EP1503991A1 - Hexahydropyridazin-3-carbonsäurederivate, diese enthaltende pharmazeutische zusammensetzungen und verfahren zu deren herstellung - Google Patents

Hexahydropyridazin-3-carbonsäurederivate, diese enthaltende pharmazeutische zusammensetzungen und verfahren zu deren herstellung

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Publication number
EP1503991A1
EP1503991A1 EP03749907A EP03749907A EP1503991A1 EP 1503991 A1 EP1503991 A1 EP 1503991A1 EP 03749907 A EP03749907 A EP 03749907A EP 03749907 A EP03749907 A EP 03749907A EP 1503991 A1 EP1503991 A1 EP 1503991A1
Authority
EP
European Patent Office
Prior art keywords
group
carbon atoms
acid
carboxylic acid
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03749907A
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English (en)
French (fr)
Inventor
Neerja Bhatnagar
Jean-François Gourvest
Jacques Mauger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
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Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Publication of EP1503991A1 publication Critical patent/EP1503991A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new derivatives of hexahydro-pyridazine-3-carboxylic acid, the chemical libraries (or libraries) containing them, their preparation, their use as medicaments, in particular as inhibitors of cathépsine K, as well as pharmaceutical compositions containing.
  • Metabolic enzymes such as proteases or kinases are enzymes widely distributed in the animal kingdom.
  • proteases capable of selectively catalyzing the hydrolysis of polypeptide bonds, mention may be made of the four main classes: aspartic protease, serine, cysteine and metallo-protease.
  • aspartic protease mention may be made in particular of HIV-1 protease, renin, plasmepsins, cathépsine D. "convertase supplements", the NS3 hepatitis C protease
  • cysteine proteases there are three structurally distinct groups, the papain group and the cathepsins, the ICE group (the caspases) and the picorna-viral group (similar to the serine proteases in which the serine is replaced by a cysteine).
  • cathépsine K cathépsine K
  • cathépsine B cathépsine L
  • cathépsine S caspases
  • rhinovirus 3C protease and papains and calpains.
  • metalloprotease there may be mentioned in particular the angiotensin converting enzyme, the neutral endopeptidase and the mixture of the two, the metalloprotease matrix as well as the Tumor-necrosis Factor- ⁇ -Converting Enzyme.
  • kinase or protease enzymes are involved in catabolization and inter and intracellular communication processes: they play an important role in a large number of diseases in different fields such as in particular the cardiovascular field, oncology, the central nervous system, inflammation, osteoporosis and also infectious, parasitic, fungal or viral diseases. This is why these proteins are targets of great interest for pharmaceutical research.
  • OA-0023421 describes compounds useful as inhibitors of ICE and more generally of enzymes of the cysteine protease type. Although its synthesis is not described, this document claims the compounds whose formula is as follows:
  • R 1 is an aryl or heteroaryl group
  • R 9 is an alkyl, cycloalkyl (alkyl), aryl (alkyl) group
  • B is chosen from the groups CH 2 NHR 16 , CH 2 OCOaryl, CH 2 OCO heteroaryl, the groups aryl and heteroaryl above which may be substituted.
  • O-A-997545 describes compounds useful for the treatment, for example bone disorders (among which is cited 1 Osteoporosis). Although its synthesis is not described, this document claims the compounds whose formula is as follows:
  • R 8 is an alkyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) group, the aryl and heteroaryl groups above being able to be substituted. None of the above documents teaches the invention.
