WO2003082839A1 - (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors - Google Patents

(4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors Download PDF

Info

Publication number
WO2003082839A1
WO2003082839A1 PCT/EP2003/002287 EP0302287W WO03082839A1 WO 2003082839 A1 WO2003082839 A1 WO 2003082839A1 EP 0302287 W EP0302287 W EP 0302287W WO 03082839 A1 WO03082839 A1 WO 03082839A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
compound
alkyl
different
Prior art date
Application number
PCT/EP2003/002287
Other languages
French (fr)
Inventor
Fabrice Vergne
Patrick Bernardelli
Edwige Lorthiois
Pierre Ducrot
Original Assignee
Warner-Lambert Company Llc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company Llc filed Critical Warner-Lambert Company Llc
Priority to EP03708184A priority Critical patent/EP1492778A1/en
Priority to JP2003580307A priority patent/JP2005531526A/en
Priority to AU2003212310A priority patent/AU2003212310A1/en
Priority to MXPA04009476A priority patent/MXPA04009476A/en
Priority to CA002480679A priority patent/CA2480679A1/en
Priority to BR0308765-4A priority patent/BR0308765A/en
Publication of WO2003082839A1 publication Critical patent/WO2003082839A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present invention relates to (4,2-disubstituted-thiazol-5-yl)amine derivatives, a process for their preparation, and pharmaceutical compositions containing them. These new compounds are useful as phosphodiesterase 7 (PDE7) inhibitors. Further contained in this invention are pharmaceutical compositions containing these phosphodiesterase 7 inhibitors as active principle for the treatment of disease for which treatment by PDE7 inhibitor is relevant. These medicinal products are useful in particular for treating T-cell- related diseases, autoimmune diseases, visceral pain, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome, allergy, fertility diseases or inflammatory bowel disease.
  • T-cell- related diseases autoimmune diseases, visceral pain, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome, allergy, fertility diseases or inflammatory bowel
  • Phosphodiesterases play an important role in various biological processes by hydrolysing the key second messengers adenosine and guanosine 3',5'-cyclic monophosphates (cAMP and cGMP respectively) into their corresponding 5'-monophosphate nucleotides. Therefore, inhibition of PDE activity produces an increase of cAMP and cGMP intracellular levels that activate specific protein phosphorylation pathways involved in a variety of functional responses.
  • At least eleven isoenzymes of mammalian cyclic nucleotide phosphodiesterases numbered PDE 1 through PDE 11, have been identified on the basis of primary structure, substrate specificity or sensitivity to cofactors or inhibitory drugs.
  • PDE7 is a cAMP-specific PDE.
  • PDE7 activity or protein has been detected in T-cell lines, B-cell lines, airway epithelial (AE) cell lines and several foetal tissues.
  • AE cells actively participate in inflammatory airway diseases by liberating mediators such as arachidonate metabolites and cytokines. Selective inhibition of PDE7 may be a useful anti- inflammatory approach for treating AE cells related diseases.
  • the applicant has identified novel (4,2-disubstituted-thiazol-5-yl)amine compounds that are phosphodiesterase inhibitors, and more specifically compounds that are selective PDE7 inhibitors.
  • Ri a represents a group selected from hydrogen, (C ⁇ -C 6 )alkyl, and aryl(C ⁇ -C 6 )alkyl,
  • Ri b represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, those groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, trifluoromethyl, nitro, cyano, oxo, -N ⁇ Rs, -CO 2 RJ, -CONP R J , -OR t , -S(O) n R 4 , -S(O) n NR 4 R 5 , tetrazolyl, and (C ⁇ -C 6 )alkyl which is optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from -OR 4 , -NR 4 R 5 , and -CO 2 R 4 , wherein: ⁇ S n is an integer from 0 to 2 inclusive, ⁇ / R t and R 5 , identical or different, independently of each other, represent a hydrogen atom or a group of formula -X ⁇ -R
  • - Xi represents a single bond or a (C ⁇ -C 6 )alkylene group
  • R a represents a group selected from (C ⁇ -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
  • R 2 represents a group selected from (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl and cycloalkyl,
  • Re and R 7 identical or different, independently of each other, represent a hydrogen atom or a group of formula -X 2 -R b wherein:
  • - X 2 represents a single bond or a (C ⁇ -C 6 )alkylene group
  • R b represents a group selected from (d-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy,
  • R 8 represents a hydrogen atom or a (Ci -C 6 )alkyl group, optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
  • the present invention relates to compounds of formula (I) wherein R ⁇ a , Ri b , R 2 and R 3 are as defined above, with the exclusion of the following compounds:
  • the present invention relates to compounds of formula (I)
  • R ⁇ a , Ri b , R 2 and R 3 are as defined above, with the exclusion of the following compounds:
  • the substituent R ⁇ a that is preferred according to the invention is the hydrogen atom or a (C ⁇ -C 6 )alkyl group
  • the substituent Ri b that is preferred according to the invention is the group selected from cycloalkyl and aryl, each of those groups being optionally substituted by 1 to 3 groups selected from halogen, trifiuoromethyl, -CO 2 P , -OR 4 , and tetrazolyl, in which R 4 represents a hydrogen atom or a (C ⁇ -C 6 )alkyl group.
  • the substituent R ⁇ a that is preferred according to the invention is the hydrogen atom
  • the substituent R ⁇ that is preferred according to the invention is the cyclohexyl group optionally substituted by one hydroxy group, or the phenyl group optionally substituted by one tetrazolyl group or one -CO 2 R 4 group in which R represents a hydrogen atom or a (C 1 -C 6 )alkyl group.
  • the substituent R 2 that is preferred according to the invention is a (C]-C 6 )alkyl group.
  • the substituent R 2 that is preferred according to the invention is the methyl group.
  • the substituent R 3 that is preferred according to the invention is a group selected from aryl and heteroaryl which are optionally substituted by one to three groups, identical or different, independently of each other, as defined in the general definition of compounds of formula (I).
  • the substituent R 3 that is preferred according to the invention is a group selected from phenyl, pyridyl, thienyl, isoxazolyl, pyrazolyle, pyrazinyl, quinolyl, quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl, 3H-quinazolinyl-4-one, 1H- quinazolinyl-2,4-dione, indolyle, benzisoxazolyl, phtalazinyl, and benzo[l,3]dioxolyle, which are optionally substituted by one to three groups, identical or different, independently of each other, as defined in the general definition of compounds of formula (I).
  • the substituent R 3 that is particularly interesting for the invention is the phenyl group substituted by one to three groups, identical or different, selected independently of each other from halogen, -OR 6 , -CO 2 R ⁇ , -CONReR , -S(O)mR ⁇ , -S(O) m -NR 6 R 7 , -NR 6 COR 7 , and tetrazolyl, wherein: V m is an integer from 0 to 2 inclusive,
  • ⁇ S Rg and R 7 identical or different, independently of each other, represent a hydrogen atom or a group of formula -X 2 -R b wherein:
  • - X 2 represents a single bond or a (d-C 6 )alkylene group
  • R b represents a group selected from (C ⁇ -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (C ⁇ -C 6 )alkoxy, (C ⁇ -C 6 )alkyl, amino, mono(C]-C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino (each alkyl being identical or different, independently of each other), carboxy, (C]-C 6 )alkoxycarbonyl, and benzyl.
  • the substituent R 3 that is particularly interesting for the invention is the group selected from quinoxalinyl, lH-quinoxalinyl-2- one, quinazolinyl, 3H-quinazolinyl-4-one, and lH-quinazolinyl-2,4-dione, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, (C ⁇ -C 6 )alkyl, OR 6 , and NR 6 R 7 , wherein: R ⁇ and R 7 , identical or different, independently of each other, represent a hydrogen atom or a group of formula -X 2 -R b wherein:
  • Rb represents a group (C ⁇ -C 6 )alkyl, which is optionally substituted by one group selected from hydroxy, (C ⁇ -C 6 )alkoxy, amino, mono(C ⁇ -C 6 )alkylamino, and di(C ⁇ -C 6 )alkylamino (each alkyl amino being identical or different, independently of each other).
  • the invention relates to compounds of formula (I) wherein: • Ri a represents a hydrogen atom, • Ri b represents a cyclohexyl group optionally substituted by one hydroxy group, or a phenyl group optionally substituted by one tetrazolyl group or one -CO 2 P group in which R ⁇ represents a hydrogen atom or a (C]-C 6 )alkyl group,
  • R 2 represents a methyl group
  • R 3 represents a phenyl group substituted by one to three groups, identical or different, selected independently of each other from halogen, -OR ⁇ , -CO 2 R ⁇ , -CONR ⁇ R ? , -S(O) m R 6 , -S(O) m -NReR 7 , -NReCOR 7 , and tetrazolyl, wherein: ⁇ m is an integer from 0 to 2 inclusive,
  • - X 2 represents a single bond or a (C ⁇ -C 6 )alkylene group
  • R b represents a group selected from (C ⁇ -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (C ⁇ -C 6 )alkoxy, (C ⁇ -C 6 )alkyl, amino, mono(C ⁇ -C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino
  • the invention relates to compounds of formula (I) wherein: • Ri a represents a hydrogen atom,
  • Ri represents a cyclohexyl group optionally substituted by one hydroxy group, or a phenyl group optionally substituted by one tetrazolyl group or one -CO R 4 group in which R t represents a hydrogen atom or a (C ⁇ -C 6 )alkyl group,
  • R 2 represents a methyl group
  • R 3 represents a group selected from quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl, 3H-quinazolinyl-4-one, lH-quinazolinyl-2,4-dione, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, (C ⁇ -C 6 )alkyl, -OR ⁇ , and -NR ⁇ 5 R 7 , wherein R 6 and R 7 , identical or different, independently of each other, represent a hydrogen atom or a group of formula -X 2 -R b wherein:
  • R b represents a (Cj-C 6 )alkyl group, which is optionally substituted by one group selected from hydroxy, (C ⁇ -C 6 )alkoxy, amino, mono(C ⁇ -C 6 )alkylamino, and di(C ⁇ -C 6 )alkylamino (each alkyl amino being identical or different, independently of each other).
