JPH0412271B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel fused pyrimidine derivatives useful as pharmaceuticals. More specifically, the present invention relates to the general formula [In the formula, Ar represents 1 to 2 halogens, nitro,
a phenyl group or a 2,1,3-benzoxadiazolyl group which may be substituted with trifluoromethyl, lower alkyl or lower alkoxy group; R ¹ , R ² and R ³ each represent hydrogen or a lower alkyl group; R ⁴ is an amino group substituted with one or two of (i) lower alkoxy, (ii) lower alkyl or phenyl lower alkyl, or (iii) (i) phenyl lower alkyl or (lower alkyl) as a substituent. ) A compound represented by a lower alkyl group optionally having a heterocycle optionally substituted with a phenyl group optionally substituted with lower alkyl or halogen, and X represents an oxygen or sulfur atom; The present invention also provides salts thereof and methods for their production. Regarding the above general formula (), the phenyl group or 2,1,3-benzoxadiazolyl group represented by Ar contains 1 to 2 halogen, nitro, trifluoromethyl, lower alkyl, or lower alkoxy groups, which are the same or different. may be substituted at any position, and such halogens include fluorine, chlorine, bromine, and iodine, with fluorine or chlorine being particularly preferred. The lower alkyl or lower alkoxy group preferably has 1 to 3 carbon atoms, for example, the alkyl group includes methyl, ethyl, propyl, and isopropyl, and the alkoxy group includes methoxy, ethoxy, propoxy, and isopropoxy groups. . 2,1,3
-Particularly preferred among the benzoxadiazolyl groups is 2,1,3-benzoxadiazole-4
-yl group. The lower alkyl group represented by R ¹ , R ² , and R ³ preferably has 1 to 6 carbon atoms, and may be linear or branched, such as methyl, ethyl, propyl, isopropyl, Examples include butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and those having 1 to 4 carbon atoms are particularly preferred. These alkyl groups may further have lower cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) at the terminal. As the lower alkyl group represented by R ⁴ , the above-mentioned
The same lower alkyl groups as R ¹ , R ² and R ³ are preferred. These lower alkyl groups may have a substituent, and such substituents include:
For example, lower (C _1-4 ) alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, t-butoxy, etc.), lower (C _1-4 ) alkyl or phenyl lower (C _1-4 ) alkyl, or phenyl lower (C _1-4 ) _-4 ) Heterocycle optionally substituted with a phenyl group optionally substituted with alkyl or lower (C _1-4 ) alkyl or halogen (e.g., pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, thiomorpholine) 5- to 7-membered rings). Examples of the lower alkyl group having lower alkoxy represented by R ⁴ include methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2- Examples include ethoxy-1-methylethyl. Examples of the lower alkyl group having an amino group substituted with 1 or 2 of lower alkyl or phenyl lower alkyl represented by R ⁴ include, for example, [In the formula, n represents an integer of 2 to 4, and R ⁵ and R ⁶ are the same or different and represent hydrogen, lower (C _1-4 ) alkyl, or phenyl lower (C _1-4 ) alkyl. ]
Examples include groups represented by: The lower (C _1-4 ) alkyl may be either linear or branched, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, and the like. It will be done. The phenyl lower (C _1-4 ) alkyl includes those in which the alkylene moiety is branched or the alkylene moiety is further substituted with a phenyl group, such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl. , 2-phenylpropyl, 1-phenylpropyl, benzhydryl, 2,2-diphenylethyl, 3,3-diphenylpropyl and the like. Examples of alkylene represented by -C _o H _2o - include ethylene, trimethylene, propylene, tetramethylene, and 1,2-dimethylethylene. A heterocycle optionally substituted with a phenyl group optionally substituted with (a) phenyl lower (C _1-4 ) alkyl or (b) lower (C _1-4 ) alkyl or halogen, represented by R ⁴ As the lower alkyl having the formula, for example, [In the formula, n represents an integer of 2 to 4, and R ⁷ and R ⁸ are
When the adjacent nitrogen atom forms a heterocycle which may further contain one more heteroatom (e.g., oxygen, nitrogen, sulfur), and when the heteroatom is a nitrogen atom, the nitrogen atom is a phenyl atom. The nitrogen atom may be substituted with lower (C _1-4 ) alkyl or a phenyl group which may be substituted with lower (C _1-4 ) alkyl or halogen. ] Examples include groups represented by the following. Examples of the alkylene represented by -C _o H _2o - include those mentioned above. Examples of the phenyl lower alkyl and the lower alkyl include those mentioned above. Examples of the halogen include those mentioned above. The compound represented by the above general formula () is, for example, a compound represented by the general formula The compound represented by [wherein R ¹ , R ² , and X have the same meanings as above] has the general formula It can be produced by reacting a compound represented by [wherein Ar, R ³ and R ⁴ have the same meanings as above]. In this production method, () is produced by reacting compounds () and () in an appropriate solvent. This reaction is usually carried out at a temperature of about 60°C to about 140°C, particularly conveniently carried out at the boiling point of the solvent used and under reflux. Any solvent may be used as long as it is inert to the reaction, such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, 2-
