US20110294786A1 - Substituted bicyclic pyrimidone derivatives - Google Patents

Substituted bicyclic pyrimidone derivatives Download PDF

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US20110294786A1
US20110294786A1 US13/197,228 US201113197228A US2011294786A1 US 20110294786 A1 US20110294786 A1 US 20110294786A1 US 201113197228 A US201113197228 A US 201113197228A US 2011294786 A1 US2011294786 A1 US 2011294786A1
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Prior art keywords
pyrimidin
oxo
benzamide
tetrahydro
pyrido
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US13/197,228
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Nathalie CHEREZE
Alistair Lochead
Mourad Saady
Franck Slowinski
Philippe Yaiche
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Sanofi SA
Mitsubishi Tanabe Pharma Corp
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Sanofi Aventis France
Mitsubishi Tanabe Pharma Corp
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Assigned to SANOFI-AVENTIS, MITSUBISHI TANABE PHARMA CORPORATION reassignment SANOFI-AVENTIS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEREZE, NATHALIE, LOCHEAD, ALISTAIR, SAADY, MOURAD, SLOWINSKI, FRANCK, YAICHE, PHILIPPE
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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, September 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, taupathies (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.
  • 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 stabilizer 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 GSK31.
  • inhibitors of GSK3 ⁇ could be used to mimic the mood stabilizing 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 leukemia and several virus-induced tumors.
  • cancers such as colorectal, prostate, breast, non-small lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.
  • 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 antagonizes 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 stabilization 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.
  • GSK3 ⁇ inhibitors may also be used for treating disorders of reduced bone mass, bone-related pathologies, osteoporosis.
  • 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).
  • GSK3beta inhibitors might be used in the treatment or prevention Pemphigus vulgaris.
  • GSK3beta inhibitor treatment improved 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:
  • Y represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2 alkyl group and a hydrogen atom
  • Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C 1-3 alkyl group, a sulfur atom, a methylene group optionally substituted by one or two groups chosen from a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-2 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 C 1-6 alkyl group, a C 1-6 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 C 1-6 alkyl group,
  • 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 II) and obesity; malaria, bipolar disorders (manic depressive illness); schizophrenia; alopecia or cancers such as colorectal, prostate, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, several virus-induced tumors and bone related pathologies.
  • the medicament could also find an application in regenerative medicine.
  • the aforementioned medicament wherein the diseases are neurodegenerative diseases and are selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies (e.g. Fronto temporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, Prion disease 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; 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
  • taupathies e.g. Fronto temporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy
  • Wilson's disease Huntington's disease
  • Huntington's disease Prion disease and other dementia including
  • the aforementioned medicament wherein the bones related pathologies are osteoporosis.
  • 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 C 1-6 alkyl group represents a straight or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group (Me or CH 3 ), 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 C 1-6 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 C 1-2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen atoms have been substituted by a halogen, for example a CF 3 or C 2 F 5 ;
  • the C 1-3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been substituted by a halogen atom;
  • the C 1-6 monoalkylamino group represents an amino group substituted by one C 1-6 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 C 1-6 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; salts with organic acids such as acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid and the like.
  • mineral acids such as hydrochloric acid, hydrobromic acid
  • organic acids such as acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid and the like.
  • 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 m, n, o 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 C 1-2 alkyl group, a C 1-2 alkoxy group or a halogen atom; and/or (2) R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, C 3-5 cycloalkyl group, a C 3-5 cycloalkyl-C 1-4 alkyl group, a halogen atom, a C 1-2 perhalogenated alkyl group, a hydroxyl group, a C 1-3 alkoxy group optionally substituted by a C 3-5 cycloalkyl group, a C 1-2 perhalogenated alkoxy group, a C 1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C 1-3 monoalky
  • Another object of the present invention includes compounds represented by formula (I) wherein m, n and o are as defined above and:
  • a further object of the present invention includes the group of compounds of table 1 of formula as defined hereunder:
  • a further object of the present invention includes the group of compounds of table 2 of formula as defined hereunder:
  • a further object of the present invention includes the group of compounds of table 3 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, R5, R6, R7, m and o are as defined for compound of formula (I), is allowed to react with a base such as triethylamine, sodium carbonate or potassium carbonate in a solvent such as tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylacetamide or chloroform at a suitable temperature ranging from 0 to 130° C.
  • a base such as triethylamine, sodium carbonate or potassium carbonate
  • a solvent such as tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylacetamide or chloroform
  • compounds of formula (I) wherein Y represents two hydrogen atoms may be prepared by reductive amination of a compound of formula (II) wherein Y represents an oxygen atom and L represents a hydrogen atom, by a compound of formula (III) wherein R1, R3, R4, R5, R6, m and o are as defined for compound of formula (I) and R7 is a hydrogen, according to well known methods to one skilled in the art.
  • 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° C. under ordinary air.
  • 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 chlorosuccinimide, 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 C 1-6 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 C 1-6 alkyl group, C 1-6 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-1H-imidazole in a solvent such as tetrahydrofuran at a temperature ranging from 20 to 70° C.
  • a coupling agent such as 1,1′-carbonylbis-1H-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) wherein m, o, R4, R5 and R6 are as defined for compound of formula (I) and a suitable protecting group Pg such as for example a phthalimido group, may be prepared according to the method defined in scheme 3, starting from compound of formula (VI).
  • a suitable protecting group Pg such as for example a phthalimido group
  • Compound of formula (VI) may be synthesized by analogy to the method described in Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20. Liebigs Annalen der Chemie (1987), (7), 647-8. Archiv der Pharmazie (Weinheim, Germany) (1989), 322(8), 499-505.
  • 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., 3rd Ed. (John Wiley & Sons, Inc., New York) 1999.
  • 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, taupathies (e.g.
  • Fronto temporal dementia corticobasal degeneration, Pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, Prion disease 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, peripheral neuropathies; retinopathies and glaucoma; and other diseases such as non-insulin dependent diabetes (such as diabetes type II) and obesity; malaria, manic depressive illness; schizophrenia; alopecia; cancers such as colorectal, prostate breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, several virus-induced tumors and in bone related pathologies.
  • the medicament could also find an application in regenerative medicine
  • 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 reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 90/10/1.
  • the residue was triturated with diethyl ether and filtered to afford 0.088 g (84%) of the pure product as a brown powder.
  • step 1.3 By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate, the compound was obtained as a white powder.
  • step 1.4 By analogy with the method described in example 1 (step 1.4), using (+/ ⁇ )2-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione in place of (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using (+/ ⁇ )9-amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • step 1.1 By analogy with the method described in example 1 (step 1.1), using 2-(2-Oxo-pyrrolidin-3-yl)-isoindole-1,3-dione (prepared by analogy to the method described in (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a white powder.
  • step 1.2 By analogy with the method described in example 1 (step 1.2), using 2-(2-methoxy-4,5-dihydro-3H-pyrrol-3-yl)isoindole-1,3-dione in place of 2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a white powder.
  • step 1.3 By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
  • step 1.4 using 2-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-isoindole-1,3-dione in place of (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using 8-Amino-2-pyrimidin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • step 1.1 By analogy with the method described in example 1 (step 1.1), using ⁇ -amino- ⁇ -caprolactam monohydrochloride (commercially available) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a yellow oil.
  • step 1.2 By analogy with the method described in example 1 (step 1.2), using 2-(7-methoxy-3,4,5,6-tetrahydro-2H-azepin-6-yl)-1H-isoindole-1,3(2H)-dione in place of 2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a white powder.
  • step 1.4 By analogy with the method described in example 1 (step 1.4), using (+/ ⁇ )2-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-1H-isoindole-1,3(2H)-dione in place of (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using (+/ ⁇ )10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • step 1.1 By analogy with the method described in example 1 (step 1.1), using 2-(3-methyl-2-oxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione (prepared by analogy to the method described in Liebigs Annalen der Chemie (1987), (7), 647-8. Archiv der Pharmazie (Weinheim, Germany) (1989), 322(8), 499-505, (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a yellow oil.
  • step 1.2 By analogy with the method described in example 1 (step 1.2), using 2-(2-methoxy-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione in place of 2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a white powder.
  • step 1.3 By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1) the compound was obtained as a white powder.
  • step 1.4 By analogy with the method described in example 1 (step 1.4), using (+/ ⁇ )2-(1-methyl-5-oxo-7-pyrimidin-4-yl-1,2,3,4,4a,5-hexahydronaphthalen-1-yl)-1H-isoindole-1,3(2H)-dione in place of (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using (+/ ⁇ )5-amino-5-methyl-3-pyrimidin-4-yl-6,7,8,8a-tetrahydronaphthalen-1(5H)-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • step 1.3 By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyridinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
  • step 1.4 using 2-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-isoindole-1,3-dione in place of (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using 8-Amino-2-pyridin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • step 1.3 By analogy with the method described in example 1 (step 1.3), using ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1), the compound was obtained as a white powder.
  • step 1.4 By analogy with the method described in example 1 (step 1.4), using (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-1H-isoindole-1,3(2H)-dione in place of (+/ ⁇ )2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using (+/ ⁇ )10-amino-2-pyridin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • (+/ ⁇ )4-fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide was separated by chiral preparative HPLC (Daicel CHIRALCEL OD-H 20 ⁇ m 50 ⁇ 220 mm) eluting with ethanol to give 0.162 g of pure product obtained in the form of free base.
  • (+/ ⁇ )4-fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide was separated by chiral preparative HPLC (Daicel CHIRALCEL OD-H 20 ⁇ m 50 ⁇ 220 mm) eluting with ethanol to give 0.174 g of pure product obtained in the form of free base.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using ( ⁇ )10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • step 1.5 By analogy with the method described in example 1 (step 1.5), using (+)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/ ⁇ )9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • a first protocol 7.5 ⁇ M of prephosphorylated GS1 peptide and 10 ⁇ M ATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mM Tris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl 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 used in the example was the same one as reported in Woodgett, J. R. (1989) Analytical Biochemistry 180, 237-241 and had the same sequence as reported therein, which reference is incorporated herein by reference in its entirety.
  • the GSK3 ⁇ inhibitory activity of the compounds of the present invention are expressed in IC 50 , and as an illustration the range of IC 50 's of the compounds in table 1 and table 2 are between 0.1 nanomolar to 3 micromolar concentrations.
  • compound No. 33 of table 1 shows an IC 50 of 0.005 ⁇ 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.

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Abstract

A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure US20110294786A1-20111201-C00001
Wherein Y, Z, R1, R2, R3, R4, R5, R6, R7, n, m, and o are as described herein. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer disease.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 12/122,111 filed May 16, 2008 which is a continuation of International application No. PCT/IB2006/004,046, filed Nov. 21, 2006, which is incorporated herein by reference in its entirety; which claims the benefit of priority of European Patent Application No. 05292457.8, filed Nov. 21, 2005.
    • BACKGROUND OF THE INVENTION
  • 1. Field of the Invention
  • 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 GSK3β.
  • 2. Background Art
  • GSK3β (glycogen synthase kinase 3β) 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 GSK3β 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.
  • Interestingly, protein kinase B (AKT) phosphorylation of GSK3β 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. Moreover, phosphorylation by GSK3β of β-catenin, a protein involved in cell survival, results in its degradation by an ubiquitinilation dependent proteasome pathway.