  • n is an integer from 0 to 6 inclusive;
  • R is one of the groups: hydrogen when m is different from 0; hydroxy or thiol; cyano; linear or branched alkoxy containing from 1 to 6 carbon atoms or aryloxy or aralkoxy; the nucleus of the aryl or aralkyl radical being optionally substituted with one to three substituents chosen from:
  • the ring of the heterocyl radical being optionally substituted with one to three substituents chosen from: OH, oxo, SH, NH 2 , NO 2 , cyano, carboxy, carboxy esterified by C 1 -C 4 alkyl, carbamoyl,
  • -NHC (0) 0-C ⁇ - 4 -alkyl halogen, trifluoromethyl, linear or branched alkyl containing 1 to 6 carbon atoms, linear or branched alkoxy containing 1 to 6 carbon atoms, acyl containing 2 to 6 carbon atoms, aryl or aralkyl, a monocyclic or bicyclic heterocyle saturated or unsaturated, these alkyl or aryl or aralkyl or heterocyl radicals being themselves optionally substituted by one to three substituents chosen from: OH, SH, NH 2 , N0 2 , cyano, carboxy, carboxy esterified by a C 5 -C 4 alkyl, carbamoyl, halogen, trifluoromethyl, an aryl group containing from 6 to 10 carbon or aralkyl atoms containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted with one to three
  • R ' identical or different, has the same meaning as R, or together with R and the nitrogen atom to which they are bonded form a nitrogen heterocycle, this heterocyle being able to be substituted by one to three substituents chosen from: OH, SH , NH 2 , N0 2 , cyano, carboxy, carboxy esterified by a C ⁇ -C 4 alkyl, carbamoyl, halogen, trifluoromethyl, linear or branched alkyl containing from 1 to 6 carbon atoms, linear or branched alkoxy containing from 1 to 6 carbon atoms, acyl containing from 2 to 6 carbon atoms, saturated or unsaturated monocyclic or bicyclic heterocyle, the latter possibly being linked directly or through a group -C (0) - or - CH 2 -C ( 0) -;
  • R ' 3 which is a linear alkyl group or branched from 1 to 6 carbon atoms, an aryl group containing from 6 to 10 carbon atoms or aralkyl grouping containing from 7 to 11 atoms carbon or a saturated or unsaturated monocyclic or bicyclic heterocyle group,
  • n is 2.
  • R 1 represents an optionally substituted alkyl group.
  • R 3 represents an alkyl group.
  • R 2 represents a group chosen from:
  • R is one of the groups: saturated or unsaturated monocyclic or bicyclic heterocyle group; the nuclei of these groups being optionally substituted, an aryl group containing from 6 to 10 carbon atoms or aralkyl group containing from 7 to 11 carbon atoms, the nuclei of these groups being optionally substituted, R ', together with R and the nitrogen atom to which they are attached form a nitrogen heterocycle, this heterocyle possibly being substituted.
  • the compound according to the invention has the following sterochemistry:
  • a subject of the invention is also the compound according to the invention for its use as a medicament.
  • the medicament is intended for the prevention or the treatment of diseases in which metabolic enzymes chosen from proteases and kinases are involved.
  • the medicament is intended for the prevention or the treatment of diseases in which cathépsine K is involved.
  • the diseases to be prevented or treated are chosen from the group of diseases consisting of cardiovascular diseases, cancers, diseases of the central nervous system, inflammatory diseases, infectious diseases and bone diseases.
  • the diseases to be prevented or treated are osteoporosis, hypercalcemia, osteopenia, gingival diseases, arthritis, Paget's disease, bone cancers.
  • the subject of the invention is also a pharmaceutical composition containing, as active principle, at least one compound according to the invention, in association with a pharmaceutically acceptable carrier.
  • the subject of the invention is also the use of a compound according to the invention, for the preparation of a medicament intended for the prevention or treatment of diseases in which metabolic enzymes chosen from proteases and kinases are involved.
  • the subject of the invention is also a chemical library of compounds according to the invention, in the form of a matrix of rank at least equal to 2, at least 2 rows each comprising at least two compounds, preferably at least five, the compounds being individualized.
  • the chemical library is in the form of a matrix of rank equal to 3, the first rank corresponding to the group R x , the second rank corresponding to the group R 2 and the third rank corresponding to the group R 3 , each rank each comprising at least two compounds.
  • the chemical library is in the form of a matrix of rank equal to 2, the first rank corresponding to the group Ri, the second rank corresponding to the group R 2 , each rank each comprising at least two compounds, the compounds being according to claim 4, the group R 3 having a predefined value.
  • the chemical library is such that: the first row corresponding to the group Ri, this group being chosen from the following residues: isopropyl; allyloxycarbonyl propionyl the second rank corresponding to the group R 2 , this group being chosen from the following residues: diazomethane; pyridine-2,5-dicarboxylic acid 2-methyl ester; 3-Pyridine-2-yl-4, 5-dihydro-isoxazole-5-carboxylic acid; (5-methyl-2,4-dioxo-3, 4-dihydro-2H-pyrimidin-1-yl) -acetic acid; pyrazine-2-carboxylic acid; [4- (2-Oxo-2-pyrrolidin-1-yl-ethyl) - piperazin-1-yl] -acetic acid; diazomethane; pyridine-2,5-dicarboxylic acid 2-methyl ester; 3-pyridine-2-yl-4, 5-dihydro-iso
  • the invention provides a library of compounds according to the invention is in the form of a set of compounds, these compounds being individualized, the set comprising at least 4 distinct compounds.