  • the preferred compounds of the invention are:
  • optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds form an integral part of the invention.
  • a (C ⁇ -C ⁇ )alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl, ...
  • a (C ⁇ -C 6 )alkylene group denotes a (C ⁇ -C 6 )alkyl group as defined hereinbefore which is comprised between two groups ;
  • example of such groups without implying any limitation are methylene (-(C ⁇ 2 )-), ethylene (-(CH 2 ) 2 -), ...
  • a (C 2 -C 6 )alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more carbon-carbon double bonds ; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, ...
  • a (C 2 -C 6 )alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more carbon-carbon triple bonds ; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl, ... a (C ⁇ -C 6 )alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such groups without implying any limitation are methoxy, ethoxy, «-propyloxy, tert-butyloxy, ....
  • a mono(C ⁇ -C 6 )alkylamino denotes an amino group substituted by one (C ⁇ -C 6 )alkyl group as defined hereinbefore ; example of such groups, without implying any limitation are methylamino, isobutylamino, ethylamino, ...
  • di(C ⁇ -C 6 )alkylamino denotes an amino group substituted by two (C ⁇ -C 6 )alkyl groups as defined hereinbefore, each alkyl group being identical or different independently of each other ; example of such groups, without implying any limitation are dimethylamino, diethylamino, methylethylamino, ...
  • an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated and it being understood that in the case of a bicyclic system when the second ring is partially hydrogenated then it may be optionally substituted by one or two oxo groups; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl, benzocylohexyl, benzocyclohex-3enyl, benzocyclopentyl, benzocyclohexyl- 1 -one, ...
  • a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different, selected independently of each other from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzisoxazolyl, phtalazinyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl, benzopyrrolinyl, quinoxalinyl, lH-quinoxalinyl, quinazolinyl, 3H-quinazolinyl-4-one, 1H
  • a cycloalkyl group denotes a monocyclic or polycyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character and it being understood that in the case of a polycyclic system each cycle could be fused together or form a link; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl, cyclo[2,2,l]heptyl, cyclo[2,2,2]octyl ...
  • a heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different selected independently of each other from oxygen, sulfur, and nitrogen, - a acyl group denotes a (C ⁇ -C 6 )alkyl group or an aryl group as defined above bound through a carbonyl group ; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl, ...
  • a (C ⁇ -C 6 )alkoxycarbonyl denotes a (C ⁇ -C 6 )alkoxy group as defined hereinbefore bound through a carbonyl group ; examples of such groups without implying any limitation are methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, ... optical isomers refer to racemates, enantiomers and diastereoisomers.
  • the invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I).
  • Pharmaceutically acceptable acids mean non-toxic mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...
  • Pharmaceutically acceptable bases mean non-toxic mineral or organic bases. Among those, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quaternary ammonium hydroxides, etc...
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (II):
  • R 3 is as defined in the compound of formula (I), compound of formula (II) reacting under peptidic coupling conditions with a compound of formula (III):
  • R 2 is as defined in the compound of formula (I), and Prot represents a protective group of carboxylic group usually used in organic synthesis, like for example and without any limitation a methyl group or a tert-butyl group, to give the compound of formula (IV):
  • R 2 and R 3 are as defined hereinbefore, and then in a second step reacting in peptidic coupling condition, using a coupling agent like for example dicyclohexylcarbodiimide or l,l '-carbonyldiimidzole, and a primary amine of formula (VI):
  • R ⁇ a - has the same definition of the group R ⁇ a in the compound of formula (I) except the definition of hydrogen atom, and Li represents a leaving group like for example and without any limitations, chloride, bromide, iodide, tosylate, triflate or mesylate group, to give the compound of formula (I/b) which is a particular case of compounds of formula (I):
  • compounds of formulae (I/a) and (I/b) constitute compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically acceptable acid or base, or into N-oxide thereof.
  • the compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
  • compounds of formula (I) of the present invention are phosphosdiesterase inhibitors, and more particularly inhibitors of the enzyme PDE7.
  • the present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, a N-oxide thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active principle an effective amount of a compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients or carriers.
  • This pharmaceutical composition is useful for the treatment of a disease for which treatment by PDE7 inhibitor is relevant.
  • the pharmaceutical composition described above is useful for treating a pathology in which the disease to be treated is selected from T-cell-related diseases, autoimmune diseases, inflammatory diseases, respiratory diseases, CNS diseases, allergic diseases, endocrine or exocrine pancreas diseases, and gastrointestinal diseases.
  • the pharmaceutical composition is useful to treat a disease which is selected from visceral pain, inflammatory bowel disease, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome (AIDS) and graft rejection.
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
  • compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
  • compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
  • compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
  • compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
  • the pharmaceutically acceptable, inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colorants, aromatizing agents etc...
  • the useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments.
  • the dosage ranges from 1 mg to 1 g per day in one or more administrations.
  • the compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 80% by weight of active principle (compound of formula (I)) and 20% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
  • the compounds of the invention are PDE inhibitors, and particularly PDE7 inhibitors.
  • the compounds of the invention are selective PDE7 inhibitors.
  • Selective PDE7 inhibitors refers to compounds which have an IC 50 for PDE7 at least 5 times lower than the IC 50 for a PDE distinct from PDE7, and preferably at least 10 times,
  • a PDE distinct from PDE7 refers preferably to a PDE chosen from PDE1, PDE3, PDE4 or PDE5.
  • the starting materials used are products that are known or that are prepared according to known operating procedures.
  • the reactions are monitored by tin layer chromatography (T.L.C.).
  • T.L.C. tin layer chromatography
  • the structures of the compounds described in the Examples are determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, .
  • Step 1 The compound obtained in the preceding Step 1 is added to a solution of 5% of trifluoroacetic acid in dichloromethane and the mixture is stirred for 3 hours until reaction completion. Then, the solvent is distilled under reduced pressure. The crude is washed several times with toluene and then used without further purification in the next step.
  • Tin chloride dihydrate is added to a solution of the compound, obtained in the preceding Step 4, in ethanol at 70°C and the mixture is refluxed for 3 hours until disappearance of starting material. The mixture is then filtered through a pad of celite and the filtrate is evaporated to dryness. The crude material is basified with a saturated solution of sodium bicarbonate then extracted with ethyl acetate. The organic layer is washed with water and brine, dried over MgSO 4 , filtered and evaporated to dryness. The residue is chromatographied through silica gel to give the pure desired product.
  • Step 1 tert-Butyl (2S)-2- ⁇ [(4-oxo-3,4-dihydroquinazolin-7-yl)carbonyl]amino ⁇ propanoate
  • Step 2 (2S)-2- ⁇ [(4-Oxo-3,4-dihydroquinazolin-7-yl)carbonyl]amino ⁇ propanoic acid
  • the compound, obtained in the preceding Step 1 is added to a solution of 5% trifluoroacetic acid in dichloromethane and the mixture is stirred for 3 hours until reaction completion. Then, the solvent is distilled under reduced pressure. The crude is washed several times with toluene and then used without further purification in the next step.
  • Step 3 N-[(lS)-2-(Cyclohexylamino)-l-methyl-2-oxoethyl]-4-oxo-3,4- dihydroquinazoline- 7-carboxamide
  • Step 4 7-[5-(Cyclohexylamino)-4-methyl-l,3-thiazol-2-yl]quinazoline-4(3H)-thione
  • Step 5 N-cyclohexyl-4-methyl-2-[4-(methylthio)quinazolin-7-yl]-l,3-thiazol-5-amine
  • Step 6 7-[5-(Cyclohexylamino)-4-methyl-l,3-thiazoI-2-yl]quinazolin-4-amine
  • Example 3 Biological results / In vitro inhibition of the phosphodiesterase 7 and of other phosphodiesterases
  • PDE3A3, PDE4D3, PDE7A1 are cloned and expressed in insect cells Sf21 using the baculovirus expression system and we uses directly the cell culture supernatant as enzyme source.
  • the sources of PDE 1 and of PDE5 are human cell lines (respectively TPH1 human monocytes and MCF7 human Caucasian breast adenocarcinoma). They are obtained partially purified on an anion exchange column (Mono Q) according to a method adapted from Lavan B.E.,Lakey T., Houslay M.D. Biochemical Pharmacology, 1989, 38 (22), 4123-4136.
  • the substrate used is cGMP for PDE1 and PDE5 and cAMP for PDE 3, PDE 4 and PDE 7.
  • the substrate concentration is 0.2 ⁇ M for PDE 1, PDE 3 and PDE 5, 0,25 ⁇ M for PDE 4 and 50nM for PDE 7.
  • the enzymatic reaction is stopped after 1 hour for PDE 1, PDE 3 and PDE 5 and 10 minutes for PDE 4 and PDE 7.
  • compounds of the invention are assayed at 8 to 11 concentrations ranging from 0.02nM to lOO ⁇ M for PDE 4 and PDE 7 and at least at 6 concentrations ranging from 0,1 ⁇ M to 30 ⁇ M for PDE 1, 3 and 5.

