According to the invention, there is provided a compound of formula A wherein either 1) ZisO; n is 0; T is a residue wherein R6 is H; C1 6alkyl optionally substituted in the terminal position by halogen, OH, NR7R8, COOH, CO-OC, 4alkyl or CO-NR7R8; Cl-6alkyl interrupted by one or more heteroatoms selected from N, O or S and substituted in the terminal position by halogen, OH, NR7R8, COOH, CO-OC1-4alkyl or CO- NR7R8; ORg; NHR10; cyano; or formyl; each of R7 and R8 independently is H, C1-4alkyl, #-HO-C1-4alkyl, CHO or heterocyclo-C,.alkyl or R7 and R8 form together with the nitrogen atom to which they are bound, a heterocyclic ring; Rg is Cl-6alkyl substituted in the terminal position by OH or NR 7R8; Rlo is C1-6alkyl substituted in the terminal position by OH or NR 7R8; and W is a residue wherein i) X is-CR1= wherein R, is H, F, CF3, C1. 4alkyl or NH2; and R2 is H, F, OH, Ci. koxy, CN, NO2, CF3 or NHCOC14alkyl; R3 is H, halogen, CN, NO2, CF3, NH2 or OH; R4 is H, halogen, CF3 or Cl-4alkoxy; and R5 is H, halogen, C1. 4alkoxy, C1 4alkylthio, CF3, NH2, C, 4alkyl or a heterocyclic group; or ii) X is-N=; and R3 is H, halogen, NH2, C1 4alkoxy, OH, NH2,-O (CH2) 3-NH2, piperidino or CF3 R4 is H, F, CF3, CN or N02; and each of R2 and R5 is H; or 2) Z is O or S; n is 0 or 1; T is a residue wherein RI, is H, CH3 or C2H5; R12 is H, halogen, C1-4alkyl or C3. 6cycloalkyl; Pis is H; halogen; hydroxy; C1-2alkoxy; phenyl-C 2alkoxy; or C1. 2alkyl substituted by NH2, NH(C1-5alkyl), NH-S02-C,. 2alkyl or NH-CO-C1alkoxy; Z is O or S; and one of R14, R15 and R16 is F, CF3, OCF3, CN, C2-4alkyl, di- (CI-2alkyl) amino or carbamoyl and the 2 other symbols are H; or one of R14, R15 and Rie's H and the 2 other symbols are each CF3; each of R14, R15 and R16 is H; or each of R14, R15 and R16 is halogen; the phenyl-amide or-thioamide group being attached to any one of the free C atoms of the indole ring; provided that, when R13 is H, at least one of R14, R, 5 and Pie is other than H, in free form or in salt form. d-eatkyi is preferably C, 4alkyl, particularly methyl or ethyl. Halogen is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. C, 4alkoxy is preferably methoxy or ethoxy or also t.-butoxy as e. g. in the group NH-CO-C, 4alkoxy. C,. 4alkylthio is preferably methylthio. In heterocyclo-C, 4alkyl, the heterocyclic moiety is preferably attached to the terminal position of the CI-4alkyl group.

By heterocyclic ring, group or moiety is meant e. g. a 5 or 6 membered saturated or unsaturated heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S, e. g. pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl, piperidyl, piperazinyl or morpholino.

Preferred are e. g. pyrrolidinyl, piperazinyl or morpholino.

Preferred compounds of formula A are compounds of formula I wherein X and R2 to R6 are as defined above.

When R6 is Ciaikyi, preferably either each of R3 and R4 is other than H or R3 is CF3.

A preferred group of compounds of formula I are those wherein R6 is H. Another group of compounds of formula I are those wherein R6 is other than H. Preferably at least one of R, to R5 is other than H when R6 is H.

R, is preferably H, CF3 or NH2 particularly H. R2 is preferably H, F, N02, CN, OCH3, OH or CF3. R3 is preferably H, F, Cl, Br, CN, NO2 or CF3. R4 is preferably H, OCH3 or CF3. R5 is preferably H, F, Br, NH2, OCH3, SCH3, CF3, morpholino or pyrrolidinyl.

In the compounds of formula 1, the following significances are further preferred: 1. X is-CCF3=, each of R2, R3 and R4 is H and R5 is CF3; 2. X is-CCF3= and each of R2 to R5 is H; 3. X is-CNH2=, each of R2, R4 and R5 is H and R3 is CF3; 4. X is-CH=, R2 is F, N02, CN, C, 4alkoxy, preferably methoxy, OH or CF3 and each of R3, R4 and R5 is H; 5. X is-CH=, R2 is CF3, R3 is CI, F, CN, or N02, and each of R4 and R5 is H; 6. X is-CH=, R2 is CF3, R4 is CF3 or C,. 4alkoxy, preferably methoxy, and each of R3 and R5 is H; 7. X is-CH=, R2 is CF3, R5 is NH2, CF3, C, 4alkoxy, preferably methoxy, Ci. 4alkylthio, preferably C1-4methylthio, Br, F or a 5 or 6 membered heterocyclic radical, preferably pyrrolidinyl or morpholino, and each of R3 and R4 is H; 8. X is-CH=, R2 is NHCOCH3, R3 is CF3 and each of R4 and R5 is H; 9. X is-N= and R3 is CF3; more preferably each of R2 to R4 is H; 10. R6 is- (CH2) i-4-OH or- ( (i-NRyRs; 11. R6 is -CH2-O-(CH2)1-4-OH, -CH2-O-(CH2)1-4-COOH, -CH2-O-(CH2)1-4-COOC1-4alkyl, -CH2-O-(CH2), 4-CONR7R8;(CH2), 4-CONR7R8 12. R6 is -CH2-NH-(CH2)1-4 NR7R8, -CH2-NH-(CH2)1-4OH, -(CH2)1-4-NH-(CH2)1-4-heterocyclic, -CH2-NH-(CH2)2-3-O-(CH2)2-3-OH or -CH2-NH-(CH2)2-3-O-(CH2)2-3-NR7R8; 13. In above definition of R6, preferably each of R7 and R8 independently is H, C, 4alkyl or #-HO-C1-4alkyl; 14. In above definition of R6, preferably R7 is H and R8 is CHO or heterocyclic-C,.alkyl; 15. X is-CH= or-N= and R6 is preferably as defined in 10 to 14 above. More preferably each of R2 and R5 is H.

