KR19990083132A - 1,2,3,4-Tetrahydropyrimidine derivatives and process for preparing them - Google Patents

Abstract

The present invention relates to 1,2,3,4-tetrahydropyrimidine derivatives represented by the following general formula (1), pharmaceutically acceptable salts thereof, and methods for preparing the same, which are effective as therapeutic agents for senile dementia.

In Chemical Formula 1, R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates.

The 1,2,3,4-tetrahydropyrimidine derivatives represented by Formula 1 according to the present invention can be applied to the treatment of dementia as a muscarinic receptor agonist, and the derivatives are already clinically identified as isoelectrons of tetrahydropyridine. It has the same therapeutic effect as the Arecoline and Millamelline drugs used for the treatment of dementia.

Description

1,2,3,4-tetrahydropyrimidine derivatives and preparation method thereof {1,2,3,4-Tetrahydropyrimidine derivatives and process for preparing them}

The present invention relates to 1,2,3,4-tetrahydropyrimidine derivatives represented by the following general formula (1), pharmaceutically acceptable salts thereof, and methods for preparing the same, which are effective as therapeutic agents for senile dementia.

Formula 1

In Chemical Formula 1, R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates.

Geriatric dementia disease, known as Alzheimer's disease, can occur in both East and West, both men and women, and is the largest health problem facing humanity, given the current development of the elderly population with the development of medicine. It is emerging. The cause of senile dementia has been suggested so far, such as viral and aluminum poisoning, but recently, the toxicity of β-amyloid protein in the brain lesions of senile dementia has been suggested as the cause, but it is still unclear. The cause is unknown.

Currently used at home and abroad, dementia treatment drugs include drugs that inhibit the degradation of acetylcholine for symptom improvement, antidiagnosing agents that non-specifically promote energy metabolism of nerve cells, and blood circulation improving agents that promote microcirculation. The effects of these drugs are temporary and insignificant, and no reports of improvement in brain lesions caused by these drugs have been published.

Therefore, there is an urgent need for the development of new drugs with excellent memory and senile dementia efficacy.

The present invention is a novel 1,2,3,4-tetrahydropyrimidine derivative represented by the above formula (1) which can be applied as a muscarinic receptor agonist useful as a treatment for senile dementia, a pharmaceutically acceptable salt thereof and a method of preparing the same. And it is an object to provide a pharmaceutical composition for treating senile dementia containing the same as an active ingredient.

The present invention is characterized by 1,2,3,4-tetrahydropyrimidine derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof.

Formula 1

In Chemical Formula 1, R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates.

More specifically illustrating the 1,2,3,4-tetrahydropyrimidine derivative represented by Formula 1 according to the present invention is as follows:

3-methyl-5- (E) -hydroxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -methoxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -ethoxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -pentoxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -allyloxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -propargoxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -benzyloxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -p -methylbenzyloxyimino-1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (E) -p -chlorobenzyloxyimino-1,2,3,4-tetrahydropyrimidine, and

Pharmaceutically acceptable salts thereof.

In addition, the 1,2,3,4-tetrahydropyrimidine derivative represented by Formula 1 according to the present invention may form a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Examples include inorganic acid salts such as hydrochloric acid, bromic acid, phosphoric acid or sulfuric acid, and organic acid salts such as formic acid, acetic acid, malic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, toluenesulfonic acid and the like.

Meanwhile, the 1,2,3,4-tetrahydropyrimidine derivative represented by Formula 1 according to the present invention and a pharmaceutically acceptable salt thereof are very effective as a muscarinic receptor agonist and a therapeutic agent for memory hypersensitivity and senile dementia. . Therefore, the present invention comprises a pharmaceutical composition comprising the novel compound represented by the formula (1) as an active ingredient, these pharmaceutical compositions are conventional non-toxic pharmaceutically acceptable carriers, adjuvant and excipients to the compound represented by the formula (1) It can be formulated into various forms that can be prepared and used as a conventional formulation in the pharmaceutical field, such as tablets, capsules, troches, solutions, suspensions or the like. The dosage of 1,2,3,4-tetrahydropyrimidine derivative represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. In general, 0.01 to 200 mg / kg / day is preferable, and may be divided several times a day, preferably 1 to 6 times at regular time intervals according to the judgment of a doctor or a pharmacist.

In addition, the present invention is prepared by carrying out condensation reaction, methylation reaction and reduction reaction of 5-pyrimidinecarboxaldehyde synthesized by a known method using 4,6-dihydroxypyrimidine as a starting material as an intermediate. It includes a method for producing 1,2,3,4-tetrahydropyrimidine derivative represented by the formula (1). The manufacturing process will be described in more detail as follows.