  • Thus, it appears that inhibition of GSK3β activity may result in neurotrophic activity. Indeed there is evidence that lithium, an uncompetitive inhibitor of GSK3β, 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.
  • Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, this hyperphosphorylation as well as the neurotoxic effects of β-amyloid are blocked by lithium chloride and by a GSK3β antisense mRNA. These observations strongly suggest that GSK3β may be the link between the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation.
  • Although tau hyperphosphorylation results in a destabilization of the neuronal cytoskeleton, the pathological consequences of abnormal GSK3β 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. Moreover, it has been shown that β-amyloid-induced increase in GSK3β activity results in the phosphorylation and, hence the inhibition of pyruvate dehydrogenase, a pivotal enzyme in energy production and acetylcholine synthesis.
  • Altogether these experimental observations indicate that GSK3β 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 GSK3β is deregulated (Nature reviews Vol. 3, June 2004, p. 479-487; Trends in Pharmacological Sciences Vol. 25 No. 9, September 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, taupathies (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. 301-309, 2005) peripheral neuropathies; retinopathies and glaucoma. Recent studies have also shown that inhibition of GSK3β results in neuronal differentiation of embryonic stem cells (ESC) and supports the renewal of human and mouse ESCs and the maintenance of their pluripotency. This suggests that inhibitors of GSK3β could have applications in regenerative medicine (Nature Medicine 10, p. 55-63, 2004).
  • Inhibitors of GSK3β may also find application in the treatment of other nervous system disorders, such as bipolar disorders (manic-depressive illness). For example lithium has been used for more than 50 years as a mood stabilizer 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 GSK31. Although the mechanism of action of lithium is unclear, inhibitors of GSK3β could be used to mimic the mood stabilizing effects of lithium. Alterations in Akt-GSK3β signaling have also been implicated in the pathogenesis of schizophrenia.
  • In addition, inhibition of GSK3β could be useful in treating cancers, such as colorectal, prostate, breast, non-small lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors. For example, the active form of GSK3β has been shown to be elevated in the tumors of colorectal cancer patients and inhibition of GSK3β in colorectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth. Inhibition of GSK3β also enhances TRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also plays a role in the dynamics of the mitototic spindle and inhibitors of GSK3β prevent chromosome movement and lead to a stabilization of microtubules and a prometaphase-like arrest that is similar to that observed with low doses of Taxol. Other possible applications for GSK3β inhibitors include therapy for non-insulin dependent diabetes (such as diabetes type II), obesity and alopecia.
  • Recently, both human genetics and animal studies have pointed out the role of Wnt/LPR5 pathway as a major regulator of bone mass accrual. Inhibition of GSK3β leads to the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, GSK3β inhibitors may also be used for treating disorders of reduced bone mass, bone-related pathologies, osteoporosis.
  • Inhibitors of human GSK3β 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).
  • According to recent data, GSK3beta inhibitors might be used in the treatment or prevention Pemphigus vulgaris.
  • According to recent studies, show that GSK3beta inhibitor treatment improved neutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitors will be useful for the treatment of neutropenia induced by cancer chemotherapy.
    • SUMMARY OF THE INVENTION
  • 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 GSK3β 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.
  • Thus, the inventors of the present invention have identified compounds possessing inhibitory activity against GSK3β. 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:
  • Figure US20110294786A1-20111201-C00002
  • wherein:
    Y represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C1-2 alkyl group and a hydrogen atom;
    Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C1-3 alkyl group, a sulfur atom, a methylene group optionally substituted by one or two groups chosen from a C1-6 alkyl group, a hydroxyl group, a C1-6 alkoxy group, a C1-2 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 C1-6 alkyl group, a C1-6 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 C1-6 alkyl group, C3-7 cycloalkyl group, a C3-7 cycloalkyl-C1-6 alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a hydroxyl group, a C1-6 alkoxy group optionally substituted by a C3-5 cycloalkyl group, a C1-2 perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-6 monoalkylamino group or a C2-12 dialkylamino group, an acetoxy group or an aminosulfonyl group;
    R3 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
    R4 represents a hydrogen atom or a C1-6 alkyl group;
    R5 represents a hydrogen atom, a C1-6 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-6alkoxy group;
    R6 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
    R7 represents a hydrogen atom or a C1-6 alkyl group; and
    n represents 0 to 3; m represents 0 to 1; o represents 0 to 2.
  • According to another aspect of the present invention, there is provided 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. As preferred embodiments of the medicament, there are provided the aforementioned medicament which is used for preventive and/or therapeutic treatment of diseases caused by abnormal GSK3β activity, and 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 II) and obesity; malaria, bipolar disorders (manic depressive illness); schizophrenia; alopecia or cancers such as colorectal, prostate, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, several virus-induced tumors and bone related pathologies. The medicament could also find an application in regenerative medicine.
    • DETAILED DESCRIPTION OF THE INVENTION
  • As further embodiments of the present invention, there are provided the aforementioned medicament wherein the diseases are neurodegenerative diseases and are selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies (e.g. Fronto temporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, Prion disease 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; 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.
  • As further embodiments of the present invention, there are provided the aforementioned medicament wherein the bones related pathologies are osteoporosis.
  • The present invention further provides an inhibitor of GSK3β 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.
  • According to further aspects of the present invention, there is provided a method for preventive and/or therapeutic treatment of neurodegenerative diseases caused by abnormal GSK3β 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.
  • As used herein, the C1-6 alkyl group represents a straight or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group (Me or CH3), 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 C1-6 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 C1-2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen atoms have been substituted by a halogen, for example a CF3 or C2F5;
  • The C1-3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been substituted by a halogen atom;
  • The C1-6 monoalkylamino group represents an amino group substituted by one C1-6 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 C2-12 dialkylamino group represents an amino group substituted by two C1-6 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. Examples of 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, δ-hydroxylysine and arginine. The base-addition salts of acidic compounds are prepared by standard procedures well known in the art.
  • When a basic group exists, examples include salts with mineral acids such as hydrochloric acid, hydrobromic acid; salts with organic acids such as acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid and the like.
  • 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. Although medicinally acceptable salts of the basic compounds are preferred, all acid-addition salts are within the scope of the present invention.
  • In addition to the pyrimidone derivatives represented by the aforementioned formula (I) and salts thereof, their solvates and hydrates also fall within the scope of the present invention.
  • 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.
  • Examples of compounds of the present invention are shown in table 1 hereinafter. However, the scope of the present invention is not limited by these compounds.
  • An object of the present invention includes also compounds represented by formula (I) wherein m, n, o are as defined above and:
  • (1) R1 represents a 3- or 4-pyridine ring alternatively a 4- or 5-pyrimidine ring; the ring being optionally substituted by a C1-2 alkyl group, a C1-2 alkoxy group or a halogen atom; and/or
    (2) R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, C3-5 cycloalkyl group, a C3-5 cycloalkyl-C1-4 alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a hydroxyl group, a C1-3 alkoxy group optionally substituted by a C3-5 cycloalkyl group, a C1-2 perhalogenated alkoxy group, a C1-6alkylsulfonyl group, a nitro, a cyano, an amino, a C1-3 monoalkylamino group or a C2-6 dialkylamino group; and/or
    (3) R3 represents a hydrogen atom, a C1-3 alkyl group or a halogen atom;
    (4) R4 represents a hydrogen atom or a C1-3 alkyl group; and/or
    (5) R5 represents a hydrogen atom, a C1-3 alkoxy carbonyl group or a C1-3 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-3 alkoxy group; and/or
    (6) R6 represents a hydrogen atom, a C1-3 alkyl group or a halogen atom; and/or
    (7) R7 represents a hydrogen atom or a C1-3 alkyl group; and/or
    (8) Y represents two hydrogen atoms, an oxygen atom or a C1-2 alkyl group and a hydrogen atom; and/or
    (9) Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C1-3 alkyl group, a methylene group optionally substituted by one or two groups chosen from a C1-3 alkyl group, a hydroxyl group, a C1-3 alkoxy group, a C1-2 perhalogenated alkyl group or an amino group; and/or
    (10) n represents 0 to 3;
    (11) m represents 0 to 1; o represents 1 to 2; and more particularly wherein R1, R2, R3, R4, R5, R6, R7, m, n, o, Y and Z are as defined here-above.
  • Another object of the present invention includes compounds represented by formula (I) wherein m, n and o are as defined above and:
      • (1) R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring; and/or
      • (2) R2 represents a benzene ring or a naphthalene; the ring being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a C1-2 perhalogenated alkyl group, a C3-4 cycloalkyl group, a C3-4 cycloalkyl-C1-3 alkyl group, a halogen atom, a hydroxyl group, a nitro, a cyano, an amino, a C1-3 alkoxy group optionally substituted by a C3-4 cycloalkyl group, a C1-2 perhalogenated alkoxy group or a C1-3alkylsulfonyl group; and/or
      • (3) R3 represents a hydrogen atom or a halogen atom; and/or
      • (4) R4 represents a hydrogen atom; and/or
      • (5) R5 represents a hydrogen atom; and/or
      • (6) R6 represents a hydrogen atom, a C1-6 alkyl group;
      • (7) R7 represents a hydrogen atom; and/or
      • (8) Y represents two hydrogen atoms, or an oxygen atom; and/or
      • (9) Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom; and/or
      • (10) n represents 0 to 1; and/or
      • (11) m represents 0 to 1 and o represents 1 to 2; and more particularly wherein R1, R2, R3, R4, R5, R6, R7, m, n, o, Y and Z are as defined here-above.
  • A further object of the present invention includes the group of compounds of table 1 of formula as defined hereunder:
    • 1. (+/−)N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 2. (+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 3. (+/−)N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-phenylacetamide
    • 4. (+/−)Phenyl(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)carbamate
    • 5. (+/−)N-(4-Fluorophenyl)-N′-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)urea
    • 6. (+/−)N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-N′-phenylurea
    • 7. (+/−)9-[(2-Methoxybenzyl)amino]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
    • 8. (+/−)3-Fluoro-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 9. (+/−)4-Isopropoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 10. (+/−)2-Chloro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 11. (+/−)4-Fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 12. (+/−)3-Cyano-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 13. (+/−)2-Chloro-5-fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 14. (+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 15. (+/−)4-Fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethyl)benzamide
    • 16. (+/−)4-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-3-(trifluoromethyl)benzamide
    • 17. (+/−)N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethyl)benzamide
    • 18. (+/−)2-Chloro-4-fluoro-5-nitro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 19. (+/−)N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-naphthamide
    • 20. (+/−)3-Chloro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 21. (+/−)2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 22. (+/−)3-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 23. (+/−)2-Fluoro-6-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 24. (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 25. (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 26. (+/−)2-Ethoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 27. (+/−)N-(3-Bromo-4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-methoxybenzamide
    • 28. (+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 29. (+/−)N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethoxy)benzamide
    • 30. (+/−)2-Isopropoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 31. (+/−)2-(Cyclopropylmethoxy)-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 32. (+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 33. (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 34. (+/−)2-(Cyclopropylmethoxy)-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 35. (+/−)N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-naphthamide
    • 36. (+/−)3-Chloro-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 37. (+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 38. (+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 39. (+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-trifluoromethyl-benzamide
    • 40. (+/−)5-(Ethylsulfonyl)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 41. (+/−)2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 42. (−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 43. (+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 44. (+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 45. (+/−)2-{[(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)amino]carbonyl}phenyl acetate
    • 46. (+/−)2-Hydroxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 47. (+/−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 48. (+)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 49. (−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 50. (+/−)4-Chloro-2-methoxy-N-methyl-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 51. (+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 52. (−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
    • 53. (+/−)5-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 54. (+/−)4-Fluoro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 55. (+/−)4-Amino-5-chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 56. (+/−)2-Methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-trifluoromethyl-benzamide
    • 57. (+/−)2-Fluoro-6-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 58. (+/−)2-Methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 59. (+/−)5-Bromo-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 60. (+/−)-4-Dimethylamino-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
    • 61. (+/−)-2,4-Dimethoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide
  • A further object of the present invention includes the group of compounds of table 2 of formula as defined hereunder:
    • 1. (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide
    • 2. (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide
    • 3. (+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide
    • 4. (+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide
    • 5. (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide.
