WO2003045951A1 - DERIVES DE TRIAZOLO[4,3-a]PYRIDO[2,3-d]PYRIMIDIN-5-ONES, COMPOSITIONS LES CONTENANT, PROCEDE DE PREPARATION ET UTILISATION - Google Patents
DERIVES DE TRIAZOLO[4,3-a]PYRIDO[2,3-d]PYRIMIDIN-5-ONES, COMPOSITIONS LES CONTENANT, PROCEDE DE PREPARATION ET UTILISATION Download PDFInfo
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Definitions
- the present invention relates to triazolo [4,3-a] pyrido [2,3-d] pyrimidin-5-ones derivatives of general formula (I):
- R 1, R 2 , X and R have the meanings given below, their regioisomers, their salts and their solvates if they exist, their preparation, the compositions which contain them and their use.
- Adenosine 3 ', 5'-cyclic monophosphate is a second ubiquitous intracellular messenger. Specifically, cAMP is an intermediate between the first messenger (hormone, neurotransmitter or autacoid) and functional cellular responses. The first messenger stimulates the enzyme responsible for the synthesis of cAMP that then intervenes, according to the cells concerned, in a large number of functions (metabolic functions, contractile or secretion for example).
- the effects of cAMP stop when degraded by cyclic nucleotide phosphodiesterases (PDEs), which are intracellular enzymes that catalyze cAMP hydrolysis to inactive adenosine 5'-monophosphate.
- PDEs cyclic nucleotide phosphodiesterases
- PDE phosphodiesterase
- Non-specific PDE inhibiting compounds i.e., which inhibit several families of enzymes, are known. This is the case for example of certain methylated xanthines such as theophylline. These compounds have a low therapeutic index, in particular because of their action on PDE types present in cells other than the target cells. Conversely, some PDE families may be selectively inhibited by various pharmacological agents. The hydrolysis of the cyclic nucleotides is then slowed down and their concentration increases accordingly, but only in cells containing the type of PDE sensitive to inhibition.
- PDE4 A particular advantage of PDE4 has been shown. Indeed, these enzymes are widely represented in inflammatory and immunocompetent cells, and induce a reduction in the cAMP level. Inhibition of these enzymes by specific PDE4 inhibitors thus leads to an intracellular increase in cAMP and a consequent decrease in inflammatory cell functions. In addition, cAMP reduces the tone of smooth muscle fibers of the airways. Thus, PDE4 inhibitors also cause bronchiorelaxation.
- Various experiments in pulmonary inflammation models such as that described in asthma have for example shown that PDE4 inhibitors induce a drastic reduction in the influx of inflammatory cells as well as a significant decrease in gill hyperreactivity.
- PDE4 inhibitors have also been advocated in the treatment of chronic obstructive pulmonary disease and rheumatoid arthritis.
- PDE4 inhibitors have been described as potential blockers of TNF ⁇ production, these compounds should be beneficial in the treatment of pathology involving this proinflammatory cytokine.
- X represents a radical chosen from: hydrogen, hydroxy, halogen, amino, nitro, mercapto, cyano, carboxy radicals, alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulphonyl radicals optionally substituted by 1, 2 or 3; halogen atoms, where the radicals -NR 3 R) with R 3 and R, identical or different, chosen from the radicals: * t * hydrogen,
- alkyl optionally substituted with 1, 2 or 3 groups selected from halogen, hydroxy, cyano and alkoxy, -C (O) R 5 with R 5 chosen from hydrogen or alkyl optionally substituted by a hydroxyl radical; alkoxy, mercapto or alkylthio,
- Qi represents an oxy radical (-O-), - ⁇ H-,
- Q 2 represents either a group - (CH 2 ) q -, q being an integer chosen from 0, 1, 2, 3 and 4, or a group - (CH 2 -CH 2 -O) r -, r being an integer selected from 2, 3 and 4, and
- Q 3 represents a hydrogen atom or a radical chosen from hydroxy, methoxy, -O-CO-Xi, -NHX 2 and -N (X ⁇ ) X, X 1 and X 2 , which may be identical or different, representing an alkyl radical; or X 1 and X 2 being bonded together so that together with the nitrogen atom to which they are attached, they form an azacycloalkyl radical comprising 3, 4, 5, 6, 7, 8, 9 or 10 members and which furthermore can comprise 1, 2 or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, the substituents -CO-Qj-Q 2 -Q 3 which may be identical or different within the same unit of formula [ N (A)] n -CO-Q1-Q 2 -Q, and where the radicals of formula:
- ring formed with the nitrogen atom comprises 3, 4, 5, 6, 7,
- 8, 9 or 10 members may further comprise 1, 2 or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, which ring may also be alkyl bridged, dialkylated or substituted with 1, 2 or 3 groups chosen from hydroxyl, oxo, alkyl and / or alkoxy radicals or by a group -CO-Q -Q 2 -Q as defined above,
- R represents a radical chosen from: the alkyl, alkenyl, alkynyl, 2-, 3- or 4-pyridylalkyl radicals, said pyridyls possibly being 1, 2 or 3 times substituted by the alkyl, alkoxy, hydroxy, halogen and / or amino radicals; following formulas:
- * t * s is an integer selected from 1, 2, 3 and 4,
- Ar represents a 5- or 6-membered aryl radical and may additionally comprise 1, 2, 3 or 4 heteroatoms chosen from oxygen, sulfur and / or nitrogen,
- X * Y and Y 3 which are identical or different, are radicals chosen from: hydrogen, hydroxy, mercapto, amino, nitro, halogen,
- R 1 and R 2 represent: alkyl radicals when R 1 and R 2 are identical, or when R 1 and R 2 are different, alkyl, aralkyl, cycloalkyl or cycloalkyl-alkyl radicals, or R 1 and R 2 2 are bonded together so that they together with the nitrogen atom to which they are attached form an azacycloalkyl radical comprising 4, 5, 6 or 7 members and may furthermore comprise 1, 2, or 3 heteroatoms chosen from oxygen , the sulfur and / or nitrogen, said ring thus formed being optionally alkyl-bridged, dialkylated or substituted with 1, 2 or 3 groups selected from hydroxy, oxo, alkyl, alkoxy, phenylalkyl and / or a group -CO-QrQ 2 -Q 3 as defined above, two of the atoms of said ring thus formed may also be part of another ring selected from phenyl and heteroaryl having 4, 5, 6, 7 or 8 members and comprising in addition to 1, 2, 3 or 4
- inhibitors of the PDE4 enzyme which constitute an alternative to previously known inhibitors which are particularly interesting because they possess a set of properties (selectivity towards the PDE4 enzyme, pharmacokinetics, toxicity %) overall favorable for a possible industrial development.
