KR100621192B1 - 1,2,3,4-Tetrahydropyrimidinyl-1, 2,4-oxadiazole derivatives as muscarinic receptor agonist, and method for preparing the same - Google Patents

Abstract

The present invention is a novel 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives acting as a muscarinic receptor agonist, a preparation method thereof, and the novel compound as an active ingredient. It relates to a pharmaceutical composition.

1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives according to the present invention exhibit activity as a muscarinic receptor agonist, thereby treating hypermembranes and senile dementia It can be applied to therapeutic drugs related to brain diseases and the central nervous system, and acts as a bioisoster of tetrahydropyridine, which shows a therapeutic effect comparable to that of arecholine and millamellin, which are already used clinically for the treatment of dementia. .

Aging Dementia Therapeutics, Muscarinic Receptor Agonists, 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole Derivatives

Description

1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives acting as muscarinic receptor agonists and preparation methods thereof {1,2,3,4-Tetrahydropyrimidinyl-1, 2 , 4-oxadiazole derivatives as muscarinic receptor agonist, and method for preparing the same}

The present invention provides 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by the following formula (1), which act as muscarinic receptor agonists, and their pharmaceutically acceptable salts, It relates to a preparation method and a pharmaceutical composition containing the compound as an active ingredient.

In Formula 1, R is a C ₁ ~ C ₁₀ Alkyl group, C ₂ ~ C ₁₀ Alkenyl group, or a phenyl group.

Geriatric dementia disease, also known as Alzheimer's disease, is a disease that can occur regardless of gender, and has recently emerged as a public health problem that should be taken seriously among future social problems due to the surge in the elderly population. .

Many theories about the cause of senile dementia have been raised so far, among them, theories of viral and aluminum poisoning have been suggested. Recently, the toxicity of β-amyloid protein infiltrating brain lesions of senile dementia patients has been suggested as the cause, but the cause has not been clarified yet.

Drugs used to treat dementia, both domestically and internationally, are only drugs that inhibit the breakdown of acetylcholine (ACh) for symptomatic improvement, alternative medicines that specifically promote energy metabolism of nerve cells, and blood circulation enhancers that promote microcirculation. Although the effects of these drugs are temporary and weak, there have been no reports of improvement in brain lesions caused by these drugs.

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

In addition, 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives characterized by the present invention are novel compounds that have not been reported in the literature to date, and are associated with central nervous system related diseases. It has not been used for the purpose of treatment or prevention.

 The present invention provides 1,2,3,4-tetrahydropyrimidinyl-1,2 that can be applied as a muscarinic receptor agonist useful as a therapeutic agent for the treatment of memory hypersensitivity and senile dementia, brain diseases and the central nervous system. The synthesis was completed by synthesizing a 4-4-diazadiazole derivative.

An object of the present invention is to provide a 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivative represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof.

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

In addition, the present invention contains a compound represented by the formula (1) as an active ingredient to provide a pharmaceutical composition that is also very effective as a therapeutic and preventive drugs related to memory hyperactivity and senile dementia, brain diseases and the central nervous system have.

The present invention provides 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof, which act as muscarinic receptor agonists It is characterized by.

[Formula 1]

In Formula 1, R is a C ₁ ~ C ₁₀ Alkyl group, C ₂ ~ C ₁₀ Alkenyl group, or a phenyl group.

Specific examples of the derivative represented by Formula 1 according to the present invention are as follows:

5-phenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole,

5-methyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole,

5-ethyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole,

5-pentyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole,

5- trans -propenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole,

5-isopropyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, or

Pharmaceutically acceptable salts thereof.

In addition, 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by Formula 1 according to the present invention are pharmaceutically acceptable according to a conventional method in the art. Acid addition salts can be formed. Examples include salts of inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid or sulfuric acid, and salts of organic acids such as formic acid, acetic acid, oxalic acid, malic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, p -toluenesulfonic acid, and the like. . Preferably it is selected from hydrochloric acid, oxalic acid, fumaric acid, tartaric acid and p -toluenesulfonic acid.

Meanwhile, the present invention includes a process for preparing 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by Chemical Formula 1 and their pharmaceutically acceptable salts.

The compound represented by Chemical Formula 1 according to the present invention is a cyclization reaction, methylation reaction, and reduction reaction using N- hydroxy-pyrimidine-5-carboxamidine as a starting material, as shown in the following scheme 1 It can be prepared by performing a method for preparing the method according to the following scheme 1.

