HETEROARYL-3-OXO-PROPANENITRILE DERIVATIVES USEFUL IN STIMULATING MYELOPOIESIS

Abstract: Heteroaryl-3-oxo-propanenitrile derivatives of formula (I) wherein X represents an oxygen atom or a -CH(R4)-, -O-CH(R4)-, -S(O)n-, -S(O)n-CH(R4)-, -CH(R4)-O-, -CH(R4)-S(O)n- or -CH(R4)-CH2- group wherein n is 0, 1 or 2; R1 represents C1-C6 alkyl, pyridyl or unsubstituted or substituted phenyl; R2, R3 and R4 are as herein defined; and Q is hydrogen, carboxy, C2-C7-alkoxycarbonyl or a -CON(Ra)Rb group, Ra and Rb being as defined herein; and their pharmaceutically acceptable salts are useful in stimulating myelopoiesis in bone marrow suppressed mammals.

Description: - 1 - HETER0ARYL-3-0X0-PR0PANENITRILE DERIVATIVES USEFUL IN STIMULATING MYELOPOIESIS Suppression of myelopoiesis is a frequent and sometimes life-threatening side-effect of the chemo- and radio-therapy in cancer and of the drugs used to treat rheumatoid arthriti and other autoimmune diseases. Suppression of myelopoiesis is common also in patients with severe burns and bone marrow disorders and in subjects that undergo organ transplantation, who are given i munosuppressant drugs to minimize the danger of rejection. To find a drug which is effective in stimulating myelopoiesi in bone marrow suppressed patients still remains an importan target for the today's Medicinal Chemistry, with large poten tial clinical application. The present invention relates, in one aspect, to a method of stimulating myelopoiesis in bone marrow suppressed mammals, including humans, which comprises administering to said mamm in need of such treatment, a therapeutically effective amoun of an active heteroaryl-3-oxo-propanenitrile derivative of formula (I), as herein defined, or a pharmaceutically accept salt thereof. In another aspect this invention relates to the use of a het aryl-3-oxo-propanenitrile derivative of formula (I), as here defined, or a pharmaceutically acceptable salt thereof in th preparation of a pharmaceutical composition for the use in stimulating myelopoiesis in bone marrow suppressed mammals, including humans. - 2 - Examples of pathological conditions in which a suppressed myelopoiesis takes place, which can be treated by the compounds of formula (I) or by the pharmaceutical compositions containing them, according to the method of treatment of the present invention, are those which occur in the case of cancer chemotherapy and cancer radiation therapy; in immunosuppressant therapy used for organ or tissue transplantation; in immunosuppressant therapy in the case of an autoimmune disease; in the case of autologous and allogenic bone marrow transplants; in the case of severe burns; in the case of accidental exposure to radiation or to certain chemicals, e.g. benzene, and in the case of aplastic anemia, myelodysplastic syndrome and congenital or acquired bone marrow disorders. The heteroaryl-3-oxo-propanenitrile derivatives, which are effective in stimulating myelopoiesis in bone marrow suppressed mammals and are useful in the method of treatment, or in the preparation of the pharmaceutical compositions, according to the present invention, are described in our patent applications EP-A-0274443, WO 89/12630, WO 89/12638 and British patent application No. 8902596.9, and can be represented by the following formula (I) (I) - 3 - wherein X represents a) an oxygen atom or a -S(0) n - group, wherein n is zero, 1 or 2; b) a -CH(R 4 )- group, wherein R 4 represents hydrogen or C^Cg alkyl; c) a -O-CH- or a -S(0) n -CH- group, wherein n and R 4 are as R 4 R 4 defined above; d) a -CH-O- or a -CH-S(0) n - group, wherein n and R 4 are as R R 4 defined above; or e) a -CH-CH 2 - group, wherein R 4 is as defined above; R 4 Ri represents Ci-Cg alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, Cj-Cg alkyl, C^-C alkoxy, nitro, amino, formylamino and C 2 -C 8 alkanoylamino; R 2 represents: a) hydrogen, halogen or C-^-Cg alkyl; b) hydroxy, C -Cg alkoxy or C 3 or C 4 alkenyloxy; c) nitro, amino, formylamino or C 2 -Cβ alkanoylamino; d) di (C^-Cg alkyl) amino or a group wherein each of R' and R" independently is C^-Cg 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-1-yl , - 4 - thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by C-^-C alkyl: e) -CH 2 OH, -CHO, -COOH or C 2 -C 7 alkoxycarbonyl; f) a -CONHCH-COOR jj group wherein R^ is hydrogen or C^-C Re alkyl and R c is hydrogen, phenyl or the side-chain of an α-aminoacid; g) a -NHCOCH-NH 2 group, wherein R c is as defined above; R c h) a , a -CH 2 OCO(CH 2 )n OOR °r a -NHCO(CH 2 ) n COOR group, wherein n is as defined above and R is hydrogen or C^Cg alkyl; k) a -CH=N-OR' 1 group wherein R 1 ± is hydrogen or a -CH 2 COOH group; i) a -CH=N-NH-R' group wherein R' 2 is hydrogen, -CH 2 CH OH, C2 or C 3 alkoxycarbonyl or a -(CH2)p-R* 3 group wherein p is 1 or 2 and R* 3 is COOH or C 2 -C 7 alkoxycarbonyl; R 1 1) a -CH=N-N=CH-N group wherein R' and R" are as defined above; or m) a group wherein R' and R" are as defined above; ^R 1 n) a C2-C7 alkoxycarbonyl group substituted by a -H-^ ^ group, wherein R' and R" are as defined above; R 3 is as R 2 defined above under a) , b) , and c) ; Q represents hydrogen, carboxy, C^-G-η alkoxycarbonyl or a - 5 - alkyl and R^ represents 2_-C 2 Q alkyl, a -CH-COOR3 group Rc wherein R^ and R c are as defined above or a -(A) m -R5 group wherein m is zero or 1, A is a C^-C alkylene chain and R 5 is a 1 ) C5-C 8 cycloalkyl; • ) pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C^-C alkyl and C^-Cg alkoxy; c') phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, CF 3 , C-^-Cg alkyl, C^C alkoxy, amino, nitro, formylamino, C 2 -C 8 alkanoylamino, alkyl)-amino, hydroxy, formyloxy and c 2~ c 8 alkanoyloxy; d') phenyl substituted by a -CH2OH, COOH, C2-C7 -R ' alkoxycarbonyl or a -Q^- group wherein R 1 and R" ^^ * R" are as defined above and optionally by another substituent chosen from halogen, C-L-Cg alkyl, Ci-Cg alkoxy, amino, nitro, formylamino, C 2 -Cs alkanoylamino, hydroxy, formyloxy and C2-C 3 alkanoyloxy, or e') 2-thienyl, 2-furyl or 1-(C^-Cg alkyl)-pyrrol-2-yl; or f 1 ) a heterocyclic ring which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C^-Cg alkyl. - 6 - It has to be noticed that the compounds of formula (I) may be represented also by a tauto eric structure, namely the enol structure of formula (la) wherein X, R ; , R 2 , R. and Q are as defined above. However, the compounds of formula (la), which fall within the scope of the present invention too, are described in th present specification as compounds of formula (I). A halogen atom is preferably chlorine or fluorine. The alkyl, alkylene, alkanoyloxy, alkoxy and alkanoylamino groups may be branched or straight chain groups . A C χ -C 20 alkyl group is preferably a C l -C_ 0 alkyl group, for example a C j -C, alkyl group. A C : -C β alkyl grou is, e.g., methyl, ethyl, propyl, isopropyl, butyl or tert.butyl. A C l - 1 alkyl group is more preferred such as methyl, ethyl or tert.butyl. A C j or C 4 alkenyloxy group is preferably allyloxy. A CJ-C J alkoxy group is, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy. Preferably it is C α -C_, alkoxy group such as methoxy, ethoxy or propoxy. A C 5 -C β cycloalkyl group is preferably cyclopentyl o cyclohexyl. 