- radicals or substituents when radicals or substituents occur more than once, they can all have the indicated directions independently of one another. In particular, they may be identical or different from each other.
- the free bond through which said radical is attached starts from the group indicated at the end of the name of said radical.
- the free bond through which said aralkyl radical is attached starts from the alkyl group which itself bears an aryl group as a substituent, ie:
- the halogen atoms are generally selected from fluorine, chlorine, bromine or iodine.
- the halogen atoms according to the present invention are chosen from bromine and chlorine.
- the alkyl radicals relate more specifically to alkyls comprising 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain, unless otherwise specified.
- This also applies to substituted alkyls or alkyls as substituents of other radicals, such as, for example, alkoxy, alkylamino, N-alkyl, N-alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, pyridylalkyl, alkoxycarbonyl, aralkyl and the like radicals.
- alkyl radicals according to the present invention can be more precisely chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl radicals.
- the alkyl radicals are chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and isopentyl, n-hexyl and isohexyl.
- the alkyl radicals are substituted by halogen atoms, it is preferably fluorine atoms, and the trisubstituted groups of the - (CH 2 ) W -CF 3 type with w integer between 0 and 3 inclusive.
- methyl trifluoromethyl is preferred.
- alkenyl and alkynyl radicals also contain 2, 3, 4, 5 or 6 carbon atoms in straight or branched chain. More preferably, the alkenyl and alkynyl radicals contain 3 or 4 carbon atoms.
- Suitable alkenyl radicals according to the present invention are for example vinyl, propen-1-yl, allyl, 3-butene-1-yl, 2-methyl-butene-1-yl, 2-methyl propen-1-yl, 2-methyl-propen-2-yl or 3-methyl-butene-2-yl.
- Suitable alkynyl radicals according to The present invention is, for example, ethynyl, propyne-1-yl, propyne-2-yl, 3-butyne-1-yl, 2-methyl-butyne-1-yl or hexynyl.
- cycloalkyl radical is understood to mean monocyclic saturated hydrocarbons comprising 3 to 10 members. More preferably, the cycloalkyl radicals according to the present invention comprise 3 to 6 members.
- the cycloalkyl radicals may be chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. These radicals may optionally, in some aspects of the present invention, be bridged by alkyl. The radical then becomes a bicycloalkyl radical.
- these cycloalkyl or bicycloalkyl radicals may further contain 1 to 3 heteroatoms selected from nitrogen, oxygen and / or sulfur, which may occupy any place on the cycle, whether bridged or not. They may also be located on the deck or, in the case of the nitrogen atom, constitute a bridgehead.
- the free bond of cycloalkyl and bicycloalkyl radicals can also occupy any place on the ring.
- bridged cycloalkyls mention may be made of the radicals which derive from norbornane (bicyclo [2.2.1] heptane), bicyclo [2.2.2] octane, bicyclo [3.2.1] octane, bicyclo [1.1.
- cycloalkyl radicals containing one or more heteroatoms include radicals which are derived from aziridine, oxirane, 1,2-oxothiolane, piperazine or morpholine.
- bridged cycloalkyl containing one or more heteroatoms mention may be made of 7-azabicyclo [2.2.1] heptane, quinuclidine or 2-oxobicyclo [2.2.1] heptane.
- the (bi) cycloalkyl radicals optionally containing one or more heteraroatoms may further contain one or more unsaturations.
- radicals mention may be made of the radicals which derive from norbornene or bornene.
- aryl radical is intended to mean univalent monocyclic or polycyclic aromatic hydrocarbon radicals comprising 6 to 14 members, unless otherwise specified.
- the aryl radicals of the present invention comprise 5 or 6 members.
- the free bond can occupy any place on said aryl radical.
- the aryl radicals may further comprise 1, 2, 3 or 4 heteroatoms chosen from oxygen, sulfur and / or nitrogen.
- said radicals become so-called heteroaryl radicals.
