KR100351629B1 - 5-(4-Substituted-[1,2,5]thiadiazol-3-yl)-3-methyl-1,2,3,4-tetrahydropyrimidine derivatives and process for preparing them - Google Patents

Abstract

The present invention is a 5- (4-substituted- [1,2,5] -thiadiazole-3- represented by the following formula (1), which is useful as a muscarinic receptor agonist and a therapeutic agent for memory hypersensitivity and senile dementia. (1) -3-methyl-1,2,3,4-tetrahydropyrimidine derivatives, pharmaceutically acceptable salts thereof, methods for their preparation, and uses thereof.

In Formula 1, X represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, or an N-methylpiperazinyl group.

Description

5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivative and its preparation method {5- (4 -Substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivatives and process for preparing them}

The present invention is a 5- (4-substituted- [1,2,5] -thiadiazole-3- represented by the following formula (1), which is useful as a muscarinic receptor agonist and a therapeutic agent for memory hypersensitivity and senile dementia. (1) -3-methyl-1,2,3,4-tetrahydropyrimidine derivatives, pharmaceutically acceptable salts thereof, methods for their preparation, and uses thereof.

Formula 1

In Formula 1, X represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, or an N-methylpiperazinyl group.

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.

Accordingly, the present inventors have tried to synthesize a novel compound that can be applied as a muscarinic receptor agonist, and as a result, a novel 5- (4-substituted- [1,2,5] thiadiazole represented by Formula 1 above. The present invention was completed by synthesizing -3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivatives.

The present invention is a 5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivative represented by Chemical Formula 1 And its pharmaceutically acceptable salts.

In addition, the present invention has another object to provide a pharmaceutical composition containing the compound represented by the formula (1) as an active ingredient useful as a therapeutic agent for memory hyperactivity and senile dementia.

Another object of the present invention is to provide a method for preparing the compound represented by Chemical Formula 1.

The present invention provides 5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivative represented by the following formula (1): And pharmaceutically acceptable salts thereof.

Formula 1

In Formula 1, X represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, or an N-methylpiperazinyl group.

Referring to the present invention in more detail as follows.

In the derivative represented by the formula (1) according to the present invention, preferably, the compound and the pharmaceutically acceptable salt thereof are exemplified as follows:

3-dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl)] amine,

3-methyl-5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine,

3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine,

4- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine,

3-methyl-5- [4- (4-methylpiperazin-1-yl)-[1,2,5] thiadiazol-3-yl] -1,2,3,4-tetrahydropyrimidine.

In addition, 5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydro represented by Chemical Formula 1 according to the present invention. The pyrimidine derivatives can form pharmaceutically acceptable acid addition salts according to methods conventional 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 and the like.

On the other hand, the present invention is the 5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyri represented by the formula (1) Preparation of midine derivatives and pharmaceutically acceptable salts thereof.

The compound represented by Chemical Formula 1 according to the present invention can be prepared by carrying out the reaction of synthesis, cyclization reaction, methylation reaction and reduction reaction of cyanohydrin compound using 5-pyrimidinecarboxaldehyde as starting material. Briefly showing the manufacturing process of the present invention as shown in Scheme 1.

In Scheme 1: X ₁ represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group or a morpholinyl group; X ₂ represents an N-methylpiperazinyl group.

First, by reacting 5-pyrimidinecarboxaldehyde represented by Chemical Formula 2 with HCN / HOAc, a hydroxy-pyrimidin-5-yl-acetonitrile represented by Chemical Formula 3 is synthesized, and then NH ₄ Cl / NH When reacted with ₄ OH, amino-pyrimidin-5-yl-acetonitrile represented by Chemical Formula 4 is obtained. The compound represented by Chemical Formula 4 is cyclized with S ₂ Cl ₂ to obtain 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine represented by Chemical Formula 5. The compound represented by the formula (5) is obtained by performing the amination reaction and methylation reaction with a suitable amine compound to obtain a compound represented by the formula (1) of the present invention. In the reaction for synthesizing the compound represented by Formula 1 from the compound represented by Formula 5, the amination reaction and the methylation reaction may vary according to the purpose. For example, by reacting the compound represented by the formula (5) with NaSH and a suitable amine compound (e.g., dialkylamine, pyrrolidine, piperidine, morpholine) to synthesize an amine-substituted compound represented by the formula (6) , Methyl trifluoromethanesulfonate (MeOTf) and methylation reaction at room temperature, followed by reduction with a reducing agent (NaBH ₄ ) to synthesize the compound represented by Formula 1a or a pharmaceutically acceptable salt thereof for the purpose of the present invention. Can be. In addition, the compound represented by Chemical Formula 5 is methylated with methyl triflate methyl trifluoromethanesulfonate (MeOTf) at room temperature, and then reduced with a reducing agent (NaBH ₄ ) to synthesize the compound represented by Chemical Formula 7, By reacting with N-methylpiperazine and n-BuLi, it is also possible to synthesize a compound represented by Formula 1b or a pharmaceutically acceptable salt thereof for the purpose of the present invention.