5 A C 2 -C β alkanoylamino group is preferably a C 2 -C alkanoylamino group, for example a C 2 -C, alkanoylamino grou such as acetylamino or propionylamino. A C 2 -C β alkanoylox group is preferably a C 3 -C 6 alkanoyloxy group, for example C 2 -C 4 alkanoyloxy group such as acetoxy or propionyloxy. TO A C 2 -C-7 alkoxycarbonyl group is preferably a C 4 -C 7 alkoxy carbonyl group, in particular a tertiary C-C 6 alkoxycarbony group such as tert.butoxycarbonyl or tert.amyloxycarbonyl. A C-.-C 6 alkylene chain is preferably a Cι-C 3 alkylen chain, such as a -CH 2 -, -(CH 2 ) 2 -, -{CH 2 ) 3 -, -CH- or -CH- chain. I I 5 CH 3 C 2 H 6 A di(C a. -C 6 alkyl)amino group is preferably a ditCi-C * alkyl)amino group, in particular a di(C α or C 2 alkyl) min group. R' -CH 2 N group, wherein R' and R" taken together with the R" nitrogen atom form a heterocyclic ring, is preferably a orpho- linomethyl, a thio orpholinomethyl or a N-piperazinyl-methyl group, wherein said heterocyclic rings may be unsubstituted or - substituted by Cj . -C 4 alkyl. - 8 - The asymmetric carbon atom to which the R-. group is linked may have either the R or S configuration. The side-chain of an α-aminoacid is specifically the residue obtained from an α-aminoacid by removing the amino and the carboxy groups together with the α-carbon atom to which they are linked. The side-chain of an α-aminoacid as defined above is preferably the side-chain 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. ) 2 (deriving from leucine) and -CH.-C S H S (deriving from phenylalanine) . Examples of pharmaceutically acceptable salts of the compounds of formula (I) are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, triethylaaine, triethanola ine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl )-amine, piperidine, N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine , β-phenethylamine, N-benzyl-g-phenethy - amine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumar c, methanesulphonic and ethanesulphonic acids. Preferred salts of the compounds of formula (I) are the sodium and the potassium salts thereof. Suitable compounds of formula (I) for use in the invention include in particular the following compounds whic are described in our above identified European. British an International patent applications: 2-cyano-3-(l , 4-dihydro-l-phenyl-[l ]-benzothiopyrano[ 4 , 3-c ] pyrazol-3-yl )-3-oxo-N-phenyl-propanamide; N-benzyl-2-cyano-3-(l , 4-dihydro-l-phenyl-[l ]-benzothiopyrano [ 4 , 3-c]pyrazol-3-yl )-3-oxo-propanam de; 2-cyano-N-(4-fluoro-phenyl )-3-( 1, 4-dihydro-l-phenyl-[ 1 ]- benzoth opyrano[ 4 , 3-c]pyrazol-3-yl )-3-oxo-propanamide ; 2-cyano-N-( 4-fluoro-phenyl)-3-[l-( 4-fluo o-phenyl )- - , 4- d hydro-! 1 ]-benzothiopyrano[ , 3-c ]pyrazol-3-yl )-3-oxo- propanamide ; 2-cyano-3-( 1 , 4-dihydro-8-methyl-l-phenyl-[ 1 ]-benzothiopyrano ( 4 , 3-c]pyrazol-3-yl ]-3-oxo-N-phenyl-propanamide ; 3-( 8-chloro-l,4-dihydro-l-phenyl-[ 1 ]-benzothiopyrano[ 4 ,3-c] pyrazol-3-yl )-2-cyano-3-oxo-N-phenyl-propanamide ; 3-( 6-amino-l , 4-dihydro-l-phenyl-[1 ]-benzothiopyrano[ 4 , 3-c] pyrazol-3-yl )-2-cyano-3-oxo-N-phenyl-propanamide ; N-( 3-chloro-phenyl)-2-cyano-3-(l,4-dihydro-l-phenyl-(l ]- benzothiopyranol 4 ,3-c]pyrazol-3-yl )-3-oxo-propanamide ; 2-cyano-3-(l , 5-dihydro-l-phenyl-[2)-benzothiopyranol , 3-c] pyrazol-3-yl )-3-oxo-N-phenyl-propanamide ; 2-cyano-3-( 4 ,5-dihydro-l-phenyl-[1 )-benz[ ]indazol-3-yl )-3- oxo-N-phenyl-propanamide ; 2-cyano-3-(8-ethoxalylamino-l,4-dihydro-l-phenyl-[1]-benzothio¬ pyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyrano[4,3-c]pyra- zol-3-yl)-N-(3-nitro-phenyl)-3-oxo-ρropanamide; 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyrano[4,3-c]pyra- zol-3-yl)-3-oxo-N-(3-trifluoromethy1-phenyl)-propanamide, • 3-(7-tert.butyl-l,4-dihydro-l-phenyl-indeno[l,2-c]pyrazol-3- -yl)-2-cγano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(7-fluoro-l,4-dihydro-l-phenyl-indeno[l,2-c]pyrazol- -3-y1)-3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1,4-dihydro-1-phenyl- -indenofl,2-c]pyrazol-3-yl-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(l,4-dihydro-7-methyl-l-phenyl- -indeno[l,2-c]pyrazol-3-yl)-3-oxo-propanamide; 3-(6-tert.butoxycarbonyl-1,4-dihydro-l-phenyl-[13-benzothio¬ pyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 3-(5-tert.butoxycarbonyl-1,4-dihydro-l-phenyl-indeno[1,2-c]py- razol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(l,4-dihydro-7-morpholinomethyl-l-phenyl-indeno [l,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1 ,4-dihydro-5-morpholinomethyl-l-phenyl-indeno [l,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(8-fluoro-1, -dihydro-6-morpholinomethyl-l-phenyl- -[1]-benzopyranot4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propana- mide; - 11 - 2-cyano-3-(1,4-dihydro-8-morpholinomethyl-l-phenyl-[1]- benzo-pyrano[4,3-cJpyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-6-N,N-dimethylaminoethoxycarbonyl-l- phenyl-[1]-benzothiopyrano[ ,3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide; 3-(6-carboxy-l,4-dihydro-l-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 3-(5-carboxy-l,4-dihydro-l-phenyl-indeno[l,2-c]pyrazol-3- yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3- (1 , 4-dihydro-l-phenyl-indeno [ 1 , 2 -c] pyrazol-3 -yl ) - 3-oxo-N-phenyl-propanamide ; 2-cyano-N- (4-f luoro-phenyl) -3- [1- (4-f luoro-phenyl) -1 , 4- dihydro-indeno [l , 2-c]pyrazol-3-yl] -3-oxo-propanamide ; 2 -cyano-N- ( 4 -f luoro-phenyl ) -3- ( 1 , 4 -dihydro-1-phenyl-indeno [l, 2-c]pyrazol-3-yl) -3-oxo-propanamide; N-(3-chloro-phenyl)-2-cyano-3-(1, -dihydro-1-pheny1-indeno [l,2-c]pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-3-(l,4-dihydro-7-methyl-l-phenyl-indeno[l,2c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-oxo-(l-phenyl-lH-benzothieno[3,2-c]pyrazol-3-yl)- N-phenyl-propanamide; 3-(8-carboxy-l,4-dihydro-l-phenyl-[1]-benzopyrano[4,3c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzopyrano[4,3c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 3-(8-amino-l, -dihydro-l-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-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; - 12 - a) reacting a compound of formula (II) wherein X, R^, R2 and R 3 are as defined above and Y is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III) CN CH 2 (III) Q' wherein Q 1 is as Q defined above, except carboxy, so obtaining a compound of formula (I) , wherein Q is as defined above except carboxy; or b) reacting a compound of formula (IV) COCHIN (IV) where n X, R , R and R are as defined above, with a compound formula (V) wherein R is as defined above, so obtaining a compound of formula (I) wherein 0 is a -C0NHR group, wherein is as defined b b above ; or c ) reacting a compound cf formula ( VI ) where in X, R. , R. and R. are as defined above and Z is a reactive i 2 3 derivative of a carboxy grcup, with a compound of formula ( (VII) - 14 - wherein R a and R D are as defined