In Formula 1, R is a C ₁ ~ C ₁₀ Alkyl group, C ₂ ~ C ₁₀ Alkenyl group, or a phenyl group.

According to the preparation method according to Scheme 1, dimethyl sulfoxide (DMSO) using N -hydroxy-pyrimidine-5-carboxamidine represented by the formula (2) and the acid anhydride represented by the formula (3) The compound represented by Chemical Formula 4 is synthesized by cyclization reaction, and then, the compound represented by Chemical Formula 4 is methylated by methyl trifluoromethanesulfonate (CF ₃ SO ₃ CH ₃ ) to be represented by Chemical Formula 5. Prepare the compound. Finally, 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by Chemical Formula 1 are prepared by reducing the compound of Chemical Formula 5, and NaBH is used as a reducing agent. ₄ can be used. In addition, the pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 may be prepared by a well-known method well known in the art, and may be easily prepared by simply treating with an acid solution after a reduction reaction.

Meanwhile, the present invention provides 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by Formula 1 and pharmaceutically acceptable salts thereof as muscarinic receptor agonists. It is also very effective as a treatment for memory hypersensitivity and senile dementia. Accordingly, the present invention includes a pharmaceutical composition for treating hypermembrane and senile dementia, a brain disease, and a central nervous system using the novel compound represented by Formula 1 as an active ingredient. The pharmaceutical composition according to the present invention may be added to a compound represented by Chemical Formula 1 by a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, so as to be a conventional formulation in the pharmaceutical field, for example, oral administration such as tablets. It can be formulated.

The dosage of 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by Formula 1 according to the present invention to the human body is the age, weight, sex, and administration of the patient. Depending on the form, health and degree of disease, and generally 0.01 to 200 mg / kg / day is preferred, and may be administered once to six times at regular intervals, depending on the judgment of the doctor or pharmacist.

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 5-phenyl-3-pyrimidin-5-yl-1,2,4-oxadiazole

Dissolve 5 mL of DMSO in 320 mg (2.32 mmol) of N -hydroxy-pyrimidine-5-carboxamidine, and add 1.05 g (4.64 mmol, 2.0 eq.) Of benzoic anhydride. Heated for hours. The reaction solution was distilled under reduced pressure to remove DMSO, and water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography (hexane / ethyl acetate, 2/1) to obtain 500 mg (96.1%) of a white solid of the compound.

96.1% yield (white solid); mp 133-134 ° C; IR (KBr) 3043, 1549 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.47 (s, 2H, C4'-H, C6'-H), 9.38 (s, 1H, C2'-H), 8.23 (m, 2H, phenyl-H) , 7.60 (m, 3H, phenyl-H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 176.5 (C-5), 164.8 (C-3), 160.5 (C-2 '), 155.5 (C-4', C-6 '), 133.3, 129.2, 128.2, 123.5 (phenyl-C), 121.7 (C-5 '); HRMS m / z calcd for C ₁₂ H ₈ N ₄ O (M ⁺ ) 224.0698, found 224.0699.

Example 2. Synthesis of 5-methyl-3-pyrimidin-5-yl-1,2,4-oxadiazole

Dissolve 10 mL of DMSO in 1.0 g (7.24 mmol) of N -hydroxy-pyrimidine-5-carboxamidine, and add 1.37 mL (14.48 mmol, 2.0 eq.) Of acetic anhydride. Heated for hours. The reaction solution was distilled under reduced pressure to remove DMSO, and water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography (hexane / ethyl acetate, 1/1) to give 723 mg (61.6%) of a white solid of the compound.

61.6% yield (white solid); mp 116-117 ° C; IR (KBr) 3040, 2925, 1587 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.38 (s, 2H, C 4′-H, C 6′-H), 9.35 (s, 1H, C 2′-H), 2.72 (s, 3H, CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 177.6 (C-5), 164.3 (C-3), 160.3 (C-2 '), 155.3 (C-4', C-6 '), 121.6 (C- 5 '), 12.4 (CH ₃ ); HRMS m / z calcd for C ₇ H ₆ N ₄ O (M ⁺ ) 162.0542, found 162.0541.

Example 3. Synthesis of 5-ethyl-3-pyrimidin-5-yl-1,2,4-oxadiazole

5 mL of DMSO was dissolved in 660 mg (4.78 mmol) of N -hydroxy-pyrimidine-5-carboxamidine, followed by adding 1.23 mL (9.56 mmol, 2.0 eq.) Of propionic anhydride to 18 at 100 ° C. Heated for hours. The reaction solution was distilled under reduced pressure to remove DMSO, and water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography (hexane / ethyl acetate, 1/1) to obtain 600 mg (71.2%) of a white solid of the compound.

