WO1989012638A1 - Tricyclic 3-oxo-propanenitrile derivatives and process for their preparation - Google Patents

Tricyclic 3-oxo-propanenitrile derivatives and process for their preparation Download PDF

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Publication number
WO1989012638A1
WO1989012638A1 PCT/EP1989/000683 EP8900683W WO8912638A1 WO 1989012638 A1 WO1989012638 A1 WO 1989012638A1 EP 8900683 W EP8900683 W EP 8900683W WO 8912638 A1 WO8912638 A1 WO 8912638A1
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phenyl
group
alkyl
defined above
dihydro
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PCT/EP1989/000683
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French (fr)
Inventor
Gianfederico Doria
Anna Maria Isetta
Mario Ferrari
Domenico Trizio
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Farmitalia Carlo Erba S.R.L.
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Application filed by Farmitalia Carlo Erba S.R.L. filed Critical Farmitalia Carlo Erba S.R.L.
Priority to KR1019900700336A priority Critical patent/KR900701790A/en
Priority to DE89906767T priority patent/DE68910523T2/en
Priority to AT89906767T priority patent/ATE96798T1/en
Publication of WO1989012638A1 publication Critical patent/WO1989012638A1/en
Priority to NO905449A priority patent/NO905449D0/en
Priority to DK300990A priority patent/DK300990A/en
Priority to FI906284A priority patent/FI906284A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to tricyclic 3-oxo- propanenitrile derivatives, to a process for their preparation and to pharmaceutical compositions containing them.
  • X represents an oxygen atom or a -S(O) n - group, wherein n is zero, 1 or 2;
  • R represents C 1 -C 6 alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro, amino, formylamino and C 2 -C 8 alkanoylamino;
  • R 1 is ao) hydrogen, di(C 1 -C 6 alkyl)-amino or a group wherein R' and R", the same or different, is C 1 -C 6 alkyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N-pyrrolidinyl, N-piperazinyl, hexahydroazepin-1-yl, thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by C 1 -C 6 alkyl; b° ) CH 2 OH, CHO, COOH or C 2 -C 7 alkoxycarbonyl; c° ) a group wherein R d is hydrogen or C 1 -C 6 alkyl and R c is hydrogen, phenyl or the side-chain of an ⁇ -aminoacid; d°) a NHCOCH-NH 2 group, wherein R c is
  • R 2 and R 3 are independently: a) hydrogen, halogen or C 1 -C 6 alkyl; b) hydroxy, C 1 -C 6 alkoxy or C 3 or C 4 alkenyloxy; or c) nitro, amino, formylamino or C 2 -C 8 alkanoylamino;
  • R 4 represents hydrogen or C 1 -C 6 alkyl; and
  • Q represents hydrogen, carboxy, C 2 -C 7 alkoxycarbonyl or a
  • R' and R" are as defined above and optionally by another substituent chosen from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, nitro, formylamino, C 2 -C 8 alkanoylamino, hydroxy, formyloxy and C 2 -C 8 alkanoyloxy, or e') 2-thienyl, 2-furyl or 1- ( C 1 -C 6 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 1 -C 6 alkyl; and the pharmaceutically acceptable salts thereof; and wherein, when R 1 is hydrogen, then Q is only a group in which R a is as defined above and either
  • R b is a group wherein R c and R d are as defined above or R b is a") a -(CH 2 ),-R' 5 group wherein z is zero, 1 or 2 and R' 5 is as R 5 defined above under d'), e') or f) or b") a or -A'-R 5 group, wherein A' is a C 3 -C 6 alkylene chain and R 5 is as defined above.
  • the present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or biprecursors of the compounds of formula (I). It has to be noticed that the compounds of formula (I) may be represented also by a tautomeric structure, namely the enol structure of formula (la)
  • X, R, R 1 , R 2 , R 3 , R 4 and Q are as defined above.
  • a halogen atom is preferably chlorine or fluorine.
  • alkyl, alkylene, alkanoyloxy, alkoxy and al-kanoylamino groups may be branched or straight chain groups.
  • a C 1 -C 20 alkyl group is preferably a C 1 -C 6 alkyl group.
  • a C 1 -C 6 alkyl group is, e.g., methyl, ethyl, propyl, iscpropyl, butyl or tert.butyl, more preferably methyl, ethyl or tert.butyl, in particular methyl or ethyl.
  • a C 3 or C 4 alkenyloxy group is preferably allyloxy.
  • a C 1 -C 6 alkoxy group is, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, preferably it is methoxy, ethoxy or propoxy.
  • a di(C 1 -C 6 alkyl)-amino is preferably a di(C 1 -C 4 alkyl)-amino group, in particular a di(C 1 or C 2 alkyl)-amino one.
  • a C 5 -C 8 cycloalkyl group is preferably cyclopentyl or cyclohexyl.
  • a C 2 -C 8 alkanoylamino group is preferably acetylamino or propionyl-amino.
  • a C 2 -C 8 alkanoyloxy group is preferably acetoxy or propionyloxy.
  • a C 2 -C 7 alkoxycarbonyl group is preferably a C 2 -C 5 alkoxycarbonyl group, in particular a C 2 or C 3 alkoxycarbonyl one.
  • a C 1 -C 6 alkylene chain is preferably a C 1 -C 3 alkylene chain, such as a-CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, or chain. 5
  • a C 3 -C 6 alkylene chain is preferably a C 3 alkylene chain, in particular a -(CH 2 ) 3 - or a In a group, wherein R d is as defined above and R c is as defined above except hydrogen, the asymmetric carbon atom to which -R c and -COOR d are linked may have either the R or S configuration.
  • the side-chain of an ⁇ -aminoacid is specifically the residue obtained from an ⁇ -aminoacid by removing the amino and the carboxy groups together with the ⁇ -carbon atom to which they are linked.
  • the side-chain of an ⁇ -aminoacid as defined above is preferably the side-chain deriving from a naturally occurring aminoacid.
  • aminoacids examples include alanine, valine, leucine, isoleucine, phenylalanine, proline, hydroxyproline, serine threonine, cysteine, cystine, methionine, tryptcphan, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine and phenylserine.
  • aminoacids are -CH 3 (deriving from alanine), -CH 2 CH(CH 3 ) 2 (deriving from leucine) and -CH 2 C 6 H 5 (deriving from phenylalanine).
  • Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, N-methyl ⁇ glucamine, trieithylamine, triethanolamine, dibenzylamine, methyl ⁇ benzylamine, di-(2-etl ⁇ yl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-diethylaminr ⁇ oethylamine, N-ethyl-morpholine, ⁇ -phenethylamine, N-benzy- ⁇ -phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e.g., hydrochloric, hydrdbrcaiiic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric
  • the present invention also includes within its scope pharmaceutically acceptable bicprecursors (otherwise known as prodrugs) of the compounds of formula (I), i.e., compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound. of formula (I).
  • pharmaceutically acceptable bicprecursors otherwise known as prodrugs
  • compounds of the invention are the compounds of formula (I),wherein X is oxygen or a -S(O)p-group, in which p is zero or 1; R represents unsubstituted pyridyl or phenyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluor ⁇ xiethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, amino and C 2 -C 8 alkanoylamino; R 1 is aoo) hydrogen, COOH, CHO, CH 2 OH, C 2 -C 7 alkoxycarbonyl or a group, wherein each of R"' and R IV independently is C 1 or C 2 alkyl, or R''' and R IV , taken together with the nitrogen atom to which they are linked, form a N-pyrrolidinyl, N-piperazinyl, morpholino or piperidino ring which is urisubsti
  • R III and R IV are as defined above
  • h°°) a C 2 -C 4 alkoxycarbonyl group substituted by a group, wherein R III and R IV are as defined above
  • R 2 and R 3 each independently is hydrogen, halogen, nitro, amino, hydroxy, C 1 -C 4 alkyl or C 1 -C 4 alkoxy
  • R 4 represents hydrogen or C 1 -C 4 alkyl
  • Q represents hydrogen, C 2 -C 5 alkoxycarbonyl or a -CONR' a R' b group, wherein R' a is hydrogen or C 1 -C 6 alkyl and R' b is C 1 -C 6 alkyl or a group, wherein Rg is hydrogen or C 1 -C 4 alkyl and R c is as defined above; or R'b, is a -(A") m -R" 5 group, wherein m is zero or 1, A" is a C 1 -C 3 alkylene chain and R" 5 is: a''') unsubstituted pyridyl or phenyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, CF 3 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro and di-(C 1 -C 4 alkyl) amino; R b ' ' ' ) phenyl
  • R' a is as defined above and R' b is (1) a group wherein R c and R g are as defined above or (2) a -(CH 2 ) z -R 5 ''' group, wherein z is zero, 1 or 2 and R 5 ''' is as R" 5 defined above under b'''), c''') and d'''), or (3) a - group wherein R'' 5 is as defined above.
  • More preferred compounds of the invention are the compounds of formula
  • R is phenyl, unsubstituted or substituted by a substituent selected frcm nitro, halogen, CF 3 , C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
  • R 1 is aooo) hydrogen, -COOH, -CHO, -CH 2 OH, C 2 -C 5 -alkoxycarbonyl, or a I - group, wherein R''' and R IV are as defined above; each of R 2 and R 3 independently is hydrogen, halogen, nitro, amino, hydroxy, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; booo) a group, wherein R'd is hydrogen or C 1 -C 4 alkyl and R c is as defined above; c°°°) a group wherein R c is as defined above; dooo) a -CH 2 COO(CH 2 ) n COOR' d or a -NHCO(CH 2
  • R 4 represents hydrogen or methyl
  • Q represents hydrogen or a -CONR" a R'' b group, wherein R" a is hydrogen or C 1 -C 4 alkyl and R'' b is C 1 -C 4 alkyl or group wherein R c - and R g are as defined above; or R"b is a -(CH 2 ) z -R 5 IV group, wherein z is zero, 1 or 2 and R IV 5 is a IV ) unsubstituted pyridyl or phenyl, unsubstituted or substituted by a substituent chosen from nitro, halogen, CF 3 , C 1 -C 4 -alkyl, C1 -C 4 alkoxy and di(C 1 -C 2 alkyl)-amino;
  • b IV phenyl, substituted by -CH 2 OH, -COOH or a group, wherein R''' and R IV are as defined above, and optionally by another substituent chosen from hydroxy and C 1 -C 4 alkoxy; or c IV ) 2-thienyl or 2-furyl; d IV ) 2-thiazolyl or 3-isoxazolyl, iinsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof; and wherein, when R 1 is hydrogen, then Q is a -CONR'' a R'' b group, wherein R" a is as defined above and R 11 b is (1) group, wherein R c and R g are as defined above; or (2) a -(CH 2 ) z -R V 5 group, wherein z is as defined above and R V 5 is as R IV 5 defined above under b IV ) , c IV ) or d I V ) .
  • Examples of preferred compounds of the invention are: N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3-oxo-propanoyl]-glycine, methyl ester; N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3- yl]-3-oxo-propanoyl]-DL-leucine, methyl ester;
  • the ccrapounds of formula (I) and the salts thereof can be prepared by a process comprising; a) reacting a compound of formula (II)
  • X, R, R 1 , R 2 , R 3 and R 4 are as defined above and Y is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III)
  • Q' 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)
  • R b is as defined above, so obtaining a compound of formula
  • X, R, R 1 , R 2 , R 3 and R 4 are as defined above and Z is a reactive derivative of a carboxy group, with a compound of formula (VII)
  • R a and R b are as defined above, so obtaining a compound of formula (I) wherein
  • Q is a group, wherein R a and R b are as defined above; or d) hydrolysing a compound of formula (I), wherein Q is C 2 -Cy alkoxycarbonyl or a - group, in which R a and R c are as defined above and R d is C 1 -C 6 alkyl, so as to obtain the corresponding compound of formula (I), wherein Q is a free carboxy group or a group, in which R a and R c axe 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.
  • Y is a reactive derivative of a carboxy group
  • it is, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or a C 2 -C 7 alkoxycarbonyl group, preferably a C 2 or C 3 alkoxycarbonyl group.
  • the reaction between a compound of formula (II) wherein Y is carboxy and a compound of formula (III) may be carried cut, for example, in the presence of a condensing agent such as diethyl cyanophosphonate, in the presence of a base such as triethylamine, in an inert solvent such as dimethylformamide at a temperature varying between about 0°C and about 50°C.
  • a condensing agent such as diethyl cyanophosphonate
  • a base such as triethylamine
  • an inert solvent such as dimethylformamide
  • reaction between a compound of formula (II) wherein Y is a reactive derivative of a carboxy group and a compound of formula (III) may be carried out, for example, in the presence of a strong base such as sodium hydride, potassium t.butoxide, thallous ethoxide, in an inert solvent such as 1,2-dimethoxyethane, dioxane, dimethylfonnamide, at a temperature varying between about 0°C and about 100°C.
  • a strong base such as sodium hydride, potassium t.butoxide, thallous ethoxide
  • an inert solvent such as 1,2-dimethoxyethane, dioxane, dimethylfonnamide
  • reaction between a compound of formula (IV) and a compound of formula (V) may be carried cut, for example, in the presence of a base such as sodium hydride or triethylamine, in an inert solvent such as toluene, dioxane, tetrahydrofuran, dimrethylformamide, at a temperature varying between about 0°C and about 100°C.
  • a base such as sodium hydride or triethylamine
  • an inert solvent such as toluene, dioxane, tetrahydrofuran, dimrethylformamide
  • Z is, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or a C 2 -C 7 alkoxycarbonyl group, preferably a C 2 -C 3 alkoxycarbonyl group.