    • 6. (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)benzamide.
  • A further object of the present invention includes the group of compounds of table 3 of formula as defined hereunder:
    • 1. (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 2. (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 3. (+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 4. (+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 5. (+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 6. (+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 7. (+/−)5-(Aminosulfonyl)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 8. (+/−)2-Hydroxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 9. (+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 10. (+/−)2,4-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 11. (+/−)2-{[(4-Oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)amino]carbonyl}phenyl acetate
    • 12. (+/−)2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 13. (+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-5-(trifluoromethoxy)benzamide
    • 14. (+/−)2,5-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 15. (+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 16. (−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 17. (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 18. (+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 19. (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 20. (+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 21. (+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 22. (+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 23. (+/−)2-{[(4-Oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)amino]carbonyl}phenyl acetate
    • 24. (+/−)2,4-Dimethoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 25. (+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
    • 26. (−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • As a further object, the present invention concerns also methods for preparing the pyrimidone compounds represented by the aforementioned formula (I).
  • These compounds can be prepared, for example, according to methods explained below.
    • Preparation Method
  • Pyrimidone compounds represented by the aforementioned formula (I), may be prepared according to the method described in the scheme 1.
  • Figure US20110294786A1-20111201-C00003
  • (In the above scheme the definition of R1, R2, R3, R4, R5, R6, R7, m, n, o, Y and Z are the same as those already described for compound of formula (I)).
  • Following this method, the pyrimidone derivative represented by the above formula (III), wherein R1, R3, R4, R5, R6, R7, m and o are as defined for compound of formula (I), is allowed to react with a base such as triethylamine, sodium carbonate or potassium carbonate in a solvent such as tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylacetamide or chloroform at a suitable temperature ranging from 0 to 130° C. under ordinary air, then with a compound of formula (II), wherein R2, Z, Y and n are as defined for compound of formula (I) and L represents a leaving group preferably chlorine, bromide or mesyl group, to obtain the compound of the aforementioned formula (I).
  • Alternatively compounds of formula (I) wherein Y represents two hydrogen atoms may be prepared by reductive amination of a compound of formula (II) wherein Y represents an oxygen atom and L represents a hydrogen atom, by a compound of formula (III) wherein R1, R3, R4, R5, R6, m and o are as defined for compound of formula (I) and R7 is a hydrogen, according to well known methods to one skilled in the art.
  • Compound of formula (II) is commercially available or may be synthesized according to well-known methods to one skilled in the art.
  • Compound of formula (III) may be prepared according to the method defined in scheme 2.
  • Figure US20110294786A1-20111201-C00004
  • (In the above scheme the definition of R1, R2, R3, R4, R5, R6, m and o are the same as already described.)
  • According to this method, the 3-ketoester of formula (IV), wherein R1 and R3 are as defined for compound of formula (I), R is an alkyl group such as for example methyl or ethyl, is allowed to react with a compound of formula (V) wherein R4, R5, R6, m and o are as defined for compound of formula (I) and Pg is a suitable protecting group such as for example a phthalimido group. 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° C. under ordinary air.
  • Additionally 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 chlorosuccinimide, or bromine.
  • In addition, compounds of formula (IV) wherein R3 represents a fluorine atom may be obtained by analogy to the method described in Tetrahedron Letters, Vol. 30, No. 45, pp 6113-6116, 1989.
  • In addition, compounds of formula (IV) wherein R3 represents a hydrogen atom may be obtained by analogy to the method described in patent DE 2705582.
  • As a further object, the present invention concerns also the compounds of formula (III) as intermediates of compounds of formula (I).
  • Compound of formula (IV) is commercially available or may be synthesized according to well-known methods to one skilled in the art.
  • For example compounds of formula (IV), wherein R1 represent a pyridine ring or a pyrimidine ring, optionally substituted by a C1-6 alkyl group, C1-6 alkoxy group or a halogen atom, can be prepared by reacting respectively an isonicotinic acid or a pyrimidine-carboxylic acid, optionally substituted by a C1-6 alkyl group, C1-6 alkoxy group or a halogen, with the corresponding malonic acid monoester. The 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-1H-imidazole in a solvent such as tetrahydrofuran at a temperature ranging from 20 to 70° C.
  • Compound of formula (V) may be synthesized according to well-known methods of one skilled in the art.
  • For example compound of formula (V), wherein m, o, R4, R5 and R6 are as defined for compound of formula (I) and a suitable protecting group Pg such as for example a phthalimido group, may be prepared according to the method defined in scheme 3, starting from compound of formula (VI). The conditions which may be used are given in the chemical examples.
  • Figure US20110294786A1-20111201-C00005
  • Compound of formula (VI) may be synthesized by analogy to the method described in Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20. Liebigs Annalen der Chemie (1987), (7), 647-8. Archiv der Pharmazie (Weinheim, Germany) (1989), 322(8), 499-505.
  • Compound of formula (VII) and formula (V) may be synthesized according to the method described in WO96/14844.
  • In the above reactions protection or deprotection of a functional group may sometimes be necessary. 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., 3rd Ed. (John Wiley & Sons, Inc., New York) 1999.
  • The compounds of the present invention have inhibitory activity against GSK3β. 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 GSK3β 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, taupathies (e.g. Fronto temporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, Prion disease 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, peripheral neuropathies; retinopathies and glaucoma; and other diseases such as non-insulin dependent diabetes (such as diabetes type II) and obesity; malaria, manic depressive illness; schizophrenia; alopecia; cancers such as colorectal, prostate breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, several virus-induced tumors and in bone related pathologies. The medicament could also find an application in regenerative medicine
  • The present invention further relates to a method for treating neurodegenerative diseases caused by abnormal activity of GSK3β 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).
  • As the active ingredient of the medicament of the present invention, 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. As the active ingredient of the medicament of the present invention, 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. For example, 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. Generally, 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.
  • Examples of excipients used for the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For the preparation of liquid compositions for oral administration, 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. Examples of 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. Generally, 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. When the medicament is used as an injection, 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.
    • CHEMICAL EXAMPLES Example 1 Compound No. 2 of Table 1 (+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide 1.1 (+/−)-2-(2-Methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione
  • To a solution of 13.474 g (91.1 mmol) of trimethyloxonium tetrafluoroborate in 294 mL of anhydrous dichloromethane was added 22.25 g (91.1 mmol) of (+/−)-3-phtalimidopiperidin-2-one (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20) and the resulting mixture was stirred at room temperature for 12 h. The mixture was hydrolyzed with a saturated aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, dried over sodium sulfate and the solvent was evaporated to afford 23.22 g (99%) of pure product as a yellow oil. The compound was used as such in the next step.
  • 1H NMR (CDCl3; 200 MHz)
  • δ (ppm): 7.92-7.66 (m, 4H); 4.87-4.69 (m, 1H); 3.74-3.60 (m, 2H); 3.56 (s, 3H); 2.40-1.62 (m, 4H).
    • 1.2 (+/−)2-(2-Amino-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1).
  • To a solution of 23.224 g (89.92 mmol) of (+/−)-2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione dissolved in 409 mL of methanol was added at room temperature 4.81 g (89.92 mmol) of ammonium chloride. The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The residue was triturated with diethyl ether and filtered to afford 23.8 g (95%) of the pure product as a white powder.
  • Mp: 242-244° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.92 (br s, 2H); 8.02-7.85 (m, 4H); 5.28 (t, 1H); 3.58-3.12 (m, 2H); 2.15-1.78 (m, 4H).
    • 1.3 (+/−)2-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione
  • To a suspension of 9.166 g (32.77 mmol) of (+/−)2-(2-Amino-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1) in 50 mL of toluene was added sodium methanolate (freshly prepared from 0.754 g (32.77 mmol) of sodium in 10 mL of methanol and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, dissolved in 50 mL of toluene and 4.87 g (25.21 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate was added. The resulting solution was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/3/0.3 led to afford 3.2 g (34%) of the desired compound as a white powder.
  • Mp: 211-213° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.50 (d, 2H); 8.09-7.78 (m, 4H); 7.60 (d, 2H); 7.08 (s, 1H); 5.60-5.39 (m, 1H); 4.28-4.06 (m, 1H); 3.88-3.65 (m, 1H); 2.55-2.08 (m, 4H).
    • 1.4 (+/−)9-Amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
  • To a solution of 3.2 g (8.59 mmol) of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione dissolved in 24 mL of ethanol was added 2.09 mL (43 mmol) of hydrazine hydrate and the resulting mixture was stirred under reflux for 2 hours. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness. The resulting residue was purified on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 98/2 to 96/4 to give 1.37 g (66%) of the desired compound as a brown powder.
  • Mp: 144-146° C.
  • 1H NMR (CDCl3; 200 MHz)
  • δ (ppm): 8.77 (d, 2H); 7.85 (d, 2H); 6.89 (s, 1H); 4.26-3.91 (m, 3H); 2.48-1.61 (m, 6H).
    • 1.5 (+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • To a solution of 0.080 g (0.33 mmol) of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 2.2 mL of tetrahydrofuran was added 60 μl (0.40 mmol) of triethylamine and 50 μl (0.40 mmol) of 2-methoxy-benzoyl chloride. The resulting mixture was stirred at room temperature for 1 h.
  • Water was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of ammonium chloride, dried and evaporated. The residue was triturated with diethyl ether and filtered to afford 0.105 g (84%) of the pure product as a yellow powder.
  • Mp: 155-157° C.
  • 1H NMR (CDCl3; 200 MHz)
  • δ (ppm): 9.26 (br s, 1H); 8.76 (d, 2H); 8.30 (d, 1H); 7.88 (d, 2H); 7.52 (t, 1H); 7.22-7.03 (m, 2H); 6.92 (s, 1H); 5.26-5.08 (m, 1H); 4.55 (dt, 1H); 3.93 (s, 3H); 3.92-3.71 (m, 1H); 3.08-2.85 (m, 1H); 2.38-1.94 (m, 2H); 1.78-1.53 (m, 1H).