Examples include alkanols such as methoxyethanol, ethers such as dioxane, tetrahydrofuran, and ethylene glycol dimethyl ether, acetic acid, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. The amounts of () and () to be used are 1 to 1.2 mol of the other compound per 1 mol of one of the compounds. The above compound () is, for example, a compound represented by the general formula Ar-CHO () [wherein Ar has the same meaning as above] and the general formula R ³ COCH ₂ COOR ⁴ () [wherein R ³ , R ⁴ can be produced by reacting a compound represented by the same meaning as above], but when producing compound (), compounds () and () are added to the reaction system instead of compound (), and the product is It is also possible to use a method of reacting the () with the coexisting () as it is, and this method is also included within the scope of the present invention. This manufacturing method can be carried out under substantially the same conditions as the aforementioned manufacturing method. The novel condensed pyrimidine derivative () produced by the above method can be obtained by separation and purification means known per se.
For example, it can be collected with any purity by appropriately using concentration, extraction, chromatography, reprecipitation, recrystallization, etc. Furthermore, when the R ⁴ moiety in () has a basic nitrogen atom, it can also be converted into an acid addition salt by known means. Such salts are preferably pharmaceutically acceptable non-toxic salts, such as salts with inorganic salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.), salts with organic acids (acetate, etc.). , succinate, maleate, fumarate, malate, tartrate, methanesulfonate, etc.). The compound () of the present invention or a salt thereof has low toxicity and exhibits blood pressure-lowering, peripheral vasodilating, coronary artery dilating, and cerebral vasodilating effects in mammals (e.g., mice, rats, rabbits, dogs, cats, and humans). For example, hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral circulation disorder (cerebral infarction,
It is useful as a preventive and therapeutic agent for cardiovascular diseases such as transient ischemic attacks (transient ischemic attacks, etc.). When compound () or a salt thereof is used as the above-mentioned drug, it is mixed with an appropriate pharmaceutically acceptable carrier, excipient, diluent, and administered orally in the form of powder, granules, tablets, capsules, injections, etc. Or it can be administered parenterally. The dosage varies depending on the route of administration, symptoms, age of the patient, etc.
For example, when administered orally to adult hypertensive patients, 0.5-100 mg/Kg/day, preferably 2-50 mg/Kg/day.
It is desirable to administer mg/Kg/day in one to several divided doses per day. The results of pharmacological tests demonstrating the usefulness of the compound () of the present invention are shown below. Experimental Example 1 Effect of increasing cerebral blood flow and coronary blood flow [Method] Mongrel adult dogs (male or female) weighing 10 to 18 kg were anesthetized by intravenous administration of sodium pentobarbital (30 mg/Kg), and endotracheal intubation was performed. After applying
Artificial respiration was performed with room air using a respirator (NSH-34RH, Harvard). After making an incision between the third and fourth left intercostals, the fourth rib was cut to expose the left subclavian artery and its branch, the left vertebral artery. After ligating the left subclavian artery distal to the branch of the vertebral artery and all branches other than the vertebral artery, a non-invasive probe for an electromagnetic flowmeter (diameter 2
mm), and blood flow was measured using an electromagnetic flowmeter (Narcomatic, Narco). On the other hand, in order to administer the drug into the vertebral artery, a cannula was retrogradely inserted into the left internal thoracic artery up to just before the vertebral artery and left at that site. Furthermore, the pericardium was incised, the heart was held in a hammock, and a polyethylene cannula was inserted into the distal side of the circumflex branch of the left coronary artery, and arterial blood was led from the left common carotid artery through the extracorporeal circulation to the circumflex branch distribution area. perfused. Coronary blood flow was measured using an invasive electromagnetic flowmeter probe attached to the extracorporeal circuit and an electromagnetic flowmeter (MF-26, Nihon Kohden). In addition, a side branch (rubber tube) for drug injection was installed in the extracorporeal circuit. The test drug was added at a final concentration of 1 mg/ml.
It was used after being dissolved in a physiological saline solution containing % polyethylene glycol-400, and 0.1 ml of the solution was injected into the vertebral artery and coronary artery through the cannula and side branch, respectively, for 10 seconds. Changes in each arterial blood flow were continuously recorded on a polygraph (142-8, Sanei Sokki). [Results] The change in blood flow after administration (average value of 3 to 6 times) was calculated using the following formula, and the maximum value (%) and blood flow were calculated using the following formula.
Table 1 shows the duration of 10% or more increase. Blood flow change (%) = (post-medication blood flow - pre-medication blood flow) / pre-medication blood flow x 100