71.2% yield (white solid); mp 37-38 ° C; IR (KBr) 3038, 2984, 1585 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.39 (s, 2H, C4'-H, C6'-H), 9.35 (s, 1H, C2'-H), 3.04 (q, 2H, CH ₂ ), 1.49 (t, 3H, CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 181.7 (C-5), 164.1 (C-3), 160.2 (C-2 '), 155.3 (C-4', C-6 '), 121.7 (C- 5 '), 20.2 (CH ₂ ), 10.6 (CH ₃ ); HRMS m / z calcd for C ₈ H ₈ N ₄ O (M ⁺ ) 176.0698, found 176.0695.

Example 4. Synthesis of 5-pentyl-3-pyrimidin-5-yl-1,2,4-oxadiazole

Dissolve 10 mL of DMSO in 0.95 g (6.88 mmol) of N -hydroxy-pyrimidine-5-carboxamidine, and add 3.18 mL (13.76 mmol, 2.0 eq.) Of hexanoic anhydride at 100 ° C. Heated for 18 hours. The reaction solution was distilled under reduced pressure to remove DMSO, and water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography (hexane / ethyl acetate, 2/1) to give 1.40 g (93.2%) of a yellow liquid of the compound.

93.2% yield (pale yellow oil); IR (neat) 3046, 2957, 1584 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.39 (s, 2H, C4'-H, C6'-H), 9.35 (s, 1H, C2'-H), 2.99 (t, 2H, CH ₂ ), 1.90 (m, 2H, CH ₂ ), 1.42 (m, 4H, ₂ × CH ₂ ), 0.94 (m, 3H, CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 181.2 (C-5), 164.2 (C-3), 160.3 (C-2 '), 155.4 (C-4', C-6 '), 121.8 (C- 5 '), 31.1, 26.5, 26.2, 22.1, 13.8 (alkyl-C); HRMS m / z calcd for C ₁₁ H ₁₄ N ₄ O (M ⁺ ) 218.1168, found 218.1167.

Example 5. 5- trans Synthesis of -propenyl-3-pyrimidin-5-yl-1,2,4-oxadiazole

Dissolve 10 mL of DMSO in 1.39 g (10.06 mmol) of N -hydroxy-pyrimidine-5-carboxamidine, and add 2.98 mL (20.12 mmol, 2.0 eq.) Of crotonic anhydride at 100 ° C. Heated for 18 hours. The reaction solution was distilled under reduced pressure to remove DMSO, and water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography (hexane / ethyl acetate, 3/1) to give 880 mg (46.5%) of a white solid of the compound.

46.5% yield (white solid); mp 115-117 ° C; IR (KBr) 3060, 2973, 1660 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.40 (s, 2H, C4'-H, C6'-H), 9.35 (s, 1H, C2'-H), 7.25 (dq, 1H, C H = CHCH ₃ ), 6.52 (dq, 1H, CH = C HCH ₃ ), 2.08 (dd, 3H, CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 175.6 (C-5), 164.3 (C-3), 160.3 (C-2 '), 155.4 (C-4', C-6 '), 144.4 ( C H = CHCH ₃ ), 121.8 (C-5 '), 114.4 (CH = C HCH ₃ ), 19.0 (CH ₃ ); HRMS m / z calcd for C ₉ H ₈ N ₄ O (M ⁺ ) 188.0698, found 188.0698.

Example 6 Synthesis of 5-isopropyl-3-pyrimidin-5-yl-1,2,4-oxadiazol

Dissolve 15 mL of DMSO in 1.54 g (6.88 mmol) of N -hydroxy-pyrimidine-5-carboxamidine, and add 3.70 mL (22.30 mmol, 2.0 eq.) Of isobutyric anhydride at 100 ° C. Heated for 18 hours. The reaction solution was distilled under reduced pressure to remove DMSO, and water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography (hexane / ethyl acetate, 2/1) to give 1.71 g (80.6%) of a yellow liquid of the compound.

80.6% yield (pale yellow oil); IR (neat) 3047, 2979, 1581 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.39 (s, 2H, C4'-H, C6'-H), 9.35 (s, 1H, C2'-H), 3.34 (sp, 1H, CH), 1.49 (d, 6H, 2 × CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 185.0 (C-5), 164.0 (C-3), 160.2 (C-2 '), 155.4 (C-4', C-6 '), 121.8 (C- 5 '), 27.5 (CH), 20.1 (CH ₃ ); HRMS m / z calcd for C ₉ H ₁₀ N ₄ O (M ⁺ ) 190.0855, found 190.0859.

