Oxopropanenitrile derivatives of condensed pyrazole or their pharmaceutically acceptable salts, manifesting immunostimulirutuyu activity, and pharmaceutical composition

 

(57) Abstract:

Usage: as immunostimulatory tools in the treatment of acute and chronic infections both bacterial and viral nature. The inventive product is the methyl ester of N-[2-cyano-3 (1,4-dihydro-1-phenylindane [1,2-C]-pyrazole-3-yl) -3-oxo-propanol]-glycine, T. pl. 253 - 255oC. the Product Is N-[2-cyano-3-(1,4-dihydro-1-phenyl indeno [1,2-C]-pyrazole-3-yl) 3-oxo-propanol]-glycine, T. pl. 247 - 249oC (decomp.). table 2.

The invention relates to 3-oxo-propanenitrile derived condensed pyrazole, method of production thereof and to pharmaceutical compositions containing them.

Compounds of the invention have the General formula (I)

< / BR>
where

X is:

(a) in which R4is hydrogen, C1-C6-alkyl, or a group in which each of R' and R" independently is C1-C6-alkyl or R' and R", taken together with the nitrogen atom to which they are bound, form a heterocyclic cycle, which is selected from N-pyrrolidinyl, N-piperazinil, hexahydroazepin-1-yl, thiomorpholine, research and piperidine and which is unsubstituted or substituted C1-C6is an alkyl group; or
UB>-alkyl, pyridyl or phenyl, where the phenyl is unsubstituted or substituted by one or two substituents selected independently from halogen, trifloromethyl, C1-C6-alkyl, C1-C6-alkoxy-, nitro-, amino-, formylamino and C2-C8-alkanolamine-group;

each of R2and R3is independently:

a') hydrogen, halogen, C1-C6-alkyl or trifluoromethyl;

b) hydroxy, C1-C6-alkoxy or C3-, or C4-alkenylacyl-group;

in') nitro-, amino-, formylamino or C2-C8-alkanolamine-group;

g') di(C1-C6-alkyl)-amino - or group where R' and R" are as defined above;

d') CH2OH, CHO, COOH or C2-C7-alkoxycarbonyl;

e') group, in which Rdis hydrogen or C1-C6-alkyl, and Rcis hydrogen, phenyl or side chain-amino-acids;

W') group, in which Rcis as defined above;

C') -CH2OCO(CH2)nCOOR or-NHCO(CH2)nCOOR group in which n is as defined above and R is hydrogen or C1-C6-alkyl;

and') -CH= N-OR'1group is R'2is hydrogen, -CH2CH2OH, C2or C3-alkoxycarbonyl or a group -(CH2)p-R'3in which p is 1 or 2, and R'3is COOH or C2-C7-alkoxycarbonyl;

l') group where R' and R" are as defined above; or

m') group where R' and R" are as defined above; or

and') C2C7-alkoxycarbonyl group substituted by the group , in which R' and R" are as defined above; and

Q represents hydrogen, carboxy, C2-C7-alkoxycarbonyl or group in which Rarepresents hydrogen or C1-C20-alkyl, and Rbrepresents C1-C20-alkyl group , in which R and Rcare as defined above, or a group -(A)m-R5in which m is zero or 1, a is C1-C6-alkalinous chain;

R5is:

a") C5-C8-cycloalkyl;

b) pyridium, unsubstituted or substituted by one or two substituents selected independently from halogen, C1-C6-alkyl and C1-C6-alkoxy;

in) phenyl, unsubstituted or substituted by one or two will replace the-, nitro, formylamino-FROM2-C8-alkanolamine, di(C1-C6-alkyl)-amino-, hydroxy-, CH2OH, COOH, C2-C7-alkoxycarbonyl, formyloxy-, C2-C8-alkanoyloxy - group in which R' and R" are as defined above;

g) 2-tanila, 2-fullam or 1-(C1-C6-alkyl)-pyrrol-2-yl; or

d) heterocyclic cycle, which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted C1-C6-alkyl;

and their pharmaceutically acceptable salts.

The invention includes within its scope all the possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites (products of metabolism), and metabolic precursors or bioresistant compounds of formula (I). It should be noted that the compounds of formula (I) can also be present in tautomeric structure, namely in the enol structure of formula (Ia)

< / BR>
where

X, R1, R2, R3and Q are as defined above.

However, the compounds of formula (Ia), which fall within the scope of the invention are also described in the description of the invention, such as compounds of formula (I).

C1-C6is an alkyl group is, for example, stands, ethyl, propylene, isopropyl, bootrom or tert-bootrom, more preferably it is stands, ethyl or tert-bootrom. C3or C4-accelerograph is preferable alixi group.

C1-C6-alkoxygroup is, for example, methoxy, ethoxy-, propoxy-, isopropoxy, butoxy - or tert-butoxypropyl, preferably it is methoxy, ethoxy or propoxyphene.

C5-C8-cycloalkyl group is preferably cyclopentyl or cyclohexyl.

C2-C8-alkanolamine is preferably acetylamino or propionamidoxime.

C2-C8-alkanoyloxy is preferably acetoxy or propionyloxy.

C2-C7-alkoxycarbonyl group is preferably C2-C5-alkoxycarbonyl group, in particular C2or C3-alkoxycarbonyl group.

C1-C6-Allenova chain is LASS="ptx2">

Di(C1-C6-alkyl)-amino is preferably di(C1-C4)-alkyl)-amino group, in particular di(C1or C2-alkyl)-amino group. In the group, in which R is as defined above and Rcis the same as defined above, except hydrogen; asymmetric carbon atom, to which Rcand -- COOR are attached, can have either R or S-configuration. Side chain-amino acids is particularly a residue derived from a-amino acids by removal of the amino - and carboxylate together with the carbon atom to which they are associated. Side chain-amino acids, as defined above, is preferably the side chain derived from naturally occurring amino acids.

Examples of such amino acids 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 fennelseed.

Preferred examples of the side chains of the above-mentioned amino acids are-CH3(derived from alanine), -CH2-CH(CH3)2(derived from leucine) salts are either those with inorganic bases, such as the hydroxide of sodium, potassium, calcium and aluminum, or those with organic bases such as lysine, arginine, N-methyl-glutamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amino, piperidine, N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine- -phenylethylamine-, N-benzyl-phenethylamine, N-benzyl-n,N-dimethylamine and the other acceptable organic amines, such as salts with inorganic acids, for example hydrochloric, nitric, Hydrobromic and sulfuric acids, and with organic acids such as citric, tartaric, maleic, malic, fumaric, methanesulfonic and econsultancy acids. Preferred salts of the compounds of formula (I) are the sodium and potassium salts.

The invention also includes within its scope pharmaceutically acceptable bioresistance (commonly known as prodrugs of compounds of formula (I), i.e. compounds that have the formula other than the formula (I), but which nevertheless when introducing people become directly or indirectly in vivo into a compound of formula (I).

Preferred compounds of the invention are the compounds of formula (I) in which X is:

a") , independently is C1or C2-alkyl, or R' and RIVtaken together with the nitrogen atom to which they are bound, form a heterocyclic cycle, which is selected from N-pyrrolidinyl, N-piperazinil, morpholino and piperidino and which is unsubstituted or substituted methyl group; or (b"') oxygen or-S(O)ngroup, in which n is as defined above;

R1is unsubstituted pyridine; or phenyl, unsubstituted or substituted by one or two substituents selected independently from halogen, trifloromethyl, C1-C6-alkyl, C1-C6-alkoxy-, nitro-, amino - and C2-C8-alkanolamines;

R2and R3each independently is:

a0)hydrogen, halogen, actigraphy, COOH, CHO, CH2OH, CF3C2-C7-alkoxycarbonyl, nitro-, amino-, C1-C4-alkyl, C1-C4-alkoxy or the group, in which RII'and RIVare as defined above;

b0) group, in which Rdis hydrogen or C1-C6-alkyl, and Rcis hydrogen, phenyl or side chain - amino acids, as defined above;

in0group, in which R2)nCOORdthe group, in which n and Rdare as defined above;

d0) -CH= N-OR'1the group, in which R'1is hydrogen or-CH2COOH group;

e0) group, in which RII'and RIVare as defined above;

W0) C2-C4-alkoxycarbonyl group substituted by the group , in which RII'and RIVare as defined above;

Q represents hydrogen, C2-C5-alkoxycarbonyl or the group,- CONR'aR'bin which R'ais hydrogen or C1-C6-alkyl, and R'bis C1-C6-alkyl - group in which R9is hydrogen or C1-C4-alkyl, and Rcis the same as defined above, or a group -(A')m-R'5in which m is zero or 1, A' is a C1-C3-alkalinous chain, and R'5is:

andIV) unsubstituted pyridium or phenyl, unsubstituted or substituted by one or two substituents selected independently from halogen, CF3C1-C4-alkyl, C1-C4-alkoxy-, nitro-, CH2OH, COOH, di(C1-C4-alkyl)-amino-, hydroxy-, f is designated above;

bIV) 2-tanila or 2-fullam; or

inIV) heterocyclic cycle, which is selected from 2-thiazolyl or 3-isoxazolyl and which is unsubstituted or substituted methyl group; and

pharmaceutically acceptable their salts.

