JPS59225188A - Condensed pyrimidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [Ar is phenyl (substituted with one or two halogen, NO2, CF3, lower alkyl or lower alkoxy) or 2,1,3-benzoxadiazolyl; R<1>, R<2> and R<3> are H or lower alkyl; R<4> is (substituted) lower alkyl; X is O or S] or its salt. EXAMPLE:1,2,3,4,5,8-Hexahydro-1, 3, 7-trimethyl-5-( 3-nitrophenyl )-2,4-dioxopyrido [2,3-d]pyrimidine-6-carboxylic acid methyl ester. USE:Useful as a preventive and remedy for circulatory diseases such as hypertension, ischemic cardiopathy, cerebral circulation disorder, etc. It has low toxicity. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II with the compound of formula III in a solvent such as methanol preferably at 60-140 deg.C under refluxing.

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 [wherein Ar is a penyl group or a 2,1.3-
The benzoxacyasiliμ group is represented by R1, R'', R3 each represents hydrogen or a lower alkyl group, R represents a lower alkyl group which may have a substituent, and X represents an oxygen or sulfur atom. The present invention provides compounds and salts thereof, as well as methods for producing them.

Regarding the above general formula (I), the phenyl group or the 2,1.3-benzoxacyasisilyl μ group represented by Ar contains 1 to 2 halogens, which are the same or different.

Nitro, trifluoromethyl/I/, lower aμyl or lower alkoxy group may be substituted at any position,
Such halogens include fluorine and chlorine.

Mention may be made of bromine and iodine, with fluorine or chlorine being particularly preferred. The lower alkyl or lower alkokene group preferably has 1 to 3 prime numbers, for example, the alkyl group includes methyl, ethyl, propyl, and isopropyl, and the alkoxy group includes methoxy, ethoxy, propoxy, and impropoxy groups. . 2.1.3
Particularly preferred among the -benzoxasiasilyl μ groups is the 2°1.3-benzoxadiazo-/l/-4- group.

The lower alkyl group represented by R1+R2+R'' preferably has 1 to 6 leg primes and is linear.

For example, methyl.

Ethyl, propyl, isopropyl-butyl, isobutyl, reduced-butyl-butyl, pentyl, isopentyl,
Examples include neopentyl, hexyl, etc., which are selective elements. Numbers 1 to 4 are preferred.

At the end of these alkyls, lower cycloalkyl/I
/ (eg, cyclopropyl/L/Icyclogutyl, cyclopentyl/L', cyclohexy/I/).

As the lower alkyl group represented by R4, the above R1, R
2. Those similar to the lower alkyl group shown as R3 are preferred. These lower alkyl groups may have a substituent, such as lower (C, -4)
Alkoxy (methoxy).

ethoxy, propoxy, isopropoxy, gutoxy, imbutoxy, mu-gutoxy, t-gutoxy, etc.), lower (C1=4) alkylthio (gutylthio, ethylthio,
(prohylthio, isopropylthio, butylthio, isobutylthio, 5ec-gutylthio, t-gutylthio, etc.), and lower (C3-6) cycloalkyl/L/(cyclopropyμ, cyclogutiμ, cyclopentyl, cyclohexV/l/, etc.). ), lower (02-4) alkanoyl/L/(acetiμ, propioni/I', gucciri/L/, etc.), aroyl (benzoino+', 7/l/
Orobenzoyl, chlorbenzoyl, methylbenzoyl, methoxypencil.

trifluoromethyl benzoyl, nitrobenzoyl, etc.), afu-μki A/(bendi ~ + 2-7 enylethyl)
L/, 1-phenylethyl, 3-phenylpropyl, 2
-phenylpropyμ, l-7,2μpropyl, benzhydryl, 2,2-diphenylethyl, 3,3-diphenylpropyμ, etc.), ary-/I/ (7eniμ, su7chiμ, etc.) and these substituent or lower (C1-4
') Amino groups or heterocycles substituted with 1-2 of the alkyl groups (pyrrolidine, piperidine, morpholine, piperazine).

homopiperazine, thiomorpholine, etc.).