Abstract

A compound selected from those of formula (I), wherein R1a, R1b, R2, R3 are as defined in the description, and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of phosphosdiesterase-7 (PDE-7).

Description

(4,2-disubstituted-thiazol-5-yl)amine compounds as PDE7 inhibitors
The present invention relates to (4,2-disubstituted-thiazol-5-yl)amine derivatives, a process for their preparation, and pharmaceutical compositions containing them. These new compounds are useful as phosphodiesterase 7 (PDE7) inhibitors. Further contained in this invention are pharmaceutical compositions containing these phosphodiesterase 7 inhibitors as active principle for the treatment of disease for which treatment by PDE7 inhibitor is relevant. These medicinal products are useful in particular for treating T-cell- related diseases, autoimmune diseases, visceral pain, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome, allergy, fertility diseases or inflammatory bowel disease.
Phosphodiesterases (PDE) play an important role in various biological processes by hydrolysing the key second messengers adenosine and guanosine 3',5'-cyclic monophosphates (cAMP and cGMP respectively) into their corresponding 5'-monophosphate nucleotides. Therefore, inhibition of PDE activity produces an increase of cAMP and cGMP intracellular levels that activate specific protein phosphorylation pathways involved in a variety of functional responses.
At least eleven isoenzymes of mammalian cyclic nucleotide phosphodiesterases, numbered PDE 1 through PDE 11, have been identified on the basis of primary structure, substrate specificity or sensitivity to cofactors or inhibitory drugs.
Among these phosphodiesterases, PDE7 is a cAMP-specific PDE. The biochemical and pharmacological characterization showed a high-affinity cAMP-specific PDE (Km=0.2 μM), that is not affected by cGMP potent selective PDE isoenzyme inhibitors. PDE7 activity or protein has been detected in T-cell lines, B-cell lines, airway epithelial (AE) cell lines and several foetal tissues.
Increasing cAMP levels by selective PDE7 inhibition appears to be a potentially promising approach to specifically block T-cell mediated immune responses. Further studies have demonstrated that elevation of intracellular cAMP levels can modulate inflammatory and immunological processes. This selective approach could presumably be devoid of the side effects associated with known selective PDE inhibitors (e.g. PDE3 or PDE4 selective inhibitors) and which limit their use.
A functional role of PDE7 in T-cell activation has also been disclosed; therefore selective PDE7 inhibitors would be candidates for the treatment of T-cell-related diseases. AE cells actively participate in inflammatory airway diseases by liberating mediators such as arachidonate metabolites and cytokines. Selective inhibition of PDE7 may be a useful anti- inflammatory approach for treating AE cells related diseases.
Thus, there is a need for selective PDE7 inhibitors, which are active at very low concentrations.
The applicant has identified novel (4,2-disubstituted-thiazol-5-yl)amine compounds that are phosphodiesterase inhibitors, and more specifically compounds that are selective PDE7 inhibitors.
More specifically, the present invention relates to compounds of formula (I) :
Figure imgf000003_0001
wherein:
• Ria represents a group selected from hydrogen, (Cι-C6)alkyl, and aryl(Cι-C6)alkyl,
• Rib represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, those groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, trifluoromethyl, nitro, cyano, oxo, -N^Rs, -CO2RJ, -CONP RJ, -ORt, -S(O)nR4, -S(O)nNR4R5, tetrazolyl, and (Cι-C6)alkyl which is optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from -OR4, -NR4R5, and -CO2R4, wherein: ■S n is an integer from 0 to 2 inclusive, ■/ Rt and R5, identical or different, independently of each other, represent a hydrogen atom or a group of formula -Xι-Ra wherein:
- Xi represents a single bond or a (Cι-C6)alkylene group,
- Ra represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
• R2 represents a group selected from (Cι-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl and cycloalkyl,
• R3 represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, nitro, cyano, trifluoromethyl, oxo, (C,-C6)alkyl, -ORs, -NRβR?, -COR6, -CO2R6, -CONHOH, -CONReR?, -S(O)mR6, -S(O)m-NR6R7, -NReCOR?, -NR6SO2R7, -N(SO2R7)2, -NR6-CO-NR7R8, C(=N-CN)NR6R7, R8-C(=N-CN)NR6R7 and tetrazolyl optionally substituted with a (C]-C4)alkyl, wherein: •f m is an integer from 0 to 2 inclusive,
Re and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond or a (Cι-C6)alkylene group,
- Rb represents a group selected from (d-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy,
(Cι-C6)alkoxy, (Cι-C6)alkyl, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino (each alkyl being identical or different, independently of each other), carboxy, (Cι-C6)alkoxycarbonyl, and benzyl,
- R8 represents a hydrogen atom or a (Ci -C6)alkyl group, optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
Preferably, the present invention relates to compounds of formula (I)
Figure imgf000005_0001
wherein Rιa, Rib, R2 and R3 are as defined above, with the exclusion of the following compounds:
(4-Methyl-2-phenyl-thiazol-5-yl)-phenyl-amine, (2,4-diphenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-(3-fluoro-phenyl)-amine, (2,4-diphenyl-thiazol-5-yl)-(4-fluoro-phenyl)-amine, (4-chloro-phenyl)- (2,4-diphenyl-thiazol-5 -yl)-amine, (2-chloro-phenyl)- (2,4-diphenyl-thiazol-5-yl)-amine, (2,4-diphenyl-thiazol-5-yl)-/?-tolyl-amine, and,
(2,4-diphenyl-thiazol-5-yl)-(4-methoxy-phenyl -amine.
Preferably, the present invention relates to compounds of formula (I)
Figure imgf000005_0002
wherein Rιa, Rib, R2 and R3 are as defined above, with the exclusion of the following compounds:
(4-Methyl-2-phenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-(3-fluoro-phenyl)-amine,
(2,4-diphenyl-thiazol-5-yl)-(4-fluoro-phenyl)-amine, (4-chloro-phenyl)- (2,4-diphenyl-thiazol-5-yl)-amine,
(2-chloro-phenyl)- (2,4-diphenyl-thiazol-5-yl)-amine,
(2,4-diphenyl-thiazol-5-yl)-j9-tolyl-amine, and,
(2,4-diphenyl-thiazol-5-yl)-(4-methoxy-phenyl)-amine, and with the proviso that R^ is other than a substituted pyrimidine or a substituted pyrimidine fused to one or several other cycles. The substituent Rιa that is preferred according to the invention is the hydrogen atom or a (Cι-C6)alkyl group, and the substituent Rib that is preferred according to the invention is the group selected from cycloalkyl and aryl, each of those groups being optionally substituted by 1 to 3 groups selected from halogen, trifiuoromethyl, -CO2P , -OR4, and tetrazolyl, in which R4 represents a hydrogen atom or a (Cι-C6)alkyl group.
More particularly, the substituent Rιa that is preferred according to the invention is the hydrogen atom, and the substituent R^ that is preferred according to the invention is the cyclohexyl group optionally substituted by one hydroxy group, or the phenyl group optionally substituted by one tetrazolyl group or one -CO2R4 group in which R represents a hydrogen atom or a (C 1 -C6)alkyl group.
The substituent R2 that is preferred according to the invention is a (C]-C6)alkyl group.
More particularly, the substituent R2 that is preferred according to the invention is the methyl group.
The substituent R3 that is preferred according to the invention is a group selected from aryl and heteroaryl which are optionally substituted by one to three groups, identical or different, independently of each other, as defined in the general definition of compounds of formula (I).
More particularly, the substituent R3 that is preferred according to the invention is a group selected from phenyl, pyridyl, thienyl, isoxazolyl, pyrazolyle, pyrazinyl, quinolyl, quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl, 3H-quinazolinyl-4-one, 1H- quinazolinyl-2,4-dione, indolyle, benzisoxazolyl, phtalazinyl, and benzo[l,3]dioxolyle, which are optionally substituted by one to three groups, identical or different, independently of each other, as defined in the general definition of compounds of formula (I). As a preferred embodiment, the substituent R3 that is particularly interesting for the invention is the phenyl group substituted by one to three groups, identical or different, selected independently of each other from halogen, -OR6, -CO2Rό, -CONReR , -S(O)mRό, -S(O)m-NR6R7, -NR6COR7, and tetrazolyl, wherein: V m is an integer from 0 to 2 inclusive,
■S Rg and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond or a (d-C6)alkylene group,
Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-C6)alkoxy, (Cι-C6)alkyl, amino, mono(C]-C6)alkylamino, di(Cι-C6)alkylamino (each alkyl being identical or different, independently of each other), carboxy, (C]-C6)alkoxycarbonyl, and benzyl.
In an another preferred embodiment, the substituent R3 that is particularly interesting for the invention is the group selected from quinoxalinyl, lH-quinoxalinyl-2- one, quinazolinyl, 3H-quinazolinyl-4-one, and lH-quinazolinyl-2,4-dione, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, (Cι-C6)alkyl, OR6, and NR6R7, wherein: Rό and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond
- Rb represents a group (Cι-C6)alkyl, which is optionally substituted by one group selected from hydroxy, (Cι-C6)alkoxy, amino, mono(Cι-C6)alkylamino, and di(Cι-C6)alkylamino (each alkyl amino being identical or different, independently of each other).
According to a first embodiment, the invention relates to compounds of formula (I) wherein: • Ria represents a hydrogen atom, • Rib represents a cyclohexyl group optionally substituted by one hydroxy group, or a phenyl group optionally substituted by one tetrazolyl group or one -CO2P group in which Rι represents a hydrogen atom or a (C]-C6)alkyl group,
• R2 represents a methyl group,
• R3 represents a phenyl group substituted by one to three groups, identical or different, selected independently of each other from halogen, -ORό, -CO2Rό, -CONRόR?, -S(O)mR6, -S(O)m-NReR7, -NReCOR7, and tetrazolyl, wherein: ■ m is an integer from 0 to 2 inclusive,
■S Rό and R , identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond or a (Cι-C6)alkylene group,
Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-C6)alkoxy, (Cι-C6)alkyl, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino
(each alkyl amino being identical or different, independently of each other), carboxy, (Cι-C6)alkoxycarbonyl, and benzyl.
According to a second embodiment, the invention relates to compounds of formula (I) wherein: • Ria represents a hydrogen atom,
• Ri represents a cyclohexyl group optionally substituted by one hydroxy group, or a phenyl group optionally substituted by one tetrazolyl group or one -CO R4 group in which Rt represents a hydrogen atom or a (Cι-C6)alkyl group,
• R2 represents a methyl group, • R3 represents a group selected from quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl, 3H-quinazolinyl-4-one, lH-quinazolinyl-2,4-dione, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, (Cι-C6)alkyl, -ORβ, and -NR<5R7, wherein R6 and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond,
- Rb represents a (Cj-C6)alkyl group, which is optionally substituted by one group selected from hydroxy, (Cι-C6)alkoxy, amino, mono(Cι-C6)alkylamino, and di(Cι-C6)alkylamino (each alkyl amino being identical or different, independently of each other).
The preferred compounds of the invention are:
- N- {4-[5-(cyclohexylamino)-4-methyl-l ,3-thiazol-2-yl]phenyl} acetamide,
- N- {4-[5-[(3-hydroxycyclohexyl)amino]-4-methyl- 1 ,3-thiazol-2-yl]phenyl} acetamide, 7-[5-(cyclohexylamino)-4-methyl-l,3-thiazol-2-yl]quinazolin-4-amine, - and 7-{5-[(3-hydroxycyclohexyl)amino]-4-methyl-l,3-thiazol-2-yl}quinazolin-4- amine.
The optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds form an integral part of the invention.
The compounds provided by this invention are those defined in formula (I). In formula (I), it is understood that: a (Cι-Cό)alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl, ... - a (Cι-C6)alkylene group denotes a (Cι-C6)alkyl group as defined hereinbefore which is comprised between two groups ; example of such groups, without implying any limitation are methylene (-(CΗ2)-), ethylene (-(CH2)2-), ... a (C2-C6)alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more carbon-carbon double bonds ; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, ... a (C2-C6)alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more carbon-carbon triple bonds ; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl, ... a (Cι-C6)alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such groups without implying any limitation are methoxy, ethoxy, «-propyloxy, tert-butyloxy, .... - a mono(Cι-C6)alkylamino denotes an amino group substituted by one (Cι-C6)alkyl group as defined hereinbefore ; example of such groups, without implying any limitation are methylamino, isobutylamino, ethylamino, ...
- a di(Cι-C6)alkylamino denotes an amino group substituted by two (Cι-C6)alkyl groups as defined hereinbefore, each alkyl group being identical or different independently of each other ; example of such groups, without implying any limitation are dimethylamino, diethylamino, methylethylamino, ... an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated and it being understood that in the case of a bicyclic system when the second ring is partially hydrogenated then it may be optionally substituted by one or two oxo groups; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl, benzocylohexyl, benzocyclohex-3enyl, benzocyclopentyl, benzocyclohexyl- 1 -one, ... - a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different, selected independently of each other from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzisoxazolyl, phtalazinyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl, benzopyrrolinyl, quinoxalinyl, lH-quinoxalinyl, quinazolinyl, 3H-quinazolinyl-4-one, 1H- quinazolinyl-2,4-dione,... a cycloalkyl group denotes a monocyclic or polycyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character and it being understood that in the case of a polycyclic system each cycle could be fused together or form a link; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl, cyclo[2,2,l]heptyl, cyclo[2,2,2]octyl ... a heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different selected independently of each other from oxygen, sulfur, and nitrogen, - a acyl group denotes a (Cι-C6)alkyl group or an aryl group as defined above bound through a carbonyl group ; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl, ... a (Cι-C6)alkoxycarbonyl denotes a (Cι-C6)alkoxy group as defined hereinbefore bound through a carbonyl group ; examples of such groups without implying any limitation are methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, ... optical isomers refer to racemates, enantiomers and diastereoisomers.
The invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I). A review of the pharmaceutically acceptable salts will be found in J. Pharm. Sci., 1977, 66, 1-19. Pharmaceutically acceptable acids mean non-toxic mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...
Pharmaceutically acceptable bases mean non-toxic mineral or organic bases. Among those, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quaternary ammonium hydroxides, etc... The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (II):
Figure imgf000012_0001
wherein R3 is as defined in the compound of formula (I), compound of formula (II) reacting under peptidic coupling conditions with a compound of formula (III):
Figure imgf000012_0002
wherein R2 is as defined in the compound of formula (I), and Prot represents a protective group of carboxylic group usually used in organic synthesis, like for example and without any limitation a methyl group or a tert-butyl group, to give the compound of formula (IV):
O CO2Prot wherein R2, R3 and Prot are as defined hereinbefore,
compound of formula (IN) being deprotected in a first step by treatment with an acid or a base depending on the nature of the protecting group, to give the corresponding free carboxylic acid compound of formula (V):
Figure imgf000012_0003
wherein R2 and R3 are as defined hereinbefore, and then in a second step reacting in peptidic coupling condition, using a coupling agent like for example dicyclohexylcarbodiimide or l,l '-carbonyldiimidzole, and a primary amine of formula (VI):
Rlb-ΝH2 (VI) wherein Rib is as defined in the compound of formula (I), to give the compound of formula (VII):
Figure imgf000013_0001
wherein Rib, R2 and R3 are as defined hereinbefore.
compound of formula (VII) being treated with Lawesson's reagent in basic medium, for example using pyridine, to give the compound of formula (I/a), which is a particular case of compounds of formula (I):
Figure imgf000013_0002
in which Rib, R2 and R3 are as defined hereinbefore,
compound of formula (I/a) being treated optionally under alkaline medium, with a compound of formula (VIII) :
R -L, (VIII) wherein Rιa- has the same definition of the group Rιa in the compound of formula (I) except the definition of hydrogen atom, and Li represents a leaving group like for example and without any limitations, chloride, bromide, iodide, tosylate, triflate or mesylate group, to give the compound of formula (I/b) which is a particular case of compounds of formula (I):
Figure imgf000013_0003
in which Rιa>, Rib, 2 and R3 are as defined hereinbefore, compounds of formulae (I/a) and (I/b) constitute compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically acceptable acid or base, or into N-oxide thereof.
The compounds of formulae (II), (III), (VI) and (VIII) are commercially available or are obtained easily by using classical reactions of organic synthesis well known by the man skilled in the art.
The compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
As mentioned above, compounds of formula (I) of the present invention are phosphosdiesterase inhibitors, and more particularly inhibitors of the enzyme PDE7.
The present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, a N-oxide thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
The invention also relates to a pharmaceutical composition comprising as active principle an effective amount of a compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients or carriers. This pharmaceutical composition is useful for the treatment of a disease for which treatment by PDE7 inhibitor is relevant.