Example 7 Synthesis of 5-phenyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate

After dissolving 300 mg (1.34 mmol) of 5-phenyl-3-pyrimidin-5-yl-1,2,4-oxadiazole in 5 mL of CH ₂ Cl ₂ , 227.48 μL (2.01) of methyl trifluoromethanesulfonate was dissolved. mol, 1.5 eq.) was added and stirred at room temperature for 30 minutes. The resulting salt was filtered, washed with Et 2 O and dried to give 500 mg (96.1%) of a white solid of the compound.

96.1% yield (white solid); IR (KBr) 3072, 2978, 1645, 1277 cm ^-1 ; ¹ H NMR (300 MHz, MeOH- d ₄ ) δ 8.68 (s, 1H, C6'-H), 8.14 (m, 2H, phenyl-H), 7.83 (d, 1H, C4'-H), 7.61 ( m, 3H, phenyl-H), 6.25 (s, 1H, C2'-H), 3.60 (s, 3H, N ⁺ CH ₃ ); HRMS m / z calcd for C ₁₃ H ₁₁ N ₄ O (M ⁺ -CF ₃ SO ₃ ) 239.0933, found 239.0934.

Example 8. Synthesis of 5-methyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate

630 mg (3.89 mmol) of 5-methyl-3-pyrimidin-5-yl-1,2,4-oxadiazole were dissolved in 20 mL of CH ₂ Cl ₂ , followed by 528.52 μL (4.67) of methyl trifluoromethanesulfonate. mol, 1.2 eq.) was added and stirred at room temperature for 1 hour. The resulting salt was filtered, washed with Et 2 O and dried to give 1.18 g (93.0%) of a white solid of the compound.

93.0% yield (white solid); IR (KBr) 3068, 2978, 1649, 1290 cm ⁻¹ ; ¹ H NMR (300 MHz, MeOH- d ₄ ) δ 8.65 (s, 1H, C6'-H), 7.71 (s, 1H, C2'-H), 6.19 (s, 1H, C4'-H), 3.57 (s, 3H, N ⁺ CH ₃ ), 2.62 (s, 3H, CH ₃ ); HRMS m / z calcd for C ₈ H ₉ N ₄ O (M ⁺ -CF ₃ SO ₃ ) 177.0776, found 177.0780.

Example 9 Synthesis of 5-ethyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate

420 mg (2.38 mmol) of 5-ethyl-3-pyrimidin-5-yl-1,2,4-oxadiazole was dissolved in 5 mL of CH ₂ Cl ₂ , followed by 404.03 μL (3.57 μL of methyl trifluoromethanesulfonate mol, 1.5 eq.) was added and stirred at room temperature for 30 minutes. The resulting salt was filtered, washed with Et 2 O and dried to give 750 mg (92.6%) of a white solid of the compound.

92.6% yield (white solid); IR (KBr) 3070, 2995, 1703, 1259 cm ⁻¹ ; ¹ H NMR (300 MHz, MeOH- d ₄ ) δ 8.65 (s, 1H, C6'-H), 7.73 (s, 1H, C4'-H), 6.20 (s, 1H, C2'-H), 3.58 (s, 3H, N ⁺ CH ₃ ), 2.97 (q, 2H, CH ₂ ), 1.39 (t, 3H, CH ₃ ); HRMS m / z calcd for C ₉ H ₁₁ N ₄ O (M ⁺ -CF ₃ SO ₃ ) 191.0933, found 191.0935.

Example 10 Synthesis of 5-pentyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate

170 mg (0.78 mmol) of 5-pentyl-3-pyrimidin-5-yl-1,2,4-oxadiazole was dissolved in 5 mL of CH ₂ Cl ₂ , followed by 132.41 μL (1.17 μL of methyl trifluoromethanesulfonate). mol, 1.5 eq.) was added and stirred at room temperature for 30 minutes. The resulting salt was filtered, washed with Et ₂ O and dried to give 250 mg (83.8%) of a white solid of the compound.