  • the reaction between a compound of formula (VI), where Z is a halocarbonyl group, and a compound of formula (VII) may be carried out, for example, in an inert solvent such as dichloroethane, dioxane, dimethylformamide, in the presence of pyridine or triethylamine as acid acceptor, at a temperature varying between about 0°C and about 100°C.
  • reaction between a compound of formula (VI) , wherein Z is C 1 -C 6 alkyl ester, and a compound of formula (VII) may be carried cut, for example, by heating at the reflux temperature in an aromatic hydrocarbon such as toluene or xylene, preferably distilling off slowly together with the diluent the free C 1 -C 6 alkyl alcohol generated during the reaction.
  • an aromatic hydrocarbon such as toluene or xylene
  • Hydrolysis of a compound of formula (I), wherein Q is a C 2 -C 7 alkoxycarbonyl group or a d group in which R a and R c are as defined above and R d is C 1 -C 6 alkyl, according to process-variant d) above, may be performed by selective basic hydrolysis, using e.g. aqueous sodium or potassium hydroxide in a solvent such as ethanol or dimethylformamide, at a temperature varying between about 0°C and about 80°C.
  • a compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods; for example, in a compound of formula (I) a nitro group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid, using, if necessary, an organic oosolvent such as acetic acid, dioxane, tetrahydofuran, at a temperature varying between room temperature and about 100°C.
  • an organic oosolvent such as acetic acid, dioxane, tetrahydofuran
  • an amino group may be converted into a formylamino or a C 2 -C 8 alkancylamino group, for example by reacting with formic acid or with the suitable C 2 -C 8 alkancyl anhydride, without any solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varying between 0°C and about 100oC.
  • R' and R" axe as defined above, respectively, by reaction with a quaternary nitrogen compound of formula (VIIa) K wherein R' and R" are as defined above, in an organic inert solvent, such as dioxane, tetrahydrofuran, chloroform, dichloromethane, 1,2-dichloroethane, benzene or toluene, in the presence of a tertiary amine, such as triethylamine, at a temperature varying between about -20°C and room terrperature, according to the experimental procedure described in GB-A-1,293,590 and in US-A-4,447,432.
  • an amino group may be converted into a - group, wherein R c is as defined above, by reaction with a suitably protected ⁇ -aminoacid of formula wherein R- is as defined above and
  • E is a protective group, such as a benzyloxycarbonyl or a tert-butoxycarbonyl group, in the presence of dicyclohexylcarbodiimide as condensing agent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0oC and room temperature, so as to obtain the protected - group, wherein R c and E are as defined above, which in turn is deprotected using well known methods in organic chemistry.
  • a protective group such as a benzyloxycarbonyl or a tert-butoxycarbonyl group, in the presence of dicyclohexylcarbodiimide as condensing agent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0oC and room temperature, so as to obtain the protected - group,
  • a carboxy group may be converted into a - group, wherein R c is as defined above, by reaction with an esterified ⁇ -aminoacid of formula , wherein R' d is C 1 -C 6 alkyl and R c is as defined above, in the presence of dicyclohexylc-arbodiimide as condensing agent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0°C and room temperature, so as to obtain the esterified C group, wherein R c and R' d are as defined above, which in turn is hydrolyzed to give the group, wherein R c is as defined above, following methods well knewn in the art, for example, those described for the process variant d) above. Furthermore, for example,
  • the optional salification of a compound of formula (I) as well as the conversion of a salt into the free cempound and the separation of a mixture of isomers into the single isomers may be carried cut by conventional methods.
  • the separation of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diastereoisomeric salts, followed by recovery of the optically active isomeric acids or, respectively, bases.
  • EP-A-274443 for example, by reacting a compound of formula (VIII)
  • R 1 , R 2 , R 3 and R 4 are as defined above and R 6 is C 1 -C6 alkyl, preferably C 1 -C 2 alkyl, with a compound of formula (IX)
  • R is as defined above.
  • the reaction between a compound of formula (VIII) and a compound of formula (IX) may be carried cut, for example, in a solvent such as C 1 -C 6 alkyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetic acid, at a temperature varying between about 0°C and about 150°C.
  • the compounds of formula (II), wherein Y is carboxy may be prepared, for example, by hydrolysis of the corresponding compounds of formula (II) wherein Y is C 2 -C 7 alkoxycarbonyl, according to standard methods well known in the art, for example, by basic hydrolysis, carried out e.g.
  • the compounds of formula (II) wherein Y is halocarbonyl, preferably chlorocarbonyl, may be prepared, for example, by reaction of the corresponding compound of formula (II) , wherein Y is carboxy, with a suitable acid halide, for example oxalyl chloride, thionyl chloride,
  • PCI 3 , PBr 3 in an inert solvent such as ether, benzene, dichloroethane, dioxane or without any solvent, at a temperature varying between about 0°C and about 100°C.
  • an inert solvent such as ether, benzene, dichloroethane, dioxane or without any solvent
  • the compounds of formula (III) are, in seme cases, commercially available products, or may be prepared by methods well known in the art.
  • cyanoacetic acid by reacting cyanoacetic acid with a compound of formula (VII) in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1- carbonyldiimadazole and the like, in an inert organic solvent such as benzene, dioxane, acetonitrile, at a temperature varying between about 0°C and about 50°C.
  • a condensing agent such as dicyclohexylcarbodiimide, 1,1- carbonyldiimadazole and the like
  • an inert organic solvent such as benzene, dioxane, acetonitrile
  • the compounds of formula (IV) are compounds of general formula (I) , wherein Q is hydrogen and may be obtained by process a) above, for example, by reacting a comp ⁇ und of formula (II), wherein Y is C 2 -C 7 alkoxycarbonyl, with acetonitrile, in the presence of a strong base e.g., sodium hydride, potassium tert.butoxide, in an inert organic solvent such as benzene, dioxane, tetrhydrofuran, at a temperature varying between about 0°C and about 100°C.
  • a strong base e.g., sodium hydride, potassium tert.butoxide
  • an inert organic solvent such as benzene, dioxane, tetrhydrofuran
  • the compounds of formula (VI), wherein Z is C 2 -C 7 alkoxycarborryl, are compounds of general formula (I) wherein Q is C 2 -C 7 alkoxycarbonyl and may be obtained by process a) above, for example, by reacting a compound of formula (II) with a compound of formula (X)
  • R 7 is C 1 -C 6 alkyl, using the same experimental conditions as described above for the reaction between a compound of formula (II) and a compound of formula (III).
  • the compounds of formula (IV), wherein Z is halocarbonyl may be prepared, for example, by basic hydrolysis of a compound of formula (VI), wherein Z is C 2 -C 7 alkoxycarbonyl, using, for example, the same experimental conditions described above for the hydrolysis of the compounds of formula (II), wherein Y is C 2 -C 7 alkoxycarbonyl, in order to obtain the corresponding carboxy derivative, which in turn may be transformed into a compound of formula (VI), wherein Z is halocarbonyl, preferably chlorocarbonyl, using, for example, the same experimental conditions described above for the preparation of the compounds of formula (II), wherein Y is halocarbonyl.
  • the compounds of formula (VIII) may be prepared, for example, by reacting a compound of formula (XI)
  • each of R 8 and R 8 ' being the same or different, is C 1 -C 6 alkyl, preferably methyl or ethyl.
  • the reaction between a compound of formula (XI) and a compound of formula (XII) may be carried out, for example, in the presence of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride, potassium tert.butoxide, in an organic solvent such as C 1 -C 6 alkyl alcohol, benzene, dioxane, dimethylformamide, at a temperature varying between about 0°C and about 100°C.
  • the compounds of formula (XI) may be prepared by synthetic methods well known in the art, for example, according to the methods described in J.A.C.S. 76, 5065 (1954) and in "Advances in Heterocyclic Chemistry", 18, 59 (1975).
  • the compounds of formula (V) , (VII) , (IX) , (X) and (XII) are known products and may be prepared by conventional methods: in some cases they are commercially available products.
  • groups are present, such as COOH, NH 2 , CHO and/or OH, which need to be protected before submitting them to the reactions described above, they may be protected before the reactions take place and then deprotected, according to well known methods in organic chemistry.
  • the compounds of formula (I) possess immunomodulating activity and can be used, for example, as immunostimulating agents e.g., in the treatment of acute and chronic infections of both bacterial and viral origin, alone or in association with antibiotic agents, and in the treatment of neoplastic diseases, alone or in association with antitumoral agents, in mammals.
  • the immunostimulating activity of the compounds of the invention is proved, for example, by the fact that they are effective in potentiating the cytotoxic activity of the macrophages towards tumour cells in vitro.
  • mice are treated i.p. with the tested compounds and then, seven days later, peritoneal cells are collected and plated for 2 hours at 37 oC. After this period the walls are washed to eliminate the non adherent cells, tumour target cells are then added and the incubation is prolonged for 48 hours. At the end of this period the target cells viability is evaluated by a colorimetric method and quantified at 570 nm.
  • the compounds of the invention can be safely used in medicine by virtue of their negligible toxicity.
  • the therapeutic regimen for the different clinical syndromes must be adapted to the type of pathology taking into account, as usual, also the route of administration, the form in which the compound is administered and the age, weight and 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 infections. For the maintenance regimens the oral or parenteral, e.g., intramuscular or suibcutaneous, route is preferred.
  • the compounds of the invention can be administered orally at doses ranging e.g., from about 0.5 to about 10 mg/kg of body weight per day in adult humans.
  • Doses of active compounds ranging e.g., from about 0.2 to about 5 mg/kg of body weight can be used for parenteral administration in adult humans. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.
  • the nature of the pharmaceutical compositions containing the compounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration.
  • compositions may be formulated in the conventional manner with the usual ingredients.
  • the compounds of the invention may be admdissered in the form of aqueous or oily solutions or suspension, tablets, pills, gelatine capsules, syrups, drops or suppositories.
  • the pharmaceutical compositions containing the compounds of this invention are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, carbojcymethylcellulose, 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, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • diluents
  • the liquid dispersions for oral administration may be e.g., syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxy-methylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g., prcpylene glycol, and if desired, a suitable amount of licodaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g., sterile water, olive oil, ethyl oleate, glycols, e.g., prcpylene glycol, and if desired, a suitable amount of licodaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.
  • the suppositions may contain together with the active compound a pharmaceutically acceptable carrier, e.g. , cocoa-butter, polyethylene glycol, a polyoxy
  • 1,4-Dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2 g) is reacted with thionyl chloride (1 ml) in dioxane (40 ml) at reflux te ⁇ perature for 2 hours. After cooling the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazole-3-carbonyl chloride as crystalline residue.
  • the crude product is dissolved in anhydrous dioxane (15 ml) and reacted for 2 h under stirring at room temperature with the carbanion obtained by treatment of cyanacetic acid, 2-morpholinomethylbenzylamide (1.95 g) with 50% sodium hydride (0.39 g) in anhydrous dioxare/dimethylformamide 9:1 (20 ml) at room temperature.
  • the reaction mixture is then diluted with ice water and acidified to pH 3 with citric acid.
  • the precipitate is filtered and dissolved in CHCI 3 .
  • the organic solution is washed with 2% citric acid solution and then with water.
  • the crude product is dissolved in anhydrous dioxane (35 ml) and reacted for 1 hour under stirring at room te ⁇ perature with the carbanion obtained by treatment of N-cyanoacetylglycine, methyl ester (1.44 mg) with 50% sodium hydride (0.54 g) in anhydrous dimethylformamide/dioxane 1:1 (30 ml) at room temperature.
  • the reaction mixture is then diluted with ice water and acidified to pH 2 with N HCl.
  • the precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with N HCl and then with water until neutral.
  • N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine, methyl ester (1.9 g) , is suspended in 1% YCH. solution in 95% ethanol (61 ml) and heated under stirring under reflux for 30 minutes. After cooling the precipitate is filtered and washed with ethanol, then dissolved in water. The aqueous basic solution is extracted with ethyl acetate and then acidified to pH 2 with 2N HCl.
  • This solution is added under nitrogen at room temperature to a stirred mixture of anhydrous tert-butanol (300 ml) in benzene (500 ml) and pyridine (470 ml).
  • the reaction mixture is allowed to react for 20 hours at room temperature and then is evaporated to dryness in vacuo.
  • the residue is dissolved in ethyl acetate and the organic solution is washed with 5 % citric acid solution, then with water until neutral and finally evaporated to dryness in vacuo.
  • the residue is purified over a SiO 2 column using hexane/ethyl acetate 90/10 as eluent.
  • the recovered product is treated with hexane under stirring to give 2,3-dihydro-4-oxo-4H-[1]-benzothiopyran-6-carboxylic acid, tert-butyl ester, m.p. 125-127°C (34.5 g), which is reacted with diethyl oxalate (83.8 g) in anhydrous ethanol (1000 ml) in the presence of sodium ethoxide (31 g) under stirring at room temperature for 2 hours.
  • the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid.
  • the precipitate is filtered, washed with water and then dissolved in ethyl acetate.
  • reaction mixture is evaporated to dryness in vacuo and the residue, 8-tert-butoxycarbonyl-1,4-dihydro- 1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazole-3-carbonyl chlo ride (24.8 g), is dissolved in anhydrous dioxane (980 ml) and added under stirring to the suspension obtained by treatment of cyanoacetanilide (10.28 g) with 50 % sodium hydride (3.75 g) in anhydrous dioxane (1230 ml) at room temperature. The reaction mixture is kept under stirring at room temperature for 1 hour and then diluted with ice water and acidified to pH 3 with 2N HCl.
  • the precipitate is filtered, washed with acetonitrile and then eliminated.
  • the organic solution is concentrated in vacuo to a small volume, diluted with water, acidified to pH 2 with IN HCl and finally basified to pH 8 with 1N NaOH.
  • the obtained precipitate is filtered, washed with water, dissolved in chloroform and washed with IN HCl and then with water until neutral.