Further preferred compounds of formula A are compounds of formula X wherein n, Z and Ril to R14 are as defined above.

When one of R, 1410 Rie is other than H, it may be in position ortho, meta or para, preferably para. When 2 of R 14 to R16 are other than H, they are preferably in positions meta.

In the compounds of formula X, the following significances are preferred: 1. n is O; 2. Rn is H; 3. R12 is H; 4. Z is O; 5. Pis is bromine, preferably in position 5, hydroxy, methoxy, benzyloxy, preferably in position 5, or butylaminomethyl, preferably in position 5; 6. R14 is CF3 or OCF3 preferably in position para and each of R 15 and Rie is H; 7. Each of R, 2, R13, R15 and R17 is H, and R14 is F, t.-butyl, OCF3 or CN, preferably in para, or CF3 in position ortho, meta para para 8. Each of R12, R13 and R16 is H and each of R 14and R15 is CF3, preferably in positions meta; 9. Each of R12 and R13 is H and each of R14, R15and R16 is F, preferably in ortho, meta and para; 10. Rn is CHs, each of Ri2, Ris and R16 is H, R13 is OCH3 or OH and R14 is CF3 or OCF3; 11. Each of Ril, R13, R15 and R16 is H, R12 is CH3, R14 is CF3, OCF3, N (CH3) 2, CN, t.-butyl or carbamoyl, preferably in position para, and X is O or S; 12. Each of R11, R13 and R16 is H, R12 is CH3 and each of R14and R15is CF3, preferably in positions meta; 13. Each of Rn, Ris, Ris and R16 is H, R12 is C2H5 and Ri4 is CF3or OCF3, preferably in position para; 14. Each of R, 1, R, 3, R15 and R, 6 is H, R, 2 is Cl and R, 4 is CF3 or OCF3, preferably in position para; 15. The phenyl-amide or-thioamide is in position 3 of the indole ring.

The Compounds of formula A may be produced by reacting a compound of formula 11 T-CO-ZH II wherein T and Z are as defined above, or a functional derivative thereof, with a compound of formula III W- (CH2)"NH2 II I wherein W and n are as defined above.

Suitable functional derivatives of a compound of formula 11 include e. g. a halogenide, e. g. a carbonyl chloride, anhydride, e. g. a mixed anhydride, or an activated ester. The amide coupling may be performed in analogy with known methods.

Compounds of formula I wherein R6 is other than H may be obtained by a) reacting a compound of formula IV wherein R'6 is as defined above for R 6 except that it is other than H and Y is a leaving group, e. g. Br, with a compound of formula V wherein R2 to R5 and X are as defined above; or b) oxidizing R"6 in a compound of formula VI wherein R2 to R5 and X are as defined above and R"6 is methyl, to formyl; or c) reducing the formyl group in a compound of formula Vil wherein R2 to R5 and X are as defined above to a corresponding hydroxy-alkyl group and, where required, further converting the resulting compound of formula I into another compound of formula I wherein R 6 is other than H.

Oxidation agents suitable for step b) are e. g. those usable for selective oxidation of a benzyl group, for example selenious acid. A reduction agent suitable for step c) is e. g.

NaBH4.

Compounds of formula I wherein R6 is a hydroxy-alkyl group, e. g.-CH2OH, as obtained in step c), may be converted by methods known in the art in compounds of formula I wherein R6 is e. g. ea-F-or-amino-alkyl. The Compounds of formula X wherein R 1 is H, may be produced by reacting a compound of formula XIII wherein R12 and R13 are as defined above with a compound of formula XIV wherein n, X, R14, R15 and R16 are as defined above.

The Compounds of formula X wherein Z is O, may be prepared by treating a compound of formula X wherein Z is S with a base, e. g. NaOH or KOH, preferably added in solid form.

Above processes may be performed in analogy with known methods.

Where required, the Compounds of formula A, e. g. the compounds of formula I or X, thus obtained in free form may be converted into salt form or vice versa.

The compounds of formula A may exist e. g. in free or salt form. Salts include acid addition salts with e. g. inorganic acids, organic acids or polymeric acids, for example hydrochloric acid, acetic acid, trifluoroacetic acid or, when free carboxy groups are present, also salts with bases, e. g. alkali metal salts such as a sodium or potassium or substituted or unsubstituted ammonium salts.

The following examples are illustrative of the invention. The following abbreviations are used: THF = tetrahydrofuran DMF = dimethylformamide EtOAc = ethyl acetate r. t. = room temperature Example 1: Quinoline-8-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide To a solution of 8-carboxyquinoline (1. 0g, 5.78mmol) in CH2CI2 containing 2-3 drops of DMF, is added dropwise oxalyl chloride (0.75moi, 8.7mmol). The resulting suspension is stirred for 1 h at r. t and then cooled to 0°C. At this temperature, a THF solution of 4-chloro- 3-trifluoromethyl-aniline (3.6g, 17. 32mmol) is slowly added and the reaction is stirred overnight. The reaction is then poured on a 1 N aqueous NaHS04 solution and extracted with ethyl acetate. The crude amide is purified by silica gel chromatography (eluent: EtOAc/hexane: 4/6) to afford the title compound. m. p. 146-148°.

