IE50099B1 - Acetic acid derivatives - Google Patents

Description

The invention relates to novel a-phenyl-2-(aza) benzothiazolylthioglycolic acids and a process for their preparation. The compounds are useful as chemical intermediates for the preparation of 2-phenylthiazolo5 [2,3-bJbenzo(and azobenzo)thiazole derivatives useful as pharmaceuticals, particularly for use as modulators of the immune response. a-Phenyl-2-benzothiazolylthioglycolic acid is disclosed in J. Org. Chem., 43, 2697-2700 (1976), The compound uas prepared by reacting 2-mercaptobenzothiazole uith α-bromophenylacetic acid in the presence of triethylamine. The product uas cyclized uith acetic anhydride in the presence of triethylamine according to the equation: (fl) (B) The cyclization product (B) uas subjected to various reactions uhereby several neu compounds uere made. Houever, no usb for these ηθυ compounds uas given.

Thus the reference envisages no technical use for a-phenyl-2-benzothiazolylthioglycolic acid (A) and its cyclization product (B).

The invention is based upon the finding that novel derivatives of a-phenyl-2-benzothiazolylthioglycolic acid are useful as chemical intermediates for the preparation of novel 2-phenylthiazolo[2,3-b]benzo (and azabenzo) thiazole derivatives useful as agents for modulating tne immune response in uarm blooded animals.

The invention provides novel compounds having the formula (I) uherein A is hydrogen, halo, amino, amino protected uith a removable protecting group, louer alkyl, Ioubt alkoxy, trifluoromethyl, hydroxy or hydroxy protected by a removable protecting group; B is phenyl or substituted phenyl, for instance, phenyl substituted by one or more substituents selected from fluorine, chlorine, bromine, louer alkyl, louer alkoxy, amino, amino protected by a removable protecting group, nitro and trifluoromethyl; X is CH or N and the dotted lines represent optional double bonds in thB 4,5 and 6, 7 positions subject to the proviso that uhen the group having the formula A (XI) is ortho-phenylene then B is other than phenyl.

The 2-phenylthiazolo[2,3-JaJbenzo(and azabenzo) thiazole derivatives obtainable as end compounds from the compounds of the invention have the formula III or IV: 50098 wherein R^ is hydrogen, halo, amino, lower alkyl, lower alkoxy, trifluoromethyl or hydroxy; R2 is phenyl or substituted phenyl, for instance, phenyl substituted by one or more substituents selected from fluorine, chlorine, bromine, lower alkyl, lower alkoxy, amino, nitro and trifluoromethyl; is hydrogen or lower alkanoyl; X is CH or N; Y is a pharmaceutically acceptable anion, for instance, trifluoroacetate or a halide; the dotted lines represent optional double bonds in the 5,6 and 7,8 positions; subject to the proviso that where the group having the formula is ortho-phenylene, then R2 is other than phenyl.

A first subgenus of these compounds consists in those having formula III or IU, wherein R2 is phenyl or phenyl substituted with a substituent selected from fluorine, chlorine, bromine, lower alkyl, lower alkoxy, amino, nitro and trifluoromethyl; and Y is CF^COgΘ or halide. 099 fl second subgsnus of these compounds consists in those having formula III or IV, uharein is hydrogen and Y is CFgCO.? ®or halide.

R,j is preferably hydrogen, halo or ΙουβΓ alkoxy, R2 is preferably phenyl or halophenyl , Rj is preferably hydrogen or acetyl. Y is preferably CF^COj θor halide.

The term lower alkyl uhen used herein includes straight and branched chain hydrocarbon radicals having from 1 to 6 carbon atoms. The terms louer alkoxy and lower alkanoyl in like manner designate radicals in which the hydrocarbon portion has 1 to about 6 carbon atoms.

The terms halo and halide uhen used herein refer to radicals of the elements fluorine, chlorine and bromine and chlorine and bromine respectively.

