WO2008056266A2 - Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a]pyrimidin-6-one derivatives - Google Patents
Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a]pyrimidin-6-one derivatives Download PDFInfo
- Publication number
- WO2008056266A2 WO2008056266A2 PCT/IB2007/004272 IB2007004272W WO2008056266A2 WO 2008056266 A2 WO2008056266 A2 WO 2008056266A2 IB 2007004272 W IB2007004272 W IB 2007004272W WO 2008056266 A2 WO2008056266 A2 WO 2008056266A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- pyrimidin
- pyrimido
- pyridinyl
- alkyl group
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
Definitions
- the present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of neurodegenerative diseases caused by abnormal activity of GSK3 ⁇ .
- GSK3 ⁇ (glycogen synthase kinase 3 ⁇ ) is a proline directed serine, threonine kinase that plays an important role in the control of metabolism, differentiation and survival. It was initially identified as an enzyme able to phosphorylate and hence inhibit glycogen synthase. It was later recognized that GSK3 ⁇ was identical to tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau protein in epitopes that are also found to be hyperphosphorylated in Alzheimer's disease and in several taupathies.
- TPK1 tau protein kinase 1
- protein kinase B (AKT) phosphorylation of GSK3 ⁇ results in a loss of its kinase activity, and it has been hypothesized that this inhibition may mediate some of the effects of neurotrophic factors.
- phosphorylation by GSK3 ⁇ of ⁇ -catenin results in its degradation by an ubiquitinilation dependent proteasome pathway.
- GSK3 ⁇ inhibition may result in neurotrophic activity. Indeed there is evidence that lithium, an uncompetitive inhibitor of GSK3 ⁇ , enhances neuritogenesis in some models and also increases neuronal survival, through the induction of survival factors such as Bcl-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax.
- GSK3 ⁇ may be the link between the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation.
- tau hyperphosphorylation results in a destabilization of the neuronal cytoskeleton
- the pathological consequences of abnormal GSK3 ⁇ activity are, most likely, not only due to a pathological phosphorylation of tau protein because, as mentioned above, an excessive activity of this kinase may affect survival through the modulation of the expression of apoptotic and antiapoptotic factors.
- ⁇ -amyloid-induced increase in GSK3 ⁇ activity results in the phosphorylation and, hence the inhibition of pyruvate dehydrogenase, a pivotal enzyme in energy production and acetylcholine synthesis.
- GSK3 ⁇ may find application in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases and other pathologies where GSK3 ⁇ is deregulated (Nature reviews Vol.3, June 2004, p.479-487; Trends in Pharmacological Sciences Vol. 25 No. 9, Sept. 2004, p. 471-480; Journal of neurochemistry 2004, 89, 1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384, 2002).
- the neurodegenerative diseases include, in a non-limiting manner, Parkinson's disease, tauopathies (e.g. Fronto temporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease (The Journal of biological chemistry Vol. 277, No. 37, Issue of September 13, pp. 33791-33798, 2002), Prion disease (Biochem. J. 372, p.129-136, 2003) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; amyotrophic lateral sclerosis (European Journal of Neuroscience, Vol. 22, pp.
- tauopathies e.g. Fronto temporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy
- Wilson's disease Huntington's disease (The Journal of biological chemistry Vol. 277, No. 37, Issue of September 13, pp. 3379
- GSK3 ⁇ peripheral neuropathies; retinopathies and glaucoma.
- ESC embryonic stem cells
- Inhibitors of GSK3 ⁇ may also find application in the treatment of other nervous system disorders, such as bipolar disorders (manic-depressive illness).
- bipolar disorders manic-depressive illness
- lithium has been used for more than 50 years as a mood stabiliser and the primary treatment for bipolar disorder.
- the therapeutic actions of lithium are observed at doses (1-2 mM) where it is a direct inhibitor of GSK3 ⁇ .
- inhibitors of GSK3 ⁇ could be used to mimic the mood stabilising effects of lithium.