More preferred compounds of the invention are the compounds of formula (I) in which X is oxygen, sulfur or , in which RII4is hydrogen, stands or group in which RII'and RIVare as defined above;

R1represents phenyl, unsubstituted or substituted Deputy selected from nitro, halogen, CF3C1-C4-alkyl and C1-C4-alkoxygroup;

each of R2and R3independently is:

and00) hydrogen, halogen, COOH, CHO, CH2OH, C2-C5-alkoxycarbonyl, CF3, nitro-, amino-, hydroxy-, C1-C4the alkyl, C1-C4-alkoxy - or group where RII'and RIVare as defined above;

b00) group, in which R'dis hydrogen or C1-C4-alkyl, and Rcis as defined above;

in00) group, in which R<-NHCO(CH2)nCOOR'dthe group, in which n and R'dare as defined above;

d00) group, in which RII'and RIVare as defined above;

e00) C2-C4-alkoxycarbonyl group substituted by the group , in which R" and RIVare as defined above;

Q represents hydrogen, C2or C3-alkoxycarbonyl or-CONR"aRinthe group in which Rais hydrogen or C1-C4-alkyl, and Rinis C1-C4-alkyl - group in which R9and Rcare as defined above, or a group, or -(CH2)p-R5in which p is zero, 1 or 2, and R5is:

andV) unsubstituted pyridine; or phenyl, unsubstituted or substituted by one or two substituents selected independently from nitro, halogen, CF3C1-C4-alkyl, C1-C4-alkoxy, CH2OH, COOH, di(C1- or2=alkyl)-amino-, hydroxy-, formyloxy-, C2-C6-alkanoyloxy - group, in which RII'and RIVare as defined above;

bV) 2-tanila or 2-fullam; or

inV) hetaeras the substituted methyl group;

and pharmaceutically acceptable salts of them.

Examples of particularly preferred compounds of the invention are:

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo - N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo - N-phenyl-propanamide;

2-cyano-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-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]-pyrazole-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-7-methyl-1-phenyl-indeno- -[1,2-c] pyrazole-3-yl)-3-oxo-propanamide;

N-(chlor-phenyl)-2-cyano-3-[1-(4-fluoro-phenyl)-1,4-dihydro-indeno- -[1,2-c] -pyrazole-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl)3-oxo-propanamide;

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-4-yl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-4-methyl-1-phenyl-indeno-[1,2-c] -pyrazole- -3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-7-methyl-1-phenyl-indeno-[1,2-c] -pyrazole- -3-yl)-3-oxo-N-phenyl-propanamide;

methyl ester of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-propanol]-glycine;

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- -3-oxo-propper-phenyl)-3-oxo-3-(1-phenyl-1H-benzothieno- -[3,2-c]-pyrazole-3-yl)-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1H-benzothieno- [3,2-c]-pyrazole-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno- -[1,2-c] -pyrazole-3-yl)-3-oxo-propanamide;

3-(7-amino-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- -2-cyano-3-oxo-N-phenyl-propanamide;

2-cyano-3-(5-etox carbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-okno-N-phenyl-propanamide;

methyl ester of N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-indeno-[1,2-c] pyrazole-7-yl]-carbonyl-glycine;

2-cyano-3-(6-amoxacillin-1,4-dihydro-1-phenyl-indeno- -[1,2-c]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-7-N, N-dimethylaminoethoxide-1- -phenyl-indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

39(7-tert-butyl-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole- -3-yl]-2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-7-trifluoromethyl-indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-propanamide;

and pharmaceutically acceptable salts of them, in particular the sodium and potassium salts.

The compounds of formula (I) and their salts can be obtained by the method, including:

a) reaction of interaction of the compounds of formula (II)

< / BR>
where

X, R1, R2and R3is that the dust, with the compound of the formula (III)

< / BR>
where

Q' is the same as defined above for Q, except carboxypropyl, thus obtaining a compound of formula (I) in which Q is as defined above, except carboxypropyl; or

b) reaction of interaction of the compounds of formula (IV)

< / BR>
where

X, R1, R3and R2is such as defined above, with a compound of formula (V)

Rin- N= C = 0 (Y)

where

Rinis the same as defined above, thus obtaining a compound of formula (I) in which Q is a group-CONHRinin which Rinis as defined above; or

C) reaction of interaction of the compounds of formula (VI)

< / BR>
where

X, R1, R2and R3is such as defined above, and is reactive derivative carboxypropyl, with the compound of formula (VII)

< / BR>
where

Randand Rinis such as defined above, thus obtaining a compound of formula (I) in which Q is a group, in which Randand Rinare as defined above; or

d) hydrolysis of compounds of formula (I) in which Q is C1-C6-alkyl, in order to obtain the corresponding compound of formula (I) in which Q is a free carboxypropyl or group in which Raand Rcis such as defined above; and, if necessary, the conversion of compounds of formula (I) into another compound of formula (I) and/or, if necessary, the conversion of compounds of formula (I) into a pharmaceutically acceptable salt and/or, if necessary, converting a salt into a free compound, and/or, if necessary, separation of the mixture of isomers of compounds of formula (I) to separate the isomers. When Y is a reactive derivative carboxypropyl, it is, for example, halogenocarboxylic group, preferably chlorocarbonyl group, or C2-C7-alkoxycarbonyl group, preferably C2-C3-alkoxycarbonyl group.

The reaction between the compound of formula (II) in which Y is carboxypropyl, and the compound of the formula (III) can be carried out, for example, in the presence of a condensing reagent such as diethyl-cyanophosphonate, in the presence of a base, such as triethylamine, in an inert solvent, such as dimethylformamide, at a temperature of, options, the fast reaction-saponin derivative carboxypropyl, and the compound of the formula (III) can be carried out, for example, in the presence of a strong base such as sodium hydride, tert-piperonyl potassium, atoxic thallium, in an inert solvent, such as 1,2-dimethoxyethane, dioxane, dimethylformamide, at a temperature varying between about 0oC and about 100oC.

The reaction between the compound of formula (IV) and the compound of the 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 0oC and about 100oC.

In the compounds of the formula (VI) Z is, for example, halogenocarboxylic group, preferably chlorocarbonyl group, or C2-C7-alkoxycarbonyl group, preferably C2-C3-alkoxycarbonyl group.

The reaction between the compound of formula (VI) in which Z is halogenocarboxylic group, and a compound of formula (VII) can 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 the rate the Torah Z is C1-C6-alkylbis complex ether, and a compound of formula (VII) can be carried out, for example, by heating at the boiling point under reflux in an aromatic hydrocarbon such as toluene or xylene, preferably driving slowly along with free diluent C1-C6-alkilany alcohol generated during the reaction. The hydrolysis of compounds of formula (I) in which Q is C2-C7-alkoxycarbonyl group or group in which Raand Rcare as defined above, and R is C1-C6-alkyl, according to the method according to the specified option g) may be carried out by selective basic hydrolysis, using, for example, aqueous sodium hydroxide or potassium hydroxide in a solvent such as dioxane, ethanol or dimethylformamide, at a temperature varying between about 0oC and approximately 80oC.

The compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods, for example, in the compound of formula (I) nitro group can be converted into amino group by treatment with, for example, douglasites tin in concentrated hydrochloric acid, using, if needed Jeremai between room temperature and about 100oC. in Addition, for example, amino group can be converted into formylamino or C2-C8-alkanolamines, for example, by reacting with formic acid or with a corresponding C2-C8-alkanoyl-anhydride without 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 0oC and about 100oC. in Addition, for example, -NH2or-CH=N-NH2the group may be converted into or group in which R' and R" are as defined above, respectively, by the reaction of interaction with the Quaternary nitrogen compound of the formula (VIIa)

< / BR>
in which

R'and R"are as defined above, in an inert organic 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 -20oC and room temperature, according to the experimental procedure described in description of the invention to the patent of England 1293590 and patent 4447432. In addition t the above by the reaction of interaction with an appropriately protected amino acid of the formula in which Rcis the same as defined above, and W is a protecting group, such as benzyloxycarbonyl or tert-butoxycarbonyl group, in the presence of dicyclohexylcarbodiimide, as a condensing reagent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0oC and room temperature, in order to get the group in which RcW are as defined above, which, in turn, freed from the protective groups, using well known methods in organic chemistry. In addition, for example, carboxypropyl can be turned into a group, in which Rcis the same as defined above, by reaction of interaction with esterified - amino acid of the formula in which R is C1-C6-alkyl, and Rcis the same as defined above, in the presence of dicyclohexylcarbodiimide as a condensing reagent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between ro> and R are as defined above, which in turn is hydrolyzed to obtain a group, in which Rcis the same as defined above, following techniques well known in the field, such as the methods described for the method according to the specified option g). In addition, for example, alkoxycarbonyl group, - group, CH2OCO(CH2)nCOOR group, or-NHCO(CH2)nCOOR group in which n is as defined above, and R is C1-C6-alkyl, can be converted to the corresponding-COOH, , -CH2OCO(CH2)nCOOH, and-NHCO(CH2)nCOOH group, respectively, in which n is as defined above, by treatment with aqueous sodium hydroxide or potassium in solution, such as dioxane, methanol, ethanol or dimethylformamide, at a temperature varying between about 0oC and approximately 80oC.