- heteroaryl mention may be made of the radicals which derive from thiophene, benzo [b] thiophene, furan, isobenzofuran, phenoxathiin, xanthene, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, iso indole, indole, purine, isoquinoline, quinoline, phthalazine, 1,8-naphthyridine, quinoxaline, cinnoline, pteridine, phenanthridine, acridine, 1,7-phenanthroline, phenazine, isothiazole, iso
- the compounds of formula (I) can be prepared by adding a compound of formula RQ in which R is as defined for general formula (I) and Q represents, for example, a mesylate, tosylate or triflate radical. or else a halogen atom, for example chosen from fluorine, chlorine, bromine or iodine, on a compound of formula (II):
- the reaction is generally carried out in a basic medium at a temperature of between 20 ° C. and 150 ° C., in a suitable organic solvent.
- a suitable organic solvent As a compatible base, it is possible to use alkali or alkaline earth carbonates, for example cesium, potassium or sodium carbonate or sodium hydride. It is preferably carried out in a suitable solvent selected from dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or 1,2-dimethoxyethane.
- the compound of formula RQ is either a commercially available product or it can be easily prepared according to the usual techniques of organic chemistry well known to those skilled in the art. To this end, it is for example refer to the methods described by Jerry March (Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 3 r Edition, Wiley-Interscience Publication, 1985).
- the compounds of general formula (II) can be prepared by N-debenzylation of the compounds of formula (III):
- R 1, R 2 and X are as previously defined.
- the N-debenzylation reaction is carried out by treatment in the presence of an acidic reactant chosen in particular from Lewis acids, for example aluminum chloride.
- an acidic reactant chosen in particular from Lewis acids, for example aluminum chloride.
- the reaction is carried out at a temperature of between 0 ° C. and 100 ° C. and in a suitable solvent preferably chosen from aromatic solvents such as benzene or toluene.
- the compounds of general formula (III) indicated above are intermediates for the preparation of certain compounds of general formula (I) but may also constitute the final compounds according to the present invention as such (in the where the substituent R is a benzyl radical).
- the compounds of general formula (III) can be purified and isolated without any further reaction step.
- the compounds of general formula ( ⁇ l) can be obtained by substitution of an amine of formula Rj-NH-R 2 , Ri and R 2 being as defined above, on the corresponding halogenated compound of formula (IV):
- Hal ' represents a chlorine, bromine or iodine atom.
- the action of the amine is generally carried out at a temperature of between 20 ° C. and 150 ° C. in the presence of an excess of the amine and optionally in the presence of a base such as, for example, baking soda, potassium bicarbonate or potassium carbonate.
- a base such as, for example, baking soda, potassium bicarbonate or potassium carbonate.
- the reaction is carried out in suitable organic solvents, advantageously an aprotic polar solvent such as pyridine, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or acetonitrile. It is also possible to operate in the absence of solvent.
- the compounds of general formula (IV) can be prepared by chlorination or bromination of the compounds of formula (V):
- the chlorination or bromination reaction is carried out by treatment with chlorine or bromine, in a suitable organic solvent such as for example chloroform and at a temperature generally between 15 ° C. and 100 ° C.
- the compounds of formula (V) can be prepared by cyclization of the hydrazino derivatives of formula (VI): H.
- the cyclization reaction is carried out by action on compounds of formula (VI) of alkyl orthoformate (for example a methyl or ethyl orthoformate), in a solvent such as chloroform or benzene, optionally in presence of an acid such as sulfuric acid or hydrochloric acid.
- alkyl orthoformate for example a methyl or ethyl orthoformate
- a solvent such as chloroform or benzene
- an acid such as sulfuric acid or hydrochloric acid.
- the reaction is carried out at a temperature of between 0 ° C. and 100 ° C.
- the compounds of formula (VI) may be prepared from the corresponding thiocarbonyl derivative of formula (VII):
- the reaction is generally carried out by treatment with hydrazine hydrate in a suitable solvent such as hydroalcoholic solutions (for example methanol or ethanol). Generally, the reaction is carried out at a temperature of between 20 ° C. and 80 ° C., and advantageously at the reflux temperature of the mixture.
- a suitable solvent such as hydroalcoholic solutions (for example methanol or ethanol).
- the thiocarbonyl derivatives of formula (VII) may be prepared by the action of benzyl isothiocyanate on 2-aminonicotinic acid derivatives of formula (VIII):
- the treatment with benzyl isothiocyanate is generally carried out at a temperature of between 20 ° C. and 120 ° C., and advantageously at the reflux temperature of the mixture, in a suitable solvent such as, for example, pyridine or acetic acid.
- the product of general formula (VIII) is commercial. If X is not a hydrogen atom, then the product of general formula (VIII) is obtained by implementing conventional techniques of organic chemistry known to those skilled in the art. For this purpose, reference may be made, for example, to the methods described by Jerry March (Advanced Organic Chemistry: Reactions, Mechanisms and Structure, Third Edition, Wiley-Interscience Publication, 1985) or in J Het. Chem., 1982, 19, 1461.
- the compounds of formula (IV) may be prepared by chlorination or bromination of the corresponding methylthio compounds of formula (V):
- the chlorination or bromination reaction is generally carried out by treatment with chlorine or bromine in a suitable solvent, especially chlorinated solvents and in particular chloroform, and at a temperature generally between 0 ° C. and 40 ° C.
- a suitable solvent especially chlorinated solvents and in particular chloroform
- the compounds of formula (V) can be prepared by alkylation of the corresponding mercapto derivatives of general formula (VF):
- the reaction is generally carried out by treatment with an alkylating agent, in particular a methylating agent, such as, for example, dimethyl sulphate.
