HU196186B - Process for production of derivatives of 3,4-dihydropirimidin - Google Patents

Abstract

A PROCESS FOR PREPARING NOVEL N-SUBSTITUTED 3,4-DIHYDROPYRIMIDINE DERIVATIVES : A N-substituted 3,4-dihydropyrimidine derivative of the formula (1): <IMG> (1) wherein R1 is -(CH2)n-X; X is substituted aminoethyl, substituted sulfide-ethyl, substituted or non-substituted heterocyclo-ethyl wherein the ethylene group is directly bonded to a hetero atom in the heterocyclic ring, or substituted or non-substituted heterocyclo-methyl wherein the methylene group is directly bonded to a carbon atom in the heterocyclic ring; n is an integer from 0 to 8; R2 is straight, branched, cyclic or cyclo-straight alkyl having from one to thirteen carbon atoms, or aralkyl having from seven to thirteen carbon atoms and pharmacologically acceptable acid addition salts thereof have substantially strong and long lasting effects. Therefore the compounds are useful as agents for treating disorders of the cardiovascular system, for example, antihypertensive agent, circulation improver and antianginal agent. A process for producing the above compounds economically and effectively is disclosed.

Description

The present invention relates to novel N-substituted-3,4-dihydropyrimidine derivatives of formula (I). In the formula

R ¹ is - (CH 2) n X - wherein

X is (C 1 -C 4) alkyl, ((C 1 -C 4) alkoxy) -phenyl (C 1 -C 4) alkyl, nitro-substituted phenyl (C 1 -C 4) alkyl, halo-substituted phenyl (C 1 -C 4) alkyl, phenyl, diphenyl (C 1-4 alkyl), phenyl (C 1-4 alkenyl), naphthyl (C 1-4 alkyl), thienylmethyl or pyridylmethyl, singly or twice substituted amino; benzothiazole-thio, pyridyl, thienyl, morpholino, 1,2,3,4-tetrahydroisoquinolyl; and C 1-4 alkyl, phenyl (C 1-4 alkyl), trihalomethylphenyl, phenyl (C 1-4 alkylene) oxy-phenyl (C 1-4 alkyl), diphenyl- piperazinyl substituted with (C 1-4 alkyl), benzhydryl, fluorenyl, halobenzhydryl, or tri- (C 1-4 alkoxy) -cinnamoyl, or (N-benzyl-2-pyrrolidinyl) n-substituted 0 -5

R ^{2 is C} 1-9 alkyl, (C 3-5 cycloalkyl) (C 1-4 alkyl), phenyl (C 1-4 alkyl). Because the dihydropyrimidine derivatives of Formula (I) are potent and long lasting vasodilators, the compounds are useful in the treatment of cardiovascular disorders, for example, as antihypertensive agents, cerebrovascular agents, and antianginal agents.

Novel formulations currently in the treatment of cardiovascular disorders are calcium antagonists (Ca ** antagonists), possess many pharmacological properties and are useful not only in the treatment of hypertension, angina pectoris and cerebral circulatory disorders, but also in the treatment of arrhythmias. also to prevent atherosclerosis and to potentiate the effect of carcinostatic agents. Accordingly, the therapeutic use of Ca ++ antagonists is of increasing importance.

Known Ca ** antagonists include Nifedipine, Nicardipine, Verapamil, Diltiazem and the like.

Dihydropyrimidine derivatives have not been very well studied in this respect. Only a few literatures refer to these derivatives [e.g., Silversmith, E.F. J., Org. Chem., 27, 4090 (1962), Nasipuri, D., et al., Synthesis 1073 (1982), Kashima, C.,

Tetrahedron Letters 209 (1983) and 73 572/59. Japanese Patent Publication No. Bayer A.C.Ij

The fact that dihydropyrimidine derivatives have not been dealt with so far is due to their unstable nature and tautomerism. More than one of the properties of Ca * 'antagonists can be improved, such as duration of action, organ selectivity, stability to light and heat, and side effects.

Studies were conducted with the most commonly used Ca * ⁴ antagonists at present. As a result, N-substituted 3,4-dihydropyrimidine derivatives have been found to have excellent vasodilator activity and high stability (214,778/85, 246,376/85;

252 471/85 and 43 171/86. Japanese Patent Laid-Open No. Studies have been conducted on Ca ++ antagonists which have the strongest vasodilator activity, long-term stability and low toxicity. As a result, N-substituted-3,4-dihydropyrimidine derivatives of formula (I) have been found which have not only excellent stability and potent vasodilator activity, but also long-lasting activity.