The optional esterification of free carboxypropyl, as well as the optional conversion of ester carboxyl in free carboxy-derivative can be carried out by known organic chemistry methods.

Described variants b) and C) of the method can be considered as examples of the transformation of compounds), as well as the conversion of a salt into a free compound and the separation of a mixture of isomers into individual isomers can be carried out by standard methods. For example, the separation of optical isomers may be carried out by salt formation with an optically active base or acid and fractionated by successive crystallization diastereoisomeric salts, followed by regeneration of the optically active isomeric acids or bases. The compounds of formula (II) in which Y is C2-C7-alkoxycarbonyl group, and X being as defined above, is a group other than the group in which R' and R" are as defined above, can be obtained, for example, by reaction of interaction of the compounds of formula (VIII)

< / BR>
where

R2and R3are as defined, E is the same as X defined above, with the exception of the group, in which R and R"are as defined above, and R6is C1-C6-alkyl, preferably C1-C2-alkyl, with a compound of formula (IX)

R1- NHNH2(IX)

where R1< / BR>
is the same as defined above.

The reaction between the compound of the Fort is lilovy alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetic acid, at a temperature varying between about 0oC and about 150oC.

The compounds of formula (II) in which Y is C2-C7-alkoxycarbonyl group, and X is a group, in which R and R" are as defined above, can be obtained, for example, by reacting the compounds of formula (II) in which X is N-halogenating, preferably N-bromosuccinimide, in an inert solvent such as carbon tetrachloride or chloroform, at a temperature that ranges from about 20oC to the boiling temperature under reflux, thus obtaining the corresponding intermediate halogenated derivatives of formula (II) in which X is CH-halogen group, in particular CH-Br group, which in turn is subjected to reaction with the compound of the formula in which R and R"are as defined above, in a solvent such as dimethylformamide, acetone, 2-butanone, in the presence of sodium carbonate or potassium carbonate, at a temperature varying between about 0oC and about 100oC.

The compounds of formula (II) in which Y is carboxypropyl can be obtained, nab the ilen group, according to standard methods well-known in this field, for example, using the basic hydrolysis is carried out, for example, by treatment with sodium hydroxide or potassium hydroxide in a solvent such as water, C1-C6-alkilany alcohol, dioxane, dimethylformamide and mixtures thereof, at a temperature varying between about 0oC and approximately 80oC.

The compounds of formula (II) in which Y is halogenocarboxylic, preferably by chlorocarbonyl can be obtained, for example, by reaction of interaction of the corresponding compounds of formula (II) in which Y is carboxypropyl, with a corresponding acid halide, for example oxalylamino (acid chloride oxalic acid), chloride tiomila, PCl3, PBr3in an inert solvent, such as a simple ether, benzene, dichloroethane, dioxane, or without any solvent, at a temperature varying between about 0oC and about 100oC.

The compounds of formula (III) are in some cases commercially available products or can be obtained by methods well known in the field. For example, the compound of formula (III) in which Q is a group, in which Raand Rbare such crystals (VII) in the presence of a condensing reagent, such as dicyclohexylcarbodiimide, 1,1-carbonyldiimidazole and the like, in an inert organic solution, such as benzene, dioxane, acetonitrile, at a temperature varying between about 0oC and about 50oC.

The compounds of formula (IV) are compounds of General formula (I) in which Q is hydrogen, and can be obtained by the method (a) above, for example, by reaction of interaction of the compounds of formula (II) in which Y is C2-C7- alkoxycarbonyl, acetonitrile, in the presence of a strong base such as sodium hydride, tert-butoxide potassium, in an inert organic solvent such as benzene, dioxane, tetrahydrofuran, at a temperature varying between about 0oC and about 100oC.

The compounds of formula (VI) in which Z is C2-C7-alkoxycarbonyl are compounds of General formula (I) in which Q is C2-C7-alkoxycarbonyl, and can be obtained by a specified method a), for example, by reaction of interaction of formula (II) with the compound of the formula (X)

< / BR>
where

R7is C1-C6-alkyl, using the same experimental conditions described for the reaction m halogenocarboxylic, can be obtained, for example, using the basic hydrolysis of the compounds of formula (VI) in which Z is C2-C7-alkoxycarbonyl using, for example, the same experimental conditions described above for the hydrolysis of compounds of formula (II) in which Y is C2-C7-alkoxycarbonyl, in order to obtain carboxypropanoyl, which in turn can be converted into a compound of formula (VI) in which Z is halogenocarboxylic, preferably by chlorocarbonyl using, for example, the same experimental conditions described for preparing compounds of the formula (II) in which Y is halogenocarboxylic.

The compound of formula (VIII) can be obtained, for example, by reaction of interaction of the compounds of formula (XI)

< / BR>
where

E, R2and R3are as defined above, with a compound of formula (XII)

< / BR>
where

each of R8and R'8being the same or different, is C1-C6-alkyl, preferably the stands or ethyl.

The reaction between the compound of formula (XI) and a compound of formula (XII) can be carried out, for example, according to methods described in J. C. S 101, 1731 (1912) and Ann., 405, 391 (1914).

The compounds of formula (V), (VII), (IX) and (X) and (XII) are known compounds and can be obtained by standard methods: in some cases, they are commercially available substances.

When in the compounds according to the invention and in the intermediate products of their present group, such as CHO, COOH, NH2and/or OH, which require protection before subjecting them to the above reactions, they can be protected before the reaction, and then released from the protection according to well-known organic chemistry methods.

The compounds of formula (I) possess immunomodulatory activity and can be used, for example, as immunostimulatory agents, e.g. in the treatment of acute and chronic infections both bacterial and viral nature, individually or in combination with antibiotic means, in the treatment of neoplastic diseases, individually or in combination with antitumor means, in mammals.

The immunomodulatory activity of compounds of the invention proved, for example, the fact that they are the two vitro.

Experimental methodology for the evaluation of this activity consists in the following: groups of 4 mice treated intraperitoneally test compounds, and then seven days later peritoneal cells are collected and inoculated in a Petri dish for 2 h at 37oC. After this period of time walls are washed to remove not connected cells, then add the tumor target cells and incubation continued for 48 hours By the end of this period, the viability of target cells evaluated by MTT colorimetric method (Abstracts of the VIII European Jmmunology Meeting, Zagreb, 1987, page 94, N2105), the main on the evaluation of optical density (OD) at 570 nm.

The percentage of specific cytotoxicity (%C)is calculated as % inhibition of growth of tumor cells TV-5 (Jmmunology, 1984, 166, 251), using the following formula:

< / BR>
Table. 1 summarizes data on the immunostimulatory activity of some exemplary compounds of the invention obtained under the specified experimental methodology, in relation to tumor cells TV-5.

On the basis of their immunomodulatory activity, the compounds according to the invention, as it turns out, are active and modules infection in mice. For example, the compounds of the FCE non cyclophosphamide (Gryz. J. Y. and others Jnfect Jmm. 1983, 39 1067).

Experimental methods for the evaluation of this activity is the following: mouse immunosupressants for 4 days before bacterial infection a single dose of 200 mg/mg of cyclophosphamide, administered intraperitoneally. Compound injected intraperitoneally on days +1 and +3 relative to injection of cyclophosphamide. Clinically isolated Pseudomonas aeruginosa are administered intravenously in the amount of 3 LD50. The resistance of the host to infection is given by the number of mice surviving after 10 days after bacterial infection.

Table. 2 summarizes the results obtained.

Compounds according to the invention can be used safely in medicine due to their low toxicity. Therapeutic (curative) scheme for different clinical syndromes should be adapted to the type of pathology, whereas,as usual,route of administration,the form in which the compound is introduced,and the age, weight and condition of the affected entity.

Oral path is used for all States that require such connections. Preference is given an intravenous injection or infusion for the treatment of acute detail ramesey or subcutaneous, the path input.

For these purposes the compounds of the invention, for example 2-cyano-3-(1,4- -dihydro-1-phenyl-indeno-[1,2] -pyrazole-3-yl)-3-oxo-N-phenyl-propanamide, can be administered orally at doses that are within, for example, from about 0.5 to about 10 mg/kg body weight per day for adult men.