Meanwhile, 5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydro represented by Chemical Formula 1 according to the present invention. Pyrimidine derivatives and their pharmaceutically acceptable salts are very effective as muscarinic receptor agonists and also for the treatment of 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 a conventional formulation in the pharmaceutical field, for example, oral administration such as tablets by the addition of.

5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine represented by Formula 1 according to the present invention The dosage of the derivative to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Generally, 0.01 to 200 mg / kg / day is preferable, and the judgment of a doctor or pharmacist Therefore, one to six divided doses may be administered at regular intervals.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Synthesis of Hydroxy-Pyrimidin-5-yl-acetonitrile

Dissolve 8.14 g (125.00 mmol, 2.5 eq) of KCN in 50 mL of water, cool to 5 ° C, add 5.40 g (50.00 mmol) of pyrimidine-5-carboxaldehyde, and dissolve not more than 10 ° C. (125.00 mmol, 2.5 eq) of acetic acid was added dropwise while maintaining the temperature at 10 ° C. or lower, and then stirred at room temperature for 2 hours. Then, the resultant was cooled to 5 ° C. and the resulting pale yellow precipitate was filtered and washed with cooling water. The resultant was dried under reduced pressure and separated by flash chromatography (SiO ₂ , EtOAc) to give 4.55 g (67%) of hydroxy-pyrimidin-5-yl-acetonitrile as a white powder.

mp 142-144 ° C .; IR (KBr) 3020 (OH), 2800, 1560, 1410 cm <^-1>; ¹ H NMR (300 MHz, acetone-d ₆ ) δ 9.23 (s, 1H, C2-H), 8.99 (s, 2H, C4-H, C6-H), 6.59 (brs, 1H, OH), 6.06 ( s, C H CN); ¹³ C NMR (75 MHz, acetone-d ₆ ) δ 159.6 (C2), 155.9 (C4, C6), 131.7 (C5), 119.1 (CN), 59.7 ( C CN); MS ( m / z ) 135.0432, Calcd for C ₆ H ₅ N ₃ O = 135.0433.

Example 2 Synthesis of Amino-pyrimidin-5-yl-acetonitrile

To 35 mL of acetonitrile, 1.35 g (10.00 mmol) of hydroxy-pyrimidin-5-yl-acetonitrile and 2.67 g (50.00 mmol, 5.0 eq) of NH ₄ Cl were added followed by 3.11 mL (20.00 mmol) of 25% NH ₄ OH. , 2.0 eq) was added and heated to reflux for 3 hours. After cooling to room temperature, the precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was flash chromatographed (SiO ₂ , EtOAc) to give 0.52 g (39%) of amino-pyrimidin-5-yl-acetonitrile as a reddish brown liquid.

IR (KBr) 3400 (NH), 2200 (CN), 1560, 1410 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.27 (s, 1H, C2-H), 8.98 (s, 2H, C4-H, C6-H), 5.03 (s, 1H, C H CN), 2.11 ( brs, 2H, NH); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 158.6 (C 2), 155.3 (C 4, C 6), 130.0 (C 5), 119.1 (CN), 43.1 ( C CN); MS ( m / z ) 134.0591, Calcd for C ₆ H ₆ N ₄ = 134.0592.

Example 3 Synthesis of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine

30 mL of dimethylformamide (DMF) was cooled to 3 ° C. and 0.89 mL (11.18 mmol, 3.0 eq) of S ₂ Cl ₂ was added. After stirring for 10 minutes at the same temperature, a solution of 0.50 g (3.73 mmol) of amino-pyrimidin-5-yl-acetonitrile in 10 mL of DMF was slowly added dropwise to not exceed 5 ° C. The temperature was gradually raised and stirred at 80 ° C. for 2 hours. After cooling to room temperature, the precipitate was filtered, the filtrate was neutralized with an aqueous NaOH solution while cooling in an ice-water bath, extracted with ethyl acetate, dried over MgSO ₄ , and concentrated under reduced pressure. The residue was flash chromatographed (SiO ₂ , 20% EtOAc-Hex) to give 0.54 g (73%) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine as a solid. White needle crystals were obtained by recrystallization from ethyl acetate.

