JPH0371430B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to novel quinazoline derivatives useful in the treatment of hypertension. [Prior Art] Conventionally, quinazoline derivatives, especially piperazinoquinazolines, include various acid amide compounds, such as prazosin (Japanese Patent Publication No. 45-22135, USP-3511836),
Terazosin (JP-A-54-27588, USP-4026894,
USP-4112097), those described in JP-A-57-116052 are known, and piperazinoquinazolines having a pyrimidine structure include those described in JP-A-57-181068. Some compounds are currently being used clinically as antihypertensive agents. These are classified as α-blockade antihypertensive agents, and while they have excellent clinical effects, they have been experienced to lack durability of action and to induce orthostatic hypotension, which is an undesirable side effect. The present inventors have discovered that the compound represented by the following general formula [] has an extremely strong and long-lasting antihypertensive effect, and that the above-mentioned orthostatic hypotension is milder or almost less severe than known compounds. The present invention was completed by demonstrating through animal experiments that it can be a compound that does not cause this. [Summary of the invention] The present invention is based on the general formula [] [In the formula, R ¹ and R ² each represent hydrogen or a lower alkoxy group, and R ³ represents a lower alkyl group. Same below. ] The quinazoline derivative represented by the formula or its pharmacologically acceptable salts is defined as a material invention, and the antihypertensive agent containing the new quinazoline derivative or its pharmacologically acceptable salts as an active ingredient is defined as a use invention. be. [Substance of the present invention] The substance of the present invention is a compound represented by the above general formula [], and the lower alkoxy groups of ^R1 and R2 include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, etc. Among them, a methoxy group is preferred. Furthermore, when R ¹ is hydrogen, R ² is also preferably hydrogen; similarly, when R ¹ is a lower alkoxy group, R ² is also preferably a lower alkoxy group. In the latter case, R ¹ and R ² may be different from each other. Examples of the lower alkyl group for ^R3 include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec
Examples include -butyl group and tert-butyl group, among which ethyl group is preferred. Specific examples of the compounds of the present invention are shown in Examples below.
The pharmaceutically acceptable salts of the compound [] of the present invention include hydrochloride, hydrobromide, sulfate,
bisulfate, phosphate, acid phosphate, acetate, maleate, fumarate, succinate, lactate,
Acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions such as tartrate, benzoate, citrate, gluconate, saccharide, methanesulfonate, p-toluenesulfonate. including salts formed from or their hydrates. [Manufacturing method] The compound of the present invention can be prepared by a known method, for example, JP-A-57
It can be manufactured according to the method described in -181068 etc. That is, it can be expressed by the following equation. The compound used in the above reaction is a known substance,
Moreover, compounds synthesized according to Reference Examples described later can be used. Further, compounds not included in the reference examples can also be synthesized and used according to the reference examples. The reaction is carried out by reacting the compound with the compound in a suitable solvent such as isoamyl alcohol or n-butanol under reflux, for example at a temperature of 100 to 150 DEG C. for about 1 to 6 hours. The temperature, time and type of solvent can be changed as appropriate depending on the type of compound. In the above reaction, the compound [] is usually obtained as a free base by adding a tertiary amine such as triethylamine to the reaction system. The hydrochloride salt can also be obtained directly by the above reaction without using a tertiary amine. The product compound [] can be isolated and purified by conventional methods. In addition, hydrochloride and other acid addition salts can be prepared by conventional methods, for example, in an inert organic solvent.
It can be obtained by reacting with an acid, isolating the resulting precipitate, and purifying it if necessary. [Medical Invention] As mentioned above, the compound of formula [ ] of the present invention has a strong antihypertensive activity. It is also expected to improve heart failure. Compounds of formula [] are usually used in the form of pharmaceutical compositions and are administered by various routes including oral, subcutaneous, intramuscular, intravenous, intranasal, percutaneous and rectal routes. The present invention encompasses pharmaceutical formulations consisting of a pharmaceutically acceptable carrier and a compound of general formula [] or an acid addition salt thereof as the active ingredient. When producing the compositions of the present invention, tablets, capsules, powders, granules, troches, troches, casseries, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, molded pads, tapes, soft and hard It can be in the form of gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Examples of pharmaceutically acceptable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, corn starch, microcrystalline cellulose, gum arabic,
Calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, gum tragacanth, gelatin, syrup, methylcellulose, carboxymethylcellulose,
Methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium esterate, inert polymers, water or mineral oil. Either solid or liquid compositions may contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweetening or flavoring agents, and the like, such as those mentioned above. The compositions can also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. For oral administration, the compound of formula [ ] is mixed with carriers and diluents and formulated into tablets, capsules, and the like. For parenteral administration, the active ingredient is 10%
It is dissolved in aqueous dextrose, isotonic saline, sterile water, or similar liquid and sealed in a vial or ampoule for administration by intravenous infusion or injection, or by intramuscular injection. Advantageously, solubilizing agents, local anesthetics, preservatives and buffers may also be included in the vehicle. To increase stability, the composition can also be lyophilized after being poured into vials or ampoules. Other examples of parenteral administration include preparations administered transdermally in the form of ointments and poultices. In this case, molded pads or tapes are advantageous. The composition may contain between 0.005 and 0.005 per unit dosage form.
