Pyrimidinone compounds, method of their production and pharmaceutical composition

 

This invention relates to new pyrimidinone compounds of formula (I) and their pharmaceutically acceptable salts, with a strong antagonistic activity against receptors for angiotensin II, thereby useful in the treatment of cardiovascular diseases, due to the binding of angiotensin II to its receptors. The invention also relates to a method for obtaining compounds of formula (I) by reaction of compound (II)with P4S10or a reagent of Lesson in a solvent selected from benzene, dichloromethane or tetrahydrofuran, and to pharmaceutical compositions based on compounds of formula (I). In the compound of formula (I)R1represents a C1-C4alkyl straight chain; R2represents a C1-C4alkyl; R3and R4are the same or different and represent H, C1-C4alkyl straight or branched chain, or R3and R4together with the N atom form a 4-8-membered heterocyclic ring, which may optionally include-O-, -S-, -SO-, -SO2-;

X represents S, and Z represents the radical tetrazol-5-yl having the following General formula

(I)(II)

Technical area

This invention relates to new pyrimidinone compounds and their pharmaceutically acceptable salts. This invention also relates to a method of obtaining new pyrimidinone compounds and pharmaceutical compositions containing pyrimidinone connection.

Background art

Pyrimidinone derivatives according to this invention and their pharmaceutically acceptable salts are used as antagonists of angiotensin II, in particular, in the treatment of cardiovascular diseases, due to the binding of angiotensin II to its receptors.

The renin-angiotensin system plays a Central role in the regulation of blood pressure in the human body. Angiotensin II, consisting of eight amino acids, is produced by the cleavage of angiotensin I angiotensinamidum enzyme (ACE), localized in the blood vessels of the lungs. Angiotensin II interacts with SP is x, causing an increase in blood pressure and concentrations of electrolytes.

Therefore, there have been several antagonistic compounds to inhibit the actions of angiotensin II by selectively blocking its receptors.

Basically have been proposed peptide antagonists, is similar to angiotensin II, but their clinical use has been limited because of their short half-life, lack of action after oral administration, and also due to the local increase of blood pressure.

Recently many studies have been published regarding ones antagonists of angiotensin II (US patents¹4207324, 4340598, 4576958, 4582847 and 4880804; European Patent Laying-Open Publication Nos. 028834, 245637, 253310, 291969, 323841 and 324377). In European Patent Laying-Open Publication Nos. 028834 and 253310 described imidazole derivatives, substituted biphenyl (eg, losartan), and in European Patent Laying-Open Publication No.245637 - imidazopyridine derivatives (for example, L158809) as strong antagonists of angiotensin II.

In European Patent Laying-Open Publication Nos.4073426, 419048 and 445811 described pyrimidinone derivatives such as compounds of this invention on their 6-membered heterocyclic ring structure containing the nitrogen, which is very different from 5-ctalnye derivatives, described in the aforementioned application.

Meanwhile, the authors of this invention have filed a PCT application (WO 96-08476) for new compounds with significantly high activity in vitro (rabbit aorta), 60-70% inhibition at 10-8-10-9mole in the study of the expansion of the blood vessel in vitro), which is 50 times higher activity of imidazole derivatives known from the above-mentioned application, or equal to it.

Description of the invention

When searching for new pyrimidinone compounds were obtained new pyrimidinone derivatives thioamide and amidine that exceed pyrimidinone derivatives described previously, or the imidazole derivatives activity and duration.

The object of this invention therefore is to obtain new pyrimidinone derivatives and their pharmaceutically acceptable salts, which effectively inhibit the action of angiotensin II, with high activity.