Doses of active compounds within, for example, from about 0.2 to about 5 mg/kg body weight, can be used to parenterale input to adults. Of course, these dose regimens can be adjusted to provide the optimum therapeutic response.

The nature of the pharmaceutical compositions containing compounds according to the invention in combination with pharmaceutically acceptable carriers or diluents, will depend of course on the desired route of administration. The composition can be receptionby usual method along with the usual ingredients. For example, the compounds according to the invention can be introduced in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules, syrups, straw or suppository. Thus, for oral administration the pharmaceutical compositions containing the compounds according to the invention, it is preferable that the mi, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatin, methylcellulose, carboxymethylcellulose, gum Arabic, tragakant, polyvinylpyrrolidone; violate aggregation tools such as starches, alginic acid, alginates, starch glycolate, sodium (krahmalevym ether sodium salt of glycolic acid); mixtures for rapid gas evolution; dyes; podslushivala; wetting, such as lecithin, Polysorbate, laurylsulfate; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.

These pharmaceutical preparations can be obtained by a known method, for example by mixing, granulating, tabletting, sugar coating, or by means of the coating film.

Liquid dispersions for oral administration can be, for example syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. Suspense is ethylcellulose, the carboxymethyl cellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the current connection pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if necessary, an appropriate amount of hydrochloride lidocaine. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of a sterilized aqueous isotonic salt solutions.

Suppositories can contain, together with the current connection pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, surface-active substance on the basis of ester polyoxyethylene-sorbitan-fatty acids or lecithin.

Example 1. 2-Ethoxalyl-indan-1-he (6 g) is subjected to reaction with phenylhydrazine (3.1 g ) in 45 ml of acetic acid at 50oC for 3 hours After cooling, the reaction mixture is diluted with ice water and then neutralized with 35% NaOH. Extraction with ethyl acetate and evaporation of the solvent under vacuum to dryness gives the rest of the AI crystallized from isopropyl ether, to obtain the ethyl ester of 1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-carboxylic acid, so pl. 110-112oC (5.7 g), which undergoes reaction with acetonitrile (14 ml) in dioxane (14 ml) in the presence of 50% sodium hydride (0.9 g) with stirring at 60oC within 15 minutes After cooling, the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. Drop down the precipitate is filtered and purified through a column of SiO2using ethyl acetate as eluent. Crystallization from a mixture of methylene chloride/isopropyl alcohol to give 3-(1,4-dihydro-1-phenylindane- -[1,2-c]-pyrazole-3-yl)-3-oxo-propanenitrile, so pl. 189-190oC (2.8 g), which undergoes reaction with phenyl-isocyanate (1,17 g) in dimethylformamide (2 ml) in the presence of triethylamine (1.06 g) at 25 - 30oC for 25 minutes, the Reaction mixture is diluted with ice water and acidified with 2n. HCl to pH 3. Drop down the precipitate is filtered and washed with water.Crystallization from a mixture of methylene chloride/methanol gives 3.5 g of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl)-oxo-N-phenyl-propanamide, so pl. 273-277oC NMR (CDCl3) memorial plaques: 3,91 (singlet) (2H, C-4 protons), and 7.1-8.0 (multiplet) (15H, phenyl protons and CONH), 16,2 (broadened singlet) (1H, -OH).


3-[1-(4-chloro-phenyl)-1,4-dihydro-indeno-[1,2-C] -pyrazole-3-yl] -2-cyano - 3-oxo-N-phenyl-propanamide;

3-[1-(3-chloro-phenyl)-1,4-dihydro-indeno-[1,2-C] -pyrazole-3-yl]-2-cyano-3 - oxo-N-phenyl-propanamide;

3-[1-(2-chloro-phenyl)-1,4-dihydro-indeno-[1,2-C] -pyrazole-3-yl] -2-cyano - 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1-(3-fluoro-phenyl)-1,4-dihydro-indeno-[1,2-C] -pyrazole-3-yl] - 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(4-methyl-phenyl)-indeno-[1,2-C] -pyrazole-3-yl] - 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(3-methyl-phenyl)-indeno-[1,2-C] -pyrazole-3-yl] - 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(2-methyl-phenyl)-indeno-[1,2-C] -pyrazole-3-yl] - 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(4-methoxy-phenyl)-indeno-[1,2-C]-pyrazole-3-yl]- 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(3-methoxy-phenyl)-indeno-[1,2-C]-pyrazole - 3-yl] -3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(4-phenyl)-indeno-[1,2-C] -pyrazole-3-yl] - 3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-(3-nitro-phenyl)-indeno-[1,2-C] -pyrazole-3-yl- ] -3-oxo-N-phenyl-propanamide; and

2-cyano-3-[1,4-dihydro-1-methyl-indeno-[1,2-C] -pyrazole-3-yl]- 3-oxo-N-phenyl-propanamide;

Example 2. Following the procedure of example 1, using the corresponding isocyanates, can bit-propanamide, so pl. 269-271oC;

N-(4-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo-propanamide;

N-(2-[chloro-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxopropanoic, so pl. 295-297oC;

2-cyano-N-(3-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- 3-oxo-N-(3-trifluoromethyl-phenyl)-propanamide, so pl. 278-284oC;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(4-methyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(3-methyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(2-methyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] -piperazin-3-yl)-N- (4-methoxy-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)-N- (3-methoxy-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -piperazin-3-yl)-N- (3-nitro-phenyl)-3-oxo-propanamide, so pl. 280 - 284oC;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-yl)-N-(4 - nitro-phenyl)-3-oxo-propanamide;

N-(3-bromo-phenyl)-2-cyano-[1,2-c] -pyrazole-3 - yl)-3-oxo-propanamide, so pl. 289 - 290oC;

N-benzyl-2-cyano-3-[1-(4-fluoro-phenyl)-1,4-dihydro-indeno-[1,2-c] - pyrazole-3-ml]-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1,4-dihydro-indeno- [1,2-c] -pyrazole-3-yl]-3-oxo-propanamide, so pl. 281 - 286oC. (decomp.);

N-(3-chloro-phenyl)-2-cyano-3-[1-(4-fluoro-phenyl)-1,4-dihydro-indeno- [1,2-c] -pyrazole-3-yl]-3-oxo-propanamide, so pl. 288 - 291oC;

N-butyl-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole - 3-yl)-3-oxo-propanamide and

N-tert-butyl-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-propanamide.

Example 3. Acting according to examples 1 and 2, based on the relevant indan-1-ions receive the following connections:

2-cyano-3-(1,4-dihydro-4-methyl-1-phenyl-indeno-[1,2-c] -pyrazole - 3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-5-methyl-1-phenyl-indeno-[1,2-c] -pyrazole-3 - yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-6-methyl-1-phenyl-indeno-[1,2-c] -pyrazole-3 - yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-7-methyl-1-phenyl-indeno-[1,2-c] -pyrazole-3 - yl)-3-oxo-N-phenyl-propanamide, so pl. 249 - 251oC;

3-(5-chloro-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)-2 - cyano-3-oxo-N-phenyl-propanamide;

3-(6-chloro-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)-2 - cyano-3-oxo-N-phenyl-propanamide;
oC;

2-cyano-3-(1,4-dihydro-5-methoxy-1-phenyl-indeno-[1,2-c] -pyrazole-3 - yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-7-dimethylamino-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-7-trifluoromethyl - indeno-[1,2-c]-Persil-3-yl)-3-oxo-propanamide;

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-7-trifluoromethyl-indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-propanamide;

N-(3-Flor-phenyl)-2-cyano-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno -[1,2-c] -pyrazole-3-yl)-3-oxo-propanamide;

3-(7-tert-butyl-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3 - yl)-2-cyano-3-oxo-N-phenyl-propanamide; so pl. 249 - 252oC;

3-(7-tert-butyl-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- 2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-7-morpholinomethyl-1-phenyl-indeno- [1,2-c]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-6-morpholinomethyl-1-phenyl-indeno- [1,2-c]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-5-morpholinomethyl-1-phenyl-indeno-[1,2-c]- pyrazole-3-yl)-3-oxo-NN-phenyl-propanamide; so pl. 265-275oC.

N-(3-chlorophenyl)-2-cyano-3-(1,4-dihydro-7-metil-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-7-methyl-1-phenyl-ind is evil-3-yl)-3-oxo-propanamide; and

2-cyano-3-(1,4-dihydro-1-phenyl-7-trifluoromethyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-N-phenyl-propanamide.

