GB2227741A

GB2227741A - Condensed 3-pyrazolyl-3-oxo-propanenitrile derivates

Info

Publication number: GB2227741A
Application number: GB8902596A
Authority: GB
Inventors: Gianfederico Doria; Anna Maria Isetta; Mario Ferrari; Domenico Trizio
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1989-02-06
Filing date: 1989-02-06
Publication date: 1990-08-08
Anticipated expiration: 2009-02-06
Also published as: DE3940074A1; JPH02240064A; IT9019068A1; IT9019068A0; GB2227741B; GB8902596D0; IT1237992B

Description

CONDENSED 3-OXO-PRC)PALIEIJITRILI:' DERIVATIVES A:1D PIRMrSS FOR THEIR

PREPARATION 1 - The present invention relates to condensed 3-oxo-propaneitrile derivatives, to a process for their preparation and to pharmaceutical compositions containing them. The compounds of the invention have the general formula (I) R - 1 92 R 2 wherein COCH / 8 3 % Q R 3 7 6 5 CN X represents an oxygen atom or a -CH 2_ or -S(O) n_ greup, wherein n is zero, 1 or 2; (1) R 1 represents C I- C 6 alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C 1_ C 6 alkyl, C 1_ C 6 alkoxy, nitro, amino, formylamino and C 2_ C 8 alkanoylamino; R 2 represents: a) hydrogen, halogen or C l_ C 6 alkyl; b) hydroxy, C I-C 6 alkoxy or C 3 or C 4 alkenyloxy; c) nitro, amino, formylamino or C 2-C 8 alkanoylamino; d) di (C 1-C 6 alkyl) amino or a 2.

-CH -N 2 i S group wherein each of R' and R" independently c 1-C 6 alkyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N-pyrrolidinyl, N-piperazinyl, hexahydro- azepin-l-yl, thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by C l_ c 6 alkyl; e) -CH 2 OH, -CHO, -COOH or C 2-C 7 alkoxycarbonyl; f) a -CONH H-COOR d group wherein R d is hydrogen or C, 6 RC alkyl and RC is hydrogen, phenyl or the side-chain of an G(-aminoacid; g) a -NHCOCH-NH 2 group, wherein Rc is as defined above; c h) a -CH OR a -CH OCO(CH) COOR or a -NHCO(CH) WOR 2 '-OR 2 2 n 2 n group, wherein n is as defined above and R is hydrogen or C 1 -C 6 alkyl; k) a -CH=N-OR1 1 group wherein R' 1 is hydrogen or a -CH 2 COOH group; i) a -CH=N-NH-RI 2 group wherein R' 2 is hydrogen, -CH 2 CH 2 OH, C 2 or C 3 alkoxycarbonyl or a -(CH 2) p-R' 3 group wherein p is 1 or 2 and R' 3 is-COOH or C 2-C 7 alkoxycarbonyl; 1 1) a CH=N-N=CH-N group wherein R' and W' are as defined above; or m) a -N=CH-NI..IIR' above; group wherein R' and W' are as defined 7 i i 1 3.

R 3 is as R 2 defined above under a), b), and c); R 4 represents hydrogen or C l_ c 6 alkyl; Q represents hydrogen, carboxy, C 2-C 7 alkoxycarbonyl or a a,) c') -CON Ra group wherein Ra represents hydrogen or C 1_ c 20 --Rb alkyl and R b represents C l_ c 20 alkyl, a -CH-COOR group wherein C R and R c are as defined above or a -(A) M-R 5 group wherein m is zero or 1, A is a C 1_ c 6 alkylene chain and R 5 is c 5_ c 8 cycloalkyl; bl) pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C Calkyl and C 1_ c 6 alkoxy; phenyl, unsubstituted or substituted by one or two sub- stituents independently chosen from halogen, CF 3' n 1_ c 6 alkyl, C 1_ c 6 alkoxy, amino, nitro, formylaminc, C 2_ c 8 alkanoylamino, di(C l- c 6 alkyl)-amino, hydroxy, --,"orrnyloxy and C 2_ c 8 alkanoyloxy; d') phenyl substituted by a -CH 2 OH,-COOH, C 2-C 7 R@ alkoxycarbonyl or a -CH 2-N ---,,R%' group wherein R' and R" are as defined above and optionally by another substituent chosen from halogen, C 1-C 6 alkyl, C l_ c 6 alkoxy, amino, nitro, formylamino, C 2_ c 8 alkanoylamino, hydroxy, formyloxy and C 2-C 8 alkanoyloxy, or ef) 2-thienyl, 2-furyl or 1-(C 1-C 6 alkyl)-pyrrol-2-yl; or -1.

fl) a heterocyclic ring which is selected from 2-Pyr4,midyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C 1-C 6 alkyl; and the pharmaceutically acceptable salts thereof.

Z_ The present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I). It has to be noticed that the compounds of formula (I). may be represented also by a tautomeric structure, namely the enol structure of formula (Ia) 1 L % L Q ('a) R 2 1 X R4 i whe re in X, Rig R 2' R 3Y R 4 and Q are as defined above. However, the compounds of formula (Ia), which fall within the scope of the present invention too, are described in the present specification as compounds of formula (I). A halogen atom is preferably chlorine or fluorine.

is 11 il The alkyl, alkylene, alkanoyloxy, alkoxy and groups may be branched or straight chain groups. A C 1- C 20 alkyl group is preferably a C 1 -C 6 alkyl group. A C 1-C 6 alkyl group is, e.g., methyl, ethyl, propyl, is2propyl, butyl or tert.butyl, more preferably methyl, ethyl or tert. butyl, in particular methyl or ethyl. A C 3 or C 4 alkenyloxy group is preferably allyloxy. A C 1- C 6 alkoxy group is, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, preferably it is me-hcx-;, ethoxy or propoxy. A C 5- C 8 cycloalkyl group is preferably cyclopenty!:r hexyl. A C 2- C 8 alkanoylam.i4no group is preferably acetylam-'--propionylamino. A C 2- C 8 A C 2- C 7 carbonyl A C I- C 6 such as -TH- or CH 3 alkanoyloxy group is preferably acetoxy or pr:24znvloxy. alkoxycarbonyl group is preferably a C 2- C 5 a-'.k::xygroup, in particular a C 2 or C 3 alkoxycarbzny-' ne. alkylene chain is preferably a C 1- C 3 alkylene 2hain, a -CH (CH - - (CH) - 2 2'2 2 3 T- chain.

C 2 H 5 A di(C 1-C 6 alkyl)amino is preferably a di(C l- C 4 alky'.,,a-'Lno group, in particular a di(C 1 or C 2 alkyl)amino one. In a -CH-COOR 1 group, wherein R is as defined above and h C R C is as defined above except hydrogen, the asymmetric carbon atom to which -R and -COOR are linked may have either the R C or S configuration.

1 6.

The side-chain of an a-aminoacid is specifically the residue obtained from an a-aminoacid by removing the amino and the carboxy groups together with the a-carbon atom to which they are linked.

The side-chain of an a-aminoacid as defined above is preferably the sidechain deriving from a naturally occurring aminoacid. Examples of such aminoacids are alanine, valine, leucine, isoleucine, phenylalanine, proline, hydroxyproline, serine, threonine, cysteine, cystine, methionine, tryptophan, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine and phenylserine. Preferred examples of said chains of the above mentioned aminoacids are -CH 3 (deriving from alanine), -CH 2-CH(CH 3)2 (deriving from leucine) and -CH 2_ c 6 H. (deriving from phenylalanine). Examples of pharmaceutically acceptable salts are either those with inorganic bases such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases such as lysine, arginine, N-methyl-glutamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, Nethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine, 0phenethylamine, N-benzy1-0-phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic acids, e.g. hydrochloric, nitric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulphonic acids.