The compounds having formula I can be prepared in known manner. In particular a compound having the formula V (wherein A, X and thB dotted lines are as defined above) is reacted uith a compound having the formula Hal-CHB-COOH (VI) (in uhich Hal ia chlorine or bromine and B is as defined above). If the reaction is carried out in the presence of a condensing agent, for instance, acetic anhydride or trifluoroacetic anhydride, a 2phenylthia2olo[2,3-bJbenzo (or azabenzo)thiazole derivative may be formed. Accordingly the use of a condensing agent should be avoided for the preparation of the compounds having formula I.

The 2-phenylthiazolo[2,3-bJbenzo(and azabenzo) thiazole derivatives may be prepared by a process comprising (a) cyclizing a compound having the formula 50089 S-CHR2*-C00H (UI) (wherein X and the dotted lines are as defined above and R * and R2* are the same as R^ and Rg respectively save that, where necessary or desired, an amino or hydroxy group may be protected with a removable protecting group) and, if desired, (b) a compound having the formula © (VII) (wherein R^*, R2*, Rg, X, and the dotted lines are as 10 defined above and Y is an anion) is subjected to (i) deacylation and removal of the acid HY, if Rg is lower alkanoyl, or (ii) removal of thB acid HY, if Rg is hydrogen; or (c) a compound having the formula Θ (VII) (wherein R^*, Rg*, X and the dotted lines are as defined above, Y is a pharmaceutically acceptable anion and Rg is lower alkanoyl) is subjected to deacylation to form a compound where Rg is hydrogen; and, where necessary, a removable protecting group is removed. 50089 The product obtained by the cyclization steps depends upon the reactants used and the reaction conditions. Uhere the reactants used do not serve to provide a suitable anion Y or uhere the cyclization is carried out with a base such as triethylamine thB cyclization product is in the form of a mesoionic didehydro derivative. Uhere a salt of formula III is prepared, the anion Y is preferably provided by one of the reactants used, for example, use of trifluoroacetic anhydride as condensing agent may give a trifluoroacetate salt. Uhere the cyclization product is in the form of a salt, it may exist in the form of a 3-hydroxy compound, or in the form in uhich Rg is in the residue of the condensing agent.

In those instances uhere is amino or hydroxy, or Rg contains amino or hydroxy, the groups can be protected from acylation during the cyclization reaction by use of conventional protecting groups, for example, tosyl, benzyloxycarbonyl, tert-butyloxycarbonyl and the like for the amino group and acetyl, benzoyl, tertbutyl, benzyl and the like for thB hydroxy group. The protecting groups can be readily removed by conventional techniques after cyclization is complete.

The cyclization step uses a condensing agent. As condensing agents there may be used acetic anhydride, uhich may be in admixture uith acetic acid, or trifluoroacetic anhydride and the like. The cyclization may be carried out by heating the reactants in an organic solvent such as, for example, acetone.

Uhere a salt is formed uhere Rg is louer alkanoyl residue from the condensing agent and it is desired to obtain the product uhere Rg is hydrogen in accoranoe uith stBp (c), the condensing agent residue can readily be removed by conventional means, as for example deacylation by heating in certain solvents. - 8 The transformation of step (b) can be carried out by dissolving the salt in a methylene chloride/uater mixture, separating the organic and aqueous layers and concentrating the organic (methylene chloride) layer to recover the mesoionic didehydro derivative, uhich can then be further purified by reerystallization.

Although it is recommended to avoid undBsired acylation by protecting an amino or hydroxy group for the cyclization steps, the presence of a removable protecting group in the compounds of formula VII for steps (b) and (c) is optional.

The preparation and use of the compounds of the invention is preferably carried out as follows. A mercapto compound (VIII) is reacted uith a suitably substituted α-haloacetic acid (IX) in the absence of a condensing agent to prepare a suitably substituted 2-benzothiazolylthioglycolic acid (X) and cyclization of the product (X) is carried out in a subsequent step: (III) - 9 In those instances where is amino or hydroxy, the latter groups can be protected from acylation during the cyclization reaction by use of conventional protecting groups.

