JPH0730036B2 - Pyrimidinylglycine derivative - Google Patents

Description

TECHNICAL FIELD The present invention is α- (2) which is a novel compound having anticoagulant activity.
-Imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) glycine N-arylsulfonyl derivative, which is useful for prevention, recurrence prevention and treatment of thrombosis.

[Prior Art] In the field of the present invention, various compounds having an arginine residue as a serine protease inhibitor, for example, N ^α- (p
-Toluenesulfonyl) -L-arginine esters (US Pat. No. 5,622,615) are also (2R, 4R) -1- [N ^α-
It is known that (3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-pyridinecarboxylic acid has antithrombin activity (Japanese Patent Application Laid-Open No. 2004-242242). 56-15267).

[Constitution of the Invention] The present invention has the general formula I And a acid addition salt thereof. In the formula, R ¹ represents a phenyl group which may be substituted with lower alkyl, mono-lower alkylamino or di-lower alkylamino, a quinolyl group or a tetrahydroquinolyl group, and R ² represents a hydroxyl group, a lower alkoxyl group or a cycloalkylamino group. It means a cyclic amino group which may be substituted by a group or lower alkyl. Examples of the acid that can be added include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromide, and organic acids such as maleic acid, fumaric acid and methanesulfonyl acid.

The compounds of the present invention are compounds of formula I-1 or I-2
It may also exist as a tautomer having an aminotetrahydropyrimidine structure.

The compound of the present invention can be prepared by the method of Bicroft et al. [BWBycroft
et.al., J. Chem. Soc., 1971, page 3040]
Can be used as a starting material.

The compound of formula II is a mixture of compounds of formula II-1 and formula II-2, namely threo-α- (2-imino-1,2,3,4,5,
6-hexahydro-4-pyrimidinyl) glycine (capreomycidine), and a mixture of compounds of formula II-3 and formula II-4, namely erythro-α- (2-imino-1,
2,3,4,5,6-Hexahydro-4-pyrimidinyl) glycine (epi-capreomycinidin), as well as a mixture of the two, namely α- (2-imino-1,2,3,4,5 , 6
-Hexahydro-4-pyrimidinyl) glycine can take any of the three forms.

When the compound of formula II is heated in water or a mixed solvent of dioxane or dimethylformamide and water in the presence of potassium carbonate with the desired sulfonyl chloride to room temperature to around 100 ° C., R ^{2 in} formula I is a hydroxyl group. A compound is produced.

This compound is suspended in lower alcohols such as methanol, ethanol, n-propanol, n-butanol, etc., and saturated dry hydrogen chloride gas is cold-conducted or thionyl chloride is added and stirred for 2 to 10 hours to give a compound of formula In I, a compound in which R ² is a lower alkoxyl group can be prepared.

Further, in the formula I, a compound in which R ² is a hydroxyl group is mixed with thionyl chloride in the cold state and then heated and stirred for 1 to 2 hours to form an acid chloride (R ² = Cl) in the presence of a solvent such as dimethylformamide. By heating with desired amines at room temperature to 70 ° C. for 1 to 3 hours, a compound of the formula I in which R ² is cycloalkylamino or a cyclic amino group can be prepared.

[Effect of the Invention] The compound of the present invention is useful as a compound having a chemical structure different from conventional ones and exhibiting an anticoagulant action.

Next, the anticoagulant effect will be specifically described.

Antithrombin action (Fibrinogen-Trobin time): A sample was dissolved in 100 µs of Tris buffered saline, and 100 µl of commercially available bovine fibrinogen 0.6 mg of Tris buffered saline was added thereto, and the mixture was incubated at 37 ° C. 100 μ of bovine thrombin (about 10 units / ml) was added to the solution, and the coagulation time was measured by Klotech (manufactured by Sanko Junyaku).

A standard straight line was prepared by changing the amount of thrombin, and the inhibition rate was calculated by converting the coagulation time when the sample was added to the unit of thrombin. The inhibition rate was plotted on a lognormal probability paper, and the concentration of the sample showing 50% inhibition rate was determined. This is shown in the table as the 50% inhibitory concentration.