Example 4. Ethyl ester of 1,4-dihydro-1-phenyl-indeno-[1,2-c]-Pirat-3-carboxylic acid (7,35 g) obtained in example 1, is dissolved in carbon tetrachloride (100 ml) and subjected to reaction with N-bromosuccinimide (4,75 g) with stirring at the boiling temperature under reflux for 2 h in the presence of benzoyl peroxide (150 mg). After cooling, the reaction mixture is filtered and the solution evaporated under vacuum to a small volume. Precipitating the reaction product is purified with hot isopropyl ether to obtain ethyl ester 4-bromo-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-carboxylic acid, so pl. 181-182oC (9,29 g), which undergoes reaction with morpholine (2.5 g) in dimethylformamide (175 ml) in the presence of anhydrous potassium carbonate with stirring at room temperature for 2 hours, the Reaction mixture is diluted with ice water and drop the precipitate is filtered and washed with water until neutral. Crystallization from a mixture of methylene chloride/isopropyl ether gives ethyl ester 1,4-dihydro-4-morpholino-2-phenyl-indeno-[1,2-c] -pyrazole-3-carboxylic acid, so is the temperature value of the boil under reflux for 20 minutes After cooling, the reaction mixture is diluted with ice water and acidified with citric acid to pH 4. Drop down the precipitate is filtered, washed with water until neutral and crystallized from a mixture of methylene chloride/ethanol to obtain 1,4-dihydro-4-morpholino-1-phenyl-indeno-[1,2-c] -pyrazole-3-carboxylic acid, so pl. 244-245oC (4.15 g), which undergoes reaction with chloride tiomila (1.65 ml) in dioxane (200 ml) at the boiling point under reflux for 1 h After cooling, the reaction mixture is evaporated to dryness under vacuum, to obtain the acid chloride 1,4-dihydro-4-morpholino-1-phenyl-indeno-[1,2-c] -pyrazole - 3-carboxylic acid in the form of a crystalline residue. The crude reaction product is dissolved in anhydrous dioxane (300 ml) and subjected to reaction for 2 h with stirring at room temperature with the carbanion obtained by treating 2-cyano-acetanilide (1,87 g) of 50% sodium hydride (1.2 g) in anhydrous dioxane (100 ml) at room temperature. The reaction mixture is neutralized by treatment with 1 N. HCl solution (7 ml) and then concentrated under vacuum to small volume.

The residue is diluted with ice water and acidified 1 N. HCl solution to pH 4. Wipg 2-cyano-3-(1,4-dihydro-4-morpholino-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- 3-oxo-N-phenyl-propanamide, so pl. 272-277oC decomp.

Acting in a similar way, you receive the following connections:

2-cyano-3-(1,4-dihydro-1-phenyl-4-piperidino-indeno-[1,2-c] -pyrazole - 3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-1-phenyl-4-(pyrrolidin-1-yl)-indeno-[1,2-c]- pyrazole-3-yl]-3-oxo-N-phenyl-propanamide;

2-cyano-3-[1,4-dihydro-4-(4-methyl-piperazine-1-yl)-1-phenyl-indeno- [1,2-c]-pyrazole-3-yl]-3-oxo-N-phenyl-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-4-morpholino-1-phenyl-indeno- [1,2-c]-pyrazole-3-yl)-3-oxo-propanamide; and

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-4-morpholino-1-phenyl-indeno- [1,2-c]-pyrazole-4-yl-)-3-oxo-propanamide.

Example 5. Ethyl ester of 1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-carboxylic acid (3 g) obtained in example 1, is heated together with 10% solution of KOH in ethanol (100 ml) at the boiling point under reflux for 20 minutes, the Reaction mixture is diluted with ice water and acidified to pH 3 with 37% HCl. Drop down the precipitate is filtered, washed with water until neutral and dried under vacuum to obtain 1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-carboxylic acid (2.5 g), which undergoes reaction with chloride tiomila (1.2 ml) in dioxane (60 ml) at the temperature to which womam, to obtain the acid chloride 1,5-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-carboxylic acid in the form of a crystalline residue. The crude reaction product is dissolved in anhydrous dioxane (30 ml) and subjected to reaction for 2 h with stirring at room temperature together with the carbanion obtained by treating 2-cyano-acetanilide (1.6 g) of 50% sodium hydride (0.5 g) in anhydrous mixture of dimethylformamide and dioxane 1:1 (10 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 2 using HCl. Drop down the precipitate is filtered and washed with water until neutral. Crystallization from a mixture of methylene chloride/methanol to give 1.6 g of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-N - phenyl-propanamide, so pl. 273-277oC.

Acting in a similar way, you receive the following connections:

2-cyano-N-(4-fluoro-benzyl)-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)-3-oxo-N- (2-pyridyl)-methyl-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-yl)-3-yl-oxo-N- (3-pyridyl)-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)-3-oxo - N-phenethyl-propanamide;

Hydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-yl)-N- (2-morpholinomethyl-benzyl)-3-oxo-propanamide;

2-cyano-3-(1,40 dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl) - N-(3-morpholinomethyl-benzyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl) - N-(2-morpholinomethyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dinitro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(3-morpholinomethyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(3-dimethylaminomethyl-avenel)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl) - N-(3-hydroxy-4-oxymethyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(2-dimethylaminomethyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- 3-oxo-N-[2-(pyrrolidin-1-yl)-methyl-phenyl]-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- NI-[2-(4-methyl-piperazine-1-yl)-methyl-phenyl]-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(methoxy-3-morpholinomethyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-(2-methoxy-5-morpholinomethyl-phenyl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl) N-methyl-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl) 3-OC-phenyl)-3-oxo-propanamide;

2-cyano-N-(2-furfuryl)-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl)-3-oxo-propanamide;

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- N-[1-methyl-pyrrol-2-yl]-ethyl-3-oxo-propanamide;

2-cyano-3-oxo-3-(1-phenyl-IH-benzothieno-[3,2-C] -pyrazole-3-yl) - N-phenyl-propanamide, so pl. 288-291oC;

2-cyano-N-(4-fluoro-phenyl)-3-oxo-3-(1-phenyl-1H-benzothieno- [3,2-C] -pyrazole-3-yl)-propanamide;

N-(3-chloro-phenyl)-2-cyano-3-oxo-3-(1-phenyl-1H-benzothieno- [3,2-c] pyrazole-3-yl)-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1H-benzothieno- [3,2-C]-pyrazole-3-yl]-3-oxo-propanamide.

Example 6. Ethyl ester tsianuksusnogo acid (1.4 g) is treated with 50% sodium hydride (0,58 g) in anhydrous dioxane (20 ml) with stirring at room temperature until, until you fall down a rapid evolution of gas. To this solution is added with stirring at room temperature the acid chloride 1,4 - dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-carboxylic acid (3 g) obtained in example 5, dissolved in anhydrous dioxane (50 ml). The reaction mixture was allowed to undergo reaction for 20 h, then, it is diluted with ice water and acidified to pH 3 with 37% HCl. Drop down the precipitate is extracted with ethyl acetate and the organic solution using a mixture of hexane and ethyl acetate 80:20 as eluent, to obtain the ethyl ester of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl)-3 - oxo - propanoic acid (2.2 g), which undergoes reaction with aniline (3.4 g) in xylene (100 ml) at the boiling point under reflux for 48 hours After drop-down cooling the precipitate is filtered and washed with xylene, and then crystallized from a mixture of methylene chloride and methanol, to obtain 1.2 g of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl)-3-oxo-N - enyl-propanamide, so pl. 273-277oC.

Example 7. The acid chloride 1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-carboxylic acid (2.3 g) obtained in example 5, is dissolved in anhydrous dioxane (35 ml) and subjected to reaction for 2 h with stirring at room temperature together with carbonate obtained by treating the methyl ester of N-cyanoacetyl-glycine (1.45 g) of 50% sodium hydride (0.54 g) in anhydrous mixture of dimethylformamide and dioxane 1:1 (30 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 3 with 2 N. HCl.

Drop down the precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with 1N. HCl solution and then with water until until it becomes neutral is La and 30% NH4OH 85: 15;0.5 as eluent. The final treatment with acetone purified fractions gives 1.5 g of methyl ester of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] pyrazolo-3-yl)-3-oxo-propanol]-glycine, T. pl. 253-255oC.

Acting in a similar way, you receive the following connections:

methyl ester of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl] -3-oxo-propanol]-DL-leucine;

methyl ester of N-(2-cyano-3-(1,40 dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl)- 3-oxo-propanoic-DL-phenylalanine;

methyl ester of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3 - oxo-propanol]-DL-phenylglycine and

methyl ester of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3 - oxo-propanol]-DL-isoleucine.

This way can be obtained pure D and L enantiomers of the listed compounds.

Example 8. Methyl ester of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl)-3 - oxo-propanol]-glycine (1.7 g) suspendered in 1% solution of KOH in 95% ethanol (60 ml) and heated with stirring at the boiling temperature under reflux for 30 minutes After cooling dropdown precipitate is filtered and washed with ethanol, then dissolved in water. Water is extracted with ethyl acetate and the organic solution washed with 1N. the HCl solution and then with water until neutral. Evaporation to dryness under vacuum giving a residue that breaks down ethanol to obtain 1.2 g of N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo - propanol]-glycine, T. pl. 247-249oC decomp.