More particularly, the pharmaceutical composition described above is useful for treating a pathology in which the disease to be treated is selected from T-cell-related diseases, autoimmune diseases, inflammatory diseases, respiratory diseases, CNS diseases, allergic diseases, endocrine or exocrine pancreas diseases, and gastrointestinal diseases. In a preferred embodiment the pharmaceutical composition is useful to treat a disease which is selected from visceral pain, inflammatory bowel disease, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome (AIDS) and graft rejection.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
Pharmaceutical compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
Pharmaceutical compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
The pharmaceutical compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
Among the pharmaceutically acceptable, inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colorants, aromatizing agents etc... The useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments. The dosage ranges from 1 mg to 1 g per day in one or more administrations. The compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 80% by weight of active principle (compound of formula (I)) and 20% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
The compounds of the invention are PDE inhibitors, and particularly PDE7 inhibitors.
Preferably, the compounds of the invention are selective PDE7 inhibitors. "Selective PDE7 inhibitors" refers to compounds which have an IC50 for PDE7 at least 5 times lower than the IC50 for a PDE distinct from PDE7, and preferably at least 10 times,
15 times, 20 times, 30 times, 40 times, 50 times or 100 times lower than the IC50 value for a PDE distinct from PDE7.
A PDE distinct from PDE7 refers preferably to a PDE chosen from PDE1, PDE3, PDE4 or PDE5.
The examples that follow illustrate the invention but do not limit it in any way. The compounds described in these examples could be obtained by the following synthetic ways.
The starting materials used are products that are known or that are prepared according to known operating procedures.
The reactions are monitored by tin layer chromatography (T.L.C.). The structures of the compounds described in the Examples are determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, ...).
EXAMPLES Example 1 : iV-{4-[5-(cyclohexylaιnino)-4-methyl-l,3-thiazol-2-yl]phenyl} acetamide
Figure imgf000017_0001
Step 1: tert-Butyl (2S)-2-[(4-nitrobenzoyl)amino]-propanoate
To a solution of />αrø-nitrobenzoic acid in tetrahydrofuran, 1.2 equivalents of 1,1 '- carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, 1.1 equivalents of the (S)-L-alanine tert-butyl ester are added and the mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated under vacuum and the residue is purified by column chromatography to give the desired compound.
Step 2: (2S)-2-[(4-Nitrobenzoyl)amino]-propanoic acid
The compound obtained in the preceding Step 1 is added to a solution of 5% of trifluoroacetic acid in dichloromethane and the mixture is stirred for 3 hours until reaction completion. Then, the solvent is distilled under reduced pressure. The crude is washed several times with toluene and then used without further purification in the next step.
Step 3: N-[(lS)-2-(cyclohexylamino)-l-methyl-2-oxoethyl]-4-nitrobenzamide
To a solution of the compound, obtained in the preceding Step 2, in tetrahydrofuran, 1.2 equivalents of 1,1 '-carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, the cyclohexylamine is added and the mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired product. Step 4: N-cyclohexyl-4-methyl-2-(4-nitrophenyl)-l,3-thiazol-5-amine
To a solution of the compound, obtained in the preceding Step 3, in pyridine is added Lawesson's reagent and the mixture is heated at 100°C for 6 hours until disappearance of starting material. After being cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the product is extracted with chloroform/methanol. The organic layer is washed with water and brine, and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired product.
Step 5: 2-(4-Aminophenyl)-N-cyclohexyl-4-methyl-l,3-thiazol-5-amine
Tin chloride dihydrate is added to a solution of the compound, obtained in the preceding Step 4, in ethanol at 70°C and the mixture is refluxed for 3 hours until disappearance of starting material. The mixture is then filtered through a pad of celite and the filtrate is evaporated to dryness. The crude material is basified with a saturated solution of sodium bicarbonate then extracted with ethyl acetate. The organic layer is washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue is chromatographied through silica gel to give the pure desired product.
Step 6: N-{4-[5-(cyclohexylamino)-4-methyl-l,3-thiazol-2-yl]phenyl}acetamide
To a solution of the compound, obtained in the preceding Step 5, and triethylamine (1.1 equivalents) in tetrahydrofuran at 0°C, 1 equivalent of acetyl chloride is added and after 15 minutes of stirring the mixture is allowed to warm-up to room temperature for 5 hours until reaction completion. The mixture is concentrated under reduced pressure and the residue is purified by chromatography on silica gel to give the expected compound. Example 2: 7-[5-(Cyclohexylamino)-4-methyl-l,3-thiazol-2-yl]quinazolin-4-amine
Figure imgf000019_0001
Step 1: tert-Butyl (2S)-2-{[(4-oxo-3,4-dihydroquinazolin-7-yl)carbonyl]amino} propanoate
To a solution of 4-oxo-3,4-dihydro-quinazoline-7-carboxylic acid in tetrahydrofuran , 1.2 equivalents of 1,1' -carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, the fS^-L-Alanine tert-butyl ester is added and the mixture is stirred for 24 hours until disappearance of starting material. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired compound.
Step 2: (2S)-2-{[(4-Oxo-3,4-dihydroquinazolin-7-yl)carbonyl]amino}propanoic acid
The compound, obtained in the preceding Step 1, is added to a solution of 5% trifluoroacetic acid in dichloromethane and the mixture is stirred for 3 hours until reaction completion. Then, the solvent is distilled under reduced pressure. The crude is washed several times with toluene and then used without further purification in the next step.
Step 3: N-[(lS)-2-(Cyclohexylamino)-l-methyl-2-oxoethyl]-4-oxo-3,4- dihydroquinazoline- 7-carboxamide
To a solution of the compound, obtained in the preceding Step 2, in tetrahydrofuran, 1.2 equivalents of 1,1 '-carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, the cyclohexylamine is added and the mixture is stirred for 24 hours until disappearance of starting material. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired compound.
Step 4: 7-[5-(Cyclohexylamino)-4-methyl-l,3-thiazol-2-yl]quinazoline-4(3H)-thione
To a solution of the compound, obtained in the preceding Step 3, in pyridine is added Lawesson's reagent and the mixture is heated to 100°C for 6 hours until disappearance of starting material. After being cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the product is extracted with chloroform/methanol. The organic layer is washed with water and brine, and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired compound.
Step 5: N-cyclohexyl-4-methyl-2-[4-(methylthio)quinazolin-7-yl]-l,3-thiazol-5-amine
To a stirring solution of the compound, obtained in the preceding Step 4, and potassium carbonate (1.2 equivalents) in methanol is added methyl iodide. After 30 minutes the solvent is removed by rotary evaporation and the residue purified via column chromatography to give a powder corresponding to the desired compound.
Step 6: 7-[5-(Cyclohexylamino)-4-methyl-l,3-thiazoI-2-yl]quinazolin-4-amine
A solution of the compound, obtained in the preceding Step 5, in saturated butanolic amonnia is sealed in a steel bomb and heated at 100°C for 2 days. The solvent is removed by rotary evaporation and the residue purified via column chromatography to give the title compound.
Example 3: Biological results / In vitro inhibition of the phosphodiesterase 7 and of other phosphodiesterases
The capacity of the compounds of the invention to inhibit cyclic nucleotide phosphodiesterases is evaluated by measuring their IC50 (concentration necessary to inhibit the enzymatic activity by 50 %). PDE3A3, PDE4D3, PDE7A1 are cloned and expressed in insect cells Sf21 using the baculovirus expression system and we uses directly the cell culture supernatant as enzyme source. The sources of PDE 1 and of PDE5 are human cell lines (respectively TPH1 human monocytes and MCF7 human Caucasian breast adenocarcinoma). They are obtained partially purified on an anion exchange column (Mono Q) according to a method adapted from Lavan B.E.,Lakey T., Houslay M.D. Biochemical Pharmacology, 1989, 38 (22), 4123-4136.
Measurement of the enzymatic activity for the various types of PDE is then made according to a method adapted from W.J. Thompson et al. 1979, Advances in Cyclic Nucleotide Research, Vol. 10 : 69-92, ed. G. Brooker et al. Raven Press, NY.
The substrate used is cGMP for PDE1 and PDE5 and cAMP for PDE 3, PDE 4 and PDE 7. The substrate concentration is 0.2μM for PDE 1, PDE 3 and PDE 5, 0,25μM for PDE 4 and 50nM for PDE 7.
The enzymatic reaction is stopped after 1 hour for PDE 1, PDE 3 and PDE 5 and 10 minutes for PDE 4 and PDE 7.
In order to determine their IC50, compounds of the invention are assayed at 8 to 11 concentrations ranging from 0.02nM to lOOμM for PDE 4 and PDE 7 and at least at 6 concentrations ranging from 0,1 μM to 30μM for PDE 1, 3 and 5.