Plasma coagulation time doubled action Plasma 100μ centrifuged from expired human blood for transfusion
100 μl of a Tris buffer solution of the sample was added to and preincubated at 37 ° C. for 3 minutes. To this, 100 μ of 0.02 M calcium chloride solution was added, and the coagulation time was measured by Klotech. The concentration of the sample that doubles the coagulation time of the control was determined and used as the index of the anticoagulant action. The results are shown in the table below.

Example 1: Synthesis of α- (2-imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonyl glycine: α- (2-imino-1,2 , 3,4,5,6-Hexahydro-4-
2.2 g of pyrimidinyl) glycine is dissolved in 30 ml of water and 2.5 g of potassium carbonate is added. Heat to 60-70 ° C and add 2.1 g paratoluenesulfonyl chloride over 20 minutes. After stirring for 2 hours as it is, 0.5 g of potassium carbonate and 0.7 g of paratoluenesulfonyl chloride are further added, and the reaction is continued for 3 hours. After cooling, the reaction solution is 60 ml of ion exchange resin (DOWEX H ⁺ 50w-X4).
After that, the resin is washed well with water and then eluted with 2.8% ammonia water. The eluate was evaporated to dryness under reduced pressure, and the residue was recrystallized from water to obtain 1.26 g of the desired product.

Melting point 243 to 246 ℃ (decomposition) IR (KBr): 1665,1635,1600,1575,1460,1385,1360,1320c
m ^-1 elemental analysis calculated as C ₁₃ H ₁₈ N ₄ O ₄ S C 47.84 H 5.56 N 17.17 experimental value C 47.61 H 5.49 N 17.12 Example 2: threo-α- (2-imino-1,2,3, Synthesis of 4,5,6-hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonyl glycine In the same manner as in Example 1, 0.31 g of the desired product was obtained from 0.4 g of capreomycin.

Melting point 247-249 ° C (decomposition) IR (KBr): 1660,1640,1595,1560,1495,1380,1360,1320c
m ^-1 Elemental analysis Calculated as C ₁₃ H ₁₈ N ₄ O ₄ S C 47.84 H 5.56 N 17.17 Experimental value C 47.67 H 5.64 N 17.02 Example 3: Erythro-α- (2-imino-1,2,3, 4,5,6-
Synthesis of Hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonyl glycine: In the same manner as in Example 1, 0.49 g of epicapreomycidine
From this, 0.56 g of the desired product was obtained.

Melting point 247-248 ° C (decomposition) IR (KBr): 1635,1565,1450,1395,1345,1320cm ^-1 Elemental analysis C ₁₃ H ₁₈ N ₄ O ₄ S Calculated value C 47.84 H 5.56 N 17.17 Experimental value C 47.47 H 5.53 N 17.36 example 4: N α ^- (5- dimethylamino-1-naphthalenesulfonyl)-.alpha.-(2-imino-hexahydro-4-pyrimidinyl) glycine Synthesis: In the same manner as in Example 1, α- (2-imino-1,2,3,4,5,
2.0 g of 6-hexahydro-4-pyrimidinyl) glycine was dissolved in 20 ml of water and 10 ml of dioxane, 2.25 g of potassium carbonate.
Add. A solution of 1-dimethylamino-5-naphthalenesulfonyl chloride in dioxane (20 ml) is added below 15 ° C, and the mixture is stirred at room temperature overnight. The deposited precipitate was collected by filtration, dissolved in 10% hydrochloric acid, reprecipitated with 10% aqueous ammonia and collected by filtration.