Acting in a similar way, you receive the following connections:

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl - oxo-propanol]-DL-leucine;

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo-propanol]-DL-phenylalanine;

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo-propanol]-DL-phenylglycine and

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- 3-oxo-propanol]-DL-isoleucine.

This way can be obtained pure D and L enantiomers of the listed compounds.

Cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-N-(3 - nitro-phenyl)-3-oxo-propanamide (4.5 g) is treated with SnCl22H2O (22,5 g) in 37% HCl (16 ml) and acetic acid (144 ml) with stirring at 50oC for 5 hours After cooling dropdown precipitate is filtered and washed with acetic acid, then dissolved in a mixture of dimethylformamide 2n. NaOH 1:1. Dilution with an excess of aqueous solution of NaH2P, the button to obtain 2.3 g of N-(3-amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno- [1,2-C]-pyrazole-3-yl)-3-oxo-propanamide.

Acting in a similar way,you receive the following connections:

N-(4-amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]- pyrazole-3-yl]-3-oxo-propanamide and

3-[1-(4-amino-phenyl)-1,4-dihydro-indeno-[1,2-C] -pyrazole-3-yl] - 2-cyano-3-oxo-N-phenyl-propanamide.

Example 10. N-(3-Amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-3 - oxo-propanamide (1.8 g) dissolved in dimethylformamide (30 ml) was subjected to the reaction with acetic anhydride (5 ml) in the presence of pyridine (5 ml) at 40oC for 8 h, the Reaction mixture is diluted with ice water and drop the precipitate is filtered and washed with water, its crystallization from dimethylformamide gives 1.2 g of N-(3-acetylamino-phenyl)-2-cyano-3-(1,4-phenyl-indeno-[1,2-C]-pyrazole-3 - yl)-3-oxo-propanamide.

Acting in a similar way, you receive the following connections:

N-(4-acetylamino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno- [1,2-C] -pyrazole-3-yl)-3-oxo-propanamide and

3-[1-(4-acetylamino-phenyl)-1,4-dihydro-indeno-[1,2-C] -pyrazole-3-yl] -2-cyano-3-oxo-N-phenyl-propanamide.

Example 11. 2-Cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl] -3-oxo-N - phenyl-propanamide to dryness under vacuum and the reaction product is treated with acetone. Filtration and washing with acetone gives the pure sodium salt of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3-yl]-3-oxo-N - phenyl-propanamide, so pl. > 300oC.

Acting in a similar way, get the sodium salts of the following compounds:

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1,4-dihydro-indeno- [1,2-C] -pyrazole-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno- [1,2-C] -pyrazole-3-yl)-3-oxo-propanamide.

Example 12. Acting analogously to example 5 starting from the corresponding ethyl ester of tert-butoxycarbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-C]-pyrazole-3 - carboxylic acid, receive the following connections:

3-(5-tert-butoxycarbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide, so pl. 253-255oC;

3-(5-carboxy-1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- 2-cyano-3-oxo-N-phenyl-propanamide, so pl. 265-268oC decomp.;

3-(7-carboxy-1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl - 2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide;

3-(7-carboxy-1,4-dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)- 2-cyano-N-(3-chloro-phenyl)-3-oxo-propanamide;

3-(7-tert-butoxide-1-phenyl-indeno-[1,2-C] -pyrazol-3-yl)- 2-cyano-3-oxo-N-phenyl-propanamide.

Example 13. 3-(5-Carboxy-1,4-dihydro-1-phenyl-indeno-[1,2-C]- Pirat-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.3 g) dissolved in dimethylformamide (25 ml) was subjected to the reaction with ethyl iodide (1.55 g) in the presence of anhydrous potassium carbonate (1.4 g) with stirring at room temperature for 2 hours, the Reaction mixture is diluted with ice water in the drop-down precipitate is filtered, soluble in chloroform and washed with 1 N. HCl solution and then with water. Evaporation of solvent under vacuum giving a residue which crystallized from a mixture of methylene chloride and methanol, to obtain 1.9 g of 2-cyano-3-(5-etoxycarbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-C]- pyrazole-3-yl)-3-oxo-N-phenyl-propanamide, so pl. 233-236oC decomp.

Acting in a similar way, you receive the following connections:

2-cyano-3-(7-etoxycarbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide;

2-cyano-3-(7-hexyloxybenzoyl-1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(7-ethoxycarbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-C] - pyrazole-3-yl)-N-(4-fluoro-phenyl)-3-oxo-propanamide and

N-(3-chloro-phenyl)-2-cyano-3-(7-etoxycarbonyl-1,4-dihydro-1-phenyl - indeno-[1,2-C]-pyrazole-3-yl)-3-oxo-propanamide.

2using a mixture of chloroform and methanol 90/10 as eluent. The final crystallization from methylene chloride/ethyl acetate to give 1.2 g of pure methyl ester N - [1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyano-acetyl)-indeno- [1,2-c] pyrazole-7-yl]-carbonyl-glycine.

Acting in a similar way, you receive the following connections:

methyl ester of N-[1,4-dihydro-1-phenyl-dihydro-1-phenyl-3-(2 - phenylcarbamoyl-cyanoacetyl)-indeno-[1,2-c] pyrazole-7-yl]-carbonyl - 1-leucine;

methyl ester of N-[1,4-dihydro-1-phenyl-3-(2 - phenylcarbamoyl-cyanoacetyl)-indeno-[1,2-c]pyrazole-7-yl]-carbonyl - 1-phenylalanine;

methyl ester of N-[3-[2-(4-the fluorine-phenyl-carbarnoyl)- cyano-acetyl] -1,4-dinitro-1-phenyl-indeno-[1,2-c] pyrazole-7-yl]- carbonyl-glycine and

methyl ester of N-[1,4-dihydro-1-phenyl-3-(2 - phenylcarbamoyl-cyanoacetyl)-indeno-[1,2-c]-pyrazole-5-yl]-carbonyl - glycine.

Example 15. Methyl ester of N-[1,4-dihydro-1-phenyl-3-(2 - phenylcarbamoyl-cyanoacetyl)-indeno-[1,2-c] pyrazole-7-yl]-carbonyl - glycine (0.84 g) suspendered in 1% solution of KOH in 95% ethanol (22,3 ml) and heated with stirring at the boiling temperature under reflux for 30 minutes After cooling, the reaction mixture is acidified to pH 2 with 23% HCl, and then diluted with ice water. Drop down the precipitate is filtered, washed with water and then crystallized from a mixture of methylene chloride/ethanol to obtain 0.65 g of pure N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl - cyanoacetyl)-indeno-[1,2-c] pyrazole-7-yl]-carbonyl-glycine.

Acting in a similar way, you receive the following connections:

N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- indeno-[1,2-c] pyrazole-7-yl]-carbonyl-L-alanine,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- indeno-[1,2-c] pyrazole-7-yl]-carbonyl-L-phenylalanine;

N-[3[2-(4-tortenelmebol)-cyanoacetyl] -1,4-dihydro - L-phenyl-indeno-[1,2-c] pyrazole-7-yl]-carbonyl-glycine and

N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- indeno-[1,2-c] -pyrazole-5-yl]-carbonyl-glycine.

Example 16. 6 Tosylamide-indan-1-he (I. pl. 202 - 204oC) 4,2 g is subjected to the reaction with diethyl ether oxalic acid (20.5 g) in anhydrous ethanol (125 ml) containing ethoxide sodium (3.75 g), with stirring in an inert atmosphere at room temperature for 2 hours, the Reaction mixture is diluted with ice water and extracted with hexane. The aqueous phase is acidified to pH 3 using 1 N. HCl and extracted with ethyl acetate. The organic solution is washed with water until neutral and then evaporated to dryness under vacuum to obtain crude 2-ethoxalyl-6-tosylamide-indan-1-he who is subjected to reaction with phenylhydrazine (1.65 g) in acetic acid (60 ml) at 60oC for 2 h, the Reaction mixture is diluted with ice water and drop the precipitate is filtered, washed with water, dissolved in chloroform and evaporated to dryness under vacuum. Purification through a column of SiO2using a mixture of hexane-ethyl acetate 7/3 as eluent, to give pure ethyl ester of 1,4-dihydro-1-phenyl-7-Dailami the om dioxane (50 ml) in the presence of 50% sodium hydride (1.1 g) with stirring at 60oC for 4 h After cooling, the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. Drop down the precipitate is extracted with ethyl acetate, washed with 5% aqueous solution of NaHCO3and then water. By concentrating to a small volume under vacuum, the reaction product crystallizes. Drop down the precipitate is filtered and washed with ethyl acetate to obtain pure 3-(1,4-dihydro-1-phenyl-7-tosylamide-indeno-[1,2-c] -pyrazole-3-yl)- 3-oxopropanenitrile (2.1 g), which undergoes reaction with phenylisocyanate (0.55 g) in dimethylformamide (15 ml) in the presence of triethylamine (0,65 ml) at room temperature for 30 minutes, the Reaction mixture is diluted with ice water and acidified to pH 2 using 2 N. HCl.Drop down the precipitate is filtered and washed with water until neutral. Crystallization from a mixture of chloroform/ethanol gives 2-cyano-3-(1,4-dihydro-1-phenyl-7-tosylamide-indeno-[1,2-c] -pyrazole-3-yl)-3-oxo-N-phenyl-propanamide (2.3 g), which undergoes reaction with methanesulfonic acid (11 ml) in the presence of anisole (1.3 ml) with stirring at 50oC for 20 h After cooling, the reaction mixture is diluted with ice water and drop the precipitate is filtered and prom is-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)-2 - cyano-3-oxo-N-phenylpropanamide, so pl. 231-234oC.

