HK1140190A - Arylamide pyrimidone derivatives for the treatment of neurodegenerative diseases - Google Patents

Description

Arylamide pyrimidinone derivatives for the treatment of neurodegenerative diseases

Technical Field

The present invention relates to a compound useful as an active ingredient of a medicament for preventing and/or treating a neurodegenerative disease caused by abnormal activity of GSK3 β.

Background

GSK3 β (glycogen synthase kinase 3 β) is a proline-directed serine, threonine kinase that plays an important role in controlling metabolism, differentiation, and survival. Initially, it was thought to be an enzyme capable of phosphorylation and thus inhibition of glycogen synthase. Later, it was recognized that GSK3 β is equivalent to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein at epitopes that are thought to be hyperphosphorylated also in alzheimer's disease and several tauopathies (tauopathies). Interestingly, GSK3 β phosphorylation by protein kinase b (akt) results in loss of its kinase activity, and it is postulated that this inhibition may modulate some of the effects of neurotrophic factors. Furthermore, phosphorylation of GSK3 β of β -catenin, a protein involved in cell survival, leads to its degradation via the proteasome pathway which is dependent on ubiquitination.

Thus, it appears that inhibition of GSK3 β activity may result in neurotrophic activity. Indeed, there is evidence that lithium, a non-competitive inhibitor of GSK3 β, enhances neurogenesis and increases neuronal survival in several models by inducing the expression of survival factors such as Bcl-2 and inhibiting apoptotic (proapoptotic) factors such as p53 and Bax.

Recent studies have demonstrated that β -amyloid increases GSK3 β activity and tau phosphorylation. Furthermore, the hyperphosphorylation and neurotoxic effects of β -amyloid are blocked by lithium chloride and GSK3 antisense mRNA. These observations strongly suggest that GSK3 β may be the junction between two major pathological processes in alzheimer's disease, the abnormal APP (amyloid precursor protein) process and tau hyperphosphorylation.

Although tau hyperphosphorylation results in instability of the neuronal cytoskeleton, it is most likely that the pathological consequences of aberrant GSK3 β activity are not solely due to pathological phosphorylation of tau protein, as described above, since excessive activity of this kinase may influence survival by modulating apoptotic and anti-apoptotic factors. Furthermore, it has been shown that an increase in β -amyloid-induced GSK3 β activity leads to phosphorylation and thus to inhibition of pyruvate dehydrogenase, a key enzyme in energy production and acetylcholine synthesis.

Taken together, the observations from these experiments indicate that GSK3 β can be used to treat neuropathic problems and cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases, and other pathologies in which GSK3 β is deregulated (deragged) (Naturervews, Vol.3, 6.2004, pp.479-487; Trends in pharmacological sciences, Vol.25, Vol.9, 9.2004, pp.471-480; Journal of neurochemistry 2004, 89, 1313-1317; Medicinal Research Reviews, Vol.22, Vol.4, pp.373-384, 2002).

Such neurodegenerative diseases include, in a non-limiting manner, Parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease (The Journal of biological chemistry, Vol. 277, Vol. 37, 9/13, p. 33791, p. 33798, 2002), prion disease (biochem. J.372, p. 129-; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; amyotrophic lateral sclerosis (European Journal of Neuroscience, Vol.22, p.301-309, 2005) peripheral neuropathy; retinopathy and glaucoma. Recent studies have also shown that inhibition of GSK3 β leads to neural differentiation of Embryonic Stem Cells (ESC) and supports regeneration of human and mouse ESC and maintenance of its pluripotency. This suggests that GSK3 β inhibitors may be useful in regenerative Medicine (Nature Medicine 10, pages 55-63, 2004).

GSK3 β inhibitors may also be useful in the treatment of other neurological disorders, such as bipolar disorder (manic-depressive illness). For example, lithium has been used as a mood stabilizer and for the primary treatment of bipolar disorder for over 50 years. The therapeutic effect of lithium was observed at doses (1-2mM), when it was a direct inhibitor of GSK3 β. Although the mechanism of action of lithium is unclear, GSK3 β inhibitors may be used to mimic the mood stabilising effect of lithium. Alterations to the Akt-GSK3 beta signaling are also involved in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3 β can be used to treat cancers such as colorectal, prostate, breast, non-small cell lung, thyroid, T or B cell leukemia and some virus-induced tumors. For example, the active form of GSK3 β is shown to be elevated in tumors in colorectal cancer patients, while inhibition of GSK3 β in colorectal cancer cells activates p 53-dependent apoptosis and antagonizes tumor growth. Inhibition of GSK3 β also increased TRAIL-induced apoptosis in prostate cancer cell lines. GSK3 β also plays a role in mitotic spindle dynamics, and GSK3 β inhibitors can prevent chromosome movement, leading to stabilization of microtubules and prometaphase-like arrest (prometaphase-like arrest) similar to that observed with low doses of paclitaxel. Other possible uses for GSK3 β inhibitors include the treatment of non-insulin dependent diabetes (such as type II diabetes), obesity and alopecia.

Human GSK3 β inhibitors also inhibit pfGSK3, a homolog of the enzyme found in p.falciparum (ortholog), and as such are useful in the treatment of malaria (Biochimica et biophysica Acta 1697, 181-196, 2004). Recently, both human genetics and animal studies have indicated that the Wnt/LPR5 pathway is a major regulator of bone mass increase. Inhibition of GSK3 β results in the corresponding activation of canonical Wnt signaling. Since Wnt signaling deficits are implicated in osteopenic disorders, GSK3 β inhibitors may also be useful in the treatment of osteopenic disorders, skeletal related pathologies, osteoporosis. According to recent data, GSK3 β inhibitors are useful for the treatment or prevention of pemphigus vulgaris. Recent studies have shown that treatment with GSK3 β inhibitors improves neutrophil and megakaryocyte recovery. Therefore, GSK3 β inhibitors would be useful in the treatment of cancer chemotherapy-induced neutropenia.