Claims

1. A compound selected from those of formula (I):
Figure imgf000022_0001
wherein: • Ria represents a group selected from hydrogen, (Cι-C6)alkyl, and aryl(Cι-C6)alkyl,
• Rib represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, those groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, trifluoromethyl, nitro, cyano, oxo, -NR4R5, -CO2R4, -CONR4R5, -ORt, -S(O)„R4, -S(O)nNR4R5, tetrazolyl, and (C C6)alkyl which is optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from -OR4, -NR4R5, and -CO2 t, wherein: ■S n is an integer from 0 to 2 inclusive,
R_t and R5, identical or different, independently of each other, represent a hydrogen atom or a group of formula -Xι-Ra wherein: - Xi represent a single bond or a (Cι-C6)alkylene group,
- Ra represents a group selected from (C]-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
• R2 represents a group selected from (Cι-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl and cycloalkyl,
• R3 represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, nitro, cyano, trifluoromethyl, oxo, (Cι-C6)alkyl, -ORe, -NR6R7, -CORe, -CO2Re, -CONHOH, -CONReR?, -S(O)mR6, -S(O)m-NR6R7, -NR<5COR7, -NR6SO2R7, -N(SO2R7)2, -NR6-CO-NR7R8, C(=N-CN)NR6R7, NR8-C(=N-CN)NR6R7 and tetrazolyl optionally substituted with a (Cι-C4)alkyl, wherein: ■S m is an integer from 0 to 2 inclusive,
■ Re and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond or a (Cι-C6)alkylene group,
Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-C6)alkoxy, (Cι-C6)alkyl, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino
(each alkyl amino being identical or different, independently of each other), carboxy, (Cι-C6)alkoxycarbonyl, and benzyl,
R8 represents a hydrogen atom or a (Cι-C6)alkyl group, optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof, with the exclusion of the following compounds:
(4-Methyl-2-phenyl-thiazol-5-yl)-phenyl-amine, (2,4-diphenyl-thiazol-5-yl)-phenyl-amine, (2,4-diphenyl-thiazol-5-yl)-(3-fluoro-phenyl)-amine, (2,4-diphenyl-thiazol-5-yl)-(4-fluoro-phenyl)-amine, (4-chloro-phenyl)- (2,4-diphenyl-thiazol-5-yl)-amine, (2-chloro-phenyl)- (2,4-diphenyl-thiazol-5-yl)-amine, (2,4-diphenyl-thiazol-5-yl)-p-tolyl-amine, and, (2,4-diphenyl-thiazol-5-yl)-(4-methoxy-phenylj-amine; it being understood that: an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated and it being understood that in the case of a bicyclic system when the second ring is partially hydrogenated then it may be optionally substituted by one or two oxo groups, a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different, selected independently of each other from oxygen, sulfur and nitrogen, a cycloalkyl group denotes a monocyclic or polycyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character and it being understood that in the case of a polycyclic system each cycle could be fused together or form a link, a heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different selected independently of each other from oxygen, sulfur, and nitrogen.
2. A compound of formula (I) according to claim 1 with the proviso that Rib is other than a substituted pyrimidine or a substituted pyrimidine fused to one or several other cycles.
3. A compound of formula (I) according to claim 1 or 2 characterized in that :
• Ria represents a hydrogen atom or a (Cι-C6)alkyl group, • Rib represents a group selected from cycloalkyl and aryl, each of these groups being optionally substituted by 1 to 3 groups selected from halogen, trifluoromethyl, -CO2R4, -ORt, and tetrazolyl, in which j represents a hydrogen atom or a (Cι-C6)alkyl group,
• R2 and R3 being as described in the compound of formula (I), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
4. A compound of formula (I) according to anyone of claims 1 to 3, characterized in that:
• Ria represents a hydrogen atom,
• Rib represents :
■ a cyclohexyl group optionally substituted by one hydroxy group, ■ or a phenyl group optionally substituted by one tetrazolyl group or one -CO2R4 in which ι represents a hydrogen atom or a (Cι-C6)alkyl group,
• R2 and R3 being as described in the compound of formula (I), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof
5. A compound of formula (I) according to claim 1 or 2 characterized in that R2 represents a (Cι-C6)alkyl group,
Ria, Rib and R3 being as described in the compound of formula (I), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
6. A compound of formula (I) according to claim 1 or 2 characterized in that R2 represents a methyl group,
Ria, Rib and R3 being as described in the compound of formula (I), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
7. A compound of formula (I) according to claim 1 or 2 characterized in that R3 represents a group selected from aryl and heteroaryl which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, nitro, cyano, trifluoromethyl, oxo, (C,-C6)alkyl, -OR6, -NR6R7, -CORe, -CO2Re, -CONHOH, -CONReR?, -S(O)mR6, -S(O)m-NR6R7, -NReCOR?, -NRgSOzRy, -N(SO2R7)2,
Figure imgf000025_0001
and tetrazolyl, wherein: m is an integer from 0 to 2 inclusive, Rό and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein: - X2 represents a single bond or a (Cι-C6)alkylene group,
- Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-C6)alkoxy, (Cι-C6)alkyl, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino (each alkyl amino being identical or different, independently of each other), carboxy,
(Cι-C6)alkoxycarbonyl, and benzyl, R8 represents a hydrogen atom or a (Cι-C6)alkyl group Ria, Rib and R2 being as described in the compound of formula (I), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
8. A compound of formula (I) according to anyone of claims 1 or 7 characterized in that R3 represents a group selected from phenyl, pyridyl, thienyl, isoxazolyl, pyrazolyle, pyrazinyl, quinolyl, quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl,
3H-quinazolinyl-4-one, lH-quinazolinyl-2,4-dione, indolyle, benzisoxazolyl, phtalazinyl, and benzo[l,3]dioxolyle, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, nitro, cyano, trifluoromethyl, oxo, (Cι-C6)alkyl, -OR6, -NR6R7, -CORe, -CO2R6, -CONΗOΗ, -CONReR?, -S(O)mR6, -S(O)m-NR6R7, -NRsCOR,, -NReSOzR?, -N(SO2R7)2, -NRe-CO-NR7R8, and tetrazolyl, wherein: m is an integer from 0 to 2 inclusive,
•/ Rό and R , identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein: - X2 represents a single bond or a (Cι-C6)alkylene group,
- Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-C6)alkoxy, (C]-C6)alkyl, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino (each alkyl amino being identical or different, independently of each other), carboxy,
(Cι-C6)alkoxycarbonyl, and benzyl, R8 represents a hydrogen atom or a (Cι-C6)alkyl group Ria, Rib and R2 being as described in the compound of formula (I), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
9. A compound of formula (I) according to anyone of claims 1, 2, 7 and 8, characterized in that R3 represents a phenyl group substituted by one to three groups, identical or different, selected independently of each other from halogen, -ORό, -CO2R6, -CONRόR-?, - S(O)mR6, -S(O)m-NR6R7, -NReCOR7, and tetrazolyl, wherein: m is an integer from 0 to 2 inclusive, Rό and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond or a (Cι-C6)alkylene group,
- Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-Cό)alkoxy, (Cι-C6)alkyl, amino, mono(C]-C6)alkylamino, di(Cι-C6)alkylamino (each alkyl amino being identical or different, independently of each other), carboxy, (Cι-C6)alkoxycarbonyl, and benzyl, optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
10. A compound of formula (I) according to anyone of claims 1, 2, 7 and 8, characterized in that R3 represents a group selected from quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl, 3H-quinazolinyl-4-one, and lH-quinazolinyl-2,4-dione, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, (Cι-C6)alkyl, -OR<5, and -NR6R7, wherein:
Rό and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond, - Rb represents a group (Cι-C6)alkyl, which is optionally substituted by one group selected from hydroxy, (Cι-C6)alkoxy, amino, mono(Cι-C6)alkylamino, and di(Cι-
C6)alkylamino (each alkyl amino being identical or different, independently of each other), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
11. A compound of formula (I) according to anyone of claims 1 to 9, characterized in that : • Ria represents a hydrogen atom, • Rib represents a cyclohexyl group optionally substituted by one hydroxy group, or a phenyl group optionally substituted by one tetrazolyl group or one -CO2 1 group in which represents a hydrogen atom or a (Cι-C6)alkyl group,
• R2 represents a methyl group,
• R3 represents a phenyl group substituted by one to three groups, identical or different, selected independently of each other from halogen, -ORό, -CO2R6, -CONR6R , -S(O)mR6, -S(O)m-NR6R7, -NR6COR7, and tetrazolyl, wherein: ■S m is an integer from 0 to 2 inclusive,
R6 and R7, identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein:
- X2 represents a single bond or a (Cι-C6)alkylene group,
- Rb represents a group selected from (Cι-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (Cι-C6)alkoxy, (Cι-C6)alkyl, amino, mono(Cι-C6)alkylamino, di(C]-C6)alkylamino
(each alkyl amino being identical or different, independently of each other), carboxy, (Cι-C6)alkoxycarbonyl, and benzyl, optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
12. A compound of formula (I) according to anyone of claims 1 to 10, characterized in that
• Ria represents a hydrogen atom,
• Rib represents a cyclohexyl group optionally substituted by one hydroxy group, or a phenyl group optionally substituted by one tetrazolyl group or one -CO2R4 group in which R represents a hydrogen atom or a (Cι-C6)alkyl group,
• R2 represents a methyl group, • R3 represents a group selected from quinoxalinyl, lH-quinoxalinyl-2-one, quinazolinyl, 3H-quinazolinyl-4-one, lH-quinazolinyl-2,4-dione, which are optionally substituted by one to three groups, identical or different, selected independently of each other from halogen, (Cι-C6)alkyl, -ORβ, and -NRόR-7, wherein R and R , identical or different, independently of each other, represent a hydrogen atom or a group of formula -X2-Rb wherein: X2 represents a single bond, - Rb represents a (Cι-C6)alkyl group, which is optionally substituted by one group selected from hydroxy, (Cι-C6)alkoxy, amino, mono(Cι-C6)alkylamino, and di(Cι-C6)alkylamino (each alkyl amino being identical or different, independently of each other), optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
13. A compound according to claim 1, which is selected from:
- N- {4-[5-(cyclohexylamino)-4-methyl- 1 ,3-thiazol-2-yl]phenyl} acetamide, - N- {4-[5-[(3-hydroxycyclohexyl)amino]-4-methyl- 1 ,3-thiazol-2-yl]phenyl} acetamide,
- 7-[5-(cyclohexylamino)-4-methyl-l,3-thiazol-2-yl]quinazolin-4-amine,
- and 7- {5-[(3-hydroxycyclohexyl)amino]-4-methyl- 1 ,3-thiazol-2-yl} quinazolin-4- amine, optionally its racemics forms, its isomers, and its pharmaceutically acceptable acid or base salts.
14. A process for the preparation of compounds of formula (I) according to claim 1 characterized in that it is used as starting material a compound of formula (II):
Figure imgf000029_0001
wherein R3 is as defined in the compound of formula (I), compound of formula (II) reacting under peptidic coupling conditions with a compound of formula (III):
Figure imgf000030_0001
wherein R2 is as defined in the compound of formula (I), and Prot represents a protective group of a carboxylic group, to give the compound of formula (IV):
Figure imgf000030_0002
wherein R2, R and Prot are as defined hereinbefore,
compound of formula (IV) being deprotected in a first step by treatment with an acid or a base depending on the nature of the protecting group, to give the corresponding free carboxylic acid compound of formula (V):
° c°iH wherein R2 and R3 are as defined hereinbefore, and then in a second step reacting in peptidic coupling condition, in the presence of a coupling agent and a primary amine of formula (VI):
Rlb-NH2 (VI) wherein R^ is as defined in the compound of formula (I),
to give the compound of formula (VII):
Figure imgf000030_0003
wherein Rib, R2 and R3 are as defined hereinbefore, compound of formula (VII) being treated with Lawesson's reagent in basic medium, to give the compound of formula (I/a), which is a particular case of the compounds of formula (I):
Figure imgf000031_0001
in which R^, R2 and R3 are as defined hereinbefore,
compound of formula (I/a) being treated optionally under alkaline medium, with a compound of formula (VIII):
Figure imgf000031_0002
wherein Rιa' has the same definition of the group R)a in the compound of formula (I) except the hydrogen atom definition, and Li represents a leaving group,
to give the compound of formula (I/b) which is a particular case of the compound of formula (I):
Figure imgf000031_0003
in which Rιa-, Rib, R2 and R3 are as defined hereinbefore, compounds of formulae (I/a) and (I/b) constitute compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically acceptable acid or base, or into N-oxide thereof.
15. A pharmaceutical composition comprising as active ingredient an effective amount of a compound as claim in anyone of claims 1 to 13, alone or in combination with one or more pharmaceutically acceptable excipients or carriers.
16. A pharmaceutical composition according to claim 15 comprising as active principle an effective amount of a compound as claimed in anyone of claim 1 to 13 useful for the treatment of a disease for which treatment by PDE7 inhibitor is relevant.
17. A pharmaceutical composition according to claim 16 in which the disease to be treated is selected from T-cell-related diseases, autoimmune diseases, inflammatory diseases, respiratory diseases, CNS diseases, allergic diseases, endocrine or exocrine pancreas diseases, fertility diseases, and gastrointestinal diseases.
18. A pharmaceutical composition according to claim 16 in which the disease to be treated is selected from visceral pain, inflammatory bowel disease, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome (AIDS) and graft rejection.
PCT/EP2003/002287 2002-03-28 2003-03-06 (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors WO2003082839A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP03708184A EP1492778A1 (en) 2002-03-28 2003-03-06 (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors
JP2003580307A JP2005531526A (en) 2002-03-28 2003-03-06 (4,2-substituted-thiazol-5-yl) amine compounds as PDE7 inhibitors
AU2003212310A AU2003212310A1 (en) 2002-03-28 2003-03-06 (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors
MXPA04009476A MXPA04009476A (en) 2002-03-28 2003-03-06 (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors.
CA002480679A CA2480679A1 (en) 2002-03-28 2003-03-06 (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors
BR0308765-4A BR0308765A (en) 2002-03-28 2003-03-06 (4,2-Disubstituted-thiazol-5-yl) amine compounds as pde7 inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02290788A EP1348701A1 (en) 2002-03-28 2002-03-28 (2,4-disubstituted-thiazol-5-yl) amine compounds as PDE7 inhibitors
EP02290788.5 2002-03-28

Publications (1)

Publication Number Publication Date
WO2003082839A1 true WO2003082839A1 (en) 2003-10-09

Family

ID=27798934

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/002287 WO2003082839A1 (en) 2002-03-28 2003-03-06 (4,2-disubstituted-thiazol-5-yl)amine compounds as pde7 inhibitors

Country Status (8)