First, a 5-pyrimidinecarboxaldehyde represented by the following Chemical Formula 2 and a hydroxylamine such as O -methylhydroxylamine are condensed to synthesize a compound represented by the following Chemical Formula 3.

In the above, R ₁ represents -H or -CH ₃ .

The compound represented by the formula (2) used in the condensation reaction can be easily prepared and used by a known method using 4,6-dihydroxypyrimidine as a starting material.

In the compound represented by Chemical Formula 3 obtained by the method of the present invention, a compound wherein R ₁ is H, ethyl bromide, n-pentyl iodide, allyl bromide, propargyl chloride, benzyl bromide, α-chloro- p − By reacting with xylene or p -chlorobenzyl chloride to synthesize a compound represented by the following formula (4).

In the above, R ₂ is _{-CH 2 CH 3, -CH 2 (} CH 2) 3 CH 3, -CH 2 CH = CH 2, -CH 2 C≡CH, , or Represents; X represents a halogen atom.

The compound represented by Chemical Formula 3 or 4 obtained above is methylated with CH ₃ I to synthesize a compound represented by the following Chemical Formula 5.

Wherein R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates.

Finally, when the compound represented by Chemical Formula 5 is reduced with NaBH ₄ , 1,2,3,4-tetrahydropyrimidine derivative represented by Chemical Formula 1, which is the object of the present invention, is synthesized.

Wherein R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates.

The present invention as described above will be described in more detail by the following examples and experimental examples, but the present invention is not limited by the following examples and experimental examples.

Example 1

Preparation of 3-methyl-5- (E) -hydroxyimino-1,2,3,4-tetrahydropyrimidine

5.36 g (49.58 mmol) of 5-pyrimidinecarboxaldehyde was dissolved in 50 mL of toluene, and 3.79 g (54.54 mmol, 1.1 eq) of hydroxylamine hydrochloride was added thereto, followed by heating to reflux for 1 hour. After cooling to room temperature, the mixture was washed with 200 ml of water and separated into an organic layer and a water layer. The organic layer was concentrated under reduced pressure as it was, the water layer was neutralized with solid K ₂ CO ₃ , concentrated and purified by flash chromatography with a concentrated residue of the preceding organic layer. 2.43 g (yield: 40%) of midine carboxidosis was obtained.

E-isomer

mp 141-142 ° C; IR (KBr) 3300-2800, 1560, 1430, 1400, 1310, 980, 880, 710, 640 cm ^-1 ; ¹ H NMR (200 MHz, CD ₃ OD) δ 9.09 (1H, s, C-2 H), 8.96 (2H, s, C-4, 6H), 8.13 (1H, s, C H = N).

Z-isomer

mp 143-143.5 ° C; ¹ H NMR (300 MHz, CD ₃ OD) δ9.37 (2 H, s, C-4, 6 H), 9.31 (1 H, s, C-2 H), 7.46 (1 H, s, C H = N).

0.30 g (2.44 mmol) of (E) -5-pyrimidinecarboxoxime prepared above was dissolved in 10 ml of acetone, and heated to reflux for 48 hours after adding 1.82 ml (29.24 mmol, 12.0 eq) of CH ₃ I. . Concentrated under reduced pressure, dried in vacuo and dissolved in 10 mL of THF, cooled to -20 ° C, and 0.14 g (3.66 mmol, 1.5 eq) of NaBH ₄ was added thereto to maintain -10 ° C. After further stirring at room temperature for 1 hour, the mixture was quenched with 1 ml of water, concentrated under reduced pressure, and the residue was purified by flash chromatography to obtain 3-methyl-5- (E) -hydroxyimino-1, as a white solid. 0.17 g (yield: 50%) of 2,3,4-tetrahydropyrimidine was obtained.

mp> 143 ° C .; IR (KBr) 3400 (NH), 3200 (OH), 3000, 2350, 1650, 1490, 1170, 940 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.64 (1 H, s, C H = N), 6.70 (1 H, s, C-6 H), 3.95 (2 H, ABq, J = 12.0 Hz, C-2H), 3.57 (2H, ABq, J = 17.0 Hz, C-4H), 2.52 (3H, s, NCH ₃ ).