mp 135-136 ° C; IR (KBr) 3050, 1590, 1550, 1460, 1180 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.39 (s, 2H, C 4 -H, C 6 -H), 9.35 (s, 1H, C 2 -H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 159.2 (C 2), 155.9 (C 4, C 6), 152.3 (C 3 ′), 143.5 (C 4 ′), 125.2 (C 5); Elemental analysis, calculated for C ₆ H ₃ ClN ₄ S: C 36.28, H 1.52, N 28.21, S 16.14, found: C 36.28, H 1.52, N 28.21, S 16.14

Example 4 Synthesis of 5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) pyrimidine

0.50 g (2.52 mmol) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine, 0.63 mL (7.55 mmol) of pyrrolidine, and Hunig base (N, N-di 2.19 mL (12.59 mmol) of isopropylethylamine) was added to 10 mL of DMF and stirred at 60-70 ° C. for 48 hours. After cooling to room temperature, it was diluted with 50 mL of water and extracted with ether (100 mL × 3). The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, EtOAc: Hex = 1: 1) to afford 5- (4-pyrrolidin-1-yl- [1,2) as a tan liquid. , 5] thiadiazol-3-yl) pyrimidine 0.50 g (84.7%) was obtained.

IR (neat) 2965, 2870, 2360, 1510 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.25 (s, 1H, C2-H), 8.99 (s, 2H, C4, C6-H), 3.32 (t, 4H, 2 × NCH ₂ ), 1.95 (m , 4H, 2 × CH ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.3 (C 3 ′), 158.1 (C 2), 155.9 (C 4, C 6), 142.9 (C 4 ′), 128.8 (C 5), 51.1, 25.6 (pyrrolidine C); HRMS ( m / z ) 233.0735 ([M] ⁺ ), ^Calcd for C ₁₀ H ₁₁ N ₅ S = 233.0735.

Example 5 Synthesis of 5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) pyrimidine

To 5 mL of DMSO, add 0.08 g (0.40 mmol) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine and 0.20 mL (2.0 mmol) of piperidine. Stir at 15 ° C. for 15 hours. After cooling to room temperature, it was diluted with 50 mL of water and extracted with ether (50 mL × 3). The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, EtOAc: Hex = 1: 4) to give 5- (4-piperidin-1-yl- [1,2) as a white solid. , 5] thiadiazol-3-yl) pyrimidine 0.10 g was obtained.

mp 82-84 ° C .; IR (KBr) 2935, 2830, 1400 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 99.35 (s, 2H, C4, C6-H), 9.26 (s, 1H, C2-H), 3.15 (t, 4H, 2 × NCH ₂ ), 1.70 (m , 6H, 3 × CH ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 163.9 (C 3 ′), 158.5 (C 2), 155.1 (C 4, C 6), 145.9 (C 4 ′), 128.0 (C 5), 51.4, 25.3, 23.7 (piperidine C ); Elemental Analysis for C ₁₁ H ₁₃ N ₅ S, Calcd: C 53.42, H 5.30, N 28.32, S 12.97, found: C 53.41, H 5.38, N 27.73, S 12.58.

Example 6 Synthesis of 4- (4-pyrimidin-5-yl- [1,2,5] thiadiazol-3-yl) morpholine

To 5 mL of DMSO, add 0.13 g (0.65 mmol) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine and 0.58 mL (6.50 mmol) of morpholine. Stir for hours. After cooling to room temperature, it was diluted with 20 mL of water and extracted with ether (50 mL × 3). The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, EtOAc: Hex = 1: 1) to give 0.15 g (93.8%) as a white solid, 4- (4-pyrimidine-5-. Yl- [1,2,5] thiadiazol-3-yl) morpholine was obtained.

mp 87-88 ° C .; IR (KBr) 2965, 2840, 1425 cm <^-1>; ¹ H NMR (300 MHz, CDCl ₃ ) δ9.34 (s, 2H, C4, C6-H), 9.27 (s, 1H, C2-H), 3.84 (t, 4H, J = 4.6 Hz, 2 × OCH ₂ ), 3.22 (t, 4H, J = 4.6 Hz, 2 × NCH ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.7 (C3 ′), 158.7 (C2), 155.2 (C4, C6), 145.7 (C4 '), 127.7 (C5), 66.2 (OCH ₂ ), 50.3 (NCH ₂ ); Elemental analysis for C ₁₀ H ₁₃ N ₅ OS, calculated: C 48.18, H 4.45, N 28.09, S 12.86, found: C 48.22, H 4.52, N 27.67, S 12.67.

