacted to acyl halides of formula (XVIII), for instance, the acyl chloride derivative may be prepared using thionyl chloride. ##STR17## ##STR18##

The intermediate of formula (XVIII) may be reacted with an intermediate of formula (XIX-a) wherein Y is O, S or NR.sup.3, to form an intermediate of formula (XX) in the presence of a base such as, for example, pyridine. Said intermediate of formula (XX) may further be cyclised to a compound of formula (I) wherein --X--R.sup.2 is an optionally substituted benzothiazole or benzoxazole, said compounds being represented by formula (I-d-1), in the presence of a suitable solvent such as, for example, acetic acid, at an elevated temperature, preferably at reflux temperature. It may be convenient to prepare compounds of formula (I-d-1) without isolating intermediates of formula (XX). Analogously, an intermediate of formula (XVIII) may be reacted with an intermediate of formula (XIX-b) to form an intermediate of formula (XXI) which is cyclised to a compound of formula (I) wherein --X--R.sup.2 is an optionally 3-substituted 1,2,4-oxadiazole, said compounds being represented by formula (I-d-2), in a reaction-inert solvent such as, for example, toluene, at an elevated temperature, preferably at reflux temperature. Also analogously, an intermediate of formula (XVI) may be reacted with an intermediate of formula (XIX-c) wherein Y is O, S or NR.sup.3, to form an intermediate of formula (XXII) which is cyclised to a compound of formula (I) wherein --X--R.sup.2 is an optionally substituted 1,2,4-triazole, 1,3,4-thiadiazole or 1,3,4-oxadiazole, said compounds being represented by formula (I-d-3), in a suitable solvent such as, for example, phosphorus oxychloride.

Also analogously, an intermediate of formula (XVIII) may be reacted with an intermediate of formula (XIX-d) wherein Y is O, S or NR.sup.3, to form an intermediate of formula (XXIII) which is cyclised to a compound of formula (I) wherein --X--R.sup.2 is an optionally amino substituted 1,2,4-triazole, 1,3,4-thiadiazole or 1,3,4-oxadiazole, said compounds being represented by formula (I-d4) in a reaction-inert solvent such as, for example, toluene, and in the presence of an acid; or, which is cyclised to a compound of formula (I) wherein --X--R.sup.2 is a disubstituted 1,3,4-triazole, said compounds being represented by formula (I-d-5).

The nitrile derivative of formula (XVI) may also be reacted with hydroxylamine hydrochloride or a functional derivative thereof, thus forming an intermediate of formula (XXIV) which may be reacted with an intermediate of formula (XXV) to form a compound of formula (I) wherein --X--R.sup.2 is an optionally 5-substituted 1,2,4-triazole, 1,2,4-thiadiazole or 1,2,4-oxadiazole, said compounds being represented by formula (I-d-6), in a reaction-inert solvent such as, for example, methanol, butanol or a mixture thereof, and in the presence of a base such as, for example, sodium methanolate.

Compounds of formula (I-d) wherein the heterocycle is substituted 2-thiazolyl, said compounds being represented by formula (I-d-7), can be prepared by reacting an intermediate of formula (XVI) with hydrogensulfide or a functional derivative thereof, in a reaction inert solvent such as, for example, pyridine, optionally in the presence of a suitable base such as, for example, triethylamine, thus forming an intermediate of formula (XXVI), which may subsequently be reacted with an intermediate of formula (XXVII) or a functional derivative thereof such as the ketal derivative thereof, in a reaction-inert solvent such as for example, ethanol, and optionally in the presence of an acid such as, for example, hydrogenchloride. ##STR19##

Compounds of formula (I-d) wherein the heterocycle is substituted 5-thiazolyl and R.sup.1 is hydrogen, said compounds being represented by formula (I-d-8), can be prepared following the reaction procedure depicted in scheme 4. ##STR20##

Initially, an intermediate of formula (XXVIII) wherein P is a protective group such as, for example, a C.sub.1-6 alkylcarbonyl group, is reacted with a thiazole derivative of formula (XXIX) in the presence of a suitable base such as, for example, butyl lithium, in a reaction inert solvent such as, for example, tetrahydrofuran, thus forming an intermediate of formula (XXX). It may be convenient to perform said reaction under an inert atmosphere at lower temperature, preferably at about -70.degree. C. The hydroxy group and the protective group P of said intermediates (XXX) may be removed using art-known procedures such as, for example, stannous chloride and hydrochloric acid in acetic acid, thus forming an intermediate of formula (XXXI), of which the amino group may further be converted to a 6-azauracil moiety according to the procedure described in EP-A-0,170,316, thus forming a compound of formula (I-d-8).

Also, compounds of formula (I-d) wherein the heterocycle is 4-thiazolyl, said compounds being represented by formula (I-d-9), can be prepared following the reaction procedure depicted in scheme 5. ##STR21##

An intermediate of formula (XVIII) is reacted with a Grignard reagent of formula RCH.sub.2 MgBr or a functional derivative thereof to form an intermediate of formula (XXXII), which may be halogenated, preferably brominated, in the a-position using a suitable reagent such as trimethylphenylammonium tribromide in tetrahydrofuran, thus forming an intermediate of formula (XXXII). Said intermediate (XXXI) may then be reacted with a thioamide of formula (XXXIV) to form a compound of formula (I-d9), in a reaction-inert solvent such as, for example, ethanol, at an elevated temperature, preferably reflux temperature.

The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation of which some examples are. mentioned hereinabove.

The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.

Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallisation or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallisation or chromatographic techniques, e.g. liquid chromatography and the like methods; a