HK1085742B - Substituted 2-(diaza-bicyclo-alkyl)-pyrimidone derivatives - Google Patents

Description

Substituted 2- (diaza-bicyclo-alkyl) -pyrimidone derivatives

Technical Field

The present invention relates to a compound useful as an active ingredient in a prophylactic and/or therapeutic agent for neurodegenerative diseases 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 the control of metabolism, differentiation and survival. It was originally identified as an enzyme that phosphorylates and thus inhibits glycogen synthase. It was later recognized that GSK3 β and tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein at an epitope, are the same enzyme. This epitope is also found to be hyperphosphorylated in alzheimer's disease and several tauopathies (taupathy). Interestingly, protein kinase b (akt) phosphorylation of GSK3 β results in loss of its kinase activity, and it has been hypothesized that this inhibition may mediate some of the effects of neurotrophic factors. Moreover, phosphorylation of β -catenin, a protein involved in cell survival, by GSK3 β causes its degradation through an ubiquitination-dependent proteasome pathway.

Thus, it appears that inhibition of GSK3 β activity may lead to neurotrophic activity. Indeed, it is argued that lithium, an uncompetitive inhibitor of GSK3 β, enhances neurogenesis in certain models by inducing survival factors such as Bcl-2 and inhibiting the expression of pro-apoptotic factors such as P53 and Bax, and also increases neuronal survival.

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

Although tau hyperphosphorylation leads to destabilization of the neuronal cytoskeleton, the pathological consequences of abnormal GSK3 β activity are most likely not only due to pathological phosphorylation of tau protein, since, as mentioned above, overactivity of this kinase may influence survival by modulating the expression of apoptotic and anti-apoptotic factors. Furthermore, it has been shown that amyloid-beta-induced increase in GSK3 β activity results in phosphorylation of pyruvate dehydrogenase thereby inhibiting the enzyme. Pyruvate dehydrogenase is a key enzyme in energy production and acetylcholine synthesis.

All these experimental observations point to the possible use of GSK3 β in the treatment of neuropathological consequences and cognitive and attention deficits associated with alzheimer's disease as well as other acute and chronic neurodegenerative diseases. These diseases include, but are not limited to, parkinson's disease, tauopathy (e.g., fronto-temporal parietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, 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; peripheral neurodegenerative diseases; retinopathy and glaucoma.

In addition, GSK3 β may find use in the treatment of other diseases, such as non-insulin dependent diabetes (e.g. type II diabetes) and obesity; maniac depressive disorder; schizophrenia; alopecia; cancers such as breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia and some virus-induced tumors.

Thus, it appears that inhibition of GSK3 β activity may lead to neurotrophic activity. Indeed, it is argued that lithium (a non-competitive inhibitor of GSK3 β) enhances synaptogenesis and also increases neuronal survival in certain models by inducing survival factors such as Bcl-2 and inhibiting the expression of pro-apoptotic factors such as P53 and Bax.

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

Although tau hyperphosphorylation leads to destabilization of the neuronal cytoskeleton, the pathological consequences of abnormal GSK3 β activity are most likely not only due to pathological phosphorylation of tau protein, since, as mentioned above, overactivity of this kinase may influence survival by modulating the expression of apoptotic and anti-apoptotic factors. Furthermore, it has been shown that amyloid-beta-induced increase in GSK3 β activity results in phosphorylation of pyruvate dehydrogenase thereby inhibiting the enzyme. Pyruvate dehydrogenase is a key enzyme in energy production and acetylcholine synthesis.

Disclosure of Invention

An object of the present invention is to provide a compound useful as an active ingredient in a medicament for the prophylaxis and/or treatment of diseases caused by abnormal activity of GSK3 β, more specifically, neurodegenerative diseases caused by abnormal activity of GSK3 β. In particular, it is an object of the present invention to provide novel compounds useful as active ingredients in medicaments for the prevention and/or treatment of neurodegenerative diseases such as alzheimer's disease.

Thus, the present inventors have identified compounds having inhibitory activity against GSK3 β. As a result, they have found that GR compounds represented by the following formula (I) have desired activities and are useful as active ingredients in medicaments for the prophylaxis and/or treatment of the above-mentioned diseases.

The present invention therefore provides a 2- (diaza-bicyclo-alkyl) -pyrimidone derivative represented by formula (I) or a salt thereof, a solvate thereof, or a hydrate thereof:

wherein:

r1 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r2 represents a hydrogen atom, C_1-6Alkyl (optionally substituted with 1-4 substituents selected from halogen, hydroxy or C_1-4Alkoxy group), C_1-2Perhalogenated alkyl, benzyl, phenethyl, benzyloxycarbonyl, C_1-4Alkoxycarbonyl, a benzene ring, a naphthalene ring, a quinoline ring, a 2, 3-naphthyridine ring, a 5, 6, 7, 8-tetrahydronaphthalene ring, a pyridine ring, an indole ring, a pyrrole ring, a thiophene ring, a benzenesulfonyl group, a benzoyl group, a pyridazine ring, a furan ring, or an imidazole ring; benzyl, phenethyl, benzyloxycarbonyl, benzenesulfonyl, benzoyl and the ring may be optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl, benzene ring, halogen atom, C_1-2Perhalogenated alkyl, C_1-3Haloalkyl, hydroxy, C_1-4Alkoxy, nitro, cyano, amino, C_1-6Monoalkylamino or C_3-10A dialkylamino group;

r3 represents a 2, 4, or 5-pyrimidine ring or a 2, 3 or 4-pyridine ring, these rings optionally being substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen atom substitution;

r4 represents C_1-4Alkyl, optionally substituted by hydroxy, C_1-4Alkoxy or halogen atom substitution; n represents 1 or 2.