- an alkylating agent in particular a methylating agent, such as, for example, dimethyl sulphate.
- a methylating agent such as, for example, dimethyl sulphate.
- an aqueous base such as for example aqueous sodium hydroxide and at a temperature generally between 15 ° C and 60 ° C, and preferably at room temperature.
- the compounds of formula (VF) can be obtained from the compounds of formula (VI) as described above, by treatment with potassium xanthogenate or according to another alternative by treatment with carbon disulfide.
- the reaction is generally carried out at a temperature of between 20 ° C. and 120 ° C., and advantageously at the reflux temperature of the mixture, in a suitable solvent such as, for example, pyridine or acetic acid.
- Preferred compounds of general formula (I) are those for which: X represents a radical chosen from: hydrogen, hydroxy, halogen, amino, nitro, mercapto, cyano, carboxy radicals, alkyl radicals, alkoxy radicals , alkylthio, alkylsulfinyl or alkylsulfonyl optionally substituted by 1, 2 or 3 halogen atoms, -NR 3 R 4 radicals with R 3 and R 4 , identical or different, chosen from the radicals:
- n is an integer chosen from 0 and 1
- A represents either a hydrogen atom or a substituent CO-Q ⁇ -Q 2 -Q 3 ,
- Qi represents an oxy radical (-O-), - ⁇ H-, ⁇ , or: (CH 2 ) p .
- p and p ' are integers selected independently of each other from 0, 1, 2 and 3 and Z represents a group -CH-, -N- or oxy, *> Q represents either a group - (CH 2 ) q -, q being an integer chosen from 0, 1, 2, 3 or 4, ie a group - (CH 2 -CH 2 -O) r -, r being an integer chosen from 2, 3 or 4, and
- Q 3 represents a hydrogen atom or a radical selected from hydroxy, methoxy, -O-CO-X h -NHX 2 or -N (X ⁇ ) X 2, Xi and X 2, identical or different, representing a radical alkyl or X 1 and X 2 being bonded together so that they together with the nitrogen atom to which they are attached form an azacycloalkyl radical comprising 3, 4, 5, 6, 7, 8, 9 or 10 members and furthermore comprising 1, 2 or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, the substituents -CO-Q -Q 2 -Q 3 which may be identical or different within the same unit of formula [N (A)] n -CO-Q ⁇ -Q 2 -Q 3 , and where the radicals of formula:
- ring formed with the nitrogen atom comprises 3, 4, 5, 6, 7,
- 8, 9 or 10 members may further comprise 1, 2 or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, which ring may also be alkyl bridged, dialkylated or substituted with 1, 2 or 3 groups selected from hydroxyl, oxo, alkyl and / or alkoxy radicals or by a group -CO-Q ⁇ -Q 2 -Q 3 as defined above,
- R represents a radical chosen from: the alkyl, alkenyl, alkynyl, 2-, 3- or 4-pyridylalkyl radicals, said pyridyls possibly being 1, 2 or 3 times substituted by the alkyl, alkoxy, hydroxy, halogen and / or amino radicals; following formulas:
- * t * s is an integer selected from 1, 2 and 3
- Ar represents a phenyl or pyridyl radical
- Ri and R 2 represent: identical or different alkyl radicals, or R 1 and R 2 are linked together so that together with the nitrogen atom to which they are attached, they form an azacycloalkyl radical comprising 4, 5, 6 or 7 members and which may also comprise 1, 2, or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, said ring thus formed being optionally alkyl-bridged, dialkylated or substituted with 1, 2 or 3 groups selected from hydroxy, oxo, alkyl, alkoxy, phenylalkyl and / or a group -CO-Q ⁇ -Q 2 -Q 3 as defined above, two of the atoms of said ring thus formed may also be part of another ring selected from phenyl or heteroaryl having 4, 5, 6 , 7 or 8-membered and further comprising 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and / or nitrogen,
- X represents a radical chosen from: hydrogen, hydroxy, halogen, amino radicals, alkyl radicals optionally substituted by 1, 2 or 3 halogen atoms, where the radicals -NR 3 Rt with R 3 and R, identical or different, chosen from the radicals:
- R 3 represents a hydrogen atom and R 4 represents a -C (O) R 5 group with R 5 chosen from alkyls optionally substituted by a hydroxy, alkoxy, mercapto or alkylthio radical;
- R represents a radical chosen from: alkyl, alkenyl or 3-pyridylmethyl radicals, o benzyl optionally substituted with a - (CH 2 ) t -CN group, t being an integer chosen from 0, 1 and 2 or o radicals of formula
- t * s is an integer chosen from 1, 2 and 3 ">
- Ar represents a phenyl or pyridyl radical
- * t * Yi Y 2 and Y 3 , which may be identical or different, represent, as appropriate:> 1 hydrogen or the methoxy radical
- Y 1 and Y 2 represent hydrogen and Y represents an alkoxy or halogen radical
- Y 1 represents hydrogen and Y 2 and Y represent an alkoxy radical
- Ri and R 2 represent: o radicals identical or different alkyls, or R 1 and R 2 are bonded together so that they together with the nitrogen atom to which they are attached form an azacycloalkyl radical comprising 4, 5, 6 or 7 members and may further comprise 1, 2 or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, their regioisomers, their salts and their solvates if they exist.