Previous studies have shown that GSK3 activity decreases LTP, an electrophysiological related species of memory consolidation (memory consolidation), suggesting that inhibitors of this enzyme may have desirable activity. The Procognitive effect of the compound was found to be useful in the treatment of memory deficits characterized by the following conditions: alzheimer's disease, parkinson's disease, age-1 related memory deficits, mild cognitive deficits, brain trauma, schizophrenia and other conditions in which these deficits are observed. Inhibitors of GSK3 β have also been found to be useful in the treatment of parenchymal kidney disease (Nelson PJ, kidney international advanced online publication, 12 months and 19 days 2007) and in the prevention or treatment of muscle atrophy (j.biol. chem (283)2008, 358-.

Disclosure of Invention

It is an object of the present invention to provide compounds for use as active ingredients in medicaments for the prophylaxis and/or treatment of diseases caused by abnormal GSK3 β activity, more particularly neurodegenerative diseases. More specifically, the object is to provide a novel compound useful as an active ingredient of a medicament capable of preventing and/or treating neurodegenerative diseases such as alzheimer's disease.

Accordingly, the present inventors have identified compounds having inhibitory activity against GSK3 β. Thus, they found that the compounds represented by the following formula (I) have desired activities and can be used as active ingredients of medicaments for preventing and/or treating the aforementioned diseases.

Accordingly, an object of the present invention is to provide a pyrimidone derivative represented by formula (I) or a salt thereof, a solvate thereof, or a hydrate thereof:

wherein

X represents two hydrogen atoms, sulfur atoms, oxygen atoms or C_1-2Alkyl and hydrogen atoms;

z represents a bond, an oxygen atom, a hydrogen atom or C_1-3Alkyl-substituted nitrogen atom, sulfur atom, optionally substituted by one or two members selected from C_1-6Alkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkyl or amino substituted methylene;

r1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, said ring being optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen atom substitution;

r2 represents a benzene ring, a naphthalene ring or a benzyl group; said ring being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-3Haloalkyl, hydroxy, optionally substituted by C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Heteroaryl substituted by alkyl, optionally substituted by C_3-7Cycloalkyl-substituted C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Alkylsulfonyl, nitro, cyano, amino, C_1-6Monoalkylamino or C_2-12Dialkylamino, acetoxy, or aminosulfonyl;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r4 represents a hydrogen atom or C_1-6An alkyl group;

r5 represents a hydrogen atom or C_1-6An alkyl group;

r6 represents a hydrogen atom or C_1-6An alkyl group;

r7 represents a hydrogen atom or C_1-6An alkyl group;

n represents a number of 0 to 3,

and m represents 0 and m represents a number of,

in the form of the free base or of an addition salt with an acid.

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: a pyrimidone derivative represented by formula (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof. As a preferred embodiment of the medicament, there are provided the aforementioned medicament for preventing and/or treating a disease caused by abnormal GSK3 β activity, and the aforementioned medicament for preventing and/or treating a neurodegenerative disease and the following additional other diseases, such as: non-insulin dependent diabetes mellitus (such as type II diabetes) and obesity; malaria, bipolar disorder (manic depressive illness); schizophrenia; alopecia or cancer such as colorectal cancer, prostate cancer, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia, some virus-induced tumors. The medicament can also be used in regenerative medicine, pemphigus vulgaris, neutropenia and bone diseases.

As a further embodiment of the present invention, there is provided the aforementioned medicament, and the aforementioned medicament in the form of a pharmaceutical composition comprising the aforementioned substance as an active ingredient together with one or more pharmaceutical additives, wherein the disease is a neurodegenerative disease selected from the group consisting of alzheimer's disease, parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), wilson's disease, huntington's disease, prion disease and other dementias including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; amyotrophic lateral sclerosis; peripheral neuropathy; retinopathy and glaucoma.

As a further embodiment of the present invention, there is provided the aforementioned medicament, wherein the bone disease is osteoporosis.

The present invention further provides an inhibitor of GSK3 β activity comprising as an active ingredient a substance selected from the group consisting of: pyrimidone derivatives of formula (I) and salts thereof, and solvates and hydrates thereof.

According to a further aspect of the present invention there is provided a method for the prevention and/or treatment of a neurodegenerative disease caused by abnormal GSK3 β activity, comprising the step of administering to a patient a prophylactically and/or therapeutically effective amount of a compound selected from the group consisting of: pyrimidone derivatives of formula (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof; and the use of a pyrimidone derivative selected from formula (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof for the preparation of the aforementioned medicaments.

In the context of the present invention:

c wherein t and z are numbers from 1 to 12_t-zRepresents a linear or branched or cyclic chain radical having t to z carbon atoms, i.e. C_1-3Represents a linear, branched or cyclic chain having from 1 to 3 carbon atoms;

c as used herein_1-6Alkyl represents a straight or branched chain or cyclic alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl, etc.;

said C is_1-6Alkoxy represents alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like;

the halogen atom represents a fluorine, chlorine, bromine or iodine atom;

said C is_1-2Perhaloalkyl represents alkyl in which all hydrogen atoms are replaced by halogen atoms, e.g. CF₃Or C₂F₅；

Said C is_1-3Haloalkyl represents alkyl in which at least one hydrogen is not substituted by a halogen atom;

said C is_1-6Monoalkylamino radicals being represented by C_1-6Alkyl-substituted amino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino and the like;

said C is_2-12Dialkylamino represents two C_1-6Alkyl-substituted amino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, diisopropylamino, and the like;

the benzyl is CH₂-a phenyl ring;

the heteroaryl represents pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole.

The leaving group L represents a group which can be easily cleaved and substituted, and such a group may be, for example, a tosyl group, a mesyl group, a bromate group, or the like.

The compound represented by the aforementioned formula (I) may form a salt. When an acid group is present, examples of the salt include 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-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine and L-glucosamine; or salts with basic amino acids such as lysine, delta-hydroxylysine and arginine. Base addition salts of acidic compounds are prepared according to standard procedures well known in the art.