Among the lower alkyl groups having a substituent represented by R4, lower alkoxyalkyl/I/(methoxyethyl lvl
Ethoxyethyl, propoxyethyl p, isoproboxyethyl μ, gutoxyethyl, methoxypropyl, 2〒methoxy-1-methylethyl/l/, 2, R5 and R6 are each the same or different and lower μ
or may be an aryl group, or R5 and R6 together with the adjacent nitrogen atom may form a heteroatom which may contain another heteroatom, and when the petroatom is a nitrogen atom, The nitrogen atom is a lower alkyl μ.

May be substituted with aralkyl or aryl group]
The groups represented by are particularly preferred.

Here, the lower aralkyμ groups represented by R5 and R6 are preferably the same as those shown for R1, R2, and R3 above, and the aralkyμ group is one in which an alkylene moiety is branched or a phenyl group is added to the alkylene moiety. including those substituted with, for example, benzyl + 2- phenyl
, 1-phenylethy*+3-yeniμpropyμ+2
':'Anyμf9piμ, 1-7enylprovir, benzhydryl.

Examples include 2.2-diphenylμethyl/L', 3,3-diphenylpropyμ, and the same substituents as mentioned for Ar above are present on these benzene rings at any position of 1 to 3. Three pieces may be replaced. R5
,, The aryl group represented by R6 may also have 1 to 3 similar substituents at any position.

When R5 and R6 together with the adjacent nitrogen atom form a heterocycle, such ring may also contain one further heteroatom (e.g., oxygen, nitrogen, sulfur), such as pyrrolidine, piperidine, morpholine, Examples include those having a 5- to 7-membered ring such as pipewodine, homopibefudine, and thiomophorin. When a nitrogen atom is separately included, such as piperazine or homopipefudine, the nitrogen atom may be substituted with the same alkyl, aralkyl, or aryl group as mentioned for R5 and R6.

n represents an integer of 2 to 4, and examples of the alkylene represented by -〇n H2n- include ethylene, trimethylene, propylene, tetramethylene, 1,2-dimethylene μethylene, and the like.

The compound represented by the above general formula (1) is, for example, a compound represented by the general formula [wherein, R1*R2+ It can be produced by reacting a compound represented by [Significance].

In this production method, compound (I) is produced by reacting compound (If) and (m) in an appropriate solvent. This reaction is normally 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, echnol/I/, propatool, isopropano/I/, butano-μ, 5-guctuμ, 2-methoxyethanol, etc. Arcano-z'
44+ Ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, acetic acid.

Pyridine, N,N-dimethypformamide, dimeflV
Examples include sulfoxide and acetonitrile. (I
I) and (m) are used in an amount of 1 to 1.2 mol per 1 mol of one of the compounds.

The above compound (II) is, for example, a compound represented by the general formula % (%) (wherein, Ar has the same meaning as above)] (wherein, R and R have the same meaning as above) ], but when producing compound (I), adding compounds (IV) and (V) to the reaction system instead of compound (Ill), generated (
A method of reacting 11) with the coexisting (I[) as it is may be used, and a final method is also included within the scope of the present invention.

This production method can be carried out under qualitatively the same conditions as the above production method.

By the above method, l+! ! The produced novel condensed pyrimidine derivative CI) can be purified by separation and purification methods known per se, such as concentration, extraction, chromatography, and reprecipitation.

6 It can be collected as a product of arbitrary purity by appropriately using recrystallization or the like.If a portion of (I) 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 acids (hydrochlorides, hydrobromides, sulfates, phosphoric salts, etc.), salts with organic acids (
(acetate, succinate, maleate, tuma-μ salt, malate, tartrate, methanesulfonate, etc.).