Preferred salts of the compounds of formula (I) are the sodium and the potassium salts thereof.

-1k -1 1 1 i t 7 As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). Preferred compounds of the invention are the compounds of formula (I), wherein X is -CH 2-Y -0- or a -S(O) n_ group, wherein n is as defined above; R 1 represents unsubstituted pyridyl; or phenyl unsubstituted or substituted by one or two substituents chosen independently from halogen, -Urifluoror.n.ethyl, C l- C 6 alkyl, C l- C 6 alkoxy, nitro, amino and C 2 -C 6 alkanoylarnino; R 2 represents:

a") hydrogen, halogen, C l- C 4 alkyl, C l- C 4 alkoxy, amino or a -Rfl 1 -CH group, wherein each of R''' and R1v indepen 2 '---R f v dently is C lC 4 alkyl or R''' and R1v, taken together with the nitrogen atom to which they are linked, form a heterccyclic ring which is selected from N-pyrrolidinyl, N-piperazinyl, morpholino and piperidino and which is unsubstituted or substituted by methyl; b")-CH OH,-CHO,-COOH, C -C alkoxycarbonyl or a -CONHCH-COOR 2 2 5 1 9 RC group wherein R 9 is hydrogen or C 1-C 4 alkyl and R C is hydrogen, phenyl or the side-chain of ane(-aminoacid; i 1 8.

cl') a -NHCO H-NH 2 group, wherein R is as defined above; RC c 9 "---O R f d") a -CH P ' a -CH OCO(CH) -COOR or a -NHCO(CH)-COOR 2 -R f 2 2 n f 2 n f group, wherein n is as defined above and R f is hydrogen or c 1-C 4 alkyl; or lit m elf) a -N=CH-N ""-R 1 v above; group, wherein R"' and R1v are as defined R 3 represents hydrogen, halogen, C 1-C 4 alkyl or C 1-C 4 alkoxy; R 4 represents hydrogen or C 1-C 4 alkyl; represents hydrogen, C -c alkoxycarbonyl or a -CC:1R' R' 2 5 a b group wherein R' a is hydrogen or C 1-C 6 alkyl and R' b is C 1_ c 6 alkyl a- H-COOR 9 group wherein R is hydrogen or C -C alkyl Rc 9 1 4 and R c is as defined above, or a-(A') mRI 5 group wherein m is zero or 1, A' is a C 1_ c 3 alkylene chain and R' 5 is:

all') unsubstituted pyridyl; or phenyl unsubstituted or sub- stituted by a substituent chosen from halogen, C.7-,', c 1-C 4 alkyl, C I- c 4 alkoxy, nitro, CH 2 OH, COOH, di-(C 1_ c 4 alkyl) amino, hydroxy, formyloxy, C 2-C 6 alkanoyloxy and a -CH 2 N 'R 1 v above; group wherein R" and R1v are as defined bIll) 2-thienyl or 2-furyl; or 1 1 i ell#) a heterocycLic ring which is selected from 2-thiazolyl or 3- isoxazolyl and which is unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula (I) wherein X is oxygen, sulphur or -CH 2-; R 1 represents phenyl unsubstituted or substituted by nitro, halogen, W 3, C 1 -C 4 alkyl or C 1-C 4 alkoxy; R 2 represents: aiv) hydrogen, halogen, C I-C 4 alkyl, C 1 C 4 alkoxy, amino or a -CH 2-N,.'R,v group, wherein R''' and R1v are as jefined above; blv) -CH 2 OH,-CHO,-COOH, C 2-C 5 alkoxycarbonyl or a CONH H-COOR elv) a -N=CH-N Re group, wherein R C and R 9 are as defined above; C#V) a NHCOCH-NH 2 group, wherein R C is as defined above; C dIv) a -CH 2 OCO(CH 2) n COOR f or a -NHCO(CH 2) n COOR f group, wherein n and R f are as defined above; or R' v above; R 3 represents hydrogen, halog en, C 1- C 4 alkyl or C l-C 4 alkoxy; R 4 represents hydrogen; 9 group, wherein R''' and R1v are as defined l.

Q represents hydrogen, C 2 or C 3 alkoxycarbonyl or a -CONRI1 a R" b group wherein W' a is hydrogen or C 1-C 4 alkyl and W' b is C 1-C 4 alkyl, a -CH-COOR group wherein R and R are as defined above 9 9 C C or a -(CH 2 P-Rll 5 group in which p is zero, 1 or 2 and W' 5 is:

av) unsubstituted pyridyl; or phenyl unsubstituted or substitut- ed by a substituent chosen from nitro, halogen, CF 31 C 1-C 4 alkyl, C 1-C 4 alkoxy, CH 2 OH, COOH, di(C 1 or C 2 alkyl) amino, hydroxy, formyloxy, C 2-C 6 alkanoyloxy and a -ICH 2 N R group wherein R and R1v are as defined -----R 1 v above; bv) 2-thienyl or 2-furyl; or is cv) a heterocyclic ring which is selected from 2-thiazolyl or 3-isoxazolyl and which is unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof.

Examples of particularly preferred compounds of the invention are:

2-cyano-3-(4,5-dihydro-l-phenyl-Cll-benzF -3-yl)-3-oxo- _g]indazol N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(4,5dihydro-l-phenyl-Cll-benz Cg]indazol-3-yl)-3-oxo-propanamide; 2-cyano-N(4-fluoro-phenyl)-3-C1-(4-fluoro-phenyl)-4,5-dihydroClj-benzCg]indazol-3yll-3-oxo-propanamide; 2-cyano-3-(1,5-dihydro-l-phenyl-?1-benzothi-opyranoE4,3-cj pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; N-benzyl-2-cyano-3-(1,5-dihydro-l-phenyl-E2]-benzothiopyrano,3-clpyrazol3-yl)-3-oxo-propanamide; 2-cyano-N-(4-flucro-phenyl)-3-(1,5-dihydro-lphenyl-E21-benzothiopyranoE4,3-c_]pyrazol-3-yl)-3-oxo-prop.tnamide; 2cyano-N-(4-fluor,o-phenyl)-3- l-(4-fluoro-phenyl)-1, 5-dihydroC2jbenzothiopyranoE4,3-c]pyrazol-3-ylj-3-oxo-propanamide; 2-cyano-3-(1,5dihydro-8-methyl-l-phenyl-F,2j-benzothiopyrano C4,3-c]pyrazol-3-yl-3-oxopropanamide; 3-(8-chloro-1,5-dihydro-l-phenyl-C2]-benzothiopyranoE4,3-cj pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,5-dihydrol-phenyl-E2]-benzopyranoE4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(1,5-dihydro-l-phenyl-L2]-benzopyranoE4,3cjpyrazol-3-yl)-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-Cl-(4fluoro-phenyl)-1,5-dihydro-C2]-benzopyranoE4,3-cjpyrazol-3-yl-3-oxo-propanamide; and the pharmaceutically acceptable salts thereof, in particular the sodium and the potassium salts. The compounds of formula (I) and the salts thereof can be prepared by a process comprising:

1!.