above, so obtaining a compound of formula (I) wherein Q is a are as defined above; or d) hydrolysing a compound of formula (I) , wherein Q is a C2-C7 alkoxycarbonyl or which R a and R c are as defined above and R is C-^-Cg alkyl, so as to obtain the corresponding compound of formula (I) , wherein Q is a free carboxy group or a -CON group in which ^CH-COOH I Rc R 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. The details inherent the methods of preparation are described in the above-identified European, International and British patent applications, the disclosures of which are incorporated herein by reference. Surprisingly, as stressed above, we have now found that the compounds of formula (I) , here above described, and their salts are effective in stimulating myelopoiesis in bone marrow suppressed mammals, including humans. Conditions wherein suppressed myelopoiesis occurs, thus creating a life-threatening state, and wherein the use of a compound of formula (I) , as herein defined, or a pharmaceutically acceptable salt thereof is of benefit in - 15 - stimulating myelopoiesis are for example the case of cancer chemotherapy and cancer radiation therapy; immunosuppressant therapy used for organ or tissue transplantation; 5 immunosuppressant therapy in the case of an autoimmune disease; the case of autologous and allogenic bone marrow transplants; the case of severe burns, the case of accidental exposure to radiation or to certain chemicals, e.g. benzene, and the case of asplastic anemia, 0 yelodysplastic syndrome and congenital or acquired bone marrow disorders. Particular cases of cancer chemotherapy in which the compounds of formula (I) , here above described are useful in stimulating myelopoiesis are, for example, those 5 in which the chemotherapeutic treatment is carried out by administration of one or more products chosen for exammple from the group of alkylating agents, e.g. cyclophosphamide, iphosphamide and chlorambucil, antibiotics, e.g. actinomycin D and mitomycin, anthracycline antibiotics, e.g. 0 daunorubicin and doxorubicin, antimetabolites, e.g. 5- fluorouracil, methotrexate and 6-mercaptopurine vinca- alkaloids, e.g. vinblastine and vincristine, and platinum complexes, e.g. cis-platin and carboplatin. Particular cases of immunosuppressant therapy in 5 which the the compounds of formula (I) , here above described, are useful in stimulating myelopoiesis are, for example, those in which the immunosuppressant treatment is carried out by administration of cyclophosphamide, azathioprine, 6-mercaptopurine, methotrexate and 0 corticosteroids. Preferred cases of organ transplants treated by immunosuppressant therapy, in which the compounds of formula (I) , here above described, are useful in stimulating myelopoiesis are, for example, the cases of heart kidney and 5 bone marrow transplants. - 16 - Preferred cases of autoimmune diseases, treated by immunosuppressant therapy, in which the compounds of formula (I) , here above described, are useful in stimulating myelopoiesis are, for example, the cases of rheumatoid arthritis, systemic lupus erythematosus, juvenile diabetes, ulcerative colitis, glomerulonephritis and multiple sclerosis. The myelopoiesis stimulating activity of the compounds of formula (I) is proved, for example, by the fact that they are effective in accelerating the recovery of the total cound of circulating leukocytes in immunosuppressed animals, as it comes out, for example, from the experimental data herein afterwards reported. Indeed, for instance the biological data set out in the Tables of the Examples herein provided show clearly that a therapy with a representative group of compounds according to the present invnetion accelerates leukocytes recovery in cyclophosphamide treated mice. A further object of the present invention is to provide a method of treatment of a disease having auto¬ immune basis by combined administration of (1) a pharmaceutical composition containing a compound of formula (I) , as herein defined, or a pharmaceutically acceptable salt thereof and (2) a pharmaceutical composition containing an effective amount of an immunosuppressant agent. Examples of diseases having auto-immune basis, which can be treated by the method of therapy, according to the present invention, are rheumatoid arthritis, systemic lupus erythematosus, juvenile diabetes, autoimmune haemolytic anaemia, ulcerative colitis, idiopathic thrombocytopenic purpura, active chronic hepatitis, glomerulonephritis and multiple sclerosis. - 17 - Examples of immunosuppressant agents which can be used according to the method of treatment provided by the present invention includes cyclophosphamide, azathioprine, 6-mercaptopurine, methotrexate and corticosteroids. The term "combined" administration according to the method of treatment provided by the present invention is meant to include both separate and substantially contemporaneous administration of a pharmaceutical composition containing a compound of formula (I) , as herein defined, or a pharmaceutically acceptable salt thereof and of a pharmaceutical composition containing an effective amount of an immunosuppressant agent. The separate treatment with a compound of formula (I) , or a pharmaceutically acceptable salt thereof, can commence prior, e.g. one or two days, to immunosuppressant treatment or subsequent, e.g. one or two days, to commencement of immunosuppressant treatment. Doses of immunosuppressant agent to be administered in practicing the method of the invention will of course vary depending upon, e.g., the mode of administration and the condition to be treated. In general, amounts administered will be of the same order to those conventionally employed in immunosuppressant therapy. In view of their high biological activity and low toxicity the compounds of the invention can be safely used in medicine. For example, the approximate acute toxicity (LD 50 ) in the mouse of the compounds 2-cyano-3-(l,4-dihydro-l- phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl- propanamide, - 18 - and 2-cyar.o-3-(l,<s-dihydro-l-phenyl-[l_J-benzoth opyrano £4 ,3-c3pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, determin¬ ed per os with single administration of increasing doses and measured on the seventh day after the day of treatment, is higher than 80C mg/kg. Analogous toxicity data have been found for the other compounds of formula (I). As preferred examples of compounds useful in stimulating myelopciesis in bone marrow suppressed mammals, the follow¬ ing can be mentioned: 2-cyano-3-(1,4-dihydro-l-phenyl-flj-benzoth opyranoC 4 t 3-c] pyrazcl-3-yl)-3-oxo-N-phenyl-propana.τ.ide( nternal code FCE 2^578 , 2-cya.no-3-(l ,4-dihydro-l-phenyl-indencfl ,2-cJ pyrazcl-3-yl)-3-oxo-N-phenyl-propanamide (internal code FCE 25276), 2-cyanc- -(4-fluoro-phenyl)-3-Q- (4- lucrc-phenyl)- 1 ,4-dihydro-[l]-benzothiopyrano£4,3-c3pyrazol-3-yl3-3-oxo- propanar. de (internal code FCE 25611) and 2-cyano-N-(4-fluoro- phenyl )-3-Cl-(4-flucro-phenyl )-l , -dihydro-indeno[l ,2-c pyrazcl- 3-yl )-3-cxc-prcpar.a.