The compound (I) of the present invention or a salt thereof has low toxicity and has a blood pressure lowering effect, a peripheral vasodilating effect, a coronary artery dilating effect, a cerebral vasodilating effect, etc. in mammals (e.g., mice, rats, rabbits, dogs, cats, humans). For example, hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral circulation disorder (cerebral infarction, etc.) in humans.

It is useful as a prophylactic and therapeutic agent for cardiovascular diseases such as cerebral ischemic attack (A).

When compound (I) or a salt thereof is used as the above-mentioned pharmaceutical, it is mixed with appropriate pharmaceutically acceptable carriers, excipients, and diluents, and prepared in the form of powder, granules, one tablet, turnip tablet, injection, etc. It can be administered orally or parenterally.

The dosage range varies depending on the administration/7-+ symptoms, age of the patient, etc., but for example, when orally administered to adult hypertensive patients, the dosage range is 0.5-100 to 7-ky/day, preferably 2-ky/day. It is preferable to administer 501 J+9/kq/day in 181-several doses.

The results of pharmacological tests showing the usefulness of the compound (I) of the present invention are shown below.

Example Cerebral blood flow and coronary artery blood flow increasing effect [Method] Mongrel adults (male or female) weighing 10 to 18 to 9 were anesthetized by intravenous administration of bendopaviter μ sodium (3Of”lf/#). Resp after endotracheal intubation
irator (HEHI-34RM + Harva
Artificial respiration was performed with room air using a ventilator (RD). 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 at the distal side of the branch of the vertebral artery and all branches other than the vertebral artery, a non-invasive electromagnetic needle probe (diameter 2 m) was attached to the origin of the vertebral artery. , Blood flow was measured using an electromagnetic flowmeter (NarcomAtic + Suco). Meanwhile, to administer vertebral artery pressure drugs,
A cannula was retrogradely inserted into the left internal mammary artery until just before the vertebral artery and left in place.

Furthermore, the heart membrane is incised and the heart is made into a hammock for 1 yt! .

A polyethylene cannula was inserted into the distal side of the circumferential branch of the left coronary artery, and the circumferential branch distribution area was bathed with arterial blood led through the left common carotid artery and the extracorporeal circuit. Coronary artery blood flow is measured using an open-type electromagnetic flow meter attached to this extracorporeal circuit.
It was measured using a probe and an electromagnetic flowmeter (MF-26, Nihon Kohden). In addition, a side branch (rubber tube) for drug injection was installed in the extracorporeal vMm tract.

The test drug was used by dissolving it in a physiological saline solution containing 20% polyethylene glyco-1v-4,00 to a final concentration of IMI/GO, and 0.1ye of it was injected into the vertebral artery and coronary artery, respectively, as described above. The cannula and side branches were injected for 10 seconds. Changes in each arterial blood flow were continuously recorded on a polygraph (142-8, Sanei 1!'!11).

〔result〕

The change in blood flow after administration (average value of 3 to 6 times) was calculated using the following formula, and Table 1 shows the maximum value (%) and the duration for which the blood flow increased by 10% or more.

(Margins below) Example blood pressure lowering effect [Method] Male spontaneously hypertensive rats (group 1, 3-
6 animals) were used. Numb pressure is systolic pressure (systolic pressure) 20
It was around 0 tnHg. Blood pressure was measured using an automatic blood pressure measuring device (U8M-105R, Ueda Mezoika/I/), and the systolic pressure of the rat tail artery was measured.

The test compound was orally administered as a suspension in 5% Ti of gum Awobia. Animals to which only gum arabic solution was administered were designated as the control ρ group. Blood pressure measurements were taken at 1°5.8 and 24 hours after administration.

〔result〕

Table 2 shows the blood pressure lowering effect (post-medication blood pressure - pre-medication blood pressure) after 1 and 5 hours and the duration of the blood E"F lowering effect.

Table 2 Examples of the present invention are shown below to further specifically explain the present invention, but the present invention is not limited thereto.