When a basic group is present, examples include salts with inorganic 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;

acid addition salts of basic compounds are prepared by standard procedures well known in the art, including, but not limited to, dissolving the free base in an aqueous ethanol solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base with the acid in an organic solvent, in which case the salt is isolated directly, or by precipitation with a second organic solvent, or by concentrating the solution. Acids which may be used in the preparation of acid addition salts preferably include those which, when combined with the free base, are capable of forming a pharmaceutically acceptable salt, i.e. a salt whose cation is relatively non-toxic to the animal organism at the time of pharmaceutical dosage, so that the beneficial properties inherent in the free base are not impaired by side effects attributable to the anion. Although pharmaceutically acceptable salts of the basic compounds are preferred, all acid addition salts are within the scope of the invention.

In addition to the pyrimidone derivatives represented by the aforementioned formula (I) and salts thereof, solvates and hydrates thereof also fall within the scope of the present invention.

The pyrimidone derivative represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. With respect to the stereochemistry of such asymmetric carbon atoms, they may independently be in the (R) and (S) configurations, and their derivatives may exist as stereoisomers, such as optical isomers or diastereomers. Any pure stereoisomer, any mixture of stereoisomers, racemate etc. falls within the scope of the present invention.

Examples of the compounds of the present invention are shown in table 1 below. However, the scope of the present invention is not limited to these compounds.

An object of the present invention also includes compounds represented by formula (I) wherein m is 0, which are defined by the different subsets (1) to (10) selected individually or in admixture:

(1) r1 represents a 4 or 5-pyrimidine ring or a 4-pyridine ring; said ring being optionally substituted by C_1-2Alkyl radical, C_1-2Alkoxy or halogenAtomic substitution; and/or

(2) R2 represents a benzene ring, a naphthalene ring or a benzyl group; said ring being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-3Haloalkyl, hydroxy, optionally substituted by C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Heteroaryl substituted by alkyl, optionally substituted by C_3-5Cycloalkyl-substituted C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Alkylsulfonyl, nitro, cyano, amino, C_1-3Monoalkylamino or C_2-6Dialkylamino, acetoxy, or aminosulfonyl; and/or

(3) R3 represents a hydrogen atom or C_1-6An alkyl group or a halogen atom; and/or

(4) R4 represents a hydrogen atom or C_1-6An alkyl group; and/or

(5) R5 represents a hydrogen atom or C_1-6An alkyl group; and/or

(6) R6 represents a hydrogen atom or C_1-6An alkyl group; and/or

(7) R7 represents a hydrogen atom or C_1-6An alkyl group; and/or

(8) X represents two hydrogen atoms, oxygen atoms or C_1-2Alkyl and hydrogen atoms; and/or

(9) Z represents a bond, an oxygen atom, a hydrogen atom or C_1-3Nitrogen atoms substituted by alkyl radicals, optionally substituted by one or two radicals selected from C_1-3Alkyl, hydroxy, C_1-3Alkoxy radical, C_1-2Perhaloalkyl or amino substituted methylene; and/or

(10) n represents 0 to 3 in the form of the free base or of an addition salt with an acid.

Another object of the present invention includes compounds represented by formula (I) wherein m is 0, which are defined by the different subsets (1) to (10) selected individually or in admixture:

(1) r1 represents a 4-pyridine ring; and/or

(2) R2 represents a benzene ring, a naphthalene ring or a benzyl group; said ring being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl, halogen atoms, amino groups, C_1-2Perhaloalkyl radical, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy or optionally substituted by C_1-6An alkyl substituted oxadiazole; and/or

(3) R3 represents a hydrogen atom; and/or

(4) R4 represents methyl; and/or

(5) R5 represents a hydrogen atom or a methyl group; and/or

(6) R6 represents a hydrogen atom or a methyl group; and/or

(7) R7 represents a hydrogen atom; and/or

(8) X represents 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 in the form of the free base or of an addition salt with an acid.

Further objects of the invention include those of the formulaTABLE 1The compound of (1):

1.2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2.5-chloro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

4-fluoro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

(+/-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

4-fluoro-2-methoxy-N- [ 1-methyl-1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

4-chloro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

1- (4-fluoro-phenyl) -3- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -urea

1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -3-phenyl-urea

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

3-fluoro-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

4-amino-5-chloro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -4-trifluoromethyl-benzamide

2-fluoro-6-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2-chloro-5-fluoro-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

17.5-bromo-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

18.4-fluoro-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -2-trifluoromethyl-benzamide

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -trifluoromethoxy-benzamide

2, 6-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

22. Naphthalene-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 3-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2, 5-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

25.2-methoxy-4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

(+/-) 2-methoxy-4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 5-bromo-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 4-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-)2, 4-dimethoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-)2, 6-dimethoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 4-amino-5-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -4-trifluoromethyl-benzamide

(+/-) [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -carbamic acid benzyl ester

(+) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -4-trifluoromethyl-benzamide

(-) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -4-trifluoromethyl-benzamide

(+) -4-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(-) -4-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

As a further object, the present invention also relates to a process for producing the pyrimidone compound represented by the aforementioned formula (I). These compounds can be prepared, for example, according to the methods set forth below.

Preparation method

The pyrimidone compound represented by the aforementioned formula (I) can be prepared according to the method described in scheme 1.

Scheme 1

(in the above schemes, R1, R2, R3, R4, R5, R6, R7, m, n, X and Z have the same definitions as already described for the compounds of formula (I)).

According to this method, a pyrimidinone derivative represented by the above formula (III) wherein R1, R3, R4, R5, R6 and m are as defined for the compound of formula (I) is reacted with a base such as triethylamine, sodium carbonate or potassium carbonate and then with a compound of formula (II) wherein R2, X, Z and N are as defined for the compound of formula (I) and L represents a leaving group, preferably chlorine, bromine, in a solvent such as tetrahydrofuran, N-methylpyrrolidone, N-dimethylacetamide, dimethylformamide or chloroform at a temperature of 0 to 130 ℃ in ordinary air to obtain the compound of the above formula (I).

Alternatively, the compound of formula (I) wherein X represents two hydrogen atoms is prepared by reductive amination of a compound of formula (II) wherein X represents an oxygen atom and L represents a hydrogen atom from a compound of formula (III) wherein R1, R3, R4, R5, R6 and m are as defined for the compound of formula (I) and R7 is hydrogen, according to methods well known to the person skilled in the art.