Example 2

Preparation of 3-methyl-5- (E) -methoxyimino-1,2,3,4-tetrahydropyrimidine

3.72 g (34.42 mmol) of 5-pyrimidinecarboxaldehyde was dissolved in 60 ml of benzene, and 3.16 g (37.84 mmol, 1.1 eq) of O -methylhydroxylamine hydrochloride were added, followed by a Dean-Stark column (Dean- Stark column) was heated to reflux for 2 hours. After washing with aqueous NaHCO ₃ solution, the organic layer was separated, the aqueous layer was extracted with CH ₂ Cl ₂ , combined with the organic layer, dried over MgSO ₄ , and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2.94 g (yield: 62%) of (E) -O -methyl-5-hydropyrimidinecarboxoxime as a pale yellow solid.

E-isomer

IR (KBr) 3600 (NH), 2900, 1700, 1650, 1580, 1550, 1420, 1050, 860, 720 cm ^-1 ; ¹ H NMR (200 MHz, CDCl ₃ ) δ 9.19 (1 H, s, C-2 H), 8.92 (2 H, s, C-4, 6 H), 8.03 (1 H, s, aldoxime H) , 4.03 (3H, s, CH ₃ ).

Z-isomer

¹ HNMR (200 MHz, CDCl ₃ ) δ 9.21 (2 H, s, C-4, 6 H), 9.20 (s, 1 H, C-2 H), 7.26 (1 H, s, aldoxime H), 4.03 (3H, s, CH ₃ ).

1.00 g (7.29 mmol) of (E) -O -methyl-5-hydropyrimidinecarboxoxime prepared above was dissolved in 15 ml of acetone, and 3.6 ml (58.32 mmol, 8.0 eq) of CH ₃ I was added. The yellow precipitate produced by heating under reflux for hours was filtered and dried in vacuo to yield 1.69 g (yield: 83%) of salt. After dissolving it in 20 ml of methanol, it was cooled to 0 ° C. and 0.46 g (2.0 eq) of NaBH ₄ was added thereto in a batch but not exceeding 5 ° C. After stirring for 1 hour at 0 ° C., the mixture was concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ , washed with water, and the organic layer was dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography to give 0.71 g of 3-methyl-5- (E) -methoxyimino-1,2,3,4-tetrahydropyrimidine as a high viscosity tan syrup (yield: 63%). Got.

IR (NaCl, neat) 3600 (NH), 2900-2800, 1620, 1200 cm ^-1 ; ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.53 (1 H, s, aldoxime H), 6.50 (1 H, s, C-6 H), 3.89 (2 H, s, C-2 H), 3.79 (3H, s, OCH ₃ ), 3.41 (2H, s, C-4H), 2.44 (3H, s, NCH ₃ ).

Example 3

Preparation of 3-methyl-5- (E) -ethoxyimino-1,2,3,4-tetrahydropyrimidine

0.70 g (5.69 mmol) of (E) -5-pyrimidinecarboxidime prepared from Example 1 and 0.85 mL (11.37 mmol, 2.0 eq) of ethyl bromide were dissolved in 20 mL of CH ₃ CN and 1.57 g of K ₂ CO _3. (11.37 mmol, 2.0 eq) was added followed by heating to reflux for 5 hours. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated under reduced pressure, and then the residue was purified by flash chromatography. The residue was pale yellow liquid (E) -O -ethyl-5-pyrimidinecarboxidone 0.67 g (yield). : 78%).

IR (NaCl, neat) 2950-2800, 1610, 1580, 1550, 1430, 1410, 1050, 970, 940, 840, 720 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (1 H, s, C-2 H), 8.93 (2 H, s, C-4, 6 H), 8.05 (1 H, s, C H = N), 4.28 (2H, q, J = 7.2 Hz, OCH ₂ ), 1.34 (3H, t, J = 7.2 Hz, CH ₂ ).

0.28 g (1.85 mmol) of (E) -O -methyl-5-pyrimidinecarboxoxime prepared above was dissolved in 10 ml of acetone and 1.38 ml (22.23 mmol, 12.0 eq) of CH ₃ I was added for 30 hours. It was heated to reflux. Concentrated under reduced pressure, dried in vacuo and dissolved in 8 mL of THF, cooled to -20 ° C, and 0.10 g (2.78 mmol, 1.5 eq) of NaBH ₄ was added thereto little to no more than -10 ° C. After stirring for 1 hour at 0 ° C., the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give 3-methyl-5- (E) -ethoxyimino-1,2,3,4-tetrahydropyrimidine as a pale yellow liquid. Got. It slowly became a solid at room temperature.