    • Example 2 Compound No. 7 of Table 1 (+/−)9-[(2-Methoxybenzyl)amino]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (2:1)
  • To a solution of 0.080 g (0.33 mmol) of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one in 2 ml of toluene was added 0.045 g (0.33 mmol) of 2-methoxybenzaldehyde and the resulting solution was refluxed for 3 h in a Dean-Stark apparatus.
  • The resulting mixture was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 2 mL of methanol, pH was adjusted to 6 with acetic acid and 0.042 g (0.66 mmol) of sodium cyanoborohydride was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, the residue was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The base was transformed into its hydrochloride salt to give 0.081 g of pure product.
  • Mp: 230-232° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.76 (br s, 1H); 8.90 (d, 2H); 8.50 (d, 2H); 7.60-7.29 (m, 2H); 7.38 (s, 1H); 7.13-6.88 (m, 2H); 4.70-4.49 (m, 1H); 4.36 (dd, 2H); 4.06-3.65 (m, 2H); 3.72 (s, 3H); 2.70-1.87 (m, 4H).
    • Example 3 Compound No. 6 of Table 1 (+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-N′-phenylurea
  • To a solution of 0.07 g (0.29 mmol) of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 1 mL of dichloromethane at 10° C. was added 0.034 g (0.29 mmol) of phenylisocyanate dissolved in 1 mL at 10° C. The resulting mixture was stirred at 10° C. for 30 min. The mixture was stirred at room temperature for 1 h.
  • The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 90/10/1. The residue was triturated with diethyl ether and filtered to afford 0.088 g (84%) of the pure product as a brown powder.
  • Mp: 254-256° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.90 (br s, 1H); 8.61 (d, 2H); 8.03 (d, 2H); 7.43 (d, 2H); 7.27 (t, 2H); 7.11 (s, 1H); 6.92 (t, 1H); 6.72 (br s, 1H); 4.95-4.78 (m, 1H); 4.17-3.73 (m, 2H); 2.39-2.18 (m, 1H); 2.13-1.60 (m, 3H).
    • Example 4 Compound No. 4 of Table 1 (+/−)Phenyl(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)carbamate
  • To a solution of 0.07 g (0.29 mmol) of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 4 mL of tetrahydrofuran at 0° C. was added 29.2 μl (0.29 mmol) of triethylamine and 50 μl (0.32 mmol) of phenylchloroformate. The resulting mixture was stirred at 0° C. for 45 min and warmed at room temperature for 16 h.
  • A saturated aqueous solution of ammonium chloride was added and the reaction mixture extracted with ethyl acetate. The extracts were dried and evaporated. The residue was triturated with diethyl ether and filtered to afford 0.068 g (65%) of the pure product as a white powder.
  • Mp: 193-195° C.
  • 1H NMR (CDCl3; 200 MHz)
  • δ (ppm): 8.72 (d, 2H); 8.22 (br s, 1H); 8.04 (d, 2H); 7.50-7.35 (m, 2H); 7.30-7.08 (m, 3H); 7.12 (s, 1H); 4.89-4.70 (m, 1H); 3.92 (t, 2H); 2.35-1.80 (m, 4H).
    • Example 5 Compound No. 14 of Table 1 (+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide 5.1 (+/−)2-(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione
  • By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate, the compound was obtained as a white powder.
  • Mp.: 279.9-280.9° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.21 (s, 1H); 8.75 (d, 1H); 8.01-7.81 (m, 4H); 7.52 (d, 1H); 7.19 (s, 1H); 5.58-5.40 (m, 1H); 4.26-4.09 (m, 1H); 3.89-3.68 (m, 1H); 2.48-2.02 (m, 4H).
    • 5.2 (+/−)9-Amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
  • By analogy with the method described in example 1 (step 1.4), using (+/−)2-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione in place of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • Mp.: 111-113° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.29 (s, 1H); 8.99 (d, 1H); 8.43 (d, 1H); 7.18 (s, 1H); 4.02-3.75 (m, 3H); 2.25 (br s; 2H); 2.23-1.75 (m, 3H); 1.74-1.48 (m, 1H).
    • 5.3 (+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using (+/−)9-amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp: 249-251° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.30 (s, 1H); 9.02 (d, 1H); 8.96 (br s, 1H); 8.18 (d, 1H); 7.83 (d, 1H); 7.58-7.43 (m, 1H); 7.28-7.14 (m, 2H); 7.07 (t, 1H); 5.26-5.08 (m, 1H); 4.11-3.75 (m, 2H); 3.88 (s, 3H); 2.26-2.44 (m, 1H); 2.18-1.69 (m, 3H).
    • Example 6 Compound No. 42 of Table 1 (−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • 196 mg (0.476 mmol) of (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide (compound No. 29 of table 1) was separated by chiral preparative HPLC (CHIRALCEL OD-I 20 μm 350×80 mm) eluting with a mixture of methanol/dichloromethane/diisopropylethylamine/heptane to give 95 mg of pure product obtained in the form of free base.
  • Mp: 174-176° C. [α]D 20=−46.9° (c=0.387, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.40 (s, 1H); 9.15 (d, 1H); 9.05 (d, 1H); 8.25 (d, 1H); 7.90 (d, 1H); 7.35 (s, 1H); 7.3 (s, 1H); 7.15 (d, 1H); 5.20 (m, 1H); 4.11-3.85 (m, 2H); 3.35 (s, 3H); 2.44-1.80 (m, 4H).
    • Example 7 Compound No. 43 of Table 1 (+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • 196 mg (0.476 mmol) of (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide (compound No. 29 of table 1) was separated by chiral preparative HPLC (CHIRALCEL OD-I 20 μm 350×80 mm) eluting with a mixture of methanol/dichloromethane/diisopropylethylamine/heptane to give 100 mg of pure product obtained in the form of free base.
  • Mp: 175-177° C. [α]D 20=+42.5° (c=0.287, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.40 (s, 1H); 9.15 (d, 1H); 9.05 (d, 1H); 8.25 (d, 1H); 7.90 (d, 1H); 7.35 (s, 1H); 7.3 (s, 1H); 7.15 (d, 1H); 5.20 (m, 1H); 4.11-3.85 (m, 2H); 3.35 (s, 3H); 2.44-1.80 (m, 4H).
    • Example 8 Compound No. 1 of Table 2 (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide 8.1 2-(2-Methoxy-4,5-dihydro-3H-pyrrol-3-yl)isoindole-1,3-dione
  • By analogy with the method described in example 1 (step 1.1), using 2-(2-Oxo-pyrrolidin-3-yl)-isoindole-1,3-dione (prepared by analogy to the method described in (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a white powder.
  • Mp.: 139-141° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 7.95-7.70 (m, 4H); 5.20 (dd, 1H); 3.90-3.50 (m, 5H); 2.50-2.10 (m, 2H).
    • 8.2 2-(2-Amino-4,5-dihydro-3H-pyrrol-3-yl)isoindole-1,3-dione hydrochloride (1:1)
  • By analogy with the method described in example 1 (step 1.2), using 2-(2-methoxy-4,5-dihydro-3H-pyrrol-3-yl)isoindole-1,3-dione in place of 2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a white powder.
  • Mp.: 121-123° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.25-8.80 (br s, 3H); 7.95-7.70 (m, 4H); 5.65 (dd, 1H); 3.90-3.50 (m, 2H); 2.50-2.20 (m, 2H).
    • 8.3 2-(4-Oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-isoindole-1,3-dione
  • By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
  • Mp.: 180-182° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.25 (s, 1H); 8.85 (d, 1H); 8.01-7.80 (m, 5H); 7.25 (s, 1H); 5.90 (dd, 1H); 4.40-3.90 (m, 2H); 2.80-2.60 (m, 2H).
    • 8.4 8-Amino-2-pyrimidin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one
  • By analogy with the method described in example 1 (step 1.4), using 2-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-isoindole-1,3-dione in place of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • Mp.: 187-189° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.40 (s, 1H); 9.10 (d, 1H); 8.40 (d, 1H); 7.30 (s, 1H); 4.30 (dd, 1H); 4.20-3.70 (m, 2H); 2.00-1.70 (m, 2H).
    • 8.5 (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide
  • By analogy with the method described in example 1 (step 1.5), using 8-Amino-2-pyrimidin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp: 237-239° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.35 (s, 1H); 9.02 (d, 1H); 8.96 (br d, 1H); 8.20 (d, 1H); 7.80 (d, 1H); 7.35-7.20 (m, 2H); 7.15 (dd, 1H); 5.55 (dd, 1H); 4.20-3.80 (m, 5H); 2.60-2.20 (m, 2H).
    • Example 9 Compound No. 2 of Table 3 (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide 9.1 2-(7-Methoxy-3,4,5,6-tetrahydro-2H-azepin-6-yl)-1H-isoindole-1,3(2H)-dione
  • By analogy with the method described in example 1 (step 1.1), using α-amino-ε-caprolactam monohydrochloride (commercially available) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a yellow oil.
  • 1H NMR (CDCl3; 200 MHz)
  • δ (ppm): 7.92-7.66 (m, 4H); 5.10 (d, 1H); 3.90-3.70 (m, 1H); 3.50 (s, 3H); 3.40-3.30 (m, 1H); 2.70-2.50 (m, 1H); 2.1 (m, 1H); 1.90-1.20 (m, 4H).
    • 9.2 2-(2-Iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1)
  • By analogy with the method described in example 1 (step 1.2), using 2-(7-methoxy-3,4,5,6-tetrahydro-2H-azepin-6-yl)-1H-isoindole-1,3(2H)-dione in place of 2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a white powder.
  • Mp.: 120-122° C.
  • 1H NMR (CDCl3; 200 MHz)
  • δ (ppm): 9.40 (br s, 1H); 8.70 (br s, 1H); 8.20-7.60 (m, 4H); 5.28 (br t, 1H); 3.90-3.40 (m, 3H); 2.30-1.30 (m, 5H).
    • 9.3 (+/−)2-(4-Oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-1H-isoindole-1,3(2H)-dione
  • By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1), the compound was obtained as a white powder.
  • Mp.: 250-252° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.30 (s, 1H); 8.60 (d, 1H); 8.00 (m, 3H); 7.40 (m, 1H); 7.20 (m, 2H); 4.70 (d, 2H); 3.50 (m, 2H); 2.00-1.50 (m, 4H); 1.3 (m, 1H).
    • 9.4 (+/−)10-Amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one
  • By analogy with the method described in example 1 (step 1.4), using (+/−)2-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-1H-isoindole-1,3(2H)-dione in place of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • Mp.: 157-159° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.30 (s, 1H); 9.00 (d, 1H); 8.40 (d, 1H); 7.20 (s, 1H); 5.00-4.80 (m, 1H); 4.25 (d, 1H); 3.80-3.60 (dd, 1H); 2.00-1.20 (m, 6H).
    • 9.5 (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using (+/−)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp: 324-326° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.32 (m, 2H); 9.05 (d, 2H); 8.25 (d, 1H); 8.00 (t, 1H); 7.30 (s, 1H); 7.15 (d, 1H); 6.90 (dd, 1H); 5.40 (d, 1H); 5.00 (dd, 1H); 4.00 (s, 3H); 2.20-1.80 (m, 5H); 1.30 (m, 1H).
