3-{2-[4-(6-toranzo[d]isoxazol-3-yl)-3,6-dihydro-2h - pyridine-1-yl]ethyl}-2-methyl - 6,7,8,9[-tetrahydropyrido{1,2 - a] pyrimidine-4-one and its pharmaceutically acceptable salts, method thereof, a method of obtaining salt of 1-[2-(2-methyl-4 - oxo-6,7,8,9 - tetrahydro-4h-pyrido[1,2-a]pyrimidine-3-yl) ethyl]-4-(6-toranzo[d]isoxazol-3 - yl)pyridinium, pharmaceutical composition

 

(57) Abstract:

The invention relates to a compound of formula I, which has antipsychotic properties and is used in the treatment of schizophrenia and other types of psychosis. The connection I get a partial restoration of the pyridinium salts of the formula IV, where W-organic or inorganic ion, using metal borohydride in proton solvent. 4 c. and 5 C.p. f-crystals, 1 PL.

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The present invention relates to the connection 3-{2-[4-(6-toranzo[d] isoxazol-3-yl)-3,6-dihydro-2H-pyridine - 1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine - 4-one of formula (I)

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which is used as a drug active on the Central nervous system, and pharmaceutically acceptable salts of this compound.

The background to the invention

In EP-A-0196132 describes 3-piperidinyl-1,2-benzisoxazole formula (II) as having antipsychotic properties.

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In EP-A-0037265 describes 3-[1-(piperidinyl)-4H-pyrido[1,2-a]pyrimidine-4-ones of formula (III)

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where R represents hydrogen, alkyl, OH, RO or CH2OH at positions 2, 3 or 4 cores of piperidine is used as the cardiovascular the Oia differs from known compounds by the presence of a double bond between positions 3 and 4 cores of piperidine and pharmacological activity.

The compounds of this type have neuroleptic properties and are used in the treatment of schizophrenia and other types of psychosis. As is the case for other psychotropic drugs, antipsychotic effect of antipsychotics is associated with changes in Central neurotransmitter. There is a clear correlation between antipsychosis effect of this type of matter and modification work dopaminergic pathways. One of the postulated mechanisms antipsychotic effect is the antagonism of dopamine receptors that can activate the mesocortical and/or mesolimbic pathway, but neuroleptics can also act on other pathways, such as nigrostriatal pathway, which is one of the pathways responsible for the manifestation of extrapyramidal symptoms that are considered harmful for this type of treatment.

Opening different subtypes of dopamine receptors and the development of a specific antagonist of subtype D2improved treatment of schizophrenia, but have not resolved the problem. In parallel, the emergence of 5HT2antagonists, who, as has been shown, are effective for negative symptoms of schizophrenia and extrapyramidal the guard as in the case of the proposed product. Thus, this type of compounds as D2antagonist improves the positive symptoms of schizophrenia (delirious and paranoid ideas, hallucinations, changes the logic and coherence of thoughts, mannerisms and catatonic or severely disorganized behavior), and as 5HT2- antagonism they improve negative symptoms (poverty of content of language, lack of motivation, and so on), and the reduction of extrapyramidal effects. Antipsychotic effect is also observed in the reduction of hostility and lack of cooperation by the patient. Drugs of this type were atypical, to distinguish them from the older traditionally used antipsychotic means acting only on the dopamine receptor.

A brief statement of the substance of the invention

3-{ 2-[4-(6-toranzo[d] isoxazol-3-yl)-3,6-dihydro-2H-pyridine-1-yl] ethyl} - 2 - methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidine-4-one of formula (I) of the present invention possess interesting pharmacological properties, in particular in the treatment of psychotic disorders and alterations associated with the capture and/or release of dopamine and/or serotonin.

The present invention also offers the FAS pharmaceutically acceptable diluent. This composition is preferably used in the form of tablets, capsules, injectable solutions or suspensions for the treatment of humans. Its use in the treatment of psychotic diseases, in particular, is unusual.

The compound of formula (I) can be obtained by the method lies in the restoration of the pyridinium salt of the formula (IV)

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where W-is an organic or inorganic anion, such as halide or sulfonate anion.