The dihydropyrimidine derivatives of the formulas (2) and (2 '), wherein R ² is as defined above, which are tautomeric isomers, also have vasodilatory activity. However, the compounds of formula (I) are more stable and have better pharmacological activity than the compounds of formula (2) and (2 ').

The N-substituted-3,4-dihydropyrimidine derivatives of formula (I) wherein R ¹ and R ² are megado are prepared as follows:

(i) the tautomers of formulas 2 and 2 ', wherein R ² is as defined, are prepared as follows:

R ² OII wherein R ² is as defined - heated with an equivalent of diketene at 100-200 ° C, preferably 120 ° C for 30-60 minutes and thus the (k) keto ester of formula (3) in the formula the presence of R ^{2 is} as defined.

The compound of formula (3), wherein R ² is as defined, may also be prepared by treating the compound of formula (R) H, wherein R ² is as defined, with an equivalent of a base such as trialkylamine at room temperature, or the compound is treated with diketene at 0 ° C or treated with diketene in the presence of sodium hydride or potassium hydride.

To the resulting "keto ester of formula (3)" wherein R ² is benzaldehyde substituted with a nitro group in said benzene ring and the reaction mixture is subjected to a dehydration-condensation reaction.

19618G was ato and thus the benzylidene compound (4) of the formula: - wherein R ² is as defined - was prepared.

The resulting benzylidene compound (4), wherein R ² is as defined, is condensed with acetamidine or acetamidine hydrochloride to give the tetrahydropyrimidine compound (5), wherein R ² is as defined.

The condensation reaction is carried out in the presence of a base to produce the compound of formula (5) wherein R ² is as defined. The base is preferably alkoxides and metal hydrides and the preferred solvents are alcohols, ethers and dimethylformamide.

The tetrahydropyrimidine compound (5), wherein R ² is as defined, is heated in the presence of a catalyst, such as p-toluenesulfonic acid, boron trifluoride or camphorsulfonic acid, or is heated with silica gel, alumina or roolecula sieve to give (2) and ( compounds of formula 2 ') - wherein R ² is as defined - was prepared.

The compounds thus obtained are purified by known techniques, such as adsorption chromatography, ion exchange chromatography, partition chromatography, distillation or recrystallization. A (2) and (2 ') Compound of formula - wherein R ² is as stated - can be crystallized with inorganic acids such as hydrochloric, sulfuric or phosphoric acid, or organic acids, for example oxalic acid, tartaric acid or succinic acid or also as salts with maleic acid salt and these can be purified by recrystallization.

(ii) Preparation of N-substituted-3,4-dihydropyrimidine derivatives

The compounds of formula (2) and (2 ') obtained in step (i), wherein R ² is as defined, are dissolved in an organic solvent such as hydrocarbons, aromatic hydrocarbons or ethers and the solution is added to phosgene or phosgene dimer at a temperature of up to 0 ° C, preferably -10 ° C to -35 ° C, in the presence of a base such as trialkylamine, preferably triethylamine, sodium hydride or potassium hydride. and at room temperature, a solution of a nitrogen-containing alcohol of the general formula R'OH, wherein R ¹ is as defined, is prepared to form compounds of formula (I), wherein R ¹ and R ² are as defined. any solvent used in the reaction is preferred especially ethers and hydrocarbon chlorides.

In the formula N-substituted-3,4-dihydropyrimidine derivatives of formula (1), the substituent R ^{2 at} the 5-position may be, for example, straight or branched C 1 -C 9 alkyl or phenyl (C 1 -C 4) alkyl. such as benzyl, phenethyl, phenylpropyl, phenylbutyl. The R ¹ substituent of the ester group at the 3-position of the compounds of formula (I) corresponds to the formula (CH 2) n X, wherein n is 0-5. When X 2 ³ is -CH ² CH ² N, R ³ is methyl, R ^{4 is} ethyl, propyl, isopropyl, butyl, sec-butyl, phenyl, diphenylmethyl, naphthylmethyl, naphthyl ethyl, pyridylmethyl or thienylmethyl; and R ⁴ is methyl, ethyl, propyl, isopropyl. butyl, sec-butyl, phenyl, diphenylmethyl, naphthylmethyl, naphthylethyl, with the proviso that when one of R ³ and R ⁴ is an alkyl group, the other is halogen, nitro or methoxy. it may also be substituted phenylalkyl.