a) reacting a compound of formula (II) R 2 R (11) 3 R 4 wherein X, Rig R 2g R 3 and R 4 are as defined above and Y is carl,-2xy or a reactive derivative of a carboxy group, with a czmncund of formula (III) ( I T wherein Q' is as Q defined above, except carboxy, so obtaining a compound of formula (I), wherein Q is as defined abcve except carboxy; or b) reacting a compound of formula (IV) R 1 W 1 R 2 R 3 COCH 2 em (IV) "k R 4 X 1 wherein X, Rip R 2% R 3 and R 4 are as defined above, with a compound formula (V) R JN=C=0 (V) wherein R b is as defined above, so obtaining a compound of formula (I) wherein Q is a -CONHR b group, wherein R b is as defined above; or c) reacting a compound of formula (VI) 00oeN z R 2 R- m COCH .S 1 1 R 3 X R 4 (VI) wherein X, Rip R 21 R 3 ard R 4 are as defined above and Z is a reactive derivative of a carboxy group, with a compound of formula (VII) R a R b (VII) 1 __I.

wherein R a and R b are as defined above, so obtaining a compound of formula (I) wherein Q is a -CON a ,R b above; or d) hydrolysing a compound of formula (I), wherein Q is a c -c alkoxycarbonyl or -CON a 2 7 CH-COOR group, wherein R a and R b are as defined group in which R a c and R c are as defined above and R is C 1-C 6 alkyl, so as to obtain the corresponding compound of formula (I), wherein Q is a free carboxy group or a -CON R a group, 'L- -CH-COOH c which A a and R c are as defined above; and, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt and!or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of a compound of formula (I), into the single isomers. When Y is a reactive derivative of a carboxy group, it is, for example, a halocarbonyl group, preferably a chlorocarbonyl i 1 1 i group, or a C 2- C 7 alkoxycarbonyl group, preferably a C 2- C 3 alkoxycarbonyl group. The reaction between a compound of formula (II) wherein Y is carboxy and a compound of formula (III) may be carried out, for example, in the presence of a condensing agent such as diethyl cyanophosphonate, in the presence of a base such as triethylamine, in an inert solvent such as dimethylformamide at a temperature varying between about OOC and about 500C. The reaction between a compound of formula (II) wherein Y is a reactive derivative of a carboxy group and a compound of formula (III) may be carried out, for example, in the presence of a strong base such as sodium hydride, potassium t.butoxide, thallous ethoxide, in an inert solvent such as 1,2-dimethoxyethane, dioxane, dimethylformamide, at a temperature varying between about OOC and about 1000C. The reaction between a compound of formula (IV) and a compound of formula (V) may be carried out, for example, in the presence of a base such as sodium hydride or triethylamine, in an inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide, at a temperature varying between about OOC and about 1000C. In the compounds of formula (VI), Z is, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or a C 2- C 7 alkoxycarbonyl group, preferably a C 2-C 3 alkoxycarbonyl group. The reaction between a compound of formula (VI), wherein Z is a halocarbonyl group, and a compound of formula (VII) may 16.

be carried out, for example, in an inert solvent such as dichloroethane, dioxane, dimethylformamide, in the presence of pyridine or triethylamine as acid acceptor, at a tempera ture varying between about OOC and about 1000C.

The reaction between compound of formula (VI), wherein Z is c 1-C 6 alkyl ester, and a compound of formula (VII) may be car ried out, for example, by heating at the reflux temperature in an aromatic hydrocarbon such as toluene or xylene, pre ferably distilling off slowly together with the diluent -he free C 1-C 6 alkyl alcohol generated during the react4zn.

Hydrolysis of a compound of formula (I), wherein Q.4s a C 2-C 7 alkoxycarbonyl or a -CON a grcu;: J-r. -..---ch c R a and R c are as defined above and R is C 1-C 6 alkyl,,---rd'ng to process - variant d) above, may be performed by basic hydrolysis, using e. g. aqueous sodium or potass--.-. hydroxide in a solvent such as dioxane, ethanol or d.;---nylformamide at a temperature varying between about OOC inj about 800C. A compound of formula (I) may be converted, as stated i---ve, into another compound of formula (I) by known methods; f2r example, in a compound of formula (I) a nitro group may te converted into an amino group by, treatment, for examp'.e. with stannous chloride in concentrated hydrochloric acid, using:.' necessary, an organic cosolvent such as acetic acid, dioxane. tetra- i 1 17.

hydrofuran at a temperature varying between room temperature and about 1000C. Furthermore, for example, an amino group may be converted into a formylamino or a C 2_ C 8 alkanoylamino group, for example by reacting with formic acid or with the suitable C 2 -C 8 alkanoyl anhydride without any solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varying between OOC and about 1000C. Furthermore, for example, a -NH 2 or a -CH=N-NH 2 group may be R:, group, converted into a -N=CH-N -R or into a -CH=N-N=CH-NIIR" wherein R' and R" are as defined above, respectively, by reaction with a quaternary nitrogen compound of formula ('Jlia') R +) = N CHCl cl R"I" (VIIa) wherein R' and W' are as defined above, in an organic inert solvent, such as dioxane, tetrahydrofuran, chloroform, dichloromethane, 1,2- dichloroethane, benzene or toluene, in the presence of a tertiary amine, such as triethylamine, at a temperature varying between about -200C and the room temperature, according to the experimental procedure described in British patent specification 1293590 and in U.S. patent 4,447,432. Furthermore, for example, an amino group may be converted into a -NHCO HNH 2 group,

C wherein R C is as defined above, by reaction with a suitably protected aminoacid of formula HOOC-CH-NW, wherein R C is as A defined above and W is a protective g oup, such as as a benzyl- oxycarbonyl or a tert-butoxycarbonyl group, in the presence of 41 k_ is I B. dicyclohexylcarbodiimide, as condensing agent, in inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about OOC and the room temperature, so as to obtain the protected -NHCO HNHW Z group, wherein R c and W are as defined above, which in turn is deprotected using well known methods in organic chemistry. Furthermore, for example, a carboxy group may be converted into a -CONH HCOOH group, wherein R c is as defined above, by reaction wi5 c an esterified c(-aminoacid of formula H 2 IN-YH-COOR, c wherein R is C i_ c 6 alkyl and R c is as defined above, in the presence of dicyclohexylcarbodiimide as condensing agent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about -_;OC and the room temperatu.re, so as to obtain the esterified -CONH H- Z COOR group, wherein R c and R are as defined above, which in turn is hydrolized to yield the -CONHH-COOH group, wherein R c is as defined above, following met Gds well known in the art, for example, those described for the process variant d'. above.

Furthermore, for example, an alkoxycarbonyl group, a -CH.,OR 2 --- 0 R group or a -NHCO(CH 2) n COOR group, wherein n is as defined above and R is C 1-C 6 alkyl, may be converted into the corresponding 9 OH -COOH, -CH P"- and -NHCO(CH) COOH group, respectively, 2 %^. OH 2 n wherein n is as defined above, by treatment with aqueous sodium or potassium hydroxide in a solvent such as dioxane, methanol, i 1 ethanol or dimethylformamide, at a temperature varying between about OOC and about 800C. Process-variants b) and c) described above may be considered as examples of conversion of a compound of formula (I) into another compound of formula (I) too. Also the optical salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods. For example, 1Che separa- tion of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diasterecisomeric salts, followed by recovering of the optically active isomeric acids or, respectively, bases. The compounds of formula (II), in which Y is a C 2_ c 7 alkoxycarbonyl group and X is as defined above, may be prepared, for example, by reacting a compound of formula (VIII) 0 R 2 e 1 R 4 0, C OC OOR 6 (VIII) wherein X, R 29 R 3 and R 4 are as defined above and R 6 is C 1-C 6 a-kyl, preferably C 1-C 2 alkyl, with a compound of formula ('LX) R l-NHNH 2 (IX) wherein R 1 is as defined above. The reaction between a compound of formula (VIII) and a compound of formula (IX) may be carried out, for example, in a solvent such as C l- c 6 alkyl alcohol, dioxane, tet. rahydrofuran, dimethylformamide, acetic acid, at a temperature varying between about OOC and about 1500C. The compounds of formula (II), wherein Y is carbexy may be prepared, for example, by hydrolysis of the correspc- j.'ng compounds of formula (II) wherein Y is C 2_ c 7 alkoxycartcnyl, according to standard methods well known in the a-rt, for example, by basic hydrolysis, carried out e.g. by treatment with sodium or potassium hydroxide.in a solvent sue', as water, c 1-C 6 alkyl alcohol, dioxane, dimethylformamide and their.mixtures, at a temperature varying between about 7,: and about 800C. The compounds of formula (II), wherein Y is halocarbonyl, preferably chlorocarbonyl, may be prepared, for example, by reaction of the corresponding compound of formula (II), wherein Y is carboxy, with the suitable acid halide, for example oxalyl chloride, thionyl chloride, PC1 3' PBr., in an inert solvent such as ether, benzene, dichloroethane, dioxane or without any solvent, at a temperature varying between about OIC and about 1000C.