By following above disclosed procedure but using the appropriate starting materials, the following compounds may be prepared: Ex R R2 RZ X mip. °C 2 H F H H H 103-105 3 H N02 H H H 178-181 4 H CN H H H 143-146 5 H OMe H H H 115-117 6 H OH H H H 178-180 7 H CF3 H H H 123-124 8 H CF3 Br H H 163-165 Ex R1 R2 R3 R4 R5 m.p. °C 9 H CF3 F H H 157-159 10 H CF3 CN H H 218-220 11 H CF3 N02 H H 190-192 12 H CF3 H H NH2 180-182 13 H H CF3 H NH2 205-207 14 H CF3 H H OMe 161-163 15 H CF3 H H SMe 117-118 16 H CF3 H H Br 165-167 17 H CF3 H H morpholino 189-191 18 H CF3 H H F 164-166 19 H CF3 H H pyrrolidinyl 138-139 20 H CF3 H CF3 H 190-191 21 H CF3 H OCH3 H 125-127 22 H CF3 H H CF3 141-142 23 H CF3 H H F 164-166 24 F CF3 H H H 148-150 25 H C F3 Cl H Br 165-167 26 H H CF3 H H 111-112 27 NH2 H H CF3 H 180-182 28 CF3 H H H H 128-130 Example 29: Quinoline-8-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide By repeating the procedure of Example 1 starting from 0.30 g quinoline-8-carboxylic acid activated with 0.23 mi oxalyl chloride and using 0.89 g 2-amino-5-trifluoromethyl-pyridine, the title compound is obtained. m. p. 170-172° C.

Example 30: 2-Methyl-quinoline-8-carboxylic acid (4-trifluoromethyl-phenyl)-amide a) To a solution of 2-methyl-quinoline-8-carboxylic acid (5.0 g, 26.7 mmol) in dry DMF, there is slowly added a 50% DMF solution of 5,2,4,6- trioxatriphosphorinan-2,4,6-trioxide (53.4 mmol). The resulting suspension is stirred for 45 min at r. t. and then pyridine (26.5 ml, 330 mmol) is slowly added. The solution is stirred for 30 min and a solution of 4-trifluoromethylaniline (5.5 ml, 33.4 mmol) in DMF is added. After stirring for 30 min a brown suspension occurs which is further stirred overnight. The reaction is quenched with water and the product extracted whith EtOAc. The organic phase is dried over MgSO4, filtered over active carbon and concentrated to yield the title compound which is recrystallized from EtOAc. m. p. 169- 170 °C. b) Above title compound may also be prepared as follows: To a cooled (-78°C) solution of 8-bromo-2-methyl-quinoline (1.0 g, 4.5 mmol) in diethyl ether containing N, N, N', N'-tetramethyl-ethylenediamine (2.0 ml, 13.5 mmol) is slowly added BuLi (3.12 mi of a 1.6M solution in hexan, 4.6 mmol). After stirring at this temperature for 30 min, 4-trifluoromethylphenylisocyanate (0.71 ml, 4.9 mmol) is added dropwise, then the cooling bath removed and the reaction allowed to reach r. t.

After addition of water and extraction of the product with EtOAc, the organic phase is dried over MgS04 and concentrated to yield the title compound.

Example 31: 2-Formyl-quinoline-8-carboxylic acid (4-trifluoromethyl-phenyl)-amide To a refluxing suspension of selenious acid (2.0 g, 14.5 mmol) in dioxane (200 ml), a solution of Example 30 (3.2 g, 9.7 mmol) is added dropwise. The reaction is refluxed overnight, allowed to cool and concentrated. The crude product is partitioned between NaHCO3 and EtOAc and the organic layer recovered, dried and concentrated to yield the crude aldehyde as a solid. Recrystallization from EtOAc affords the title compound. m. p.

193-195 °C.

Example 32: 2-Hydroxymethyl-quinoline-8-carboxylic acid (4-trifluoromethyl- phenyl)-amide Sodium borohydride (0.53 g, 13.51 mmol) is added in small portions at r. t. to a suspension of the compound of Ex. 31 (1.16 g, 3.37 mmol) in ethanol. After stirring for 3h, the reaction is quenched with water and extracted with EtOAc. The organic layer is recovered, washed with aqueous Na2SO4, dried over MgSO4 and concentrated to dryness. The crude alcohol is crystallized from diethyl ether to yield the title compound. m. p. 204-207 °C.

Example 33: 2-Chloromethyl-quinoline-8-carboxylic acid (4-trifluoromethyl-phenyl)- amide Thionyl chloride (1.4 ml) is slowly added to a suspension of Compound of Ex. 32 (1.1 g, 3.2. mmol) in toluene at 0°C. After 5 hours at this temperature the crude product is concentrated and filtered over a silica gel pad to afford the title compound in pure form. m. p. 161-166°C.

Example 34: 2-Diformylaminomethyl-quinoline-8-carboxylic acid (4-trifluoro- methyl-phenyl)-amide and 2-formylaminomethyl-quinoline-8- carboxylic acid (4-trifluoromethyl-phenyl)-amide To a suspension of sodium diformylamide (0.5 g, 5.3 mmol) in dry DMF is added a solution of Compound of Ex. 33 (0.9 g, 2.4 mmol) in DMF. The reaction mixture is stirred at r. t. overnight and then poured over water. The product is extracted with EtOAc, the organic layer collecte, dried and concentrated. Chromatographic purification over silica gel with hexane/AcOEt: 3/2 as eluent, affords the diformyl compoud (m. p. 202-203°C) and the monoformyl compoud (m. p. 221-222°C).