  • the organic solution is evaporated in vacuo to dryness and the residue is purified over a SiO column using chloroform/methanol 90/10 as eluent.
  • Example 11 N-[1,4-Dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4,3-c]pyrazol-8-yl]carbonyl-glycine methyl ester (0.9 g) is suspended in 1 % KOH solution in 95 % ethanol (22.3 ml) and heated under stirring at the reflux temperature for 30 minutes. After cooling the reaction mixture is acidified to pH 2 with 23 % HCl and then diluted with ice water.
  • reaction mixture is allowed to react at about 0°C under stirring for 1 hour and then 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 in vacuc. The residue is purified over a SiO 2 column using hexane/ethyl acetate 7/3 as eluent. Crystallization from CH 2 Cl 2 /isopropyl ether yields pure 1,4-dihydro-8-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazole-3-carboxylic acid ethyl ester, m.p.
  • reaction mixture is evaporated to dryness in vacuo and the residue, crude 1,4-dihydro-8-(2-methoxyethoxymethoxy)methyl-1-phenyl-[1] -benzothiopyrano[4 ,3-c]pyrazole-3-carbonyl chloride, is dissolved in anhydrous dioxane (50 ml) and reacted for 1 hour under stirring at room temperature with the carbanion obtained by treatment of cyano-acetanilide (1.76 g) with 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 with 2N HCl.
  • N,N-dimethylaminoethanol (0.73 g)
  • dicyclohexylcarbodiimide (1.12 g)
  • 4-dimethylaminopyridine 0.265 g
  • the precipitate is filtered off and the organic solution is concentrated in vacuo to a small volume.
  • the residue is diluted with water, acidified to pH 2 with NHCl and then basified to.pH 8 with N NaOH.
  • the precipitate is filtered and purified over a SiO 2 column using chloroform/methanol/30 % NH 4 OH 80/20/0.3 as eluent.
  • the recovered product is dissolved in dimethylformamide (20 ml), acidified to pH 2 with 2N HCl, diluted with water (50 ml), and then basified to pH 8 with 2N NaOH.
  • the precipitate is filtered and washed with water to yield 0.4 g of 2-cyano-3-(1,4-dihydro-8-N,N-dimethyl-aminoethoxy ⁇ carbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 217-220°C.
  • N-Formylmorpholine (7.58 g) dissolved in anhydrous ethyl ether (200 mi) is reacted with oxalyl chloride (8.02 g) under stirring at room temperature for 20 hours.
  • the precipitate is filtered, washed with anhydrous ethyl ether and dried in vacuo at room temperature for 1 hour to yield 8.9 g of 4-chlo ⁇ romethylene-morpholinium chloride.
  • This compound (5.47 g) is added portionwise at -15°C to a stirred solution of 3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (3 g) in anhydrous tetrahydrofuran (130 ml) containing triethylamine (8.96 ml). The reaction mixture is kept under stirring at -15°C for 2 hours and then at about 0°C for 2 hours again. Finally it is diluted with ice water and actified to pH 4 with citric acid.
  • the precipitate is filtered, dried in vacuo at 50°C and then purified over a SiO 2 column using chlorofcrm/methancl/30 % NH 4 OH 85/12/0.5 as eluent.
  • the recovered product is crystallized frcm methanol to yield 1.4 g of 2-cyano-3(1,4-dihydro-8-morpholinomethyleneamino-1-phenyl-[1]-benzothiopyrano3-4c]pyrcazopl-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 205-210°C.
  • the organic solution is evaporated in vacuo to dryness and the residue is extracted with ethyl acetate ( 2 x 100 ml ) .
  • the insoluble residue is filtered off and the clear organic solution is evaporated in vacuo to dryness .
  • the crude product is purified over a flash column using chloroform/methanol/acetic acid 85/15/0.5 as eluent.
  • the recovered product is crystallized from chloroform-ethyl acetate to yield 3-[8-(N-tert-burtoxycarbonylglycyl)amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phen propanamide, m.p. 190-200°C (0.36 g) , which is suspended in ethyl acetate containing gaseous HCl (about 2.5 N solution) and kept under stirring at room temperature for 4 hours.
  • gaseous HCl about 2.5 N solution
  • Tablets each weighing 150 mg and containing 50 mg of active substance, can be manufactured as follows:
  • composition for 10,000 tablets

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Abstract

Compounds having general formula (I), wherein X represents an oxygen atom or a -S(O)n-group, wherein n is zero, 1 or 2; R represents C1-C6 alkyl, pyridyl or substituted or unsubstituted phenyl; R2, R3 and R4 are as defined herein; and Q represents hydrogen, carboxy, C2-C7 alkoxycarbonyl or a -CON(Ra)'Rb group wherein Ra and Rb are as defined herein; and their pharmaceutically acceptable salts have immunomodulating activity and are useful in particular as immunostimulating agents, in the treatment of neoplastic diseases and acute and chronic infections of both bacterial and viral origin in mammals.

Description

TRICYCLIC 3-OXO-PROPANENITRILE DERIVATIVES AND PROCESS FOR
THEIR PREPARATION
The present invention relates to tricyclic 3-oxo- propanenitrile derivatives, to a process for their preparation and to pharmaceutical compositions containing them.
The compounds of the invention have the general formula (I)
Figure imgf000003_0001
wherein
X represents an oxygen atom or a -S(O)n- group, wherein n is zero, 1 or 2;
R represents C1-C6 alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, formylamino and C2-C8 alkanoylamino;
R1 is aº) hydrogen, di(C1-C6 alkyl)-amino or a
Figure imgf000003_0002
group wherein R' and R", the same or different, is C1-C6 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 C1-C6 alkyl; b° ) CH2OH, CHO, COOH or C2 -C7 alkoxycarbonyl; c° ) a group wherein Rd is hydrogen or C1-C6
Figure imgf000004_0005
alkyl and Rc is hydrogen, phenyl or the side-chain of an α-aminoacid; d°) a NHCOCH-NH2 group, wherein Rc is as defined above;
e°) a -CH2OCO(CH2)nCOORd or a
Figure imgf000004_0001
-NHCO(CH2 )nCOORd group wherein n and Rd are as defined above; fº) a -CH-N-OR'1 group wherein R'1 is hydrogen or a -CH2COOH group; g°) a -CH=N-NH-R'2 group wherein R'2 is hydrogen, -CH2CH2OH, C2 or C3 alkoxycarbonyl or a -(CH2)p-R'3 group wherein p is 1 or 2 and R'3 is COOH or C2-C7 alkoxycarbonyl;
h°) group wherein R' and R" are as
Figure imgf000004_0002
defined above; or
k°) group wherein R' and R" are as defined
Figure imgf000004_0003
above;
1°) a C2-C7 alkoxycarbonyl group substituted by a group wherein R' and R" are as defined above; each of R2 and R3 is independently: a) hydrogen, halogen or C1-C6 alkyl; b) hydroxy, C1-C6 alkoxy or C3 or C4 alkenyloxy; or c) nitro, amino, formylamino or C2-C8 alkanoylamino; R4 represents hydrogen or C1-C6 alkyl; and Q represents hydrogen, carboxy, C2-C7 alkoxycarbonyl or a
group wherein Ra pepresents hydrogen or C1 -C2 0
Figure imgf000005_0001
alkyl and Rb represents C1-C20 alkyl, a group
Figure imgf000005_0003
wherein Rc and Rd are as defined above or a -(A)n-R5 group wherein m is zero or 1, A is a C1-C6 alkylene chain and R5 is: a') C5-C8 cycloalkyl; b') pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C1 -C6 alkyl and C1-C6 alkoxy; c') phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, CF3 , C1 -C6 alkyl, C1 -C6 alkoxy, amino, nitro, formylamino, C2-C8 alkanoylamino, di(C1-C6 alkyl)-amino, hydroxy, formyloxy and C2-C8 alkanoyloxy; d') phenyl substituted by a -CH2OH, COOH, C2-C7
alkoxycarbonyl or a group wherein R' and R" are as
Figure imgf000005_0002
defined above and optionally by another substituent chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, formylamino, C2-C8 alkanoylamino, hydroxy, formyloxy and C2-C8 alkanoyloxy, or e') 2-thienyl, 2-furyl or 1- ( C1 -C6 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 C1 -C6 alkyl; and the pharmaceutically acceptable salts thereof; and wherein, when R1 is hydrogen, then Q is only a group in which Ra is as defined above and either
Figure imgf000006_0001
Rb is a group wherein Rc and Rd are as defined
Figure imgf000006_0003
Figure imgf000006_0005
above or Rb is a") a -(CH2),-R'5 group wherein z is zero, 1 or 2 and R'5 is as R5 defined above under d'), e') or f) or b") a or -A'-R5 group, wherein A' is a C3-C6 alkylene
Figure imgf000006_0004
chain and R5 is as defined above.
The present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or biprecursors of the compounds of formula (I). It has to be noticed that the compounds of formula (I) may be represented also by a tautomeric structure, namely the enol structure of formula (la)
Figure imgf000006_0002
wherein
X, R, R1, R2, R3, R4 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 the present specification as cαipounds of formula (I).
A halogen atom is preferably chlorine or fluorine.
The alkyl, alkylene, alkanoyloxy, alkoxy and al-kanoylamino groups may be branched or straight chain groups.
A C1-C20 alkyl group is preferably a C1-C6 alkyl group. A C1-C6 alkyl group is, e.g., methyl, ethyl, propyl, iscpropyl, butyl or tert.butyl, more preferably methyl, ethyl or tert.butyl, in particular methyl or ethyl.
A C3 or C4 alkenyloxy group is preferably allyloxy.
A C1-C6 alkoxy group is, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, preferably it is methoxy, ethoxy or propoxy.
A di(C1-C6 alkyl)-amino is preferably a di(C1-C4 alkyl)-amino group, in particular a di(C1 or C2 alkyl)-amino one.
A C5-C8 cycloalkyl group is preferably cyclopentyl or cyclohexyl.
A C2-C8 alkanoylamino group is preferably acetylamino or propionyl-amino.
A C2-C8 alkanoyloxy group is preferably acetoxy or propionyloxy.
A C2-C7 alkoxycarbonyl group is preferably a C2-C5 alkoxycarbonyl group, in particular a C2 or C3 alkoxycarbonyl one.
A C1-C6 alkylene chain is preferably a C1-C3 alkylene chain, such as a-CH2-, -(CH2)2-, -(CH2)3-, or chain.
Figure imgf000007_0001
5
Figure imgf000007_0002
A C3-C6 alkylene chain is preferably a C3 alkylene chain, in particular a -(CH2)3- or a In a group, wherein Rd is as
Figure imgf000007_0003
Figure imgf000007_0004
defined above and Rc is as defined above except hydrogen, the asymmetric carbon atom to which -Rc and -COORd are 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, tryptcphan, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine and phenylserine.
Preferred examples of side chains of the above mentioned, aminoacids are -CH3 (deriving from alanine), -CH2CH(CH3)2 (deriving from leucine) and -CH2C6H5 (deriving from phenylalanine). Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, N-methyl¬glucamine, trieithylamine, triethanolamine, dibenzylamine, methyl¬benzylamine, di-(2-etlιyl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-diethylaminrκoethylamine, N-ethyl-morpholine, β-phenethylamine, N-benzy-β-phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e.g., hydrochloric, hydrdbrcaiiic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulphonic acids. Preferred salts of the compounds of formula (I) are the sodium and the potassium salts thereof.
As stated above, the present invention also includes within its scope pharmaceutically acceptable bicprecursors (otherwise known as prodrugs) of the compounds of formula (I), i.e., compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound. of formula (I).
Preferred. compounds of the invention are the compounds of formula (I),wherein X is oxygen or a -S(O)p-group, in which p is zero or 1; R represents unsubstituted pyridyl or phenyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluorαxiethyl, C1-C4 alkyl, C1-C4 alkoxy, nitro, amino and C2-C8 alkanoylamino; R1 is aºº) hydrogen, COOH, CHO, CH2OH, C2-C7 alkoxycarbonyl or a group, wherein each of R"' and RIV independently is C1
Figure imgf000009_0001
or C2 alkyl, or R''' and RIV, taken together with the nitrogen atom to which they are linked, form a N-pyrrolidinyl, N-piperazinyl, morpholino or piperidino ring which is urisubstituted or substituted by methyl; b°°) a group wherein Rd is hydrogen or C1-C6 alkyl and Rc
Figure imgf000009_0002
is hydrogen, phenyl or the side-chain of an α-aminoacid as defined above; c°°) group, wherein Rc is as defined above;
Figure imgf000009_0006
d°°) a -CH2COO(CH2)nCOORd or a -NHOO(CH2)nCOORd group, wherein n and Rd are as defined above; e°°) a -CH=N-OR'1 group, wherein R'1 is hydrogen or a -CH2COOH group; f°°) a -CH=N-NHR'2 group, wherein R'2 is hydrogen or -CH2CH2OΗ;
g°°) a group, wherein RIII and RIV are as defined above;
Figure imgf000009_0003
h°°) a C2-C4 alkoxycarbonyl group substituted by a
Figure imgf000009_0004
group, wherein RIII and RIV are as defined above; R2 and R3 each independently is hydrogen, halogen, nitro, amino, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; R4 represents hydrogen or C1-C4 alkyl;
Q represents hydrogen, C2-C5 alkoxycarbonyl or a -CONR'aR'b group, wherein R'a is hydrogen or C1-C6 alkyl and R'b is C1-C6 alkyl or a group, wherein Rg is hydrogen or C1-C4 alkyl and Rc is as
Figure imgf000009_0005
defined above; or R'b, is a -(A")m-R"5 group, wherein m is zero or 1, A" is a C1-C3 alkylene chain and R"5 is: a''') unsubstituted pyridyl or phenyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro and di-(C1-C4 alkyl) amino; R b ' ' ' ) phenyl, substituted by -CH2OH, COOH or a group,
Figure imgf000010_0001
wherein R''' and RIV are as defined above, and optionally by another substituent chosen frαm C1-C4 alkyl, C1-C4 alkoxy, hydroxy, formyloxy and C2-C6 alkanoyloxy; or c''') 2-thienyl or 2-furyl; or d''') 2-thiazolyl or 3-isoxazolyl, wherein said heterocyclic rings may be unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof; and wherein, when R1
is hydrogen, then Q is only a group, wherein R'a is as
Figure imgf000010_0002
defined above and R'b is (1) a group wherein Rc and Rg are as
Figure imgf000010_0007
defined above or (2) a -(CH2)z-R5''' group, wherein z is zero, 1 or 2 and R5''' is as R"5 defined above under b'''), c''') and d'''), or (3) a - group
Figure imgf000010_0003
wherein R''5 is as defined above.