mp 70-74 ° C .; IR (KBr) 3400 (NH), 2950, 2350, 1640, 1480, 1180, 1050 cm ^-1 ; ¹ HNMR (300 MHz, CDCl ₃ ) 57.58 (1H, s, C H = N), 6.53 (1H, d, J = 4.5 Hz C-6 H), 4.42 (1 H, brs, NH), 4.10 (1H, m, C-2H), 4.04 (2H, q, J = 7.0 Hz, OCH ₂ ), 3.91 (1H, ddd, J = 12.0, 5.0, 2.5 Hz, C-2H), 3.68 (2H, ABq, J = 17.0 Hz, C-4H), 2.57 (3H, s, NCH ₃ ), 1.24 (3H, t, J = 7.0 Hz, CH ₂ C H ₃ ).

Example 4

Preparation of 3-methyl-5- (E) -pentoxyimino-1,2,3,4-tetrahydropyrimidine

0.25 g (2.03 mmol) of (E) -5-pyrimidinecarboxoxime prepared from Example 1 and 0.40 mL (3.0 mmol, 1.5 eq) of i-pentyl iodide were dissolved in 5 mL of CH ₃ CN and K ₂ CO ₃ 0.56 g (4.06 mmol, 2.0 eq) was added and then heated to reflux for 6 hours. After cooling to room temperature, the solid was filtered off, and the filtrate was concentrated under reduced pressure, and then the residue was purified by flash chromatography. The residue was pale yellow liquid (E) -O -pentyl-5-pyrimidinecarboxoxime 0.33 g (yield). : 85%).

IR (NaCl, neat) 2950, 1550, 1410 cm ⁻¹ ; ¹ H NMR (200 MHz, CDCl ₃ ) δ 9.18 (1 H, s, C-2 H), 8.92 (2 H, s, C-4, 6 H), 8.04 (1 H, s, C H = N), 4.22 (2H, t, J = 6.7 Hz, OCH ₂ ), 1.8 to 1.7 (2H, m, CH ₂ ), 1.35 (4H, m, CH ₂ ), 0.93 (3H, m, CH ₃ ).

0.32 g (1.66 mmol) of (E) -O -pentyl-5-pyrimidinecarboxoxime prepared above was dissolved in 10 ml of acetone and 1.24 ml (19.87 mmol, 12.0 eq) of CH ₃ I was added for 30 hours. It was heated to reflux. Concentrated under reduced pressure, dried in vacuo and dissolved in 10 ml of THF, cooled to -20 ° C, and 0.09 g (2.49 mmol, 1.5 eq) of NaBH ₄ was added little by little so as not to exceed -10 ° C. After stirring for 1 hour at 0 ° C., the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give 3-methyl-5- (E) -pentoxyimino-1,2,3,4-tetrahydropyrimidine as a pale yellow liquid. Got. It slowly became a solid at room temperature.

mp 39-42 ° C .; IR (KBr) 3350 (NH), 2950, 2350, 1640, 1480, 1180, 1050 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 57.59 (1 H, s, C H = N), 6.54 (1 H, d, J = 4.5 Hz, C-6 H), 4.65 (1 H, brs, NH), 4.07 (1H, dd, J = 12.0, 2.5, C-2H), 3.97 (2H, t, J = 7.0 Hz, OCH ₂ ), 3.91 (1H, ddd, J = 12.0, 5.0, 2.5 Hz, C-2 H), 3.65 (2 H, ABq, J = 17.0 Hz, C-4 H), 2.56 (3 H, s, NCH ₃ ), 1.60 (2 H, m, CH ₂ ), 1.30 (4H, m, CH ₂ ), 0.91 (3H, t, J = 7.0 Hz, CH ₂ C H ₃ ).

Example 5

Preparation of 3-methyl-5- (E) -allyloxyimino-1,2,3,4-tetrahydropyrimidine

0.30 g (2.44 mmol) of 5-pyrimidinecarboxoxime prepared from Example 1, 0.67 g (4.88 mmol, 2.0 eq) of K ₂ CO ₃ and 0.32 mL (3.66 mmol, 1.5 eq) of allyl bromide were added to CH ₃ CN. It was added to 10 ml and heated to reflux for 2 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure, and then purified by flash chromatography to obtain 0.28 g (yield: 70%) of (E) -O -allyl-5-pyrimidinecarboxoxime as a pale yellow liquid.