To achieve the above objectives, the invention is pyrimidinone derivatives and their pharmaceutically acceptable salts, having the formula (I):

1-C4alkylalkoxy or C1-C4allylmercaptan;

R2represents H, halogen, C1-C4alkyl, aryl or arylalkyl;

R3, R4are the same or different and represent H, C1-C4alkyl straight or branched chain, cycloalkyl, aryl, arylalkyl, C1-C4alkyl - or arylcarbamoyl, C1-C4alkoxycarbonyl or substituted aminocarbonyl, which is optionally substituted by H, halogen, hydroxy, C1-C4alkoxy, amino, alkylamino or dialkylamino (where each alkyl is C1-C5), C1-C4alkoxycarbonyl, carboxy or substituted by aminocarbonyl,

R3and R4together with the N atom form a 4-8-membered heterocyclic ring, which may optionally be substituted by one or two substituents selected from the group consisting of cycloalkyl, aryl or arylalkyl, halogen, hydroxy and C1-C4alkoxy, amino, alkylamino or dialkylamino (each alkyl residue has a C1-C5), C1-C4alkoxycarbonyl, carboxy or substituted aminocarbonyl and C1-C4Alki the additional include-O-, -S-, -SO-, -SO2-, >N-R5;

R5represents H, C1-C4alkyl, aryl, arylalkyl, replaced alkenyl, pyridyl, pyrimidyl, C1-C4alkyl or arylcarbamoyl, C1-C4alkoxycarbonyl, substituted aminocarbonyl, CN or SO2NR3R4;

X represents S or >N-R5and

Z is CN, COOR3, SO2NR3R4or tetrazol-5-ilen radical having the following General formula

where R6represents H, tert-butyl or triphenylmethyl;

m is 1 or 2;

n is 1, 2, 3, 4, 5 or 6.

Pyrimidinone compounds according to this invention and their pharmaceutically acceptable salts exhibit high activity.

Preferred are such compounds in which R1represents ethyl, n-propyl, n-butyl, cyclopropyl, ethoxy or propoxy; R2represents H, halogen or C1-C4alkyl straight or branched chain; R3and R4are the same or different and represent H, methyl, which may be optionally substituted by one or two substituents, selected from the group consisting of cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C1-C4alconox, amino, alkylamino or dialkylamino (each alkyl residue has a C1-C5), C1-C4alkoxycarbonyl, carboxy and substituted aminocarbonyl and C1-C4the alkyl straight or branched chain, optionally substituted by N; and the heterocyclic ring may optionally include-O-, -S-, -SO-, -SO2-, >N-R5; R5represents H, C1-C4alkyl, aryl, arylalkyl, replaced alkenyl, pyridyl, pyrimidyl, C1-C4alkyl or arylcarbamoyl, C1-C4alkoxycarbonyl, substituted aminocarbonyl, CN or SO2NR3R4more preferably, H, C1-C4alkyl, C1-C4alkoxycarbonyl, substituted aminocarbonyl, CN or SO2NR3R4; X represents S or >N-R5; Z is tetrazol-5-ilen radical and m is 1.

The best way of carrying out the invention

Pharmaceutically acceptable salts of this invention include inorganic salts obtained by reaction of the corresponding pyrimidinone compounds (I) with hydroxylamine or magnesium hydroxide, carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate or alcoholate of alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, and organic salts obtained by reaction with an organic amine in N2O, alcohols, such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc., tetrahydrofuran or their mixtures.

The compound (I) can be obtained according to reaction scheme (I) of the following compounds (II).

[Reaction scheme I]

where R1, R2, R3, R4, X, Z, m and n have the meanings defined above.

Starting materials for the compounds of formula II can be obtained by the method described in PCT application Laying-Open Publication No. WO 96-08476, the authors of this application. The compound of the formula I, in which X represents S can be easily obtained by reaction of compound (II) with P4S10, bis(tricyclohexyltin)sulfide or reagent of Lesson in the solvent, wyboi NR5can be easily obtained from the compound (II) by attaching substituted amine after receiving the intermediate imine using a reagent such as oxalicacid, phosphorus oxychloride or ethylchloride in a solvent selected from benzene, ether or tetrahydrofuran.

Typical compounds of this invention are the following compounds, and is specified in brackets the number of connections is the name used in the description.