Example 35: 2-Aminomethyl-quinoline-8-carboxylic acid (4-trifluoromethyl- phenyl)-amide hydrochloride Stirring Compound of Ex. 34 (0.1 g, 0.26 mmol) in 2N HCI (12 ml) for 2 hours at r. t. followed by concentration of the solvent leads to the title compound. m. p. 180-184°C (free base).

Example 36: 2- (Hydroxyimino-methyl)-quinoline-8-carboxylic acid (4- trifluoromethyl-phenyl)-amide Compound of Ex. 31 (0.20 g, 0.58 mmol) is added to a solution of hydroxylamine hydrochloride (0.04 g, 0.58 mmol) in toluene containing pyridine (0.1 ml). After refluxing the reaction overnight, water is added and the crude product is extracted with EtOAc. The organic phase is collecte, dried and concentrated to yield the title compound. m. p. 221- 223 °C.

Example 37: 2-Cyano-quinoline-8-carboxylic acid (4-trifluoromethyl-phenyl)-amide 5 Drops of triethylamine followed by a solution of methyl cyanoformate (0.023 ml, 0.28 mmol) in acetonitrile are added to a suspension of the compound of Ex. 32 (0.10 g, 0.28 mmol) in acetonitrile. After stirring at r. t. for 2h, the solid formed is filtered and dried to give the title compound. m. p. 173-175°C.

Example 38: 2-Fluoromethyl-quinoline-8-carboxylic acid (4-trifluoromethyl-phenyl)- amide To a cold solution (-78°C) of diethylamino sulfur trifluoride (0.12 ml, 0.87 mmol) in CH2CI2 is added dropwise a solution of the compound of Ex. 32 (0.30g, 0.87 mmol) in CH2CI2. The temperature is allowed to reach-10°C and the reaction is quenched with water and extracted with EtOAc. The organic layer is recovered, dried and concentrated to yield the title compound. m. p. 169-171 °C.

Example 39: [8- (4-Chloro-3-trifluoromethyl-phenyl-carbamoyl) quinoline-2-yl]-acetic acid ethyl ester To a suspension of the compound of Ex. 47 (0.3 g, 0.8 mmol) in dry dichloroethane containing a catalytic amount of rhodium acetate, there is added dropwise at r. t. methyl diazoacetate (0.2 ml, 1.6 mmol). After stirring for 2 h, methyl diazoacetate (0.2 ml, 1.6 mmol) is again added dropwise and the reaction is further stirred for 1 h. Quenching with water followed by silica gel chromatography the crude reaction mixture with hexane/EtOAc : 4/1, affords the ethyl ester. m. p. 118-119 °C.

Example 40: [8- (4-Chloro-3-trifluoromethyl-phenylcarbamoyl) quinoline-2-yi]-acetic acid Lithium hydroxide (36 mg, 0.86 mmol) is added to a solution of the ester of Ex. 39 (0.2 g, 0.43 mmol) in a mixture of THF/water. After stirring for 2 h at r. t, 2N HCI is added and the product is extracted with EtOAc. The organic layer is dried and evaporated to afford the title compound which is recrystallized from EtOAc. m. p. 163-165 °C.

Example 41: 2- { [2- (2-Hydroxy-ethoxy)-ethylamino] methyl}-quinoline-8-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide To a suspension of compound of Ex. 46 (0,10 g, 0.3 mmol) in ethanol is added 2- (2- aminoethoxy)-ethanol and the reaction is stirred at r. t overnight. The precipitate is filtered, washed with diethyl ether and dried to afford the imine. The latter (100mg) is suspended in ethanol containing 1-2 drops of acetic acid and treated with sodium cyanoborohydride (36.3 mg, 0.6 mmol). After stirring for 2 h at r. t, the solution is concentrated, and the crude residue partitioned between water and EtOAc. The organic phase is dried and concentrated to give the title compound. m. p. 113-115 °C.

Example 42: 2- (3-Hydroxy-propyl)-quinoline-8-carboxylic acid (5-trifluoromethyl- pyridin-2-yl)-amide a) 3- [8- (5-Trifluoromethyl-pyridin-2-ylcarbamoyl)-quinoline-2-yi]-ac rylic acid ethyl ester To a solution of the compound of Example 46 (1.0 g, 3.0 mmol) and ethyl dimethylphosphonoacetate (0.51 mi, 3.1 mmol) in dry THF at 0°C, is added sodium hydride (60%, 0.026 g, 6.6 mmol) in small portions. The reaction is stirred for 2 h, carefully quenched with water and extracted with EtOAc. The organic phase is dried and concentrated to give a solid which, after recrystallization from EtOAc/Et20, affords the acrylic ester. m. p. 189-191 °C. b) 3- [8- (5-Trifluoromethyl-pyridin-2-ylcarbamoyl)-quinoline-2-yi]-pr opionic acid ethyl ester Triphenylphosphine cupper hydride (0,78g, 0.4 mmol) is added to an argon degassed suspension of the acrylate a) (0.55 g, 1.3 mmol) in toluene and the reaction is stirred at r. t overnight. Filtration followed by silica gel chromatography (hexane/EtOAc: 2/1) of the concentrated filtrate yields the proprionate. m. p. 149-151 °C. c) Calcium borohydride (0.051 g, mmol) is added to a solution of the propionate b) (0.1 g, 0.24 mmol) in dry THF and the reaction is stirred for 3 h at r. t. Then, sodium borohydride (0.051 g, mmol) is added again and stirring is continued for 2 h. The reaction is quenched with water and the product extracted with EtOAc.

Chromatography of the crude residue over silica gel using a hexane/EtOAc gradient (2/1 to 1/2) affords the title compound. m. p. 125-126 °C.