- the compounds according to the present invention are chosen from those of general formula (I) for which:
- X represents a hydrogen atom, a halogen atom, an alkyl radical or an alkylamino radical
- R represents a radical chosen from radicals of formula:
- R 1 and R 2 represent: o identical or different alkyl radicals, o or else R 1 and R 2 are linked so that together with the nitrogen atom to which they are attached, they form an azacycloalkyl radical comprising 4, 5 , 6 or 7 members and may further comprise 1, 2 or 3 heteroatoms selected from oxygen, sulfur and / or nitrogen, their regioisomers, their salts and their solvates if they exist.
- X represents a hydrogen atom, a halogen atom, an alkyl radical or an alkylamino radical
- R represents a radical chosen from radicals of formula:
- R 1 and R 2 are either identical and represent methyl radicals, or R 1 and R 2 are linked together so that they together with the nitrogen atom to which they are attached form a pyrrolidine or azepane radical, their regioisomers, their salts; and their solvates if they exist.
- the present invention finally relates more specifically to the derivatives of triazolo [4,3-ajpyrido [2,3-d] pyrimidin-5-ones chosen from 1- (azepin-1-yl) -4-benzyl-4H-triazolo [ 4,3-a] pyrido [2,3-d] pyrimidin-5-one, 1- (azepin-1-yl) -4-cinnamyl-4H-triazolo [4,3-a] pyrido [2,3-a] pyrido [2,3-d] pyrimidin-5-one pyrimidin-5-one, 4-benzyl-1- (pyrrolidin-1-yl) -4H-triazolo [4,3-a] pyrido [2,3-d] pyrimidin-5-one, 4 (3-Pyridinylmethyl) -1- (pyrrolidin-1-yl) -4H-triazolo [4,3-a] pyrido [2,3
- the compounds of general formula (I) may optionally in certain cases be converted into physiologically acceptable salts, in particular non-toxic and pharmaceutically usable salts. More specifically, the compounds of formula (I) according to the invention may in certain cases be converted into salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid and with organic carboxylic acids or sulphonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid or p-toluenesulphonic acid.
- inorganic acids such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid
- organic carboxylic acids or sulphonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid or p-toluenesulphonic acid.
- salts can be prepared from the compounds of general formula (1) according to the usual procedures well known to those skilled in the art, for example by combining an organic or inorganic acid in a solvent or a dispersant, or according to a other alternative from other salts by exchange of anions or cations. More generally, those skilled in the art can refer, for example, to the publication "Pharmaceutical salts" by Berge S.M. et al. J Pharm Sci., 1997, 66, 1-19).
- the present invention also relates to other forms and pharmaceutically acceptable derivatives of compounds of general formula (I) such as solvates, in particular hydrates.
- the invention also relates to the regioisomers (or isomers of position) of the compounds according to the present invention, namely the compounds of formula:
- X, R, R 1 and R 2 are as defined above for the compounds of general formula (I).
- These regioisomers can in particular be obtained in the form of a mixture with the compounds of formula (I) during the last synthesis step as described above.
- the two regioisomers can then be separated using standard separation techniques in this case, for example by chromatography.
- compositions that can be used in human or veterinary medicine comprising as active principle at least one compound of general formula (I).
- the compositions according to the invention further comprise a pharmaceutically acceptable vehicle, in general one or more compatible and pharmaceutically acceptable diluents and / or adjuvants (for example buffers, flavoring agents, binders, surfactants, thickeners, preservatives, etc.).
- the compositions are prepared according to common methods well known to those skilled in the art. They generally comprise 0.5% to 60% by weight of active ingredient and 40% to 99.5% by weight of suitable pharmaceutical carrier.
- the compositions of the present invention are prepared in forms compatible with the desired route of administration. Many routes of administration can be considered.
- the compositions according to the invention may be formulated for administration by the topical, oral, parenteral, nasal, pulmonary, intravenous, intramuscular, subcutaneous, transdermal, intratracheal, intraperitoneal, etc. routes.
- compositions according to the invention may for example be in the form of tablets, cachets, sachets of powder for oral suspension, capsules, gastroesistant capsules, release forms. prolonged, emulsions, lyophilisates to melt under the tongue or drinkable solutions.
- the powders, tablets, cachets or encapsulated forms preferably contain from 5% to 70% of active principle.
- Suitable carriers are, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax or cocoa butter. Tablets, powders, cachets and capsules may also be used as a unit dosage for oral administration.
- the support is preferably a finely divided solid, which is in mixture with the compound of general formula (I) according to the invention finely divided.
- the active compound is mixed with a carrier having required binding properties in an appropriate amount, and then the mixture is compressed to the required shape and size.
- aqueous solutions for oral administration these can be prepared by dissolving the active ingredient and adding, if necessary, colorants, flavoring agents, flavors, stabilizers, thickeners or any other suitable adjuvant.
- the active ingredient can be dispersed as a finely divided powder in water with a viscous material such as synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other agents. suspension well known in the field of galenic.
- the compositions according to the invention may for example be in the form of aqueous solutions, water / cosolvent solutions, solutions using one or more solubilizers, colloidal suspensions, emulsions. of nanoparticulate suspensions suitable for injection of sustained-release forms, dispersed forms or liposomes.
- Sterile water and / or propylene glycol solutions of the active ingredient may be mentioned as examples of liquid preparations suitable for parenteral administration.
- Liquid preparations may also be formulated as aqueous solutions of polyethylene glycol. All these presentations are particularly useful in the context of an intravenous administration.