- Alterations in Akt-GSK3 ⁇ signaling have also been implicated in the pathogenesis of schizophrenia.
- GSK3 ⁇ could be useful in treating cancers, such as colorectal, prostate, breast, non-small lung carcinoma, thyroid cancer, T or B-cell leukaemia and several virus-induced tumours.
- cancers such as colorectal, prostate, breast, non-small lung carcinoma, thyroid cancer, T or B-cell leukaemia and several virus-induced tumours.
- the active form of GSK3 ⁇ has been shown to be elevated in the tumors of colorectal cancer patients and inhibition of GSK3 ⁇ in colorectal cancer cells activates p53-dependent apoptosis and antagonises tumor growth. Inhibition of GSK3 ⁇ also enhances TRAIL-induced apoptosis in prostate cancer cell lines.
- GSK3 ⁇ also plays a role in the dynamics of the mitototic spindle and inhibitors of GSK3 ⁇ prevent chromosome movement and lead to a stabilisation of microtubules and a prometaphase-like arrest that is similar to that observed with low doses of Taxol.
- Other possible applications for GSK3 ⁇ inhibitors include therapy for non-insulin dependent diabetes (such as diabetes type II), obesity and alopecia.
- Inhibitors of human GSK3 ⁇ may also inhibit pfGSK3, an ortholog of this enzyme found in Plasmodium falciparum, as a consequence they could be used for the treatment of malaria (Biochimica et Biophysica Acta 1697, 181- 196, 2004).
- pfGSK3 an ortholog of this enzyme found in Plasmodium falciparum
- Wnt/LPR5 pathway As a major regulator of bone mass accrual.
- Inhibition of GSK3 ⁇ leads to the consequent activation of canonical Wnt signalling.
- GSK3 ⁇ inhibitors may also be used for treating disorders of reduced bone mass, bone-related pathologies, osteoporosis. According to recent data, GSK3 ⁇ inhibitors might be used in the treatment or prevention of Pemphigus vulgaris.
- GSK3beta inhibitor treatment improves neutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitors will be useful for the treatment of neutropenia induced by cancer chemotherapy.
- An object of the present invention is to provide compounds useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of a disease caused by abnormal GSK3 ⁇ activity, more particularly of neurodegenerative diseases. More specifically, the object is to provide novel compounds useful as an active ingredient of a medicament that enables prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease.
- the inventors of the present invention have identified compounds possessing inhibitory activity against GSK3 ⁇ . As a result, they found that compounds represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of the aforementioned diseases.
- the present invention thus provides as an object of the invention the pyrimidone derivatives represented by formula (I) or salts thereof, solvates thereof or hydrates thereof:
- X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1 - 2 alkyl group and a hydrogen atom;
- Y represents a bond, a carbonyl group or a methylene group optionally substituted by one or two groups chosen from a C 1 - 6 alkyl group, a hydroxyl group, a Ci -6 alkoxy group, a Ci -2 perhalogenated alkyl group or an amino group;
- R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted by a Ci -6 alkyl group, a Ci -6 alkoxy group or a halogen atom;
- R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted by 1 to 4 substituents selected from a Ci -6 alkyl group, a methylendioxy group, a halogen atom, a Ci -2 perhalogenated alkyl group, a C 1 - 3 halogenated alkyl group, a hydroxyl group, a Ci -6 al
- a medicament comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivatives represented by formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof.
- the aforementioned medicament which is used for preventive and/or therapeutic treatment of diseases caused by abnormal GSK3 ⁇ activity
- the aforementioned medicament which is used for preventive and/or therapeutic treatment of neurodegenerative diseases and in addition other diseases such as: Non-insulin dependent diabetes (such as diabetes type Il ) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non- small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus- induced tumors.
- the aforementioned medicament wherein the diseases are neurodegenerative diseases and are selected from the group consisting of Alzheimer's disease, Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma, and the aforementioned medicament in the form of pharmaceutical composition containing the above substance as an active ingredient together with one or more pharmaceutical additives.