Melting point 250 ° C (decomposition) IR (KBr): 1685,1610,1450,1370,1325cm ^-1 Elemental analysis Calculated as C ₁₈ H ₂₃ N ₅ O ₄ S C 53.32 H 5.72 N 17.27 Experimental value C 52.95 H 5.80 N 16.78 Example 5: Synthesis of α- (2-imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) -N ^α- (8-quinolinesulfonyl) glycine In the same manner as in Example 4, α- (2-imino-1,2,3,4,5,
2.0 g of 6-hexahydro-4-pyrimidinyl) glycine are dissolved in 15 ml of water and 10 ml of dimethylformamide, and 2.25 g of potassium carbonate is added. Below 15 ° C. add a solution of 8-quinolinesulfonyl chloride in 20 ml of dimethylformamide. Thereafter, the same treatment was carried out to obtain 1.09 g of the desired product. Melting point 271-274
℃ (decomposition) IR (KBr): 1680,1630,1600,1495cm ^-1 Elemental analysis Calculated as C ₁₅ H ₁₇ N ₅ O ₄ S C 49.58 H 4.72 N 19.27 Experimental value C 49.22 H 4.63 N 19.21 Example 6: α- (2-Imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) -N ^α- (1,2,3,4-tetrahydro-8-quinolinesulfonyl) glycine Synthesis α- (2-imino-1,2,3,4,5,6-hexahydro-4-
Pyrimidinyl) -N ^α- (8-quinolinesulfonyl) glycine (0.30 g) is dissolved in a mixed solution of ethanol (10 ml) and water (10 ml), and 30 mg of platinum oxide is added and catalytically reduced under normal pressure. After completion of the reaction, the catalyst is filtered off and the filtrate is dried under reduced pressure. Water was added to the residue to make it alkaline with ammonia, and the precipitate was collected by filtration.

Yield 0.16g Melting point 165-175 ° C (decomposition) IR (KBr): 1670,1620,1595,1505cm ^-1 Elemental analysis Calculated as C ₁₅ H ₂₁ N ₅ O ₄ S C 49.03 H 5.76 N 19.06 Experimental value C 48.93 H 5.87 N 18.84 Example 7: Synthesis of α- (2-imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonylglycine methyl ester hydrochloride α- (2 -Imino-1,2,3,4,5,6-hexahydro-4-
2.285 g of pyrimidinyl) -N ^α- paratoluenesulfonylglycine is suspended in 15 ml of methanol to saturate hydrogen chloride gas. After heating under reflux for 5 hours, the mixture was dried under reduced pressure and crystallized with a small amount of ethanol.

Yield 0.24g Melting point 170 ° C (decomposition) IR (KBr): 1750,1670,1630,1330,1150cm ^-1 Elemental analysis C ₁₄ H ₂₀ N ₄ O ₄ S ・ HCl ・ 1 / 2H ₂ O Calculated value C 43.58 H 5.75 N 14.52 Experimental value C 43.53 H 5.64 N 14.64 Hereinafter, the compounds of Examples 8 to 19 were synthesized in the same manner as in Example 7.