2-n-butyl-5-iminodicarboxylate-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he(compound 1),

2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he(compound 2),

2-n-butyl-5-diethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he(compound 3),

2-n-butyl-5-heptanedicarboxylic-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 4),

2-n-butyl-5-dimorpholinyldiethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]pyrimidine-4(3H)-he(compound 5),

2-n-butyl-5-p style="padding-top:5px;">2-n-butyl-5-piperidinecarboxylate-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 7),

2-n-butyl-5-pyrrolidinecarbonyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 8),

2-n-butyl-5-setidentifier-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 9),

2-n-butyl-5-(2'-iminodicarboxylate)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 10),

2-n-butyl-5-(2'-dimethylaminocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4 (3H)-he (compound 11),

2-n-butyl-5-(2'-diethylaminocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 12),

2-n-butyl-5-(2'-dimorpholinyldiethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 13) and

2-n-butyl-5-(2'-morpholinosydnonimine-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 14).

The compound of formula I and its pharmaceutically acceptable salts can be administered orally or parent is nsii or solutions manufactured in accordance with conventional pharmaceutical practice.

The compounds of formula I and so on, you can enter in a dosage of about 40 mg/kg to about 100 mg/kg body weight, preferably at night.

The compounds of this invention have extremely low toxicity. LD50mice is more than 5000 mg/kg body weight, as shown in experimental test 2.

The invention will be described in more detail hereafter in relation to preferred implementations, and as such, they should not be construed as limiting the scope of the invention.

EXAMPLE 1

2-n-butyl-5-iminodicarboxylate-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]'pyrimidine-4(3H)-he (compound 1)

METHOD 1

1.2 g of 2-n-butyl-5-aminocarbonylmethyl-6-methyl-3-[[2'-(N-triphenylmethanol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-she (WO 96-08476) was dissolved in 20 ml of benzene at room temperature and there is added 600 mg of the reagent of Lesson. After heating the mixture and stirring for 5 hours the mixture is cooled to room temperature, unnecessary solid is filtered off and concentrate the topic of 700 mg (57%) of the intermediate product.

After dissolving the intermediate product in 100 ml of tetrahydrofuran, the solution is cooled to 0-5°and to him slowly add 5 ml of 4 M hydrochloric acid solution. The solution is heated in a flask under reflux for 4 hours and then neutralized by adding 4 M sodium hydroxide solution. The aqueous layer was saturated with solid sodium chloride and extracted three times with chloroform. The organic solution thus obtained, washed with brine and then dried and concentrated using anhydrous magnesium sulfate. The residue after chromatography elute using chloroform and a mixture of chloroform/methanol (9:1) to give 310 mg (65%) of compound 1.

METHOD 2

500 mg of 2-n-butyl-5-aminocarbonylmethyl-6-methyl-3-[[(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-she (WO 96-08476) was dissolved in 20 ml of tetrahydrofuran at room temperature and there adds 400 mg of the reagent of Lesson. After heating the mixture and stirring for 5 hours the mixture is cooled to room temperature, unnecessary solid is filtered off and the residue concentrated under reduced pressure. The residue is isolated and purified by chromatography using chloroform and a mixture of chloroform/methanol (9:1) with sub>)

1H NMR(DMSO-d6):of 0.83 (t, 3H), 1,19-of 1.40 (m, 2H), 1,48~of 1.65 (m, 2H), of 2.21 (s, 3H), 2,60 (s, 2H), 3,35 (s, 2H), 5,27 (s, 2H), 7,01~to 7.09 (m, 4H), 7,39~to 7.61 (m, 4H), 6,83 (s, 1H), 7,07 (s, 4H), 7,30 (s, 1H), 7,40~to 7.68 (m, 4H).

In the same way we obtain the following connections.

EXAMPLE 2

2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 2)

So pl.: 96,8~101,8°C

TCXRf: 0,28 (5% Meon in l3)

1H NMR(Dl3):to 0.89 (t, 3H), 1,28~of 1.45 (m, 2H), 1,58~of 1.74 (m, 2H), and 2.26 (s, 3H), 2.63 in (s, 2H), 3,44 (s, 3H), 3.46 in (s, 3H), of 3.77 (s, 2H), with 5.22 (s, 2H), 7,07(s, 5H), 7,33-of 7.60 (m, 3H), 7,94 (DD, 1H).