83.8% yield (white solid); IR (KBr) 3066, 2940, 1645, 1257 cm ⁻¹ ; ¹ H NMR (300 MHz, MeOH- d ₄ ) δ 8.65 (s, 1H, C6'-H), 7.73 (d, 1H, C4'-H), 6.20 (s, 1H, C2'-H), 3.57 (s, 3H, N ⁺ CH ₃ ), 2.95 (t, 2H, CH ₂ ), 1.83 (m, 2H, CH ₂ ), 1.39 (m, 4H, 2xCH ₂ ), 0.92 (m, 3H, CH ₃ ) ; HRMS m / z calcd for C ₁₂ H ₁₇ N ₄ O (M ⁺ -CF ₃ SO ₃ ) 233.1402, found 233.1405.

Example 11. 5- trans Synthesis of -propenyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate

770 mg (4.09 mmol) of 5- trans -propenyl-3-pyrimidin-5-yl-1,2,4-oxadiazole was dissolved in 10 mL of CH ₂ Cl ₂ , followed by methyl fluoromethanesulfonate 555.68 μL (4.91 mol, 1.2 eq.) was added thereto, followed by stirring at room temperature for 30 minutes. The resulting salt was filtered, washed with Et ₂ O and dried to give 1.18 g (81.9%) of a white solid of the compound.

81.9% yield (white solid); IR (KBr) 3074, 2978, 1705, 1279 cm ⁻¹ ; ¹ H NMR (300 MHz, MeOH- d ₄ ) δ 8.66 (s, 1H, C6'-H), 7.73 (d, 1H, C4'-H), 7.20 (dq, 1H, C H = CHCH ₃ ), 6.53 (dq, 1H, CH═C H CH ₃ ), 6.21 (s, 1H, C 2′-H), 3.58 (s, 3H, N ⁺ CH ₃ ), 2.04 (dd, 3H, CH ₃ ); HRMS m / z calcd for C ₁₀ H ₁₁ N ₄ O (M ⁺ -CF ₃ SO ₃ ) 203.0933, found 203.0936.

Example 12. Synthesis of 5-isopropyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate

1.54 g (8.10 mmol) of 5-isopropyl-3-pyrimidin-5-yl-1,2,4-oxadiazole was dissolved in 15 mL of CH ₂ Cl ₂ , followed by 1.10 mL of methyl trifluoromethanesulfonate. 9.72 mol, 1.2 eq.) Was added and stirred at room temperature for 30 minutes. The resulting salt was filtered, washed with Et ₂ O and dried to give 2.06 g (71.8%) of a white solid of the compound.

71.8% yield (white solid); IR (KBr) 3070, 2980, 1710, 1288 cm ^-1 ; ¹ H NMR (300 MHz, MeOH- d ₄ ) δ 8.66 (s, 1H, C6'-H), 7.74 (s, 1H, C4'-H), 6.20 (s, 1H, C2'-H), 3.58 (s, 3H, N ⁺ CH ₃ ), 3.30 (sp, 1H, CH), 1.42 (d, 6H, 2 × CH ₃ ); HRMS m / z calcd for C ₁₀ H ₁₃ N ₄ O (M ⁺ -CF ₃ SO ₃ ) 205.1089, found 205.1085.

Example 13. Synthesis of 5-phenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazoloxalate

Dissolve 560 mg (1.44 mmol) of 5-phenyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate in 10 mL of methanol and 108.95 mg of NaBH ₄ at -20 ° C. 2.88 mmol, 2.0 eq.) Was added little by little and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered and the solvent was removed to yield 330 mg of 5-phenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole. Got. The product was dissolved in 3 mL of acetone without purification, and then 183.68 mg (2.04 mmol) of oxalic acid was added thereto, followed by stirring at room temperature for 30 minutes. The product was filtered and recrystallized (MeOH / AcOEt) to give 60 mg (12.5%) of a white solid of the compound.

12.5% yield (white solid); mp 153-155 ° C; IR (KBr) 3195, 2990, 1642, 1211 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.08 (m, 2H, pheny-H), 7.61 (m, 3H, pheny-H), 7.52 (m, 1H, C6'-H), 7.21 (br) s, 1H, NH), 5.86 (br s, 2H, 2xCO ₂ H), 4.21 (s, 2H, C2'-H), 3.78 (s, 2H, C4'-H), 2.64 (s, 3H, NCH ₃ ); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 173.5 (C-5), 167.4 (C-3), 164.4 (CO), 136.4 (C-6 '), 133.2, 129.7, 128.0, 123.9 (phenyl- C), 88.2 (C-5 '), 61.4 (C-2'), 49.4 (C-4 '), 39.1 (NCH ₃ ); HRMS m / z calcd for C ₁₃ H ₁₄ N ₄ O (M- (CO ₂ H) ₂ ) ⁺ 242.1168, found 242.1170.