It contains 200 mg of active ingredient, more commonly 0.02 to 50 mg. Compounds of formula [] are effective over a wide dosage range. For example, daily dosages usually range from 0.0001 mg/Kg to 200 mg/Kg.
The actual amount of compound administered will be determined by the physician depending on the compound being administered and on the age, weight, response, severity of the patient's symptoms, route of administration, etc. of the individual patient. Therefore, the above dosage ranges are not intended to limit the scope of the invention. The appropriate number of administrations per day is 1 to 6 times, usually 1 to 4 times. Compounds of formula [] are effective antihypertensive agents in themselves, but can also be administered in combination with one or more other antihypertensive agents and/or diuretics, if desired. Such additional drugs include methyldopa, hydralazine, nifedipine, nicardipine, amiloride, propranolol, pindolol, timolol, reserpine,
Indapamide, hydrochlorothiazide, trichlormethiazide, indacrinone and the like. The physical properties and biological activities of the compounds of the present invention will be explained below using Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto. The following reference examples relate to the preparation of intermediates of compounds of formula [], and the following examples relate to the preparation of compounds of formula []. Test examples are shown in [Effects of the invention]. Reference example 1 2-(4-benzylpiperazino)-4
-Methylpyrimidine-5-carboxylic acid methyl 1-amidino-4-benzylpiperazine sulfate [J.Am.Chem.Soc., 66 . 263 (1944). ] 100 ml of 1M sodium hydroxide methanol solution was added to a methanol suspension (60 ml) of 26.8 g (0.1 mol), and then 15.8 g (0.1 mol) of a-methoxymethyleneacetoacetic acid methyl ester was added dropwise. After stirring overnight at room temperature, the precipitated sodium sulfate was separated, and the methanol was distilled off under reduced pressure. The resulting residue was dissolved in 500 ml of ethyl acetate and diluted with 100 ml of water.
Washed twice. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure to obtain 28.7 g of the target product as an orange oil (yield: 88%). After distillation under reduced pressure, the oil crystallized upon standing at room temperature. Boiling point: 205-208℃/1mmHg Melting point: 38-40℃ Infrared absorption spectrum (neat, cm ^-1 ) 1710, 1580, 1520 ¹ H-NMR spectrum (CDCl ₃ solution, δppm) 2.50 (4H, m), 2.63 ( 3H,s), 3,54(2H,
s), 3.83 (3H, s), 3.94 (4H, m), 7.32 (5H,
s), 8.78 (1H, s) Reference example 2 2-(4-benzylpiperazino)-N
-ethyl-4-methylpyrimidine-5-carboxylic acid amide 2-(4-benzylpiperazino) obtained in Reference Example 1
Methyl -4-methylpyrimidine-5-carboxylate
8.16g (25mmol), ethylamine 5.64g (125mmol)
and 1.24 g (5 mmol) of a 21.8 wt% methanol solution of sodium methoxide were placed in a 50 ml autoclave and reacted at 100°C for 3.5 hours. The resulting reaction mixture was poured into 150 ml of water and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and then ethyl acetate was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 7.71 g of the target product as pale yellow crystals (yield 91%). Melting point: 110-111°C Infrared absorption spectrum (KBr tablet, cm ^-1 ) 3290, 1625, 1585 ¹ H-NMR spectrum (CDCl ₃ solution, δppm) 1.22 (3H, t, J = 7.0Hz), 2.49 (4H, m),
2.51 (3H, s), 3.42 (2H, m), 3.55 (2H, s),
3.88 (4H, m), 5.76 (1H, m), 7.32 (5H, s),
8.30 (1H, s) Reference example 3 2-(4-benzylpiperazino)-6
-ethylpyrido[4,3-d]pyrimidine-5-
(6H)-on Sodium hydride 240mg (60% in oil, 6mmol)
After washing with hexane, it was suspended in 3 ml of N,N-dimethylformamide (DMF). Then,
2-(4-benzylpiperazino)-N-ethyl-4