- the compositions according to the invention may, for example, be in the form of suspensions, dispersed forms, sustained release gels as well as release implants. extended.
- compositions according to the invention can be in many forms.
- topical forms the most usual, there are creams, gels (aqueous phases gelled by polymers), patches, which are dressings to stick directly on the skin and can be used to treat dermatoses without percutaneous penetration of the active substance, sprays, emulsions and solutions.
- the compositions of the invention may be in the form of aerosol solutions or inhalant powders, although other forms may also be considered.
- the compositions may be aerosols, for use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, in serum or any other pharmaceutically acceptable vehicle.
- the active ingredient is finely divided and associated with a water-soluble diluent or solid carrier.
- the active ingredient is finely divided and associated with a diluent or solid water-soluble carrier with a particle size of 30 microns to 80 microns, for example dextran, mannitol or lactose.
- compositions according to the invention are mainly in the form of solutions or suspensions for drops, although other forms may also be considered.
- compositions according to the invention are mainly in the form of suppositories or gels, although other forms may also be considered.
- a low melting point wax such as a mixture of glycerides of fatty acids and cocoa butter is first melted and then the active ingredient is dispersed therein, for example by mechanical agitation. The molten homogeneous mixture is then poured into suitably shaped molds and allowed to cool and solidify.
- Another important category of pharmaceutical form that can be used in the context of the present invention relates to forms for improving the solubility of the active ingredient.
- forms for improving the solubility of the active ingredient By way of example, it is possible to envisage the use of aqueous solutions of cyclodextrin, and more particularly of the forms comprising hydroxypropyl ⁇ -cyclodextrin.
- a detailed review of this type of dosage form is presented in the Journal of Pharmaceutical Sciences, 1996, 85 (11), 1142-69).
- the various pharmaceutical forms recommended above are also described in detail in the book “Galenic Pharmacy” by A. LEHIR (Ed Masson, 1992, 6 ed.).
- the physician will determine the most appropriate dosage based on the patient's age, condition, weight, sex, nature and extent of the condition to be treated, the possible combination with other treatments, and any other factor specific to the subject to be treated and the disease concerned.
- the daily dosage in humans is usually between 2 mg and 1 g of active product (for a man of average weight, that is to say weighing about 70 kg) that can be administered in one or more doses.
- the compounds of formula (I) according to the invention possess PDE4 inhibiting properties and / or the release of TNF ⁇ .
- the compounds of the invention can thus be used as a medicament, in particular for the treatment or prevention of conditions involving the production of TNF ⁇ and in particular for the treatment or prevention of inflammatory diseases such as asthma or chronic obstructive pulmonary disease. (COPD).
- COPD chronic obstructive pulmonary disease.
- the compounds of the invention may also be used as a medicament, in particular for the treatment or the prevention of diseases including cancer, acquired immunodeficiency syndrome, fibrosis, excessive formation of scars including excessive formation of scars in the body.
- Dermal level such as normal or abnormal scarring in the dermis after surgery or injury, osteoporosis, osteoporosis, multiple sclerosis, anxiety, depression, atopic dermatitis, arthritis rheumatoid arthritis, septic shock, immune diseases including systemic lupus erythematosus, psoriasis, transplant rejection, allergic rhinitis as well as post-ischemic lesion diseases, pulmonary hypertension, congestive heart failure, acute respiratory distress, inflammatory bowel diseases (irritable bowel syndrome) such as Cr ohn and ulcerative colitis.
- the compounds of formula (I) can be used for the manufacture of a medicament for treating diseases that can be treated by inhibition of the PDE4 enzyme and the resulting increase.
- the level of cAMP in particular the diseases mentioned above, and more specifically inflammatory conditions such as asthma or chronic obstructive pulmonary disease (COPD).
- COPD chronic obstructive pulmonary disease
- the present invention thus provides a particularly advantageous method for treating diseases by administering a compound of formula (I) or a composition comprising it under the conditions defined above. More particularly, this method is applicable to diseases that can be treated / prevented by inhibition of the PDE4 enzyme and the resulting increase in cAMP level, such as the aforementioned diseases and more specifically inflammatory diseases of the asthma type. or chronic obstructive pulmonary disease (COPD).
- another object of the present invention is to provide methods for the treatment or prevention of a condition through inhibition of the PDE4 enzyme and the resulting increase in the level of cAMP, said method comprising a patient of an effective concentration of a compound of formula (I) as defined above.
- the present invention also includes other features and advantages which will emerge from the examples which follow, and which should be considered as illustrating the invention without limiting its scope.
- various operating protocols as well as reaction intermediates that can be used to prepare the compounds of general formula (I).
- reaction intermediates that can be used to prepare the compounds of general formula (I).
- the ability of the compounds of formula (I) to inhibit the phosphodiesterases of cyclic nucleotides is evaluated by measuring their IC 50 (concentration necessary to inhibit 50% of the enzymatic acvtivity). In the case of PDE4, this value is often compared to the IC 50 of rolipram (INN), a PDE4 reference inhibitor.
- Phosphodiesterase type 4 are obtained from a cytosolic preparation extracted from a cell line of human origin U937 according to the method adapted from T. J. Torphy et al. (J. Pharm Exp Ther, 1992, 263, 1195-205).