IR (neat) 3400, 2900, 1610, 1580, 1550, 1410, 1020, 930, 720 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (1 H, s, C H = N), 8.93 (2 H, s, C-4, 6 H), 8.09 (1 H, s, C-2 H), 6.04 (1H, ddt, J = 17.0, 10.0, 6.0 Hz, C H = CH ₂ ), 5.37 (1H, ddd, J = 17.0, 3.0, 1.5 Hz, C = CH _trans ), 5.29 ( 1 H, ddd, J = 10.0, 3.0, 1.1 Hz, C = CH _cis ), 4.73 (2H, ddd, J = 6.0, 1.5, 1.1 Hz, OCH ₂ ).

0.25 g (1.53 mmol) of (E) -O -allyl-5-pyrimidinecarboxoxime prepared above was dissolved in 10 ml of acetone and 1.2 ml (18.36 mmol, 12.0 eq) of CH ₃ I was added for 30 hours. It was heated to reflux. Concentrated under reduced pressure and dried in vacuo and dissolved in 10 ml of THF, cooled to -20 ℃, and then added 0.09 g of NaBH ₄ little by little to not exceed -10 ℃. After stirring for 1 hour at 0 ° C., the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give 3-methyl-5- (E) -allyloxyimino-1,2,3,4-tetrahydropyrimidine as a pale yellow liquid. Got. It slowly became a solid at room temperature.

mp 62-65 ° C .; IR (KBr) 3400 (NH), 2950-3100, 2350, 1640, 1470, 1180, 1040, 940 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63 (1 H, s, C H = N), 6.58 (1 H, d, J = 4.5 Hz C-6 H), 5.98 (1 H, ddt, J = 17.0, 10.0, 6.0 Hz, C H = CH ₂ ), 5.29 (1 H, ddd, J = 17.0, 3.0, 1.5 Hz, C = CH _trans ), 5.21 (1 H, ddd, J = 10.0, 3.0 and 1.1 Hz, C = CH _2cis ), 4.87 (1H, brs, NH), 4.48 (2H, ddd, J = 6.0, 1.5, 1.1 Hz, OCH ₂ ), 4.05 (1H, dd, J = 2.5, 12.0 Hz, C-2 H), 3.91 (1 H, ddd, J = 2.5, 4.5, 12.0 Hz, C-2 H), 3.63 (2 H, ABq, J = 17.0 Hz, C-4 H), 2.55 (3H, s, NCH ₃ ).

Example 6

Preparation of 3-methyl-5- (E) -propargoxyimino-1,2,3,4-tetrahydropyrimidine

0.31 g (2.52 mmol) of (E) -5-pyrimidinecarboxoxime prepared from Example 1, 0.70 g (5.04 mmol, 2.0 eq) of K ₂ CO ₃ and 0.27 mL (3.78 mmol, 1.5) of propargyl chloride eq) was added to 10 ml CH ₃ CN and heated to reflux for 1 hour. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure and purified by flash chromatography to obtain 0.34 g (yield: 83%) of (E) -O -propargyl-5-pyrimidinecarboxoxime as a pale yellow liquid. . It slowly became a solid at room temperature.

mp 76-79 ° C .; IR (KBr) 3300, 2100, 1610, 1580, 1560, 1410, 1020, 940, 720 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.22 (1 H, s, C H = N), 8.96 (2 H, s, C-4, 6 H), 8.13 (1 H, s, C-2 H), 4.83 (2H, d, J = 2.4 Hz, OCH ₂ ), 2.57 (1H, t, C = CH).

0.31 g (1.92 mmol) of (E) -O -propargyl-5-pyrimidinecarboxoxime prepared above was dissolved in 10 ml of acetone, and 1.7 ml (24.09 mmol, 12.5 eq) of CH ₃ I was added. It was heated to reflux for a time. Concentrated under reduced pressure, dried in vacuo and dissolved in 10 ml of THF, cooled to -20 ° C, and 0.11 g of NaBH ₄ was added thereto little to no more than -10 ° C. After stirring for 1 hour at 0 ° C., the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give 3-methyl-5- (E) -propargoxyoxyimino-1,2,3,4-tetrahydro as a pale yellow liquid. 0.17 g (yield: 50%) of pyrimidine was obtained. It slowly became a solid at room temperature.

mp 84-87 ° C .; IR (KBr) 3400, 3260, 2950, 2400, 1640, 1480, 1180, 1040, 1000 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.63 (1 H, s, C H = N), 6.61 (1 H, d, J = 4.5 Hz, C-6 H), 4.83 (1 H, brs, NH), 4.59 (2H, d, J = 2.5, OCH ₂ ), 4.08 (1H, dd, J = 2.5, 12.0 Hz, C-2H), 3.92 (1H, ddd, J = 2.5, 4.5 , 12.0 Hz, C-2 H), 3.63 (2H, ABq, J = 17.0 Hz, C-4H), 2.56 (3H, s, NCH ₃ ), 2.49 (1H, t, J = 2.5 Hz , C = C H ).