EXAMPLE 3

2-n-butyl-5-diethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 3)

So pl.: 96,8~98,6°C

TCXRf: 0,31 (5% Meon in l3)

1H NMR(Dl3):of 0.91 (t, 3H), of 1.26 (t, 3H), 1,31~of 1.45 (m, 2H), 1.61 of the~of 1.80 (m, 2H), 2,31 (s, 3H), to 2.67 (t, 2H), 3,76 (kV, 2H), 3,81 (s, 2H), 3,99 (kV, 2H), 5,26 (s, 2H), 7,01~to 7.18 (m, 3H), 7,20-7,28 (m, 1H), 7,33~7,41 (m, 1H), 7,45~a 7.62 (m, 2H), of 8.06 (DD, 1H).

EXAMPLE 4

So pl.: 104,2~107,3°C

TCXRf: 0,47 (7% Meon in l3)

1H NMR (CDCl3):of 0.83 (t, 3H), 1,21~of 1.30 (m, 2H), 1,40~to 1.70 (m, 8H), 1,71~of 1.95 (m, 4H), of 2.21 (s, 3H), of 2.53 (t, 2H), 3,60~3,88 (m, 4H), was 4.02 (s, 2H), further 5.15 (s, 2H), 6,98~to 7.09 (m, 5H), 7,22~7,58 (m, 3H), to 7.77(DD, 1H).

EXAMPLE 5

2-n-butyl-5-dimorpholinyldiethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 5)

So pl.: 115,5~119,1°C

TCXRf: 0,33 (7% Meon in l3)

1H NMR (CDCl3):of 0.91 (t, 3H), 1,31~to 1.48 (m, 2H), 1.61 of the~of 1.74 (m, 2H), 2,30 (s, 3H), 2,65 (t, 2H), 2,72~2,84 (m, 4H), 3,81 (s, 2H), 4,22 (t, 2H), 4,59 (t, 2H), 5.25 in (s, 2H), 7.03 is~to 7.15 (m, 5H), 7,35~to 7.61 (m, 3H), of 8.00 (DD, 1H).

EXAMPLE 6

2-n-butyl-5-morpholinosydnonimine-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 6)

So pl.: 91,8~94,3°C

TCXRf: 0,30 (7% Meon in l3)

1H NMR (Dl3):to 0.92 (t, 3H), 1,31~to 1.48 (m, 2H), 1,63~is 1.81 (m, 2H), 2,34 (s, 3H), 2,69 (t, 2H), 2,68~2,82 (m, 4H), 3,85 (s, 2H), of 3.97 (s, 2H), 4,34 (t, 2H), 5,27 (s, 2H), 7,05~7,20 (m, 5H), 7,35~the 7.65 (m, 3H), with 8.05 (DD, 1H).

EXAMPLE 7

So pl.: 94,2~97,6°C

TCXRf: 0,37 (5% Meon in l3)

1H NMR (Dl3):of 0.91 (t, 3H), 1,31~to 1.48 (m, 2H), 1.61 of the~of 1.80 (m, 8H), is 2.30 (s, 3H), to 2.67 (t, 2H), 3.72 points~3,90 (m, 4H), 4.26 deaths (s, 2H), 5.25 in (s, 2H), 7.03 is~to 7.15 (m, 5H), 7,35~to 7.61 (m, 3H), 8,01 (DD, 1H).

EXAMPLE 8

2-n-butyl-5-pyrrolidinecarbonyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 8)

So pl.: 94,4~97,3°C

TCXRf: 0,26 (5% Meon in l3)

1H NMR (Dl3):of 0.91 (t, 3H), 1,31~to 1.48 (m, 2H), 1.61 of~1.8 m (m, 2H), 1.91 a~to 2.18 (m, 4H), 2,32 (s, 3H), to 2.67 (t, 2H), 3,60~3,90 (m, 6N), of 5.24 (s, 2H), 7.03 is~to 7.15 (m, 5H), 7,35~to 7.61 (m,3H), 8,02 (DD, 1H).