- Alzheimer's disease Parkinson's disease
- tauopathies e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy
- other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retin
- the present invention further provides an inhibitor of GSK3 ⁇ activity comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivatives of formula (I) and the salts thereof, and the solvates thereof and the hydrates thereof.
- a method for preventive and/or therapeutic treatment of neurodegenerative diseases caused by abnormal GSK3 ⁇ activity which comprises the step of administering to a patient a preventively and/or therapeutically effective amount of a substance selected from the group consisting of pyrimidone derivatives of formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof; and a use of a substance selected from the group consisting of the pyrimidone derivatives of formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof for the manufacture of the aforementioned medicament.
- the Ci -6 alkyl group represents a straight or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n- propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- butyl group, n-pentyl group, isopentyl group, neopentyl group, 1 ,1-dimethylpropyl group, n-hexyl group, isohexyl group, and the like;
- the Ci -6 alkoxy group represents an alkyloxy group having 1 to 4 carbon atoms for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like;
- the halogen atom represents a fluorine, chlorine, bromine or iodine atom;
- the Ci- 2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen have been subsituted by a halogeno, for example a CF 3 or C2F 5 ;
- the Ci- 3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been subsituted by an halogen atom;
- the Ci- 6 monoalkylamino group represents an amino group substituted by one Ci -6 alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, isopentylamino group and the like;
- the C 2 - 12 dialkylamino group represents an amino group substituted by two Ci -6 alkyl groups, for example, dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group and diisopropylamino group and the like;
- a leaving group L represents a group which could be easily cleaved and substituted, such a group may be for example a tosyl, a mesyl, a bromide and the like.
- the compounds represented by the aforementioned formula (I) may form a salt.
- the salt include, when an acidic group exists, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N, N- bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N- methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, ⁇ -hydroxylysine, and arginine.
- the base-addition salts of acidic compounds are prepared by standard procedures well known in the art.
- examples include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, and salicylic acid; or salts with acidic amino acids such as aspartic acid, and glutamic acid.
- mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
- organic acids such as methanesulfonic acid, benzenesulfonic acid, p- toluen
- the acid-addition salts of the basic compounds are prepared by standard procedures well know in the art which include, but are not limited thereto, dissolving the free base in an aqueous alcohol solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and an acid in an organic solvent, in which case the salt separates directly, or is precipitated with a second organic solvent, or can be obtained by concentration of the solution.
- the acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not compromised by side effects ascribable to the anions.
- pharmaceutically-acceptable salts that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not compromised by side effects ascribable to the anions.
- the pyrimidone derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may independently be in either (R) and (S) configuration, and the derivative may exist as stereoisomers such as optical isomers, or diastereoisomers. Any stereoisomers in pure form, any mixtures of stereoisomers, racemates and the like fall within the scope of the present invention.
- An object of the present invention includes also compounds represented by formula (I) wherein X, m, n, o, p and q are as defined above and:
- R1 represents a 3- or 4-pyridine ring alternatively a 4- or 5-pyrimidine ring; the ring being optionally substituted by a Ci -2 alkyl group, a Ci -2 alkoxy group or a halogen atom; and/or
- R2 represents a benzene ring or a naphthalene ring; the ring being optionally substituted 1 to 4 substituents selected from a Ci -3 alkyl group, a halogen atom, a hydroxyl group or a Ci -2 alkoxy group; and/or
- R3 represents a hydrogen atom, a Ci -3 alkyl group or a halogen atom; and/or (4) R4 represents a hydrogen atom, a Ci_ 4 alkoxy carbonyl group or a Ci -3 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group or a Ci- 2 alkoxy group; and/or
- Y represents a bond, a carbonyl group or a methylene group optionally substituted by one or two groups chosen from a Ci -3 alkyl group, a hydroxyl group or a Ci -2 alkoxy group; and more particularly wherein R1 , R2, R3, R4 and Y are as defined here-above.