  • these compounds being individualized, the assembly comprising the compounds in which the groups R 1 # R 2 and R 3 are as defined above.
  • Another subject of the invention is the use of a chemical library according to the invention as a tool for screening drugs intended for the prevention or treatment of diseases in which metabolic enzymes chosen from proteases and kinases are involved.
  • the products of the present invention as defined above and below have inhibitory properties of metabolic enzymes as defined above in particular of kinases or proteases such as in particular the cysteine proteases or serine proteases.
  • the products of the present invention can thus in particular be useful in the prevention or treatment of diseases in which such metabolic enzymes are involved such as certain cardiovascular diseases, diseases of the central nervous system, inflammatory diseases, bone diseases such as for example osteoporosis, infectious diseases requiring in particular for their therapy anti-infectives or certain cancers.
  • diseases in which such metabolic enzymes are involved such as certain cardiovascular diseases, diseases of the central nervous system, inflammatory diseases, bone diseases such as for example osteoporosis, infectious diseases requiring in particular for their therapy anti-infectives or certain cancers.
  • the bivalent group represented by - (CH 2 ) - can be linear or branched.
  • aryl containing 6 to 10 carbon atoms denotes an unsaturated radical, comprising one or two fused rings, optionally interrupted by one to three heteroatoms chosen from nitrogen, oxygen and sulfur.
  • aryl containing 6 to 10 carbon atoms denotes an unsaturated radical, comprising one or two fused rings, optionally interrupted by one to three heteroatoms chosen from nitrogen, oxygen and sulfur.
  • aralkyl containing from 7 to 11 carbon atoms denotes an aryl radical as above, linked by a linear or branched alkyl radical, this alkyl radical having from 1 to 5 carbon atoms. Mention may in particular be made of benzyl.
  • alkoxy, aryloxy and aralkyloxy indicate the presence of a terminal oxygen on the alkyl, aryl or aralkyl group.
  • the term monocyclic heterocyclic radical denotes a saturated or unsaturated radical consisting of 5 or 6 links such that one or more of the links represents an oxygen, sulfur or nitrogen atom: such a heterocyclic radical thus denotes a carbocyclic radical interrupted by one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms, it being understood that the heterocyclic radicals may contain one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms and that when these heterocyclic radicals contain more a heteroatom, the heteroatoms of these heterocyclic radicals can be the same or different.
  • piperazinyl piperazinyl radical substituted by an
  • bicyclic heterocyclic radical denotes a saturated or unsaturated radical consisting of 8 to 12 members such that one or more of the members represents an oxygen, sulfur or nitrogen atom and in particular condensed heterocyclic groups containing at least one heteroatom chosen from sulfur, nitrogen and oxygen, for example benzothienyl such as 3-benzothienyl, benzothiazolyl, quinolyl, tetralone, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.
  • the compounds of formula (1) can be salified by various groups known to those skilled in the art, among which there may be mentioned, for example:
  • mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxy-methyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine, -
  • the addition salts with mineral or organic acids of the products of formula (1) can be, for example, the salts formed with hydrochloric acids , hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, as
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of ethane derivatives.
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, which is often called geometric isomerism or cis-trans isomerism.
  • stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • the present invention thus also relates to chemical libraries.
  • These libraries are in particular in the form of matrices of variable rank, the rank being at least 2, at least 2 rows containing at least 2 compounds, each compound being individualized. It is understood that these matrices can be made available in a form which is not necessarily of the same rank; thus it is possible to obtain a row 3 matrix in the form of plates with test pieces, the plates being of order 2. It is also understood that the matrices, for example of row 3, when they are available in a order form 3 or lower, are not necessarily ordered.
  • the invention also covers the chemical libraries in the form of sets comprising a plurality of compounds according to the invention, each compound being individualized.
  • This set of compounds notably comprises plates with wells each comprising a compound according to the invention.
  • These sets comprise at least 4 individualized compounds according to the invention.
  • the chemical libraries according to the invention are in particular discreet.
  • the chemical libraries generally comprise a large number of compounds, typically of the order of a hundred or a thousand.
  • the compounds are prepared in the form of chemical libraries, as indicated above. It is also possible to prepare them in a conventional manner by implementing the process, compound by compound.
  • the method according to the invention thus comprises the following steps:
  • X is a halogen atom
  • Reaction (i) is conventionally carried out in an aprotic dipolar solvent in the presence of a base.
  • Reaction (ii) is conventionally carried out in a polar solvent such as methanol in the presence of a base such as LiOH or NaOH.