In 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), a physiologically acceptable salt thereof, a solvate thereof, and a hydrate thereof. As a preferred pharmaceutical embodiment, there is provided the above-mentioned medicament useful for the prevention and/or treatment of diseases caused by abnormal activity of GSK3 β, and for the prevention and/or treatment of neurodegenerative diseases and other diseases such as non-insulin dependent diabetes (e.g., type II diabetes) and obesity; maniac depressive disorder; schizophrenia; alopecia; such drugs for cancer (e.g., breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and some virus-induced tumors).

In another preferred embodiment of the present invention, there is provided the medicament as described above, wherein said disease is a neurodegenerative disease selected from the group consisting of alzheimer's disease, parkinson's disease, tauopathy (e.g. dementia with frontal and temporal parietal (frontotemporal), degeneration of cerebral cortex (corticobasal), pick's disease, progressive supranuclear palsy) 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; peripheral neurodegenerative diseases; retinopathy and glaucoma; the above-mentioned medicaments are presented in the form of pharmaceutical compositions containing the above-mentioned substances as active ingredients in admixture with one or more pharmaceutical additives.

The present invention also provides an inhibitor of GSK3 β activity, comprising as an active ingredient a substance selected from the group consisting of: 2- (diaza-bicyclo-alkyl) -pyrimidone derivatives of formula (I) and salts thereof, solvates thereof, and hydrates thereof.

In 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, the method comprising the step of administering to a patient a prophylactically and/or therapeutically effective amount of a compound selected from the group consisting of: 2- (diaza-bicyclo-alkyl) -pyrimidone derivatives of formula (I), physiologically acceptable salts thereof, solvates thereof and hydrates thereof; and the use of a substance selected from the group consisting of: 2- (diaza-bicyclo-alkyl) -pyrimidone derivatives of formula (I), physiologically acceptable salts thereof, solvates thereof, and hydrates thereof.

C as used herein_1-6Alkyl represents a straight or branched chain having 1 to 6 carbon atomsAn alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl and the like;

C_1-4alkoxy 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;

C_1-2perhaloalkyl represents alkyl in which all hydrogens have been replaced by halogen, e.g. CF₃Or C₂F₅；

C_1-3Haloalkyl represents alkyl in which at least one hydrogen is not substituted by a halogen atom;

C_1-6monoalkylamino radicals being represented by a C_1-6Alkyl-substituted amino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino;

C_2-10dialkylamino represents two C_1-5Alkyl-substituted amino groups, such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino;

the leaving group represents a group which is easily cleaved and substituted, such as tosyl, mesyl, bromo, etc.

The compound represented by the above formula (I) may form a salt. Examples of the salts include, when an acidic group is present, salts of alkali metals or 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-glucamine; or salts with basic amino acids, such as lysine, -hydroxylysine and arginine. Base addition salts of acidic compounds are prepared according to standard procedures known in the art.

When a basic group is present, examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids, such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid and salicylic acid; or salts with acidic amino acids such as aspartic acid, glutamic acid.

Acid addition salts of basic compounds are prepared by standard procedures known in the art including, but not limited to, dissolving the free base in a hydroalcoholic solution containing the appropriate acid, isolating the salt by evaporating the solution, or reacting the free base and acid in an organic solvent, in which case the salt is isolated directly, or precipitated with a second organic solvent, or may be obtained by concentrating the solution. Acids which may be used to prepare acid addition salts preferably include those which, when combined with the free base, produce a pharmaceutically acceptable salt, i.e., whose anion is relatively harmless to animal tissue at the pharmaceutical dosage of the salt, so that the beneficial properties inherent in the free base are not impaired by the side effects produced by the anion. Although it is preferred to use pharmaceutically acceptable salts of the basic compounds, all acid addition salts are within the scope of the invention.

In addition to the 2- (diaza-bicyclo-alkyl) -pyrimidone derivatives of formula (I) and salts thereof described above, solvates and hydrates thereof are also within the scope of the present invention. The 2- (diaza-bicyclo-alkyl) -pyrimidone derivatives of formula (I) above may have one or more asymmetric carbon atoms. The stereochemistry of such asymmetric carbon atoms may be independently in the (R) and (S) configurations, while the derivatives may exist as stereoisomers, such as optical isomers or diastereomers. Any stereoisomer in pure form, any mixture of stereoisomers, racemates and the like are 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 embodiment of the invention represented by formula (I) also includes compounds wherein R3 represents a 4-or 5-pyrimidine ring, more preferably a 4-pyrimidine ring, or R3 represents a 3-or 4-pyridine ring, more preferably a 4-pyridine ring, which rings may optionally be substituted by C_1-2Alkyl radical, C_1-2Alkoxy or halogen atom.

Another embodiment of the present invention includes the following compounds represented by formula (I):

(1) a compound wherein R1 represents a hydrogen atom, C_1-3An alkyl group or a halogen atom; more preferably a hydrogen atom; and/or

(2) A compound wherein when R3 represents an optionally substituted pyrimidine ring, R2 represents a hydrogen atom, benzyl, phenethyl, benzyloxycarbonyl, C_1-4Alkoxycarbonyl, a benzene ring, a quinoline ring, a 2, 3-naphthyridine ring, a pyridine ring, benzenesulfonyl, benzoyl or pyridazine ring; benzyl, phenethyl, benzyloxycarbonyl, benzenesulfonyl, benzoyl and these rings may be optionally substituted with 1 to 4 substituents; or when R3 represents an optionally substituted pyridine ring, R2 represents a hydrogen atom, C_1-4Alkoxycarbonyl, pyridine ring, benzene ring, naphthalene ring, benzyl, benzoyl; these groups or rings may be optionally substituted; and/or

(3) A compound wherein R3 represents an unsubstituted 4-pyrimidine ring; and/or

(4) R4 represents C_1-2Alkyl, preferably methyl.