Example 7: Synthesis of Dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] amine

Dissolve 0.15 g (0.72 mmol) of dimethyl- (4-pyrimidin-5-yl- [1,2,5] thiadiazol-3-yl) amine in 1.5 mL of dichloromethane, where methyl trifluoromethane 0.09 mL (0.80 mmol) of sulfonate was added and then stirred at room temperature for 2 hours. Since no precipitate formed, it was concentrated under reduced pressure as it was and 0.27 g (quantitative yield) of a tan liquid was obtained. It was dissolved in methanol, cooled to 0 ° C. and 0.03 g (0.79 mmol) of NaBH ₄ were added. After stirring for 10 minutes at the same temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was separated by MPLC (ODS-S-50B, 26 × 300 mm, H ₂ O: MeOH = 1: 4, 10 mL / min, R _T = 14.4 min). 77 mg of dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] amine as a yellow liquid ( 48.1%).

IR (NaCl, neat) 3340, 2945, 2850, 2360 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.49 (s, 1H, C6-H), 3.93 (s, 2H, C2-H), 3.67 (s, 2H, C4-H), 2.86 (s, 6H, N (CH ₃ ) ₂ ), 2.50 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.2 (C3 '), 151.7 (C4'), 133.1 (C6), 101.4 (C5), 63.6 (C2), 52.5 (C4), 41.9 (N (CH ₃ ) ₂ ), 41.3 (NCH ₃ ); HRMS ( m / z ) 225.1049 ([M] ⁺ ), ^Calcd for C ₉ H ₁₅ N ₅ S = 225.1048.

Example 8 of 3-methyl-5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine synthesis

Dissolve 0.47 g (2.01 mmol) of 5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) pyrimidine in 5 mL of dichloromethane, and add methyl trifluoro 0.25 mL (2.22 mmol) of methanesulfonate was added and stirred at room temperature for 1 hour to yield 0.66 g (85.7%) of yellow leaf crystals. 0.64 g (1.68 mmol) of this crystal was dissolved in 10 mL of methanol, cooled to 3 ° C., and 0.06 g (1.68 mmol) of NaBH ₄ was added little by little so as not to exceed 10 ° C. Stirred at 3 ° C. for 10 min, then concentrated under reduced pressure and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was separated by MPLC (ODS-S-50B, 26 × 300 mm, H ₂ O: MeOH = 1: 4, 10 mL / min, R _T = 22.4 min). As a result, 3-methyl-5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine as a tan liquid 0.32 g (76.2%) was obtained (total yield: 65.3%).

IR (neat) 3330 (NH), 2965, 1630 cm <^-1>; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.97 (s, 1H, C 6 -H), 3.91 (s, 2H, C 2 -H), 3.64 (s, 2H, C 4 -H), 3.42 (m, 4H, 2 × NCH ₂ ), 2.50 (s, 3H, NCH ₃ ), 1.92 (m, 4H, 2 × CH ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.3 (C3 '), 150.9 (C4'), 133.0 (C6), 102.1 (C5), 63.9 (C2), 53.2 (C4), 50.4, 25.1 (pyrrolidine C), 41.2 (NCH ₃ ); HRMS ( m / z ) 251.1206 ([M] ⁺ ), ^Calcd for C ₁₁ H ₁₇ N ₅ S = 251.1205

Example 9 of 3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine synthesis

0.38 g (1.54 mmol) of 5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) pyrimidine in 5 mL of dichloromethane (distilled from CaH ₂ ) It was dissolved and 0.21 mL (1.85 mmol) of methyl trifluoromethanesulfonate was added thereto. After stirring for 3 hours at room temperature, the mixture was concentrated under reduced pressure to yield 0.63 g (quantitative yield) of a yellow solid. It was dissolved in 10 mL of methanol, cooled to 0 ° C. and 0.06 g (1.54 mmol) of NaBH ₄ were added. After stirring for 10 minutes at the same temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was separated by MPLC (ODS-S-50B, 26 × 300 mm, H ₂ O: MeOH = 1: 4, 10 mL / min, R _T = 29.2 min). As a result, 3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine as a yellow liquid 0.30 mg (73.2%) was obtained.