- Another object of the present invention includes compounds represented by formula (I) wherein n, p and q are as defined above and: (1) R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring; more particularly an unsubstituted 4-pyridine ring; and/or
- R2 represents a benzene ring; the ring being optionally substituted 1 to 4 substituents selected from a Ci -3 alkyl group, a halogen atom, a hydroxyl group or a C 1 . 4 alkoxy group; and/or (3) R3 represents a hydrogen atom; and/or
- R4 represents a hydrogen atom, a Ci -4 alkoxy carbonyl group or a Ci. 3 alkyl group;
- X represents two hydrogen atoms
- Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group
- m represents 2 and o represents 2; and more particularly compounds wherein R1 , R2, R3, R4, X, Y, p, m, o and q are as defined here-above.
- a further object of the present invention includes the group of compound of formula as defined hereunder:
- the present invention concerns also methods for preparing the pyrimidone compounds represented by the aforementioned formula (I).
- Pyrimidone compounds represented by the aforementioned formula (I) may be prepared according to the method described in the scheme 1.
- the pyrimidone derivative represented by the above formula (III), wherein R1 , R3, R4, m, o, p and q are as defined for compound of formula (I), is allowed to react with a base such as sodium hydride, sodium carbonate or potassium carbonate in a solvent such as N, N- dimethylformamide, ⁇ /-methylpyrrolidone, ⁇ /, ⁇ /-dimethylacetamide or chloroform at a suitable temperature ranging from 0 to 130 0 C under ordinary air, then with a compound of formula (II), wherein R2, X, Y and n are as defined for compound of formula (I) and L represents a leaving group preferably bromide or mesyl group, to obtain the compound of the aforementioned formula (I).
- a base such as sodium hydride, sodium carbonate or potassium carbonate
- a solvent such as N, N- dimethylformamide, ⁇ /-methylpyrrolidone, ⁇ /, ⁇ /-dimethylacetamide
- Compound of formula (III) may be prepared according to the method defined in scheme 2.
- the reaction may be carried out in the presence of a base such as potassium carbonate, in an alcoholic solvent such as methanol, ethanol and the like or without, at a suitable temperature ranging from 25° to 140 0 C under ordinary air.
- compound of formula (III), wherein R4 represents a hydrogen atom is allowed to react with a base such, sodium carbonate or triethylamine in a mixture of solvent such as tetrahydrofuran and water, then with a compound R4L of formula (Vl).
- R4 is as defined for compound of formula (I), beside the hydrogen atom, and L represents a leaving group preferably chloride, mesyl group or bromide, to give another compound of formula (III), wherein R4 is not a hydrogen atom.
- compound of formula (III) wherein R3 represents a hydrogen atom may be halogenated in order to give compounds of formula (III) wherein R3 is a halogen atom such as a bromine atom or a chlorine atom.
- the reaction may be carried out in an acidic medium such as acetic acid or propionic acid, in presence of bromosuccinimide or chlorosuccimide, or bromine.
- the present invention concerns also the compounds of formula (III) as intermediates of compounds of formula (I).
- compounds of formula (IV), wherein R1 represent a pyridine ring or a pyrimidine ring, optionally substituted by a Ci -6 alkyl group, C 1-6 alkoxy group or a halogen atom can be prepared by reacting respectively an isonicotinic acid or a pyrimidine-carboxylic acid, optionally substituted by a Ci -6 alkyl group, Ci- 6 alkoxy group or a halogen, with the corresponding malonic acid monoester.
- reaction can be carried out using methods well known to one skilled in the art, such as for example in presence of a coupling agent such as 1 , 1 '-carbonylbis-1 H- imidazole in a solvent such as tetrahydrofuran at a temperature ranging from 20 to 70 0 C.
- a coupling agent such as 1 , 1 '-carbonylbis-1 H- imidazole
- a solvent such as tetrahydrofuran
- Compound of formula (V) may be synthesized according to well-known methods of one skilled in the art.