EXAMPLE 9

2-n-butyl-5-setidentifier-6-methyl-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 9)

So pl.: 92,4~93,8°C

TCXRf: 0,24 (5% Meon in l3)

1H NMR (Dl3):of 0.91 (t, 3H), 1,31~of 1.45 (m, 2H), 1.61 of the~of 1.75 (m, 2H), 2,20~2,35 (m, 2H), 2,39 (s, 3H), to 2.67 (t, 2H) and 3.59 (s, 2H), is 4.21 (t, 2H), 4,47 (t, 2H), 5,24 (s, 2H), 7.03 is-to 7.15 (m, 4H), 7.18 in~7,25 (m, 1H), 7,35~to 7.61 (m, 3H), of 8.04 (DD, 1H).

EXAMPLE 10

2-what s 10)

So pl.: of 97.8~99,0°C

TCXRf: 0,43 (5% Meon in l3)

1H NMR (Dl3):of 0.93 (t, 3H), 1.32 to~to 1.48 (m, 2H), 1,62~of 1.80 (m, 2H), 2.40 a (s, 3H), 2,60 is 2.80 (m, 4H), 2,87 (t, 2H), 5,27 (s, 2H), 7,10~7,25 (m, 4H), 7,35~the 7.65 (m, 4H), 8,10 (DD, 1H).

EXAMPLE 11

2-n-butyl-5-(2'-dimethylaminocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 11)

So pl.: 76,2~81,2°C

TCXRf: 0,21 (5% Meon in l3)

1H NMR (DMSO-d6):of 0.90 (t, 3H), 1,28~of 1.45 (m, 2H), 1,58~of 1.74 (m, 2H), is 2.37 (s, 3H), 2.63 in (t, 2H), 2,85~3,05 (m, 4H), 3,42 (s, 3H), 3,47 (s, 3H), 5,23 (s, 2H), 6,95~6,13 (m, 4H), 7,27~the 7.65 (m, 4H), 7,87 (DD, 1H).

EXAMPLE 12

2-n-butyl-5-(2'-diethylaminocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 12)

So pl.: 77,8~81,1°C

TCXRf: 0,37 (5% Meon in l3)

1H NMR (Dl3):to 0.88 (t, 3H), 1,12~of 1.45 (m, 8H), 1,55~of 1.74 (m, 2H), is 2.37 (s, 3H), at 2.59 (t, 2H), 2,85~3.15 in (m, 4H), 3,70 (kV, 2H), 3,37 (kV, 2H), 5,20 (s, 2H), 6.90 to~7,05 (m, 4H), 7,20~of 7.55 (m, 4H), 7,78 (DD, 1H).

EXAMPLE 13

2-n-butane 13)

So pl.: 80,1~83,3°C

TCXRf: 0,28 (5% Meon in l3)

1H NMR (Dl3):of 0.91 (t, 3H), 1,30~of 1.45 (m, 2H), 1,60~1,70 (m, 2H), 2,39 (s, 3H), 2,55~2,90 (m, 8H), of 2.97 (t, 2H), 4,22 (t, 2H), 4,58 (t, 2H),? 7.04 baby mortality~of 7.25 (m, 5H), 7,35~7,42 (m, 1H), 7,45~the 7.65 (m, 2H), 8,08 (DD, 1H).

EXAMPLE 14

2-n-butyl-5-(2'-morpholinoethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 14)

So pl.: 92,2~94,7°C

TCXRf: 0,39 (7% Meon in l3)

1H NMR (Dl3):of 0.91 (t, 3H), 1,30~of 1.45 (m, 2H), 1,60~of 1.75 (m, 2H), 2,39 (s, 3H), to 2.67 (t, 2H), 2,88 (t, 2H), 3,05 (t, 2H), 3,65~of 3.80 (m, 4H), of 3.94 (t, 2H), or 4.31 (t, 2H), 5,27 (s, 2H),? 7.04 baby mortality~7,30 (m, 5H), 7,38-7,42 (m, 1H), 7,50-to 7.68 (m, 2H), 8,08 (DD, 1H).

Antagonistic activity of compounds (I) in relation to angiotensin II, which is obtained by the method in accordance with the preferred embodiment of the present invention, was evaluated in rats. The results are presented in table 1.

Experimental test of the I

Antagonism against angiotensin II in vivo from in the minds of rats with normal blood pressure.