Example 7

Preparation of 3-methyl-5- (E) -benzyloxyimino-1,2,3,4-tetrahydropyrimidine

0.30 g (2.44 mmol) of (E) -5-pyrimidinecarboxidime prepared from Example 1, 0.67 g (4.88 mmol, 2.0 eq) of K ₂ CO ₃ and 0.43 mL (3.66 mmol, 1.5 eq) of benzyl bromide Was added to 10 mL of CH ₃ CN and heated to reflux for 1.5 h. After removing the precipitate was filtered off, the filtrate was concentrated under reduced pressure, and then as a pale yellow liquid was purified by flash chromatography (E), - O- benzyl-5-pyrimidine carboxylic boksal doksim 0.32 g (yield: 60%) was obtained.

mp 42-44 ° C .; IR (neat) 3000, 1580, 1410, 1010 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.17 (1 H, s, C H = N), 8.89 (2 H, s, C-4, 6 H), 8.07 (1 H, s, C-2 H), 7.35-7.40 (5H, m, Ph-H), 5.24 (2H, s, OCH ₂ ).

0.30 g (1.41 mmol) of (E) -O -benzyl-5-pyrimidinecarboxoxime prepared above was dissolved in 7 ml of acetone and 1.05 ml (16.88 mmol, 12.0 eq) of CH ₃ I was added for 30 hours. It was heated to reflux. Concentrated under reduced pressure, dried in vacuo and dissolved in 10 ml of THF, cooled to -20 ° C, and 0.08 g (2.12 ml, 1.5 eq) of NaBH ₄ was added little by little so as not to exceed -10 ° C. After stirring for 1 hour at 0 ° C., the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give 3-methyl-5- (E) -benzyloxyimino-1,2,3,4-tetrahydropyrimidine as a pale yellow liquid. 0.16 g (yield: 50%) was obtained. It slowly became a solid at room temperature.

mp 86-88 ° C .; IR (KBr) 3350 (NH), 2900, 2350, 1640 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26 (1 H, s, C H = N), 7.35 (5 H, m, aromatic H), 6.47 (1 H, d, J = 4.5 Hz, C- 6H), 5.00 (2H, s, OCH ₂ ), 4.60 (1H, brs, NH), 4.03-3.82 (2H, m, C-2H), 3.63 (2H, ABq, 17.0 Hz, C-4 H), 2.51 (3H, s, NCH ₃ ).

Example 8

3-methyl-5- (E)- p Preparation of -methylbenzyloxyimino-1,2,3,4-tetrahydropyrimidine

0.30 g (2.44 mmol) of (E) -5-pyrimidinecarboxidime prepared from Example 1, 0.67 g (4.88 mmol, 2.0 eq) of K ₂ CO ₃ and 0.48 mL (3.66) of α-chloro- p -xylene mmol, 1.5 eq) was added to 10 mL CH ₃ CN and heated to reflux for 1.5 h. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure, and then purified by flash chromatography. As a pale yellow liquid, 0.38 g of (E) -O- ( p -methylbenzyl) -5-pyrimidinecarboxoxime (yield: 69% )

mp 85-88 ° C .; IR (KBr) 2900, 1610, 1580, 1550, 1430, 1000 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.17 (1 H, s, C H = N), 8.89 (2 H, s, C-4, 6 H), 8.06 (1 H, s, C-2 H), 7.20 (4H, 2xd, J = 8.0 Hz, xylene-H), 5.20 (2H, s, OCH ₃ ), 2.35 (3H, s, CH ₃ ).

Prepared in (E), - O - (p- methyl) -5-pyrimidine-carboxylic boksal doksim added 0.34 g (1.50 mmol) of _{CH 3 I 1.12 ㎖ (17.95 mmol} , 12.0 eq) was dissolved in acetone and 5 ㎖ After heating to reflux for 48 hours. Concentrated under reduced pressure, dried in vacuo and dissolved in 10 ml of THF, cooled to -20 ° C, and 0.08 g (2.24 mmol, 1.5 eq) of NaBH ₄ was added thereto little to no more than -10 ° C. After stirring for 1 h at room temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give a pale yellow viscous liquid as 3-methyl-5- (E) -p -methylbenzyloxyimino-1,2,3, 0.11 g (yield: 30%) of 4-tetrahydropyrimidine was obtained.