1 1 i _f t_ 21.

The compounds of formula (III) are, in some cases, commercially available products, or may be prepared by methods well known in the art. For example a compound of R formula (III), wherein Q, is a -CON group, wherein R Rb Rb are as defined above, may be prepared by reacting cyanoacetic acid with a compound of formula (VII) in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1-carbonyldiimidazole and the like, in an inert organic solvent such as benzene, dioxane, acetonitrile, at a temperature varying between about CC and about SO'C. The compounds of formula (IV) are compounds of general formula (1), wherein Q is hydrogen and may be obtained by a process a) above, for example, by reacting a compound of formula II), wherein Y is C,_C7 alkoxycarbonyl, with acetonitrile, in the presence of a strong base e.g. sodium hydride, potassium tert.butoxide, in an inert organic solvent such as benzene, dioxane, tetrahydrofuran, at a temperature varying between about OOC and about 1000C.

The compounds of formula (VI), wherein Z is C2-C7 alkoxycarbonyl, are compounds of general formula (I) wherein Q is C,_C7 alkoxycarbonyl and may be obtained by process a) above, for example, by reacting a compound of formula (II) with a compound of formula (X) , CN COOR 7 1 t wherein R 7 is C 1-C 6 alkyl, using the same experimental conditions as described above for the reaction between a compound of formula (I1) and a compound of formula (III).

The compounds of formula (VI), wherein Z is halocarbonyl, may be prepared, for example, by basic hydrolysis of a compound of formula (VI), wherein Z is C 2-C 7 alkoxycarbonyl, using, for example, the same experimental conditions described above for the hydrolysis of the compounds of formula (II), wherein Y is C 2-C 7 alkoxycarbonyl, in order to obtain the corresponding carboxy derivative, which in turn may be transformed into a compound of formula (VI), wherein Z is halocarbonyl, preferably chlorocarbonyl, using, for example, the same experimental conditions described above for the preparation of the compounds of formula (II), wherein Y is halocarbonyl. The compounds of formula (VIII) may be prepared, for example, by reacting A compound of formula (XI) 0 R 2 4 1 X (Xl) 1 23.

wherein X, R 29 R 3 and R 4 are as defined above, with a compound of formula (XII) OOR 8 COORI 8 (M) wherein each of R 8 and R being the same or different, is C 1- C alkyl, preferably methyl or ethyl. The reaction between a compound of formula (XI) and a compound of formula (XII) may be carried out, for example, according to the methods described in J.C.S., 1C1, 1731 (1912) and Ann., 405, 391 (1914). The compounds of formula (XI) may be prepared by synthetic methods well known in the art, for example, according to the methods described in J.A.C.S., 75, 1891 (1953), in Bull. Soc. Chim. Fr., 1351 (1971) and Advances in Heterocyclic Chemistry, 18, 84 (1975). The compounds of formula (V), (VII), (IX), (X), and (XII) are known products and may be prepared by conventional methods: in some cases they are commercially available products. When in the compounds of the present invention and in the intermediate products thereof, groups are present, such as CHO,-COOH,-NH 2 and/or-OH, which need to be protected before submitting them to the hereabove illustrated reactions, they may be protected before the reactions take place and then deprotected, according to well known methods in organic chemistry.

1 24.

The compounds of formula (I) possess immunomodulating activity and can be used in particular as immunostimulant agenics e.g. in the treatment of acute and chronic infections of both bacterial and viral origin, alone or in association with antibiotic agents, and in the treatment of neoplastic diseases, alone or in association with antitumoral agents, in mammals. The compounds of the invention can be safely used in medicine by virtue of their negligible toxicity. The therapeutic regimen for the different clinical syndromes must be adapted to the type of pathology taking into account, as usual, also the route of administration, the form in which the compound is administered and the age, weight and c::nditions of the subject involved. The oral route is employed, in general, for all conditions requiring such compounds. Preference is given to intravenous injection or infusion for the treatment of acute infections. For maintenance regimens the oral or parenteral, e.g. int-ramuscular or subcutaneous, route is preferred. For these purposes the compounds of the invention Can be administered orally at doses ranging e.g. from about 0.5 to about 10 mg/kg of body weight per day in adult humans. Doses of active compounds ranging e.g. from about 0.2 to about 5 mg/kg of body weight can be used for the parenteral administration in adult humans. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.

i 1 i i The nature of the pharmaceutical compositions c--nta-in-n.g the compounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration. The compositions may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oilysolutions or suspension, tablets, pills, gelatine capsules, syrups, drops or suppositories. Thus, for oral administration, the pharmaceutical compositions containing the compounds of this invention, are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium. or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, carboxymethylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents, such as starches, alginic acid, algi nates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugarcoating, or film-coating processes.

i 26.

The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups, may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoabutter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following Examples illustrate but do not limit the invention:

i 27.

Example 1

2-Ethoxalyl--,-tetralone (7.8 g) is reacted with phenyl hydrazine (3.76 g) in acetic acid (78 ml) at room tempera ture for 4 hours. The reaction mixture is diluted with ice water and then neutralized with 30% NH 4 OH. The precipi tate is filtered and washed with water.

Two crystallizations from isopropyl alcohol give pure 4,5 dihydro-l-phenyl-1-1]-benzFg]indazole-3-carboxylic acid, ethyl ester, m.p. 157-1580C (6.3 g), which is reacted with acetonitrile (63 ml) in dioxane (38 ml) in the presence of 50% sodium hydride (1.9 g) under stirring at 650C for 30 minutes. After cooling the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The preci pitate is filtered, washed with water and purified over a Sio 2 column using chloroform as eluent. Washing with isopro pyl ether at the reflux temperature gives pure 3(4,5-dihydro 1-phenyl-ll-benzEg3indazol-3-yl)-3-oxo-propanenitrile' M.P.

150-1511C (4.8 g), which is reacted with phenyl isocyanate (1.9 g) in dimethylformamide (25 ml) in the presence of tri ethylamine (1.7 g) at 25-300C for 30 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 2N HCl. The precipitate is filtered and washed with water.

Crystallization from chloroform/ethanol gives 5.2 g of 2 cyano-3-(4,5-dihydro-l-phenyl-Clj-benzCg]indazol-3-yl)-3oxo-N-phenyl-propanamide, m.p. 210-2120C, NMR (CDC1 3) 5 ppm:

1.89 (m) (4H, -CH 2_ CH 2_), 6.60-7.60 (m) (9H, phenyl protons), 7.84(sM1H, -CONH-), 16.20 (s) (1H, -OH).

28.