The compounds of formula (II) are commercially available or may be synthesized according to methods well known to those skilled in the art.

The compounds of formula (III) may be prepared according to the methods defined in scheme 2.

Scheme 2

(in the above scheme, R1, R3, R4, R5, R6 and m have the same meanings as already described)

According to this process, a 3-ketoester of formula (IV), wherein R1 and R3 are as defined for a compound of formula (I), R is an alkyl group such as for example methyl or ethyl, is reacted with a compound of formula (V), wherein R5, R6, and m are as defined for a compound of formula (I), Pg is a suitable protecting group such as for example phthalimido or alkoxycarbonyl. This reaction can be carried out at 25 to 140 ℃ in ordinary air in the presence of a base such as potassium carbonate or sodium hydroxide, in an alcohol solvent such as methanol, ethanol, etc., or in the absence of a solvent, to give the compound of the aforementioned formula (VI). Compounds of formula (VI) may be alkylated with compounds of formula R4L, wherein R4 is as defined for compounds of formula (I) and L represents a leaving group, preferably chlorine or bromine, in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as dioxane or dimethylformamide after removal of the protecting group (Pg) to give compounds of formula (III).

In addition, in order to obtain a compound of formula (III) in which R3 is a halogen atom, such as a bromine atom or a chlorine atom, a compound of formula (III) in which R3 represents a hydrogen atom may be halogenated. The process should be carried out in an acidic medium, such as acetic acid or propionic acid, in the presence of bromosuccinimide or chlorosuccinimide or bromine.

In addition. Compounds of the formula (IV) in which R3 represents a fluorine atom can be obtained by methods analogous to those described in Tetrahedron Letters, Vol.30, No. 45, p.6113-6116, 1989.

In addition, the compounds of formula (IV) in which R3 represents a hydrogen atom can be obtained by a process similar to that described in patent DE 2705582.

As a further object, the present invention also relates to compounds of formula (III) for use as intermediates for compounds of formula (I).

The compounds of formula (IV) are commercially available or may be synthesized according to methods well known to those skilled in the art.

For example, a compound of formula (IV) wherein R1 represents optionally substituted by C_1-6Alkyl radical, C_1-6The pyrimidine ring substituted by alkoxy or halogen atoms may be substituted by a substituent selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy-or halogen-substituted isonicotinic acids or pyrimidine-carboxylic acids, respectively, with the corresponding malonic acid monoesters. The reaction may be carried out using methods well known to those skilled in the art, such as, for example, in a solvent such as tetrahydrofuran at a temperature in the range of 20 to 70 ℃ in the presence of a coupling agent such as 1, 1' -carbonyldi-1H-imidazole.

The compounds of formula (V) may be synthesized according to methods well known to those skilled in the art.

For example, compounds of formula (V) wherein m, R5 and R6 are as defined for compounds of formula (I), suitable protecting groups Pg such as for example phthalimido or alkoxycarbonyl, can be prepared starting from compounds of formula (VII) according to the method defined in scheme 3. The conditions that can be used are given in the chemical examples.

Scheme 3

The compounds of formula (VII) are commercially available or may be synthesized according to methods well known to those skilled in the art.

The compound of formula (VIII) may be synthesized according to the method described in Bulletin of the Chemical Society of Japan (1979), 52(10), 2938-41.

The compounds of formula (V) may be synthesized according to the methods described in WO96/14844 and Journal of organic chemistry (1981), 46(12), 2455-65.

Alternatively, compounds of formula (III) wherein R5 and R6 are as defined for compounds of formula (I) may be prepared according to the method defined in scheme 4.

Scheme 4

(in the above scheme, R1, R3, R4, R5 and R6 have the same meanings as already described)

The compounds of formula (IX) are commercially available or may be synthesized according to methods well known to those skilled in the art.

The compounds of formula (XI) can be synthesized according to the methods described in Ger (East) (1986), page 3, DD 238974.

In the above reaction, protection or deprotection of a functional group may sometimes be necessary. Suitable protecting groups Pg may be selected according to the type of functional group, and methods described in the literature may be employed. Examples of protecting groups, protection and deprotection methods are given, for example, in Greene et al Protective groups in Organic Synthesis, 3 rd edition (John Wiley & Sons, Inc., New York), 1999.

The compounds of the invention have inhibitory activity against GSK3 β. Accordingly, the compounds of the present invention are useful as active ingredients for the preparation of medicaments, which can prevent and/or treat diseases caused by abnormal GSK3 β activity, more particularly neurodegenerative diseases such as alzheimer's disease. In addition, the compounds of the present invention are also useful as active ingredients for the preparation of medicaments for the prevention and/or treatment of the following diseases: neurodegenerative diseases such as parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), wilson's disease, huntington's disease, prion diseases, and other dementias including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; amyotrophic lateral sclerosis, peripheral neuropathy; retinopathy and glaucoma; and other diseases such as non-insulin dependent diabetes mellitus (such as type II diabetes) and obesity; malaria, manic depressive illness; schizophrenia; alopecia; cancers such as colorectal cancer, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia, some virus-induced tumors, and bone-related pathologies. The medicament may also be used in regenerative medicine.

The invention further relates to a method for the treatment of neurodegenerative diseases caused by abnormal GSK3 β activity, said diseases comprising administering to a mammalian organism in need thereof an effective amount of a compound of formula (I).

As the active ingredient of the medicament of the present invention, a substance selected from the group consisting of the compound represented by the aforementioned formula (I) and a pharmacologically acceptable salt thereof, and a solvate thereof and a hydrate thereof can be used. The substance itself may be used as a medicament according to the invention, however, it is desirable to administer the medicament in the form of a pharmaceutical composition comprising 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 foregoing may be used in combination. The above pharmaceutical composition may be supplemented with an active ingredient of another drug for the treatment of the above diseases. The type of the pharmaceutical composition is not particularly limited, and the composition may be provided as any preparation for oral or parenteral administration. For example, the pharmaceutical composition may be prepared, 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 parenteral administration, such as injections, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories, and the like, for intravenous, intramuscular, or subcutaneous administration. Injections or infusion solutions may be prepared as powder preparations, for example, as freeze-dried preparations, and may be prepared by dissolving them in a suitable aqueous medium such as physiological saline immediately before use. Sustained release formulations such as those coated with polymers can be administered directly intracerebrally.