IR (neat) 3335, 2935, 1625 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.65 (s, 1H, C6-H), 3.92 (s, 2H, C2-H), 3.67 (s, 2H, C4-H), 3.16 (m, 4H , 2 × NCH ₂ ), 2.50 (s, 3H, NCH ₃ ), 1.68 (m, 6H, 3 × CH ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.1 (C3 '), 151.9 (C4'), 132.6 (C6), 102.1 (C5), 63.7 (C2), 52.6 (C4), 41.4 (NCH3), 51.0, 25.7, 23.9 (piperidine C); HRMS m / z 265.1368 ([M] ⁺ ), ^Calcd for C ₁₂ H ₁₉ N ₅ S = 265.1361.

Example 10 of 4- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine synthesis

Dissolve 0.59 g (2.37 mmol) of 4- (4-pyrimidin-5-yl- [1,2,5] thiadiazol-3-yl) morpholine in 10 mL of dichloromethane and add 0.29 mL (3.08 mmol) ) Methyl trifluoromethanesulfonate was added. After stirring for 2 hours and 30 minutes at room temperature, the resulting yellow precipitate was filtered and washed with dichloromethane to give 4- (4-pyrimidin-5-yl- [1,2,5] thiadiazol-3-yl) 0.86 g (87.8%) of porin oxalate salt was obtained. 0.80 g (1.94 mmol) of the obtained salt was dissolved in 10 mL of methanol, cooled to 5 DEG C, and 0.07 g (1.94 mmol) of NaBH ₄ was added thereto. After stirring for 10 minutes at the same temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was separated by MPLC (ODS-S-50B, 26 × 300 mm, H ₂ O: MeOH = 1: 4, 10 mL / min, R _T = 14.4 min). As a result, 4- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine as a tan liquid 0.45 g (86.5%) was obtained (total yield: 75.9%).

IR (neat) 3360, 2960, 2850, 1625 cm <^-1>; ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.59 (s, 1H, C6-H), 4.18 (brs, 1H, NH), 3.92 (s, 2H, C2-H), 3.83 (m, 4H, 2 × OCH ₂ ), 3.66 (s, 2H, C4-H), 3.26 (m, 4H, 2 × NCH ₂ ), 2.50 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.7 (C 3 ′), 151.7 (C 4 ′), 132.7 (C 6), 101.7 (C 5), 66.6 (morpholine OCH ₂ ), 63.7 (C ₂ ), 52.5 (C 4) , 50.1 (morpholine NCH ₂ ), 41.4 (NCH ₃ ); HRMS ( m / z ) 267.1157 ([M] ⁺ ), ^Calcd for C ₁₁ H ₁₇ N ₅ OS = 267.1154.

Example 11 Synthesis of 5- (4-Chloro- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine

Dissolve 0.60 g (3.02 mmol) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine in 12 mL of dichloromethane and add 0.45 mL of methyl trifluoromethanesulfonate to 3.39 mmol) was added. 1.09 g (100) of a semi-solid 5- (4-chloro- [1,2,5] thiadiazol-3-yl) pyrimidine oxalate salt, which is stirred at room temperature for 1 hour 30 minutes and concentrated under reduced pressure, insoluble in dichloromethane. %) Was obtained. 0.50 g (1.34 mmol) of the obtained salt was dissolved in 7 mL of methanol, cooled to 5 ° C., and 0.05 g (1.34 mmol) of NaBH ₄ was added thereto. After stirring for 10 minutes at the same temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was separated by MPLC (ODS-S-50B, 26 × 300 mm, H ₂ O: MeOH = 1: 4, 10 mL / min, R _T = 21.6 min) 0.13 g (44.8%) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine was obtained, H Recrystallization from ₂ O-MeOH gave a yellow leafy solid (72 mg) (total yield: 44.8%).

mp 114-117 ° C .; IR (KBr) 3170, 2940, 2795, 1620 cm <^-1>; ¹ H NMR (300 MHz, CDCl ₃ ): δ 77.85 (d, 1H, C6-H), 4.40 (brs, 1H, NH), 3.97 (s, 2H, C2-H), 3.71 (s, 2H, C4- H), 2.51 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 156.2 (C 3 ′), 139.5 (C 4 ′), 134.5 (C 6), 99.4 (C 5), 63.2 (C 2), 52.4 (C 4), 41.2 (NCH ₃ ); HRMS ( m / z ) 216.0239 ([M] ⁺ ), Calcd for C ₇ H ₉ ClN ₄ S = 216.0236.