Specific compounds of the invention represented by formula (I) wherein R3 is a pyrimidine ring include the following compounds:

1: (1S) -1-methyl-2- [5- (5-phenyl-pyridin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1H- [4, 4' ] bipyridinyl-6-one,

2: (1S) -1-methyl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

3: (1S) -1-methyl-2- (5-quinolin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

4: (1R) -1-methyl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

5: (1S) -2- [5- (4-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

6: (1R) -2- [5- (6-chloro-quinolin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

7: (1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) 2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester,

8: (1S) -2- [5- (6-bromo-pyridin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

9: (1S) -2- [5- (6-chloro-pyridazin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

10: (1S) -2- [5- (5-bromo-pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

11: (1S) -2- [5- (4-chloro-2, 3-naphthyridin-1-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

12: (1S) -2- [5- (4-chloro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

13: (1S) -2- [5- (3-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

14: (1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

15: (1S) -1-methyl-2- (5-p-tolyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

16: (1S) -2- (5-benzoyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

17: (1S) -1-methyl 2- [5- (toluene-4-sulfonyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1H- [4, 4' ] bipyrimidin-6-one,

18: (1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid benzyl ester,

19: (1S) -1-methyl-2- (5-phenethyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1H- [4, 4' ] bipyrimidin-6-one,

20: (1S) -2- (5-benzyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

21: (1S) -2- [5- (2(S) -hydroxy-2-phenyl-ethyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

22: (1S) -1-methyl-2- (5-pyridin-2-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

23: (1S) -1-methyl-2- (5-pyridin-4-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

24: (1S) -2- (5- (4-bromo-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

25: (1S) -2- (5- (4-chloro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

26: (1S) -2- (5- (4-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

27: (1S) -2- (5- (4-methoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

28: (1S) -2- (5- (4-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

29: (1S) -2- (5- (4-phenyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

30: (1S) -2- (5- (4-trifluoromethyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

31: (1S) -2- (5- (3-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

32: (1S) -2- (5- (3-methoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

33: (1S) -2- (5- (3-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

34: (1S) -2- (5- (3-bromo-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

35: (1S) -2- (5- (3-cyano-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

36: (1S) -2- (5- (3-chloro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one; and a compound of the present invention represented by formula (I), wherein R3 is a pyridine ring:

1': (1S) -5- (1-methyl-6-oxo-4-pyridin-4-yl-1, 6-dihydro-pyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester,

2': (1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3': (1S) -2- [5- (4-chloro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

4': (1S) -3-methyl-6-pyridin-4-yl-2- (5-p-tolyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3H-pyrimidin-4-one,

5': (1S) -2- [5- (4-bromo-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

6': (1S) -2- [5- (4-chloro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

7': (1S) -2- (5-benzyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

8': (1S) -2- [5- (4-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

9': (1S) -2- [5- (4-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

10': (1S) -2- [5- (4-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

11': (1S) -2- [5- (3-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

12': (1S) -3-methyl-6-pyridin-4-yl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3H-pyrimidin-4-one,

13': (1S) -2- [5- (3-methoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

14': (1S) -2- [5- (3-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

15': (1S) -2- [5- (4-ethoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

16': (1S) -2- [5- (4-trifluoromethyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

17': (1S) -2- [5- (4-phenyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one, and

18': (1S) -2- [5- (3-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.

As a further object, the present invention also relates to a process for preparing the 2- (diaza-bicyclo-alkyl) -pyrimidone compound represented by the above formula (I).

These compounds can be prepared, for example, by the following methods.

Preparation method

2- (diaza-bicyclo-alkyl) -pyrimidone compounds represented by the above formula (I), wherein R2 is as defined above but is not hydrogen, can be prepared according to the method of reaction formula 1.

Reaction scheme 1

(in the above reaction scheme, R1, R3, R4 and n are as defined for the compound of formula (I)).

According to this process, a pyrimidone derivative represented by the above formula (II) wherein R1, R3, R4 and n are as defined for the compound of the formula (I) is reacted with a compound of the formula (III) wherein R2 is as defined for the compound of the formula (I) but is not hydrogen, according to a method known in the art. For example, the reaction may be carried out in the presence of a base such as an alkoxide, amine or carbonate base (e.g. sodium tert-butoxide, triethylamine or cesium carbonate) in a solvent such as tetrahydrofuran or dimethylformamide and the like to give the compound of formula (I).

More particularly, when R2 is aryl or heteroaryl as defined for a compound of formula (I), the reaction can be carried out by palladium catalysed amination as described in Buchwald et al (J.org.chem.1997, 62, 6066-. That is, the reaction is carried out in an inert atmosphere in the presence of an alkoxide, amine or carbonate base (e.g., sodium tert-butoxide, triethylamine or cesium carbonate) and a palladium catalyst (e.g., palladium (II) acetate with a ligand such as (R) - (+) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl) in a solvent such as tetrahydrofuran, dimethylformamide, tetraglyme or polyethylene glycol at a suitable temperature (25 to 130 ℃).