-.ide (internal code FCE 26317). The therapeutic regimen for the different pathological condi- tions 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 conditions 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 syndromes. - 19 - For maintenance regimens the oral or parenteral, e.g. intramuscular or subcutaneous, route is preferred. For these purposes the compounds of the invention, for example 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (internal code FCE 24578) and 2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)- 3-oxo-N-phenyl-propanamide (internal code FCE 25276) , 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. The present invention also refers, in another aspect, to pharmaceutical compositions suitable for stimulating myelopoiesis in bone marrow suppressed mammals, including humans, comprising a compound of formula (I) , as defined above, in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent) . The nature of the pharmaceutical compositions containing the compounds of formula (I) 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 oily solutions or suspension, tablets, pills, gelatine capsules, syrups, drops or suppositories. Thus, for oral administration, the pharmaceutical compositions SUBSTITUTESHEET - 20 - containing tr.e ccrr.pc r.ds cf tr.is ir.ver.tiεr., are preferably tablets, pills cr gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, manni ol, scrbitcl, cellulose; lubricants, for i.-.sta.-.ce silica, talc, stearic acid, magnesium or calciur. stearate, a d.' cr polyethylene glyccls; or they may also contain binders, such as starches, gelatine, methylcellulose, carboxymethylcell icεe, gum-arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents, such as starches, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, ir. 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, tablett- ing, sugar-coating, or film-coating processes. 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, methyl- cellulose, 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, sesame oil, miglyol, ethyl oleate, glycols, e.g. propylene glycol, and one or more customary ingredients according to the pharmaceutical formulation techniques, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injec- tions or infusions may contain as carrier , for example , ster water or preferably they may be in the form of sterile aque isotonic saline solutions . The suppositories may contain together with the active compo a pharmaceutically acceptable carrier , e . g. cocoa-butt polyethylene glycol , a polyoxyethylene sorbitan fatty a ester surfactant or lecithin. Preferred ocπpounds of formul (I) , suitable for stimulating myelopoiesis in bone marrow suppressed normals, including hunans, are the cαrpounds of formula (I) wherein X represents: a) a -S(0)„- group wherein n is as defined above; b) a -CH(R β )-group wherein R 6 represents hydrogen or C α or C 2 alkyl; c) an -0-CH- or a -S(0)„-CH- group, wherein n and R 6 are as d I « Re Re fined above; or d) a -CH-CH 2 - group, wherein R β is as defined above; Re Ri represent C^-C * alkyl or phenyl, the phenyl bei unsubstituted or svibstituted by a εubstituent chosen fr halogen, trifluoromethyl, C α -C 6 alkyl and C x -C β alkoxy; Rz represents: a) hydrogen, halogen, C_-C Λ alkyl or C^C alkoxy; b) nitro, amino, formylamino or C 2 -C_, alkanoylamino; c) di(Cj . or C 2 alkyl)amino or a -CH 2 -N group, wherein each Re of R- 7 and R β independently is Ci-C, alkyl or R-, and R β , taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N-pyrrolidinyl, N-piperazinyl, morpholino, thiomorpholino and piperidino an which is unsubstituted or substituted by Cι-C_, alkyl; d) -CH 2 OH, -COOH or C 2 -C- 7 alkoxycarbonyl; e) a -CON -COOR β group, wherein R β is hydrogen or Ci-C. alkyl and Re is as defined above; f) a -CH 2 0C0(CH J2 ) τ -C00R :C or a -NHCO(CH 2 )„COOR* group, wherein is as defined above and R £ is hydrogen or C ι -C 4 alkyl; R v g) C 2 -C 7 alkoxycarbonyl substituted by a -N group, wherei R β R-7 and R a are as defined above; R 3 is as R 2 defined above under a); Q represents hydrogen or a -CON group wherein R 9 represent hydrogen or Cι-C 6 alkyl and Rι β represents Ci-Ci o alkyl, a -CH-COOR β group wherein Rc and R β are as defined above or a R e -(A')m-Rn group wherein m is as defined above, A' is a C ι -C alkylene chain and R iX is: - 23 - a) pyridyl, unsubstituted or substituted by a substitue chosen from halogen, C_ or C 2 alkyl and Ci or C 2 alkoxy; b) phenyl, unsubstituted or substituted by one or t substituents independently chosen from halogen, CF 3 , Ci- alkyl, Ci-C * alkoxy, amino, nitro, formylainino, C 2 -C 4 alkanoylamino and di(Cι-C « alkyl)amino; c) phenyl substituted by C 2 -C v alkoxycarbonyl or by a -CH 2 -N / *' group, wherein R-, and R β are as defined above, a optionally by another substituent chosen from halogen, Ci- alkyl and Ci-C * alkoxy; d) 2-thienyl or 2-furyl; e) a heterocyclic ring which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C or C 2 alkyl; and the pharmaceutically accep table salts thereof. Further preferred compounds of formula (I) are those in which represents: a') a sulphur atom; b 1 ) a -CH- or a -CH-CH 2 - group, wherein R α2 is hydrogen or methyl; or c') a -O-CH- or a -S-CH- group, wherein R α2 is as defined above; Ri represents phenyl unsubstituted or substituted by a substituent chosen from halogen, trifluoromethyl and C x -C » - alkyl; R 2 represents: a' ) hydrogen, halogen, C x -C_, alkyl, C x -C_» alkoxy, amino or a -CH 2 -N group, wherein each of R X3 and R x _ » independently * is C__-C Λ alkyl or R x3 and B. Λ f taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N-pyrrolidinyl , N-piperazinyl, morpholino, thiomorpholino and piperidino and which is unsubstituted or substituted by methyl; b' ) -COOH, Ca-C-7 alkoxycarbonyl or a -CONHCH-COOR β group, wherein R β is hydrogen or C x -C* alkyl and e is hydrogen, phenyl or the side-chain of an α-aminoacid; c') a group, wherein n is as defined above and R o is hydrogen or C x -C« alkyl; d' ) a C 2 -C alkoxycarbonyl group substituted by a -N group, wherein R x3 and R x « are as defined above; R 3 represents hydrogen, halogen or C x -C„ alkyl; °- represents hydrogen or a group wherein R 15 is hydrogen or C x -C 2 alkyl and R xβ is C x -C β alkyl, a - -COOR α group, wherein ΕLg is hydrogen or C x -C« alkyl and Rβ is as - - defined above, or a -(A') m -R 17 group wherein is zero or 1, A' is a C x -C 3 alkylene chain and R x7 is: a") unsubstituted pyridyl; or phenyl unsubstituted or substituted by a substituent chosen from halogen, CF 3 , C x -C 2 alkyl, C x -C 2 alkoxy, nitro, di(C x -C 2 alkyl)amino and a -CH 2 N group, wherein R X3 and R x « are as defined above; •K-X* b") 2-thienyl or 2-furyl; or c") 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. In particular preferred compounds of formula (I) are those in which X represents: a"') a sulphur atom or a -CH 2 - or -CH 2 -CH 2 - group; or b"' ) a -0-CH 2 - or a -S-CH 2 - group; R x represents phenyl unsubstituted or substituted by halogen; R 2 represents hydrogen, halogen, C x -C * alkyl, C 2 -C-, alkoxycarbonyl or a -CH 2 - group, wherein R xβ and R xβ , taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N- -piperazinyl morpholino and thiomorpholino and which is — 2o — unsubstituted or substituted by methyl; R 3 represents hydrogen, halogen or C x -C alkyl; Q represents a -CONH-(A")τn-R 2 o group wherein m is zero or 1, A" is a C x -C 2 alkylene chain and R ao is phenyl unsubstituted or substituted by a substituent chosen from halogen, nitro and trifluoromethyl; and the pharmaceutically acceptable salts thereof. Specific examples of preferred compounds of formula (I) suitable for treating autoimmune diseases, are the followin ones: 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; N-benzyl-2-cyano-3-(1, -dihydro-l-phenyl-[1]-benzothiopyrano f4,3-c]pyrarol-3-yl)-3-oxo-propanamide; 2-cyano-N-( -fluoro-phenyl)-3-(1,4-dihydro-l-phenyl-11]- benzothiopyrano! ,3-c]pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-[l-(4-fluoro-phenyl)-l,4- dihydro-[l ]-benzothiopyrano[ ,3-c]pyrazol-3-yl]-3-oxo- propanamide; 2-cyano-3-(l ,4-dihydro-8-methyl-l-phenyl-[1]-benzothiopyrano [4 ,3-c]pyrazol-3-yl.-3-oxo-N-phenyl-propanamide; 3-(8-chloro-l,4-dihydro-l-phenyl-[1]-benzothiopyrano!4,3-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; N- ( 3-chloro-phenyl ) -2-cyano-3- ( l, -dihydro-l-phenyl-tl]- benzothiopyrano! ,3-c}pyrazol-3-yl )-3-oxo-propanamide; - 27 - 2-cyano-3-(1,4-dihydro-l-phenyl-indeno[l,2-c]pyrazol-3-yl)- 3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1,4- dihydro-indeno[1,2-c]pyrazol-3-yl]-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(1 , -dihydro-l-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide; N-(3-chloro-phenyl)-2-cyano-3-(l, -dihydro-l-phenyl-indeno [l,2-c]pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-3-(l,4-dihydro-l-phenyl-[l]-benzopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-phenylpropanamide; 2-cyano-3-(l,4-dihydro-7-methyl-l-phenyl-indeno[l,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 3-(7-tert.butyl-l,4-dihydro-l-phenyl-indeno[l,2-c]pyrazol-3- yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(7-fluoro-l,4-dihydro-l-phenyl-indeno[l,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-l,4-dihydro-l- phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide; 3-(7-tert.butyl-l,4-dihydro-l-phenyl-indeno[l,2-c]pyrazol-3- yl)-2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide; 2-cyano-N- ( 4-fluoro-phenyl ) -3- ( l,4-dihydro-7-methyl-l-phenyl -indenoC1,2-c]pγrazol-3-yl)-3-oxo-propanamide; 3- ( 6-tert.butoxycarbonyl-1,4-dihydro-l-phenyl-[l]-benzothio¬ pyrano!4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide 3- ( 5-tert.butoxycarbonyl-1,4-dihydro-l-phenyl-indeno!1,2-c]p razol-3-yl ) -2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1, -dihydro-5-morpholinomethyl-l-phenyl-indeno [l,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-l-phenγl- -[1]-benzopyrano!4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propana¬ mide; and t h e pharmaceutically acceptable salts thereof, in particular the sodium and the potassium salts. The following examples illustrate but do not limit the prese invention. • 29 - Example 1 Recovery of the total count of circulating leukocytes in cyclophosphamide immunosuppressed mice. Groups of 4 mice were injected once with the powerf bone marrow suppressant cyclophosphamide (CPA), at the dose of 200 mg/kg i.p. Beginning on the day after CPA injection and up to the day before the sacrifice, the mice were injected i.p. with the vehicle (5% methocel) or the test compou suspended in 5% methocel at the doses of 10 mg/kg. Periferal blood was drawn from the retroorbital plexus at different times after CPA treatment and total leukocytes were counted in a Biirker's hemocytometer. Following Table I summarizes the test data obtained for a representative compound of formula (I) according to the present invention, i.e. 2-cyano-3-(l,4-dihydro-l- phenyl-t1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo- -propanamide (internal code FCE 24578). - 30 - Table I - Recovery of the total count of circulating leukocytes in cyclophosphamide imr.unodepres- sed mice by FCE 24578 therapy. 0 Arithmetic mean from four mice +_ Standard error. ** - P <0.01 vs. vehicle treated mice (Dunnett's "t" test) 31 - Example 2 Recovery of the total count of circulating leukocytes in cyclophosphamide immunodepressed mice. Groups of 3 mice were injected once with cyclophosphamide (CPA) at the dose of 200 mg/kg i.p. Beginning on the day after CPA injection and for five consecutive days (from the day+1 up to the day+5) , the mice were injected i.p. with the vehicle (5% Methocel) or with the test compound, suspended in 5% Methocel, at the dose of 10 mg/kg. Peripheral blood was drawn from the retroorbital plexus at different times after CPA treatment and total leukocytes were counted in a Burker's hemocytometer. Following Table II summarizes the test data obtained for th following representative compounds of formula (I) according to the present invention; 2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1, -dihy dro-indenot1,2-c]pyrazol-3-yl]-3-oxo-propanamide (internal code FCE 26317); 2-cyano-3-(7-fluoro-l,4-dihydro-l-phenyl-indeno!1,2-c]pyra- zol-3-yl)-3-oxo-N-phenyl-propanamide (internal code FCE 26676); and 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyrano!4,3-c) pyrazol-3-yl)-3-oxo-propanamide (internal code FCE 24578) Table II - Recovery of the total count of circulating leuko¬ cytes in CPA i munodepressed mice by treatment with compounds FCE 26317, FCE 26676 and FC 24578. ° Arithmetic mean for three mice ± standard error. °° Days after CPA injection. ** P< 0.01 vs controls (Dunnett's "t" test). - 33 - Example 3 Recovery of the total count of circulating leukocytes in cyclophosphamide immunosuppressed mice. By proceeding according to the schedule of treatment descr bed in the Example 2, the following representative compoun of formula (I) accrding to the present invention were evaluated in the title biological test: 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzopyrano!4,3-c]pyra zol-3-yl)-3-oxo-N-phenyl-propanamide (internal code FCE 25158); 2-cyano-3-(1,4-dihydro-l-phenyl-indeno!1,2-c]pyrazol-3-yl) -3-oxo-N-phenyl-propanamide (internal code FCE 25276); N-benzyl-2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyra [4,3-c]pyrazol-3-yl)-3-oxo-prσpanamide (internal code FCE 25324); and 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyrano!4,3-c] pyrazol-3-yl)-3-oxo-propanamide (internal code FCE 24578). The test data obtained are summarized in the following Tab III. Table III -Recovery of the total count of circulating leuko- cites in CPA im unodepressed mice by treatment with coumpounds FCE 25158, FCE 25276, FCE 25324 and FCE 24578. ° Arithmetic mean for three mice ± Standard error. 