By proceeding analogously the following compounds can be prepared:

2-cyano-3-C1-(4-fluoro-phenyl)-4,5-dihydro-r13-benzCjj indazol-3-ylj-3-oxo-N-phenyl-propanamide; 2cyano-N-(4-fluoro-phenyl)-3-(4,5-dihydro-l-phenyl-Eilbenz_rgjindazol-3-yl)-3-oxo-propanamide; N-(3-chlorophenyl)-2-cyano-3-(4,5-dihydro-l-phenyl-Cll-benz Cgjindazol-3-yl)-3oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-F1-(4-fluoro-phenyl)-4,5dihydro-El]-benzCgjindazol-3-yl]-3-oxo-propanamide; N-benzyl-2-eyano-3-(4,5-dihydro-l-phenyl-C:Ci-benzCglindazol3-yl)-3-oxo-propana-iide; 2-cyano-3-(4,5-dihydro-l-phenyl-Clj-benzF gJindazol-3-yl)-N- (3-nitro-phenyl)-3-oxo-propanamide; and 2-cyano-3-(4,5-dihydro-l-phenyl-Clj-benzCgjindazol-3-yl)-3oxo-N-(3-trifluoroT.ethyl-phenyl)-propanamide.

Example 2

By proceeding according to Example-1, starting from suitable 2-ethoxalyl-C-tetralones, the following compounds can be pre- pared:

2-cyano-3-(4,5-dihydro-5-methyl-l-phenyl-[1-benzi- Q indazol3-yl)-3-oxo-N-phenyl-propanamide; 3-(8-nitro-4,5-dihydro-l-phenyl-rl]-benzgindazol-3-yl)-2cyano-3-oxo-N-phenyl-propanamide; 3-(8-chloro-4,5-d4-hydro-l-phenylrll-benzFgjindazol-3-yl)2-cyano-3-oxo-N-phenyl-propanamide;and 2-cyano-3-(4,5-dihydro-8-methyl-l-phenyl-/!-7-benz /gi-7 indazol- 1 i i 29.

3-yl)-3-oxo-N-phenyl-propanamide.

Example 3

By proceeding according to Examples 1 and 2, starting from suitable 3ethoxalyl-/7-benzopyran-4-ones and 3-ethoxalyl27-benzothiopyran-4-ones,the following compounds can be prepared: 3-(1,5dihydro-l-phenyl-/-27-benzothiopyrano /,3-c-ipyrazol3-yl)3-oxopropanenitrile, m.p. 149-150OC; 3-(1,5-dihydro-l-phenyl-/2 7-benzopyrano /,3-C7 pyraz--1-3-yl)- 3-oxo-propanenitrile; 2-cyano-3-(1,5-dihydro-l-phenyl-/-2-,/-benzothiopyrano /4,3-c7 pyrazol-3yl)-3-oxoN-phenyl-propanamide,m.p.239-24,) OC; N-benzyl-2-cyano-3-(1,5-dihydro-l-phenyl-/ 27-benzoth4opyrano /-4,3-c7pyrazol-3-yl)-3-oxo-propanamide; 2-eyano-N-(4-fluoro-phenyl)-3-(1,5-dihydro-l-phenyl-/ - 217-benzo thiopyrano / 4,3c7pyrazol3yl)-3-oxo-propanam4-de; 2-cyano-N-(4-fluoro-phenyl)-3-/1-(4-fluoro-phenyl)-1,5-di-hydro/-27-benzothiopyrano /Z,3-c/Pyrazol-3-Y1/-3-oxo-propana.-iide; 3-(8-chloro-1,5-dihydro-l-phenyl-/-27-benzothiopyrano /-4,3-c7 pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; N-(3-chloro-phenyl)-2-cyano-3-(1,5-dihydro-l-phenyl-/ 7-benzo thiopyrano / 4,3-c/pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-3-(1,5-dihydro-8-nitro-l-phenyl-/ 2/-benzothiopyrano /4,3-c/ pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,5-dihydro-l-phenyl-/-27-benzothiopyrano / 4,3-c/ pyrazol-3-yl)-N-(3-nitro-phenyl)-3-oxo-propanamide; 2-cyano-3-(1,5dihydro-l-phenyl-/ 27-benzothiopyrano /5,3-c7 pyrazol-3-yl)-N-(3trifluoromethyl phenyl)-3-oxo-propanamide; 2-cyano-3-(1,5-dihydro-lphenyl-/-27-benzopyrano -3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-N- (4f luo re-phenyl) -3- (1, 5-dihydro-1 -phenyl- /- 2 7-benzopyrano / 4,3c7Pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-/ 1-(4fluoro-phenyl)-1,5-d-hydro- -/_2 7-benzopy.rano /Z,3-c7Pyrazol-3-Y17-3-oxo-pr2nanamide; N-(3-chloro-phenyl)-2-cyano-3-(1,5-dihydro-l-pheny'--i'-2 7-benzo- pyrano /5,3-c7 pyrazol-3-yl)-3-oxo-propanamide; and 2-cyano-3(1,5-dihydro-8-methyl-l-phenyl-ú27-benzothiooyranoJ4,3-c7ovrazol-3-yl)-3-oxo-propanamide.

Example 4

1,5-dihydro-1 -phenyl - / 2/-benzothiopyrano / 4,3-c/pyrazo'-.--3carboxylic acid, ethyl ester, m.p. 127-1291C (3.3 g), prepared according to Example 1 starting from 3-ethoxalyl-/ 2/ -benzopyran-4-one, is hydrolysed by treatment with 1% KOH solution in ethanol (100 ml) at reflux temperature for 20 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HCl. The precipitate is filtered, washed with water until neutral and dried in vacuo to give 1,5-dihydro-lphenyl-/-2 7-benzo- i i 31.

thiopyrano [4,3-cl pyrazole-3-carboxylic acid, m.p. 248-250 0 C (2.75 g), which is reacted with thionyl chloride (1.2 ml) in dioxane (80 M1) at the reflux temperature for 2 hours. After cooling the reaction mixture is evaporated to dryness in vacuo to give 1,5-dihydro-l-phenyl-[23-benzothiopyrano [4,3-cl pyrazole-3-carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (50 ml) and reacted for 1 hour under stirring at room temperature with the carbanion obtained by treatment of 2-cyanoacetanilide (1.6 g) with 50% sodium hydride (0.5 g) in anhydrous dioxane (120 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH2 with 2N HCl. The precipitate is filtered ans washed with water until neutral. Crystallization from dichloromethane/methanol gives 1.4 g of 2-cyano-3(1,5-dihydro-l-phenyl-[2]-benzothiopyrano [4.3-cl pyrazol-3-yl)-3-oxo-Nphenyl-propanamide, m.p. 239-2400C. By proceeding analogously the following compounds can be prepared: 2-cyano-3-(1,5-dihydro-l-phenyl-[21benzopyrano [4,3-cl- pyrazol-3--yl)-3-oxo-N-phenyl-propanamide; N-benzyl-2-cyano-3-(1,5- dihydro-l-phenyl-[21-benzothiopyrano [4,3-cl pyrazol-3-yl)-3-oxo- propanamide; 2-cyano-3-(1,5-dihydro-l-phenyl-[23-benzothiopyrano [4,3-cl pyrazol-3-yl)-N-(4-dimethylamino-phenyl)-3-oxo-propanamide; 3-(8-tert-butoxycarbonyl-1,5-dihydro-l-phenyl-[2]-benzothiopyrano [4,3-cl pyrazol-3-yl)-2-cyano-3-oxo-N-phenylpropanamide..