Example 14 Synthesis of 5-methyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazol oxalate

1.04 g (3.19 mmol) of 5-methyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate was dissolved in 10 mL of methanol and 241.36 mg of NaBH ₄ at −20 ° C. 6.38 mmol, 2.0 eq.) Was added little by little, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered and the solvent removed to remove 5-methyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole (490 mg) to obtain a residue. The product was dissolved in 5 mL of acetone without purification, and then 244.91 mg of oxalic acid was added and stirred at room temperature for 30 minutes. The product was filtered and washed with acetone to give 506 mg (58.7%) of a white solid of the compound which was recrystallized from MeOH / AcOEt.

58.7% yield (white solid); mp 143-145 ° C; IR (KBr) 3258, 3008, 1648 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.93 (br s, 2H, 2xCO ₂ H), 7.38 (s, 1H, C6'-H), 7.31 (br s, 1H, NH), 4.29 (s , 2H, C2'-H), 3.84 (s, 2H, C4'-H), 2.70 (s, 3H, NCH ₃ ), 2.50 (s, 3H, CH ₃ ); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 175.3 (C-5), 166.7 (C-3), 164.4 (CO), 135.8 (C-6 '), 88.5 (C-5'), 61.4 ( C-2 '), 49.3 (C-4'), 39.1 (NCH ₃ ), 12.0 (CH ₃ ); Anal. Calcd for C ₈ H ₁₂ N ₄ O. (CO ₂ H) ₂ : C, 44.44; H, 5. 22; N, 20.73. Found: C, 44.55; H, 5. 26; N, 20.69.

Example 15 Synthesis of 5-ethyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole oxalate

550 mg (1.62 mmol) of 5-ethyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate are dissolved in 10 mL of methanol and 122.57 mg of NaBH ₄ at −20 ° C. 3.24 mmol, 2.0 eq.) Was added little by little and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered and the solvent was removed to obtain 300 mg of 5-ethyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4 oxadiazole. Got it. The product was dissolved in 3 mL of acetone without purification, and 208.0 mg (2.31 mmol) of oxalic acid was added thereto, followed by stirring at room temperature for 30 minutes. The product was filtered and recrystallized (MeOH / AcOEt) to give 215 mg (46.7%) of a white solid of the compound.

46.7% yield (white solid); mp 144-146 ° C; IR (KBr) 3265, 2985, 1649 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.37 (s 1H, C6'-H), 7.21 (br s, 1H, NH), 4.25 (s, 2H, C2'-H), 3.79 (s, 2H, C4'-H), 2.84 (q, 2H, CH ₂ ), 2.67 (s, 3H, NCH ₃ ), 1.24 (t, 3H, CH ₃ ); ¹³ C NMR (75 MHz, MeOH- d ₄ ) δ 181.5 (C-5), 167.7 (C-3), 166.8 (CO), 136.6 (C-6 '), 91.4 (C-5'), 63.5 ( C-2 '), 51.6 (C-4'), 39.8 (NCH ₃ ), 21.2 (CH ₂ ), 11.3 (CH ₃ ); Anal. Calcd for C ₉ H ₁₄ N ₄ O. (CO ₂ H) ₂ : C, 46.48; H, 5.67; N, 19.71. Found: C, 46.28; H, 5.63; N, 19.62.

Example 16 Synthesis of 5-pentyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole oxalate

Dissolve 1.41 g (3.69 mmol) of 5-pentyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate in 10 mL of methanol and 279.19 mg of NaBH ₄ at -20 ° C. 7.38 mmol, 2.0 eq.) Was added little by little and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered and the solvent was removed to give 770 mg of 5-pentyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole. Got. The product was dissolved in 10 mL of acetone without purification, and then 440.30 mg (4.89 mmol) of oxalic acid was added thereto, followed by stirring at room temperature for 30 minutes. The product was filtered and recrystallized (MeOH / AcOEt) to give 467 mg (38.8%) of a white solid of the compound.