The compounds of formulae III and IU are immunomodulators of high selectivity, having particular activity on the cell-mediated immune system without impeding the humoral immune mechanisms. The compounds of formulae III and IU have therapeutic application in a variety of situations in which immunomodulation is indicated. Thus, the compounds of formulae III and IU permit the host to accept the graft without destroying the host's immunity to other infections. The compounds of formulae III and IU arB also useful in the treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE). Further, the compounds of formulae III and IU inhibit the production of the immunoglobulins, which arB so pathologic to autoimmune disease such as SLE, as wall as the production of antigen-antibody complexes which are the causative agents of renal and inflammatory processes in arthritis and auto-immune diseases. Thus, the oompounds of formulae III and IU are also useful in the treatment of such conditions as rheumatoid arthritis.

The thiazolo[2,3-bjbenzo(and azabenzo)thiazole derivatives having formulae III and IU are described and claimed in our copending Application No. 5003? Further particulars such as the pharmacological evaluation of such compounds, dosages and pharmaceutical compositions are also described in thB aforesaid application.

The following Example illustrates the invention: 50093 - 10 EXAMPLE 2-Phenylthiazolo[2',3'-2,3]thiazolo[5,4-bj-pyridin-3(2H) -one mesoionic didehydro derivative A. 6.5g (0.03 moles) α-bromophenylacetic acid and 6.2 g. (0.03 moles) potassium salt of 2-mercaptothiazolo[5,4-bJpyridine are suspended in 200 ml. acetone and the mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate concentrated to dryness.

The resulting compound is an oil and is not isolated.

B. 3-Hydroxy-2-phenylthiazolo[2’,3'-2,3]thiazolo[5,4-_b]pyridinium trifluoroacetate The compound of A above is dissolved in ether and 20 ml. of trifluoroacetic anhydride is added to the solution. The solid which forms immediately is collected, washed with ether and dried. The product weighs 9.7 g.

C. 2-Phenylthiazolo[2',3'-2,3jthiazolo[5,4-b]pyridin3(2H.)-one mesoionic didehydro derivative 8.5 g. of the compound of B above is suspended in a 20 mixture of 200 ml. methylene chloride and 150 ml. water and the mixture is stirred at room temperature for 30 minutes. The orange solid is collected and dried at 100° in vacuo. The compound weighing 5.0 g (80% yield) at 216-21B°C. (dec.) Analysis for: ®η4^θ^2θ32 Calculated: C, 59.13; H, 2.83; N, 9.85; S, 22.55 C, 59.06; H, 2.90; N, 9.79; S, 22.14

Claims (6)

1. A compound having the formula uherein A is hydrogen, halo, amino, amino protected 5 by a removable protecting group, Ioubt alkyl, lower alkoxy, trifluoromethyl, hydroxy or hydroxy protected by a removable protecting group; B is phenyl or substituted phenyl; X is CH or N and the dotted lines represent optional double bonds in the 4,5 and 6,7 10 positions subject to the proviso that when the group having the formula is ortho-phenylene then B is other than phenyl. A compound having the formula ,S ^S-CHCOOH (X) 50098 wherein is hydrogen, halo, amino, lower alkyl, louer alkoxy, trifluoromethyl or hydroxy and Rg is phenyl or phenyl substituted with a substituent selected from fluorine, chlorine, bromine, louer 5 alkyl, lower alkoxy, amino, nitro and trifluoromethyl and X and the dotted lines are as defined in Claim 1 subject to the proviso that uhere the group having the formula Ila 10 is ortho-phenylene, then Rg is other than phenyl.

2. 3. A compound as claimed in Claim 2, uherein R^ is hydrogen, halo or louer alkoxy. /

3. 4. A compound as claimed in Claim 2 or 3, uherein Rg is phenyl or halophenyl. 15 5. a-(Thiazolo[5,4-bJpyridin-2-ylthio)phenylacetic acid.

4. 5. A process for the preparation of a compound as claimed in Claim 1, uherein a compound having the formula (V) - 13 (uherein A, X and the dotted lines are as defined in Claim 1) is reacted uith a compound having the formula Hal-CHB-COOH (Vi) 5 (wherein Hal is chlorine or bromine and B is as defined in Claim 1).

5. 7. A process for the preparation of a compound as claimed in Claim -1, carried out substantially as described in the Example herein.

6. 10 8. A compound as claimed in Claim 1, whenever prepared by a process as claimed in Claim 6 or 7.