Alternatively, 2- (diaza-bicyclo-alkyl) -pyrimidone compounds represented by formula (I) above, wherein R2 is as defined above for the compound of formula (I), can be prepared according to reaction scheme 2.

Reaction formula 2

(in the above reaction scheme, R1, R2, R3, R4 and n are as defined above for the compound of formula (I)). According to this process, a compound of formula (XI) wherein R1, R3, R4 are as described for the compound of formula (I) and L represents a leaving group such as an oxygen and bromine atom, is reacted with a compound of formula (X) wherein n and R2 are as defined for the compound of formula (I). The reaction can be carried out in the presence of a base such as sodium hydride or triethylamine in a solvent such as dimethylformamide or tetrahydrofuran at a temperature in the range of 20-60 ℃.

The compound of formula (II) may be prepared according to the process of reaction scheme 3.

Reaction formula 3

(in the above reaction scheme, R1, R3, R4 and n are as defined above for the compound of formula (I)).

According to this process, a 3-keto ester of formula (IV), wherein R1 and R3 are as defined for the compound of formula (I) and R is an alkyl group such as methyl or ethyl, is reacted with an N-alkylthiourea of formula (V), wherein R4 is as defined for the compound of formula (I). The reaction may be carried out in the presence of a base such as 1, 8-diazabicyclo [5.4.0] undec-7-ene in an alcohol solvent such as ethanol, at a suitable temperature range of 25-140 ℃ in air, to give the thiopyrimidinone derivatives of formula (VI). The thiopyrimidone derivative of formula (VI) is reacted with phosphorus oxychloride in a solvent such as dimethylformamide at a suitable temperature range of 0-55 deg.C under argon atmosphere to give the 2-chloropyrimidinone derivative of formula (VII). The compound of formula (VII) is then reacted with a compound of formula (VIII) wherein Pg is a protecting group such as tert-butyloxycarbonyl, in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran at a suitable temperature range of 0-25 ℃ to give a compound of formula (IX). The compound of formula (IX) is then deprotected according to methods known in the art, for example when the protecting group is t-butyloxycarbonyl, in the presence of trifluoroacetic acid in a solvent such as dichloromethane at room temperature to give the compound of formula (II) above.

Alternatively, compounds of formula (II) wherein R1 represents a halogen atom such as a bromine atom or a chlorine atom, can be obtained by halogenation of compounds of formula (II) wherein R1 is hydrogen. The reaction can be carried out in an acidic medium such as acetic acid or propionic acid in the presence of bromosuccinimide or chlorosuccinimide or bromine.

Furthermore, the compounds of the formula (II) in which R1 represents a fluorine atom can be prepared in analogy to Tetrahedron Letters, Vol.30, No. 45, p.6113-6116, 1989.

The compounds of the formulae (III), (IV), (V), (VIII), (IX), (X) are commercially available or can be prepared by methods known to the person skilled in the art.

For example, compounds of formula (IV) wherein R3 and R1 are as defined for compounds of formula (I) and R is alkyl such as methyl and ethyl may be prepared by reacting a pyrimidine carboxylic acid or pyridine carboxylic acid (optionally substituted with C)_1-4Alkyl radical, C_1-4Alkoxy or halogen atom substituted) with the corresponding malonic acid monoester. The reaction can be carried out by methods known in the art, for example, in the presence of a coupling agent such as 1, 1' -carbonyldi-1H-imidazole in a solvent such as tetrahydrofuran at a temperature in the range of 20-70 ℃.

For example, compounds of the formula (VIII) having the absolute configuration (1R) can be prepared according to European patent EP-400661.

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

In the above reaction, protection and deprotection of a functional group is sometimes necessary. The appropriate protecting group Pg may be selected according to the type of functional group, and the methods described in the literature may be used. Examples of protecting Groups, methods of protection and deprotection are found, for example, in Greene et al Protective Groups in organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York).

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 for the prevention and/or treatment of diseases caused by abnormal GSK3 beta activity, more particularly neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention can be used as active ingredients for the preparation of medicaments useful for the prevention and/or treatment of neurodegenerative diseases. These diseases include, but are not limited to, parkinson's disease, tauopathy (e.g., frontotemporal parietal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy) 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; peripheral neurodegenerative diseases; retinopathy and glaucoma; other diseases such as non-insulin dependent diabetes (e.g., type II diabetes) and obesity; maniac depressive disorder; schizophrenia; alopecia; cancers (e.g., breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and some virus-induced tumors).

The invention also relates to methods of treating neurodegenerative diseases caused by abnormal GSK3 beta activity and to methods of the above diseases comprising administering to a mammal in need thereof an effective amount of a compound of formula (I).

As an active ingredient of the medicament of the present invention, a substance selected from the compounds represented by the above formula (I) and pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof can be used. The substance itself may be used as the medicament of the present invention, but it is more desirable to administer the medicament in the form of a pharmaceutical composition comprising the above-mentioned substance as an active ingredient and one or more pharmaceutically acceptable additives. As the active ingredient of the medicament of the present invention, two or more of the above-mentioned compounds may be used in combination. The pharmaceutical composition may be supplemented with other drugs for treating the above diseases. The type of the pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the compositions may be formulated as oral compositions, such as capsules, microcapsules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, and the like, or as compositions for parenteral administration, such as intravenous, intramuscular, or subcutaneous injection, infusion drops, transdermal preparations, transmucosal preparations (nasal drops), inhalants, suppositories, and the like. Injections or drops for infusion can be prepared as powder preparations such as freeze-dried preparations, which are dissolved in a suitable aqueous medium such as physiological saline before use. Sustained release formulations such as those coated with polymers can be administered directly into the brain.