By following above disclosed procedure but using the appropriate starting materials, the following compounds may be prepared: wherein X and R3, R4 and R6 are as defined in table 2 below.

Table 2 Ex I X R3 | R4 mFp. °C 43 CH CI CF3 CH3 155-157 44 N CF3 H CH3 152 - 154 45 CH Cl CF3 CHO 245-247 46 N CF3 H CHO 175-176 47 CH Cl CF3 CH2OH 191-192 48 N CF3 H CH2OH 178-180 49 CH CF3 CH2NHCHO 196-198 50 CH CF3 CH2NH2 268-269 51 N CF3 H CH2F 141-143 Ex X-m. p. °C 52 CH CF3 CH2F 1 78-1 83 53 N CF3 H CN 210-211 54 CF3 CHrNH-CH2CH20H 1 72-1 74 Example 55: 2- [ (4-Amino-butylamino)-methyll-quinoline-8-carboxylic acid (5-trifluoromethyl-pyridin-2-yl-amide To solution of (4-{[8-(5-Trifluoromethyl-pyridin-2-ylcarbamoyl)-quinoline-2 -yl-methyl]-amino}- butyl)-carbamic acid tert.-butyl ester (0.24g, 0.46 mmol), obtained from reacting the compound of Ex. 46 with mono-Boc-diaminobutane according to the procedure of Ex. 41, in 10mol AcOEt is added dropwise at r. t tintetrachloride (0.33ml, 2.8mmol) and the mixture is stirred for 3 h. The reaction is quenched with sat. NaHCO 3 and the resulting precipitate is filtered. It is first dissolved in 2N HCI and then the solution is made basic with 2N NaOH and extracted with AcOEt. After drying and evaporation of the solvent, the crude solid is purified by recrystallization (AcOEt/Et20) to afford the title compound. mp. 145-150 C Example 56: 2-Methyl-1 H-indole-3-carboxylic (4-trifluoromethyl-phenyl)-thioamide 2-Methylindole (1.16g, 10mmol) and 4-trifluoromethylisothiocyanate (1.9g, 10mmol) are kept at 90°C for 48 hours (no solvent). After cooling to room temperature the reaction mixture is purified on silica gel (mobile phase: toluene/ethyl acetate 9/1) to give the title compound. m. p. 185-185°C Example 57: 2-Methyl-1H-indole-3-carboxylic acid (4-trifluoromethyl-phenyl) amide To a solution of 2-methyl-1H-indole-3-carboxylic acid (4-trifluoromethyl-phenyl)-thioamide (335mg, 1mmol) in 11ml ethanol/water (10/1) is added 1.5ml H202 (35%) and solid KOH (0.2g). After 30 min. at room temperature, the title compound is precipitated by addition of 200 ml of water. Recristallisation from ethanol/water (2/1) gives pure and homogeneous title compound. m. p. 202-203°C By following above disclosed procedure but using the appropriate starting materials, the compounds of formula Z wherein Ra, Rb, R and A are as defined in following Table 3, may be obtained.

Table 3 Ex R A Ra Rb Position m.p.°C in ndole Ring 58 p-OCF3 O CH3 190-191 59 p-N (CH3) 2 O CH3 H 3 235-238 60 p-CN O CH3 H 3 232-233 61 p-CO-NH2 O CH3 H 3 250-255 62 p-OCF3 S CH3 H 3 176-177 63 p-N(CH3)2 S CH3 H 3 241-242 64 p-CN S CH3 234-235 65 p-tert.butyl O CH3 H 3 208-209 66 p-tert. butyl S CH3 H 3 215-216 67 o-CF3 O CH3 H 3 165-166 68 m-CF3 O CH3 H 3 166-167 69 m, m-di-CF3 O CH3 190-191 70 p-CF3 O 220-221 71 p-CF3 O ethyl 145-146 72 p-CF3 O cyclopropyl H 3 167-169 73 p-CF3 O CH3 5-CHrNHSO2CH3 273-274 74 p-CF3 O CH3 5-CH2-NHBoc 3 230-231 75 p-CF3 O CH3 5-CH2-NH2 196-198 Example R A Ra Rb Position Mp.(°C) in ndole Ring 76 p-CF3 O CH3 5-oCO-N (C2Hsk amorphous 77 p-CF3 O CH3 5-OH 3 amorphous 78 p-CF3 O CH3 5-OMe 198-200 79 p-F 0 H H 2 223-225 80p-CFa0"HH ! 464-70 81 p-CF3 O H H 5 225-227 82 p-OCF3 O H 198-200 Example 83: 1 H-indole-3-carboxylic acid (4-trifluoromethyl-phenyl)-amide A solution of indole-3-carboxylic acid (322mg, 2mmol) and carbonyidiimidazole (322mg, 2mmol) in dimethylformamide is kept at room temperature for 1 hour. Then 4- trifluoromethylaniline (750µl, 6mmol) is added and the reaction mixture is heated up to 120°C for 18 hours. After removal of the solvent under reduced pressure the crude title compound is purified on a silica gel column {eluant: toluene----> toluene/ethyl acetate (9/1)} to afford the title compound. m. p. 227-228°C.

By following above disclosed procedure but using the appropriate starting materials, the compounds of formula Z wherein A is O, Ra is H and R and Rb are as defined in the Table 4 below may be obtained.