The compounds of formula (I) prepared by the above reaction, wherein R ¹ and R ² are as defined, are known to be adsorbed. column chromatography, ion exchange chromatography or recrystallization. The resulting products can be treated with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid or an inorganic acid such as oxalic acid, succinic acid or maleic acid to give the corresponding salts which can then be recrystallized by adsorption chromatography or ion exchange purification.

The compounds of formula (I) as hereinbefore prepared, wherein R ¹ and R ² are as defined, may be administered intraarterially (ia), intravenously (iv) and orally (po) and exhibit strong coronary vasodilatory activity in isolated guinea pig hearts (Langendorff). however, they have potent cerebral vasodilator and antihypertensive effects in anesthetized dogs (iv) and alert spontaneous hypertensive rats (po,). These effects of the chemical are all stronger than those of the known active substances, such as Nicardipine and Thus, the compounds of the present invention are effective in the treatment of angina pectoris (myocardial infarction), cerebral blood flow and hypertension.

The compounds of formula (1) wherein R ¹ and R ² may be administered alone or in various dosage forms, together with excipients. Suitable dosage forms include tablets, lozenges, pills, granules, powders, capsules, ampoules, suppositories and the like, for example, starch, dextrin, sucrose, lactose, silicic acid, carboxymethylcellulose, cellulose, gelatin, polyvinylpyrrolidine, glycerol, agar, calcium carbonate, sodium bicarbonate, paraffin , cetyl alcohol, stearic acid esters, kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, water, ethanol, isopropyl alcohol, propylene glycol.

For parenteral administration, the compounds of the present invention are converted into water-soluble salts and dissolved in sterile distilled water or sterile physiological saline, and then filled into ampoules for injection. If desired, stabilizers and / or buffering agents may be included in the ampoules.

For oral administration, the optimum dosage range for the compounds of Formula I, wherein R ¹ and R ² are as defined, is 5-500 mg / day. This dosage will, of course, depend on the age, weight, severity and other factors of the patient being treated.

The invention is further illustrated by the following examples, without limitation. The temperatures indicated are in ° C unless otherwise stated.

Example 1

3- [2- (N-Benzyl-N-methylamino) ethoxycarbonyl] -5- (cyclopropylmethoxycarbonyl) -2,6-dimethyl-4- (2-nitrophenyl) -3, Preparation of 4-dihydropyrimidine (6)

Trichloromethyl chloroformate (144 µl) was dissolved in 10 mL of tetrahydrofuran (THF). To the resulting solution was added a mixture of 5-cyclopropylmethoxycarbonyl-2,6-dimethyl-4- (2-nitrophenyl) 1,4-dihydropyrimidine (329 mg) and triethylamine (607 ml) in tetrahydrofuran (20 ml) with stirring. At -23 ° C, the reaction mixture was stirred for 1 hour. To the resulting mixture was added 2- (N-benzyl-N-methylamino) -ethan-1-ol (991 mg) in tetrahydrofuran (10 mL) at 0 ° C and the resulting mixture was stirred for one hour. After stirring for another hour at room temperature, the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with chloroform. After drying the extract, the solvent was evaporated and the residue (1.32 g) was chromatographed on a silica gel column. Elution with 1% methanol / chloroform gave 354 mg (68%) of the title compound. The physicochemical properties of the compound are given in Table 1 below.

Example 2-27 was prepared analogously to Example 1. compounds. The compounds and their properties are listed in Table 1 below.

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3- [2- [N-benzyl-N- (3-phenylpropyl) amino] ethoxycarbonyl} -5- (methoxycarbonyl-cyclopropyl carbonyl) -2 ₁ 6-dimethyl-4- (2-nitro- phenyl) 3,4-dihydropyridinidine (7)

Procedure 1

Trichloromethyl chloroformate (719 μΐ) was dissolved in 40 mL of tetrahydrofuran. To the resulting solution was added 5- (cyclopropylmethoxycarbonyl) -2,6-dimethyl-4- (2-nitrophenyl 1-1,4-dihydropyrimidine (1.6Sg)) at -23 ° C with stirring and A mixture of triethylamine (3.04 g) in tetrahydrofuran (80 ml) and the resulting reaction mixture was stirred for an additional hour at -23 ° C. To the resulting reaction mixture was added 2- [N-benzyl-N- ( A mixture of 3-phenylpropyl) amino] -elan-1-ol (6.73 g) in tetrahydrofuran (40 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous sodium chloride and After drying the extract, the solvent was evaporated and the residue (about 12 g) was chromatographed on a silica gel column eluting with ethyl acetate / n-hexane (1: 1) to give the title compound (2.24 g, 69%).