The type of the pharmaceutical additive used for manufacturing the pharmaceutical composition, the content ratio of the pharmaceutical additive 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. In general, the pharmaceutically acceptable additives may be incorporated in an amount of 1 to 90% by weight based on the weight of the active ingredient.

Examples of excipients used to prepare 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, conventional inert diluents such as water or vegetable oils may be used. In addition to the inert diluent, the liquid composition may contain 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. Solvents or suspending media for preparing compositions for parenteral administration (e.g., injections, suppositories) include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like. Examples of bases for suppositories include, for example, cocoa butter, emulsified cocoa butter, lauryl ester, witepsol.

The dose and frequency of administration of the medicament of the present invention are not particularly limited and may be suitably selected depending on the circumstances such as the purpose for 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 dosage for oral administration to an adult is 0.01-1000mg (weight of active ingredient), and the dosage may be administered once daily or divided into several portions to be administered several times daily, once daily. When the medicament is used as an injection, it is preferably administered continuously or intermittently to an adult at a daily dose of 0.001 to 100mg (weight of active ingredient).

Chemical examples

The present invention will be more specifically explained with reference to the following general examples, however, the scope of the present invention is not limited by these examples.

Example 1 (Table)1 Compound 7)

(1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (free base)

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

A mixture of 77.0g (0.4mol) of ethyl 3- (4-pyrimidinyl) -3-oxopropanoate (prepared analogously to DE 2705582), 107.0g (1.19mol) of N-methylthiourea, 60.4g (0.4mol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene in 773ml of ethanol is heated to reflux for 2 hours.

The cooled mixture was treated with 25.8ml (0.40mol) of methanesulfonic acid diluted in 157.2ml of water and the precipitate was collected by filtration to give 72g of pure product as a yellow solid.

Mp：219-221℃

1.22-chloro-1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one

To a solution of 300ml of dimethylformamide was added 70ml (0.75mol) of phosphorus oxychloride at 0 ℃ and the resulting solution was stirred at the same temperature for 15 minutes.

67.1g (0.305mol) of 2-mercapto-1-methyl-1H- [4, 4' ] bipyrimidin-6-one were added and the resulting solution was stirred at 55 ℃ for 2 hours.

The mixture was poured into ice water, adjusted to pH8 with sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to yield 44.6g (66%) of the desired compound.

Mp：150-152℃

3- (1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

A mixture of 1.95ml (14mmol) triethylamine, 2.45g (11mmol) 2-chloro-1-methyl-1H- [4, 4' ] bipyrimidin-6-one, 2.58g (13mmol) tert-butyl (1S) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate in 100ml tetrahydrofuran was stirred at room temperature for 2 hours. Water was added to the cooled mixture and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride solution and evaporated. The crude product was chromatographed on silica gel eluting with a dichloromethane/methanol mixture (ratio 100/0-98/2) to give 4.2g of pure product as a white solid.

Mp：198-200℃

RMN(200 MHz；DMSO-d⁶)：δ9.25(s，1H)；8.97(d，1H)；8.19(s，1H)；6.81(s，1H)；4.85(brs，1H)；4.42(brs，1H)；3.84(dd，1H)；3.56-3.74(m，1H)；3.35-3.54(m，2H)；3.35(s，3H)；1.88(brs，2H)；1.34(s，9H).

Example 2 (Compound 14 of Table 1)

(1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one hydrochloride (1: 1).

To a solution of 4.45g (11.58mmol) of tert-butyl (1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate in 25ml of anhydrous dichloromethane was added 10.71ml (139mmol) of trifluoroacetic acid and the resulting mixture was stirred at room temperature for 2 hours.

The mixture was poured into ice water, adjusted to pH8 with potassium carbonate, and extracted with chloroform. The organic extracts were dried over sodium sulfate and evaporated. The resulting product in the form of the free base was converted to the hydrochloride salt to give 4g (69%) of the pure compound as a yellow solid.

Mp：275-277℃

RMN(200 MHz；DMSO-d⁶)：δ9.28(s，1H)；9.15(brs，1H(NH))；8.96(d，1H)；8.22(d，1H)；6.88(s，1H)；4.88(brs，1H)；4.43(brs，1H)；3.89(dd，1H)；3.69(brd，1H)；3.24-3.64(m，2H)；3.33(s，3H)；2.03(AB，2H).

Example 3 (Compound 2 of Table 1)

(1S) -1-methyl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one hydrochloride (1: 1).

A mixture of 1.76g (6.28mmol) of (1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4 ' ] bipyrimidin-6-one, 2.18ml (22.67mmol) of 3-bromopyridine, 3.44g (10.56mmol) of cesium carbonate, 187mg (0.3mmol) of (R) - (+) -2, 2 ' -di (diphenylphosphino) -1, 1 ' -binaphthyl and 67mg (0.3mmol) of palladium (II) acetate in 100ml of anhydrous tetrahydrofuran was stirred under reflux in an argon atmosphere for 18 hours. The mixture was filtered, water was then added to the mixture, and the resulting solution was extracted with chloroform. The combined extracts were washed with saturated aqueous ammonium chloride solution and evaporated. The crude product is chromatographed on silica, eluting with a dichloromethane/methanol mixture (ratio 100/0-95/5). The resulting product in free base form was converted to the hydrochloride salt to give 650mg (26%) of the pure product as a solid.