Table 4 Ex Rb m. p. °C 84 p-F H 208-210 85 o-CF3 H 200-202 86 m, m-di-CF3 H 208-209 87 o, m, p-tri-F H 208-209 88 p-tert. butyl H 201-203 89 p-OCF3 H 222-223 90 p-CN H 241-246 91 m-CF3 186-187 Ex R Rb m. p. °C 92 p-CF3 5-Br 250-256 93 p-OCF3 7-OMe 203-207 94 p-OCF3 5-OBzl 196-199 95 p-OCF3 7-OH 241-244 96 p-CF3 7-OH 222-224 97 p-CF3 5-OH 243-244 98 p-OCF3 5-OH 219-224 99 p-CF3 5-OMe 210-213 100 p-CF3 4-OMe 257-258 101 p-CF3 5-CH2-NH-153-155 (CH2) 3CH3 1 02 p-CF3 7-OMe 232-236 103 p-CF3 5-OBzl 199-205 By repeating above disclosed procedure but using the appropriate starting materials, following compounds may be obtained R, Ra and Rb being as defined in Table 5 below.

Table 5 Ex Ra Rb m. p. °C 104 OCF3 H OCH3 155-157 105 OCF3 H OH 223-228 106 CF3 H OCH3 166-167 107 CF3 OH 166-167 108 CF3 CH3 H 189-190 Example 109: 2-Methyl-1H-indole-3-carboxylic acid (4-t.-butyl-benzyl) amide By repeating the procedure of Ex. 57 but using the appropriate starting materials, the title compound may be obtained. m. p. 102-115°C (foam) The compounds of formula A in free form or in the form of a pharmaceutically acceptable salt exhibit valable pharmacological properties as indicated in following tests and are therefore indicated for therapy. In particular, it has been found that they are capable of inhibiting B cell activation without blocking the dihydroorotate dehydrogenase (DHODH) activity and are useful to prevent or reduce antibody mediated immune responses.

A. In vitro inhibition assav of murine T can-independent B cell taM antibodv production to TNP-LPS antiaen (TNP-LPS= trinitrophenyl-lipopolysaccharide) Spleen cells from C57BI/6 nu/nu and C57BU6 (BRL, Switzerland) are removed aseptically and transferred into a petri dish (Falcon) containing 10 ml HBSS. Single spleen cell suspension is prepared by teasing the cells from the capsule with a spatula. Clumps of cells are further dispersed by pipetting up and down with a 10 ml pipette. Suspension is transferred to a 14 ml polypropylene tube (Becton Dickinson) and allowed to settle for 2-3 min. The cell suspension is decanted into another tube and centrifuged at 300 x g for 10 min at 4°C. Cells are washed twice in HBSS (Gibco). Cells are resuspended in IMDM+ATL (Iscove's Modified Dulbecco's Medium supplemented with Albumin, Transferin and Lipids) (M. Schreier et al. Long-term culture and cloning of specific Helper T cells. Immunological Methods, Vol. ll, 263-275, Academic Press, 1981) + 10 % FCS. Viable cells are directly counted in the spleen cell preparation using the fluorescein diacetate method (LB. Rotman et al, PNAS, 55,134-142,1966). A solution of 5 mg/ml fluorescein diacetate in acetone is kept at-20°C. A 1: 100 dilution of this stock solution in buffered saline (Gibco) is prepared fresh daily and kept on ice. It is mixed with the cell suspension at a 1: 10 dilution. After 1-5 min at room temperature brightly fluorescing viable cells are counted in Neubauer chamber under a fluorescent light microscope using appropriate excitation and barrier filters. Cells are adjusted to 2x107/ml. Cultures are set up in duplicate in flat bottomed microtiter plates (Costar). The cells are further diluted to 2x106 with culture medium.

2x10 cells per well are added to appropriate serial dilutions of samples in IMDM-ATL + 10% FCS (final volume 0.2 ml) in the presence of optimal concentration of TNP-LPS antigen (T-6769; ratio of 16 Rg TNP/mg LPS; Sigma). The stimulated spleen cells are cultured for 4 days at 37°C in a humidified CO2 incubator (5.5%). On day 4, microtiter plates are centrifuged at 300 x g for 10 min, and supematant from each of the two replicate cultures are pooled and diluted 4 fold in PBS/BSA and then assayed in an ELISA.

Elisa plates MaxisorpR (Nunc Corp.) are coated with BSA-DNP, 31ug/ml diluted in PBS by overnight incubation at 4°C. After removal of BSA-DNP solution residual protein-binding sites are blocked with 2% BSA in PBS (2 hours, 37°C). Plates are washed three times with PBS containing 0.05% Tween@ 20 and 0.02% NaNg (SLT 96 PW washer). This washing procedure is applied between each step. Serial dilutions of the supernatants in 2% BSA- PBS are incubated overnight at 4°C. Bound IgM Abs is revealed using biotin-labelled affinity-purified goat anti-mouse IgM antibody (1: 15000; 2 hours at 37°C) and subsequently, streptavidin conjugated to alkaline phosphatase (1: 10000 for 1 hour at 37°C). Enzyme activity is determined after addition of substrate p-nitrophenyl phosphate (1 mg/ml) in 1 M diethanolamine, pH 9.8, by measuring the absorbency at 405/490nm with a Spectra Maux) reader (Molecular Devices) usually after 30-45 min incubation at room temperature.

Absorbance values obtained in the absence of stimulus are used as low control, absorbency values obtained in the presence of the stimulus are taken as high control. % inhibition of the signal by the samples is calculated as follows: Inhibition'J = ( (high-low)- (sample-low) Jl (high-low) x 100.

The concentration required for 50% inhibition (IC50 values) are determined using a four parameter logistic function within the curve fitting application of the commercial software package ORIGINE (Micro Calc Software Inc.). In this assay, for example compounds of formula A, e. g. the compounds of formula 1, inhibit the B cell IgM antibody production with an IC50 of from 0.1 to 10RM. For example, the compounds of Examples 56 and 83 have an IC50 of 34,0.4 and 2.4, respectively.