C 32, 3-(8-tert-butoxycarbonyl-IL,5-dihydro-l-phenyl-/7- benzopyrano /4,3-c/ pyrazol-3-yl)-2cyano-3-oxo-N-phenyl-propanamide; 3-(8-tert-butoxycarbonyl- 4,5-dihydro-l-phenyl-/1 7-benz/-g 7 indazol3-yl)-2-cyano-3-oxo-N-phenyl- carboxamide; and 2-cyano-3-(1,5-dihydro-l-phenyl-/-27-benzothiopyrano /Z, 3-c7 pyrazol-3-yl)3-oxo-N-(3-pyridyl)-propanamide.

Example 5

3-(8-tert-butoxycarbonyl-1,5-dihydro-l-phenyl-/-7-benzothiopyrano / 4,3c/ pyrazol-3-yl)-2-cyano-3-oxo-N-phenylpropanamide (1.8 g) is treated with trifluoroacetic acid (50 ml) at room temperature for 3 hours. The reaction mixture is evaporated in vacuo to a small volume and then diluted with ice water. The precipitate is filtered and washed with water until neutral. Crystallization from dichloromethane/methanol gives 1.3 g of 3-(8-carboxy-1,5-dihydro-l-phenyl-/ 27-benzothiopyrano 4,3-c/ pyrazol3-yl)-2-cyano-3-oxo-N-phenyl-propanamide.

1 By proceeding analogously the following compounds can be Drepared: 3-(8carboxy-1,5-dihydro-1 -phenyl-/ 2 _/-benzopyrano /4,3-c/ pyrazol-3-yl)-2cyano-3-oxo-N-phenyl-propanamide; and 3-(8-carboxy-4,5dihydro-l-phenyl-/17-benz g _ indazol-3-yl)2-cyano-3-oxo-N-phenyl-carboxamide.

3 3.

Example 6

Ethyl cyanoacetate (1.4 g) is treated with 50% sodium hydride (0.58 g) in dimethylformamide (10 mi) under stirring at room temperature until the effervescence subsides. To this solution 1,5-dihydro-l-phenyl-/-27benzothiopyrano 4,3-c/pyrazole-3-carbonyl chloride (3.26 g), prepared according to Example 4, dissolved in anhydrous dioxane (120 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 20 hours, then it is diluted with ice water and acidified to pH 3 with 37% HCl. The pre cipitate is extracted with ethyl acetate and the organic solution washed with water and then evaporated to dryness in vacuo. The residue is purified over a SiO 2 column, using hexane-ethyl acetate 80:20 as eluent, to give 2-cyano-3 (1,5-dihydro-l-phenyl-/-27-benzothiopyrano pyrazol 3-yl)-3-oxo-propanoic acid, ethyl ester (2.4 g), which is reacted with aniline (1.7 g) in xylene (100 ml) at the re flux temperature for 48 hours. After cooling the precipitate is filtered and washed with xylene, then crystallized from dichloromethane/methanol to give 1.5 g of 2-cyano-3-(1,5 dihydro-l-phenyl-/-27-benzothiopyrano /Z,3-c7 pyrazol-3-Y1) 3-oxo-N-phenyl-propanamide, m.p. 239-240'C.

Example 7

1,5-dihydro-l-phenyl-/ 2/-benzothiopyrano /4,3-c/-pyrazol-3carbonylchloride (2.6 g) dissolved in anhydrous dioxane (50 ml) 34.

is reacted for 1 hour under stirring at room temperature with the carbanion obtained by treatment of N-cyanoacety1glycine, methyl ester (1. 44 g) with 50% sodium hydride (0.54 g) in anhydrous dimethylformamide/dioxane 1:1 (30 ml) at room temperature, The reaction mixture is then diluted with ice water and acidified to pH 2 with N HCl. The precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with N HCl and then with water until neutral. Evaporation to dryness yields a residue which is purified over a Flash column using chloroform/methanol/30% NH 4 OH 80:20:0.5 as eluent. Final treatment with acetone of the purified fractions gives 1.95 g of N-/cyano3-(1,5-dihydro-l-phenyl-/ 2/-benzothiopyrano /4,3-c/pyrazol3-yl)-3oxo-propanoyl)7-glycine, methyl ester.

By proceeding analogously the following compounds can be pre pared: N-/-2cyano-3-(1,5-dihydro-l-phenyl-/ 27-benzothiopyrano /,3-c7 pyrazol-3-yl)-3oxo-propanoyl/-DL-leucine,methy1 ester; N- / -cyano-3- (1, 5-dihydro-1 phenyl-/ 2 /-benzothiopyrano /4,3-c/ pyrazol-3-yl)-3-oxo-propanoyl/-DLphenylalanine, methyl ester; N-/-2-cyano-3-(1,5-dihydro-l-phenyl-/-27benzothiopyrano /j,3-c7. pyrazol-3-yl)3-oxo-propanoyl/-DL-phenylglycine, methyl ester; and N-/-cyano-3-(1,5-dihydro-l-phenyl-/-7-benzothiopyrano/4, 3-c/ pyrazol-3-yl)-3-oxo-propanoyl/DL-isoleucine,methyl ester.

i z 1.

Similarly the pure D and L enantiomers of the above-listed compounds can be prepared.

Example 8

N-/-cyano-3-(1,5-dihydro-l-phenyl-/ 27-benzothiopyrano /z,3-c7 pyrazol-3yl)-3-oxo-proparPyl/-glycine, methyl ester (1.9 g), is suspended in 1% KOH solution in 95% ethanol (61 n'L) and heated under stirring at the reflux rtemperature for ---: min. After cooling the precipitate is filtered and washed with ethanol, then dissolved in water. The aqueous basic solution is extracted with ethyl acetate and then acidified to cH 2 with 2N HCl. The precipitate is extracted with ethyl acetate and the organic solution washed with N HCl and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crumbled with ethanol to yield 1.05 g of N-7::-cyano3-(1,5-dihydro-l-phenyl-/2-/- benzothiopyrano /4,3-c/pyrazo'L3-yl)-3-oxo-propanoyl7-glycine.

By proceeding analogously the folloxing compounds can 'De prepared: N-1 2cyano-3- (1, 5-dihydro-l-phenyl-/ 27-benzothiopyrano /-4,3-c7 pyrazol-3yl)-3-oxo-propanoy17-DL-leucine; N-/-cyano-3-(1, 5-dihydro- 1 -phenyl/_27-benzothiopyrano /Z,3-c7 pyrazol-3-yl)-3-oxo-propanoyl7-DLphenylalanine; N/-cyano-3-(1,5-dihydro-l-phenyl-/ 2/-benzothiopyrano/4,3c/ pyrazol-3-yl)-3-oxo-propanoyl7-DL-phenylglycine; and N-/2-cyano-3-(1,5dihydro-1 -phenyl-/ 2/-benzothiopyrano/4,3-c/ pyrazol-3-yl)-3-oxopropanoyl7-DL-iscieucine.

36.

Similarly the pure D and L enantiomers of the above-listed compounds can be obtained.

i Example 9

2-cyano-3-(4,5-dihydro-l-phenyl-Cll-benzlgjindazol-3-yl)N-(3-nitrophenyl)-3-oxo-propanamide (4.5 a) is treated with SnCl242H 20 (22.5 g) in 37% HCl (16 ml) and acetic acid (144 ml) under stirring at 500C for 5 hours. After cooling the precipitate is filtered and washed with acetic acid, then dissolved in dimethylformamide / 2N NaOH 1:1. Dilution with excess aqueous citric acid gives a precipitate, which is filtered, washed with water and crystallized from dimethylformamide to give 2.5 g of N-(3amino-phenyl)-2-cyano-3(4, 5-dihydro- 1 -phenyl - [11 -benz rgi indazol-3y1) -3-oxo-propanamide.