    • Example 10 Compound No. 15 of Table 3 (+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • 143 mg (0.35 mmol) of (+/−)4-fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide (compound No 2, table 3) was separated by chiral preparative HPLC (CHIRALCEL OD-CSP 50×250) eluting with ethanol to give to give 0.033 g of pure product obtained in the form of free base. tR: 9.0 min.
  • Mp: 241.7° C. [α]D 20=+4.6° (c=0.167, DMSO).
  • δ (ppm): 9.32 (m, 2H); 9.05 (d, 2H); 8.25 (d, 1H); 8.00 (t, 1H); 7.30 (s, 1H); 7.15 (d, 1H); 6.90 (dd, 1H); 5.40 (d, 1H); 5.00 (dd, 1H); 4.00 (s, 3H); 2.20-1.80 (m, 5H); 1.30 (m, 1H).
    • Example 11 Compound No. 16 of Table 3 (−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • 143 mg (0.35 mmol) of (+/−)4-fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide (compound No 2, table 3) was separated by chiral preparative HPLC (CHIRALCEL OD-CSP 50×250) eluting with ethanol to give 0.035 g of pure product obtained in the form of free base. tR: 7.1 min.
  • Mp: 232.7-233.2° C. [α]D 20=−5.3° (c=0.135, DMSO).
  • δ (ppm): 9.32 (m, 2H); 9.05 (d, 2H); 8.25 (d, 1H); 8.00 (t, 1H); 7.30 (s, 1H); 7.15 (d, 1H); 6.90 (dd, 1H); 5.40 (d, 1H); 5.00 (dd, 1H); 4.00 (s, 3H); 2.20-1.80 (m, 5H); 1.30 (m, 1H).
    • Example 12 Compound No. 47 of Table 1 (+/−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide 12.1 2-(2-Methoxy-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione
  • By analogy with the method described in example 1 (step 1.1), using 2-(3-methyl-2-oxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione (prepared by analogy to the method described in Liebigs Annalen der Chemie (1987), (7), 647-8. Archiv der Pharmazie (Weinheim, Germany) (1989), 322(8), 499-505, (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a yellow oil.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 7.80 (m, 4H); 3.40 (m, 4H); 2.30-2.10 (m, 1H); 1.90-1.70 (m, 5H); 1.65-1.40 (m, 2H).
    • 12.2 2-(2-Amino-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1)
  • By analogy with the method described in example 1 (step 1.2), using 2-(2-methoxy-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione in place of 2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a white powder.
  • Mp.: 165-167° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 7.70-7.10 (m, 4H); 3.20-3.00 (m, 2H); 2.40-2.20 (m, 1H); 1.80-1.60 (m, 3H); 1.20 (s, 3H).
    • 12.3 (+/−)2-(1-Methyl-5-oxo-7-pyrimidin-4-yl-1,2,3,4,4a,5-hexahydronaphthalen-1-yl)-1H-isoindole-1,3(2H)-dione
  • By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1) the compound was obtained as a white powder.
  • Mp.: 184-186° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.25 (s, 1H); 8.80 (d, 1H); 8.00 (d, 2H); 7.80 (m, 4H); 7.20 (s, 1H); 4.30-4.10 (dt, 1H); 3.80-3.60 (m, 1H); 2.50 (m, 1H); 2.15 (s, 3H); 2.10-1.80 (m, 2H).
    • 12.4 (+/−)5-Amino-5-methyl-3-pyrimidin-4-yl-6,7,8,8a-tetrahydronaphthalen-1(5H)-one
  • By analogy with the method described in example 1 (step 1.4), using (+/−)2-(1-methyl-5-oxo-7-pyrimidin-4-yl-1,2,3,4,4a,5-hexahydronaphthalen-1-yl)-1H-isoindole-1,3(2H)-dione in place of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • Mp.: 138-140° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.25 (s, 1H); 9.00 (d, 1H); 8.40 (d, 2H); 7.15 (s, 1H); 4.00-3.70 (m, 2H); 2.30 (br s, 2H); 2.10-1.70 (m, 3H); 1.45 (s, 3H).
    • 12.5 (+/−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using (+/−)5-amino-5-methyl-3-pyrimidin-4-yl-6,7,8,8a-tetrahydronaphthalen-1(5H)-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp: 192-194° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.30 (s, 1H); 9.00 (d, 1H); 8.80 (br s, 1H); 8.20 (d, 1H); 7.50 (d, 1H); 7.20 (d, 1H); 7.15 (s, 1H); 7.05 (dd, 1H); 4.40-4.20 (br d, 1H); 3.90 (s, 3H); 3.70-3.50 (m, 1H); 2.50 (m, 1H); 2.20-1.90 (m, 3H); 1.70 (s, 3H).
    • Example 13 Compound No. 48 of Table 1 (+)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • 480 mg (1.13 mmol) of (+/−)4-chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide (compound No. 47 of table 1) was separated by chiral preparative HPLC (CHIRALCEL OD-CSP 20 μm 250×50 mm) eluting with a mixture of isopropanol/heptane to give 181 mg of pure product obtained in the form of free base.
  • Mp: 181.7° C. [α]D 20=+132.4° (c=0.2618, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.30 (s, 1H); 9.00 (d, 1H); 8.80 (br s, 1H); 8.20 (d, 1H); 7.50 (d, 1H); 7.20 (d, 1H); 7.15 (s, 1H); 7.05 (dd, 1H); 4.40-4.20 (br d, 1H); 3.90 (s, 3H); 3.70-3.50 (m, 1H); 2.50 (m, 1H); 2.20-1.90 (m, 3H); 1.70 (s, 3H).
    • Example 14 Compound No. 49 of Table 1 (−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • 480 mg (1.13 mmol) of (+/−)4-chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide (compound No. 47 of table 1) was separated by chiral preparative HPLC (CHIRALCEL OD-CSP 20 μm 250×50 mm) eluting with a mixture of isopropanol/heptane to give 202 mg of pure product obtained in the form of free base.
  • Mp: 182.7° C. [α]D 20=−126.1° (c=0.4055, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.30 (s, 1H); 9.00 (d, 1H); 8.80 (br s, 1H); 8.20 (d, 1H); 7.50 (d, 1H); 7.20 (d, 1H); 7.15 (s, 1H); 7.05 (dd, 1H); 4.40-4.20 (br d, 1H); 3.90 (s, 3H); 3.70-3.50 (m, 1H); 2.50 (m, 1H); 2.20-1.90 (m, 3H); 1.70 (s, 3H).
    • Example 15 Compound No. 5 of Table 2 (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide 15.1 (+/−)2-(4-Oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-isoindole-1,3-dione
  • By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyridinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
  • Mp.: 224-226° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.60 (d, 2H); 8.00-7.70 (m, 6H); 7.05 (s, 1H); 5.90 (t, 1H); 4.40-4.20 (m, 1H); 3.80-4.10 (m, 1H); 2.70-2.40 (m, 2H).
    • 15.2 (+/−)8-Amino-2-pyridin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one
  • By analogy with the method described in example 1 (step 1.4), using 2-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-isoindole-1,3-dione in place of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • Mp.: 187-189° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.70 (d, 2H); 8.00 (d, 2H); 7.00 (s, 1H); 4.40-4.20 (m, 1H); 3.90-4.10 (m, 1H); 3.90-3.60 (m, 1H); 2.60-2.30 (m, 1H); 1.70-2.00 (m, 1H).
    • 15.3 (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using 8-Amino-2-pyridin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp: 303-305° C.
  • RMN 1H (DMSO-d6; 200 MHz)
  • δ (ppm): 8.90 (d, 1H); 8.70 (d, 2H); 8.00 (d, 2H); 7.80 (d, 1H); 7.25 (s, 1H); 7.15-6.90 (m, 2H); 5.50 (m, 1H); 4.20 (m, 1H); 3.95-3.70 (m, 4H); 2.60 (m, 1H); 2.20 (m, 1H).
    • Example 16 Compound No. 19 of table 3) (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide 16.1 (+/−)2-(4-Oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-1H-isoindole-1,3(2H)-dione
  • By analogy with the method described in example 1 (step 1.3), using ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1), the compound was obtained as a white powder.
  • Mp.: 250-252° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.40 (d, 2H); 8.00-7.80 (m, 4H); 7.50 (d, 2H); 7.08 (s, 1H); 5.65 (brd, 1H); 5.10 (brd, 1H); 3.75 (m, 1H); 2.80-2.3 (m, 1H); 2.10-1.70 (m, 4H); 1.4 (m, 1H).
    • 16.2 (+/−)10-Amino-2-pyridin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one
  • By analogy with the method described in example 1 (step 1.4), using (+/−)2-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-1H-isoindole-1,3(2H)-dione in place of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.
  • Mp.: 181-183° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 8.70 (d, 2H); 8.10 (d, 2H); 7.50 (d, 2H); 7.10 (s, 1H); 4.90 (brd, 1H); 4.25 (d, 1H); 3.75 (ddd, 1H); 2.00-1.70 (m, 2H); 1.60-1.20 (m, 4H).
    • 16.3 (+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using (+/−)10-amino-2-pyridin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp: 218-220° C.
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.40 (d, 1H); 8.80 (d, 2H); 8.00 (m, 3H); 7.20-6.85 (m, 3H); 5.40 (m, 1H); 5.00 (m, 1H); 3.95 (s, 3H); 3.65 (m, 1H); 2.25-1.15 (m, 6H).
    • Example 17 Compound No. 51 of Table 1 (+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • 0.556 g (1.42 mmol) of (+/−)4-fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide was separated by chiral preparative HPLC (Daicel CHIRALCEL OD-H 20 μm 50×220 mm) eluting with ethanol to give 0.162 g of pure product obtained in the form of free base.
  • Mp: >240° C. (dec.). [α]D 20=+54.7° (c=0.321, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.40 (s, 1H); 9.05 (d, 1H); 8.90 (d, 1H); 8.20 (d, 1H); 7.90 (dd, 1H); 7.25 (s, 1H); 7.10 (dd, 1H); 6.90 (ddd, 1H); 5.15 (m, 1H); 4.00 (m, 2H); 3.90 (s, 3H); 2.30 (m, 1H); 2.10 (m, 2H); 1.80 (m, 1H).
    • Example 18 Compound No. 52 of Table 1 (−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide
  • 0.556 g (1.42 mmol) of (+/−)4-fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide was separated by chiral preparative HPLC (Daicel CHIRALCEL OD-H 20 μm 50×220 mm) eluting with ethanol to give 0.174 g of pure product obtained in the form of free base.
  • Mp: >240° C. (dec.). [α]D 20=−53.9° (c=0.231, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.40 (s, 1H); 9.05 (d, 1H); 8.90 (d, 1H); 8.20 (d, 1H); 7.90 (dd, 1H);
  • 7.25 (s, 1H); 7.10 (dd, 1H); 6.90 (ddd, 1H); 5.15 (m, 1H); 4.00 (m, 2H); 3.90 (s, 3H); 2.30 (m, 1H); 2.10 (m, 2H); 1.80 (m, 1H).
    • Example 19 Compound No. 25 of Table 3 (+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide 19.1 (−)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one
  • 20 g (77.73 mmol) of 9.4 (+/−)10-Amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one (compound 9.4 of example 9) was separated by chiral preparative HPLC (Daicel CHIRALPACK AD 20 μm 50×220 mm) eluting with ethanol to give 9.05 g of pure product obtained in the form of free base.