B. In vitro Inhibition assav of human DHODH activitv Enzyme activity of E. coli overexpressed human DHODH is measured spectrophotometrically at room temperature by following the reduction of the dye 2,6- dichlorophenolindophenol (DCIP). The enzyme preparation (5111/ml medium) is added to the assay buffer consisting of 100 mM Tris-HCI, pH 7.7,0.1% (w/v) Triton X-100,75 RM DCIP and 100 RM ubiquinone-50. The reaction is started by addition of dihydroorate (0.5 mM) and followed for 5 min at 600 nm (spectrophotometer on microtiter plate reader) in the presence or absence of the test compound. % inhibition is calculated for each different concentration of the test compound and the IC50 (50% inhibition) determined graphically. A compound does not inhibit human DHODH activity when its ICso in this assay is > 50 I1M. For example, the compounds of formula I have an IC so > 50 RM in this assay.

C. Inhibition of T-independent antibody production TNP-LPS is diluted in pyrogen-free water (2mg/ml). For immunization it is diluted in PBS, Gibco, adjusted to 150pg/ml and injected i. v. to OF1 females (20g) from BRL, Switzerland (0.2ml/mouse or 30pg TNP-LPS/mouse). Serum is collected before and on day 6 after immunization. The compound to be tested is administered in a suitable solvent per os or s. c. The volume administered is 0.2mU20g mouse (10 ml/kg body weight). Administration is started on the day of antigen injection and continued for 3 days (4 applications in total).

The ELISA detection of TNP-specific Abs is performed as disclosed above, with the following modification: after enzyme activity determination as disclosed above, the reaction is stopped with 1.5 M NaOH. Absorbance is measured at 405/490nm with a Spectra Maux@ reader (Molecular Devices). Serum titers are defined as the reciprocal value of the highest serum dilution showing an optical density of 0.1, equivalent to twice the background. In this assay, the B cell inhibitors of the invention inhibit T-independent antibody formation significantly, e. g. the compounds of Examples 1,26 and 29 induce a 90% inhibition of the antibody formation at 30 mg/kg s. c.

D. Xenotransplantation The heart of a Syrian hamster is heterotopically transplanted in the abdomen of a congenitally athymic nude (nu/nu) C57BI/6 mouse, with anastomoses between the donor and recipient aorta and between the donor right pulmonary artery and the recipient's inferior vena cava. The test compound is dissolve in DMSO/CsA iv Infusion Placebo 2: 3 and applied sc. or i. p. minipump (a catheter extension from the pump is introduced for i. p. application). The graft is monitored daily by palpation of the abdomen. Rejection is concluded with cessation of heart beat. In the present series of experiments, the endpoint is set to 28 days. Animals are terminated and the transplant is subjected to conventional histology.

Athymic mice lack a functionally T-cell system and hence only can reject a xenograft by a T- cell independent (antibody) response (and cannot mount a T cell-dependent anti-xenograft antibody response). Both euthymic and athymic mice reject a hamster xenograft in an antibody-mediated fashion 4-6 days after transplantation (with histology of vessel damage and some thrombosis, myocyte dilatation, extravasation of erythrocytes, influx of polymorphonuclear granulocytes): if this rejection is adequately prevented, euthymic animals can develop a cellular rejection of the xenograft later on.

I. p. administration by minipump of 5-50 mg/kg/day of a B-cell inhibitor, results in prolonge xenograft survival in this assay. For example, compound of Example 1 protects the hamster xenograft from humoral rejection in these nude mice when administered at 10 mg/kg/day.

The compounds of formula A, preferably the compounds of formula 1, are accordingly useful as B-cell inhibitors, preferably as B-cell inhibitors not blocking the DHODH activity, e. g. in allo-or xeno-transplantation, e. g. for preventing development of, delaying onset of, delaying progression of, attenuating severity of, suppressing, mitigating or treating of graft rejection, e. g. antibody mediated xenograft rejection, e. g. heart, lung, combined heart-lung, liver, pancreatic (e. g. Islet cells), skin, bowel, trachea, oesophagus, corneal transplants or other (parts of) organs, tissue or cell preparations, in the prevention of graft-versus host diseases, such as following bone marrow transplantation, in the treatment or prevention of transplant vasculopathies, e. g. atherosclerosis or chronic rejection, or for preventing development of, delaying onset of, delaying progression of, attenuating severity of, suppressing, mitigating or treating an autoimmune disorder or disease, e. g. autoimmune hematological disorders, systemic lupus erythematosus, myasthenia gravis.

For the above uses the appropriate dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of from about 1 to 100 mg/kg animal body weight preferably of from 1 to 50 mg/kg. Suitable daily dosage rates for larger mammals, for example humans, are of the order of from about 10 mg to 3 g/day, conveniently administered once, in divided dosages 2 to 4x/day, or in sustained release form.

The compounds of formula A may be administered in free form or in pharmaceutically acceptable salt form. Such salts may be prepared in conventional manner and ex hibit the same order of activity as the free compounds. The compounds of formula A may be administered by any conventional route, for example enterally, e. g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally e. g. in form of inject able solutions or suspensions, pulmonary, e. g. by inhalation, or in a nasal or suppository form.

Pharmaceutical compositions comprising the compounds of formula A may be manufactured in conventional manner.

The replacement of dysfunctional tissue and organs, has over the last four decades become a common place therapy in clinical management of late state failure of tissues and organs, particularly kidney and heart. Organ allotransplantation has undergone significant development with modern immunosuppressants and the demand for organ transplantation has increased rapidly. Because of the current shortage of human donors for transplantable allografts, attention has focused on the possibility of using xenografts (transplants between species) in transplantation. The formation of T cell independent antibodies is a major obstacle in organ xenotransplantation and is also leading to graft vessel disease.