38.8% yield (white solid); mp 148-149 ° C; IR (KBr) 3252, 2958, 1644 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (br s, 2H, 2xCO ₂ H), 7.37 (s, 1H, C6'-H), 7.23 (br s, 1H, NH), 4.26 (s , 2H, C2'-H), 3.80 (s, 2H, C4'-H), 2.81 (t, 2H, CH ₂ ), 2.67 (s, 3H, NCH ₃ ), 1.68 (m, 2H, CH ₂ ) , 1.29 (m, 4H, 2xCH ₂ ), 0.85 (m, 3H, CH ₃ ); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 178.2 (C-5), 166.5 (C-3), 164.4 (CO), 135.8 (C-6 '), 88.5 (C-5'), 61.4 ( C-2 '), 49.4 (C-4'), 39.1 (NCH ₃ ), 30.8, 25.9, 25.7, 21.8, 14.0 (alkyl-C); Anal. Calcd for C ₁₂ H ₂₀ N ₄ O. (CO ₂ H) ₂ : C, 51.52; H, 6.79; N, 17.17. Found: C, 51.52; H, 6. 78; N, 17.37.

Example 17. 5- trans Synthesis of -propenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole oxalate

Dissolve 1.12 g (3.18 mmol) of 5- trans -propenyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate in 10 mL of methanol and NaBH ₄ at -20 ° C. 240.60 mg (6.36 mmol, 2.0 eq.) Was added little by little and stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered and the solvent removed to remove 5- trans -propenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiaza A sol residue was obtained. The product was dissolved in 15 mL of acetone without purification, and then 343.95 mg (3.82 mmol, 1.2 eq.) Of oxalic acid was added thereto and stirred at room temperature for 30 minutes. The product was filtered and recrystallized (MeOH / AcOEt) to give 550 mg (58.4%) of a white solid of the compound.

58.4% yield (white solid); mp 171-173 ° C; IR (KBr) 3250, 3030, 1645 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.38 (s, 1H, C6′-H), 7.18 (br s, 1H, NH), 6.99 (dq, 1H, C H = CHCH ₃ ), 6.50 ( dq, 1H, CH = C H CH ₃ ), 6.25 (br s, 2H, 2xCO ₂ H), 4.23 (s, 2H, C2'-H), 3.78 (s, 2H, C4'-H), 2.65 ( s, 3H, NCH ₃ ), 1.95 (dd, 3H, CH ₃ ); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 172.7 (C-5), 167.0 (C-3), 163.7 (CO), 143.2 ( C H = CHCH ₃ ), 136.0 (C-6 '), 114.8 (CH = C HCH ₃ ), 88.5 (C-5 ′), 61.6 (C-2 ′), 49.6 (C-4 ′), 39.1 (NCH ₃ ), 18.7 (CH ₃ ); Anal. Calcd for C ₁₀ H ₁₄ N ₄ O. (CO ₂ H) ₂ : C, 48.65; H, 5. 44; N, 18.91. Found: C, 48.54; H, 5.47; N, 18.87.

Example 18. Synthesis of 5-isopropyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole oxalate

Dissolve 1.94 g (5.48 mmol) of 5-isopropyl-3- (3-methylpyrimidium-5-yl) -1,2,4-oxadiazole triflate in 20 mL of methanol and 414.62 mg of NaBH ₄ at -20 ° C. (10.96 mmol, 2.0 eq.) Was added little by little and then stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered and the solvent was removed to give 5-isopropyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole residue Got. The product was dissolved in 15 mL of acetone without purification, and then 592.46 mg (6.58 mmol, 1.2 eq.) Of oxalic acid was added thereto, followed by stirring at room temperature for 30 minutes. The product was filtered and recrystallized (MeOH / AcOEt) to give 1.28 g (78.3%) of a white solid of the compound.

78.3% yield (white solid); mp 148-149 ° C; IR (KBr) 3285, 2977, 1650 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.36 (s, 1H, C6'-H), 7.11 (br s, 1H, NH), 6.15 (br s, 2H, 2xCO ₂ H), 4.20 (s , 2H, C2'-H), 3.74 (s, 2H, C4'-H), 3.17 (sp, 1H, CH), 2.63 (s, 3H, NCH ₃ ), 1.28 (dd, 6H, 2xCH ₃ ); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 181.9 (C-5), 166.7 (C-3), 163.7 (CO), 135.9 (C-6 '), 88.6 (C-5'), 61.7 ( C-2 '), 49.6 (C-4'), 39.1 (NCH ₃ ), 26.7 (CH), 20.1 (CH ₃ ); Anal. Calcd for C ₁₀ H ₁₆ N ₄ O. (CO ₂ H) ₂ : C, 48.32; H, 6.08; N, 18.78. Found: C, 47.92; H, 6.04; N, 18.63.

[Example]

The following formulation example describes a general pharmaceutical composition according to the present invention, the active ingredient is 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivative represented by the formula (1) In some cases, it may be replaced by an effective dose equivalent to other compounds included in the present invention.