More preferred compounds of the invention are the compounds of formula
(I) wherein X is oxygen or sulphur;
R is phenyl, unsubstituted or substituted by a substituent selected frcm nitro, halogen, CF3, C1-C4 alkyl and C1-C4 alkoxy; R1 is aººº) hydrogen, -COOH, -CHO, -CH2OH, C2-C5-alkoxycarbonyl, or a I - group, wherein R''' and RIV are as defined above;
Figure imgf000010_0004
each of R2 and R3 independently is hydrogen, halogen, nitro, amino, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; bººº) a group, wherein R'd is hydrogen or C1-C4 alkyl
Figure imgf000010_0005
and Rc is as defined above; c°°°) a group wherein Rc is as defined above;
Figure imgf000010_0006
dººº) a -CH2COO(CH2)nCOOR'd or a -NHCO(CH2)n COOR'd group, wherein n and R'd are as defined above;
e°ºº) a group, wherein RIII and RIV are as defined
Figure imgf000011_0001
above;
fººº) a C2-C4 alkoxycarbonyl group substituted by a group,
Figure imgf000011_0002
wherein RIII and RIV are as defined above;
R4 represents hydrogen or methyl; Q represents hydrogen or a -CONR"aR''b group, wherein R"a is hydrogen or C1-C4 alkyl and R''b is C1-C4 alkyl or group wherein Rc- and Rg are as defined above;
Figure imgf000011_0003
or R"b is a -(CH2)z-R5 IV group, wherein z is zero, 1 or 2 and RIV 5 is aIV) unsubstituted pyridyl or phenyl, unsubstituted or substituted by a substituent chosen from nitro, halogen, CF3, C1-C4 -alkyl, C1-C4 alkoxy and di(C1-C2 alkyl)-amino;
bIV) phenyl, substituted by -CH2OH, -COOH or a group,
Figure imgf000011_0004
wherein R''' and RIV are as defined above, and optionally by another substituent chosen from hydroxy and C1-C4 alkoxy; or c IV) 2-thienyl or 2-furyl; dIV) 2-thiazolyl or 3-isoxazolyl, iinsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof; and wherein, when R1 is hydrogen, then Q is a -CONR''aR''b group, wherein R"a is as defined above and R11b is (1) group, wherein Rc and Rg are
Figure imgf000011_0005
as defined above; or (2) a -(CH2)z-RV 5 group, wherein z is as defined above and RV5 is as RIV5 defined above under bIV) , cIV) or dI V) . Examples of preferred compounds of the invention are: N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3-oxo-propanoyl]-glycine, methyl ester; N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3- yl]-3-oxo-propanoyl]-DL-leucine, methyl ester;
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3- oxo-propanyl]-DL-pherylalanine, methyl ester;
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl]-3-oxo-propano yl]-DL-phenylglyc-lne, methyl ester; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3-oxo-N-(2-thenyl)-propanamide; 2-cyano-N-(2-furfuryl)-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-3-oxo-propanamide; 2-cyano-3-(8-fluoro-1,4-dihydr o-6-mo pholinomethyl pyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-8-morpho [1]-benzopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-N-(2-morpholinonmethyl-benzyl)-3-oxo-propanamide; N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propancyl]-DL-leucine;
2-cyano-3-(8-ethoxycarbonyl-1,4-d-lhydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-prcpanamide; 2-cyano-3-(6-ethoxy-carbonyl-1,4-d-lhydro-1-phenyl-[1]-benzαthiqpyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrarno[4,3-c]pyrazol-8-yl]carbxonyl-glycine methyl ester; N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzo¬thiopyrano[4,3-c]pyrazol-6-yl]carbonyl-glycine methyl ester; 2-cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothicpyrano [4,3-c]pyrazol-3-yl)-3- oxo-N-phenyl-propanamide;
2-cyano-3-(1,4-dihydro3-8-oxalamino-1-phenyl-[1]-benzothicpyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-pherιyl-prcpanamide; 2-cyano-3-(1,4-dihydro-8-N,N-dimethylaminoethoxycarbonyl-1-phenyl-[1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-pherγl-propanamide;
2-cyano-3-(1,4-dihydro-6-N,N-dimethylaminoethoxycarbonyl-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-pherιyl-propanamide; and the pharmaceutically acceptable salts thereof, in particular the sodium and the potassium salts.
The ccrapounds of formula (I) and the salts thereof can be prepared by a process comprising; a) reacting a compound of formula (II)
Figure imgf000013_0001
wherein
X, R, R1, R2, R3 and R4 are as defined above and Y is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III)
Figure imgf000013_0002
wherein
Q' 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)
Figure imgf000013_0003
wherein
X, R, R1, R2, R3 and R4 are as defined above, with a compound of formula (V)
Rb-N=C=O (V)
wherein
Rb is as defined above, so obtaining a compound of formula
(I) wherein Q is a -CONHRb group, wherein Rb is as defined above; or
c) reacting a compound of formula (VI)
Figure imgf000014_0001
wherein
X, R, R1, R2, R3 and R4 are as defined above and Z is a reactive derivative of a carboxy group, with a compound of formula (VII)
Figure imgf000014_0002
wherein
Ra and Rb are as defined above, so obtaining a compound of formula (I) wherein
Q is a group, wherein Ra and Rb are as defined above; or
Figure imgf000015_0001
d) hydrolysing a compound of formula (I), wherein Q is C2-Cy alkoxycarbonyl or a - group, in which Ra and Rc are as
Figure imgf000015_0002
defined above and Rd is C1-C6 alkyl, so as to obtain the corresponding compound of formula (I), wherein Q is a free carboxy group or a
Figure imgf000015_0003
group, in which Ra and Rc axe as defined above; and, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of a compound of formula (I), into the single isomers. When Y is a reactive derivative of a carboxy group, it is, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or a C2-C7 alkoxycarbonyl group, preferably a C2 or C3 alkoxycarbonyl group. The reaction between a compound of formula (II) wherein Y is carboxy and a compound of formula (III) may be carried cut, for example, in the presence of a condensing agent such as diethyl cyanophosphonate, in the presence of a base such as triethylamine, in an inert solvent such as dimethylformamide at a temperature varying between about 0°C and about 50°C. The reaction between a compound of formula (II) wherein Y is a reactive derivative of a carboxy group and a compound of formula (III) may be carried out, for example, in the presence of a strong base such as sodium hydride, potassium t.butoxide, thallous ethoxide, in an inert solvent such as 1,2-dimethoxyethane, dioxane, dimethylfonnamide, at a temperature varying between about 0°C and about 100°C. The reaction between a compound of formula (IV) and a compound of formula (V) may be carried cut, for example, in the presence of a base such as sodium hydride or triethylamine, in an inert solvent such as toluene, dioxane, tetrahydrofuran, dimrethylformamide, at a temperature varying between about 0°C and about 100°C.
In the compounds of formula (VI) , Z is, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or a C2-C7 alkoxycarbonyl group, preferably a C2-C3 alkoxycarbonyl group. The reaction between a compound of formula (VI), where Z is a halocarbonyl group, and a compound of formula (VII) may be carried out, for example, in an inert solvent such as dichloroethane, dioxane, dimethylformamide, in the presence of pyridine or triethylamine as acid acceptor, at a temperature varying between about 0°C and about 100°C. The reaction between a compound of formula (VI) , wherein Z is C1-C6 alkyl ester, and a compound of formula (VII) may be carried cut, for example, by heating at the reflux temperature in an aromatic hydrocarbon such as toluene or xylene, preferably distilling off slowly together with the diluent the free C1-C6 alkyl alcohol generated during the reaction.
Hydrolysis of a compound of formula (I), wherein Q is a C2-C7 alkoxycarbonyl group or a d group in which Ra and Rc are as
Figure imgf000016_0001
defined above and Rd is C1-C6 alkyl, according to process-variant d) above, may be performed by selective basic hydrolysis, using e.g. aqueous sodium or potassium hydroxide in a solvent such as ethanol or dimethylformamide, at a temperature varying between about 0°C and about 80°C.
A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods; for example, in a compound of formula (I) a nitro group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid, using, if necessary, an organic oosolvent such as acetic acid, dioxane, tetrahydofuran, at a temperature varying between room temperature and about 100°C. Furthermore, for example, an amino group may be converted into a formylamino or a C2-C8 alkancylamino group, for example by reacting with formic acid or with the suitable C2-C8 alkancyl anhydride, without any solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varying between 0°C and about 100ºC. Furthermore, for example, a -NH2
or a -CH=N-NH2 group may be converted into a group or into a
Figure imgf000017_0002
group, wherein R' and R" axe as defined above,
Figure imgf000017_0001
respectively, by reaction with a quaternary nitrogen compound of formula (VIIa) K
Figure imgf000017_0003
wherein R' and R" are as defined above, in an organic inert solvent, such as dioxane, tetrahydrofuran, chloroform, dichloromethane, 1,2-dichloroethane, benzene or toluene, in the presence of a tertiary amine, such as triethylamine, at a temperature varying between about -20°C and room terrperature, according to the experimental procedure described in GB-A-1,293,590 and in US-A-4,447,432. Furthermore, for example, an amino group may be converted into a - group,
Figure imgf000017_0004
wherein Rc is as defined above, by reaction with a suitably protected α-aminoacid of formula wherein R- is as defined above and
Figure imgf000017_0005
E is a protective group, such as a benzyloxycarbonyl or a tert-butoxycarbonyl group, in the presence of dicyclohexylcarbodiimide as condensing agent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0ºC and room temperature, so as to obtain the protected - group,
Figure imgf000017_0006
wherein Rc and E are as defined above, which in turn is deprotected using well known methods in organic chemistry. Furthermore, for example, a carboxy group may be converted into a - group,
Figure imgf000017_0007
wherein Rc is as defined above, by reaction with an esterified α-aminoacid of formula , wherein R'd is C1-C6 alkyl and Rc
Figure imgf000018_0001
is as defined above, in the presence of dicyclohexylc-arbodiimide as condensing agent, in an inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0°C and room temperature, so as to obtain the esterified C
Figure imgf000018_0002
group, wherein Rc and R'd are as defined above, which in turn is hydrolyzed to give the group, wherein Rc is as defined
Figure imgf000018_0003
above, following methods well knewn in the art, for example, those described for the process variant d) above. Furthermore, for example,
an alkoxycarbonyl group, a group, a -CH2OCO(CH2)nCOOR'd
Figure imgf000018_0004
group or a -NHCO(CH2)nCOOR, d group, wherein n and R'd are as defined
above, may be converted into the corresponding -COOH, -
Figure imgf000018_0005
-CH2OCO(CH2)nCOOH and -NHCO(CH2)nCOOH group, respectively, wherein n is as defined above, by treatment with aqueous sodium or potassium hydroxide in a solvent such as dioxane, methanol, ethanol or dimethylformamide, at a temperature varying between about 0°C and about 80°C. The optional esterification of a free carboxy group as well as the optional conversion of a carboxylic ester into the free carboxy derivative may be carried cut according to knewn methods in organic chemistry. Process-variants b) and c) described above may be considered as examples of conversions of a compound of formula (I) into another compound of formula (I) too. Also the optional salification of a compound of formula (I) as well as the conversion of a salt into the free cempound and the separation of a mixture of isomers into the single isomers may be carried cut by conventional methods. For example, the separation of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diastereoisomeric salts, followed by recovery of the optically active isomeric acids or, respectively, bases.
The compounds of formula (II), wherein Y is a C2-C7 alkoxycarbonyl group, may be prepared, according to the methods described in
EP-A-274443, for example, by reacting a compound of formula (VIII)
Figure imgf000019_0001
wherein
X, R1, R2, R3 and R4 are as defined above and R6 is C1-C6 alkyl, preferably C1-C2 alkyl, with a compound of formula (IX)
R-NHNH2 (IX) wherein
R is as defined above. The reaction between a compound of formula (VIII) and a compound of formula (IX) may be carried cut, for example, in a solvent such as C1-C6 alkyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetic acid, at a temperature varying between about 0°C and about 150°C. The compounds of formula (II), wherein Y is carboxy may be prepared, for example, by hydrolysis of the corresponding compounds of formula (II) wherein Y is C2-C7 alkoxycarbonyl, according to standard methods well known in the art, for example, by basic hydrolysis, carried out e.g. by treatment with sodium or potassium hydroxide in a solvent such as water, C1-C6 alkyl alcohol, dioxane, dimirethylformamide and their mixtures, at a temperature varying between about 0°C and about 80°C. The compounds of formula (II) , wherein Y is halocarbonyl, preferably chlorocarbonyl, may be prepared, for example, by reaction of the corresponding compound of formula (II) , wherein Y is carboxy, with a suitable acid halide, for example oxalyl chloride, thionyl chloride,
PCI3, PBr3, in an inert solvent such as ether, benzene, dichloroethane, dioxane or without any solvent, at a temperature varying between about 0°C and about 100°C.