- compound of formula (V) where p, q, m, o and R4 are as defined for compound of formula (I), may be prepared according to the method defined in scheme 3, starting from compound of formula (VIII).
- the conditions which may be used are given in the chemical examples.
- Compound of formula (VII) may be synthesized by analogy to the method described in J.Org.Chem. 1977, 42, 221-225.
- Compound of formula (VIII) may be synthesized according to the method described in J. Med. Chem. 1978, 21, 623-628.
- a suitable protecting group Pg can be chosen depending on the type of the functional group, and a method described in the literature may be applied. Examples of protecting groups, of protection and deprotection methods are given for example in Protective groups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York) 1985.
- the compounds of the present invention have inhibitory activity against GSK3 ⁇ . Accordingly, the compounds of the present invention are useful as an active ingredient for the preparation of a medicament, which enables preventive and/or therapeutic treatment of a disease caused by abnormal GSK3 ⁇ activity and more particularly of neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient for the preparation of a medicament for preventive and/or therapeutic treatment of neurodegenerative diseases such as Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g.
- Parkinson's disease tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g.
- age related macular degeneration brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma; and other diseases such as non-insulin dependent diabetes (such as diabetes type Il ) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non- small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus- induced tumors.
- diseases such as non-insulin dependent diabetes (such as diabetes type Il ) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non- small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus- induced tumors.
- the present invention further relates to a method for treating neurodegenerative diseases caused by abnormal activity of GSK3 ⁇ and of the aforementioned diseases which comprises administering to a mammalian organism in need thereof an effective amount of a compound of the formula (I).
- a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically acceptable salts thereof, and solvates thereof and hydrates thereof.
- the substance, per se, may be administered as the medicament of the present invention, however, it is desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more pharmaceutical additives.
- a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more pharmaceutical additives.
- two or more of the aforementioned substances may be used in combination.
- the above pharmaceutical composition may be supplemented with an active ingredient of another medicament for the treatment of the above mentioned diseases.
- the type of pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration.
- the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like.
- Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline. Sustained-release preparations such as those coated with a polymer may be directly administered intracerebrally.
- Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content ratios of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen by those skilled in the art.
- Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives.
- the pharmaceutical additives may be incorporated in a ratio ranging from 1% by weight to 90% by weight based on the weight of an active ingredient.
- excipients used for the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like.
- a conventional inert diluent such as water or a vegetable oil may be used.
- the liquid composition may contain, in addition to the inert diluent, auxiliaries such as moistening agents, suspension aids, sweeteners, aromatics, colorants, and preservatives.
- the liquid composition may be filled in capsules made of an absorbable material such as gelatin. Examples of solvents or suspension mediums used for the preparation of compositions for parenteral administration, e.g.
- injections, suppositories include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.
- base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol.
- the dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease, the body weight or age of a patient, severity of a disease and the like.
- a daily dose for oral administration to an adult may be 0.01 to 1 ,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days.
- administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.
- the suspension was hydrogenated under 40psi pressure at 50 0 C temperature during 8h.
- the catalyst was removed by filtration and the solvent evaporated under reduced pressure.
- Isopropanol was added and the resulting solution was refiltered and the solvent removed by evaporation under reduced pressure to give 4.0g (55%) of compound as a white powder which was used as such.
- Example 3 (Compound No. 2 of table 1) (+/-)Ethyl 4-[6-oxo-1-(2-oxo-2-phenylethyl)-8-(4-pyridinyl)-1 ,3 ,4,6-tetrahydro-2H- pyrimido[1 ,2-a]pyrimidin-2-yl]-1 -piperidinecarboxylate.
- Example 4 (Compound No. 4 of table 1) (+/-)8-(1-Methyl-4-piperidinyl)-9-(2-oxo-2-phenylethyl)-2-(4-pyridinyl)-6,7,8,9- tetrahydro-4H-pyrimido[1 ,2-a]pyrimidin-4-one. Hydrochloride (2:1).