Acting in a similar way, you receive the following connections:

3-(5-amino-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- 2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide;

3-(7-amino-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- 2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide;

3-(7-amino-1,4-dihydro-1-phenyl-indeno-[1,2-c] pyrazole-3-yl)-N- (3-chloro-phenyl)-2-cyano-3-oxo-propanamide; and

3-(7-amino-1,4-dihydro-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- 2-cyano-N-(3-trifluoromethyl-phenyl)-3-oxo-propanamide.

Example 17. 3-(7-Amino-1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (1.1 g) dissolved in anhydrous dimethylformamide (70 ml) containing pyridine (1 ml) was subjected to the reaction with the acid chloride of monoethylene ester of oxalic acid (0.7 g) with stirring at room temperature for 6 hours, the Reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. Drop down the precipitate is filtered and washed with water. Crystallization from a mixture of chloroform/ethanol gives 1.1 g of 2-cyano-3-(7 - amoxacillin-1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-3-yl)-3 - oxo-N-phenyl-propanamide.

Acting in a similar way, you receive the following connections:

2-cyano-3-(5-ateno-1,4-dihydro-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-N-(4-fluoro-phenyl)-3-oxo-propanamide and

N-(3-chloro-phenyl)-2-cyano-3-(7-amoxacillin-1,4-dihydro-1 - phenyl-indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-propanamide.

Example 18. 2-Cyano-3-(7-amoxacillin-1,4-dihydro-1-phenyl - indeno-[1,2-c] -pyrazole-3-yl)-3-oxo-N-phenyl-propanamide (1.1 g) is treated with 1% solution of KOH in 95% ethanol (34 ml), diluted with 95% ethanol (50 ml), with stirring at room temperature for 3 hours, the Reaction mixture is concentrated under vacuum to small volume, and then diluted with ice water and acidified to pH 4 with citric acid. Drop down the precipitate is filtered, washed with water. Crystallization from a mixture of chloroform/ethanol gives 0.65 g of 2-cyano-3-(1,4-dihydro-7-oxalylamino-1-phenyl-indeno-[1,2-c]- pyrazole-3-yl)-3-oxo-N-phenyl-propanamide.

Acting in a similar way, you receive the following connections:

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-7-oxolamine-1-phenyl - indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-propanamide;

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-7-oxolamine-1-fenil - indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-propanamide and

2-cyano-3-(1.4-dihydro-5-oxolamine-1-phenyl-indeno-[1,2-c] -pyrazole - 3-yl)-3-oxo-N-phenyl-propanamide.

Example 19. 3-(7-Amino-1,4-dihydro-1-phenyl-inadelaide reaction with the anhydride of succinic acid (0.71 g) at the boiling point under reflux with stirring for 3 hours After cooling, the reaction mixture is diluted with ice water. Drop down the precipitate is filtered and washed with water. Crystallization from a mixture of chloroform /methanol gives 0.75 g of 3-[7-(3-carboxy-propanolamine)-1,4-dihydro-1-phenyl-indeno- [1,2-c] -pyrazole-3-yl] -2-cyano-3-oxo-N-phenyl-propanamide.

Acting in a similar way, you receive the following connections:

3-[5-(3-carboxy-propanolamine)-1,4-dihydro-1-phenyl-indeno- [1,2-c]-pyrazole-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide and

3-[7-(2-carboxymethylamino)-1,4-dihydro-1-phenyl-indeno-[1,2-c]- pyrazole-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.

Example 20. 5-tert-Butoxycarbonyl-1,4-dihydro-1-phenyl-indeno- [1,2-c]-pyrazole-3-carboxylic acid ethyl ester (11 g) obtained in example 16 is treated with stirring triperoxonane acid (130 ml) at room temperature for 3 hours, the Reaction mixture is diluted with ice water and drop the precipitate is filtered and washed with water until neutral. Crystallization from isopropanol gives 3-etoxycarbonyl-1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-5-carboxylic acid (8,4 g), which undergoes reaction with chloride tiomila (5,3 ml) in anhydrous dioxane (90 ml) at the boiling point under reflux in those who 1,4-dihydro-1-phenyl-indeno-[1,2-c]-pyrazole-5-carboxylic acid, dissolved in anhydrous diglyme (dimethyl ether of diethylene glycol) (100 ml) and added dropwise in an inert atmosphere to a stirred solution of lithium tri-tert-butoxyaniline-hydride (15,4 g) in anhydrous diglyme (90 ml) in such a way as to maintain the temperature between 0 and 4oC. the Reaction mixture was allowed to react at about 0oC with stirring for 1 h, and then it is diluted with ice water, acidified to pH 1 with 23% HCl and extracted with chloroform. The organic solution is washed with water and then evaporated to dryness under vacuum. The residue is purified through a column of SiO2using a mixture of hexane-ethyl acetate 7/3 as eluent. Crystallization from a mixture of methylene chloride/isopropyl ether gives pure ethyl ester of 1,4-dihydro-5-oxymethyl-1-phenyl-indeno-[1,2-c]-pyrazole-3-carboxylic acid (3.8 g), which undergoes reaction with chloride 2-methoxyethoxymethyl (2.1 g) in methylene chloride (60 ml) in the presence of diisopropylethylamine (2,96 ml) at room temperature for 20 hours, the Reaction mixture is washed in a separating funnel first 5% solution of Na2HPO4and then water until neutral. The organic phase is evaporated to dryness under vitexymyca)-methyl-1-phenyl-indeno-[1,2-c]- pyrazole-3-carboxylic acid (4,65 g), which is treated with a solution of KOH (0.4 g) in 95% ethanol (52 ml) with stirring at 45oC for 40 minutes, the Reaction mixture was then diluted with ice water and acidified to pH 4 with citric acid. Drop down the precipitate is filtered, washed with water until neutral and dried under vacuum at 80oC to obtain 1,4-dihydro-5-(2-methoxyethoxyethoxy)-methyl-1-phenyl-indeno-[1,2-c] - pyrazole-3-carboxylic acid (3,95 g) which is dissolved in anhydrous dioxane (50 ml) and subjected to reaction with accelerom chloride (1.9 ml) in the presence of dimethylformamide (11 mg) at room temperature for 1 h, the Reaction mixture was evaporated to dryness under vacuum and the residue, the crude acid chloride 1,4-dihydro-5-(2 - methoxyethoxyethoxy)-methyl-1-phenyl-indeno-[1,2-c] -pyrazole-3-carboxylic acid, dissolved in anhydrous dioxane (50 ml) and subjected to reaction for 1 h with stirring at room temperature with the carbanion obtained by treating the cyano-acetanilide (1,76 g) of 50% sodium hydride (0.6 g) in anhydrous dioxane (140 ml). The reaction mixture is then diluted with ice water and acidified to pH 3 2n. HCl solution.

Drop down the precipitate is filtered, washed with water and crystallized the l-1 - phenyl-indeno-[1,2-c]-pyrazole-3-yl] -3-oxo-N-phenyl-propanamide (1.5 g), which suspendered with stirring in methanol (800 ml) containing 37% HCl solution (8 ml) and heated at 45oC for 20 h After cooling, the reaction mixture is concentrated under vacuum to small volume and diluted with ice water. Drop down the precipitate is filtered and washed with water until neutral. Crystallization from a mixture of methylene chloride/methanol yields of 1.05 g of 2-cyano-3-(1,4-dihydro-5-oxymethyl-1-phenyl-indeno-[1,2-c] -pyrazole-3-yl)- 3-yl)-3-oxo-N-phenyl-propanamide, so pl. 233 - 235oC.

Acting in a similar way, you receive the following connections:

2-cyano-3-(1,4-dihydro-7-oxymethyl-1-phenyl-indeno-[1,2-c] - pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-5-oxymethyl-1-phenyl-indeno-[1,2-c]-pyrazole-3-yl)-3-oxo-propanamide and

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-5-oxymethyl-1-phenyl-indeno-[1,2-c]pyrazole-3-yl)-3-oxo-propanamide.