The compounds of formula (III) are, in seme cases, commercially available products, or may be prepared by methods well known in the art. For example, a compound of formula (III), wherein Q is a
Figure imgf000020_0001
by reacting cyanoacetic acid with a compound of formula (VII) in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1- carbonyldiimadazole and the like, in an inert organic solvent such as benzene, dioxane, acetonitrile, at a temperature varying between about 0°C and about 50°C. The compounds of formula (IV) are compounds of general formula (I) , wherein Q is hydrogen and may be obtained by process a) above, for example, by reacting a compαund of formula (II), wherein Y is C2-C7 alkoxycarbonyl, with acetonitrile, in the presence of a strong base e.g., sodium hydride, potassium tert.butoxide, in an inert organic solvent such as benzene, dioxane, tetrhydrofuran, at a temperature varying between about 0°C and about 100°C. The compounds of formula (VI), wherein Z is C2-C7 alkoxycarborryl, are compounds of general formula (I) wherein Q is C2-C7 alkoxycarbonyl and may be obtained by process a) above, for example, by reacting a compound of formula (II) with a compound of formula (X)
Figure imgf000021_0001
herein
R7 is C1-C6 alkyl, using the same experimental conditions as described above for the reaction between a compound of formula (II) and a compound of formula (III).
The compounds of formula (IV), wherein Z is halocarbonyl, may be prepared, for example, by basic hydrolysis of a compound of formula (VI), wherein Z is C2-C7 alkoxycarbonyl, using, for example, the same experimental conditions described above for the hydrolysis of the compounds of formula (II), wherein Y is C2-C7 alkoxycarbonyl, in order to obtain the corresponding carboxy derivative, which in turn may be transformed into a compound of formula (VI), wherein Z is halocarbonyl, preferably chlorocarbonyl, using, for example, the same experimental conditions described above for the preparation of the compounds of formula (II), wherein Y is halocarbonyl.
The compounds of formula (VIII) may be prepared, for example, by reacting a compound of formula (XI)
Figure imgf000022_0001
wherein
X, R1, R2, R3 and R4 are as defined above, with a compound of formula (XII)
Figure imgf000022_0002
wherein each of R8 and R8', being the same or different, is C1-C6 alkyl, preferably methyl or ethyl.
The reaction between a compound of formula (XI) and a compound of formula (XII) may be carried out, for example, in the presence of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride, potassium tert.butoxide, in an organic solvent such as C 1-C6 alkyl alcohol, benzene, dioxane, dimethylformamide, at a temperature varying between about 0°C and about 100°C. The compounds of formula (XI) may be prepared by synthetic methods well known in the art, for example, according to the methods described in J.A.C.S. 76, 5065 (1954) and in "Advances in Heterocyclic Chemistry", 18, 59 (1975). The compounds of formula (V) , (VII) , (IX) , (X) and (XII) are known products and may be prepared by conventional methods: in some cases they are commercially available products.
When in the compounds of the present invention and in the intermediate products thereof, groups are present, such as COOH, NH2, CHO and/or OH, which need to be protected before submitting them to the reactions described above, they may be protected before the reactions take place and then deprotected, according to well known methods in organic chemistry.
The compounds of formula (I) possess immunomodulating activity and can be used, for example, as immunostimulating agents e.g., in the treatment of acute and chronic infections of both bacterial and viral origin, alone or in association with antibiotic agents, and in the treatment of neoplastic diseases, alone or in association with antitumoral agents, in mammals. The immunostimulating activity of the compounds of the invention is proved, for example, by the fact that they are effective in potentiating the cytotoxic activity of the macrophages towards tumour cells in vitro.
The experimental procedure to evaluate this activity is as follows: groups of 4 mice are treated i.p. with the tested compounds and then, seven days later, peritoneal cells are collected and plated for 2 hours at 37 ºC. After this period the walls are washed to eliminate the non adherent cells, tumour target cells are then added and the incubation is prolonged for 48 hours. At the end of this period the target cells viability is evaluated by a colorimetric method and quantified at 570 nm.
The compounds of the invention can be safely used in medicine by virtue of their negligible toxicity.
The therapeutic regimen for the different clinical syndromes must be adapted to the type of pathology taking into account, as usual, also the route of administration, the form in which the compound is administered and the age, weight and 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 infections. For the maintenance regimens the oral or parenteral, e.g., intramuscular or suibcutaneous, route is preferred.
For these purposes the compounds of the invention can be administered orally at doses ranging e.g., from about 0.5 to about 10 mg/kg of body weight per day in adult humans.
Doses of active compounds ranging e.g., from about 0.2 to about 5 mg/kg of body weight can be used for parenteral administration in adult humans. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response. The nature of the pharmaceutical compositions containing the compounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration.
The compositions may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be admdnistered 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 containing the compounds of this invention, are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, carbojcymethylcellulose, 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, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in kncwn manner, for example by means of mixing, granulating, tabletting, 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, methylcellulose, carboxy-methylcellulose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g., prcpylene glycol, and if desired, a suitable amount of licodaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions. The suppositions may contain together with the active compound a pharmaceutically acceptable carrier, e.g. , cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
The following examples illustrate but do not limit the invention:
Example 1
1,4-Dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2 g) is reacted with thionyl chloride (1 ml) in dioxane (40 ml) at reflux teπperature for 2 hours. After cooling the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazole-3-carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (15 ml) and reacted for 2 h under stirring at room temperature with the carbanion obtained by treatment of cyanacetic acid, 2-morpholinomethylbenzylamide (1.95 g) with 50% sodium hydride (0.39 g) in anhydrous dioxare/dimethylformamide 9:1 (20 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 3 with citric acid. The precipitate is filtered and dissolved in CHCI3. The organic solution is washed with 2% citric acid solution and then with water. Evaporation to dryness in vacuo gives a residue which is purified over a flash column using chloroform/methanol 10:0.5 as eluent. Final crystallization from chloroform/methanol yields 1.1 g of 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(2-morpholincmethyl-benzyl)-3-oxo-propanamide, m.p. 243-245°C. By proceeding analogously the following cxmpounds can be prepared: 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-N-(3-morpholinomethyl-benzyl)-3-oxo-propanamide, mp.150°C dec.; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]-pyrazol-3-yl)-N-(3-dimethylaminomethyl-benzyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-N-(2-methoxy-3-morpholinomethylbenzyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(4-methoxy-3-morpholinomethylbenzyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-N-[2-(4-methyl-piperazin-1-yl)methyl-benzyl]- 3-oxo-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-[2-(pyrrolidin-1-yl) methyl-benzyl]-propanamide;
2-cyano-3-(1,4-d-Lhydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(2-morpholinomethyl-phenyl)-3-oxo-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]Pyrazol-3-yl)-N-(3-morpholinomethyl-phenyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(3-dimethylamdnomethyl-phenyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-pheryl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(2,dimethylamdnomethyl-phenyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(2-methoxy-3-morpholinomethylphenyl)-3-oxo-propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(2,hydroxy-3-morpholinomethyl-phenyl)-3-oxo-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-N-(4-methoxy-3-morpholinomethylphenyl)-3-oxo- propanamide;
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-N-(3-hydroxy-4-hydroxymethyl-phenyl)-3-oxo- propanamide; and
2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-N-(3-hydroxy-4-hydroxymethyl-benzyl)-3-oxo- propanamide.
Example 2
By proceeding according to Example 1, by reaction with suitable cyanacetamides, the following ccmpounds can be prepared:
2-cyano-N-(2-furfuryl)-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-clpyrazol-3-yl)-3-oxo-propanamide, m.p. 236-238°C; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-(2-thenyl)-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-N-[2-(1-methyl-pyrrol-2-yl)-ethyl]-3-oxo-propanamide, m.p. 171-176°C; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-(2-thiazolyl)-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(3-isoxazolyl)-3-oxo-propanamide; and 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-(1-phenylethyl)-propanamide, m.p. 228-230°C. Example 3
By proceeding according to Example 2, starting frcm suitable substituted 1,4-dihydro-[1] -benzopyrano[4, 3-c]pyrazole-3-carboxylic acids the following compounds can be prepared: 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 249-253°;
2-cyano-3-(1,4-dihydro-8-morpholinomethyl-1-phenyl-[1]-benzopyrano
[4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 200-210ºC dec; 2-cyano-3-(8-fluoro-1,4-dihydro-6- dimethylaminomet yl-1-phenyl-[1]-benzcpyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide;
2-cyano-3-[8-fluoro-1,4-dihydro-6-(4-methyl-piperazin-1-yl)-1-phenyl- [1]-benzcpyrano[4,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide;
2-cyano-3-[8-fluoro-1,4-dihydro-1-phenyl-6-(pyrrolidin-1-yl)-[1]-benzcpyrano[4,3-c]pyrazol-3-yl]-3-oxo-N-pheryl-propanamide;
2-cyano-3-[1,4-dihydro-8-(4-methyl-piperazin-1-yl)-1-phenyl-[1]-benzcpyrano[4,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-prcpanamide;
2-cyano-3-[1,4-dihydro-1-phenyl-8-(pyrrolidin-1-yl)-[1]-benzcpyrano [4,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; N-benzyl-2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl- [1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide;
N-benzyl-2-cyano-3-(1,4-dihydro-8-morpholinomethyl-1-phenyl-[1]-benzo¬pyrano[4,3-c]pyrazol-3-yl) -3-oxo-propanamide;
2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-8-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide; and,
N-(3-dhloro-phenyl)-2-cyano-3-(1,4-dihydro-8-morpholinomethyl-1-phenyl- [1]-benzcpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide. Example 4
1-4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester (3,2 g) is heated with 1% KOH solution in ethanol (80 ml) under reflux for 30 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HC1. The precipitate is filtered, washed with water and dried in vacuo at 50°C to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2.6 g) which is reacted with thionyl chloride (0.9 ml) in dioxane (50 ml) under reflux for 2 hours. After cooling, the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride as a crystalline residue. The crude product is dissolved in anhydrous dioxane (35 ml) and reacted for 1 hour under stirring at room teπperature with the carbanion obtained by treatment of N-cyanoacetylglycine, methyl ester (1.44 mg) with 50% sodium hydride (0.54 g) in anhydrous dimethylformamide/dioxane 1:1 (30 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 2 with N HCl. The precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with N HCl and then with water until neutral. Evaporation to dryness yields a residue which is purified over a Flash column using chloroform/methanol/30% NH4OH 80:20:0.5 as eluent. Final treatment with acetone of the purified fractions gives 1.65 g of N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine,methyl ester, m.p. 208-210°C, NMR (CDCl3) δppm: 3.81(S) (3H, -COOCH3), 4.18 (d) (2H, -CONHCH2-) , 4.21(s) (2H, -S-CH2-), 6.82(t) (1H, -CONHCH2), 6.85-7.7 (m) (9H, phenyl protons), 16.32(ss) (1H, -OH) .
By proceeding analogously the following ccmpounds can be prepared: N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propancyl]-DL-leucine, methyl ester, m.p. 115-125°C; N-[2-cyano-3-(1,4-d-dihydr-o1-phenyl-[1]-berizcthiαpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-DL-phenylglycine, methyl ester, m.p. 180-182 °C; N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propancyl]-DL-phenyleilanine, methyl ester; and N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-DL-isoleucine, methyl ester.
Similarly the pure D and L enantiomers of the above-listed ccmpounds can be prepared.
Example 5
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine, methyl ester (1.9 g) , is suspended in 1% YCH. solution in 95% ethanol (61 ml) and heated under stirring under reflux for 30 minutes. After cooling the precipitate is filtered and washed with ethanol, then dissolved in water. The aqueous basic solution is extracted with ethyl acetate and then acidified to pH 2 with 2N HCl. The precipitate is extracted with ethyl acetate and the organic solution washed with N HCl and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crumbled with ethanol to yield 1.35 g of N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3--c]pyrazol-3-yl)-3-oxo-propanoy l]-glycine, m.p. 224-226°C, NMR (EMSO d6) δppm: 3.94 (s) (2H, -CONHCH2-) , 4.19(s) (2H, -S-CH2), 6.8-7.7(m) (9H, phenyl protons). By proceeding analogously the following compounds can be prepared: N-[2-cyano-3-(1,4-dihydro-1-pheπyl-[1]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-prcpanqyl]-DL-leucine, m.p. 220-222ºC;
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3- yl)-3-oxo-propanoyl]-DL-phenylalanine;
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol- 3-yl)-3-oxo-propanoyl]-DL-phenylglycine, m.p. 210-213°C; and N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-prcpanoyl]-DL-isoleucine. Similarly the pure D and L enantiomers of the above-listed compounds can be obtained. Example 6
8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c] pyrazole-3-carboxylic acid, ethyl ester (5.6 g) is reacted with acetonitrile (15 ml) in dioxane (15 ml) in the presence of 50% sodium hydride (0.6 g) under stirring at 60°C for 30 minutes. After cooling the reaction mixture is diluted with ice water and acidified to pH 3 with citric acid. The precipitate is extracted with ethyl acetate and the organic phase washed with water until neutral and then evaporated to dryness in vacuo. The residue is purified over a Si02 column usingchlororoform/methanol 95:5 as eluent to give 2.4 g of 3-(8-fluoro-1,4-dihydro-6-morpholinomtethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile, m.p. 187-189°C.