Example 8: Threo-α- (2-imino-1,2,3,4,5,6-hexadohydro-4-pyrimidinyl) -N ^α- paratoluenesulfonylglycine methyl ester hydrochloride Yield 70% Melting point 170- 173 ℃ (decomposition) IR (KBr): 1730,1660,1620,1330,1150cm ^-1 Elemental analysis Calculated as C ₁₄ H ₂₀ N ₄ O ₄ S ・ HCl ・ 1 / 2H ₂ O C 43.58 H 5.75 N 14.52 experiment Value C 43.62 H 5.81 N 14.69 Example 9: Erythro-α- (2-imino-1,2,3,4,5,6-
Hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonylglycine methyl ester hydrochloride Yield 62% Melting point 199-202 ° C (decomposition) IR (KBr): 1725,1660,1620,1330,1155cm ^-1 Elemental analysis C ₁₄ Calculated value as H ₂₀ N ₄ O ₄ S.HCl C 44.62 H 5.62 N 14.87 Experimental value C 44.38 H 5.51 N 14.89 Example 10: α- (2-imino-1,2,3,4,5,6-hexahydro -4-Pyrimidinyl) -N ^α- paratoluenesulfonylglycine ethyl ester hydrochloride Yield 57% Melting point 169-177 ° C (decomposition) IR (KBr): 1730,1665,1620,1335,1150cm ^-1 Elemental analysis C ₁₅ H Calculated value for ₂₂ N ₄ O ₄ S.HCl C 46.09 H 5.93 N 14.33 Experimental value C 45.84 H 5.73 N 14.26 Example 11: α- (2-imino-1,2,3,4,5,6-hexahydro- 4-pyrimidinyl) -N ^α- paratoluenesulfonyl glycine n-propyl ester hydrochloride Yield 71% Melting point unclear (amorphos solid) IR (KBr): 17 35,1670,1635,1340,1160cm ^-1 Elemental analysis Calculated as C ₁₆ H ₂₄ N ₄ O ₄ S ・ HCl C 47.46 H 6.22 N 13.84 Experimental C 47.13 H 6.24 N 13.17 Example 12: Threo-α- ( 2-imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonylglycine n-propyl ester hydrochloride yield 86% melting point 147-149 ° C (decomposition) IR ( KBr): 1745,1680,1620,1460,1390,1340,1200,1160c
m ^-1 Elemental analysis Calculated as C ₁₆ H ₂₄ N ₄ O ₄ S.HCl C 47.46 H 6.22 N 13.84 Experimental value C 47.14 H 6.14 N 13.74 Example 13: Erythro-α- (2-imino-1,2, 3,4,5,6-
Hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulfonylglycine n-propyl ester hydrochloride Yield 75% Melting point 142-144 ° C (decomposition) IR (KBr): 1730,1665,1630,1330,1155cm ^-1 Elemental analysis Calculated as C ₁₆ H ₂₄ N ₄ O ₄ S.HCl C 47.46 H 6.22 N 13.84 Experimental value C 47.4214 H 6.104 N 13.8774 Example 14: α- (2-imino-1,2,3,4,5,6 -Hexahydro-4-pyrimidinyl) -N ^α- paratoluenesulphonylglycine n-butyl ester hydrochloride Yield 69% Melting point unclear (Amorphos solids) IR (KBr): 1740,1665,1620,1335,1160cm ^-1 Elemental analysis C ₁₇ H ₂₆ N ₄ O ₄ S ・ HCl ・ 1 / 2H ₂ O Calculated value C 47.71 H 6.59 N 13.09 Experimental value C 47.74 H 6.31 N 12.94 Example 15: N ^α- (5-dimethylamino-1-naphthalene Sulfonyl) -α- (2-imino-1,2,3,4,5,6-hexahydro-4-pyrimidinyl) glycine n-propyl ester Salt Yield 73% mp indistinct [140-150 ° C. (decomposition)] IR (KBr): 1740,1670,1630,1510,1460cm -1 elemental analysis C ₂₁ H ₂₉ N ₅ O ₄ Calculated S · 2HCl C 48.46 H 6.00 N 13.46 Experimental value C 48.61 H 6.23 N 12.79 Example 16: N ^α- (5-dimethylamino-1-naphthalenesulfonyl) -α- (2-imino-1,2,3,4,5, 6-hexahydro-4-pyrimidinyl) glycine n-butyl ester hydrochloride 80% yield unclear melting point [120-130 ° C (decomposition)] IR (KBr): 1735,1665,1625,1510,1460cm ^-1 Elemental analysis C Calculated value as ₂₂ H ₃₁ N ₅ O ₄ S.2HCl C 49.44 H 6.22 N 13.10 Experimental value C 50.10 H 6.16 N 12.83 Example 17: α- (2-imino-1,2,3,4,5,6- Hexahydropyrimidin-4-yl) -N ^α- (8-quinolinesulfonyl) -glycine n-butyl ester hydrochloride Yield 85% Melting point 98-105 ° C (decomposition) IR (KBr): 1740,1670,1625cm ^-1 Elemental analysis C ₁₉ H ₂₅ N ₅ O ₄ S ・ 2 HCl Calculated value C 46.34 H 5.53 N 14.22 Experimental value C 47.03 H 5.46 N 14.29 Example 18: α- (2-imino-1,2,3,4,5,6-hexahydropyrimidin-4-yl) -N ^α- (1,2,3,4-Tetrahydro-8-quinolinesulfonyl) glycine n-Butyl ester hydrochloride Yield 74% Melting point unclear (Amorphos solids) IR (KBr): 1740,1670,1625cm ^-1 Elemental analysis Calculated as C ₁₉ H ₂₉ N ₅ O ₄ S.2HCl C 45.97 H 6.29 N 14.11 Experimental value C 45.70 H 5.90 N 14.03 Example 19: N ^α- (5-dimethylamino-1-naphthalenesulfonyl) -α- ( Synthesis of 2-imino-1,2,3,4,5,6-hexahydropyrimidin-4-yl) glycine cyclohexyl amide dihydrochloride N ^α- (5-dimethylamino-1-
After adding 0.35 g of naphthalenesulfonyl) -α- (2-iminohexahydropyrimidin-4-yl) glycine, the mixture was allowed to stand at room temperature for 30 minutes and then heated at 60 ° C for 1 hour. After drying under reduced pressure, the residue is dissolved in 3 ml of dimethylformamide, and 1.2 g of cyclohexylamine is added under ice cooling. The mixture is stirred at room temperature for 3 hours and dried under reduced pressure. The residue is added to 2N sodium hydroxide and extracted with chloroform. Wash with water, dry, and dry under reduced pressure. The residue was reprecipitated with methanol-ether, dissolved in a small amount of 10% hydrochloric acid-methanol and treated with ether to obtain the desired product.