00 Days after CPA injection. * P < 0.05 vs controls (Dunnett's "t" test) ** P < 0.01 vs controls (Dunnett's "t" test). Example 4 Recovery of the total count of circulating leukocytes in cyclophosphamide immunodepressed mice. By proceeding according to the schedule of treatment described in the Example 2, the following representative compounds of formula (I) according to the present inventio were evaluated in the title biological test: 2-cyano-3-(1,4-dihydro-7-methyl-l-phenyl-indeno[l,2-c]pyra zol-3-yl)-3-oxo-N-phenyl-propanamide (internal code FCE 26418); and 2-cyano-3-(1,4-dihydro-l-phenyl-[1]-benzothiopyrano!4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (internal code FCE 24578) . The test data obtained are summarized in the following Tab IV. - 36 - Table IV - Recovery of the total count of circulating leuko¬ cytes in CPA immunodepressed mice by treatment with compounds FCE 26418 and FCE 24578. 0 Arithmetic mean for three mice ± Standard error. βo Days after CPA injection. ** P < 0.01 vs controls (Dunnett's "t" test). 37 - FORMULATION EXAMPLES Formulation 1: Tablets Tablets, each weighing 150 mg and containing 50 mg of the active substance are manufactured as follows: Composition (for 10000 tablets) 2-cyano-3-(1 ,4-dihydro-l-phenyl-[lj-benzothio¬ pyrano ,3-c}pyrazol-3-yl)-3-σxo-N-phenyl- propanamide 500 g Lactose 710 g Corn starch 238 g Talc powder 36 g Magnesium stearate 16 g 2-cyano-3-(1,4-dihydro-l-phenyl-[ " jj-benzothiopyrano ζfi,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propan»amide, 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, com¬ minuted 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 β mm diameter. - 38 - Formulation 2: Capsules (50 mg; 2-cyano-3-( 1, -dihydro-l-phenyl- Q-benzothio¬ pyrano [4,3-cJρyrazol-3-yl )-3-oxo-N-phenyl- propanamide Lactose Corn starch Magnesium stearate Total 400 mg Encapsulate in two-piece hard gelatin capsules. Fcr- a ior. 3: Suppository (100 mg) 2-cy.ar.c-3-' 1 , [i]-benzothiopyrano [4, 3-c] pyrazcl-3-yl )-3-cxo-N-pher.yl-propan»amide 0.10 g Lecithin 0.07 " 0.53 " Total nr. r_. . ~ .. — _ a. :icn £ : Syrup 2-cyano-3-( 1, 4-dihydro-l-phenyl- lj-benzothiopyrano £4, 3-c3pyrazol-3-yl )-3-oxo-N-phenyl-propanamide , Sodium salt 1.0 g Gum tragacanth 1.0 Methyl-£-hydroxybenzoate 0.135 Propyl-£-hydroxybenzoate 0.015 Polyoxymethylene sorbitan monolaurate 5 Glycerine 30 Be 5 Saccharose 50 Natural Flavour q.s. Purified water to make 100 Formulation 5: Cream mg/g 2-cyano-3- ( 1 , 4-dihydro-l-phenyl- i} -benzothiopyrano C 4 .3-cJpyrazol-3-yl)-3-oxo-N-phenyl-propanamide 20.0 White petrolatum * " .O Cetylstearyl alcohol 72.0 Mineral oil 60.0 Polypropylene glycol 22.5 4-Chloro-m-cresol 1.0 Purified water to make 1.0 g Formulation 6: Ointment "ig/g 2-cyanc-3-( 1 , 4-dihydro-l-phenyl- £l] -benzothiopyrano [4, 3-c] pyrazcl-3-yl )-3-oxo-N-phenyl-propana.mide 50.0 Mineral oil 50.0 Propylene glycol 50.0 Petrolatum, to make 1.0 g Formulation 7: Suspension for intramuscular injection 2-cyano-3- ( 1 , 4-dihydro-l-phenyl- [l} -benzothiopyrano C 4 .3-c] pyrazol-3-yl) -3-oxo-N-phenyl-propanamide 5.0 g Aluminum monostearate 2.0 g Sesame oil to make 100 ml,

Claims: - 40 - CLAIMS 1. The use of a heteroaryl-3-oxo-propanenitrile derivative of formula (I) wherein X represents: a) an oxygen atom or a -S(0) n - group, wherein n is zero, 1 or 2; b) a -CH(R 4 )- group, wherein R represents hydrogen or Cτ_- C 6 alkyl; c) an -O-CH- or a -S(0) n -CH- group, wherein n and R 4 are as R4 R defined above; d) a -CH-O- or a -CH-S(0) n - group, wherein n and R 4 are as R 4 R 4 defined above; or e) a -CH-CH 2 - group, wherein R 4 is as defined above; R 4 ^ represents Cι-C 6 alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, ^- β alkyl, C^-Cg alkoxy, nitro, amino, formylamino and C 2 -C 8 alkanoylamino; - 41 - R 2 represents: a) hydrogen, halogen or Ci-Cg alkyl; b) hydroxy, Ci^Cg alkoxy or C3 or C 4 alkenyloxy; 5 c) nitro, amino, formylamino or C2-C8 alkanoylamino; d) di (Ci-Cg alkyl) amino or a -CH 2 -N group wherein each of R' and R M independently 10 is C-^-Cg 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-1-yl, thiomorpholino, morpholino and 15 piperidino and which is unsubstituted or substituted by j^ -C β alkyl; e) -CH 2 0H, -CHO, -COOH or C 2 -C 7 alkoxycarbonyl; f) a -CONHCH-COOR- j group wherein R^ is hydrogen or C_i-C 6 Rc 20 alkyl and R c is hydrogen, phenyl or the side-chain of an α-aminoacid; g) a -NHC0CH-NH 2 group, wherein R c is as defined above; Rc 25 h) a , a -CH 2 OCO(CH 2 ) n COOR or a -NHCO(CH 2 ) n COOR group, wherein n is as defined above and R is hydrogen or C -C β alkyl; k) a is hydrogen or a -CH 2 COOH 30 group; i) a -CH=N-NH-R' 2 group wherein R' 2 is hydrogen or a -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 -Cy alkoxycarbonyl; _ :rcuo wherein P.' ar.d ar defined aocvs rr.) a group wherein R' and R" are as defined above; R' n) a C 2 -C 7 alkoxycarbonyl group substituted by a -N group, R" wherein R' and R" are as defined above; R is as defined above under a), b), and c); 0 represents hydrogen, carboxy, C,,-C_ alkoxycarbonyl or a group wherein Ra represents hydrogen or Ci-C2_„ 0 alkyl and R represents C -C alkyl, a -CH-COOR group wherein R c Ruand Rc are as defined above or a -(A)m-R5_ group wherein m is zero or 1, A is a Cl.-Cb. alkylene chain and RD_ is a 1 ) C -C_ cycloalkyl; b') pyridyl, unsubstituted or substituted by one or two • j _5 substituents chosen independently from halogen, C -C alkyl and C1-Cb_ alkoxy; c') phenyl, unsubstituted or substituted by one or two sub¬ stituents independently chosen from halogen, CF-, C,-C 3 I D alkyl, C. -C . alkcxy, arπino, nitro, formylamino, C„-C a 1 o _ 8 2o alkancylaminc, dι(C -C alkyl)-ammo, hydroxy, fcrr.ylcxy and C _-C alkanoyloxy; _ 6 ' ; p.nenvl substituted by a -CH.OK, COOK, C-C, 2 _ 1 alkoxycarbonyl or a group where: are as defined above and optionally by another substir e: chosen from halogen, C -C. alkyl, C -C. alkoxy, amino, r.: I D 1 6 formylamino, C -C_ alkanoylamino, hydroxy, formyloxy and C 2 -C alkanoyloxy, or e 1 ) 2-thienyl, 2-furyl or i-tC^C alkyl)-pyrrol-2-yl ; or f) a heterocyclic ring which is selected from 2-pyrimidyl , 2-thiazolyl .and 3-isoxazolyl and which is unsubstituted or substituted by C -C. alkyl; or a pharmaceutically 1 5 acceptable salt thereof, in the preparation of a pharma¬ ceutical composition useful in stimulating myelopoiesis in bone marrow suppressed mammals. _ M _ '2. The use of a heteroaryl-3-oxo-propanenitrile derivative of formula (I), or a pharmaceutically acceptabl salt thereof, according to claim 1, wherein in the compoun of formula (I) X represents: a) a -S(0)„- group wherein n is as defined above; b) a -CH(R β )-group wherein R 6 represents hydrogen or C or C 2 - alkyl; c) an -O-CH- or a -S(0)„-CH- group, wherein n and R β are as de- I I R β R β fined above; or d) a -CH-CH 2 - group, wherein R 6 is as defined above; I R 6 Ra. represent C^-d alkyl or phenyl, the phenyl bein unsubstituted or substituted by a substituent chosen fro halogen, trifluoromethyl, C α -C 6 alkyl and C x -C β alkoxy; R 2 represents: a) hydrogen, halogen, C x -C_, alkyl or C- J .