Mp：180-182℃

RMN(200 MHz；DMSO-d⁶)：δ9.22(d，1H)；8.98(d，1H)；8.22(dd，1H)；8.13(brs，1H)；7.98(t，1H)；7.63-7.78(m，2H)；6.77(s，1H)；5.02(s，1H)；4.87(s，1H)；3.90(d，1H)；3.72(s，2H)；3.58(d，1H)；3.31(s，3H)；2.10(AB，2H).

Example 4 (Compound 16 of Table 1)

(1S) -2- (5-benzoyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one.

To a solution of 0.13g (0.46mmol) of (1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1 methyl-1H- [4, 4' ] bipyrimidin-6-one in 3ml of anhydrous dimethylformamide was added 24mg (0.6mmol) of sodium hydride and the mixture was stirred at 0 ℃ for 15 minutes.

0.07ml (0.6mmol) of benzoyl chloride was added and the resulting solution was stirred at 0 ℃ for 2 hours.

Water was added to the mixture, followed by extraction with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride solution and evaporated. The crude product was chromatographed on silica gel eluting with a dichloromethane/methanol mixture (ratio 100/0-97/3) to give 90mg (50%) of the pure compound as a solid.

Mp：133-135℃

RMN (200 MHz; DMSO-d 6): (two conformers are present in the NMR spectrum. only the major one of the chemical shifts is given) delta 9.31(s, 1H); 9.05(d, 1H); 8.30(d, 1H); 7.37-7.60(m, 5H); (ii) a 6.89(s, 1H); 4.96(s, 1H); 4.92(s, 1H); 3.72-3.94(m, 2H); 3.39(s, 3H); 3.22-3.35(m, 2H); 1.91-2.12(m, 2H).

Example 5 (Compound 1' of Table 2)

(1S) -5- (1-methyl-6-oxo-4-pyridin-4-yl-1, 6-dihydro-pyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (free base)

5.12-mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

A mixture of 70.0g (0.36mol) of ethyl 3- (4-pyridyl) -3-oxopropanoate, 98.1g (1.09mol) of N-methylthiourea, 55.0g (0.36mol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene in 551ml of ethanol was heated to reflux for 2 hours.

The cooled mixture was treated with 34.9ml (0.36mol) of methanesulfonic acid in 143.6ml of water and the precipitate was collected by filtration to give 60.4g of pure product as a white solid.

Mp：250-252℃

5.22-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one hydrochloride (1: 1)

To a solution of 180ml of dimethylformamide was added 16ml (0.17mol) of phosphorus oxychloride at 0 ℃ and the resulting solution was stirred at the same temperature for 20 minutes.

24.15g (0.11mol) of 2-mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one were added and the resulting solution was stirred at 70 ℃ for 5 hours.

The mixture was poured into ice water and the precipitate was collected by filtration to give 28g of pure product as a white solid.

Mp：261-263℃

5.3(1S) -5- (1-methyl-6-oxo-4-pyridin-4-yl-1, 6-dihydro-pyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (free base)

A mixture of 10.7ml (78.14mmol) triethylamine, 13.6g (52.7mmol) 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one hydrochloride (1: 1), 6.0g (30.24mmol) tert-butyl (1S) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate in 500ml anhydrous dimethylformamide was stirred at 20 ℃ for 6H. Water was added to the cooled mixture, followed by extraction with ethyl acetate. The combined organic extracts were washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride and evaporated. The crude product was refluxed in ether for 1 hour to give 8.36g of pure product as a brown solid.

Mp：174-176℃

RMN(200 MHz；CDCl₃)：δ8.73(d，2H)；7.78(d，2H)；6.58(s，1H)；4.83(brs，1H)；4.62(brd，1H)；3.69-4.02(m，1H)；3.77(dd，1H)；3.34-3.64(m，2H)；3.49(s，3H)；2.00(brs，2H)；1.49(s，9H).

Example 6 (Compound 2' of Table 2)

(1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one hydrochloride (1: 2)

To a solution of 8.36g (21.8mmol) of tert-butyl (1S) -5- (1-methyl-6-oxo-4-pyridin-4-yl-1, 6-dihydro-pyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate in 50ml of anhydrous dichloromethane was added 20ml (261.6mmol) of trifluoroacetic acid and the resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into ice water, adjusted to pH8 with potassium carbonate, and extracted with chloroform. The organic extracts were dried over sodium sulfate and evaporated. The crude product was triturated with ethyl acetate to give 5g of pure product as a brown solid which was then converted to the dihydrochloride.

Mp：240-242℃

RMN(200 MHz；DMSO-d⁶)：δ9.18(brs，1H(NH))；8.88(d，2H)；8.38(d，2H)；6.90(s，1H)；4.89(brs，1H)；4.43(brd，1H)；3.84(AB，2H)；3.55-3.78(m，2H)；3.38(s，3H)；2.03(AB，2H).

Example 7 (Compound 12' of Table 2)

(1S) -3-methyl-6-pyridin-4-yl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3H-pyrimidin-4-one

A mixture of 0.2g (0.71mmol) of (1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one, 3.335g (2.12mmol) of 3-bromopyridine, 0.322g (0.99mmol) of cesium carbonate, 18mg (0.028mmol) of (+/-) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl and 6mg (0.028mmol) of palladium (II) acetate in 100ml of anhydrous tetrahydrofuran is stirred under argon reflux for 18 hours. The mixture was filtered. Water was added to the filtrate, and the resulting solution was extracted with chloroform. The combined extracts were washed with saturated ammonium oxide and evaporated. The crude product was purified by silica gel chromatography. Elution with a dichloromethane/methanol mixture (ratio 100/0-95/5) gave 119mg of pure product as a solid.