The type of the pharmaceutical additive used for preparing the pharmaceutical composition, the content ratio of the pharmaceutical additive with respect to the active ingredient, and the method for preparing the pharmaceutical composition may be appropriately selected by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Typically, the pharmaceutical additive may be added in an amount of 1% to 90% by weight based on the weight of the active ingredient.

Examples of excipients used in the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. For preparing liquid compositions for oral administration, conventional inert diluents such as water or vegetable oils may be used. The liquid composition may contain, in addition to the inert diluent, adjuvants such as wetting agents, suspending aids, sweeteners, aromatics, colorants, and preservatives. The liquid composition may be filled into capsules made of an absorbable material such as gelatin. Examples of solvents or suspension media for preparing compositions for parenteral administration, such as injections, suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like. Examples of base materials for suppositories include, for example, cocoa butter, emulsified cocoa butter, lauric lipid, witepsol.

The dose and frequency of administration of the drug of the present invention are not particularly limited, and may be appropriately selected depending on the circumstances such as the purpose of prevention and/or treatment, the type of disease, the body weight or age of the patient, the severity of the disease, and the like. In general, the daily dose for oral administration to an adult may be 0.01 to 1,000mg (weight of active ingredient), and the dose may be administered once a day, or divided into multiple portions to be administered multiple times a day, or administered once a few days. When the medicament is used as an injection, it is preferably administered to an adult continuously or intermittently in a daily dose of 0.001 to 100mg (weight of active ingredient).

Chemical examples

Example 1(Compound No.20 of Table 1)

Naphthalene-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

1.12-methyl-1H- [4, 4' ] bipyridinyl-6-one

To a suspension of 200g (2.11mol) of acetamidine hydrochloride (1: 1) in 1.2L of ethanol were added 84g (2.11mol) of sodium hydroxide and 410g (2.11mol) of ethyl 3- (4-pyrimidinyl) -3-oxopropanoate (prepared analogously to the process described in DE 2705582). The resulting mixture was stirred at reflux for 12 hours. The cooled solution was evaporated to remove the solvent. The mixture was treated with water and the precipitate was filtered, washed with diethyl ether and ethyl acetate. The precipitate was stirred in an ethanol/water mixture in a ratio of 2/1 to give 200g (50%) of the desired compound as a brown powder.

Mp：320-322℃。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：12.70(br s，1H)；9.30(s，1H)；9.00(d，1H)；8.20(d，1H)；7.15(s，1H)；2.40(s，3H)。

1.21, 2-dimethyl-1H- [4, 4' ] bipyridinyl-6-one

To a suspension of 96g (0.51mol) of 2-methyl-1H- [4, 4' ] bipyrimidinyl-6-one in 480mL of anhydrous dimethylformamide was added 77.55g (0.56mol) of potassium carbonate. The resulting mixture was stirred at room temperature for 15mn, cooled at 0 deg.C, and 31.78ml (0.51mol) of methyl iodide was added dropwise. The mixture was heated at room temperature and stirred for 3 hours. Cold water was added and the mixture was extracted with a mixture of chloroform/methanol at a ratio of 90/10, dried and evaporated. The residue was triturated with diisopropyl ether and filtered to give 81g (78%) of the pure product as a brown powder.

Mp：179-181℃。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)；9.30(s，1H)；9.00(d，1H)；8.25(d，1H)；7.20(s，1H)；3.55(s，3H)；2.60(s，3H)。

1.32-iodomethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one

To a suspension of 17g (0.084mol) of 1, 2-dimethyl-1H- [4, 4' ] bipyrimidinyl-6-one in 45mL of water was added 8.5mL of sulfuric acid, 25mL of carbon tetrachloride and 9.6g (0.037mol) of iodide. The resulting mixture was refluxed and 16.38mL of hydrogen peroxide (35% aqueous solution) was added dropwise. The mixture was stirred under reflux for 5 hours, cooled at room temperature, and 100mL of saturated aqueous ammonium chloride and 100mL of chloroform were added. The resulting precipitate was filtered off, the filtrate extracted with chloroform, dried and evaporated to give 13.6g of product, which was used as such in the next step.

1.42- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -isoindole-1, 3-dione

To a solution of 14.80g (45.11mmol) of 2-iodomethyl-1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one in 30ml of anhydrous dimethylformamide was added 16.71g (90.21mmol) of potassium phthalimide. The resulting mixture was stirred at 130 ℃ for 3 hours. After cooling, water was added and the resulting mixture was stirred at 0 ℃ for 12 h. The precipitate was filtered, heated in ethyl acetate, and the precipitate was filtered. The product was dried to give 5.3g (30%) of pure compound as a brown solid.

Mp：273-275℃。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.40(s，1H)；8.85(d，1H)；8.20(m，4H)；7.50(d，1H)；7.40(s，1H)；5.35(s，2H)；3.80(s，3H)

1.52-aminomethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one

To a solution of 5.3g (15.26mmol) of 2- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -isoindole-1, 3-dione in 40mL of ethanol was added 2.37mL (76.30mmol) of hydrazine hydrate, and the resulting mixture was heated under reflux for 3 hours. The mixture was filtered, the resulting solid was triturated with dichloromethane for 24 hours, filtered and the resulting filtrate was evaporated to dryness. The residue was triturated with ether and filtered to give 1.8g of pure compound as a solid.

Mp：153-155℃

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.40(s，1H)；9.10(d，1H)；8.50(d，1H)；7.30(s，1H)；3.95(s，2H)；3.50(s，3H)；2.15(br d，2H)。

1.6 naphthalene-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

To a solution of 0.07g (0.32mmol) of 2-aminomethyl-1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one in 6mL of tetrahydrofuran were added 50. mu.l (0.39mmol) of triethylamine and 0.074g (0.39mmol) of naphthalene-2-carbonyl chloride. The resulting mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous ammonium chloride solution, dried and evaporated. The residue was purified by preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in a ratio of 90/10/1 to give 0.045g (38%) of the desired compound as a white powder.