Manufacture of tablets

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, followed by grinding to pass through a 14 mesh sieve. Thereafter, the resultant was dried, and then 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate were added thereto to obtain a mixture, which was then tableted in a conventional manner.

Experimental Example Muscarinic receptor binding rate

Some compounds according to the invention were tested for their activity as anhydrous carine receptor agonists in the following manner.

To study the effect of each drug on receptor-ligand interactions with muscarinic receptor subtypes 1 and 2 (M ₁ , M ₂ ) (NEW, USA), radioisotope attached ligands were used to After the reaction, the resultant is filtered with a glass fiber filter to remove the unbound extra ligand, and then the amount of isotope remaining in the washed filter disk is 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 was bio-rad. It was measured with a Bio-Rad DC Protein Assay Kit and then adjusted to a concentration of 70-75 μL / mL. At this time, the setting of the 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.

All test samples were repeated in duplicate 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 start of the reaction was allowed to react in a shaking incubator (Rosi 1000, Thermolyne) for 60 minutes at 27 ° C. by adding 100 μL of receptor suspension. After incubation for 1 hour, the reaction was terminated with about 0.5 mL of cold 50 mM Tris buffer pH 7.4 and Inotech cell Harvester (96-) using a Wallac glass fiber filtermat GF / C. Well) isotope bound to the receptor was isolated and washed, and the amount of isotope trapped on the filler mat was measured by a liquid scintillation counter (MicroBeta 1450 Plus).

In the first phase drug search, the affinity of the drug for a certain concentration of the drug was searched for, and as a comparative substance, arecoline and mimelaline were used. 1 nM of [ ³ H] N- methyl-scopolamine (NEN, NET-636) was used as a radioisotope labeling substance, and 1 μM of atropine sulfate (RBI, A-105). The experimental results are shown in Table 1 below.

compound Inhibitory concentration (% inhibition rate) 10 μM 100 μM  Example 13 9.0 16.6  Example 16 8.0 66.1  Example 17 10.8 33.3  Example 18 32.9 46.1 Arecoline <0 31.0 Milamelanin 11.7 60.1

According to the results of Table 1, the novel compound of the example according to the present invention shows a comparable effect of the M ₁ receptor inhibitory effect compared to the comprehension Arecholine, in particular, in the case of Example 16 shows the most excellent effect Able to know.

As described above, 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives prepared by the method of the present invention are muscarinic receptor agonists and related to dementia treatment and brain disease. It can be applied to therapeutic drugs, and acts as a bioisoster of tetrahydropyridine, which has a therapeutic effect comparable to that of arecholine and millamellin already used clinically for the treatment of dementia.

Claims (6)

1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivatives represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1]

In Formula 1, R is a C ₁ ~ C ₁₀ Alkyl group, C ₂ ~ C ₁₀ Alkenyl group, or a phenyl group According to claim 1, wherein the compound represented by the formula (1) 5-phenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, 5-methyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, 5-ethyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, 5-pentyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, 5- trans -propenyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, 5-isopropyl-3- (3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl) -1,2,4-oxadiazole, or A compound characterized in that it is selected from pharmaceutically acceptable salts thereof. The compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt of an organic or inorganic acid selected from hydrochloric acid, oxalic acid, fumaric acid, tartaric acid and p -toluenesulfonic acid. a) preparing a compound represented by the following Chemical Formula 4 by performing a cyclization reaction from an N -hydroxy-pyrimidine-5-carboxamidine represented by the following Chemical Formula 2 and an acid anhydride represented by the following Chemical Formula 3; b) preparing a compound represented by Chemical Formula 5 by 3-methylating the compound represented by Chemical Formula 4 from methyl trifluoromethanesulfonate (CF ₃ SO ₃ CH ₃ ); And c) preparing a compound represented by Chemical Formula 1 by reducing the compound represented by Chemical Formula 5; Manufacturing method characterized in that it comprises:

[Formula 1]

In the above formula, R is a C ₁ ~ C ₁₀ Alkyl group, C ₂ ~ C ₁₀ Alkenyl group, or a phenyl group. The method according to claim 4, wherein the cyclization reaction is performed using an acid anhydride represented by Formula 3 in the presence of dimethyl sulfoxide (DMSO). Senile dementia comprising 1,2,3,4-tetrahydropyrimidinyl-1,2,4-oxadiazole derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical compositions for treatment: [Formula 1]

In Formula 1, R is a C ₁ ~ C ₁₀ Alkyl group, C ₂ ~ C ₁₀ Alkenyl group, or a phenyl group.