Example 21. 3-(7-Carboxy-1,4-dihydro-1-phenyl-indeno-[1,2-c]- pyrazole-yl)-2-cyano-3-oxo-N-phenyl-propanamide (1.6 g) dissolved in anhydrous acetonitrile (110 ml) was subjected to the reaction with N,N-dimethylaminoethanol (0.73 g), in the presence of dicyclohexylcarbodiimide (1.12 g) and 4-dimethylaminopyridine (0,265 g) with stirring at room of tempea under vacuum to small volume. The residue is diluted with water, acidified to pH 2 using 1 N. HCl, and then podslushivaet to pH 8 using 1 N. NaOH. Drop down the precipitate is filtered and purified through a column of SiO2using chloroform/methanol/30% NH4in the ratio of 80/20,03 as eluent. The selected reaction product is dissolved in dimethylformamide (20 ml), acidified to pH 2 using 2n. HCl, diluted with water (50 ml), and then podslushivaet to pH 8 with 2n. NaOH. Drop down the precipitate is filtered and washed with water to obtain 0.4 g of 2-cyano-3-(1,4-dihydro-7-N, N-dimethylaminoethoxide-1-phenyl-indeno- [1,2-C]-pyrazole-3-yl]-3-oxo-N-phenyl-propanamide.

Acting in a similar way, you receive the following connections:

2-cyano-3-(1,4-dihydro-5-N,N-dimethylaminoethoxide - 1-phenyl-indeno-[1,2-C]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide;

2-cyano-3-(1,4-dihydro-7-morpholinomethyl-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl)-3-oxo-N-phenyl-propanamide and

2-cyano-3-(7-N,N-dimethylaminopropylamine-1,4-dihydro- -1-phenyl-idene-[1,2-C]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide.

Example 22. 2-Cyano-3-(1,4-dihydro-5-oxymethyl-1-phenyl-idene-[1,2-C] - pyrazole-3-yl)-3-oxo-N-phenyl-propanamide(1.1 g) is subjected to reaction with succinic acid anhydride (0.8 g is izbavlyatsa in ice-cold water and drop the precipitate is filtered and washed with water. Crystallization from a mixture of methylene chloride/isopropanol gives of 0.85 g of 3-[5-(3-carboxy-propenolatomethyl)1,4 - dihydro-1-phenyl-indeno-[1,2-C] -pyrazole-3-yl] -2-cyano-3-oxo-N-phenylpropanamide.

Acting in a similar way, I have got the following link:

3-[7-(3-carboxy-propenolatomethyl)-1,4-dihydro-1-phenyl-indeno- [1,2, -C]-pyrazole-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.

Example 23. Tablets, each weighing 150 mg, containing 50 mg of active substance, can be obtained as follows.

Composition (for 10,000 tablets), g:

2-Cyano-3-(1,4-dihydro-1-phenyl-idene-[1,2-C]-pyrazole-3-yl)-3-oxo-N-phenyl-propanamide - 500

Lactose - 710

Corn starch - 238

Powdered talc - 36

Magnesium stearate - 16

2-Cyano-3-(1,4-dihydro-1-phenyl-idene-[1,2-C] pyrazole-3-yl) -3-oxo-N-phenyl-propanamide, lactose and half the corn starch are mixed; the mixture is then sifted through a sieve with holes of 0.5 mm Corn starch (18 g) suspendered in warm water (180 ml). The resulting paste is used to pelletize the powder. The granules are dried, sieved through a sieve with openings of 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, tweeting way get tablets having the same composition, but containing, for example, as active substance one of the following connections:

2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1,4-dihydro-idene-[1,2-C] -pyrazole-3-yl]-3-oxo-propanamide;

2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno- [1,2-C] -pyrazole-3-yl)-3-oxo-propanamide and

2-cyano-N-(4-fluoro-phenyl)-3-)1.4-dihydro-7-methyl-1-phenyl-indeno- [1,2-C] -pyrazole-3-yl)-3-oxo-propanamide.

1. Oxopropanenitrile condensed derivatives of pyrazole of the General formula

< / BR>
where H - CHR4group or sulfur atom, where R4is hydrogen or the group where R' and R" together with the nitrogen atom to which they are bound, form morpholino group;

R1is a phenyl group which is unsubstituted or substituted by one or two halogen substituents;

R2is hydrogen, halogen, C1- C6-alkyl, amino, hydroxymethyl, carboxypropyl,1- C6-alkoxycarbonyl or morpholinomethyl;

Q is hydrogen or a group - CON HRb, where Rb is a group CH2COOR, where R is hydrogen or C1- C4-alkyl, or the group (A)m-R5where m = 0 or 1;

A - C1- C6-Allenova chain;

R5is phenyl, unsubstituted SS="ptx2">

2. Connection on p. 1, characterized in that X - CH2group or a sulfur atom;

Q is a group of the formula-CONHRb, where Rb is the group -(A)m-R5where m = 0;

R5is phenyl, unsubstituted or substituted with halogen;

R1is phenyl, unsubstituted or substituted with halogen;

R2is hydrogen, halogen, C1- C6-alkyl, C1- C6-alkoxycarbonyl or morpholinomethyl.

3. Connection on p. 1, characterized in that it is a 2-cyano-3-(1,4-dihydro-1-phenyl-indeno-(1,2-C)pyrazole-3-yl)-3-oxo-N-phenyl-propanamide,

N-(3-chlorophenyl)-2-cyano-3-(1-(4-forfinal)-1,4-dihydroindeno-(1,2-C)pyrazole-3-yl)-3-oxopropanoic,

2-cyano-3-(1,4-dihydro-1-phenyl-indeno-(1,2-C)pyrazole-3-yl)-N-(4-forfinal)-3-oxo-propanamide,

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno-[1,2-C] pyrazole-3-yl)-3-oxo-propanamide,

2-cyano-3-(1,4 - dihydro-7-methyl-1-phenyl-indeno-[1,2-C] pyrazole-3-yl)-3 - oxo-N-phenyl-propanamide,

2-cyano-3-oxo - 3-(1-phenyl-1H - benzothieno-[1,2-C] -N-pyrazole-3-yl)- N-phenyl-propanamide,

2-cyano-N-(4-fluoro-phenyl)-3-[1-( 4-fluoro-phenyl)-1,4 - dihydro-indeno-[1,2-C] pyrazole]-3-oxo-propanamide,

3-(5-butoxycarbonyl-1,4 - dihydro-1-phenyl-indeno- [1,2-C] pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide,

2-cyano-3-(1,4-dihydro-nil - indeno-[1,2-C] pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide and its pharmaceutically acceptable salt.

4. Connection on p. 1 or its pharmaceutically acceptable salt, manifesting immunostimulirutuyu activity.

5. The pharmaceutical composition exhibiting together with immunomodulating activity, including an active ingredient and a pharmaceutically acceptable carrier or diluent, characterized in that it contains as active ingredient an effective amount of the compounds of formula I or its pharmaceutically acceptable salt according to p. 1.

 

Same patents:

The invention relates to new 1-aryl-5-(substituted)alkylidene the pyrazoles, methods for their preparation, to compositions containing these compounds, to methods of their use for combating arthropods, nematodes, helminths or protozoa pests

The invention relates to imidazolium and pyridium derived phenylsilane 1,4-dihydropyridines, to the way they are received and containing pharmaceutical compositions

The invention relates to new chemical compounds having valuable properties, in particular derivatives of dihydropyridines of General formula (I)

< / BR>
where R1aryl with 6-10 carbon atoms, unsubstituted or once-three times substituted by identical or different substituents from the group comprising halogen atom, a nitro-group, cyano, trifluoromethyl, cryptometer and triptoreline,

or substituted unbranched or branched alkyl with 1-8 carbon atoms, which is not substituted or substituted aryl with 6-10 carbon atoms, or substituted unbranched or branched alkoxygroup or alkoxycarbonyl with 1-8 carbon atoms, carboxypropyl, an amino group or a group of the formula-NR4R5in which

R4and R5the same or different and mean a hydrogen atom, an unbranched or branched alkyl with 1-8 carbon atoms, phenyl or benzyl,

or thienyl,

R2a hydrogen atom or cycloalkyl with 5-8 carbon atoms or an unbranched or branched alkyl, alkenyl, alkadienes, or quinil with 1-10 carbon atoms, unsubstituted or once or twice substituted od the cyano and nitro-group, or unbranched or branched alkylthiol, alkoxygroup, alkoxycarbonyl, acyl or alloctype with 1-8 carbon atoms, or cycloalkyl with 3-8 carbon atoms, fenoxaprop or phenyl, the latter is not substituted or once or twice substituted by identical or different substituents from the group comprising halogen atom, an unbranched or branched alkyl and alkoxygroup with 1-6 carbon atoms, or substituted by the group-NR4R5in which R4and R5have the above values,

R3a hydrogen atom or an unbranched or branched alkyl with 1-8 carbon atoms,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerable salts

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to new derivatives of pyrazole and their pharmaceutically acceptable salts

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase
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