  • Reaction (iii) is conventionally carried out in dichloromethane or DMF using a peptide coupling agent such as TBTU in the presence of an organic base such as DIEA.
  • Reaction (iv) is conventionally carried out with a solution of hydrobromic acid in acetic acid and in the presence of dichloromethane.
  • Reaction (v) is conventionally carried out in a dichloromethane / DMF mixture using a mineral base such as KF or a supported tertiary amine such as supported triethylamine.
  • the compound of formula (IV) is obtained by diazomethylation of the corresponding precursor carboxylic acid.
  • the invention also provides a method for preparing a chemical library according to the invention, by simultaneous and / or sequential implementation of the method according to the invention on a plurality of reagents.
  • the process according to the invention can also comprise one or more of the following optional reactions, in an appropriate order, to obtain the desired compound:
  • the optional steps are generally conventional reactions, well known to those skilled in the art.
  • the reactive functions which it is appropriate, if necessary, to protect are generally the carboxylic acid, amino, amide and hydroxy functions.
  • the protection of the acid function is in particular carried out in the form of alkyl esters, allylic esters, benzyl, benzhydryl or p-nitrobenzyl. Deprotection is carried out by saponification, acid hydrolysis, hydrogenolysis, or even cleavage using soluble complexes of Palladium O.
  • the protection of amines and amides is in particular carried out in the form of benzylated derivatives, in the form of carbamates, in particular of allyl, benzyl, phenyl or tertbutyl, or also in the form of silylated derivatives such as the tertbutyl dimethyl, trimethyl, triphenyl or else diphenyl tertbutyl-silyl.
  • Deprotection is carried out, depending on the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or using soluble complexes of Palladium O, by the action of an acid, or by the action of tetrabutylammonium fluoride.
  • the protection of alcohols is carried out in a conventional manner, in the form of ethers, esters or carbonates.
  • the ethers may be alkyl or alkoxyalkyl ethers, preferably methyl or methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for example benzyl, or silyl ethers, for example derivatives silylates cited above.
  • the esters can be any cleavable ester known to a person skilled in the art and preferably acetate, propionate or benzoate or p-nitrobenzoate.
  • the carbonates can be, for example, methyl, tert-butyl, allyl, benzyl or p-nitrobenzyl carbonates.
  • Deprotection is carried out by means known to those skilled in the art, in particular saponification, hydrogenolysis, cleavage by soluble complexes of Palladium O, hydrolysis in an acid medium or, for silylated derivatives, treatment with tetrabutylammmonium fluoride.
  • the amidification reaction is carried out starting from the carboxylic acid using an activating agent such as an alkyl chloroformate or EDCI, by the action of ammonia or an appropriate amine. or their acid salts.
  • an activating agent such as an alkyl chloroformate or EDCI
  • the acylation and sulfonylation reactions are carried out on the hydroxyureas by the action respectively of an appropriate halide or anhydride of carboxylic acid or an appropriate halide of sulfonic acid.
  • the alkylation reaction is carried out by action on the hydroxylated derivatives of an alkyl halide or of substituted alkyl, in particular by a free or esterified carboxy radical.
  • the possible final introduction of a double bond is carried out by the action of a halogen derivative of selenium and then oxidation, according to methods known to those skilled in the art.
  • the reduction of acids into alcohols can be carried out by the action of a borane or, via an intermediate mixed anhydride, by the action of an alkaline borohydride.
  • the mixed anhydride is prepared for example using an alkyl chloroformate.
  • Salification with acids is optionally carried out by adding an acid in the soluble phase to the compound.
  • Salification with bases can relate to either the compounds comprising an acid function, in particular carboxy, or those comprising a sulfooxy function or those comprising a heterocycle of acidic nature.
  • the procedure is carried out by adding an appropriate base such as those mentioned above.
  • the pyridinium salt is obtained directly during the action of the SO 3 -pyridine complex and the other salts are obtained from this pyridinium salt. In either case, it is still possible to operate by ion exchange on resin. Examples of salifications appear below in the experimental part.
  • the products of the present invention can thus be endowed with inhibitory properties of one or more metabolic enzymes as defined above, in particular kinases or proteases.
  • Certain products of formula (I) of the present invention as defined above, can therefore in particular have inhibitory properties of certain protein kinases or proteases.
  • the levels, regulation and activity of a number of protein kinases or proteases play a role in several human pathologies.
  • the activity of a protein kinase or protease can in particular be associated with receptors having transmembrane domains or with intracellular proteins.