Mp：179-181℃

RMN(200 MHz；DMSO-d⁶)：δ9.65(d，2H)；7.98(s，2H)；7.91(d，2H)；7.79(d，1H)；6.90-7.15(m，2H)；6.55(s，1H)；4.92(brs，1H)；4.69(brd，1H)；3.85(dd，1H)；3.67(dd，1H)；3.42-3.60(m，2H)；3.28(s，3H)；2.05(brs，2H).

Example 8 (Compound 10' of Table 2)

(1S) -2- [5- (4-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

To a solution of 0.10g (0.35mmol) of (1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one in 3ml anhydrous tetrahydrofuran was added 0.06ml (0.46mmol) anhydrous triethylamine, and the resulting mixture was stirred at room temperature for 20 minutes. To the cooled mixture was added 0.064ml (0.46mmol) of 4-methyl-benzoyl chloride, and the resulting solution was stirred at room temperature for 2 hours. Water was added and extracted with dichloromethane. The combined extracts were washed with saturated aqueous ammonium chloride solution and evaporated. The crude product was purified by silica gel chromatography. Elution with a dichloromethane/methanol mixture (ratio 97/3) gave 106mg of pure product as a solid.

Mp；118-120℃

RMN(200 MHz；CDCl₃)；δ8.72(brs，2H)；7.75(brd，2H)；7.45(brs，2H)；7.15-7.35(m，2H)；6.58(brs，1H)；4.90(AB，2H)；3.65-4.26(m，4H)；3.50(s，3H)；2.41(brs，3H)；2.09(brd，2H).

Table 1 shows the chemical structures and physical data of the above compounds of formula (I) according to the invention. These compounds are prepared according to the methods of the examples.

In tables 1 and 2, (S) or (R) represents the stereochemistry of carbon atoms, and Ph represents a phenyl group.

In Table 1R 3 is an unsubstituted 4-pyrimidine ring and R4 is methyl.

In Table 2R 3 is an unsubstituted 4-pyridine ring and R4 is methyl.

TABLE 1

TABLE 2

Test examples: the inhibitory activity of the medicine of the invention on GSK3 beta is as follows:

two different schemes may be used.

The first scheme is as follows: 7.5 μ M of the pre-phosphorylated GS1 peptide and 10 μ M ATP (containing 300000cpm 33P-ATP) in the presence of GSK3 β in 25mM Tris-HCl, pH7.5, 0.6mM DTT, 6mM MgCl₂0.6mM EGTA, 0.05mg/ml BSA buffer (total reaction volume 100. mu.l) was incubated at room temperature for 1 hour.

The second scheme is as follows: 4.1 μ M of the pre-phosphorylated GS1 peptide and 42 μ M ATP (containing 260000cpm 33P-ATP) in GSK3Beta in the presence of 80mM Mes-NaOH, pH6.5, 1mM Mg (OAc)₂0.5mM EGTA, 5mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer at room temperature for 2 hours. The inhibitor was dissolved in DMSO (final solvent concentration in the reaction medium is 1%).

The reaction was stopped with 100 microliters of a solution having the following composition: 25g polyphosphoric acid (85% P)₂O₅)，126ml 85％H₃PO₄Water was added to 500ml and then diluted to 1: 100 before use. Then 1 aliquot of the reaction mixture was transferred to a Whatman P81 cation exchange filter and rinsed with the above solution. Bound 33P radioactivity was measured with a liquid scintillation spectrometer.

The sequence of the phosphorylated GS-1 peptide is as follows:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH。

GSK3 beta inhibitory Activity of Compounds of the invention as IC₅₀Illustrative IC of the Compounds shown in Table 1₅₀In the range of 1 nanomolar to 1 micromolar.

For example, IC for Compound 24 of Table 1₅₀IC at 0.006 μ M, Compound 4' of Table 2₅₀0.004. mu.M.

Formulation examples

(1) Tablet formulation

The following ingredients were mixed by conventional methods and tableted by conventional machinery.

EXAMPLE 1 Compound 30mg

Crystalline cellulose 60mg

Corn starch 100mg

Lactose 200mg

Magnesium stearate 4mg

(2) Soft capsule

The following ingredients were mixed by a conventional method and filled into soft capsules.

EXAMPLE 1 Compound 30mg

Olive oil 300mg

Lecithin 20mg

(1) Parenteral formulation

The following ingredients were mixed by a conventional method to prepare an injection, and the injection was filled in a 1ml ampoule.

EXAMPLE 1 Compound 3mg

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 for the prevention and/or treatment of diseases caused by abnormal GSK3 beta activity, more specifically neurodegenerative diseases.

Claims (10)

1. A 2- (diaza-bicyclo-alkyl) -pyrimidone derivative represented by formula (I) or a salt thereof:

wherein:

r1 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r2 represents a hydrogen atom, optionally substituted by 1 to 4 groups selected from halogen atoms, hydroxy or C_1-4Alkoxy radicalC substituted by a substituent of a radical_1-6Alkyl radical, C_1-2Perhalogenated alkyl, benzyl, phenethyl, benzyloxycarbonyl, C_1-4Alkoxycarbonyl, a benzene ring, a naphthalene ring, a quinoline ring, a 2, 3-naphthyridine ring, a 5, 6, 7, 8-tetrahydronaphthalene ring, a pyridine ring, an indole ring, a pyrrole ring, a thiophene ring, a benzenesulfonyl group, a benzoyl group, a pyridazine ring, a furan ring, or an imidazole ring; benzyl, phenethyl, benzyloxycarbonyl, benzenesulfonyl, benzoyl and these rings are optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl, benzene ring, halogen atom, C_1-2Perhalogenated alkyl, C_1-3Haloalkyl, hydroxy, C_1-4Alkoxy, nitro, cyano, amino, C_1-6Monoalkylamino or C_2-10A dialkylamino group;

r3 represents a 2, 4, or 5-pyrimidine ring or a 2, 3 or 4-pyridine ring, these rings optionally being substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen atom substitution;

r4 represents C_1-4Alkyl, optionally substituted by hydroxy, C_1-4Alkoxy or halogen atom substitution; n represents 1.