IR (neat) 3340 (NH), 2900, 2350, 1640 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.61 (1 H, s, C H = N), 7.20 (4 H, ABq, J = 8.0 Hz, aromatic H), 6.47 (1 H, d, J = 4.5 Hz, C-6 H), 4.96 (2 H, s, OCH ₂ ), 4.55 (1 H, brs, NH), 4.04-3.83 (2 H, m, C-2 H), 3.64 (2 H, ABq, J = 17.0 Hz, C-4H), 2.52 (3H, s, NCH ₃ ), 2.33 (3H, s, CH ₃ ).

Example 9

3-methyl-5- (E)- p Preparation of -chlorobenzyloxyimino-1,2,3,4-tetrahydropyrimidine

0.30 g (2.44 mmol) of (E) -5-pyrimidinecarboxoxime prepared from Example 1, 0.67 g (4.88 mmol, 2.0 eq) of K ₂ CO ₃ and 0.67 g (3.66 mmol, of p -chlorobenzyl chloride, 1.5 eq) was added to 10 ml CH ₃ CN and heated to reflux for 5 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure, and then purified by flash chromatography. As a pale yellow liquid, 0.45 g of (E) -O- ( p -chlorobenzyl) -5-pyrimidinecarboxoxime (yield: 75% )

mp 75-77 ° C .; IR (KBr) 2950, 1600, 1550, 1490, 1410, 960 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18 (1 H, s, C H = N), 8.89 (2 H, s, C-4, 6 H), 8.08 (1 H, s, C-2 H), 7.34 (4H, s, aromatic-H), 5.20 (2H, s, OCH ₂ ).

Prepared in (E) - O - a (p- chlorobenzyl) -5-pyrimidine-carboxylic boksal doksim 0.40 g (1.61 mmol) of _{CH 3 I 1.20 ㎖ (19.83 mmol} , 12.0 eq) was dissolved in acetone was added 8 ㎖ After heating to reflux for 48 hours. Concentrated under reduced pressure, dried in vacuo and dissolved in 10 ml of THF, cooled to -20 ° C, and 0.09 g (2.42 mmol, 1.5 eq) of NaBH ₄ was added little by little so as not to exceed -10 ° C. After stirring for 1 h at room temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography to give a pale yellow viscosity liquid as 3-methyl-5- (E) -p -chlorobenzyloxyimino-1,2,3, 0.18 g (yield 42%) of 4-tetrahydropyrimidine was obtained.

mp 100-102 ° C .; IR (KBr) 3340 (NH), 2900, 2350, 1630, 1490 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.62 (1 H, s, C H = N), 7.28 (4 H, m, aromatic H), 6.52 (1 H, d, J = 4.5 Hz, C- 6H), 4.96 (2H, s, OCH ₂ ), 4.63 (1H, brs, NH), 4.06-3.85 (2H, m, C-2H), 3.62 (2H, ABq, J = 17.0 Hz, C-4H), 2.53 (3H, s, NCH ₃ ).

The following formulation example is an example of a formulation which can be prepared by containing 1,2,3,4-tetrahydropyrimidine derivative represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. . Therefore, this invention is not limited by the following formulation example.

Formulation Example 1 Preparation of Tablet for Oral Administration

Tablets for oral administration were prepared using the 3-methyl-5- (E) -benzyloxyimino-1,2,3,4-tetrahydropyrimidine obtained in Example 7 as follows.

Effective Drug (Example 7) 100 mg

Light anhydrous silicic acid 10 mg

Microcrystalline cellulose 190 mg

Magnesium Stearate 5 mg

Sodium starch glycolate60 mg

Calcium monohydrogen anhydride135 mg

Formulation Example 2 Preparation of Injection

Injection was prepared using the 3-methyl-5- (E) -benzyloxyimino-1,2,3,4-tetrahydropyrimidine obtained in Example 7 as follows.

Effective Drug (Example 7) 100 mg

Mannitol180 mg

₂ HPO ₄ · 12H ₂ O26 Na mg

Distilled water2974 mg

On the other hand, for some compounds according to the present invention was tested as a muscarinic receptor agonist in the same manner as in Experimental Example 1.