-Methylpyrimidine-5-carboxylic acid amide (Reference Example 2) 1.7 g ((5 mmol) in DMF solution (10 ml) was added and reacted at 150°C for 1.5 hours. After distilling off DMF under reduced pressure, 100 ml of water was added. Extraction was carried out with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over magnesium sulfate, and then the ethyl acetate was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the desired product as pale yellow crystals. 1.5g was obtained (yield
87%). Melting point: 116-118°C Infrared absorption spectrum (KBr tablet, cm ^-1 ) 1660, 1638, 1585 ¹ H-NMR spectrum (CDCl ₃ solution, δppm) 1.32 (3H, t, J = 7H _z ), 2.50 (4H, t, J
= _6Hz ), 3.54 (2H, s), 3.76~4.08 (6H, m),
6.24 (1H, d, J = _7Hz ), 7.23 (1H, d, J =
7H _z ), 7.31 (5H, s), 9.20 (1H, s) Reference example 4 6-ethyl-2-piperazinopyrido[4,3-d]pyrimidin-5(6H)-one 2-(4-benzylpiperazino) obtained in Reference Example 3
300 mg (0.83 mmol) of -6-ethyl-pyrido[4,3-d]pyrimidin-5(6H)-one, 6 ml of ethanol, 2 ml of acetic acid and 30 mg of 10% palladium on carbon
was added and stirred for 3.5 hours at 45°C under a hydrogen atmosphere.
Palladium-carbon was removed from the reaction mixture, and the mixture was concentrated under reduced pressure. 20 ml of water was added to the concentrate and potassium carbonate was added until no more effervescence. Extracted three times with 50 ml of chloroform, dried the chloroform layer over sodium sulfate, and concentrated under reduced pressure to give 6-ethyl-2-piperazinopyrid[4,3-d]pyrimidine-5(6H)-
200 mg of On was obtained as colorless crystals (yield 88%). Melting point: 149-152°C Reference example 5 4,5-dimethoxy-2-nitrobenzaldehyde 3,4-dimethoxybenzaldehyde and concentrated nitric acid
After reacting 500ml at 10℃ for 20 hours, dilute the reaction solution with ice water for 3 hours.
The resulting crystals were obtained by filtration. The crystals were dissolved in a mixed solvent of 8 toluene and 500 ml of ethyl acetate, washed once with saturated aqueous sodium bicarbonate, three times with water, and once with saturated saline, concentrated under reduced pressure to about 500 ml, and then cooled to room temperature. , produces yellow crystals
77.71 g was obtained by filtration (yield 61%). Reference example 6 6,7-dimethoxy-2-hydroxyquinazoline 4,5-dimethoxy-2- synthesized in Reference Example 5
3.17g of nitrobenzaldehyde in dichloromethane
Dissolved in a mixed solvent of 30ml and methanol 30ml, 5%
0.16 g of palladium-carbon was added, and the mixture was stirred for 4 hours under a hydrogen atmosphere. The palladium-carbon was filtered off, the solvent was distilled off under reduced pressure, and the residue was dissolved in 30 ml of acetic acid.
Potassium isocyanate was added to this, and the mixture was reacted overnight at room temperature, and then further reacted for 1 hour under heating and reflux. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel, dichloromethane:
The resulting product was purified using MeOH (5:1 mixed solvent) to obtain 1.51 g of white crystals of the title compound (yield: 49%). Melting point: 260-263℃ Reference example 7 2-hydroxyquinazoline Reference Example 6 using o-nitrobenzaldehyde
The title compound was obtained in the same manner as above. Melting point: 189°C Reference example 8 2-chloro-6,7-dimethoxyquinazoline 6,7-dimethoxy-2- synthesized in Reference Example 6
Hydroxyquinazoline 5.0g and phosphorus oxychloride 50ml
was added and reacted under heating and reflux for 8 hours. After cooling, phosphorus oxychloride was distilled off under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane solution was washed once with saturated aqueous sodium bicarbonate, once with water, and once with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel, dichloromethane: methanol =
When purified with a 50:1 mixed solvent, crystals of the target product are obtained.