-C,, alkoxy; b) nitro, amino, formylamino or C 2 -C_, alkanoylamino; c) di(C x or C 2 alkyl)amino or a -CH 2 - group, wherein eac R β of R-, and R β independently is C-i-C, alkyl or 7 and R β , take together with the nitrogen atom to which they are linked, for a heterocyclic ring which is selected from N-pyrrolidiny1, N-piperazinyl, morpholino, thiomorpholino and piperidino an which is unsubstituted or substituted by Ci-C, alkyl; - 45 - d) -CH 2 OH, -COOH or C 2 -C»7 alkoxycarbonyl; e) a -CONHCH-COOR-, group, wherein R-, is hydrogen or C x -C « alk I Ro and R c is as defined above; f) a -CH 2 OCO(CH 2 )„COOR._. or a -NHCO(CH 2 ) r -COOR. * group, wherein is as defined above and R_ is hydrogen or Ca.-C Λ alkyl; R^ g) C 2 -C v alkoxycarbonyl substituted by a -N group, where R β -7 and R β are as defined above; R 3 is as R 2 defined above under a) ; Q represents hydrogen or a -CON * group wherein R 9 represen hydrogen or C α -C 6 alkyl and R αo represents Ci-C 10 alkyl, a -CH-COOR w group wherein R c and R β are as defined above or a I R c -(A')ι-n-Rχχ group wherein is as defined above, A' is a C-.- alkylene chain and R X1 is: a) pyridyl, unsubstituted or substituted by a substitue chosen from halogen, C x or C 2 alkyl and C x or C 2 alkoxy; b) phenyl, unsubstituted or substituted by one or t substituents independently chosen from halogen, CF 3 , C α - alkyl, C- J .-C., alkoxy, amino, nitro, formylamino, C 2 -C alkanoylamino and di(C x -C 4 alkyl)amino; c ) phenyl substituted by C 2 -C 7 alkoxycarbonyl or by a 7 / -CH 2 -N group, wherein R-, and R β are as defined above, optionally by another substituent chosen from halogen, C x alkyl and C x -C_, alkoxy; d) 2-thienyl or 2-furγl; e) a heterocyclic ring which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C x or C 2 alkyl. 3. The use of a heteroaryl-3-oxo-propanenitrile derivative o formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein in the compound of formula (I) X represents: a' ) a sulphur atom; b' ) a - CH 2 - group, wherein R X2 is hydrogen or methyl; or c' ) a -O- group, wherein R i2 is as defined above; R x represents phenyl unsubstituted or substituted by substituent chosen from halogen, trifluoromethyl and Cχ-C « - alkyl; R 2 represents: a') hydrogen, halogen, C X -C Λ alkyl, C x -C 4 alkoxy, amino or a R x3 -CH 2 -N group', wherein each of R X3 and R X4 independent is C x -C_, alkyl or R x3 and R 1<€ , taken together with the nitr atom to which they are linked, form a heterocyclic ring w is selected from N-pyrrolidinyl, N-piperazinyl, morpholi thiomorpholino and piperidino and which is unsubstituted substituted by methyl; b' ) -COOH, C 2 -C-, alkoxycarbonyl or a -CONHCH-COOR β group, I R,, wherein R β is hydrogen or Cχ-C_» alkyl and R c is hydrog phenyl or the side-chain of an α-aminoacid; c') a group, wherein n is as defined above R„ is hydrogen or C x -C * alkyl; d') a C 2 -C-, alkoxycarbonyl group substituted by a -N x* group, wherein R X3 and R x * are as defined above; R 3 represents hydrogen, halogen or C x -C_, alkyl; Q represents hydrogen or a group wherein R x5 is hydrogen or C α -C 2 alkyl and R X6 is Cχ-C β alkyl, a -COOR ff group, wherein R ^ is hydrogen or C x -C« alkyl and R e is as - 48 - defined above, or a - (A' ) m -R_-. group wherein is zero or 1, A' is a C x -C 3 alkylene chain and R x7 is: a" ) unsubstituted pyridyl; or phenyl unsubstituted or substituted by a substituent chosen from halogen, CF 3 , C x -c 2 alkyl, C x -C 2 alkoxy, nitro, di{C x -C 2 alkyl)amino and a group, wherein R X3 and R « are as defined above ; b") 2-thienyl or 2-furyl; or c" ) a heterocyclic ring which is selected from 2-thiazolyl or 3-isoxazσlyl and which is unsubstituted or substituted by methyl, 4 . The use of a heteroaryl-3-oxo-propanenitrile derivative of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein in the compound of formula ( I) X represents: a'") a sulphur atom or a -CH 2 - or -CH 2 -CH 2 - group; or b'") a -0-CH 2 - or a -S-CH 2 - group; R x represents phenyl unsubstituted or substituted by halogen; R 2 represents hydrogen, halogen, C x -C« alkyl, C 2 -C-, / *" alkoxycarbonyl or a -CH 2 -N group, wherein R α . and R xβ , taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N- -piperazinyl morpholino and thiomorpholino and which is - 49 - unsubstituted or substituted by methyl; R 3 represents hydrogen, halogen or C x -C_ alkyl; Q represents a -C0NH-(A")„,-R 2O group wherein m is zero or 1, A" is a C x -C 2 alkylene chain and R ao is phenyl unsubstitute or substituted by a substituent chosen from halogen, nitr and trifluoromethyl; and the pharmaceutically acceptabl salts thereof. 5. The use of a heteroaryl-3-oxo-propanenitrile derivative o formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein said derivative is chosen from the group consisting of: 2-cyano-3- ( 1, -dihydro-l-phenyl-[1.-benzothiopyrano[ ,3-c ) pyrazol-3-yl ) -3-oxo-N-phenyl-propanaaide; N-benzyl-2-cyano-3- ( l,4-dihydro-l-phenyl-[1J-benzothiopyrano 14,3-c]pyrazol-3-yl ) -3-oxo-propanamide; 2-cyano-N- ( 4-fluoro-phenyl )-3-(l,4-dihydro-l-phenyl-[1 ]- benzothiopyrano! , 3-c]pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-N-( -fluoro-phenyl)-3-[l-( -fluoro-phenyl )-l,4- dihydro-[1 )-benzothiopyrano[ ,3-c]pyrazol-3-yl ]-3-oxo- propanaπide; 2-cyano-3-{1,4-dihydro-8-me hyl-l-phenyl-[1)-benzothiopyrano [4 ,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; 3-(8-chloro-l, -dihydro-l-phenyl-[1 J-benzothiopyrano!4 ,3-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; N- ( 3-chloro-phenyl)-2-cyano-3-(l, -dihydro-l-phenyl-[1 ]- benzothiopyrano!4,3-c]pyrazol-3-yl)-3-oxo-propanamide; - 50 - 2-cyano-3-(l,4-dihydro-l-phenyl-indeno[1,2-c]pyrazol-3-yl)- 3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-[l-(4-fluorophenyl)-l,4- dihydro-indeno[1 ,2-c]pyrazol-3-yl]-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(1 # 4-dihydro-l-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide; N-(3-chloro-phenyl)-2-cyano-3-(1, -dihydro-l-phenyl-indeno [l,2-c]pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-3-(l,4-dihydro-l-phenyl-[l]-benzopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-7-methyl-l-phenyl-indeno[1,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 3-(7-tert.butyl-1,4-dihydro-l-phenyl-indeno[1,2-c]pyrazol-3- yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(7-fluoro-l,4-dihydro-l-phenyl-indeno[1,2c] pyrazol-3-y1)-3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-l,4-dihydro-l- phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide; 3-(7-tert.butyl-1,4-dihydro-l-phenyl-indeno[1,2-c]pyrazol-3- yl)-2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(l,4-dihydro-7-methyl-l- phenyl-indeno[l,2-c]pyrazol-3-yl)-3-oxo-propanamide; 3-(6-tert.butoxycarbonyl-1,4-dihydro-l-phenyl-[1]- benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl- propana ide; 3-(5-tert.butoxycarbonyl-1,4-dihydro-l-phenyl-indeno[1,2-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-5-morpholinomethyl-l-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-l-phenyl- [1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl- propanamide. 