By proceeding analogously the following compound can be prepared; 3-(1,4-dihydro-8-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile, m.p. 189-190°C. Example 7
3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile (2.8 g) is reacted with phenylisocyanate (0.8 g) in dimethylformamide (20 ml) in the presence of triethylamine (0.7 g) at 25-30°C for 30 min. The reaction mixture is diluted with ice water and acidified with citric acid to pH 3. The precipitate is filtered and dissolved in chloroform. The organic solution is washed with 2% citric acid solution and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crystallized from chloroform/ethanol to yield 1.9 g of 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholino¬methyl-1-phenyl-[1]-benzopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 249-253°C.
By proceeding analogously the following compound can be prepared:
2-cyano-3-(1,4-dihydro-8-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 200-210°C dec.
Example 8
2,3-Dihydro-4-oxo-4H-[1]-benzothiopyran-6-carboxylic acid, m.p. 223-225°C (40.5 g) is reacted with thionyl chloride (46.3 g) in anhydrous dioxane (810 ml) at reflux temperature for 4 hours. After cooling the solution is evaporated to dryness in vacuo and the residue of crude 2,3-dihydro-4-oxo-4H-[1]-benzothiopyran-6-carbonyl chloride is dissolved in anhydrous benzene (500 ml). This solution is added under nitrogen at room temperature to a stirred mixture of anhydrous tert-butanol (300 ml) in benzene (500 ml) and pyridine (470 ml). The reaction mixture is allowed to react for 20 hours at room temperature and then is evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate and the organic solution is washed with 5 % citric acid solution, then with water until neutral and finally evaporated to dryness in vacuo. The residue is purified over a SiO2 column using hexane/ethyl acetate 90/10 as eluent.
The recovered product is treated with hexane under stirring to give 2,3-dihydro-4-oxo-4H-[1]-benzothiopyran-6-carboxylic acid, tert-butyl ester, m.p. 125-127°C (34.5 g), which is reacted with diethyl oxalate (83.8 g) in anhydrous ethanol (1000 ml) in the presence of sodium ethoxide (31 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered, washed with water and then dissolved in ethyl acetate. The organic solution is evaporated to dryness in vacuo to yield 3-ethoxalyl-2,3-dihydro-4-oxo-4H-[1]-benzothiopyran-5-carboxylic acid, tert- butyl ester (45 g) , which is reacted with phenylhydrazine (15 g) in acetic acid (1560 ml) at 25-30°C for 90 minutes. The reaction mixture is diluted with ice water and the precipitate is filtered, dissolved in chloroform and washed with water. After evaporation of the solvent in vacuo, the residue is purified by treatment with isopropyl ether under stirring to yield 8-tert-butoxycarbonyl-1,4-dihydro-1-phenyl- [1]-benzothiopyrano[4 ,3-c]pyrazole-3-carboxylic acid, ethyl ester, m.p. 146-149°C (27.5 g), which is hydrolyzed by treatment with potassium hydroxide (5.3 g) in 95 % ethanol (1200 ml) under stirring at room temperature for 20 hours. The reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered, washed with water until neutral and dried in vacuo at 80°C to give 8-tert-butoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid, m.p.295-297°C (23.9 g) which is dissolved in anhydrous dioxane (1000 ml) arid reacted with oxalyl chloride (16.3 g) in the presence of a catalytic amount of dimethylfonramide (70 mg) at room teπperature for 4 hours. The reaction mixture is evaporated to dryness in vacuo and the residue, 8-tert-butoxycarbonyl-1,4-dihydro- 1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazole-3-carbonyl chlo ride (24.8 g), is dissolved in anhydrous dioxane (980 ml) and added under stirring to the suspension obtained by treatment of cyanoacetanilide (10.28 g) with 50 % sodium hydride (3.75 g) in anhydrous dioxane (1230 ml) at room temperature. The reaction mixture is kept under stirring at room temperature for 1 hour and then diluted with ice water and acidified to pH 3 with 2N HCl. The precipitate is filtered and dissolved in ethyl acetate, the organic solution is washed with IN HCl and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is purified by treatment with ethanol under reflux. After cooling the precipitate is filtered and washed with ethanol to yield 3-(8- tert-butoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-prcpanamide, m.p. 229-230°C (12.8 g), which is reacted with trifluoroacetic acid (128 ml) under stirring at room temperature for 1 hour. The reaction mixture is diluted with ethanol (128 ml) and the precipitate is filtered and washed with ethanol to yield 11.3 g of 3-(8-carboxy-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide, m.p. 284-287°C.
By proceeding analogously the following cαrpounds can be prepared:
3-(6-carboxy-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[ 4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide, m.p. 283- 287°C; 3-(8-carboxy-1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; and 3-(6-carboxy-1,4-dihydro-l-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide.
Example 9
3-(8-Carboxy-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (0.65 g) dissolved in dimethylformamide (50 ml) is reacted with methyl iodide (0.37 g) in the presence of anhydrous potassium carbonate (0.36 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered, dissolved in chloroform and washed with IN HCl and then with water. Evaporation of the solvent in vacuo gives a residue which is crystallized from CH2Cl2/methanol to yield 0.48 g of 2-cyano-3-(1,4-dihydro-8-methoxy¬carbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 228-230°C.
By proceeding analogously the following compounds can be prepared: 2-cyano-3-(8-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 241-242°C; 2-cyano-3-(6-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 263-264°C;
N-(3-chloro-phenyl)-2-cyano-3-(6-ethoxycarbonyl-1,4-dihydro- 1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-pro¬panamide;
2-cyano-3-(6-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(4-fluoro-phenyl)-3-oxo-propanamide; 2-cyano-3-(6-ethoxycarbonyl-1,4-dihydro-l-phenyl-[1]-benzo¬thiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-(3-firifluoromethyl-phenyl)-3-oxo-propanamide;
2-cyano-3-[6-ethoxycarbonyl-1-(4-fluoro-phenyl)-1,4-dihydro-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; and
2-cyano-3-(8-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide.
Example 10
Glycine methyl ester hydrochloride (0.7 g) suspended in anhydrous acetonitrile (250 ml) is treated with triethylamine (0.56 g) under stirring at room temperature. To the suspension first 3-(8-carboxy-1,4-dihydro-1-phenyl-[1]-benzothio pyrano[4 ,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.5 g) and then dicyclohexylcarbodiimide (1.25 g) are added. The reaction mixture is kept under stirring at room temperature for 4 hours and then is basified to pH 8 by adding dimethylaminoethanol. The precipitate is filtered, washed with acetonitrile and then eliminated. The organic solution is concentrated in vacuo to a small volume, diluted with water, acidified to pH 2 with IN HCl and finally basified to pH 8 with 1N NaOH. The obtained precipitate is filtered, washed with water, dissolved in chloroform and washed with IN HCl and then with water until neutral. The organic solution is evaporated in vacuo to dryness and the residue is purified over a SiO column using chloroform/methanol 90/10 as eluent. Final crystallization from CH2Cl2/ethyl acetate yields 1.48 g of N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4,3-c]pyrazol-8-yl]carbonyl glycine methyl ester, m.p. 253-256°C.
By proceeding analogously the following compounds can be prepared: N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- [l]-benzothiopyrano[4,3-c]pyrazol-6-yl]carbonyl-glycine methyl ester, m.p.268-273°C dec; N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- [1]-benzothiopyrano[4,3-c]pyrazol-8-yl]carbonyl-L-alaninemethyl ester;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- D]-benzothiopyrano[4,3-c]pyrazol-6-yl]carbonyl-L-alanine methyl ester;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- [1]-benzothiopyrano[4,3-c]pyrazol-8-yl]carbonyl-L-leucine methyl ester; N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- [1]-benzothiopyrano[4,3-c]pyrazol-6-yl]carbonyl-L-leucine methyl ester;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4,3-c]pyrazol-6-yl]-carbonyl-L-phenylalanine methyl ester; and
N- {3-[2-(4-fluorophenylcarbamoyl)-cyanoacetyl]-1,4-dihydro- 1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-8-yl}carbonylglycine methyl ester.
Example 11 N-[1,4-Dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4,3-c]pyrazol-8-yl]carbonyl-glycine methyl ester (0.9 g) is suspended in 1 % KOH solution in 95 % ethanol (22.3 ml) and heated under stirring at the reflux temperature for 30 minutes. After cooling the reaction mixture is acidified to pH 2 with 23 % HCl and then diluted with ice water. The precipitate is filtered, washed with water and then crystallized from CHCl3/ethanol to yield 0.73 g of N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl¬cyanoacetyl)-[1]-benzothiopyrano[4 ,3-c]pyrazol-8-yl]carbonyl glycine, m.p. 244-250°C.
By proceeding analogously the following compounds can be prepared:
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4,3-c]pyrazol-6-yl]carbonyl-glycine;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[ 4 ,3-c]pyrazol-8-yl]carbonyl-L-alanine; N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4 ,3-c]pyrazol-6-yl]carbonyl-L-alanine;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothiopyrano[4 ,3-c]pyrazol-8-yl]carbonyl-L-leucine;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-D]-benzothiopyrano[4 ,3-c]pyrazol-6-yl]carbonyl-L-leucine; and
N-[1, 4-dihydro-1-phenyl-3-( 2-phenylcarbamoyl-cyanoacetyl ) - [1]-benzothiopyrano[4 , 3-c]pyrazol-6-yl] carbonyl-L-phenylalanine . Example 12
3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)- 2-cyano-3-oxo-N-phenyl-propanamide (1.1 g) dissolved in anhydrous tetrahydrofuran (23 ml) is reacted with succinic anhydride (0.71 g) at the reflux temperature under stirring for 3 hours. After cooling the reaction mixture is diluted with ice water. The precipitate is filtered and washed with water. Crystallization from CHCl3/methanol yields 0.9 g of 3-[8-(3-carboxy-propanoylamino)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl¬propanamide, m.p. 230-233°C.
By proceeding analogously the following compounds can be prepared:
3-[6-(3-carboxy-propanoylamino)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl¬propanamide;
3-[8-(2-carboxy-acetylamino)-1,4-dihydro-1-phenyl-[1]-benzo¬thiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-pro¬panamide; and 3-[8-(3-carboxy-propanoylamino)-1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-pro¬panamide. Examp le 13
3-(8-Amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (1.2 g) dissolved in anhydrous dimethylformamide (70 ml) containing pyridine (1 ml) is reacted with ethyl oxalyl chloride (0.7 g) under stirring at room temperature for 6 hours. The reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water. Crystallization from CHCl3/ethanol yields 1.2 g of 2-cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 273-277°C.
By proceeding analogously the following compounds can be prepared: 2-cyano-3-(6-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-N-(4-fluoro-phenyl)-3-oxo-propanamide; N-(3-chloro-phenyl)-2-cyano-3-(3-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-3-oxo-propanamide;
2-cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-y1)-N-(3-nitro-pheny1)-3-oxo-propanamide; 2-cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl—[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-(3-trifluoromethylphenyl)-propanamide; and
2-cyano-3-[8-ethoxalylamino-1-(4-fluoro-phenyl)-1,4-dihydro- [1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide.
Example 14
2-Cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzo¬thiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1.1 g) is treated with 1 % KOH solution in 95 % ethanol
(28.6 ml) diluted with 95 % ethanol (50 ml) under stirring at room temperature for 3 hours. The reaction mixture is concentrated in vacuo to a small volume and then diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water. Crystallization from CHCl3/ethanol yields 0.7 g of 2-cyano-3-(1,4-dihydro-8-oxalamino-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 236-242°C dec.
By proceeding analogously the following compounds can be prepared:
2-cyano-3-(1,4-dihydro-6-oxalamino-1-phenyl-[1]-benzothio¬pyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-8-oxalamino-1-phenyl-[1]-benzothiopyrano[4,3-cJpyrazol-3-yl)-3-oxo-propanamide;
N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-8-oxalamino-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide;
2-cyano-3-[1-(4-fluoro-phenyl)-1,4-dihydro-8-oxalamino-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-3-oxo-propanamide; and 2-cyano-3-(1,4-dihydro-8-oxalamino-1-phenyl-[1]-benzopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide.
Example 15
8-Tert-butoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothicpyrano [4,3-c]pyrazole-3-carboxylic acid ethyl ester (11.9 g), prepared according to Example 8, is treated under stirring with trifluoroacetic acid (132 ml) at room temperature for 3 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water until neutral. Crystallization from isopropanol yields 3-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-8-carboxylic acid, m.p. 222-225°C (9.2 g) , which is reacted with thionyl chloride (5.3 ml) in anhydrous dioxane (90 ml) at the reflux temperature for 2 hours. After cooling, the solu tion is evaporated to dryness in vacuo and the residue, 3- ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4 ,3-c]pyrazole-8-carbonyl chloride, is dissolved in anhydrous diglyme (100 ml) and added dropwise, under inert atmosphere, to a stirred solution of lithium tri-tert-butoxyaluminum hydride (15.4 g) in anhydrous diglyme (90 ml) in such a way as to maintain the temperature between 0°C and 4°C. The reaction mixture is allowed to react at about 0°C under stirring for 1 hour and then 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 in vacuc. The residue is purified over a SiO2 column using hexane/ethyl acetate 7/3 as eluent. Crystallization from CH2Cl2/isopropyl ether yields pure 1,4-dihydro-8-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4,3-c] pyrazole-3-carboxylic acid ethyl ester, m.p. 160-152°C (4.2 g), which is reacted with 2-methoxyethoxymethyl chloride (2.13 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 separatory funnel first with 5 % Na2HPO4 solution and then with water until neutral. The organic phase is evaporated to dryness in vacuo and the residue is crystallized from isopropyl ether to yield 1,4-dihydro-8-(2-methoxyethoxymethoxy)methyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid ethyl ester, m.p. 66-68°C (5 g) , which is treated with KOH (0.4 g) in 95 % ethanol (52 ml) under stirring at 45°C for 40 minutes. The reaction mixture is then diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered, washed with water until neutral and dried in vacuo at 80°C to yield 1,4-dihydro-8-(2-methoxyethoxymethoxy)-methyl-1-phenyl-[1]-benzothiopyrano[4.3-c]pyrazole-3-carboxylic acid, m.p. 136-139°C (4.26 g) , which is dissolved in anhydrous dioxane (50 ml) and reacted with oxalyl chloride (1.9 ml) in the presence of dimethylfonramide (11 mg) at room temperature for 1 hour. The reaction mixture is evaporated to dryness in vacuo and the residue, crude 1,4-dihydro-8-(2-methoxyethoxymethoxy)methyl-1-phenyl-[1] -benzothiopyrano[4 ,3-c]pyrazole-3-carbonyl chloride, is dissolved in anhydrous dioxane (50 ml) and reacted for 1 hour under stirring at room temperature with the carbanion obtained by treatment of cyano-acetanilide (1.76 g) with 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 with 2N HCl.