Country Link
US (1) US6753340B2 (en)
EP (2) EP1348701A1 (en)
JP (1) JP2005531526A (en)
AU (1) AU2003212310A1 (en)
BR (1) BR0308765A (en)
CA (1) CA2480679A1 (en)
MX (1) MXPA04009476A (en)
WO (1) WO2003082839A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004044235A1 (en) * 2002-11-13 2004-05-27 Bayer Healthcare Ag DIAGNOSTICS AND THERAPEUTICS FOR DISEASES ASSOCIATED WITH HUMAN PHOSPHODIESTERASE 7A1 (PDE7a1)
WO2008119057A2 (en) 2007-03-27 2008-10-02 Omeros Corporation The use of pde7 inhibitors for the treatment of movement disorders
WO2012064667A2 (en) 2010-11-08 2012-05-18 Omeros Corporation Treatment of addiction and impulse-control disorders using pde7 inhibitors
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
US10730868B2 (en) 2016-07-14 2020-08-04 Bristol-Myers Squibb Company Bicyclic heteroaryl substituted compounds
WO2024038089A1 (en) 2022-08-18 2024-02-22 Mitodicure Gmbh Use of a therapeutic agent with phosphodiesterase-7 inhibitory activity for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and/or exertional intolerance

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2217956B1 (en) * 2003-01-23 2006-04-01 Almirall Prodesfarma, S.A. NEW DERIVATIVES OF 4-AMINOTIENE (2,3-D) PIRIMIDIN-6-CARBONITRILE.
EA009902B1 (en) 2004-02-13 2008-04-28 УОРНЕР-ЛАМБЕРТ КОМПАНИ Эл-Эл-Си Androgen receptor modulators
BRPI0509759A (en) 2004-04-13 2007-10-16 Warner Lambert Co androgen modulators
JP2007533726A (en) 2004-04-22 2007-11-22 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー Androgen modulator
TW200724139A (en) 2005-05-05 2007-07-01 Warner Lambert Co Androgen modulators
US8067433B2 (en) 2005-11-09 2011-11-29 Zalicus Inc. Methods, compositions, and kits for the treatment of ophthalmic disorders
GB0701426D0 (en) * 2007-01-25 2007-03-07 Univ Sheffield Compounds and their use
FR2943673B1 (en) * 2009-03-27 2013-03-29 Sanofi Aventis THERAPEUTIC APPLICATIONS OF QUINAZOLINEDIONE DERIVATIVES
US20130184280A1 (en) * 2011-12-21 2013-07-18 Telik, Inc. Substituted thiazoles as vegfr2 kinase inhibitors
CN109689664B (en) 2016-07-14 2022-04-15 百时美施贵宝公司 Tricyclic heteroaryl substituted quinoline and azaquinoline compounds as PAR4 inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998008844A1 (en) * 1996-08-26 1998-03-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Thiazole derivatives useful as selective inhibitors of pde-iv
WO2001046184A1 (en) * 1999-12-23 2001-06-28 Icos Corporation 3-thiazol-4-yl-pyprolidine derivatives as amp-specific phosphodiesterase inhibitors
EP1125932A2 (en) * 1994-07-27 2001-08-22 G.D. Searle & Co. Substituted thiazoles for the treatment of inflammation
WO2001064674A1 (en) * 2000-03-01 2001-09-07 Janssen Pharmaceutica N.V. 2,4-disubstituted thiazolyl derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1125932A2 (en) * 1994-07-27 2001-08-22 G.D. Searle & Co. Substituted thiazoles for the treatment of inflammation
WO1998008844A1 (en) * 1996-08-26 1998-03-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Thiazole derivatives useful as selective inhibitors of pde-iv
WO2001046184A1 (en) * 1999-12-23 2001-06-28 Icos Corporation 3-thiazol-4-yl-pyprolidine derivatives as amp-specific phosphodiesterase inhibitors
WO2001064674A1 (en) * 2000-03-01 2001-09-07 Janssen Pharmaceutica N.V. 2,4-disubstituted thiazolyl derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CASTRO A ET AL: "CoMFA of benzyl derivatives of 2,1,3-benzo and benzothieno[3,2-a]thiadiazine 2,2-dioxides: clues for the design of phosphodiesterase 7 inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 36, no. 4, May 2001 (2001-05-01), pages 333 - 338, XP004255695, ISSN: 0223-5234 *
KATRITZKY, ALAN R. ET AL: "Convenient Synthesis of Novel N-Substituted-5-aminothiazole Derivatives", JOURNAL OF ORGANIC CHEMISTRY (2000), 65(23), 8077-8079, XP002203041 *
OSAMU UCHIKAWA: "Aminothiazole derivatives. I. A convenient synthesis of monocyclic and condensed 5-aminothiazole derivatives", JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 31, no. 4, July 1994 (1994-07-01), pages 877 - 887, XP002137194, ISSN: 0022-152X *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004044235A1 (en) * 2002-11-13 2004-05-27 Bayer Healthcare Ag DIAGNOSTICS AND THERAPEUTICS FOR DISEASES ASSOCIATED WITH HUMAN PHOSPHODIESTERASE 7A1 (PDE7a1)
WO2008119057A2 (en) 2007-03-27 2008-10-02 Omeros Corporation The use of pde7 inhibitors for the treatment of movement disorders
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
US9119822B2 (en) 2007-03-27 2015-09-01 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
WO2012064667A2 (en) 2010-11-08 2012-05-18 Omeros Corporation Treatment of addiction and impulse-control disorders using pde7 inhibitors
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
US11207275B2 (en) 2010-11-08 2021-12-28 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
US11464785B2 (en) 2010-11-08 2022-10-11 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
EP4275752A2 (en) 2010-11-08 2023-11-15 Omeros Corporation Treatment of addiction and impulse-control disorders using pde7 inhibitors
US10730868B2 (en) 2016-07-14 2020-08-04 Bristol-Myers Squibb Company Bicyclic heteroaryl substituted compounds
WO2024038089A1 (en) 2022-08-18 2024-02-22 Mitodicure Gmbh Use of a therapeutic agent with phosphodiesterase-7 inhibitory activity for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and/or exertional intolerance

Also Published As

Publication number Publication date
US20030191167A1 (en) 2003-10-09
JP2005531526A (en) 2005-10-20
EP1492778A1 (en) 2005-01-05
CA2480679A1 (en) 2003-10-09
AU2003212310A1 (en) 2003-10-13
EP1348701A1 (en) 2003-10-01
BR0308765A (en) 2005-01-11
US6753340B2 (en) 2004-06-22
MXPA04009476A (en) 2005-01-25

Similar Documents

Publication Publication Date Title
US6753340B2 (en) (4,2-disubstituted-thiazol-5-yl)amine compounds as PDE7 inhibitors
KR100617435B1 (en) New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors
EP1758857B1 (en) Indole derivatives as antiviral agents
SK16972002A3 (en) Beta-carboline derivatives useful as inhibitors of phosphodiesterase
JP2004532233A (en) Dual inhibitors of PDE7 and PDE4
US4772606A (en) Purine derivatives
US6828315B1 (en) 1-Amino triazoloc4,3-a! quinazoline-5-ones and/or -5-thiones inhibiting phosphodiesterase IV
EP1456207A2 (en) Heterocyclic acridone inhibitors of impdh enzyme
WO2009026701A1 (en) Sirtuin inhibitors
MXPA05004435A (en) 1-acyl-pyrrolidine derivatives for the treatment of viral infections.
EP1807431B1 (en) Pyrrolo[1,2-d][1,2-4]triazine as inhibitors of c-jun n-terminal kinases (jnk) and p-38 kinases
US6852720B2 (en) Thiazol-2-yl-imine compounds as PDE-7 inhibitors
EP3750886A1 (en) Tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition containing same, and use thereof
BRPI0713784A2 (en) organic compounds
WO2005058315A1 (en) Novel heterocyclic compounds as ikk2 inhibitors with anti-hbv activity
EP0178178A2 (en) Purine derivatives
NZ301831A (en) Bicyclic isothiourea derivatives useful in therapy
US4952693A (en) Oxazolo-pyrimidine derivatives
JPH0819121B2 (en) Pyrimidine derivatives for enhancing antitumor activity
AU744528B2 (en) 6,7-disubstituted-4-aminopyrido(2,3-d)pyrimidine compounds
WO2003035066A1 (en) 2-aminoquinolone derivatives for use as impdh inhibitors
KR20010033842A (en) N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity
JP3805677B2 (en) Novel 5-pyrimidinecarboxamide derivatives and pharmaceutical compositions containing the derivatives
CA2286592A1 (en) 5,6,7-trisubstituted-4-aminopyridol[2,3-d]pyrimidine compounds
KR100852366B1 (en) Carboline derivatives useful as inhibitors of phosphodiesterase T

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003708184

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2003580307

Country of ref document: JP

Ref document number: 2480679

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/A/2004/009476

Country of ref document: MX

WWP Wipo information: published in national office

Ref document number: 2003708184

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2003708184

Country of ref document: EP