Yield 0.25g Melting point unclear [170-180 ° C (decomposition)] IR (KBr): 1660,1630cm ^-1 Elemental analysis C ₂₄ H ₃₄ N ₆ O ₃ S ・ 2HCl ・ 3 / 2H ₂ O Calculated value C 49.14 H 6.70 N 14.33 Experimental value C 48.91 H 6.53 N 14.29 The compounds of Example 20 to Example 22 were synthesized in the same manner as in Example 19 below.

Example 20: N ^α- (5-dimethylamino-1-naphthalenesulfonyl) -α- (2-imino-1,2,3,4,5,6-hexahydro-4-pyrimidyl) glycine piperidine amide dihydrochloride Yield 45% Melting point unclear IR (KBr): 1670,1630,1510,1470,1440cm ^-1 Elemental analysis Calculated as C ₂₃ H ₃₂ N ₆ O ₃ S ・ 2HCl ・ 3 / 2H ₂ O C 48.25 H 6.51 N 14.68 Experimental value C 48.79 H 6.63 N 14.85 Example 21: N ^α- (5-dimethylamino-1-naphthalenesulfonyl) -α- (2-imino-1,2,3,4,5,6-hexahydro-4 -Pyrimidyl) glycine 4-methylpiperidine amide dihydrochloride Yield 41% Melting point unclear [165-175 ° C (decomposition)] IR (KBr): 1670,1630,1505,1450cm ^-1 Elemental analysis C ₂₄ H ₃₄ N ₆ O ₃ calculated _{S · 2HCl · 2H 2 O C} 48.40 H 6.77 N 14.11 Found C 48.79 H 6.63 N 13.85 example 22: α- (2- imino-1,2,3,4,5,6 hexa Hydropyrimidin-4-yl) -N ^α- (8-quinolinesulfonyl) glycine piperidine amide dihydrochloride Yield 35% Melting point unclear [160-170 ° C (decomposition)] IR (KBr): 1650,1535cm ^-1 Elemental analysis C ₂₁ H ₂₈ N ₆ O ₃ Calculated as S ・ 2HCl ・ 1 / 2H ₂ O C 47.91 H 5.93 N 15.96 Experimental value C 47.88 H 6.26 N 15.95

Claims (1)

[Claims] 1. A general formula I A compound represented by and an acid addition salt thereof. In the formula, R ¹ represents a phenyl group which may be substituted with lower alkyl, mono-lower alkylamino or di-lower alkylamino, a quinolyl group or a tetrahydroquinolyl group, and R ² represents a hydroxyl group, a lower alkoxyl group or a cycloalkylamino group. It means a cyclic amino group which may be substituted by a group or lower alkyl.