Mp：250-252℃。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.40(s，1H)；9.25(brs，1H)；8.90(d，1H)；8.60(d，1H)；8.20-8.00(m，5H)；7.50(brs，2H)；7.30(s，1H)；4.80(s，2H)；3.75(s，3H)。

Example 2(Compound No.4 of Table 1)

(+/-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

2.12-Ethyl-1H- [4, 4' ] bipyridinyl-6-one

By analogy withExample 1(step 1.1) Using propioamidine hydrochloride (1: 1) instead of acetamidine hydrochloride (1: 1), the compound was obtained as a brown powder.

Mp：227-229℃。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.30(s，1H)；9.10(d，1H)；8.30(d，1H)；7.15(s，1H)；3.50(brs，1H)；2.70(q，2H)；1.35(t，3H)。

2.22-Ethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one

By analogy withExample 1(step 1.2) Using 2-Ethyl-1H- [4, 4']Dipyrimidinyl-6-one for 1, 2-dimethyl-1H- [4, 4']Dipyrimidin-6-one to give the compound as a brown powder.

Mp.：150-152℃。

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.40(s，1H)；9.10(d，1H)；8.40(d，1H)；7.30(s，1H)；3.60(s，3H)；3.00(q，2H)；1.40(t，3H)。

2.3(+/-)2- (1-iodo-ethyl) -1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one

By analogy withExample 1(step 1.3) Using 2-Ethyl-1-methyl-1H- [4, 4']Dipyrimidinyl-6-one for 1, 2-dimethyl-1H- [4, 4']Bipyrimidinyl-6-one, which is used as such in the next step.

2.4(+/-)2- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -isoindole-1, 3-dione

By analogy withExample 1(step 1.4) Using (+/-)2- (1-iodo-ethyl) -1-methyl-1H- [4, 4']Dipyrimidinyl-6-one instead of 2-iodomethyl-1-methyl-1H- [4, 4']Bipyrimidinyl-6-one, which is used as such in the next step.

2.5(+/-)2- (1-amino-ethyl) -1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one

By analogy withExample 1(step 1.5) Using (+/-)2- [1- ((1-methyl-6-oxo-1, 6-dihydro- [4, 4']Dipyrimidinyl-2-yl) -ethyl-isoindole-1, 3-dione instead of 2- (1-methyl-6-oxo-1, 6-dihydro- [4, 4']Dipyrimidinyl-2-ylmethyl) -isoindole-1, 3-dione, giving the compound as a brown powder.

Mp.：158-160℃。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.40(s，1H)；9.20(d，1H)；8.70(d，1H)；8.50(brs，2H)；7.35(s，1H)；4.90(m，1H)；3.60(s，3H)；1.55(d，3H)。

2.6(+/-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

To a solution of 0.112g (0.48mmol) of (+/-)2- (1-amino-ethyl) -1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one in 5mL of dimethylformamide were added 0.082g (0.48mmol) of 4-fluoro-2-methoxybenzoic acid and 90. mu.l (0.58mmol) of diethyl cyanophosphate (DEPC). The resulting mixture was cooled at 0 ℃ and 70. mu.l (0.53mmol) of triethylamine was added and stirred at room temperature for 1 hour. Water was added and the mixture was extracted with diethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, dried and evaporated. The residue was purified by preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia (29%) in a ratio 95/5/0.5 to give 0.12g (66%) of the desired compound as a white powder.

Mp.：201-203℃。

RMN¹H(DMSO-d⁶，200MHz)

δ(ppm)：9.40(s，1H)；9.20(d，1H)；8.90(d，1H)；8.30(d，1H)；7.90(m，1H)；7.30(S，1H)；7.15(m，1H)；6.90(m，1H)；5.50(m，1H)；3.90(s，3H)；3.60(s，3H)；1.65(d，3H)。

Example 3(Compound No.5 of Table 1)

4-fluoro-2-methoxy-N- [ 1-methyl-1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

[ 1-methyl-1- (6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -carbamic acid benzyl ester

By analogy withExample 1(step 1.1) Using (1-Iminoformyl (Carbamimidyl) -1-methyl-ethyl) -carbamic acid benzyl ester hydrochloride (1: 1) instead of acetamidine hydrochloride (1: 1), the compound was obtained as a brown powder.

Mp：210-212℃

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.30(s，1H)；9.00(d，1H)；8.20(d，1H)；7.50(brs，1H)；7.30(m，5H)；7.10(s，1H)；5.00(s，2H)；1.60(s，6H)。

[ 1-methyl-1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -carbamic acid benzyl ester

To a suspension of 0.13g (0.36mmol) of [ 1-methyl-1- (6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -carbamic acid benzyl ester in 1.5ml of anhydrous dioxane was added 0.003g (0.39mmol) of lithium hydride. The resulting mixture was stirred at 40 ℃ for 45 mn. After cooling to room temperature, 0.058g (0.46mmol) of dimethyl sulfate was added and the reaction mixture was heated at 60 ℃ for 12 hours. After cooling to 0 ℃, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried and evaporated. The residue was purified by preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in a ratio of 95/5/0.5 to give 0.015g (11%) of the desired compound as a colourless oil.

RMN¹H(CDCl3；200MHz)

δ(ppm)：9.30(s，1H)；8.80(d，1H)；8.10(brs，1H)；7.50(brs，1H)；7.30-7.10(m，5H)；4.90(brs，2H)；3.60(s，3H)；1.70(brs，6H)。

3.32- (1-amino-1-methyl-ethyl) -1-methyl-1H- [4, 4' ] bipyridinyl-6-one hydrobromide

0.015g (0.04mmol) of [2- (1-methyl-6-oxo-1, 6-dihydro [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -carbamic acid benzyl ester was dissolved in 0.017g (0.04mmol) of hydrobromic acid in acetic acid. The resulting mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether to give 0.012g of pure product as a yellow oil.