Example 12 3-Methyl-5- [4- (4-methylpiperazin-1-yl)-[1,2,5] -thiadiazol-3-yl] -1,2,3,4- Synthesis of Tetrahydropyrimidine

0.44 mL (3.97 mmol) of N-methylpiperazine was dissolved in 10 mL of anhydrous THF and cooled to -78 ° C. 1.59 mL of 2.5 M n-BuLi (in hexanes) was added thereto, stirred for 10 minutes, and heated to 0 ° C. After stirring for 10 minutes at the same temperature, it was cooled to -78 ℃ again. To this was added 15 mL of 0.43 g (1.98 mmol) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine. The solution dissolved in anhydrous THF was cooled to -30 ° C and added dropwise with a needle. After stirring at the same temperature for 30 minutes, the temperature was raised to 0 ° C and 10 mL of water was added thereto. Extracted with dichloromethane and the organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The dark reddish brown residue is slowly dried to form a solid. A small amount of acetone is added and triturated at -15 ° C to give 3-methyl-5- [4- (4-methylpiperazin-1-yl) as a yellow leafy solid. 0.12 g (21.4%) of-[1,2,5] -thiadiazol-3-yl] -1,2,3,4-tetrahydropyrimidine were obtained.

mp> 95 ° C. (decomp); IR (KBr) 3185, 2935, 2845, 1620 cm <^-1>; ¹ H NMR (300 MHz, CDCl ₃ ): δ 97.06 (d, 1H, C6-H), 4.71 (brs, 1H, NH), 3.92 (d, 2H, C2-H), 3.44 (s, 2H, C4- H), 3.30 (m, 4H, 2 x NCH ₂ ), 2.51 (m, 4H, 2 x NCH ₂ ), 2.42 (s, 3H, NCH ₃ ), 2.31 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 136.6 (C3 '), 128.5 (C6), 109.8 (C4'), 107.9 (C5), 63.7 (C2), 55.7, 54.8 (piperazin C), 49.9 (C4 ), 46.0, 41.2 (2xNCH ₃ ); HRMS ( m / z ) 280.1473 ([M] ⁺ ), ^Calcd for C ₁₂ H ₂₀ N ₆ S = 280.1470.

Example 13: Dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] amine oxalate Salt synthesis

Dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] amine in 1 mL of acetone 0.07 g (0.31 mmol) was dissolved and a solution of 0.03 g (0.31 mmol) of oxalic acid in 0.5 mL of acetone was added thereto. After stirring for 30 minutes at room temperature the resulting yellow precipitate was filtered and washed with acetone to give a pale yellow powder of dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) 0.06 g (63.3%) of-[1,2,5] thiadiazol-3-yl] amine oxalate salt were obtained.

mp 128-130 ° C .; IR (KBr) 3280, 2945, 1630 cm <^-1>; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.87 (brs, 2H, 2 × CO ₂ H), 7.49 (s, 1H, C6-H), 7.10 (brs, 1H, NH), 4.32 (s, 2H, C2-H), 4.02 (s, 2H, C4-H), 2.77 (s, 6H, N (CH ₃ ) ₂ ), 2.75 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 164.6 (C = O), 162.3 (C3 '), 150.6 (C4'), 133.7 (C6), 96.5 (C5), 61.1 (C2), 51.0 (C4 ), 41.9 (39.1 (N (CH ₃ ) ₂ ), 38.9 (NCH ₃ ); HRMS ( m / z ) 225.1049 ([MC ₂ H ₂ O ₄ ] ⁺ ), ^Calcd for C ₉ H ₁₅ N ₅ S = 225.1048 .

Example 14 3-methyl-5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine oxal Synthesis of Rate Salt

3-methyl-5- (4- (pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyridine in 5 mL of acetone 0.29 g (1.15 mmol) of midine was dissolved and 0.10 g (1.15 mmol) of oxalic acid was added to 1 mL of acetone, followed by stirring at room temperature for 2 hours, and the precipitate was filtered to give a pale yellow powder of 3-methyl-5. 0.25 g (64.1%) of-(4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine oxalate salt Got it.

mp: 149-151 ° C .; IR (KBr) 3290, 2965, 1630 cm <^-1>; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 77.02 (s, 1H, C6-H), 6.84 (brs, 3H, 2 x CO ₂ H, NH), 4.29 (s, 2H, C2-H), 3.99 (s, 2H, C4-H), 3.32 (s, 4H, 2 x NCH ₂ ), 2.72 (s, 3H, NCH ₃ ), 1.84 (s, 4H, 2 x CH ₂ ); ¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 164.5 (C = O), 160.2 (C3 '), 149.8 (C4'), 133.7 (C6), 96.6 (C5), 61.4 (C2), 51.5 (C4 ), 38.8 (NCH ₃ ) 50.5, 24.9 (pyrrolidine C); HRMS ( m / z ) 251.1206 ([MC ₂ H ₂ 0 ₄ ] ⁺ ), ^Calcd for C ₁₁ H ₁₇ N ₅ S = 251.1205.