Pyridinium salt of the formula (IV) can easily recover the metal borohydride such as sodium borohydride, in an adequate proton solvent, such as water, alkanols or carboxylic acids (R. E. Lyle and P. S. Anderson, Adv. Heterocycl. Chem. 6, 45-93 (1966)).

Intermediate products and the starting compound used in the method of the present invention are known products or they can be easily obtained from known products.

Intermediates of formula (IV) can be easily obtained N-alkylation of the pyridine of the formula (V) with a reagent of formula (VI), where W is a corresponding delete the group, such as, for example, halide or sulphonate group.

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The reaction of N-alkylation is carried out in a solvent, inade, perhaps at a slightly elevated temperature and adding potassium iodide as a catalyst.

The pyridine of the formula (V) can be obtained by cyclization of the oxime of formula (VII) in an inert solvent, for example tetrahydrofuran, dioxane or N,N-dimethylformamide, in the presence of a suitable base such as a carbonate of an alkali metal or hydride or alkoxide of an alkali metal.

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Alternative pyridine of the formula (V) can also be obtained by cyclization of an acetylated derivative of the formula (VIII) oxime of the formula (IX) (L. Davis et al., Drug Design and Discovery, 8, 225-240 (1992)).

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The ketone of formula (X), the predecessor of the compounds of formula (VII) can be obtained by acylation according to the Friedel-Crafts 1,3-diferente chloride isonicotinoyl (F. I. Villani et al., I.Org. Chem., 17, 249 (1952)).

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Similarly ketone of formula (XI), which is the predecessor of the oxime of formula (IX) can be obtained by reaction of fries from 3-terfenol and chloride of isonicotinoyl.

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The compounds of formula (VI) described (H. Fujita et al., Ann. Rep. Sankyo Res. Lab. 29, 75-98 (1977)).

Preferred pharmaceutically acceptable salts are salts of joining with acids. Pharmaceutically acceptable salts of joining compounds vortices acceptable anions. These salts can be obtained from inorganic acids, for example hydrochloric, Hydrobromic, sulfuric or nitric acid, or organic acids such as lactic, succinic, oxalic, maleic, or other acid.

Salt can be obtained by conventional means, such as, for example, mixing of solutions containing equimolar amounts of the free base and the desired acid. Formed salt allocate by filtration if it is insoluble, or by evaporating the solvent.

The compound of formula (I) and its pharmaceutically acceptable salts are very active as antipsychotic drugs.

Pharmacological results

Study of the binding of D2-receptors (D-dopamine)

The study was performed as described Leysen et al. (1978) with some modifications. Got striped fabric of rat brain by homogenization in 20 volumes of buffer Tris-HCl in ice (50 mm, pH of 7.7, 4oC). The homogenate was centrifuged (40000 g, 10 min) and the precipitate suspended in 10 volumes of unlabeled buffer and again centrifuged. The final precipitate suspended in 10 volumes of buffer 50 mm Tris-HCl, 120 mm NaCl and 5 mm KCl (pH of 7.7). Research replacement was performed with 25 μl of3H-spiroperidol (0.2 nm, Singing through the filters Whatman GF/C. Unlabeled standard product was haloperidol.

Study of the binding of 5-HT2-receptors (5HT-serine)

The study was performed as described Leysen et al. (1978) with some modifications. Received the frontal cortex part of the brain of rats with homogenization in 20 volumes of buffer Tris-HCl in ice (50 mm, pH 7,4, 4oC). The homogenate was centrifuged (40000 g, 10 min) and the precipitate suspended in 10 volumes of unlabeled buffer and again centrifuged. The final precipitate suspended in 400 ml of buffer 50 mm Tris-HCl. Research replacement was performed with 25 μl of3H-ketanserina (0.5 nm, NEN), 25 μl of unlabeled substitute and 500 μl of tissue. Incubation (37oC, 15 min) was completed by rapid filtration through filters Whatman GF/C Unlabeled standard product has been cyproheptadine at.