RMN ¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.30(s，1H)；9.00(d，1H)；8.20(d，1H)；7.20(s，1H)；3.50(s，3H)；3.25(brs，2H)；3.10-2.80(m，4H)。

3.4.4-fluoro-2-methoxy-N- [ 1-methyl-1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

By analogy withExample 2(step 2.6) Using 2- (1-amino-1-methyl-ethyl) -1-methyl-1H- [4, 4']Dipyrimidinyl-6-one hydrobromide instead of (+/-)2- (1-amino-ethyl) -1-methyl-1H- [4, 4']Dipyrimidin-6-one to give the compound as a white powder.

Mp.：200-202℃。

RMN ¹H(CDCL3；200MHz)δ(ppm)：9.20(s，1H)；8.80(d，1H)；8.20(d，1H)；8.00(m，2H)；7.50(s，1H)；6.70(m，2H)；4.00(s，3H)；3.60(s，3H)；1.80(s，6H)。

Example 4(Compound No.33 of Table 1)

(+) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

0.105g (0.27mmol) of (+/-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4 'are isolated by chiral preparative HPLC (Daicel CHIRALCEL AD-H20 μm 50X 220)']Dipyrimidinyl-2-yl) -ethyl]Benzamide (compound 4 of table 1), eluting with isopropanol, to give 0.045g of pure product in free base form. t is t_R：8.3min。

Mp.：158-160℃。[α]_D ²⁰＝+17.43°(c＝0.272，DMSO)。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.40(s，1H)；9.20(d，1H)；8.90(d，1H)；8.30(d，1H)；7.90(m，1H)；7.30(s，1H)；7.15(m，1H)；6.90(m，1H)；5.50(m，1H)；3.90(s，3H)；3.60(s，3H)；1.65(d，3H)。

Example 5(Compound No.34 of Table 1)

(-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

0.105g (0.25mmol) of (+/-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4 'are isolated by chiral preparative HPLC (Daicel CHIRALCEL AD-H20 μm 50X 220)']Dipyrimidinyl-2-yl) -ethyl]Benzamide (compound 4 of table 1), eluting with isopropanol, to give 0.048g of pure product in free base form. t is t_R：13.7min.

Mp.：158-160℃。[α]_D ²⁰＝-17.59°(c＝0.079，DMSO)。

RMN¹H(DMSO-d⁶；200MHz)

δ(ppm)：9.40(s，1H)；9.20(d，1H)；8.90(d，1H)；8.30(d，1H)；7.90(m，1H)；7.30(s，1H)；7.15(m，1H)；6.90(m，1H)；5.50(m，1H)；3.90(s，3H)；3.60(s，3H)；1.65(d，3H)。

A series of chemical structures and physical data for the compounds of formula (I) set forth above to illustrate the invention are given in table 1. The compounds have been prepared according to the methods of the examples. In table 1, Ph represents phenyl, (Rot.) refers to the levorotatory or dextrorotatory nature of the enantiomeric compound, and m is 0.

TABLE 1

Test examples: the inhibitory activity of the drug of the invention on GSK3 beta:

two different experimental designs may be used.

In the first experimental design: in the presence of GSK3 beta (total reaction volume: 100. mu.l), at room temperature, in 25mM Tris-HCI, pH 7.5, 0.6mM DTT, 6mM MgCl₂7.5. mu.M of the pre-phosphorylated GS1 peptide and 10. mu.M of ATP (containing 300,000cpm of 33P-ATP) were incubated for 1 hour in 0.6mM EGTA, 0.05mg/ml BSA buffer.

In a second experimental design: 4.1 μ M of the pre-phosphorylated GS1 peptide and 42 μ M ATP (containing 260,000 cpm) were cultured in 80mM MES-NaOH, pH 6.5, 1mM Mg acetic acid, 0.5mM EGTA, 5mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer at room temperature in the presence of GSK3 β³³P-ATP) for 2 hours. The inhibitors were dissolved in DMSO (final solvent concentration in the reaction medium, 1%).

The reaction was stopped with 100 microliters of the following solutions: with 25g of polyphosphoric acid (85% P)₂O₅) 126ml of 85% H₃PO₄Then, water was added to 500ml to prepare a solution, which was then diluted 1: 100 before use. Aliquots of the reaction mixture were then transferred to Whatman P81 cation exchange filters and washed with the above solution. Determination of binding by liquid scintillation spectrometry³³P is radioactive.

The phosphorylated GS-1 peptide has the following sequence:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.(Woodgett，J.R.(1989)Analytical Biochemistry 180，237-241。

IC for GSK3 beta inhibitory Activity of Compounds of the present invention₅₀Shows, as an example, the IC of the compounds in Table 1₅₀In the range of 0.1 nanomolar to 3 micromolar. For example, IC shown in Compound No.1 of Table 1₅₀It was 0.023 μ M.

Formulation examples

(1) Tablet formulation

The following components were mixed by a conventional method and pressed using a conventional apparatus.

Compound of example 130 mg

Crystalline cellulose 60mg

Corn starch 100mg

Lactose 200mg

Magnesium stearate 4mg

(2) Soft capsule

The following components were mixed by a conventional method and filled in a soft capsule.

Compound of example 130 mg

Olive oil 300mg

Lecithin 20mg

(1) Parenteral formulations

The following components were mixed by a conventional method to prepare an injection contained in a 1ml ampoule.

Compound of example 13 mg

Sodium chloride 4mg

1ml of distilled water for injection

Industrial applicability

The compounds of the present invention have GSK3 beta inhibitory activity and are useful as active ingredients of medicaments for the prevention and/or treatment of diseases caused by abnormal GSK3 beta activity, more particularly neurodegenerative diseases.