  • Certain kinases or proteases may play a role in the initiation, development and completion of cell cycle events and thus, inhibitory molecules of such kinases or proteases are capable of limiting unwanted cell proliferation such as those observed in cancers, psoriasis, growth of fungi, parasites (animals, protists): such molecules which inhibit these kinases or proteases are thus also likely to intervene in the regulation of neurodegenerative diseases such as Alzheimer's disease.
  • Certain products of formula (I) as defined above may, as kinase or protease inhibitors, have in particular the property of inhibiting bone resorption mediated by osteoclasts. They can therefore be useful for the therapeutic or prophylactic treatment of diseases which are caused at least in part by an unwanted increase in bone resorption, for example osteoporosis.
  • Certain products of formula (I) of the present invention can thus, for example, inhibit the adhesion of osteoclasts to the surface of the bone and thus the bone resorption by osteoclasts.
  • the bone diseases whose treatment or prevention require the use of the compounds of formula (I), are in particular osteoporosis, hypercalcemia, osteopenia, for example caused by bone metastases, dental disorders by example the periodontitis, hyperparathyroidism, periarticular erosion in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia.
  • the compounds of formula (I) can be used to relieve, prevent or treat bone disorders which are caused by treatments, by glucocorticoids, therapies linked to the taking of steroids or corticosteroids or by deficiencies. male or female sex hormones.
  • Certain products of formula (I) of the present invention may have, in addition to their specific inhibitory properties of kinases or proteases, interesting cellular effects such as antiproliferative properties and in particular effects on apoptosis.
  • the products of the present invention are particularly useful for the therapy of tumors.
  • the products of the invention can thus also increase the therapeutic effects of commonly used anti-tumor agents.
  • the products of formula (I) of the present invention also have antimitotic and anti-neurodegenerative properties.
  • Certain products of the present invention can be inhibitors of vasoconstrictor and hypertensive effects and thus produce an anti-ischemic effect, or else oppose stimulating effects at the level of certain cellular types in particular smooth muscle cells, fibroblasts, cells. neuronal and bone cells.
  • the products according to the present invention can thus be used in the treatment of diseases such as proliferative diseases, cancer, restenosis, inflammation; allergies, cardiovascular disease or certain infectious diseases.
  • diseases such as proliferative diseases, cancer, restenosis, inflammation; allergies, cardiovascular disease or certain infectious diseases.
  • the products of the present invention can also be used in the treatment of certain gastrointestinal, gynecological disorders and in particular for a relaxing effect on the uterus.
  • the products of formula (I) of the present application can thus have interesting pharmacological properties justifying their application in therapy.
  • the invention therefore also relates to the compounds according to the invention for their use as medicaments, intended for the prevention or treatment of the diseases mentioned above.
  • the invention particularly relates to pharmaceutical compositions containing as active principle at least one of the compounds according to 1 the invention in association with a pharmaceutically acceptable carrier.
  • compositions of the present invention as defined above can be administered by the oral route, by parenteral route or by local route in topical application on the skin and the mucous membranes or by injection by intravenous or intramuscular route.
  • compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, pills, tablets, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.
  • the active ingredient can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • the usual dosage which varies according to the product used, the subject treated and the condition in question, can be, for example, from 0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day.
  • Another subject of the invention is the use of the compounds according to the invention for the manufacture of medicines intended for the prevention or treatment of the diseases mentioned above.
  • DCM Dichloromethane
  • DMF N, N-dimethylformamide
  • DIEA Diisopropylethylamine
  • DIC Diisopropylcarbodiimide
  • TFA Trifluoroacetic acid
  • AcOEt Ethyl acetate
  • HOBt 1-hydroxybenzotriazole hydrate
  • NMM N-methyl Morpholine
  • TBTU Tetrafluoroborate N, N, N ', N' -tetramethyluronium.
  • KF Potassium fluoride
  • Example 1 Synthesis of the compound of formula II.
  • the backbone of formula II is prepared by synthesis from intermediate hexahydropyridazic-3-carboxylic acid (see also the description as an intermediate product in documents WO-A-9955724, WO-A-9722619 and EP-A- 25941). a) Esterification of the acid function.
  • Hexahydropyridazic acid (40g; 0.151 mol) is dissolved in 200ml of methanol and cooled to 0 ° C. S0C1 2 (36ml; 0.45mol) is added dropwise. The solution becomes clear; the temperature is allowed to slowly return to room temperature and then heated to reflux for one hour. The mixture is poured onto a DCM (200 ml) / ice (500 g) / NaHCO 3 (60 g) mixture. The sentence aqueous is extracted with DCM. The organic phase is washed with a saturated NaHCO 3 solution and then dried over MgSO 4 . A colorless oil is obtained (41 g; 99%) used as it is. b) Amidation of the amino function (coupling with alanine).