  • Mp.: 117.8° C. [α]D 20=−59.76° (c=0.619, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.3 (s, 1H); 9.0 (d, 1H); 8.4 (d, 1H); 7.2 (s, 1H); 5.0-4.8 (m, 1H); 4.25 (d, 1H); 3.8-3.6 (dd, 1H); 2.0-1.2 (m, 6H).
    • 19.2 (+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using (−)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp.: 210-212° C. [α]D 20=+8.99° (c=0.403, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.47 (bd, 1H); 9.40 (s, 1H); 8.90 (d, 1H); 8.20 (m, 2H); 7.55 (s, 1H); 7.10 (m, 2H); 7.15 (d, 1H); 5.50 (m, 2H); 4.00 (s, 3H); 3.55 (m, 1H); 2.50 (bd, 1H); 2.20 (m, 2H); 1.80-1.40 (m, 3H).
    • Example 20 Compound No. 26 of Table 3 (−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide 20.1 (+)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one
  • 20 g (77.73 mmol) of (+/−)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one was separated by chiral preparative HPLC (Daicel CHIRALPACK AD 20 μm 50×220 mm) eluting with ethanol to give 9.17 g of pure product obtained in the form of free base.
  • Mp.: 118° C. [α]D 20=+59.97° (c=0.691, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.3 (s, 1H); 9.0 (d, 1H); 8.4 (d, 1H); 7.2 (s, 1H); 5.0-4.8 (m, 1H); 4.25 (d, 1H); 3.8-3.6 (dd, 1H); 2.0-1.2 (m, 6H).
    • 20.2 (−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide
  • By analogy with the method described in example 1 (step 1.5), using (+)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one in place of (+/−)9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the compound was obtained as a white powder.
  • Mp.: 212-214° C. [α]D 20=−8.8° (c=0.510, DMSO).
  • 1H NMR (DMSO-d6; 200 MHz)
  • δ (ppm): 9.47 (bd, 1H); 9.40 (s, 1H); 8.90 (d, 1H); 8.20 (m, 2H); 7.55 (s, 1H); 7.10 (m, 2H); 7.15 (d, 1H); 5.50 (m, 2H); 4.00 (s, 3H); 3.55 (m, 1H); 2.50 (bd, 1H); 2.20 (m, 2H); 1.80-1.40 (m, 3H).
  • A list of chemical structures and physical data for compounds of the aforementioned formula (I), illustrating the present invention, is given in table 1. The compounds have been prepared according to the methods of the examples. In the table, m and o represent 1, Ph represents a phenyl group, Me represent a methyl group, (Rot.) indicates the levorotatory or dextrorotatory properties of the enantiomeric compound.
  • Figure US20110294786A1-20111201-C00006
  • TABLE 1
    No. Rot R2 Z R1 R4 R5 R6 R7 Y R3 n Mp ° C. salt
    1 (+/−) Ph bond
    Figure US20110294786A1-20111201-C00007
         		H H H H O H 0 208-210 Free base
    2 (+/−)
    Figure US20110294786A1-20111201-C00008
         		bond
    Figure US20110294786A1-20111201-C00009
         		H H H H O H 0 155-157 Free base
    3 (+/−) Ph bond
    Figure US20110294786A1-20111201-C00010
         		H H H H O H 1 200-202 Free base
    4 (+/−) Ph O
    Figure US20110294786A1-20111201-C00011
         		H H H H O H 0 193-195 Free base
    5 (+/−)
    Figure US20110294786A1-20111201-C00012
         		NH
    Figure US20110294786A1-20111201-C00013
         		H H H H O H 0 251-253 Free base
    6 (+/−) Ph NH
    Figure US20110294786A1-20111201-C00014
         		H H H H O H 0 254-256 Free base
    7 (+/−)
    Figure US20110294786A1-20111201-C00015
         		bond
    Figure US20110294786A1-20111201-C00016
         		H H H H H,H H 0 230-232 Hydrochloride (2:1)
    8 (+/−)
    Figure US20110294786A1-20111201-C00017
         		bond
    Figure US20110294786A1-20111201-C00018
         		H H H H O H 0 204-206 Free base
    9 (+/−)
    Figure US20110294786A1-20111201-C00019
         		bond
    Figure US20110294786A1-20111201-C00020
         		H H H H O H 0 229-231 Free base
    10 (+/−)
    Figure US20110294786A1-20111201-C00021
         		bond
    Figure US20110294786A1-20111201-C00022
         		H H H H O H 0 205-207 Free base
    11 (+/−)
    Figure US20110294786A1-20111201-C00023
         		bond
    Figure US20110294786A1-20111201-C00024
         		H H H H O H 0 194-196 Free base
    12 (+/−)
    Figure US20110294786A1-20111201-C00025
         		bond
    Figure US20110294786A1-20111201-C00026
         		H H H H O H 0 219-221 Free base
    13 (+/−)
    Figure US20110294786A1-20111201-C00027
         		bond
    Figure US20110294786A1-20111201-C00028
         		H H H H O H 0 198-200 Free base
    14 (+/−)
    Figure US20110294786A1-20111201-C00029
         		bond
    Figure US20110294786A1-20111201-C00030
         		H H H H O H 0 249-251 Free base
    15 (+/−)
    Figure US20110294786A1-20111201-C00031
         		bond
    Figure US20110294786A1-20111201-C00032
         		H H H H O H 0 187-189 Free base
    16 (+/−)
    Figure US20110294786A1-20111201-C00033
         		bond
    Figure US20110294786A1-20111201-C00034
         		H H H H O H 0 200-202 Free base
    17 (+/−)
    Figure US20110294786A1-20111201-C00035
         		bond
    Figure US20110294786A1-20111201-C00036
         		H H H H O H 0 204-206 Free base
    18 (+/−)
    Figure US20110294786A1-20111201-C00037
         		bond
    Figure US20110294786A1-20111201-C00038
         		H H H H O H 0 187-189 Free base
    19 (+/−)
    Figure US20110294786A1-20111201-C00039
         		bond
    Figure US20110294786A1-20111201-C00040
         		H H H H O H 0 262-264 Free base
    20 (+/−)
    Figure US20110294786A1-20111201-C00041
         		bond
    Figure US20110294786A1-20111201-C00042
         		H H H H O H 0 213-215 Free base
    21 (+/−)
    Figure US20110294786A1-20111201-C00043
         		bond
    Figure US20110294786A1-20111201-C00044
         		H H H H O H 0 200-202 Free base
    22 (+/−)
    Figure US20110294786A1-20111201-C00045
         		bond
    Figure US20110294786A1-20111201-C00046
         		H H H H O H 0 197-199 Free base
    23 (+/−)
    Figure US20110294786A1-20111201-C00047
         		bond
    Figure US20110294786A1-20111201-C00048
         		H H H H O H 0 181-183 Free base
    24 (+/−)
    Figure US20110294786A1-20111201-C00049
         		bond
    Figure US20110294786A1-20111201-C00050
         		H H H H O H 0 234-236 Free base
    25 (+/−)
    Figure US20110294786A1-20111201-C00051
         		bond
    Figure US20110294786A1-20111201-C00052
         		H H H H O H 0 218-220 Free base
    26 (+/−)
    Figure US20110294786A1-20111201-C00053
         		bond
    Figure US20110294786A1-20111201-C00054
         		H H H H O H 0 190-192 Free base
    27 (+/−)
    Figure US20110294786A1-20111201-C00055
         		bond
    Figure US20110294786A1-20111201-C00056
         		H H H H O Br 0   256-257.3 Free base
    28 (+/−)
    Figure US20110294786A1-20111201-C00057
         		bond
    Figure US20110294786A1-20111201-C00058
         		H H H H O H 0 249-251 Free base
    29 (+/−)
    Figure US20110294786A1-20111201-C00059
         		bond
    Figure US20110294786A1-20111201-C00060
         		H H H H O H 0 172-174 Free base
    30 (+/−)
    Figure US20110294786A1-20111201-C00061
         		bond
    Figure US20110294786A1-20111201-C00062
         		H H H H O H 0 170-172 Free base
    31 (+/−)
    Figure US20110294786A1-20111201-C00063
         		bond
    Figure US20110294786A1-20111201-C00064
         		H H H H O H 0 202-204 Free base
    32 (+/−)
    Figure US20110294786A1-20111201-C00065
         		bond
    Figure US20110294786A1-20111201-C00066
         		H H H H O H 0 228-230 Free base
    33 (+/−)
    Figure US20110294786A1-20111201-C00067
         		bond
    Figure US20110294786A1-20111201-C00068
         		H H H H O H 0 221-223 Free base
    34 (+/−)
    Figure US20110294786A1-20111201-C00069
         		bond
    Figure US20110294786A1-20111201-C00070
         		H H H H O H 0 169-171 Free base
    35 (+/−)
    Figure US20110294786A1-20111201-C00071
         		bond
    Figure US20110294786A1-20111201-C00072
         		H H H H O H 0 223-225 Free base
    36 (+/−)
    Figure US20110294786A1-20111201-C00073
         		bond
    Figure US20110294786A1-20111201-C00074
         		H H H H O H 0 202-204 Free base
    37 (+/−)
    Figure US20110294786A1-20111201-C00075
         		bond
    Figure US20110294786A1-20111201-C00076
         		H H H H O H 0 229-231 Free base
    38 (+/−)
    Figure US20110294786A1-20111201-C00077
         		Bond
    Figure US20110294786A1-20111201-C00078
         		H H H H O H 0 246-248 Free base
    39 (+/−)
    Figure US20110294786A1-20111201-C00079
         		Bond
    Figure US20110294786A1-20111201-C00080
         		H H H H O H 0 206-208 Free base
    40 (+/−)
    Figure US20110294786A1-20111201-C00081
         		Bond
    Figure US20110294786A1-20111201-C00082
         		H H H H O H 0 227-229 Free base
    41 (+/−)
    Figure US20110294786A1-20111201-C00083
         		Bond
    Figure US20110294786A1-20111201-C00084
         		H H H H O H 0 202-204 Free base
    42 (−)
    Figure US20110294786A1-20111201-C00085
         		Bond
    Figure US20110294786A1-20111201-C00086
         		H H H H O H 0 174-176 Free base
    43 (+)
    Figure US20110294786A1-20111201-C00087
         		Bond
    Figure US20110294786A1-20111201-C00088
         		H H H H O H 0 175-177 Free base
    44 (+/−)
    Figure US20110294786A1-20111201-C00089
         		Bond
    Figure US20110294786A1-20111201-C00090
         		H H H H O H 0 216-218 Free base
    45 (+/−)
    Figure US20110294786A1-20111201-C00091
         		bond
    Figure US20110294786A1-20111201-C00092
         		H H H H O H 0 322-324 Free base
    46 (+/−)
    Figure US20110294786A1-20111201-C00093
         		bond
    Figure US20110294786A1-20111201-C00094
         		H H H H O H 0 214-216 Free base
    47 (+/−)
    Figure US20110294786A1-20111201-C00095
         		bond
    Figure US20110294786A1-20111201-C00096
         		H H CH3 H O H 0 192-194 Free base
    48 (+)
    Figure US20110294786A1-20111201-C00097
         		bond
    Figure US20110294786A1-20111201-C00098
         		H H CH3 H O H 0 181.7 Free base
    49 (−)
    Figure US20110294786A1-20111201-C00099
         		bond
    Figure US20110294786A1-20111201-C00100
         		H H CH3 H O H 0 182.7 Free base
    50 (+/−)
    Figure US20110294786A1-20111201-C00101
         		bond
    Figure US20110294786A1-20111201-C00102
         		H H H Me O H 0 167-169 Free base
    51 (+)
    Figure US20110294786A1-20111201-C00103
         		bond
    Figure US20110294786A1-20111201-C00104
         		H H H H O H 0 >240   (dec.) Free base
    52 (−)
    Figure US20110294786A1-20111201-C00105
         		bond
    Figure US20110294786A1-20111201-C00106
         		H H H H O H 0 >240   (dec.) Free base
    53 (+/−)
    Figure US20110294786A1-20111201-C00107
         		bond
    Figure US20110294786A1-20111201-C00108
         		H H Me H O H 0 188-190 Free base
    54 (+/−)
    Figure US20110294786A1-20111201-C00109
         		bond
    Figure US20110294786A1-20111201-C00110
         		H H Me H O H 0 191-193 Free base
    55 (+/−)
    Figure US20110294786A1-20111201-C00111
         		bond
    Figure US20110294786A1-20111201-C00112
         		H H Me H O H 0 256-258 Free base
    56 (+/−)
    Figure US20110294786A1-20111201-C00113
         		bond
    Figure US20110294786A1-20111201-C00114
         		H H ME H O H 0 181-183 Free base
    57 (+/−)
    Figure US20110294786A1-20111201-C00115
         		bond
    Figure US20110294786A1-20111201-C00116
         		H H Me H O H 0 210-212 Free base
    58 (+/−)
    Figure US20110294786A1-20111201-C00117
         		bond
    Figure US20110294786A1-20111201-C00118
         		H H Me H O H 0 180-182 Free base
    59 (+/−)
    Figure US20110294786A1-20111201-C00119
         		bond
    Figure US20110294786A1-20111201-C00120
         		H H Me H O H 0 206-208 Free base
    60 (+/−)
    Figure US20110294786A1-20111201-C00121
         		bond
    Figure US20110294786A1-20111201-C00122
         		H H Me H O H 0 275-277 Free base
    61 (+/−)
    Figure US20110294786A1-20111201-C00123
         		bond
    Figure US20110294786A1-20111201-C00124
         		H H Me H O H 0 198-200 Free base
  • A list of chemical structures and physical data for compounds of the aforementioned formula (I), illustrating the present invention, is given in table 2. The compounds have been prepared according to the methods of the examples. In the table, m represents 0 and o represents 1, (Rot.) indicates the levorotatory or dextrorotatory properties of the enantiomeric compound.