Claims (18)

1. A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein

X represents two hydrogen atoms, sulfur atoms, oxygen atoms or C_1-2Alkyl and hydrogen atoms;

z represents a bond, an oxygen atom, a hydrogen atom or C_1-3Alkyl-substituted nitrogen atom, sulfur atom, optionally substituted by one or two members selected from C_1-6Alkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkyl or amino substituted methylene;

r1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, said ring being optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen atom substitution;

r2 represents a benzene ring, a naphthalene ring or a benzyl group; said ring being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-3Haloalkyl, hydroxy, optionally substituted by C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7alkyl-C_1-6Heteroaryl substituted by alkyl, optionally substituted by C_3-7Cycloalkyl-substituted C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Alkylsulfonyl, nitro, cyano, amino, C_1-6Monoalkylamino or C_2-12Dialkylamino, acetoxy, or aminosulfonyl;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r4 represents a hydrogen atom or C_1-6An alkyl group;

r5 represents a hydrogen atom or C_1-6An alkyl group;

r6 represents a hydrogen atom or C_1-6An alkyl group;

r7 represents a hydrogen atom or C_1-6An alkyl group;

n represents a number of 0 to 3,

and m represents 0 and m represents a number of,

in the form of the free base or of an addition salt with an acid.

2. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein R1 represents an unsubstituted 4-pyrimidine ring.

3. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein:

r1 represents a 4-or 5-pyrimidine ring or a 4-pyridine ring, said ring being optionally substituted by C_1-2Alkyl radical, C_1-2Alkoxy or halogen atom substitution; and/or

R2 represents a benzene ring, a naphthalene ring or a benzyl group; said ring being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-3Haloalkyl, hydroxy, optionally substituted by C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Heteroaryl substituted by alkyl, optionally substituted by C_3-5Cycloalkyl-substituted C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Alkylsulfonyl, nitro, cyano, amino, C_1-3Monoalkylamino or C_2-6Dialkylamino, acetoxy, or aminosulfonyl; and/or

R3 represents a hydrogen atom or C_1-6An alkyl group or a halogen atom; and/or

R4 represents a hydrogen atom or C_1-6An alkyl group; and/or

R5 represents a hydrogen atom or C_1-6An alkyl group; and/or

R6 represents a hydrogen atom or C_1-6An alkyl group; and/or

R7 represents a hydrogen atom or C_1-6An alkyl group; and/or

X represents two hydrogen atoms, oxygen atoms or C_1-2Alkyl and hydrogen atoms; and/or

Z represents a bond, an oxygen atom, a hydrogen atom or C_1-3Nitrogen atoms substituted by alkyl radicals, optionally substituted by one or two radicals selected from C_1-3Alkyl, hydroxy, C_1-3Alkoxy radical, C_1-2Perhaloalkyl or amino substituted methylene; and/or

n represents 0 to 3 in the form of the free base or of an addition salt with an acid.

4. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein:

r1 represents a 4-pyridine ring; and/or

R2 represents a benzene ring, a naphthalene ring or a benzyl group; said ring being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl, halogen atoms, amino groups, C_1-2Perhaloalkyl radical, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy or optionally substituted by C_1-6An alkyl substituted oxadiazole; and/or

R3 represents a hydrogen atom; and/or

R4 represents methyl; and/or

R5 represents a hydrogen atom or a methyl group; and/or

R6 represents a hydrogen atom or a methyl group; and/or

R7 represents a hydrogen atom; and/or

X represents an oxygen atom; and/or

n represents 0 in the form of the free base or of an addition salt with an acid.

Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom; and/or.

5. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, which is selected from the group consisting of:

2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

5-chloro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

4-fluoro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

(+/-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -benzamide

(-) -4-fluoro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -benzamide

4-fluoro-2-methoxy-N- [ 1-methyl-1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

4-chloro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

1- (4-fluoro-phenyl) -3- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -urea

1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -3-phenyl-urea

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

3-fluoro-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

4-amino-5-chloro-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -4-trifluoromethyl-benzamide

2-fluoro-6-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2-chloro-5-fluoro-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

5-bromo-2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

4-fluoro-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -2-trifluoromethyl-benzamide

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -trifluoromethoxy-benzamide

2, 6-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

Naphthalene-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 3-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2, 5-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

2-methoxy-4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -benzamide

(+/-) 2-methoxy-4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -benzamide

(+/-) 5-bromo-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -benzamide

(+/-) N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 4-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-)2, 4-dimethoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-)2, 6-dimethoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 4-amino-5-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide

(+/-) 2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -4-trifluoromethyl-benzamide

(+/-) [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -carbamic acid benzyl ester

(+) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -4-trifluoromethyl-benzamide

(-) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -4-trifluoromethyl-benzamide

(+) -4-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -benzamide

(-) -4-chloro-2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -benzamide.

6. A medicament comprising as an active ingredient a substance selected from the group consisting of: a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof according to claims 1 to 5.

A GSK3 β inhibitor selected from a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1.

8. A compound according to claims 1 to 5 for use in the prophylactic and/or therapeutic treatment of diseases which are caused by abnormal GSK3 β activity.

9. A compound according to claims 1 to 5 for use in the prophylactic and/or therapeutic treatment of a neurodegenerative disease.

10. The compound according to claim 9, wherein the neurodegenerative disease is selected from alzheimer's disease, parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injury; cerebrovascular accident, brain marrow trauma, spinal cord trauma; peripheral neuropathy; retinopathy or glaucoma.

11. A compound according to claims 1 to 5 for use in the prophylactic and/or therapeutic treatment of non-insulin dependent diabetes mellitus; obesity; manic depressive illness; schizophrenia; alopecia; cancer; substantial kidney disease or muscle atrophy.

12. A compound according to claim 11 wherein the cancer is breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia or a virus-induced tumor.

13. A compound according to claims 1 to 5 for the prophylactic and/or therapeutic treatment of malaria.

14. A compound according to claims 1 to 5 for the prophylactic and/or therapeutic treatment of bone diseases.

15. A compound according to claims 1 to 5 for use in the prophylactic and/or therapeutic treatment of pemphigus vulgaris.

16. A compound according to claims 1 to 5 for the prophylactic and/or therapeutic treatment of neutropenia induced by cancer chemotherapy.

17. Compounds according to claims 1 to 5 for the therapeutic treatment of characteristic diseases which represent cognitive and memory deficits.

18. A pyrimidone derivative represented by formula (III),

wherein R1, R3, R4, R5, R6 and m are as defined for a compound of formula (I) according to claim 1.