  • step a) Z ⁇ alanine (50g; 0.183 mol) in solution in DCM / DMF (200ml / 20ml) is cooled to 0 ° C; SOCl 2 (25ml; 0.32mol) is added dropwise. The mixture is left stirring for one hour at 0 ° C. The corresponding chloride is thus obtained.
  • the product obtained in step a) is dissolved in 150 ml of DCM at 0 ° C; DIEA (33 ml; 0.19 mol) is then added, then the chloride obtained previously. The mixture is left for 3 hours with stirring; the temperature slowly rises to room temperature.
  • a solution of diazoketone 12 in CH 2 C1 2 (15 ml / mmol) is treated with a solution of HBr35% / acetic acid (30/70) (0.42 ml / mmol) at room temperature. After one hour of reaction, the same amount of HBr / AcOH solution is added and the reaction mixture is stirred for 1 hr. The reaction mixture is poured into a saturated solution of sodium bicarbonate and then extracted with CH 2 C1 2 . The organic phase is washed with water, dried over MgSO 4 and then concentrated in vacuo to yield the desired bromoketone 13. It is also possible to provide flash chromatography on silica gel using CH 2 Cl 2 / MeOH 98 / 2 as eluent.
  • the enzymatic reaction is carried out in Costar ® 96-well plates.
  • the kinetics of the catalytic reaction is measured and the percentage of inhibition is determined after one hour of incubation at 37 ° C.
  • the calculation is derived from the measurement of fluorescence
  • the reaction medium (200 ⁇ l) is as follows: - 170 ⁇ l of acetate buffer (100 mM, pH5.5) containing 1 ⁇ DTA (5 mM) and L-Cysteine (20 mM). The reaction medium is preincubated at 37 ° C. then the following solutions are added. - 10 ⁇ l of compound to be tested (2.10 "5 M in
  • Excipient for one tablet finished at 1 g (detail of the excipient: lactose, talc, starch, magnesium stearate).

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  • Plural Heterocyclic Compounds (AREA)
EP03749907A 2002-05-03 2003-04-29 Hexahydropyridazin-3-carbonsäurederivate, diese enthaltende pharmazeutische zusammensetzungen und verfahren zu deren herstellung Withdrawn EP1503991A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0205573 2002-05-03
FR0205573A FR2839309B1 (fr) 2002-05-03 2002-05-03 Nouveaux derives de l'acide hexahydro-pyridazine-3- carboxylique, chimiotheques les contenant, leur utilisation comme medicaments, compositions pharmaceutiques les contenant et leurs procedes de preparation
PCT/FR2003/001335 WO2003095433A1 (fr) 2002-05-03 2003-04-29 Derives de l'acide hexahydro-pyridazine-3-carboxylique, compositions pharmaceutiques les contenant et leurs procedes de preparation

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US (1) US7034022B2 (de)
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JP (1) JP2005529147A (de)
AU (1) AU2003246868A1 (de)
BR (1) BR0304666A (de)
CA (1) CA2485083A1 (de)
FR (1) FR2839309B1 (de)
IL (1) IL164994A0 (de)
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NZ528282A (en) 1998-03-19 2005-05-27 Vertex Pharma Interleukin-1 beta converting enzyme inhibitors
US6242422B1 (en) * 1998-10-22 2001-06-05 Idun Pharmacueticals, Inc. (Substituted)Acyl dipeptidyl inhibitors of the ice/ced-3 family of cysteine proteases
FR2835835B1 (fr) * 2002-02-11 2004-04-16 Aventis Pharma Sa Nouveaux derives de la pyridazine, leur utilisation comme medicaments, compositions pharmaceutiques et leur procede de preparation
US7309701B2 (en) * 2002-11-19 2007-12-18 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them

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AU2003246868A1 (en) 2003-11-11
JP2005529147A (ja) 2005-09-29
WO2003095433A1 (fr) 2003-11-20
CA2485083A1 (fr) 2003-11-20
US7034022B2 (en) 2006-04-25
IL164994A0 (en) 2005-12-18
US20050171346A1 (en) 2005-08-04
MXPA04010129A (es) 2005-01-25
FR2839309B1 (fr) 2004-07-23
FR2839309A1 (fr) 2003-11-07

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