Linking with1- adrenalinum receptors

The study was performed as described Morrtow et al. (1985) with some modifications.3H-prazosin was associated with high affinity with a1- adrenergic receptors in the cerebral cortex of rats. Cortical brain tissue was obtained with the application of homogenization in 20 volumes of buffer Tris-HCl in ice (50 mm, pH of 7.7, 4oC). The homogenate was centrifuged (25000 rpm for 12 min at 4o3H-prazosin (0.5 nm) and 50 μl of the corresponding unlabeled substitute at various concentrations. Incubation (37oC, 15 min) was completed by rapid filtration through filters Whatman GF/C, then washed twice with 5 ml of buffer Tris-HCl, 50 mm. Unlabeled standard product was prazosin.

Leysen, I. E., Goumeren, W. and Laduron, P. M. (1978) Biochem. Pharmacol., 27, 307-316. Morrow et al. (1985), Eur. J. Pharmacol., 109:285-287.

Replacement (Ki, nm) binding3H-spiroperidol with D2-receptors (striped fabric rats),3H-ketanserina with 5-HT2receptors and 3H-prazosin1- adrenergic receptors (cerebral cortex of rats).

Experimental part

Example 1

(2,4-Differenl)pyridine-4-ylmethanol (X)

219 ml (about 3.00 mole) chloride tiomila was added into the solution 246,2 g (2,00 mol) of isonicotinic acid in 500 ml of 1,2-dichloroethane and the mixture is boiled under reflux for 4 hours. Excess chloride tiomila and the solvent was removed by evaporation under reduced pressure and the solid residue was added 392 ml of 4.00 mol) of 1,3-diferently and then in parts 533 g (4.00 mol) of aluminum trichloride. After the end of the exothermic reaction the mixture is boiled under reflux for 5 hours. Then the mixture of the cooling gap is ristoro methylene and then podslushivaet 2 liters of 40% NaOH solution and was extracted with CH2Cl2(2 x 1 l). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure, getting 179,4 g (yield 41%) of the title compound in the form of oil ochre.

IR spectrum (film): 1680 cm-1.

1H-NMR (CDCl3): 6,88 for 7.12 (m, 2H, aromatic.), 7,56-to 7.61 (m, 2H, pyrid.), of 7.64-to 7.77 (m, 1H, aromatic.), 8,81 cent to 8.85 (m, 2H, pyrid.).

Example 2

The oxime (2,4-differenl)pyridine-4-ylmethanone (VII)

and 62.6 g (to 0.900 mol) of hydroxylamine hydrochloride and 133,6 g (0,982 mole) of three-hydrate of sodium acetate was added to the suspension 179,4 g (0,818 mol) of the compound of example 1 in 1 l of ethanol and the mixture is boiled under reflux for 1 hour. The solvent was removed by evaporation at low pressure. To the residue was added 1 l of water and the mixture was filtered. After drying for 3 hours at 45oC received 181 g (yield 94%) of the title compound (mixture of SYN - and anti-isomers) as a white solid.

So pl.: 155-200oC.

IR-spectrum (KBr tablet): 1580 cm-1.

1H-NMR (d6DMSO): 7,10-of 7.70 (m, 5H, aromatic. and pyrid.), 8,50-8,80 (m, 2H, pyrid.), 12,40 (s, 1H, -OH).

Example 3

6-Fluoro-3-pyridin-4-albenza[d]isoxazol (V)

181 g (0,773 mole) mixture oximo of example 2 was added in 19 g (0.4 mole) of 50% suspension of NaH in Minel water, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 0.5 l). The combined organic phases were dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallize from methanol twice, receiving 53 g (yield 32%) of the title compound as a white solid.

So pl.: 138-146oC.

IR-spectrum (KBr): 1610, 1595 cm-1.

1H-NMR (CDCl3): 7,15-7,27 (m, 1H, aromatic.), 7,35-7,45 (m, 1H, fragrance. ), 7,80-to 7.95 (m, 3H, aromatic. and pyrid.), 8,80-8,88 (m, 2H, pyrid.).