Experimental Example 1: Muscarinic receptor binding rate

Reaction with receptors using radioisotope attached ligands to study the effect of each drug on receptor-ligand interactions on muscarinic receptor subtypes 1 and 2 (M ₁ , M ₂ ) (NEN, USA) After filtration by a glass fiber filter to remove the unbound extra ligand, the amount of isotope remaining in the washed filter disk was measured to quantify the binding reaction of the ligand to the receptor. This was used to determine the effect of the drug.

In other words, the receptor cell fractions frozen at -70 ° C were suspended in 4.5 ml of Tris buffer (500 mM Triza base, 10 mM MgCl ₂ , 1 mM EDTA, pH 7.4) per 500 µl and the protein content was Bio-Rad. After the measurement with the DC Protein Assay Kit, the concentration was adjusted to 70-75 μg / ml. At this time, the setting of protein concentration represented by the content of the receptor was determined through the basic experiment, and then dispensed by appropriate volume and stored frozen at -70 ℃. When stored as such, the binding activity was unchanged for several months.

Samples of all tests were repeated, and 50 mM Tris buffer pH 7.2 containing 10 mM MgCl ₂ and 1 mM EDTA was used as the buffer for the experiment. The final volume of the reaction was 0.25 ml, which included 50 μl of hot-ligand and 10 μl of test drug. The reaction was started in a shaking incubator (Rosi 1000, Thermolyne) at 27 ° C. for 60 minutes from the addition of 100 μl of the receptor suspension. After 1 hour of incubation, the reaction was terminated with about 0.5 ml of cold 50 mM Tris buffer pH 7.4 and Inotech cell Harvester (96-well) using a Wallac glass fiber filtermat GF / C. The isotope bound to the receptor was separated, washed, and the amount of isotope trapped on the filler mat was measured by a liquid scintillation counter (MicroBeta 1450 Plus).

In the first step drug search, the affinity of the drug for the receptor was searched for a certain concentration of the drug, and as a comparative material, arecoline and mimelaline were used. 1 nM of [ ³ H] N-methyl-scopolamine (NEN, NET-636) was used as a radioisotope label, and 1 μM of atropine sulfate (RBI, A-105).

The experimental results are shown in Table 1 below.

According to the results of Table 1, the compounds of Example 7, Example 8 and Example 9 according to the present invention was shown to show a significantly higher affinity for the M1 receptor than the comparable material, Arecholine and Millamellin.

Experimental Example 2: Toxicity Test

Some compounds according to the present invention were subjected to acute toxicity testing in rats. As a result, up to 10 mg / kg of oral dose showed no serious toxicity symptoms, and up to 100 mg / kg of death occurred. There was no at all.

As described above, the 1,2,3,4-tetrahydropyrimidine derivative represented by Chemical Formula 1 according to the present invention is an isoline that has already been used for the treatment of clinical dementia as a bioisoster of tetrahydropyridine. It has the same therapeutic effect as milameline and milameline, and is effective as a muscarinic receptor agonist.

Claims (4)

1,2,3,4-tetrahydropyrimidine derivatives and pharmaceutically acceptable salts thereof, which are represented by the following Chemical Formula 1. Formula 1 In Chemical Formula 1, R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates. Next, 1,2,3,4-tetrahydropyrimidine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for treating senile dementia. Formula 1 In Chemical Formula 1, R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates. a) condensing 5-pyrimidinecarboxaldehyde and hydroxylamine represented by Formula 2 to synthesize a compound represented by Formula 3; In the above, R ₁ represents -H or -CH ₃ . b) condensing a compound represented by Formula 3 wherein R ₁ is H and a compound represented by R ₂ -X to synthesize a compound represented by Formula 4; In the above, R ₂ is _{-CH 2 CH 3, -CH 2 (} CH 2) 3 CH 3, -CH 2 CH = CH 2, -CH 2 C≡CH, , or Represents; X represents a halogen atom. c) synthesizing the compound represented by Formula 5 by methylation of CH ₃ I with the compound represented by Formula 3 or 4; Wherein R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates. d) and reducing the compound represented by Chemical Formula 5 with NaBH ₄ to synthesize 1,2,3,4-tetrahydropyrimidine derivative represented by Chemical Formula 1 below; Method for preparing 2,3,4-tetrahydropyrimidine derivative. Wherein R is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₃ CH ₃ , -CH ₂ CH = CH ₂ , -CH ₂ C≡CH, , or Indicates. The method for preparing 1,2,3,4-tetrahydropyrimidine derivatives according to claim 3, wherein the hydroxylamine in step a) is O -methylhydrosilamine.