Example 15 3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine oxal Synthesis of Rate Salt

3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine in 5 mL of acetone 0.27 g (1.02 mmol) was dissolved and a solution of 0.09 g (1.02 mmol) oxalic acid in 1.5 mL of acetone was added thereto. Stir at room temperature for 30 minutes, then filter the resulting yellow precipitate and wash with acetone to afford 3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl 0.25 g (69.7%) of 1,2,3,4-tetrahydropyrimidine oxalate salt was obtained. Recrystallization from methanol gave a white powder.

mp 163-165 ° C; IR (KBr) 3275, 2935, 1630 cm <^-1>; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.65 (s, 1H, C6-H), 7.03 (brs, 1H, NH), 5.97 (brs, 2H, 2 × CO ₂ H), 4.29 (s, 2H, C2-H), 3.98 (s, 2H, C4-H), 3.05 (m, 4H, 2 x NCH ₂ ), 2.72 (s, 3H, NCH ₃ ), 1.63 (m, 6H, 3 x CH ₂ ); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ64.3 (C = O), 161.9 (C3 '), 150.9 (C4'), 133.3 (C6), 96.8 (C5), 61.2 (C2), 51.1 (C4 ), 50.9, 25.3, 23.7 (piperidine C), 40.5 (NCH ₃ ); HRMS ( m / z ) 265.1368 ([MC ₂ H ₂ O ₄ ] ⁺ ), ^Calcd for C ₁₂ H ₁₉ N ₅ S = 265.1361.

Example 16: 4- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine oxal Synthesis of Rate Salt

4- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine in 5 mL of acetone 0.41 g (1.53 mmol) was dissolved, and a solution of 0.14 g (1.53 mmol) of oxalic acid in 1.5 mL of acetone was added thereto. After stirring for 30 minutes at room temperature the resulting yellow precipitate was filtered, washed with acetone and triturated once more in methanol to give a pale yellow 4- [4- (3-methyl-1,2,3,4-tetra 0.39 g (70.9%) of hydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine oxalate salt was obtained.

mp 164-166 deg. IR (KBr) 3260, 2960, 2850, 1630 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.64 (s, 1H, C6-H), 7.02 (brs, 1H, NH), 6.56 (brs, 2H, 2 × CO ₂ H), 4.29 (s, 2H, C2-H), 3.98 (s, 2H, C4-H), 3.74 (m, 4H, 2 x OCH ₂ ), 3.11 (m, 4H, 2 x NCH ₂ ), 2.72 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 164.5 (C = O), 160.8 (C 3 ′), 150.9 (C 4 ′), 133.7 (C 6), 96.4 (C 5), 65.9 (morpholine OCH ₂ ), 61.2 (C2), 51.0 (C4), 50.2 (morpholine NCH ₂ ), 38.9 (NCH ₃ ); HRMS ( m / z ) 267.1157 ([MC ₂ H ₂ 0 ₄ ] ⁺ ), ^Calcd for C ₁₁ H ₁₇ N ₅ OS = 267.1154.

Example 17 Synthesis of 5- (4-Chloro- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine oxalate salt

0.10 g (0.46 mmol) of 5- (4-chloro- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine in 3.5 mL of acetone To this was added a solution of 0.04 g (0.46 mmol) of oxalic acid in 0.5 mL of acetone. Stir at room temperature for 30 minutes and filter the precipitate under reduced pressure to give 5- (4-chloro- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4- as a yellow solid. 0.12 g (85.7%) of tetrahydropyrimidine oxalate salt was obtained.

mp 129-131 ° C .; IR (KBr) 3260, 3000, 1630, 1460 cm <^-1>; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.88 (s, 1H, C6-H), 7.26 (brs, 1H, NH), 5.62 (brs, 2H, 2 × CO ₂ H), 4.21 (s, 2H, C2-H), 3.90 (s, 2H, C4-H), 2.65 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ164.4 (CO ₂ H), 155.4 (C3 '), 138.8 (C4'), 135.4 (C6), 94.9 (C5), 61.1 (C2), 51.2 (C4 ), 39.5 (NCH ₃ ); HRMS ( m / z ) 216.0239 ([MC ₂ H ₂ 0 ₄ ] ⁺ ), Calcd for C ₇ H ₉ ClN ₄ S = 216.0236.