2.1 g was obtained (yield 38%). Melting point: 237-238°C Reference example 9 2-chloroquinazoline The title compound was obtained in the same manner as in Reference Example 8 using 2-hydroxyquinazoline. ^1H -NMR spectrum (CDCl ₃ solution, ppm) 7.72 (1H, m), 7.96 (3H, m), 9.32 (1H, s) Example 1 6,7-dimethoxy-2-(4-(5,
6-dihydro-6-ethyl-5-oxopyrido[4,3-d]pyrimidin-2-yl)piperazino)quinazoline 0.67 g of 2-chloro-6,7-dimethoxyquinazoline synthesized in Reference Example 8 and 6 synthesized in Reference Example 4
-ethyl-2-piperazinopyrid [4,3-d]
0.78 g of pyrimidine-5-(6H)-one
0.43 g of propylamine was added, and reaction was carried out for 10 hours under heating under reflux using 5 g of isoamyl alcohol as a solvent.
The resulting crystals were obtained by filtration, washed first with ethyl acetate and then with hexane, and then dried to obtain 1.24 g of white crystals of the title compound. (Yield 92%). Melting point: 259-262°C ^1H -NMR spectrum (CDCl ₃ solution, δppm) 1.36 (3H, t, J = 7Hz), 3.96 (3H, s),
3.97 (2H, q, J = 7Hz), 4.02 (3H, s), 4.05
(8H, brs), 6.32 (1H, d, J=7Hz), 6.93 (1H,
s), 6.98 (1H, s), 7.30 (1H, d, J=7Hz),
8,82 (1H, s), 9.28 (1H, s). Example 2 2-(4-(5,6-dihydro-6-ethyl-5-oxopyrido[4,3-d]pyrimidin-2-yl)piperazino)quinazoline In the same manner as in Example 1 using 2-chloroquinazoline synthesized in Reference Example 9 and 6-ethyl-2-piperazinopyrido[4,3-d]pyrimidin-5(6H)-one synthesized in Reference Example 4. The synthesized title compound was obtained (yield 30%). Melting point: 222-224℃ ^1H -NMR spectrum (CDCl ₃ solution, δppm) 1.33 (3H, t, J = 7Hz), 3.92 (2H, q, J
= 7Hz), 4.08 (8H, brs), 6.30 (1H, d J =
7Hz), 7.22 (1H, d, J = 7Hz), 7.24 (2H,
m), 7.62 (2H, m), 9.0 (1H, s), 9.27 (1H,
s) The composition examples given below use as active ingredient one of the compounds described in Examples 1 and 2 or one of the other pharmaceutical compounds included in the general formula []. Example 3 Each tablet containing 0.2 mg of active ingredient is manufactured as follows. Per tablet Active ingredients 0.2mg Starch 54.8mg Microcrystalline cellulose 35mg Polyvinylpyrrolidone 4mg (as 10% aqueous solution) Carboxymethylcellulose calcium
4.5 mg Magnesium Stearate 0.5 mg Talc 1.0 mg Total 100 mg Pass the active ingredients, starch and microcrystalline cellulose through an 80 mesh sieve and mix thoroughly. The resulting powder is mixed with a polyvinylpyrrolidone solution, granulated, and then passed through an 18-mesh sieve. The granules thus produced are dried at 50-60°C and sieved again using an 18-mesh sieve. Calcium carboxymethylcellulose and magnesium stearate and talc, previously sieved through an 80 mesh sieve, are added to the granules and, after mixing, tablets weighing 100 mg each are produced in a tablet machine. Example 4 Each tablet containing 1 mg of active ingredient is manufactured as follows. Per tablet: Active ingredients 1 mg Starch 60 mg Microcrystalline cellulose 35 mg Light anhydrous silicic acid 3 mg Magnesium stearate 1 mg Total 100 mg Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The obtained powder was compression molded and weighed 100 mg.
manufactures tablets. Example 5 Capsules containing 0.5 mg of active ingredient are manufactured as follows. Per Capsule Active Ingredients 0.5 mg Dry Starch 50 mg Microcrystalline Cellulose 47.5 mg Magnesium Stearate 2 mg Total 100 mg Combine the above ingredients and pass through an 80 mesh sieve to mix thoroughly. Fill 100 mg of the obtained powder into capsules. Example 6 10 parts of ammonium polyacrylate are dissolved in 60 parts of water. On the other hand, glycerin diglycidyl ether 2
1 part is dissolved in 10 parts of water while heating. 10 parts of polyethylene glycol (grade 400) on the other hand;
Dissolve 10 parts of water and 0.1 part of the active ingredient with stirring. Next, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution containing active ingredients of polyethylene glycol were added and mixed, and a drug-containing water gel solution was applied to a flexible plastic film at a concentration of 0.005 of the active ingredient per square centimeter. The product was coated in an amount of mg, and the surface was covered with release paper and cut into 35 square centimeters to prepare a preparation. Example 7 100 parts of sodium polyacrylate, glycerin
An aqueous sol solution was prepared containing 100 parts of water, 150 parts of water, 0.2 parts of triepoxypropyl isocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25 parts of propylene glycol, and 1 part of the active ingredient. Next, apply this sol solution to the nonwoven surface of a composite film made of rayon nonwoven fabric and polyethylene film.