  • Figure US20110294786A1-20111201-C00125
  • TABLE 2
    No. Rot R2 Z R1 R4 R5 R6 R7 Y R3 n Mp ° C. salt
    1 (+/−)
    Figure US20110294786A1-20111201-C00126
         		bond
    Figure US20110294786A1-20111201-C00127
         		H H H H O H 0 237-239 Free base
    2 (+/−)
    Figure US20110294786A1-20111201-C00128
         		bond
    Figure US20110294786A1-20111201-C00129
         		H H H H O H 0 223-225 Free base
    3 (+/−)
    Figure US20110294786A1-20111201-C00130
         		bond
    Figure US20110294786A1-20111201-C00131
         		H H H H O H 0 275-277 Free base
    4 (+/−)
    Figure US20110294786A1-20111201-C00132
         		bond
    Figure US20110294786A1-20111201-C00133
         		H H H H O H 0 236-238 Free base
    5 (+/−)
    Figure US20110294786A1-20111201-C00134
         		bond
    Figure US20110294786A1-20111201-C00135
         		H H H H O H 0 242-244 Free base
    6 (+/−)
    Figure US20110294786A1-20111201-C00136
         		bond
    Figure US20110294786A1-20111201-C00137
         		H H H H O H 0 226-228 Free base
  • A list of chemical structures and physical data for compounds of the aforementioned formula (I), illustrating the present invention, is given in table 3.
  • The compounds have been prepared according to the methods of the examples. In the table 3, m represents 1 and o represents 2, (Rot.) indicates the levorotatory or dextrorotatory properties of the enantiomeric compound.
  • Figure US20110294786A1-20111201-C00138
  • TABLE 3
    No. Rot R2 Z R1 R4 R5 R6 R7 Y R3 n Mp ° C. salt
    1 (+/−)
    Figure US20110294786A1-20111201-C00139
         		bond
    Figure US20110294786A1-20111201-C00140
         		H H H H O H 0 280-282 Free base
    2 (+/−)
    Figure US20110294786A1-20111201-C00141
         		bond
    Figure US20110294786A1-20111201-C00142
         		H H H H O H 0 324-326 Free base
    3 (+/−)
    Figure US20110294786A1-20111201-C00143
         		bond
    Figure US20110294786A1-20111201-C00144
         		H H H H O H 0 218-220 Free base
    4 (+/−)
    Figure US20110294786A1-20111201-C00145
         		bond
    Figure US20110294786A1-20111201-C00146
         		H H H H O H 0 266-268 Free base
    5 (+/−)
    Figure US20110294786A1-20111201-C00147
         		bond
    Figure US20110294786A1-20111201-C00148
         		H H H H O H 0 268-270 Free base
    6 (+/−)
    Figure US20110294786A1-20111201-C00149
         		bond
    Figure US20110294786A1-20111201-C00150
         		H H H H O H 0 240-242 Free base
    7 (+/−)
    Figure US20110294786A1-20111201-C00151
         		bond
    Figure US20110294786A1-20111201-C00152
         		H H H H O H 0 274-276 Free base
    8 (+/−)
    Figure US20110294786A1-20111201-C00153
         		bond
    Figure US20110294786A1-20111201-C00154
         		H H H H O H 0 226-228 Free base
    9 (+/−)
    Figure US20110294786A1-20111201-C00155
         		bond
    Figure US20110294786A1-20111201-C00156
         		H H H H O H 0 237-239 Free base
    10 (+/−)
    Figure US20110294786A1-20111201-C00157
         		bond
    Figure US20110294786A1-20111201-C00158
         		H H H H O H 0 229-231 Free base
    11 (+/−)
    Figure US20110294786A1-20111201-C00159
         		bond
    Figure US20110294786A1-20111201-C00160
         		H H H H O H 0 177-179 Free base
    12 (+/−)
    Figure US20110294786A1-20111201-C00161
         		bond
    Figure US20110294786A1-20111201-C00162
         		H H H H O H 0 217-219 Free base
    13 (+/−)
    Figure US20110294786A1-20111201-C00163
         		bond
    Figure US20110294786A1-20111201-C00164
         		H H H H O H 0 157-159 Free base
    14 (+/−)
    Figure US20110294786A1-20111201-C00165
         		bond
    Figure US20110294786A1-20111201-C00166
         		H H H H O H 0 217-219 Free base
    15 (+)
    Figure US20110294786A1-20111201-C00167
         		bond
    Figure US20110294786A1-20111201-C00168
         		H H H H O H 0 241-243 Free base
    16 (−)
    Figure US20110294786A1-20111201-C00169
         		bond
    Figure US20110294786A1-20111201-C00170
         		H H H H O H 0 232-234 Free base
    17 (+/−)
    Figure US20110294786A1-20111201-C00171
         		bond
    Figure US20110294786A1-20111201-C00172
         		H H H H O H 0 222-224 Free base
    18 (+/−)
    Figure US20110294786A1-20111201-C00173
         		bond
    Figure US20110294786A1-20111201-C00174
         		H H H H O H 0 220-222 Free base
    19 (+/−)
    Figure US20110294786A1-20111201-C00175
         		bond
    Figure US20110294786A1-20111201-C00176
         		H H H H O H 0 218-220 Free base
    20 (+/−)
    Figure US20110294786A1-20111201-C00177
         		bond
    Figure US20110294786A1-20111201-C00178
         		H H H H O H 0 196-198 Free base
    21 (+/−)
    Figure US20110294786A1-20111201-C00179
         		bond
    Figure US20110294786A1-20111201-C00180
         		H H H H O H 0 213-215 Free base
    22 (+/−)
    Figure US20110294786A1-20111201-C00181
         		bond
    Figure US20110294786A1-20111201-C00182
         		H H H H O H 0 279-281 Free base
    23 (+/−)
    Figure US20110294786A1-20111201-C00183
         		bond
    Figure US20110294786A1-20111201-C00184
         		H H H H O H 0 125-127 Free base
    24 (+/−)
    Figure US20110294786A1-20111201-C00185
         		bond
    Figure US20110294786A1-20111201-C00186
         		H H H H O H 0 296-298 Free base
    25 (+)
    Figure US20110294786A1-20111201-C00187
         		bond
    Figure US20110294786A1-20111201-C00188
         		H H H H O H 0 210-212 Free base
    26 (−)
    Figure US20110294786A1-20111201-C00189
         		bond
    Figure US20110294786A1-20111201-C00190
         		H H H H O H 0 212-214 Free base
    • Test Example Inhibitory Activity of the Medicament of the Present Invention Against GSK3β
  • Two different protocols can be used.
  • In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μM ATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mM Tris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl2, 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).
  • In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μM ATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH, pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer for 2 hours at room temperature in the presence of GSK3beta. Inhibitors were solubilized in DMSO (final solvent concentration in the reaction medium, 1%).
  • The reaction was stopped with 100 microliters of a solution made of 25 g polyphosphoric acid (85% P2O5), 126 ml 85% H3PO4, H2O 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 used in the example was the same one as reported in Woodgett, J. R. (1989) Analytical Biochemistry 180, 237-241 and had the same sequence as reported therein, which reference is incorporated herein by reference in its entirety.
  • The GSK3β inhibitory activity of the compounds of the present invention are expressed in IC50, and as an illustration the range of IC50's of the compounds in table 1 and table 2 are between 0.1 nanomolar to 3 micromolar concentrations.
  • For example compound No. 33 of table 1 shows an IC50 of 0.005 μM.
    • Formulation Example (1) Tablets
  • The ingredients below were mixed by an ordinary method and compressed by using a conventional apparatus.
  •
    Compound of Example 1  30 mg
    Crystalline cellulose  60 mg
    Corn starch 100 mg
    Lactose 200 mg
    Magnesium stearate  4 mg
    • (2) Soft Capsules
  • The ingredients below were mixed by an ordinary method and filled in soft capsules.
  •
    Compound of Example 1  30 mg
    Olive oil 300 mg
    Lecithin  20 mg
  • (1) Parenteral Preparations
  • The ingredients below were mixed by an ordinary method to prepare injections contained in a 1 ml ampoule.
  •
    Compound of Example 1 3 mg
    Sodium chloride 4 mg
    Distilled water for injection 1 ml
    • INDUSTRIAL APPLICABILITY
  • The compounds of the present invention have GSK3β 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 GSK3β and more particularly of neurodegenerative diseases.