The following formulation examples illustrate the general pharmaceutical composition according to the present invention, in which the active ingredient is represented by the formula (5-)-(4-substituted- [1,2,5] thiadiazole-3 represented by Formula 1 above -Yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivative, and in some cases, may be replaced by an effective dose equivalent to other compounds included in the present invention.

Formulation Example: Tablet

250 g of the active ingredient was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. Then, 10% gelatin solution was added to the mixture, which was ground and passed through 14 mesh. Then, after drying, the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate to each was made into a tablet.

As described above, 5- (4-substituted- [1,2,5] thiadiazol-3-yl) -3-methyl-1,2,3,4 represented by Formula 1 according to the present invention -Tetrahydropyrimidine derivatives showed effective effects as muscarinic receptor agonists in vitro , and the biological activity was measured by the following method.

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.

That is, 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 of Bio- After the measurement by the Rad 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 from all trials were run in duplicate, 50 mM Tris buffer pH 7.2 containing 10 mM MgCl ₂ and 1 mM EDTA was used as the buffer for the experiment, and the final volume of the reaction was 0.25 ml, where 50 10 μl of hot-ligand and 10 μl of test drug were included. 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.

compound % Inhibition 10 μM 100 μM Example 12 18.6 25.3 Example 13 21.6 46.6 Example 14 25.8 62.8 Example 15 39.9 78.6 Example 16 16.2 36.1 Arecoline <0.0 25.5 Milamelanin 26.0 63.0

According to the results of Table 1, it can be seen that the novel compound according to the present invention is superior to Arecoline exemplified as a comparative drug in the M ₁ receptor inhibitory effect, and there is a compound that exhibits similar or better activity than mimelain. It can be seen.

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 novel compound represented by Chemical Formula 1 according to the present invention is useful as a drug for treating hypermemory and senile dementia because its excellent activity as a muscarinic receptor agonist.

Claims (5)

5- (4-substituted- [1,2,5] -thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyri, characterized in that Midine derivatives or pharmaceutically acceptable salts thereof. Formula 1 In Formula 1, X represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, or an N-methylpiperazinyl group. According to claim 1, wherein the compound represented by the formula (1) 3-dimethyl- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl)] amine, 3-methyl-5- (4-pyrrolidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine, 3-methyl-5- (4-piperidin-1-yl- [1,2,5] thiadiazol-3-yl) -1,2,3,4-tetrahydropyrimidine, 4- [4- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,5] thiadiazol-3-yl] morpholine, 3-methyl-5- [4- (4-methylpiperazin-1-yl)-[1,2,5] thiadiazol-3-yl] -1,2,3,4-tetrahydropyrimidine, Or a pharmaceutically acceptable salt thereof. 5- (4-substituted- [1,2,5] -thiadiazol-3-yl) -3-methyl-1,2,3,4-tetrahydropyrimidine derivative represented by the following formula (1) Pharmaceutical composition for the treatment of memory and dementia, characterized in that it contains a pharmaceutically acceptable salt. Formula 1 In Formula 1, X represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, or an N-methylpiperazinyl group. A process of synthesizing the compound represented by the following formula (6) by reacting the compound represented by the formula (5) with NaSH and an amine compound selected from dialkylamine, pyrrolidine, piperidine and morpholine, and then A process of preparing the compound represented by the following Chemical Formula 1a or a pharmaceutically acceptable salt thereof by methylating the compound represented by Chemical Formula 6 with methyl trifluoromethanesulfonate (MeOTf) and then reducing it with a reducing agent (NaBH ₄ ) Manufacturing method characterized in that it comprises a. In the above formula: X ₁ represents a dialkylamine group, a piperidinyl group, a pyrrolidinyl group or a morpholinyl group. A process of synthesizing the compound represented by the following Chemical Formula 7 by methylating the compound represented by Chemical Formula 5 at room temperature with methyl triflate methyl trifluoromethanesulfonate (MeOTf), and then reducing it with a reducing agent (NaBH ₄ ); Reacting the compound represented by Formula 7 with N-methylpiperazine and n-BuLi to prepare a compound represented by Formula 1b or a pharmaceutically acceptable salt thereof. Formula 5 In the above formula: X ₂ represents an N-methylpiperazinyl group.