The precipitate is filtered, washed with water and crystallized from CH2Cl2/isopropanol to yield 2-cyano-3-[1,4]-dihydro-8-(2-methoxyethoxymethoxy)methyl-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide, m.p. 150- 153°C (1.6 g) , which is suspended under stirring in methanol (800 ml) containing 37 % HCl (8 ml) and heated at 45°C for 20 hours. After cooling the reaction mdxture is concentrated in vacuo to a small volume and diluted with ice water. The precipitate is filtered and washed with water until neutral. Crystallization from CH2Cl2/methanol yields 1.1 g of 2-cyano-3-(1,4-dihydro-8-hydroxrrethyl-1-phenyl-[1]-benzothio-pyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 153-158°C dec.
By proceeding analogously the following compounds can be prepared: 2-cyano-3-(1,4-dihydro-6-hydroxymethyl-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-pheryl-proparamιide; 2-cyano-3-(1,4-dihydro-8-hydroxymethyl-1-phenyl-[1]-benzopyrano[4,3-c] pyrazol-3-yl)-3-oxo-N-prcpanamide;
2-cyano-N-(4-fluorophenyl)-3-(1,4-dihydro-8-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-proparamιide; and N-(3-chloro-phenyl) -2-cyano-3-(1,4-dihydro-8-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide. Example 16
3-(8-Carboxy-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-proparamide (1.35 g) dissolved in anhydrous acetonitrile (110 ml) is reacted with
N,N-dimethylaminoethanol (0.73 g), in the presence of dicyclohexylcarbodiimide (1.12 g) and 4-dimethylaminopyridine (0.265 g), under stirring at room temperature for 24 hours. The precipitate is filtered off and the organic solution is concentrated in vacuo to a small volume. The residue is diluted with water, acidified to pH 2 with NHCl and then basified to.pH 8 with N NaOH. The precipitate is filtered and purified over a SiO2 column using chloroform/methanol/30 % NH4OH 80/20/0.3 as eluent. The recovered product is dissolved in dimethylformamide (20 ml), acidified to pH 2 with 2N HCl, diluted with water (50 ml), and then basified to pH 8 with 2N NaOH. The precipitate is filtered and washed with water to yield 0.4 g of 2-cyano-3-(1,4-dihydro-8-N,N-dimethyl-aminoethoxy¬carbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 217-220°C.
By proceeding analogously the following compounds can be prepared :
2-cyano-3-(1,4-dihydro-6-N,N-dimethylamincethoxycarbonyl- 1-phenyl-[1] -benzothiopyrano [4 , 3-cJpyrazol-3-yl ) -3-oxo-N-phenyl-propanamide , m. p . 210-217 ° C dec ;
2-cyano-3-(1,4-dihydro-8-morpholinoethoxycarbonyl-1-phenyl- [1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; and
2-cyano-3-(8-N,N-diethylaminopropoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide. Example 17
N-Formylmorpholine (7.58 g) dissolved in anhydrous ethyl ether (200 mi) is reacted with oxalyl chloride (8.02 g) under stirring at room temperature for 20 hours. The precipitate is filtered, washed with anhydrous ethyl ether and dried in vacuo at room temperature for 1 hour to yield 8.9 g of 4-chlo¬romethylene-morpholinium chloride. This compound (5.47 g) is added portionwise at -15°C to a stirred solution of 3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (3 g) in anhydrous tetrahydrofuran (130 ml) containing triethylamine (8.96 ml). The reaction mixture is kept under stirring at -15°C for 2 hours and then at about 0°C for 2 hours again. Finally it is diluted with ice water and actified to pH 4 with citric acid. The precipitate is filtered, dried in vacuo at 50°C and then purified over a SiO2 column using chlorofcrm/methancl/30 % NH4OH 85/12/0.5 as eluent. The recovered product is crystallized frcm methanol to yield 1.4 g of 2-cyano-3(1,4-dihydro-8-morpholinomethyleneamino-1-phenyl-[1]-benzothiopyrano3-4c]pyrcazopl-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 205-210°C.
By proceeding analogously the following compounds can be prepared:
2-cyano-3-(1,4-dihydro-6-morpholinomethyleneamino-1-phenyl- [1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-l-phenyl-8-piperidinomethyleneamino-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-3-oxo-N-phenylpropanamide; and
2-cyano-3-(1,4-dihydro-8-dimethylaminomethyleneamino-1-phenyl-[1]-benzothiopyrano[3,3-clpyrazol-3-yl)-3-oxo-N-phenyl-propanamide.
Example 18
3- ( 8-Amino-1 , 4-dihydro-1-phenyl-[1]-benzothiopyrano [4 , 3-c]pyrazol-3-yl ) -2-cyano-3-oxo-N-phenyl-propanamide ( 1 g ) dissolved in anhydrous acetonitrile ( 10 ml ) is reacted wi th N-tert-butoxy-carbonylglycine (0.41 g) in the presence of dicyclohexylcarbodiimide (0. 53 g ) under stirring at room temperature for 2 hours . The precipitate is filtered, washed with acetonitrile and then eliminated . The organic solution is evaporated in vacuo to dryness and the residue is extracted with ethyl acetate ( 2 x 100 ml ) . The insoluble residue is filtered off and the clear organic solution is evaporated in vacuo to dryness . The crude product is purified over a flash column using chloroform/methanol/acetic acid 85/15/0.5 as eluent. The recovered product is crystallized from chloroform-ethyl acetate to yield 3-[8-(N-tert-burtoxycarbonylglycyl)amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phen propanamide, m.p. 190-200°C (0.36 g) , which is suspended in ethyl acetate containing gaseous HCl (about 2.5 N solution) and kept under stirring at room temperature for 4 hours. The precipitate is filtered, washed with ethyl acetate, suspended in water and treated with 15 % NH4OH until pH 8. The suspension is kept under stirring at room temperature and then the precipitate is filtered and washed with water. Purification with methanol at the reflux temperature yields 0.2 g of 2-cyano-3-(8-glycylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c!pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 218-221°C.
By proceeding analogously the following compounds can be prepared:
2-cyano-3-(6-glycylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; and 3-(8-L-alanylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide.
Example 19
2-Cyano-3-(1,4-dihydro-6-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1.2 g) is reacted with succinic anhydride (0.8 g) in anhydrous pyridine (40 ml) under stirring at 45°C for 20 hours, After cooling the reaction mixture is diluted in ice water and the precipitate is filtered and washed with water. Crystallization from CH2Cl /isopropanol yields 0.95 g of 3-[6-(3-carboxy-propanoyloxymethyl)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4 ,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
By proceeding analogusly the following compound can be prepared:
3-[8-(3-carboxy-propanoyloxymethyl)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
Example 20
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-propanqyl]-glycine, methyl ester is dissolved by treatment with the stoichiometric amount of sodium ethoxide in ethanol. The solution is evaporated to dryness in vacuo and the product is crumbled with acetone. Filtration and washing with acetone yields the pure sodium salt of N-[2-cyano-3-(l,4-d-ihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine, methyl ester, m.p. > 260°C. Example 21
Tablets, each weighing 150 mg and containing 50 mg of active substance, can be manufactured as follows:
Composition (for 10,000 tablets)
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine, methyl ester 500 g
Lactose 710 g
Corn starch 238 g
Talc powder 36 g
Magnesium stearate 16 g N-[2-c-yano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine, methyl ester and half of the corn starch are mixed, the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of 8 mm diameter.

Claims

1. A compound of formula (I)
Figure imgf000056_0001
wherein
X represents an oxygen atom or a -S(O)n- group, wherein n is zero, 1 or 2;
R represents C1 -C6 alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoroaethyl, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, formylamino and C2-C8 alkanoylamino;
R is aº ) hydrogen, di(C1-C6 alkyl)-amino or a -
Figure imgf000056_0002
group wherein R' and R" , the saae or different, is C1-C6 alkyl or R' and R" , taken together with the nitrogen atom to which they are linked, fora 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
C1-C6 alkyl; b° ) CH2OH, CHO, COOH or C2-C7 alkoxycarbonyl; c° ) a group whe rein Rd is hydrogen or C1 -C6
Figure imgf000057_0001
alkyl and Rc is hydrogen, phenyl or the side-chain of an α-aminoacid; d°) a group, wherein Rc is as defined above;
Figure imgf000057_0002
e° ) , a -CH2 OCO ( CH2 )n COORd or a
Figure imgf000057_0003
-NHCO ( CH2 ) n COORd group whe re in n and Rd a re as de f ined above ; f° ) a -CH-N-OR'1 group wherein R'1 is hydrogen or a -CH2COOH group; g° ) a -CH-N-NH-R'2 group wherein R'2 is hydrogen, -CH2CH2OH,
C2 or C3 alkoxycarbonyl or a -(CH2)p-R'3 group wherein p is
1 or 2 and R'3 is COOH or C2-C7 alkoxycarbonyl;
h°) a group wherein R' and R" are as
Figure imgf000057_0004
defined above; or
k°) a group wherein R' and R" are as defined
Figure imgf000057_0005
above; 1°) a C2-C7 alkoxycarbonyl group substituted by a group,
Figure imgf000057_0006
wherein R1 and R" are as defined above;
each of R2 and R3 is independently: a) hydrogen, halogen or C1 -C6 alkyl; b) hydroxy, C1-C6 alkoxy or C3 or C4 alkenyloxy; or c) nitro, aaino, formylamino or C2-C3 alkanoylamino; R4 represents hydrogen or C1-C6 alkyl; and Q represents hydrogen, carboxy, C2-C7 alkoxycarbonyl or a
group wherein Ra represents hydrogen or C1-C20
Figure imgf000058_0001
alkyl and Rb represents C1-C20 alkyl, a group
Figure imgf000058_0002
wherein Rc and Rd are as defined above or a -(A)m-R5 group wherein m is zero or 1, A is a C1-C6 alkylene chain and R5 is: a') C5-C6 cycloalkyl; b') pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C1-C6 alkyl and C1-C6 alkoxy;
C) phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, CF3 , C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, formylamino, C2-C8 alkanoylamino, di(C1-C6 alkyl)-amino, hydroxy, formyloxy and C2-C8 alkanoyloxy; d') phenyl substituted by a -CH2OH, COOH, C2-C7
alkoxycarbonyl or a group wherein R' and R" are as
Figure imgf000058_0003
defined above and optionally by another substituent chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, formylamino, C2-C8 alkanoylamino, hydroxy, formyloxy and C2-C8 alkanoyloxy, or e') 2-thienyl, 2-furyl or 1-(C1-C6 alkyl)-pyrrol-2-yl; orf') a heterocyclic ring which is selected from 2-pyrimidyl, 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or substituted by C1-C6 alkyl; and the pharmaceutically acceptable salts thereof; and wherein, when R1 is hydrogen, then Q is only a group in which R4 is as defined above and either Rb is a
Figure imgf000059_0001
group wherein Rc and Rd are as defined above or Rb is a") a
Figure imgf000059_0002
-(CH2)z-R'5 group wherein z is zero, 1 or 2 and R'5 is as R5 defined above under d'), e') or f') or b") or -A'-R5 group, wherein A'
Figure imgf000059_0003
is a C3-C6 alkylene chain and R5 is as defined above.
2. A compound of formula (I) according to claim 1, wherein X is oxygen or a -S(O)p-group, in which p is zero or 1; R represents unsubstituted pyridyl, or phenyl unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluorcmethyl, C1-C4 alkyl, C1-C4 alkoxy, nitro, amino and C2-C8 alkanoylamino; R1 is a ºº) hydrogen, COOH, CHO, CH2OH, C2-C7 alkoxycarbonyl or a
wherein each of R''' and RIV independently is C1 or C2
Figure imgf000059_0004
alkyl, or R' ' ' and RIV, taken together with the nitrogen atom to which they are linked, form a N-pyrrolidinyl, N-piperazinyl, morpholino or piperidino ring which is unsubstituted or substituted by methyl; bºº) a ; group wherein Rd is hydrogen or C1-C6 alkyl and Rc
Figure imgf000059_0005
is hydrogen, phenyl or the side-chain of an α-aminoacid as defined above; cº º) a group, wherein Rc is as defined above;
Figure imgf000060_0001
d° ° ) a -CH2OCO(CH2)nCOOR d or a -NHCO(CH2)nCOORd (group, wherein n and Rd are as defined above; e° °) a -CH=N-OR'1 group, wherein R' 1 is hydrogen or a -CH2COOH group; f° °) a -CH=N-NHR'2 group, wherein R'2 is hydrogen or -CH2CH2OH;
g° ° ) a - vdierein RIII and RIV are as defined above;
Figure imgf000060_0002
h° °) a C2-C4 alkoxycarbonyl group substituted by a
Figure imgf000060_0003
wherein RIII and RIV are as defined above;
R2 and R3 each Independently is hydrogen, halogen, nitro, amino, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; R4 represents hydrogen or C1-C4 alkyl;
Q represents hydrogen, C2-C5 alkoxycarbonyl or a -CONR'aR'b group, wherein R'a is hydrogen or C1-C6 alkyl and R'b is C1-C6 alkyl or a group, wherein Rg is hydrogen or C1-C4 alkyl and Rc is as
Figure imgf000060_0004
defined above; or R'b is a -(A")m-R"5 group, wherein m is zero or 1, A" is a C1-C3 alkylene chain and R"5 is: a''') unsubstituted pyridyl or phenyl, unsubstituted or substituted by one or two-substituents chosen independently from halogen, CF3, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro and di-(C1-C4 alkyl) amino; b' ' ' ) phenyl, substituted by -CH2CH, COOH or a group,
Figure imgf000061_0001
wherein R' ' ' and RIV are as defined above, and optionally by another substituent chosen frcm C1-C4 alkyl, C1-C4 alkoxy, hydroxy, formyloxy and C2-C6 alkanoyloxy; or c''') 2-thienyl or 2-furyl; or d''') 2-thiazolyl or 3-isoxazolyl, wherein said heterocyclic rings may be unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof; .and wherein when R1
is hydrogen, then Q is only a group, wherein R'a is as defined
Figure imgf000061_0002
above and R'b is (1) a g group wherein Rc and Rg are as
Figure imgf000061_0003
defined above or (2) a -(CH2)2-R5''' group, wherein z is zero, 1 or 2 and R5' ' ' is as R"5 defined above under b'''), c'") and d'''), or (3) a - group, wherein R"5 is as defined above.