2. A 2- (diaza-bicyclo-alkyl) -pyrimidone derivative or a salt thereof according to claim 1, wherein R3 represents an unsubstituted 4-pyrimidine ring or an unsubstituted 4-pyridine ring.

3. A 2- (diaza-bicyclo-alkyl) -pyrimidone derivative or a salt thereof according to claim 1 or 2, wherein R3 represents optionally substituted C_1-4Alkyl radical, C_1-4Alkoxy or halogen substituted 2, 4, or 5-pyrimidine ring, R2 represents hydrogen, benzyl, phenethyl, benzyloxycarbonyl, C_1-4An alkoxycarbonyl group, a benzene ring, a quinoline ring, a 2, 3-naphthyridine ring, a pyridine ring, a benzenesulfonyl group, a benzoyl group, or a pyridazine ring; benzyl, phenethyl, benzyloxycarbonyl, benzenesulfonyl, benzoyl and ring optionally substituted by 1 to 4 substituents selected from C_1-6Alkyl, benzene ring, halogen atom, C_1-2Perhalogenated alkyl, C_1-3Haloalkyl, hydroxy, C_1-4Alkoxy, nitro, cyanoAmino group, C_1-6Monoalkylamino or C_2-10Substituted with a dialkylamino group; or when R3 represents optionally substituted C_1-4Alkyl radical, C_1-4R2 represents a pyridine ring, a benzene ring, a naphthalene ring, a benzyl group, or a benzoyl group, when the 2, 3, or 4-pyridine ring is substituted with an alkoxy group or a halogen atom; these groups or rings are optionally substituted by 1 to 4 substituents selected from C_1-6Alkyl, benzene ring, halogen atom, C_1-2Perhalogenated alkyl, C_1-3Haloalkyl, hydroxy, C_1-4Alkoxy, nitro, cyano, amino, C_1-6Monoalkylamino or C_2-10A substituent of a dialkylamino group.

A 2- (diaza-bicyclo-alkyl) -pyrimidone derivative selected from:

(1S) -1-methyl-2- [5- (5-phenyl-pyridin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1H- [4, 4' ] bipyridinyl-6-one,

(1S) -1-methyl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -1-methyl-2- (5-quinolin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

(1R) -1-methyl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (4-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1R) -2- [5- (6-chloro-quinolin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) 2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester,

(1S) -2- [5- (6-bromo-pyridin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (6-chloro-pyridazin-3-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (5-bromo-pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (4-chloro-2, 3-naphthyridin-1-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (4-chloro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (3-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -1-methyl-2- (5-p-tolyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5-benzoyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -1-methyl 2- [5- (toluene-4-sulfonyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -5- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid benzyl ester,

(1S) -1-methyl-2- (5-phenethyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5-benzyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- [5- (2(S) -hydroxy-2-phenyl-ethyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -1-methyl-2- (5-pyridin-2-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -1-methyl-2- (5-pyridin-4-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-bromo-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-chloro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-methoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-phenyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (4-trifluoromethyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (3-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (3-methoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (3-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (3-bromo-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (3-cyano-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -2- (5- (3-chloro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -1-methyl-1H- [4, 4' ] bipyrimidin-6-one,

(1S) -5- (1-methyl-6-oxo-4-pyridin-4-yl-1, 6-dihydro-pyrimidin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester,

(1S) -2- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-chloro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -3-methyl-6-pyridin-4-yl-2- (5-p-tolyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3H-pyrimidin-4-one,

(1S) -2- [5- (4-bromo-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-chloro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- (5-benzyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (3-fluoro-phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -3-methyl-6-pyridin-4-yl-2- (5-pyridin-3-yl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -3H-pyrimidin-4-one,

(1S) -2- [5- (3-methoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (3-methyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-ethoxy-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-trifluoromethyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

(1S) -2- [5- (4-phenyl-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one, and

(1S) -2- [5- (3-fluoro-benzoyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

or a salt thereof.

5. A medicament comprising as an active ingredient a 2- (diaza-bicyclo-alkyl) pyrimidone derivative represented by formula (I) or a salt thereof according to claim 1.

6. The use of a compound as claimed in any one of claims 1 to 4 in the manufacture of a medicament for the prophylaxis and/or treatment of diseases which are caused by abnormal GSK3 β activity.

7. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis and/or treatment of neurodegenerative diseases.

8. The use of a compound according to claim 6, wherein the neurodegenerative disease is selected from the group consisting of: alzheimer's disease, Parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injury; cerebrovascular accident, brain cord trauma, spinal cord trauma; peripheral neurodegenerative diseases; retinopathy or glaucoma.

9. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis and/or treatment of: non-insulin dependent diabetes mellitus, obesity, maniac depression, schizophrenia, alopecia or cancer.

10. The use according to claim 8, wherein the cancer is breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia or a virus-induced tumor.