Procedure 2

Trichloromethyl chloroformate (300 µl) was dissolved in 30 ml of tetrahydrofuran. To the resulting solution was added 5- (cyclopropylmethoxycarbonyl) -1,2,6-dimethyl-4- (2-nitrophenyl) -1,4-dihydropyrimidine (1.65 g) and triethylamine at -23 ° C with stirring. (3.04 g) in tetrahydrofuran (70 ml) was added and the reaction mixture was stirred for 1 hour at -23 ° C to which was added 2-N-benzyl-N- (3-phenylpropyl) at 0 ° C. A mixture of a-amino] -ethan-1-ol (1.35 g) in tetrahydrofuran (50 mL) was stirred at room temperature for 2 hours, diluted with saturated aqueous sodium chloride solution and extracted with chloroform. After drying, the solvent was evaporated and the residue was chromatographed on a silica gel column (about 4.6 g), eluting with ethyl acetate / hexane (1: 2), to give 1.51 g (48%) of the title compound.

The characteristics of the resulting compound are given in Table 2.

Prepared according to Methods 1 and 2, described above, according to Methods 29-74. compounds. The compounds and their physical characteristics are listed in Table 2.

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Example 75

Coronary vasodilatory effect of 3N-substituted 3,4-dihydropyrimidine derivatives

The test method

Heartley guinea pigs (400-500 g in weight) are killed by punching their heads and their hearts are immediately isolated. Hearts were perfused with 10 Krebs-Henseleit solutions, whereby a mixture of 95% oxygen and 5% carbon dioxide was bubbled through at a constant rate of 6 ml / min at 37 ° C according to Langendorff [J. Pharmacol. Methods 2, 143 (1979). Perfusion pressure is continuously measured with a pressure transducer. Samples are prepared by emulsifying 1 mg of the test compound in 1 ml of dimethylsulfoxide / physiological saline (1: 9) and diluting to a predetermined concentration with physiological saline, and 0.1 ml of the diluted solution is added to the coronary artery through a rubber tube enter the ED50 values (µg / heart) given in Table 3. The number of compounds in the table corresponds to the number of examples of preparation.

Table 3

Compound number (example number) 1 • 2 3 5 6 7 ED (Pg / heart) 0013 0:52 0.0095 0036 0.0092 0.0012 Compound number (example number) 9 10 11 21 24 27 ED (Pg / heart) 0:10 0060 0030 0:45 0:01 0029

Example 76

The pharmacological activity (ED30) of the compounds of the invention was investigated in anesthetized dogs by vascular resistance of the vertebral artery according to the following procedure.

The test method

Adult dogs (7 to 14 kg body weight) were first anesthetized with thiopental sodium (35 mg / kg, i.p.), then urethane (400 mg / kg, i.v.) and chloralose (60 mg / kg, i.v.) and artificially anesthetized during the experiment. ventilated. For the first carrier, the thorax was dissected and the vertebral artery was removed and blood flow was measured with an intracorporeal flow probe connected to an electromagnetic flowmeter (MF-27, Nihon Kohden).

At the same time, the following parameters were continuously measured: systemic blood pressure (mean) α in right femoral artery, limb drainage II ECG, heart rate controlled by ECG R-wave tachometer, and electrical divider E (mean) of blood pressure and arterial blood flow to the vertebrae. Nihon Kohden) by feeding the vascular resistance. All parameters are simultaneously polygraphed (RM-600, Nihon Kohden). We recorded.

Test compounds were injected through a femoral vein cannula.

The EDm values (µg / kg) obtained by intravenous administration are given in Table 4, the number of compounds corresponding to the number of preparation examples.

-2245 196186 46

Table 4

Compound number (example number) 1 2 3 5 6 7 8 ED30 (.Mu.g / kg) 0:58 0.84 0.75 2.4 1.4 0.71 4.1 9 10 11 14 15 16 17 19 3.9 0:54 0:55 2.1 2.5 3.8 3.4 1.4 20 21 26 28 29 30 32 35 4.0 2.0 4.1 4.2 2.5 0.60 3.2 4.2 38 39 40 45 46 48 49 50 4.2 2.3 1.5 1.8 2.0 2.0 2.8 0.74 52 53 54 55 57 58 60 61 1.5 2.5 1.4 3.8 0:48 2.5 1.7 1.4 62 63 64 67 68 70 71 1.2 1.3 0.93 1.0 4.4 3.0 5.0

77 · example

The compounds of the present invention were tested for their effect on anesthetized dogs in anesthetized dogs.