By proceeding analogously the following compound can be prepared:

N-(3-amino-phenyl)-2-cyano-3-(1,5-dihydro-l-phenyl-F2- J-benzothiopyranof:4,3-clpyrazol-3-yl)-3-oxo-propanamide; 3-(8-amino-1,5-dihydro-l-phenyl-/ 2/-benzothiopyrano /4,3-cl pyrazol-3-yl)-2-cyano-3-oxo-N-phenylpropanamide; and 3- (8-amino-4, 5-dihydro-1 -phenyl- /i 7-benz/ g - _ indazol-3-yl)- 2-cyano-3-oxo-N-phenyl-propanamide.

is C 3 7.

Example 10

2-Cyano-3-(4,5-dihydro-l-phenyl-benz Egi indazol-3-yl)-3oxo-N-phenylpropanamide is dissolved by treatment with the stoichiometric amount of sodium ethoxide in ethanol. The solution is evaporated to dryness in vacuo and the product is crumbled with acetone. Filtration and washing with acetone gives the pure sodium salt of 2-cyano-3(4,5-dihydro-l-phenylbenz[gjindazol-3-yl)-3-oxo-N-phenylpropanamide, m.p. >2600C.

By proceeding analogously the following compound can be prepared: 2-cyano-3-(1,5-dihydro-l-phenyl-C2]-benzothiopyranoE4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, sodium salt.

Example- 11

Tablets, each weighing 150 mg and containing 50 mg of active substance, can be manufactured as follows:

Composition (for 10,000 tablets) 2-Cyano-3- (1, 5 -dihydro- 1 -phenyl -/2 /-benzothiopyranc//,5, 3-c] pyrazo 1 Lactose 710 g Corn starch 238 g Talc powder 36 g Magnesium stearate 16 g 33.

2-Cyano-3-(1,5-dihydro-l-phenyl-/7-benzothi-or, yrano 3c pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, lactose and half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of 8 mm diameter.

i 1 : C,.

IT C LAIL.'S 1) A compound of formula (I) t - 1 02 1 R 2 wherein CDCH 8 1 3 7 R 3 6 R 4 X r N 1 Q X represents an oxygen atom or a -CH 2- or -S(O) n - group, wherein n is zero, 1 or 2; (I) R 1 represents C 1 c A alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C 1c 6 alkyl, C 1- c 6 alkoxy, nitro, amino, formylamino and C 2- c 8 alkancylamino; R 2 represents: a) hydrogen, halogen or C 1- c 6 alkyl; b) hydroxy, C 1- c 6 alkoxy or C 3 or C 4 alkenyloxy; c) nitro, amino, formylamino or C 2- C 8 alkanoylamino; d) di (C l- c 6 alkyl) amino or a c i 4C.

-CH -N 2 i S group wherein each of R' and W' independen'"ly c 1-C 6 alkyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N- pyrrolidinyl, N-piperazinyl, hexahydroazepin-l-yl, thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by C l- c 6 alkyl; e)-CH 2 OH, -CHO, -COOH or C 2-C 7 alkoxycarbonyl; f) a -CONHH-COOR d group wherein R d is hydrogen or C l- c 6 RC alkyl and RC is hydrogen, phenyl or the side-chain of an C(-aminoacid; g) a -NHCOCH-NH 2 group, wherein Rc is as defined above; 1 KC h) a -CH ll. OR, a -CH OCO(CH) COOR or a -NHCO(CH) n CC-i'GR 2 '--,.OR 2 2 n 2 group, wherein n is as defined above and R is hydrogen or c 1-C 6 alkyl; k) a -CH=N-OR1 1 group wherein R' 1 is hydrogen or a -CH 2 CGIGH group; a -CH=N-NH-RI 2 group wherein R' 2 is hydrogen, -CH 2 CH 2 OH, c 2 or C 3 alkoxycarbonyl or a -(CH 2) p-R' 3 group wherein p is 1 or 2 and R' 3 is- COOH or C 2-C 7 alkoxycarbonyl; 1) a -CH=N-N=CH-N defined above; or m) a -N=CH-NII-11, R# above; group wherein R' and W' are as group wherein R' and W' are as defined 1 v A i , 1.

R 3 is as R 2 defined above under a), b), and c); R 4 represents hydrogen or C 1-C 6 alkyl; Q represents hydrogen, carboxy, C 2-C 7 alkoxycarbonyl or a Ra -CON alkyl and R b represents C 1-C 20 alkyl, a -CH-COOR group wherein c R and R c are as defined above or a -(A) M-R 5 group wherein m is zero or 1, A is a C 1-C 6 alkylene chain and R 5 is group wherein Ra represents hydrogen or C 1-C 20 a') C 5-C 8 cycloalkyl; bl) pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C l_ c 6 alkyl and C 1_ c 6 alkoxy; phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, CF 39 c 1_ c 6 alkyl, C 1_ c 6 alkoxy, amino, nitro, formylamino, C 2_ c 8 alkanoylamino, di(C l- c 6 alkyl)- amino, hydroxy, formyloxy and C 2_ c 8 alkanoyloxy; d') phenyl substituted by a -CH 2 OH,-COOH, C 2_ C7 alkoxycarbonyl or a -CH group wherein R' and W' -, R are as defined above and optionally by another substituent chosen from halogen, C 1-C 6 alkyl, C 1 -C 6 alkoxy, amino, nitro, formylamino, C 2-C 8 alkanoylamino, hydroxy, formyloxy and C 2-C 8 alkanoyloxy, or el) 2-thienyl, 2-furyl or 1-(C 1-C 6 alkyl)-pyrrol-2-yl; or 42.

fl) a hetkerocyclic ring which is selected from 2-pyri.m-idyl, 2thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C 1-C 6 alkyl; and the pharmaceutically acceptable salts thereof.

2) A compound of formula (I), according to claim 1, wherein X is -CH 2-9 -0- or a -S(O) n_ group, wherein n is as defined in claim 1; R 1 represents unsubstituted pyridyl; or phenyl unsubstituted or substituted by one or two substituents chosen independently from halogen, tri fluoromethyl, C 1-C 6 alkyl, C 1-C 6 alkoxy, nitro, amino and C 2-C 6 alkanoylamino; R 2 represents: all) hydrogen, halogen, C 1_ C 4 alkyl, C 1-C 4 alkoxy, amino or a -N group, wherein each of R''' and RIv indepen2 --R 'v dently is C 1_ C 4 alkyl or R''' and R1v, taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N-pyrrolidinyl, N-piperazinyl, morpholino and piperidino and which is unsubstituted or substituted by methyl; b")-CH OH,-CHO,-COOH, C -C alkoxycarbonyl or a -CONIHCH-COOR 2 2 5 1 9 RC group wherein R 9 is hydrogen or C I-C 4 alkyl and R C is hydrogen, phenyl or the side-chain of ancK-aminoacid; i A i 1 43.

ell) a -NHCO H-NH 2 group, wherein R c is as defined above; RC -CH OCO(CH -COOR or a -NHCO(CH)-COOR W) a -CH 2 p a 2 group, wherein n is asdefinedinclaim l, and Rf is hydrogen or c l- c 4 alkyl; or a -N=CH-NI-I-R' ' % "-R 1 V above; group, wherein R''' and RIv are as defined R 3 represents hydrogen, halogen, C 1-C 4 alkyl or C l- c 4 alkoxy; R 4 represents hydrogen or C l- c 4 alkyl; Q represents hydrogen, C 2_ c 5 alkoxycarbonyl or a -CONRI a R' b group wherein R' a is hydrogen or C 1-C 6 alkyl and R' b is C l- c 6 alkyl, a-(H-COOR group wherein R is hydrogen or C - C alkyl T 9 9 1 4 RC and R c is as defined above, or a-(A') -R 5 zero or 1, A' is a C l- c 3 alkylene chain and R' 5 is:

9 group wherein m is all') unsubstituted pyridyl; or phenyl unsubstituted or sub- stituted by a substituent chosen c 1-C 4 alkyl, C l- c 4 alkoxy, nitro, alkyl) amino, hydroxy, formyloxy, Rf 9 1 -CH 2 N -'Riv above; group wherein R b''') 2-thienyl or 2-furyl; or from halogen, CF 39 CH 2 OH, COOH, di-(C l- c 4 c 2_ c 6 alkanoyloxy and a and RIv are as defined 44.

cif@) a heterocyclic ring which is selected from 2-thiazolyl or 3isoxazolyl and which is unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof.