- the other types of phosphodiesterases are obtained during a partial purification by FPLC on Mono Q column (anion exchange column) according to a method adapted from Lavan B.E. et al. (Biochemical Pharmacology, 1989, 38 (22), 4123-36), and Silver PJ. et al. (Eur J. Pharmacol, 1988, 150, 85-94), either from cell lines of human origin for PDE1 (monocytic line TPH1) and PDE5 (line derived from adenocarcinoma MCF7), or from dog aorta for PDE3, for human PDE3A from cloning of genes in SF21 insect cells in baculovirus, according to the adapted method of Luckow VA et al. (Recomb DNA Technol., & Appl., Eds., Prokop, Bajpa R.K. & Ho C.S., 1991, 97-152).
- the substrate used is cAMP at a concentration of 0.25 ⁇ M.
- the enzymatic reaction implemented is stopped after 10 minutes.
- the compounds according to the present invention were tested for 8 to 11 concentrations in a concentration range between 0.02 nM and 100 ⁇ M.
- the products of the invention have an IC 50 of less than or equal to 7 ⁇ M.
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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JP2003547401A JP2005529843A (ja) | 2001-11-26 | 2002-11-25 | トリアゾロ[4,3−a]ピリド[2,3−d]ピリミジン−5−オン、それらを含有する組成物、その製造方法及び使用 |
MXPA04004429A MXPA04004429A (es) | 2001-11-26 | 2002-11-25 | Derivados de triazolo[4,3-a]pirido[2,3-d]pirimidin-5-ona, composiciones que los contienen, metodo de preparacion y uso. |
BR0214439-5A BR0214439A (pt) | 2001-11-26 | 2002-11-25 | Derivados de triazolo[4,3-a]pirido[2,3-d]pirimidin-5-onas, composições que os contêm, processo de preparação e utilização |
AU2002361407A AU2002361407A1 (en) | 2001-11-26 | 2002-11-25 | Triazolo(4,3-a)pyrido(2,3-d)pyrimidin-5-one derivatives, compositions containing same, preparation method and use thereof |
EP02796623A EP1451190A1 (fr) | 2001-11-26 | 2002-11-25 | DERIVES DE TRIAZOLO(4,3-a)PYRIDO(2,3-d)PYRIMIDIN-5-ONES, COMPOSITIONS LES CONTENANT, PROCEDE DE PREPARATION ET UTILISATION |
CA002468071A CA2468071A1 (fr) | 2001-11-26 | 2002-11-25 | Derives de triazolo[4,3-a]pyrido[2,3-d]pyrimidin-5-ones, compositions les contenant, procede de preparation et utilisation |
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FR01/15249 | 2001-11-26 | ||
FR0115249A FR2832711B1 (fr) | 2001-11-26 | 2001-11-26 | Derives de triazolo [4,3-a] pyrido [2,3-d] pyrimidin-5-ones, compositions les contenant, procede de preparation et utilisation |
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PCT/EP2002/014184 WO2003045951A1 (fr) | 2001-11-26 | 2002-11-25 | DERIVES DE TRIAZOLO[4,3-a]PYRIDO[2,3-d]PYRIMIDIN-5-ONES, COMPOSITIONS LES CONTENANT, PROCEDE DE PREPARATION ET UTILISATION |
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US (1) | US6787554B2 (fr) |
EP (1) | EP1451190A1 (fr) |
JP (1) | JP2005529843A (fr) |
AR (1) | AR038003A1 (fr) |
AU (1) | AU2002361407A1 (fr) |
BR (1) | BR0214439A (fr) |
CA (1) | CA2468071A1 (fr) |
FR (1) | FR2832711B1 (fr) |
HN (1) | HN2002000327A (fr) |
MX (1) | MXPA04004429A (fr) |
PA (1) | PA8558301A1 (fr) |
PE (1) | PE20030664A1 (fr) |
SV (1) | SV2003001410A (fr) |
TW (1) | TW200300344A (fr) |
UY (1) | UY27546A1 (fr) |
WO (1) | WO2003045951A1 (fr) |
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WO2010149783A1 (fr) * | 2009-06-26 | 2010-12-29 | Deutsches Krebsforschungszentrum | Dérivés pyrimidiniques tricycliques utilisés comme antagonistes de wnt |
WO2016203347A1 (fr) * | 2015-06-17 | 2016-12-22 | Pfizer Inc. | Composés tricycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase |
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EP2258359A3 (fr) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline |
EP1928437A2 (fr) | 2005-08-26 | 2008-06-11 | Braincells, Inc. | Neurogenese par modulation du recepteur muscarinique |
CA2625153A1 (fr) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation de la neurogenese par inhibition de la pde |
AU2006308889A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | GABA receptor mediated modulation of neurogenesis |
BRPI0618643A2 (pt) | 2005-11-09 | 2011-09-06 | Combinatorx Inc | composição compreendendo um par de fármacos, composição compreendendo um corticosteróide e um imunossupressor dependente de imunofilina não-esteróide, kits e uso |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
WO2007134077A2 (fr) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenèse induite par le récepteur 5ht |
EP2382975A3 (fr) | 2006-05-09 | 2012-02-29 | Braincells, Inc. | Neurogénèse par modulation d'angiotensine |
MX2009002496A (es) | 2006-09-08 | 2009-07-10 | Braincells Inc | Combinaciones que contienen un derivado de 4-acilaminopiridina. |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