Example 4

Iodide 1-[2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-3-yl)ethyl]-4-(6-toranzo[d]isoxazol-3-yl)pyridinium (IV)

A suspension of 55 g (0,257 mol) of the compound of the previous example, 64 g (0,282 mole) of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidine-4-it (the compound of formula VI, in which W = Cl and 42 g (0,282 mole) of sodium iodide in 1 ml of acetonitrile was heated under reflux for 10 hours. After cooling to 10oC the product was filtered, getting 135 g (yield 98%) of the title compound as a yellow solid.

So pl.: 160-166oC.

IR-spectrum (KBr): 1630 cm-1.

1H-NMR (DMSO): 1,65-1,90 (m, 4H, H-C(7) and H-C(8)), 2,15 (c, 3H, CH3) 2,70-to 2.85 (m, 2H, H-C(9)), 3,05-of 3.25 (m, 2H, CH2-C(3)), 3,55 of 3.75 (m, 2H, H76 (d, J = 6,9, 2H, pyrid.), 9.28 are (d, J = 6,9, 2H, pyrid.).

Example 5

3-{2-[4-(6-Toranzo[d]isoxazol-3-yl)3,6-dihydro-2H-pyridine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one (I)

6.0 g (0,158 mol) of NaBH4added in a suspension of 50 g (0,094 mol) of the compound of the previous example in methanol (0.5 l) while maintaining the temperature of the mixture 0oC and 5oC. At the end of the addition the mixture was stirred for another 15 min, was added 50 g (0,935 mole) NH4Cl and the methanol was removed by evaporation under reduced pressure. To the residue was added 150 ml of H2O and 30 ml of concentrated HCl and the mixture was heated to form a solution, was added 430 ml IPA and then stirred 5 hours at 20oC. After filtering received 21 g (yield 53%) of the title compound as the dihydrochloride.

So pl.: (base, DSC): 179oC.

IR-spectrum (KBr): 1680 cm-1.

1H-NMR (CDCl3): 1,80-2,10 (m, 4H, H-C(7) and H-C(8)), 2,36 (c, 3H, CH3) 2,55 is 2.75 (m, 1H, H-C(3) of pyrid.), of 2,75 2,95 (m, 9H, H-C (6), H-C(9), H-C(2) pyrid. , H-C(3) of perid. , 3,35-to 3.50 (m, 2H, H-C(6) of pyrid.), 3,90-4,00 6,65 Holy 1H, H-C(5) of pyrid.), 7,05-to 7.15 (DDD, 1H, fragrance.), 7,20-to 7.35 (DD, 1H, aromatic.), 7,75-of 7.90 (DD, 1H, fragrance.).

1. 3-{2-[4-(6-Toranzo[d]isoxazol-3-yl)-3,6-dihydro-2H-pyridine-1-yl] ethyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one]isoxazol-3-yl)-3,6-dihydro-2H-pyridine-1-yl] ethyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-it formula I partial restoration of the pyridinium salts of the formula IV

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where W-organic or inorganic ion, using metal borohydride in proton solvent.

3. The method according to p. 2, wherein the restoring is performed by metal borohydride.

4. The method according to p. 3, wherein the metal borohydride is sodium borohydride.

5. The method according to p. 2 or 3, characterized in that the recovery is carried out in the environment of the proton solvent.

6. The method according to p. 5, characterized in that the solvent used water, alkanol or carboxylic acid, preferably methanol.

7. The method of obtaining salt of 1-[2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-3-yl)ethyl]-4-(6-toranzo[d]isoxazol-3-yl)pyridinium of the formula IV, in which the pyridine derivative of the formula V N-alkylate alkylating reagent of formula VI

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where W-is an organic or inorganic ion,

in an inert solvent, optionally at high temperature.

8. Pharmaceutical composition suitable for application to humans in the treatment of disorders of the Central nervous system containing the derived pyridopyrimidines as the active agent and pharmaceutically acceptable dilute-3-yl)-3,6-dihydro-2H-pyridine-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of formula I or its pharmaceutically acceptable salt.

9. The composition according to p. 8, characterized in that it is used in the form of tablets, capsules, injectable solutions or suspensions for the treatment of humans.

 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

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