3) A compound of formula (I), according to claim 1, wherein X is oxygen, sulphur or -CH 2-; R 1 represents phenyl unsubstituted or substituted by nitro, halogerf, CF 39 c 1- c 4 alkyl or C 1-C 4 alkoxy; R 2 represents:

alv) hydrogen, halogen, C -c alkyl, C -c alkoxy, amino or ,-R t 1 1 1 4 1 4 a -CH 2-N --RIV group, wherein R and RIv are as defined in claim 2; bfv) CH 2 OH,-CHO,-COOH, C 2-C 5 alkoxycarbonyl or a -CONH HICOOR RC group, wherein R c and R 9 are as defined in claim 2; Cl v) a -NHCOCH-NH group, wherein R is as defined in cllaLm 2; 2 c c 9 dIv) a -CH 2 OCO(CH 2) n COOR f or a -NHCO(CH 2) n COOR f group, wherein n and R f are as def ined in claim 2; or efv) a -N=CH-N 11.1 R V group, wherein R''' and RIv are as defined in claim, 2; R 3 represents hydrogen, halogen, or C 1-C 4 alkoxy; R 4 represents hydrogen; c 1-C 4 alkyl 1 Q represents hydrogen, C 2 or C 3 alkoxycarbony'L or a -=:R11 a Rot b group wherein W' is hydrogen or C -C alkyl and R" is:-",-C a 1 4 b 4 alkyl, a -CH-COOR group wherein R and R are as defined in ziai-n, 9 9 C C or a -(CH 2 p- W@ 5 group in which p is zero, 1 or 2 and R" 5 Ils:

av) unsubstituted pyridyl; or phenyl unsubstituted or substitut- ed by a substituent chosen from nitro, halogen, CF 3' C 1-C 4 alkyl, C l- C 4 alkoxy, CH 2 OH, COOH, di(C 1 or C 2 alkyl', amino, hydroxy, formyloxy, C 2-C 6 alkanoyloxy and a -CH 2 N Root R 1 v in claim 2; group wherein Root and RIv are as def-'ned bv) 2-thienyl or 2-furyl; or CV) a heterocyclic ring which is selected from 2-th-Jazc" y-' or 3-isoxazolyl and which is unsubstituted or subs'-'t-j--e:i by methyl; and the pharmaceutically acceptable sall:s therecf.

4) A compound selected from the group consisting cf:

2-eyano-3-(4,5-dihydro-l-phenyl-[11-benzFilindazol-3-y-,-3OXON-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(4,5-dihydro-lphenylEl-,-,--,---z Eglindazol-3-yl)-3-oxo-propanamide; 2-cyano-N-(4-fluorophenyl)-3-E1-(4-fluoro-phenyl)-4,5-dit,.ydrork]-benzFg]indazol-3-yl]-3oxo-propanamide; 1 C; 46.

2-cyano-3-(1,5-dihydro-l-phenyl-[2]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3oxo-N-phenyl-propanamide; N-benzyl-2-cyano-3-(1,5-dihydro-l-phenyl-[21benzothiopyrano [4,3-cjpyrazol-3-yl)-3-oxo-propanamide; 2-eyano-N-(4fluoro-phenyl)-3-(1,5-dihydro-l-phenyl-[23benzothiopyrano[4,3-cl pyrazol3-yl)-3-oxo-propanamide; 2-eyano-N-(4-fluoro-phenyl)-3-[1-(4-fluorophenyl)-1,5dihydro-[21-benzothiopyrano[4,3-clpyrazol-3-yll-3oxopropanamide; 2-cyano-3-(1,5-dihydro-8-methyl-l-phenyl-[21-benzothiopyrano [4,3clpyrazol-3-yll-3-oxo-propanamide; 3-(8-chloro-1,5-dihydro-l-phenyl-[2jbenzothiopyrano[4,3-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-eyano-3-(1,5-dihydro-l-phenyl-[21-benzopyrano[4,3-clpyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-eyanoN-(4-fluoro-phenyl)-3-(1, 5-dihydro-l-phenyl-[2] benzopyrano[4,3-clpyrazol-3-yl)-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluorc-phenyl)-1,5dihydro-[23benzopyrano[4,3-clpyrazol-3-yll-3-oxo- propanamide; and the pharmaceutically acceptable salts thereof.

5) Process for the preparation of a compound of formula (I) and the salts thereof, according to claim 1, the process comprising:

1 X 1 47.

a reacting a compound of formula (II) R R 3 X R 4 (11) wherein X, R1 9 R 21 R 3 and R 4 are as defined inclainl, and Y is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III) wherein Q' is as Q definedinclairn 1 except carboxy, so obtaining a compound of formula (I), wherein Q is as def ined in 1 except carboxy; or b) reacting a compound of formula (IV) R 2 R 3 COCH em R 4 X z (M 118.

wherein X, Ri 1 R 2' R 3 and R 4 are as defined in claim 1, with a compound formula (V) R JN=C=0 (V) wherein R b is as defined in claim 1, so obtaining a compound of formula (I) wherein Q is a -CONHR b group, wherein R b is as defined in claim. 1; or c) reacting a compound of formula (VI) R r- % COCH R 2 1 R 3 R 4 X ,o.c H z (VI) wherein X, Ri 9 R 2' R 3 and R 4 a--e as defined in claim 1,and Z is a reactive derivative of a carboxy group, with a compound of formula (VII) R a R (VII) i j 1 ( 1 49.

wherein R and R b are as defined in claim ll, so obtaining a compound of formula (I) wherein R is a -CON a group, wherein R and R b are as defined b in claim 1; or d) hydrolysing a compound of formula (I), wherein Q is a c C alkoxycarbonyl or -CON a group in which R CH-COOR c a and R c are as defined in claim 1,and R is C 1_ c 6 alkyl, so as to obtain the corresponding compound of formula (I), wherein Q is a free carboxy group or a -CON a "'CH-COOH c group, in which R and R are as defined in claim 1, and, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a compound oL formula (I) into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of a compound of formula (I), into the single isomers.

6) A pharmaceutical compos4.","-ion cnntaining a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

f& 4 50.

7. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy. 8. A compound of formula (I) or salt thereof according to claim 7 for use as an immunostimulant agent. 9. A compound of formula (I) or salt thereof according to claim 8 for use in the treatment of an acute or chronic infection of bacterial or viral origin.

A compound of formula (I) or salt thereof according to claim 8 for use in the treatment of a neoplastic disease.

11. A process for the preparation of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, said processbeing substantially as hereinbefore described in any one of Examples 1 to 10.

12. A pharmaceutical composition substantially as hereinbefore described in Example 11.

PubILahd1990 at The Patent OZice.StatoRoum.CA'71 H4hHolbr,,z,.1,ordonWC I R 4Tp P-.C.er copies rnay be obuunedft-m The Patentomce Me& Branch. St Mary Cray. OrpLreon. kenj BM 3RD PrLnied by M,11tjplex tachrijque. M.St 3. Izxi Cray, Kent. GDn 1,87 1 1