EP2804603A1 (fr) | 2012-01-10 | 2014-11-26 | President and Fellows of Harvard College | Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation |
JP6505023B2 (ja) | 2013-02-19 | 2019-04-24 | ファイザー・インク | Cnsおよび他の障害を治療するための、pde4アイソザイムの阻害薬としてのアザベンゾイミダゾール化合物 |
SI3597649T1 (sl) * | 2014-04-23 | 2022-04-29 | Dart Neuroscience Llc | Sestavki, ki vsebujejo substituirane (1,2,4)triazolo(1,5-a)pirimidin-7-ilne spojine, kot zaviralci pde2 |
EP3172210B1 (fr) | 2014-07-24 | 2020-01-15 | Pfizer Inc | Composés de pyrazolopyrimidine |
MX2017001565A (es) | 2014-08-06 | 2017-04-27 | Pfizer | Compuestos de imidazopiridazina. |
CA2962826C (fr) | 2014-10-03 | 2023-08-08 | Sanofi | Derives d'imidazole pentacycliques fusionnes |
AR103598A1 (es) | 2015-02-02 | 2017-05-24 | Forma Therapeutics Inc | Ácidos bicíclicos[4,6,0]hidroxámicos como inhibidores de hdac |
MY191591A (en) | 2015-02-02 | 2022-06-30 | Forma Therapeutics Inc | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as hdac inhibitors |
US10555935B2 (en) | 2016-06-17 | 2020-02-11 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
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2001
- 2001-11-26 FR FR0115249A patent/FR2832711B1/fr not_active Expired - Fee Related
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2002
- 2002-11-04 TW TW091132503A patent/TW200300344A/zh unknown
- 2002-11-22 SV SV2002001410A patent/SV2003001410A/es not_active Application Discontinuation
- 2002-11-22 PA PA20028558301A patent/PA8558301A1/es unknown
- 2002-11-22 US US10/303,103 patent/US6787554B2/en not_active Expired - Fee Related
- 2002-11-22 UY UY27546A patent/UY27546A1/es not_active Application Discontinuation
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- 2002-11-25 MX MXPA04004429A patent/MXPA04004429A/es not_active Application Discontinuation
- 2002-11-25 CA CA002468071A patent/CA2468071A1/fr not_active Abandoned
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- 2002-11-25 JP JP2003547401A patent/JP2005529843A/ja active Pending
- 2002-11-25 WO PCT/EP2002/014184 patent/WO2003045951A1/fr active Application Filing
- 2002-11-25 BR BR0214439-5A patent/BR0214439A/pt not_active IP Right Cessation
- 2002-11-25 AU AU2002361407A patent/AU2002361407A1/en not_active Abandoned
- 2002-11-25 EP EP02796623A patent/EP1451190A1/fr not_active Withdrawn
- 2002-11-26 HN HN2002000327A patent/HN2002000327A/es unknown
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WO1999006404A1 (fr) * | 1997-07-29 | 1999-02-11 | Almirall Prodesfarma S.A. | Derives de 1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine et compositions pharmaceutiques a base de ces derives |
WO2000066584A1 (fr) * | 1999-04-28 | 2000-11-09 | Warner-Lambert Company | 1-AMINO TRIAZOLO¢4,3-a! QUINAZOLINE-5-ONES ET/OU -5-THIONES INHIBITRICES DE PHOSPHODIESTERASES IV |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010149783A1 (fr) * | 2009-06-26 | 2010-12-29 | Deutsches Krebsforschungszentrum | Dérivés pyrimidiniques tricycliques utilisés comme antagonistes de wnt |
EP2266985A1 (fr) * | 2009-06-26 | 2010-12-29 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Dérivés de pyrimidine tricycliques en tant qu'antagonistes Wnt |
US8629272B2 (en) | 2009-06-26 | 2014-01-14 | Deutsches Krebsforschungszentrum | Tricyclic pyrimidine derivatives as wnt antagonists |
WO2016203347A1 (fr) * | 2015-06-17 | 2016-12-22 | Pfizer Inc. | Composés tricycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase |
EP3766885A1 (fr) * | 2015-06-17 | 2021-01-20 | Pfizer Inc | Composés tricycliques comme inhibiteurs de la phosphodiesterase |
EA039714B1 (ru) * | 2015-06-17 | 2022-03-03 | Пфайзер Инк. | Трициклические соединения и их применение в качестве ингибиторов фосфодиэстераз |
US11472805B2 (en) | 2015-06-17 | 2022-10-18 | Pfizer, Inc. | Tricyclic compounds and their use as phosphodiesterase inhibitors |
Also Published As
Publication number | Publication date |
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AR038003A1 (es) | 2004-12-22 |
BR0214439A (pt) | 2004-11-03 |
TW200300344A (en) | 2003-06-01 |
US6787554B2 (en) | 2004-09-07 |
PE20030664A1 (es) | 2003-08-28 |
EP1451190A1 (fr) | 2004-09-01 |
CA2468071A1 (fr) | 2003-06-05 |
FR2832711A1 (fr) | 2003-05-30 |
HN2002000327A (es) | 2003-06-09 |
US20030187257A1 (en) | 2003-10-02 |
JP2005529843A (ja) | 2005-10-06 |
AU2002361407A1 (en) | 2003-06-10 |
PA8558301A1 (es) | 2003-09-17 |
UY27546A1 (es) | 2003-06-30 |
SV2003001410A (es) | 2003-04-03 |
MXPA04004429A (es) | 2005-05-16 |
FR2832711B1 (fr) | 2004-01-30 |
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