The test method

The animals are the test compounds

Doses corresponding to ED x 1 were injected and the time course of the vascular resistance changed as shown schematically in Figure 1. Figure 1 shows the Ti / z values (minutes) (the time it takes for the resistance to drop to 50%). The results are shown in Table 5, the number of compounds corresponding to the number of preparation examples.

Table 5

Number of compound 28 29 32 33 36 37 38 Eg (min) 13.5 9.5 7.0 30.5 12.0 10.3 8.0 Number of compound 39 45 47 52 53 55 56 T1 / 2 (min) 7.0 15.6 13.0 8.0 7.7 9.2 11.9

Example 78

The antihypertensive activity of the compounds of the present invention was investigated in alert spontaneously hypertensive rats (SHR).

The test procedure

Table 6 The compound Decrease in blood pressure (%) number maximum reduction is 6 hours 28 2 hours 35% 10-20% Example 79

17-20 week old SHR rats were anesthetized with ether and cannulated into the left femoral artery. At least one day after implantation, the cannulae were connected to a pressure transducer for at least one day and blood pressure was continuously measured under wakeful free conditions to give the results shown in Table 6. Test compounds were administered orally as a clear solution in 10% ethanol in 10% ethanol to fasted animals at 10 mg / kg body weight overnight.

The acute toxicity (LD50) of Compound # 28 was determined. The compound was administered to two groups of 5 or 6 week old male ddY mice according to the Lichtfield-Wilcoxon method. The results are shown in Table 7. A group of mice was fasted overnight before oral administration. To each group of mice, the test compound was administered as a 10% emulsion in dimethylsulfoxide.

-2 347

Table 7

The compound has an LD 50 (mg / kg) number intravenously orally

180-200> 1000

The compounds of the present invention have potent and long-lasting vasodilatory activity. Therefore, the compounds are effective in the treatment of cardiovascular disorders such as angina pectoris, arrhythmia, hypertension and cerebrovascular disorders. These diseases can also be treated by administering a small amount of the compounds of the present invention and administering them at very frequent intervals. Thus, diseases can be treated safely and easily.

Claims (3)

PATENT CLAIMS A process for the preparation of N-substituted-3,4-dihydropyrimidine derivatives of the formula (I) R ¹ is - (CH 2) n X - wherein X is (C 1 -C 4) alkyl, (C 4 -C 4 alkoxy) -phenyl (C 1 -C 4) alkyl, nitro-substituted phenyl (C 1 -C 4) alkyl, halo-substituted phenyl (C 1 -C 4) alkyl ), phenyl diphenyl (C 1 -C 4 alkyl), phenyl (C 1 -C 4 alkenyl), naphthyl (C 1 -C 4 alkyl), thienylmethyl or pyridylmethyl or a bis-substituted amino group, a benzothiazole thio group, a pyridyl group, a thienyl group, a morpholino group, a 1,2,3,4-lelaltidroisoquinoyl group, and a (1-4C) alkyl, phenyl (C 1 -C 1) alkyl), 1-arylalogenomethylphenyl, phenyl (C 1 -C 10 alkylene) -oxyphenyl (C 1 -C 4 alkyl), benzhydryl, fluorenyl, halobenzhydryl or tri- (Piperazinyl substituted with C 1-4 alkoxy-cinnamoyl or (N-benzyl-2-pyrrolidinyl, tube port n = 0-5, R ^{2 is C} 1 -C 9 alkyl, (C 3 -C 5 cycloalkyl) - (C 1 -C 4 alkyl 2) -, phenyl (C 1 -C 4 alkyl), characterized in that (2) and (2 ¹⁾ compound of formula - wherein R ² is as defined - base 25 are added together with a solution containing phosgene or phosgene dimer and the reaction mixture is treated with an alcohol of the formula R ¹ OH, wherein R ¹ is as defined above, in the presence or absence of a base at a temperature of 0 ° C to 70 ° C. 2. A process according to claim 1 wherein the compound of formula (2) or (2 '), wherein R ² is as defined in claim 1, is 35 at 0 ° C. 3. A process according to claim 1 wherein the base is trialkylamine.