- 0.45g (1.45 mmol) of (+/-)8-(4-piperidinyl)-2-(4-pyridinyl)-6,7,8,9- tetrahydro-4/7-pyrimido[1 ,2-a]pyrimidin-4-one 0.452g (14.45 mmol) of paraformaldehyde in 10 ml of acetic acid was added 0.364g (6.99 mmol) of sodium cyanoborohydride.
- step 1.4 and using (+/-)8-(1-Methyl-4-piperidinyl)-2-(4-pyridinyl)-6,7,8,9- tetrahydro-4/-/-pyrimido[1 ,2-a]pyrimidin-4-one.
- Test Example Inhibitory activity of the medicament of the present invention against GSK3 ⁇ :
- a first protocol 7.5 ⁇ M of prephosphorylated GS 1 peptide and 10 ⁇ M ATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mM Tris-HCI, pH 7.5, 0.6 mM DTT, 6 mM MgCI 2 , 0.6 mM EGTA, 0.05 mg/ml BSA buffer for 1 hour at room temperature in the presence of GSK3beta (total reaction volume : 100 microliters).
- the reaction was stopped with 100 microliters of a solution made of 25 g polyphosphoric acid (85% P 2 O 5 ), 126 ml 85% H 3 PO 4 , H 2 O to 500 ml and then diluted to 1 : 100 before use. An aliquot of the reaction mixture was then transferred to Whatman P81 cation exchange filters and rinsed with the solution described above. Incorporated 33P radioactivity was determined by liquid scintillation spectrometry.
- the phosphorylated GS-1 peptide had the following sequence : NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.(Woodgett, J. R. (1989)
- the GSK3 ⁇ inhibitory activity of the compounds of the present invention are expressed in IC 5 O, and as an illustration the range of IC 50 1 S of the compounds in table 1 is between 10 nanomolar to 1 micromolar concentrations.
- compound No. 3 of table 1 shows an IC 5 o ⁇ f 0.012 ⁇ M.
- the compounds of the present invention have GSK3 ⁇ inhibitory activity and are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by abnormal activity of GSK3 ⁇ and more particularly of neurodegenerative diseases.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Obesity (AREA)
- Psychology (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Hospice & Palliative Care (AREA)
- Emergency Medicine (AREA)
- Oncology (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Child & Adolescent Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009535149A JP2010509203A (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a] pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimid [1,2-a] pyrimidin-6-one derivatives |
NZ576773A NZ576773A (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a]pyrimidin-6-one derivatives |
CA002668682A CA2668682A1 (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a]pyrimidin-6-one derivatives |
BRPI0718519-7A BRPI0718519A2 (en) | 2006-11-07 | 2007-11-06 | 8-PIPERIDINYL-2-PRIDINYL-PYRIMED- [1,2-A] PYRIDIMIN-6-ONA SUBSTITUTED AND DERIVATIVES OF 8-PIPERIDINYL-2-PYRIMIDINYL-PYRIMED-6-ONA |
AU2007318927A AU2007318927A1 (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido [1,2-a]pyrimidin-6-one derivatives |
MX2009004884A MX2009004884A (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[ 1,2-a]pyrimidin-6-one derivatives. |
EA200970455A EA016251B1 (en) | 2006-11-07 | 2007-11-06 | 8-PIPERIDINYL-2-PYRIDINYL-PYRIMIDO [1,2-a] PIRIMIDIN-4-ONE DERIVATIVES |
EP07859310A EP2081938A2 (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido ý1,2-a¨pirimidin-6-one and 8-piperidinyl-2-pyrimidi nyl-pyrimidoý1,2,-a¨pyrimidin-6-one derivatives |
IL198239A IL198239A0 (en) | 2006-11-07 | 2009-04-20 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a] pyrimidin -6- one and 8-piperidinyl-2- pyrimidinyl [1,2-a] pyrimidin -6- one derivatives |