Claims (14)

1. A compound of formula (III):
Figure US20110294786A1-20111201-C00191
or a pharmaceutically acceptable salt thereof
wherein:
m represents 0 or 1; o represents 0 to 2.
R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted by a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom;
R3 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
R4 represents a hydrogen atom or a C1-6 alkyl group;
R5 represents a hydrogen atom, a C1-6 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-6 alkoxy group;
R6 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom; and
R7 represents a hydrogen atom or a C1-6 alkyl group.
2. A pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof, according to claim 1 in combination with at least one pharmaceutically acceptable excipient.
3. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies, non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I):
Figure US20110294786A1-20111201-C00192
or a pharmaceutically acceptable salt thereof
wherein:
Y represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C1-2 alkyl group and a hydrogen atom;
Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C1-3 alkyl group, a sulfur atom, a methylene group optionally substituted by one or two groups chosen from a C1-6 alkyl group, a hydroxyl group, a C1-6 alkoxy group, a C1-2 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 C1-6 alkyl group, a C1-6 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 C1-6 alkyl group, C3-7 cycloalkyl group, a C3-7 cycloalkyl-C1-6 alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a hydroxyl group, a C1-6 alkoxy group optionally substituted by a C3-5 cycloalkyl group, a C1-2 perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-6 monoalkylamino group, a C2-12 dialkylamino group, an acetoxy group or an aminosulfonyl group;
R3 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
R4 represents a hydrogen atom or a C1-6 alkyl group;
R5 represents a hydrogen atom, a C1-6 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-6 alkoxy group;
R6 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
R7 represents a hydrogen atom or a C1-6 alkyl group; and
n represents 0 to 3; m represents 0 to 1; o represents 0 to 2.
4. The method according to claim 3 where in the compound or salt thereof,
R1 represents an unsubstituted 4-pyridine ring or unsubstituted 4-pyrimidine ring.
5. The method according to claim 3 where in the compound or salt thereof R1 represents a 3- or 4-pyridine ring or alternatively a 4- or 5-pyrimidine ring;
the rings being optionally substituted by a C1-2 alkyl group, a C1-2 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 C1-3 alkyl group, C3-5 cycloalkyl group, a C3-5 cycloalkyl-C1-4 alkyl group, a halogen atom, a C1-3 halogenated alkyl group, a hydroxyl group, a
C1-3 alkoxy group optionally substituted by a C3-5 cycloalkyl group, a
C1-2 perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-3 monoalkylamino group or a C2-6 dialkylamino group;
R3 represents a hydrogen atom, a C1-3 alkyl group or a halogen atom;
R4 represents a hydrogen atom or a C1-3 alkyl group;
R5 represents a hydrogen atom, a C1-3 alkoxy carbonyl group or a C1-3 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-3 alkoxy group;
R6 represents a hydrogen atom, a C1-3 alkyl group or a halogen atom;
R7 represents a hydrogen atom or a C1-3 alkyl group;
Y represents two hydrogen atoms, an oxygen atom or a C1-2 alkyl group and a hydrogen atom;
Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C1-3 alkyl group, a methylene group optionally substituted by one or two groups chosen from a C1-3 alkyl group, a hydroxyl group, a C1-3 alkoxy group, a C1-2 perhalogenated alkyl group or an amino group;
n represents 0 to 3; m represents 0 or 1 and o represents 1 to 2.
6. The method according to claim 3 where in the compound or salt thereof,
R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;
R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a C1-2 perhalogenated alkyl group, a C3-4 cycloalkyl group, a C3-4 cycloalkyl-C1-3 alkyl group, a halogen atom, a hydroxyl group, a nitro, a cyano, an amino, a C1-3 alkoxy group optionally substituted by a C3-4 cycloalkyl group, a C1-2 perhalogenated alkoxy group or a C1-3 alkylsulfonyl group;
R3 represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a C1-6 alkyl group;
R7 represents a hydrogen atom;
Y represents two hydrogen atoms, or an oxygen atom;
Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom;
n represents 0 to 1;
m represents 0 to 1 and o represents 1 to 2.
7. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies, non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 1.
8. The method according to claim 3 wherein the compound or salt thereof is
(+/−)N-(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-phenylacetamide;
(+/−)Phenyl(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)carbamate;
(+/−)N-(4-Fluorophenyl)-N′-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)urea;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-N′-phenylurea;
(+/−)9-[(2-Methoxybenzyl)amino]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;
(+/−)3-Fluoro-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Isopropoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Chloro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)3-Cyano-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Chloro-5-fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethyl)benzamide;
(+/−)4-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-3-(trifluoromethyl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethyl)benzamide;
(+/−)2-Chloro-4-fluoro-5-nitro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-naphthamide;
(+/−)3-Chloro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)3-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Fluoro-6-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Ethoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(3-Bromo-4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-methoxybenzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethoxy)benzamide;
(+/−)2-Isopropoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-(Cyclopropylmethoxy)-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-(Cyclopropylmethoxy)-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-naphthamide;
(+/−)3-Chloro-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-trifluoromethyl-benzamide;
(+/−)5-(Ethylsulfonyl)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-{[(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)amino]carbonyl}phenyl acetate;
(+/−)2-Hydroxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-methyl-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)4-Fluoro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)2-Methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-trifluoromethyl-benzamide;
(+/−)2-Fluoro-6-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)2-Methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)5-Bromo-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)-4-Dimethylamino-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)-2,4-Dimethoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-(Aminosulfonyl)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Hydroxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2,4-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-{[(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)amino]carbonyl}phenyl acetate;
(+/−)2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-5-(trifluoromethoxy)benzamide;
(+/−)2,5-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-{[(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)amino]carbonyl}phenyl acetate;
(+/−)2,4-Dimethoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+)4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide; and
(−)4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
9. A method of inhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β), which comprises administering to a patient in need of said inhibition an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure US20110294786A1-20111201-C00193
wherein:
Y represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C1-2 alkyl group and a hydrogen atom;
Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C1-3 alkyl group, a sulfur atom, a methylene group optionally substituted by one or two groups chosen from a C1-6 alkyl group, a hydroxyl group, a C1-6 alkoxy group, a C1-2 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 C1-6 alkyl group, a C1-6 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 C1-6 alkyl group, C3-7 cycloalkyl group, a C3-7 cycloalkyl-C1-6 alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a hydroxyl group, a C1-6 alkoxy group optionally substituted by a C3-5 cycloalkyl group, a C1-2 perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-6 monoalkylamino group, a C2-12 dialkylamino group, an acetoxy group or an aminosulfonyl group;
R3 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
R4 represents a hydrogen atom or a C1-6 alkyl group;
R5 represents a hydrogen atom, a C1-6 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-6 alkoxy group;
R6 represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;
R7 represents a hydrogen atom or a C1-6 alkyl group; and
n represents 0 to 3; m represents 0 to 1; o represents 0 to 2.
10. The method according to claim 9 where in the compound or salt thereof, R1 represents an unsubstituted 4-pyridine ring or unsubstituted 4-pyrimidine ring.
11. The method according to claim 9 where in the compound or salt thereof, R1 represents a 3- or 4-pyridine ring or alternatively a 4- or 5-pyrimidine ring; the rings being optionally substituted by a C1-2 alkyl group, a C1-2 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 C1-3 alkyl group, C3-5 cycloalkyl group, a C3-5 cycloalkyl-C1-4 alkyl group, a halogen atom, a C1-3 halogenated alkyl group, a hydroxyl group, a
C1-3 alkoxy group optionally substituted by a C3-5 cycloalkyl group, a
C1-2 perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-3 monoalkylamino group or a C2-6 dialkylamino group;
R3 represents a hydrogen atom, a C1-3 alkyl group or a halogen atom;
R4 represents a hydrogen atom or a C1-3 alkyl group;
R5 represents a hydrogen atom, a C1-3 alkoxy carbonyl group or a C1-3 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a phenyl group, a hydroxyl group or a C1-3 alkoxy group;
R6 represents a hydrogen atom, a C1-3 alkyl group or a halogen atom;
R7 represents a hydrogen atom or a C1-3 alkyl group;
Y represents two hydrogen atoms, an oxygen atom or a C1-2 alkyl group and a hydrogen atom;
Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C1-3 alkyl group, a methylene group optionally substituted by one or two groups chosen from a C1-3 alkyl group, a hydroxyl group, a C1-3 alkoxy group, a C1-2 perhalogenated alkyl group or an amino group;
n represents 0 to 3; m represents 0 or 1 and o represents 1 to 2.
12. The method according to claim 9 where in the compound or salt thereof,
R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;
R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a C1-2 perhalogenated alkyl group, a C3-4 cycloalkyl group, a C3-4 cycloalkyl-C1-3 alkyl group, a halogen atom, a hydroxyl group, a nitro, a cyano, an amino, a C1-3 alkoxy group optionally substituted by a C3-4 cycloalkyl group, a C1-2 perhalogenated alkoxy group or a C1-3 alkylsulfonyl group;
R3 represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a C1-6 alkyl group;
R7 represents a hydrogen atom;
Y represents two hydrogen atoms, or an oxygen atom;
Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom;
n represents 0 to 1;
m represents 0 to 1 and o represents 1 to 2.
13. A method of inhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β), which comprises administering to a patient in need of said inhibition an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1.
14. The method according to claim 9 wherein the compound or salt thereof is
(+/−)N-(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-phenylacetamide;
(+/−)Phenyl(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)carbamate;
(+/−)N-(4-Fluorophenyl)-N′-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)urea;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-N′-phenylurea;
(+/−)9-[(2-Methoxybenzyl)amino]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;
(+/−)3-Fluoro-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Isopropoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Chloro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)3-Cyano-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Chloro-5-fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethyl)benzamide;
(+/−)4-Methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-3-(trifluoromethyl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethyl)benzamide;
(+/−)2-Chloro-4-fluoro-5-nitro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-naphthamide;
(+/−)3-Chloro-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)3-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Fluoro-6-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Ethoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(3-Bromo-4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-methoxybenzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-(trifluoromethoxy)benzamide;
(+/−)2-Isopropoxy-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-(Cyclopropylmethoxy)-N-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-(Cyclopropylmethoxy)-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)N-(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-naphthamide;
(+/−)3-Chloro-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-trifluoromethyl-benzamide;
(+/−)5-(Ethylsulfonyl)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)2-{[(4-Oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)amino]carbonyl}phenyl acetate;
(+/−)2-Hydroxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(−)4-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-methyl-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)4-Fluoro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)2-Methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-trifluoromethyl-benzamide;
(+/−)2-Fluoro-6-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)2-Methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)5-Bromo-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)-4-Dimethylamino-2-methoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)-2,4-Dimethoxy-N-(9-methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)-benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-(Aminosulfonyl)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Hydroxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2,4-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-{[(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)amino]carbonyl}phenyl acetate;
(+/−)2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-5-(trifluoromethoxy)benzamide;
(+/−)2,5-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Bromo-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Fluoro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-Methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)5-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)4-Amino-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+/−)2-{[(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)amino]carbonyl}phenyl acetate;
(+/−)2,4-Dimethoxy-N-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
(+)4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide; and
(−)4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)benzamide;
US13/197,228 2005-11-21 2011-08-03 Substituted bicyclic pyrimidone derivatives Abandoned US20110294786A1 (en)

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