Figure imgf000061_0004
3. A compound of formula (I) , according to claim 1, wherein X is oxygen or sulphur;
R is phenyl, unsubstituted and substituted by a substituent selected from nitro, halogen, CF3, C1-C4 alkyl and C1-C4 alkoxy;
R1 ia aººº) hydrogen, -COOH, -CHO, -CH2OH, C2-C5-alkoxycarbonyl, or a
wherein R''' and RIV axe as defined above;
Figure imgf000061_0005
each of R2 and R3 independently is hydrogen, halogen, nitro, amino, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; bººº) a group, wherein R'd is hydrogen or C1-C4 alkyl
Figure imgf000062_0001
and Rc is as defined above; cººº) a group wherein Rc is as defined above;
Figure imgf000062_0002
dººº) a -CH2COO(CH2)nCOOR'd or a -NHCO(CH2)nCOORd group, wherein n and R'd are as defined above;
eººº) a , wherein RIII and RIV are as defined above;
Figure imgf000062_0003
fººº) a C2-C4 alkoxycarbonyl group substituted by a
Figure imgf000062_0004
wherein RIII and RIV are as defined above;
R4 represents hydrogen or methyl; Q represents hydrogen or a -CONR"aR"b group, wherein R"a is hydrogen or C1-C4 alkyl and R"b is C1-C4 alkyl or a group wherein Rc and Rg are as defined above;
Figure imgf000062_0005
or R IV "b is a -(CH2)z-R 5 group, wherein z is zero, 1 or 2 and RIV 5 is aIV) unsuibstituted pyridyl or phenyl, unsubstituted or substituted by a substituent chosen from nitro, halogen, CF3, C1-C4 alkyl, C1-C4 alkoxy and di(C1-C2 alkyl)-amino; bIV) phenyl, substituted by -CH2OH, -COOH or a
Figure imgf000063_0001
wherein R''' and RIV are as defined above, and optionally by another substituent chosen from hydroxy and C1-C4 alkoxy; or cIV) 2-thienyl or 2-furyl; dIV) 2-thiazolyl or 3-isoxazolyl, imsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof; and wherein, when R1 is hydrogen, then Q is a -CONR"aR"b, group, wherein R"a is as defined above and R"b is
(1) a - g group, wherein Rc and Rg are as defined above;
Figure imgf000063_0002
or
(2) a -(CH2)z-RV5 group wherein z is as defined above and RV 5 is as RIV 5 defined above under bIV), cIV) or RIV) .
4. A compound according to claim 1 selected from:
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanσyl]-glycine, methyl ester;
N-[2-cyano-3-(1,4-dihydro-1-pheryl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-DL-leucine, methyl ester;
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-p-xpancyl]-DL-pherylalanine, methyl ester;
N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoyl]-DIr-phenylglycine, methyl ester; 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-(2-thenyl)-prcpanamide;
2-cyano-N-(2-furfuryl)-3-(1,4-dihydro-1-phenyl-[1]-berizothiopyrano
[4,3-c]pyrazol-3-yl)-3-oxo-propanamide;
2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide;
2-cyano-3-(1,4-dilιydro-8-morpholinomethyl-1-phenyl-[1]-benzopyrano
[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-prop anamide;
2-cyano-3-(1,4-dihydro-1-pherιyl-[1]-benzothicpyrano[4,3-c]pyrazol-3-yl)-N-(2-mo--pholinomethyl-benzyl)-3-oxo-propanamide; N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propancyl]-DL-leucine;
2-cyano-3-(8-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano [4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(6-ethoxycarbonyl-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-pnenyl-propanamide; N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- [1]-benzothiopyrano[4,3-c]pyrazol-8-yl]carbonyl-glycine methyl ester;
N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)-[1]-benzothicpyrano[4,3-c]pyrazol-6-yl]carbonyl-glycinemethylester;
2-cyano-3-(8-ethoxalylamino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide;
2-cyano-3-(1,4-dihydro-8-oxalamino-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-8-N,N-dimethylaminoethoxycarbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide;
2-cyano-3-(1,4-dihydro-6-N,N-dimethylaminoethoxycarbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; and the pharmaceutically acceptable salts thereof.
5. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which process comprises; a) reacting a compound of formula (II)
Figure imgf000066_0001
wherein claim 1
X, R, R1, R2 , R3 and R4 are as defined in/ and Y is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III)
Figure imgf000066_0002
wherein claim 1
Q' is as 0 defined in/ , except carboxy, so obtaining acompound of formula (I), wherein Q is as defined in claim 1 except carboxy; or b) reacting a compound of formula (IV)
Figure imgf000066_0003
wherein claim 1
X, R, R1, R2, R3 and R4 are as defined in/ , with a compound of formula (V)
Rb-N=C=O (V)
wherein claim 1 Rb is as defined in/ , so obtaining a compound of formula
(I) wherein Q is a -CONHRb group, wherein Rb is as defined in claim 1; or c) reacting a compound of formula (VI)
Figure imgf000067_0001
wherein claim 1
X, R, R1, R2, R3 and R4 are as defined in/ and Z is a reactive derivative of a carboxy group, with a compound of formula (VII)
Figure imgf000067_0002
wherein
Ra and Rb are as defined in claim 1, so obtaining a compound of formula
(I) wherein
Q is a group, wherein Ra and Rb are as defined in claim 1; or
Figure imgf000068_0001
d) hydrolysing a compound of formula (I) , wherein Q is C2-C7 alkoxycarbonyl or a group, in which Ra and Rc are as
Figure imgf000068_0002
defined in claim 1 and Rd is C1-C6 -alkyl, so as to obtain the corresponding cαxpcund of formula (I) , wherein Q is a free carboxy group or a - H group, in which Ra and Rc are as defined in
Figure imgf000068_0003
claim 1; 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.
6. A pharmaceutical ccmposition ccaitaining a pharmaceutically acceptable carrier and/or diluent and, as an active principle, a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1.
7. A compound of formula (I) , or a pharmaceutically acceptable salt thereof, according to claim 1, for use as an immunostimulating agent.
8. A compound of formula (I) or salt thereof according to claim 7, for use in the treatment of an acute or chronic infection of bacterial or viral origin.
9. A compound of formula (I) or salt thereof according to claim 7, for use in the treatment of a neoplastic disease.
10. Use of a compound of formula (I) , or pharmaceutically acceptable salt thereof, as claimed in claim 1, in the preparation of a medicament for use as an immunostimulating agent.
PCT/EP1989/000683 1988-06-20 1989-06-16 Tricyclic 3-oxo-propanenitrile derivatives and process for their preparation WO1989012638A1 (en)

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KR1019900700336A KR900701790A (en) 1988-06-20 1989-06-16 Tricyclic 3-oxo-propanenitrile derivatives and preparation method thereof
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AT89906767T ATE96798T1 (en) 1988-06-20 1989-06-16 TRICYCLIC 3-OXO-PROPANNITRILE DERIVATIVES AND PROCESS FOR THEIR PREPARATION.
NO905449A NO905449D0 (en) 1988-06-20 1990-12-18 TRICYCLIC 3-OXO-PROPANNITRIL DERIVATIVES AND THEIR PREPARATION.
DK300990A DK300990A (en) 1988-06-20 1990-12-19 TRICYCLIC 3-OXO PROPANNITRILLER DERIVATIVES AND PROCEDURES FOR PRODUCING THEREOF
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WO1990011760A1 (en) * 1989-04-06 1990-10-18 Farmitalia Carlo Erba S.R.L. Heteroaryl-3-oxo-propanenitrile derivatives useful in the treatment of rheumatoid arthritis and other autoimmune diseases
WO1991001309A1 (en) * 1989-07-17 1991-02-07 Farmitalia Carlo Erba S.R.L. Heteroaryl-3-oxo-propanenitrile derivatives useful in stimulating myelopoiesis
US5260328A (en) * 1989-04-06 1993-11-09 Farmitalia Carlo Erba Srl Phenyl-indenopurazol 3-oxo-propanamide derivatives useful in the treatment of rheumatoid arthritis
WO1999016753A2 (en) * 1997-10-01 1999-04-08 Pharmacia & Upjohn S.P.A. Tricyclic 3-oxo-propanenitrile compounds
WO1999016771A1 (en) * 1997-10-01 1999-04-08 Pharmacia & Upjohn S.P.A. Condensed benzothiopyranic compounds
WO2015196759A1 (en) * 2014-06-23 2015-12-30 Tocopherx, Inc. Pyrazole compounds as modulators of fshr and uses thereof
US11365199B2 (en) 2013-06-24 2022-06-21 Merck Patent Gmbh Pyrazole compounds as modulators of FSHR and uses thereof

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GB8814587D0 (en) * 1988-06-20 1988-07-27 Erba Carlo Spa Condensed pyrazole 3-oxo-propanenitrile derivatives & process for their preparation
AU6668896A (en) * 1995-08-31 1997-03-19 Idemitsu Kosan Co. Ltd Process for producing thiochroman derivatives
WO1997012885A1 (en) * 1995-10-04 1997-04-10 Idemitsu Kosan Co., Ltd. Pyrazole derivatives
US9073940B2 (en) * 2009-11-13 2015-07-07 Merck Serono Sa Tricyclic pyrazol amine derivatives
CN103626787B (en) * 2013-12-10 2016-06-15 沈阳药科大学 Thienothio compound and application thereof

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Cited By (15)

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Publication number Priority date Publication date Assignee Title
WO1990011760A1 (en) * 1989-04-06 1990-10-18 Farmitalia Carlo Erba S.R.L. Heteroaryl-3-oxo-propanenitrile derivatives useful in the treatment of rheumatoid arthritis and other autoimmune diseases
US5196445A (en) * 1989-04-06 1993-03-23 Farmitalia Carlo Erba Srl Heteroaryl-3-oxo-propanenitrile derivatives useful in the treatment of rheumatoid arthritis and other autoimmune diseases
US5260328A (en) * 1989-04-06 1993-11-09 Farmitalia Carlo Erba Srl Phenyl-indenopurazol 3-oxo-propanamide derivatives useful in the treatment of rheumatoid arthritis
US5352676A (en) * 1989-04-06 1994-10-04 Farmitalia Carlo Erba Srl Morphalinomethyl-substituted 1-phenyl-indero-[1,2-c]pyrazol-3-yl derivatives of 2-cyano-3-oxo-propanamides useful in the treatment of rheumatoid arthritis
WO1991001309A1 (en) * 1989-07-17 1991-02-07 Farmitalia Carlo Erba S.R.L. Heteroaryl-3-oxo-propanenitrile derivatives useful in stimulating myelopoiesis
US5206258A (en) * 1989-07-17 1993-04-27 Farmitalia Carlo Erba S.R.L. Use of heteroaryl-3-oxo-propanenitrile derivatives in treating clinical wherein myelopoiesis suppression occurs
WO1999016753A2 (en) * 1997-10-01 1999-04-08 Pharmacia & Upjohn S.P.A. Tricyclic 3-oxo-propanenitrile compounds
WO1999016771A1 (en) * 1997-10-01 1999-04-08 Pharmacia & Upjohn S.P.A. Condensed benzothiopyranic compounds
WO1999016753A3 (en) * 1997-10-01 1999-05-20 Pharmacia & Upjohn Spa Tricyclic 3-oxo-propanenitrile compounds
US11365199B2 (en) 2013-06-24 2022-06-21 Merck Patent Gmbh Pyrazole compounds as modulators of FSHR and uses thereof
WO2015196759A1 (en) * 2014-06-23 2015-12-30 Tocopherx, Inc. Pyrazole compounds as modulators of fshr and uses thereof
WO2015196335A1 (en) * 2014-06-23 2015-12-30 Tocopherx, Inc. Pyrazole compounds as modulators of fshr and uses thereof
US10208055B2 (en) 2014-06-23 2019-02-19 Tocopherx, Inc. Pyrazole compounds as modulators of FSHR and uses thereof
AU2014398875B2 (en) * 2014-06-23 2019-11-21 Ares Trading S.A. Pyrazole compounds as modulators of FSHR and uses thereof
US10941152B2 (en) 2014-06-23 2021-03-09 Ares Trading S.A. Pyrazole compounds as modulators of FSHR and uses thereof

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