US12/434,053 US20090281121A1 (en) | 2006-11-07 | 2009-05-01 | SUBSTITUTED 8-PIPERIDINYL-2-PYRIDINYL-PYRIMIDO[1,2-a] PYRIMIDIN-6-ONE AND 8-PIPERIDINYL-2-PYRIMIDINYL-PYRIMIDO[1,2-a] PYRIMIDIN-6-ONE DERIVATIVES |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06291725A EP1921080B1 (en) | 2006-11-07 | 2006-11-07 | Subsitituted 8-piperidinyl-2-pyridinyl-pyrimido(1,2-a)pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido(1,2-a)pyrimidin-6-one derivatives |
EP06291725.7 | 2006-11-07 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/434,053 Continuation US20090281121A1 (en) | 2006-11-07 | 2009-05-01 | SUBSTITUTED 8-PIPERIDINYL-2-PYRIDINYL-PYRIMIDO[1,2-a] PYRIMIDIN-6-ONE AND 8-PIPERIDINYL-2-PYRIMIDINYL-PYRIMIDO[1,2-a] PYRIMIDIN-6-ONE DERIVATIVES |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2008056266A2 true WO2008056266A2 (en) | 2008-05-15 |
WO2008056266A3 WO2008056266A3 (en) | 2008-07-10 |
WO2008056266A8 WO2008056266A8 (en) | 2009-06-18 |
Family
ID=38331403
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2007/004272 WO2008056266A2 (en) | 2006-11-07 | 2007-11-06 | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a]pyrimidin-6-one derivatives |
Country Status (16)
Country | Link |
---|---|
US (1) | US20090281121A1 (en) |
EP (2) | EP1921080B1 (en) |
JP (1) | JP2010509203A (en) |
KR (1) | KR20090091123A (en) |
CN (1) | CN101535314A (en) |
AR (1) | AR063577A1 (en) |
AU (1) | AU2007318927A1 (en) |
BR (1) | BRPI0718519A2 (en) |
CA (1) | CA2668682A1 (en) |
EA (1) | EA016251B1 (en) |
IL (1) | IL198239A0 (en) |
MX (1) | MX2009004884A (en) |
NZ (1) | NZ576773A (en) |
TW (1) | TW200835495A (en) |
WO (1) | WO2008056266A2 (en) |
ZA (1) | ZA200902630B (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
WO2011157827A1 (en) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
WO2011161030A1 (en) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators |
WO2012004270A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament |
WO2012004269A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals |
WO2012010413A1 (en) | 2010-07-05 | 2012-01-26 | Sanofi | Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2992316A1 (en) * | 2012-06-22 | 2013-12-27 | Sanofi Sa | PYRIMIDINONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005000800A1 (en) * | 2003-06-30 | 2005-01-06 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
EP1557417A1 (en) * | 2003-12-19 | 2005-07-27 | Sanofi-Aventis | Substituted 8'-pyri(mi)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2a] pyrimidin-6-one derivatives |
-
2006
- 2006-11-07 EP EP06291725A patent/EP1921080B1/en not_active Expired - Fee Related
-
2007
- 2007-11-06 NZ NZ576773A patent/NZ576773A/en not_active IP Right Cessation
- 2007-11-06 CN CNA200780041338XA patent/CN101535314A/en active Pending
- 2007-11-06 WO PCT/IB2007/004272 patent/WO2008056266A2/en active Application Filing
- 2007-11-06 CA CA002668682A patent/CA2668682A1/en not_active Abandoned
- 2007-11-06 KR KR1020097009377A patent/KR20090091123A/en not_active Application Discontinuation
- 2007-11-06 ZA ZA200902630A patent/ZA200902630B/en unknown
- 2007-11-06 MX MX2009004884A patent/MX2009004884A/en active IP Right Grant
- 2007-11-06 JP JP2009535149A patent/JP2010509203A/en not_active Withdrawn
- 2007-11-06 EA EA200970455A patent/EA016251B1/en not_active IP Right Cessation
- 2007-11-06 TW TW096141872A patent/TW200835495A/en unknown
- 2007-11-06 AU AU2007318927A patent/AU2007318927A1/en not_active Abandoned
- 2007-11-06 AR ARP070104932A patent/AR063577A1/en unknown
- 2007-11-06 BR BRPI0718519-7A patent/BRPI0718519A2/en not_active IP Right Cessation