6. Products containing a heteroaryl-3-oxo-propane- nitrile derivative of formula (I) wherein 5 X represents: a) .an oxygen atom er a -S(0J n ~ group, wherein n is zero, 1 or b) a -CK(R^)- roup, wherein R 4 represents hydrogen or C -C alkyl c) an -O-CH- or a -S(0) -CH- group, wherein n -and R are as I n j 4 R 4 R 4 defined above; 10 d) a -CIH-O- or a -CjH-S(O)n- group, wherein n and R A are as defined above; or e) a -C IH-CH _- group, wherein is as defined above; • χ represents C j -C alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen '5 independently frorr, halogen, trifluoromethyl, C -C alkyl, C -C 1 6 ' 1 6 alkoxy, nitro, a.τ.;no, fcr-.y latino and C -C alJβncylanir.o; - 52 - R2 represents: a) hydrogen, halogen or C j^ -Cg alkyl; b) hydroxy, Ci-Cg alkoxy or C 3 or C alkenyloxy; c) nitro, amino, formylamino or C2~Cg alkanoylamino; d) di (C^-Cg alkyl) amino or a -CH 2 ~ N group wherein each of R' and R w independently is C^-Cg 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-1-yl, thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by C -C 6 alkyl; e) -CH2OH, -CHO, -COOH or C2-C7 alkoxycarbonyl; f) a -CONHCH-COOR-j group wherein R3 is hydrogen or C^-Cg Rc alkyl and R c is hydrogen, phenyl or the side-chain of an α-aminoacid; g) a -NHCOCH-NH 2 group, wherein R c is as defined above; Rc 0 OR h) a -CH 2 P , a -CH 2 0C0(CH 2 ) n C00R or a ^^ OR -NHCO(CH 2 ) n COOR group, wherein n is as defined above and R is hydrogen or C^-Cg alkyl; k) a group wherein R'j. is hydrogen or a -CH 2 COOH group; i) a -CH=N-NH-R' 2 group wherein R' 2 is hydrogen or a -CH2CH2OH, C2 or C3 alkoxycarbonyl or a -(CH2) -R*3 group wherein p is 1 or 2 and R » 3 is COOH or C 2 -C 7 alkoxycarbonyl; . - 53 - 1) a group wherein R' and R" are as defined above; or m) a group wherein R 1 .and R" are as defined above; R » n ) a Ca-C-7 alkoxycarbonyl group substituted by a - group, R" wherein R' and R" are as defined above; ^ is as R defined above under a), b), .and c); 0 represents hydrogen, carboxy, C,-C, alkoxycarbonyl or a t_ I group wherein R represents hydrogen or C ι -C alkyl and R represents C -C alkyl, a -CH-COOR group wherein R c R.and R are as defined above or a -(A) -R-. group wherein m d c m 5 is zero or l, A is a C -C alkylene chain and R g is a') C -C 8 cycloalkyl; b') pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C -C •1 6 alkyl and C.-C, alkoxy; 1 6 C) phenyl, unsubstituted or substituted by one or two sub¬ stituents independently chosen from halogen, CF,, C -C, alkyl, C -C, alkcxy, a^ino, nitro, formyl-amino, C,-C e 6 _ o alkanoylamino, di (C -C alkyl )-amino, hydroxy, forr.yloxy and C -C alkanoyloxy; d') phenyl substituted by a -CH OH, COOH, C -C- alkoxycarbonyl or a group wherein R' and ?.' are as defined above and optionally by another substituent chosen from halogen, . -C^ alkyl, ^-C alkoxy, amino, nit formylamino, C.-C 8 alk-anoylamino, hydroxy, formyloxy and C -C alkanoyloxy, or e') 2-thienyl, 2-furyl or 1-(C 1 «C alkyl)-pyrrol-2-yl; or f) a heterocyclic ring which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C..-C, alkyl; or a pharmaceutically _ o acceptable salt thereof, and an immunosuppressant agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease having auto¬ immune basis. - 55 - 7. A metho d of treatment of a disease having auto¬ immune b asis by combined administration of ( 1 ) a p h armaceutical composition containing a compound of formula (I) wherein X represents: a ) an oxygen atom or a -S(0) n - group, wherein n is zero, 1 or 2; b ) -c'(R^-group,wherein 4 represents hydrogen or C -C alkyl; c) an -O-CIH- or a -S(0)n-C j H- group, wherein n .and R4 are as « R 4 defined above; d ) a -C IH—0- or a -CjH-S(O)n- group, wherein n and R A are as defined above; or e) a -C IH-CH2- grcup, wherein 4„ is as defined above; R. represents alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently frorr. halogen, trifluoromethyl, C -C alkyl, C -C 1 6 ' 1 6 alkoxy, nitro, amino, fcrr.yl mino .and C -C aDencylamir.o; - 56 - R2 represents: a) hydrogen, halogen or C^-Cg alkyl; b) hydroxy, C^-C alkoxy or C 3 or C 4 alkenyloxy; c) nitro, amino, formylamino or C2-C8 alkanoylamino; d) di (Ci-Cs alkyl) amino or a R « -CH 2 -N group wherein each of R' and R" independently is C^-Cg 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-1-yl, thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by Cχ-Cβ alkyl; e) -CH 2 OH, -CHO, -COOH or C 2 -C 7 alkoxycarbonyl; f) a -CONHCH-COOR-j group wherein R is hydrogen or C -Cg Rc alkyl and R c is hydrogen, phenyl or the side-chain of an α-aminoacid; g) a -NHCOCH-NH 2 group, wherein R c is as defined above; Rc h) a , a -CH 2 OCO(CH 2 ) n COOR or a -NHCO(CH 2 ) n COOR group, wherein n is as defined above and R is hydrogen or C^-Cg alkyl; k) a -CH=N-OR* 1 group wherein R^ is hydrogen or a -CH 2 COOH group; i) a -CH=N-NH-R' 2 group wherein '2 is hydrogen or a -CH2CH2OH, C or C 3 alkoxycarbonyl or a -(CH 2 )p-R'3 group wherein p is 1 or 2 and R' 3 is COOH or C2-C7 alkoxycarbonyl; - - I ) a group wherein R * and P." are as defined above ; or m) a group wherein R ' .and R" are as defined above ; R' n) a C 2 -C-, alkoxycarbonyl group substituted by a -N group, R" wherein R* and R" are as defined above; R^ is as defined above under a), b), and c); 0 represents hydrogen, carboxy, C,,-C 7 alkoxycarbonyl or a alkyl and R represents C -C alkyl, a -CH-COOR group wherein R c R,and R are as defined above or a -(A) -R, group wherein ra d c 5 is zero or 1, A is a C -C. alkylene chain and R. is 1 O 3 a') C -C 8 cycloalkyl; b') pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C.-C 1 6 alkyl and C -C. alkoxy; c*) phenyl, unsubstituted or substituted by one or two sub¬ stituents independently chosen from halogen, CF_, C -C. 3 1 6 alkyl, C,-C. alkoxy, a.*aino, nitro, formylamino, C,-C. 1 D 2 8 alkanoylamino, di(C -C alkyl )-amino, hydroxy, forr.yloxy and C -C alkanoyloxy; - 58 - d 1 ) phenyl substituted by a -CH OH, COOH, C 2 -C R - alkoxycarbonyl or a -CH2-N group wherein R* and R" ^R" are as defined above and optionally by another substituent chosen from halogen, C^-Cg alkyl, C^-C alkoxy, amino, nitro, formylamino, C2-C8 alkanoylamino, hydroxy, formyloxy and C 2 -Cs alkanoyloxy, or e') 2-thienyl, 2-furyl or l-f^-C alkyl)-pyrrol-2-yl; or f*) a heterocyclic ring which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by Ci-C. alkyl; or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutical composition containing an effective amount of an immunosuppressant agent. 8. A process for the preparation of a pharmaceutical composition active in stimulating myelopoiesis in bone marrow suppressed mammals, characterized in that the composition is prepared in unit dosage form and a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, is added, as active principle, to a pharmaceutically acceptable carrier and/or diluent in an amount of from 14 mg to 700 mg for each unit dosage.

Inventors: DORIA GIANFEDERICO, FERRARI MARIO, FERRECCIO RINALDO, FORNASIERO MARIA CHIARA, ISETTA ANNA MARIA, TRIZIO DOMENICO, DORIA, GIANFEDERICO, FERRARI, MARIO, FERRECCIO, RINALDO, FORNASIERO, MARIA, CHIARA, ISETTA, ANNA, MARIA, TRIZIO, DOMENICO
Applicants: ERBA CARLO SPA, FARMITALIA CARLO ERBA S.R.L.
Application year: 1990
Main classification: C07D491
IPC codes: A61K31, A61P7, C07D231, C07D491, C07D495