Example 1 2-(3-210benzylidene)acetoacetic acid MeflVC
4,659), 6-amino-1,3-dimethyvfy”
)VivC2,89F), -Cri/-/I/(30m
/) mixture was stirred under reflux for 3 hours. The precipitated crystals were collected by filtration and recrystallized from dichloromethane-ethanol-μ to give 1,2.3.4,5.8-hexahite I:'-
1,3,7-)rimethyl/l/-3-(3-nitropheny/l/)-2+ 4-dioxopyrido-[2゜3-
d] Methyl pyrimidine-6-capboxylic acid/I/ was obtained as colorless prism crystals. Yield 6.1 f (87,4%)6
Melting point 2T3-274℃ Calculated value as H1BN406 from elemental analysis value C c
55.96; H4,70s N 14.5 [1 experimental value C55,94; u 4.65; If 14. TT
Compounds shown in Table 3 were obtained in the same manner.

(Left below) Example 9 2-chloroμbenzaldehyde (2,36F), acetoacetic acid 2-(N-benzyl-N-methyμamino)ethyl/L
'(4,19f), 6-amino-1,3-dimethyluraci l<2.87f>, isopropano-/L'(20πt
) was stirred under reflux for 8 hours. Chloroform (30 g/) was added, unreacted 6-amino-1,3-dimethyluracil was filtered off, and the filtrate was concentrated. The residue was chromatographed on silica gel [chloroform-methanol/l/(2
5-(2-chloro/L/phenylene/l) by recrystallization from ethyl acetate.
')-1,2゜3.4.5.8-hexahydro-1,3
,7-) rimethyl/l'-2,4-dioxopyride C2,
3-d) 2-(N-benzyl-N-methyμ-amino)ethyl pyrimidine-6-carboxylate was obtained as colorless prism crystals. Yield 3.99f (46.6%). Melting point +75-
176℃ Elemental analysis value C27H29CI Calculated value as N404 c 63.71+ Tl 5.74; N 11.0
1 Experimental value c 63.51; ■5.70; N 10
．． 92, and the compounds shown in Table 4 were obtained in the same manner.

(Left below) Formulation Example When the compound (I) of the present invention is used as a t-antihypertensive agent, it can be used, for example, in the following formulation.

(1) 5-(2--chloro/I/pheni/l/)-1,2
,314,5,8-hexahydro-1,3,7-drimethyl/I/-2,4-dioxopyrido[2゜3-d]pyrimidine-6-carboxylic acid 2-(,N-bendiII/-
H-methyμamino)ethyl/l'
l0f(2) Lactose
95゜(3) Corn starch 2
99(4) Magnesium stearate
1f 1000 tablets 135 F (1), (2) and ITf corn starch are mixed and granulated with a paste made from 7f corn starch, 51 corn starch and (4) are added to the granules, and the mixture is compressed. Compress with a tablet machine to produce 1000 tablets with a diameter of 7, each containing (1) 10 capes.

Claims (2)

[Claims] (1) General formula [In the formula, Aral ~ 2 halogens, nitro, triph ρ
oromethi iv, a phenyl group optionally substituted with a lower alkyl μ or a lower alkoxy group, or a 2,1,
3-benzoxacyacyly/L' group, l111.1"
,,3 are respectively hydrogen or Ir! , a lower alkyl group, R is a lower alkyl group which may have a substituent,
X represents an oxygen or sulfur atom] or a salt thereof. (2) In the general formula 0, Ar is 1 to 2 halogens, Phenyl group optionally substituted with nitro, trifluoromethyl, lower alkyl or lower alkoxy group or B2, 1
, a 3-benzoxadiazolyl group, R3 hydrogen or a lower alkyl group, and R4 represents a lower alkyl/I/ group which may have a substituent. The general formula [wherein, Ar * R1, R''+'R3+R'
A method for producing a compound represented by [Okugi X has the same meaning as above].