Based on above results, it has been shown that a compound having B-cell inhibitory properties without inhibiting the DHODH activity, i. e. without blocking the de novo pyrimidine biosynthesis, is useful to prevent or reduce antibody immune responses, e. g. to prevent, inhibit or reverse acute xenograft rejection, e. g. at least to attenuate antibody mediated xenograft rejection, to prevent or treat chronic allo-or xenograft rejection or autoimmune diseases, or to prevent graft versus host diseases. Such a compound which 1) inhibits in vitro murine T cell-independent B cell IgM antibody production to TNP-LPS <BR> <BR> <BR> antigen (assay disclosed hereinabove) at an IC 50 value of from 0.01 to 40 ; n. M; and<BR> <BR> <BR> <BR> <BR> 2) does not inhibit human DHODH activity, i. e. it has an IC so> 50 RM in the inhibition assay of human DHOH as disclosed hereinabove, is part of the present invention as well as its uses, e. g. in the field of transplantation and autoimmune diseases, e. g. as disclosed above. Such a compound is referred to herein as a non DHODH blocking B-cell inhibitor.

Examples of such compounds are non DHODH blocking B-cell inhibitory quinoline amides, <BR> <BR> <BR> e. g. compounds of formula 1, and non DHODH blocking B-cell inhibitory indole amides, e. g. compounds of formula X. The non DHODH blocking B-cell inhibitors of the invention may be used at a dosage as disclosed above for the compounds of formula A. They may also be administered by any conventional route, e. g. as disclosed above for the compounds of formula A.

In accordance with the foregoing the present invention further provides: a) A compound exhibiting an IC50 value of from 0.01 to 40 RM in an in vitro murine T cell- independent IgM antibody production assay, e. g. as disclosed above, and an IC50 > 50 M in an in vitro inhibition assay of human DHODH activ, e. g. as disclosed above, for use as a non DHODH blocking B-cell inhibitor; b) Use of a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X, in free form or in pharmaceutically acceptable salt form, to prevent or reduce antibody mediated responses; or <BR> <BR> <BR> <BR> c) Use of a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X, in free form or in pharmaceutically acceptable salt form, to prevent development of, delay onset of, delay progression of, attenuate severity of, suppress, mitigate or treat graft rejection, e. g. antibody mediated xenograft rejection, to prevent graft-versus host diseases, such as following bone marrow transplantation, or treat or prevent transplant vasculopathies, e. g. atherosclerosis or chronic rejection; or d) Use of a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X, in free form or in pharmaceutically acceptable salt form, to prevent development of, delay onset of, delay progression of, attenuate severity of, suppress, mitigate or treat an autoimmune disorder or disease; e) A method for inhibiting B-cell antigen responses in a subject in need of such a treatment, e. g. in a cell, tissue or organ allo-or xeno-transplant recipient or in a subject with auto-immune disorders or diseases, which method comprises administering to said recipient or subject an effective amount of a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X, in free form or in pharmaceutically acceptable salt form; or f) A method for preventing development of, delaying onset of, delaying progression of, attenuating severity of, suppressing, mitigating or treating graft rejection, e. g. antibody mediated xenograft rejection, for prevening graft-versus host diseases, or for treating or prevening transplant vasculopathies, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X, in free form or pharmaceutically acceptable salt form; or g) A method for preventing development of, delaying onset of, delaying progression of, attenuating severity of, suppressing, mitigating or treating autoimmune disorders or diseases in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X, in free form or pharmaceutically acceptable salt form; or h) A compound having non DHODH blocking and B-cell inhibiting activity as defined, a compound of formula I or X in free form or in pharmaceutically acceptable salt form for use in the preparation of a pharmaceutical composition for use in the methods as defined under e), f) or g) above; or i) A pharmaceutical composition for use in the methods as defined under e), f) or g) above, comprising a non DHODH blocking B-cell inhibitor as defined, e. g. a compound of formula I or X in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable diluent or carrier.

The non DHODH blocking B cell inhibitors, e. g. a compound of formula I or X in free form or in pharmaceutically acceptable salt form, may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or anti-inflammatory agents.

For example, the non DHODH blocking B cell inhibitors may be used in combination with a macrolide, e. g. cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e. g. cyclosporin A, cyclosporin G, [DSer-OC2H4OH] 8CyA, FK-506, rapamycin, 40- 0- (2-hydroxy) ethyl-rapamycin, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; brequinar; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine; immuno-suppressive monoclonal antibodies, e. g., monoclonal antibodies to leukocyte receptors, e. g., to MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45, or CD58 or to their ligands; or other immunomodulatory compounds, e. g.

CTLA4-lg.

Where the non DHODH blocking B cell inhibitors are administered in conjunction with other immunosuppressiveAmmunomodulatory therapy, e. g. for preventing or treating xenograft rejection as hereinabove specified, dosages of the co-administered immunosuppressant or immuno-modulatory compound will of course vary depending on the type of co-drug employed, e. g. whether it is a steroid or a cyclosporin, on the specific drug employed, on the condition being treated, and so forth. In accordance with the foregoing the present invention provides in a yet further aspect: j) A method as defined above comprising co-administration, e. g. concomitantly or in sequence, of a therapeutically effective amount of a non DHODH blocking B cell inhibitor and a second drug substance (s), said second drug substance (s) being an immunosuppressant or immunomodulatory drug, e. g. as set forth above, or a combination thereof. k) A kit or package for use in any method as defined under e), ef or g) above, comprising a non DHODH blocking B cell inhibitor, e. g. a compound of formula I or X in free form or in pharmaceutically acceptable salt form, with at least one pharmaceutical composition comprising an immunosuppressant or immunomodulatory drug. The kit or package may comprise instructions for its administration.