- 2007-11-06 EP EP07859310A patent/EP2081938A2/en not_active Withdrawn
-
2009
- 2009-04-20 IL IL198239A patent/IL198239A0/en unknown
- 2009-05-01 US US12/434,053 patent/US20090281121A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005000800A1 (en) * | 2003-06-30 | 2005-01-06 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
EP1557417A1 (en) * | 2003-12-19 | 2005-07-27 | Sanofi-Aventis | Substituted 8'-pyri(mi)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2a] pyrimidin-6-one derivatives |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
WO2011157827A1 (en) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
WO2011161030A1 (en) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators |
WO2012004270A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament |
WO2012004269A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals |
WO2012010413A1 (en) | 2010-07-05 | 2012-01-26 | Sanofi | Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
Also Published As
Publication number | Publication date |
---|---|
MX2009004884A (en) | 2009-05-21 |
NZ576773A (en) | 2011-09-30 |
EA016251B1 (en) | 2012-03-30 |
EP2081938A2 (en) | 2009-07-29 |
IL198239A0 (en) | 2009-12-24 |
WO2008056266A8 (en) | 2009-06-18 |
TW200835495A (en) | 2008-09-01 |
CN101535314A (en) | 2009-09-16 |
KR20090091123A (en) | 2009-08-26 |
EP1921080B1 (en) | 2009-08-05 |
JP2010509203A (en) | 2010-03-25 |
BRPI0718519A2 (en) | 2014-04-15 |
ZA200902630B (en) | 2010-06-30 |
WO2008056266A3 (en) | 2008-07-10 |
AU2007318927A1 (en) | 2008-05-15 |
CA2668682A1 (en) | 2008-05-15 |
US20090281121A1 (en) | 2009-11-12 |
AR063577A1 (en) | 2009-02-04 |
EP1921080A1 (en) | 2008-05-14 |
EA200970455A1 (en) | 2009-12-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9073915B2 (en) | Substituted pyrimidone derivatives | |
EP1957492B1 (en) | Substituted bicyclic pyrimidone derivatives | |
US8592580B2 (en) | Substituted triazinone derivatives | |
US8507470B2 (en) | Substituted arylamide oxazepinopyrimidone derivatives | |
US9073914B2 (en) | Substituted alkyl pyrimidin-4-one derivatives | |
US20090281121A1 (en) | SUBSTITUTED 8-PIPERIDINYL-2-PYRIDINYL-PYRIMIDO[1,2-a] PYRIMIDIN-6-ONE AND 8-PIPERIDINYL-2-PYRIMIDINYL-PYRIMIDO[1,2-a] PYRIMIDIN-6-ONE DERIVATIVES | |
US8211903B2 (en) | Substituted pyrimido isoquinoline derivatives | |
US8507475B2 (en) | Substituted heteroarylamide diazepinopyrimidone derivatives | |
US8598187B2 (en) | Arylamide pyrimidone compounds | |
EP2148866B1 (en) | Arylamide pyrimidone derivatives for the treatment of neurodegenerative diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200780041338.X Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1402/KOLNP/2009 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 198239 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2009535149 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2668682 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 576773 Country of ref document: NZ Ref document number: 2007318927 Country of ref document: AU Ref document number: 1020097009377 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2009/004884 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007859310 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2007318927 Country of ref document: AU Date of ref document: 20071106 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200970455 Country of ref document: EA |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07859310 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: PI0718519 Country of ref document: BR Kind code of ref document: A2 Effective date: 20090506 |