A drug-containing adhesive layer was formed by coating to a thickness of 100 μm. The content of release aids (isopropyl myristate and propylene glycol) contained in this layer was approximately 20% by weight. Thereafter, crosslinking was carried out at 25° C. for 24 hours, a release film was attached to the surface of the adhesive layer, and this was further cut into 35 square centimeters to prepare a preparation. Example 8 Styrene-isoprene-styrene block copolymer 110 parts, terpene resin 90 parts, olive oil 60 parts
1 part of ethylene glycol diacrylate and 0.5 part of active ingredient were mixed in a kneader at 70°C. Next, this mixture was extruded and coated on one side of a 100 μm thick polyvinyl chloride film using an extruder at 60° C. to form a drug-containing adhesive layer. Thereafter, the surface of the adhesive layer was irradiated with 10 Mrad of ionizing radiation. A release film was attached to this irradiated surface and cut into a desired size to prepare a preparation. [Effects of the present invention] The compound of the general formula [] of the present invention has an extremely strong and sustained hypotensive effect as described above, and furthermore, depending on the compound, there may be undesirable side effects associated with a sudden drop in blood pressure. The present invention has revealed through animal experiments that the present invention reduces or hardly induces orthostatic hypotension compared to known compounds. Spontaneously hypertensive rats
The hypotensive effect of the compound of the present invention in hypertensive rats (SHR) and the time course and pattern of hypotension,
Table 1 shows the results of testing for duration of action. The compound of the present invention had strong antihypertensive activity, and the degree of decrease in blood pressure 1 hour after drug administration was weak, showing a slow onset of antihypertensive effect and a sustained pattern. In addition, the toxicity of the compounds of the present invention is generally weak, for example, the acute toxicity value is shown in Test Example 2.
As shown in The compounds of the present invention are thus generally considered to be highly active, less toxic, and highly safe drugs. The biological activity of the compound of the present invention is shown below with Test Example 1. Test Example 1 The antihypertensive effect of the compound according to the present invention was investigated by the following method. In other words, the animals were male spontaneously hypertensive rats (SHR), aged 20 weeks or older, weighed 350-430 g, and had a systolic blood pressure of 180 mm.
Three to four animals of Hg or higher were used as one group. Blood pressure was measured under non-anesthetized conditions using the pessimistic method (W+W electronic, BP-8005) to measure caudal artery systolic blood pressure before drug administration, 1 hour after administration, 3 hours after administration, and 6 hours after administration.
Measurements were made after 1 hour and 24 hours. Heart rate was also recorded at the same time. The compounds were dissolved or suspended in 0.5% methylcellulose solution and administered orally.
The results are shown in Table 1.

[Table] * Each compound was orally administered at 1 mg/Kg.
** Rate of change in heart rate indicates maximum value.
As shown in Table 1, the compounds according to the present invention exhibited antihypertensive effects even when administered orally at a dose of 1 mg/Kg. The onset of effects is gradual, with maximum effects seen 6 hours or more after administration. The degree of increase in heart rate is also mild. From these results, it is inferred that the compound of the present invention has an antihypertensive effect, has a weak increase in heart rate, and is unlikely to cause orthostatic hypotension associated with a sudden drop in blood pressure. These characteristics of the compounds of the present invention are considered to make them excellent for treating hypertension in mammals. Test Example 2 The acute toxicity (LD ₅₀ ) of the compounds of Examples 1 and 2 according to the present invention was examined by the following method. That is, the animals were 5-week-old male ddY mice and 8-week-old male Wistar rats, fasted for 18 hours, and 4 to 5 mice were used as one group. The compound is
It was dissolved or suspended in a 0.5% methylcellulose solution and administered orally (PO), and toxicity was determined one day and 14 days after administration, but no toxicity was observed. The results are shown below.

【table】

Claims (1)

[Claims] 1. General formula [] [In the formula, R ¹ and R ² each represent hydrogen or a lower alkoxy group, and R ³ represents a lower alkyl group. ] A quinazoline derivative or a pharmacologically acceptable salt thereof. 2 General formula [] [In the formula, R ¹ and R ² each represent hydrogen or a lower alkoxy group, and R ³ represents a lower alkyl group. ] An antihypertensive agent containing a quinazoline derivative represented by the following or a pharmacologically acceptable salt thereof as an active ingredient.