〔Method〕

10-11 week old male spontaneously hypertensive rats (3-6 rats per group) were used. The systolic blood pressure (systolic pressure) was around 200 mmHg. Blood pressure was measured using an automatic blood pressure measuring device (USM-105R, Ueda Medical), and the systolic pressure of the rat caudal artery was measured. The test compound was orally administered as a 5% gum arabic suspension. Animals administered with gum arabic solution alone served as a control group. Blood pressure measurement after medication 1,
Tests were carried out after 5, 8 and 24 hours. [Results] Blood pressure lowering effect after 1 and 5 hours (post-medication blood pressure -
Pre-medication blood pressure) and duration of blood pressure lowering effect Table 2
Shown below.

[Table] Examples of the present invention are shown below to explain the present invention more specifically, but the present invention is not limited thereto. Example 1 A mixture of methyl 2-(3-nitrobenzylidene)acetoacetate (4.65 g), 6-amino-1,3-dimethyluracil (2.89 g) and ethanol (30 ml) was stirred under reflux for 3 hours. The precipitated crystals were collected by filtration and recrystallized from dichloromethane-ethanol to give 1,2,3,4,5,8-hexahydro-1,3,7-trimethyl-5-(3-nitrophenyl)-2,4- Dioxopyride [2,3-
d] Methyl pyrimidine-6-carboxylate was obtained as colorless prism crystals. Yield: 6.1g (87.4%). Melting point 273-274℃ Elemental analysis value C ₁₈ H ₁₈ N ₄ O ₆ Calculated value C55.96; H4.70; N14.50 Experimental value C55.94; H4.65; N14.77 Similarly shown in Table 3 The compound was obtained.

[Table] Example 9 2-chlorobenzaldehyde (2.36 g), acetoacetic acid 2-(N-benzyl-N-methylamino)
Ethyl (4.19g), 6-amino-1,3-dimethyluracil (2.87g), isopropanol (20ml)
The mixture was stirred under reflux for 8 hours. Add chloroform (30ml) to remove unreacted 6-amino-1,
3-dimethyluracil was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography [eluted with chloroform-methanol (20:1, V/V)] and recrystallized from ethyl acetate to give 5-
(2-chlorophenyl)-1,2,3,4,5,8
-hexahydro-1,3,7-trimethyl-2,
4-dioxopyrido[2,3-d]pyrimidine-
2-[N-benzyl-N-methylamino)ethyl 6-carboxylate was obtained as colorless prism crystals. Yield: 3.99g (46.6%). Melting point 175-176℃ Elemental analysis value C ₂₇ H ₂₉ ClN ₄ O ₄ Calculated value C63.71; H5.74; N11.01 Experimental value C63.51; H5.70; N10.92 Similarly shown in Table 4 The compound was obtained.

【table】

【table】

[Table] Formulation Example When the compound () of the present invention is used as an antihypertensive agent, it can be used, for example, in the following formulation. (1) 5-(2-chlorophenyl)-1,2,3,
4,5,8-hexahydro-1,3,7-trimethyl-2,4-dioxopyride [2,3-
d] 2-(N-benzyl-N-methylamino)ethyl pyrimidine-6-carboxylate 10g (2) Lactose 95g (3) Corn starch 29g (4) Magnesium stearate 1g 1000 tablets 135g (1), (2) and 17 g of corn starch were mixed together and granulated with a paste made from 7 g of corn starch, 5 g of corn starch and (4) were added to the granules, and the mixture was compressed in a compression tablet machine to produce (1 tablet) per tablet. ) 7mm diameter tablet containing 10mg
Manufacture 1000 pieces.

Claims (1)

[Claims] 1. General formula [In the formula, Ar represents 1 to 2 halogens, nitro,
a phenyl group or a 2,1,3-benzoxadiazolyl group which may be substituted with trifluoromethyl, lower alkyl or lower alkoxy group; R ¹ , R ² and R ³ each represent hydrogen or a lower alkyl group; R ⁴ is an amino group substituted with one or two of (i) lower alkoxy, (ii) lower alkyl or phenyl lower alkyl, or (iii) (i) phenyl lower alkyl or (lower alkyl) as a substituent. ) A compound represented by a lower alkyl group which may have a heterocycle which may be substituted with a phenyl group which may be substituted with lower alkyl or halogen, and X represents an oxygen or sulfur atom. Or its salt.