SD rats-males (Ch the left femoral vein was inserted cannula. Filled with heparin catheter (50 U/ml) was injected subcutaneously (s/C) in the dorsal side of the neck and secured from the outside.

The rats were allowed to recover during the night after anesthesia and gave them free access to water but were denied food.

The next day, the femoral artery catheter was connected to a pressure transducer (OWL 041-500-508, USA) connected to a polygraph (GRASS Model 7, USA) to monitor arterial blood pressure. After an appropriate period of equilibration was administered angiotensin II (0.1 mg/kg) in the femoral vein three times during the monitoring period.

Compound is then administered orally (p/o) in a constant volume of 2 ml/kg

After injection of angiotensin II was repeated within the stipulated time.

ID values50the dose of the test compound required to obtain 50% suppression caused by angiotensin II Pressor response was calculated by peak percent suppression using multiple doses of the test compounds.

Experimental test II

Test for acute toxicity

The corresponding 5 mine in the conditions of reproduction temperature 23±1°With, humidity 55±5%, pumping out 10-15 times/hour, 12-hour cycle fluorescent lighting and lighting levels in 150-300 Lux.

After observing the mice for one week acclimatization period of cultivation only normal mice were selected for laboratory work. Mice were fed sterilized food for laboratory animals, which is manufactured Cheil Jedang Co., Ltd, and gave them clean water to drink.

During the period of acclimatization, mice that were rated as healthy, weighed and divided into groups by random sampling. The individual identification of laboratory animals provided by applying a pigment to the hair and labeling on the box for cultivation.

Dose determination was carried out according to preliminary test results so that the group receiving the highest dose, both males and females were administered 5000 mg/kg, and azeotrope installed 1.71. In treated groups, respectively, medium-high, medium, low and medium dose was administered following and the control group was injected by the injection of a saline solution.

The drugs tested substances before the introduction was dissolved in physiological solution. The dose was calculated from the body weight, which was determined before the introduction, and administered orally to mice, which were kept hungry for 18 hours before the test.

Observation of clinical symptoms, such as General changes, symptoms of toxicity and mortality were carried out for all laboratory animals once every hour for 6 hours after dosing on the day of injection and once daily, starting from the next day on the 14th day of introduction.

The test group, which was administered to subjects substances, and the control group were weighed on the day of introduction, on the first, third, seventh, tenth and fourteenth days after injection in a predetermined time for all animals that survived.

After finishing the test, all animals were doing light anesthesia with ether, and omertvlenie exsanguination. View internal organs of animals were carefully evaluated by naked eyes. Animals that died during the test, were examined in the same way.

Similarly received tablets containing other compounds with (2) through (14) of this invention (examples 16 to 28).

EXAMPLES 29-42

Manufacturing capsules

Normal by mixing the ingredients listed in table 2, granularit and distribute a separate capsules (200 mg) (example 29).

Similarly received capsules containing other compounds with (2) through (14) of this invention (examples 30 through 42).

Industrial applicability

In accordance with this invention it is possible to obtain new compounds of General formula (I), which is applicable as antagonists of angiotensin II.

Although the preferred embodiment of the present invention have been described for illustrative purposes, experienced professionals will understand that various modifications, additions and substitutions without departing from the scope and essence of the present invention are set forth in the accompanying claims.

Claims

1. Pyrimidinone compound of formula (I)or its pharmaceutically acceptable salts, where R1represents a C1-C4alkyl straight chain;R2represents a C1-C4alkyl;R3and R4are the same or different and represent H, C1-C4alkyl straight or branched chain, or R3and R4together with the N atom form a 4-8-membered heterocyclic ring, which may optionally include-O-, -S-, -SO-, -SO2-;X is S;Z represents a radical tetrazol-5-yl having the General formula
where R6represents H;
m = 1 or 2;
n= 1, 2, 3, 4, 5 or 6.

2. The compound or its pharmaceutically acceptable salt according to p. 1, where R1represents ethyl, n-propyl, n-butyl, and R2represents a C1-C4alkyl straight or branched chain.

3. The compound or its pharmaceutically acceptable salt according to p. 2, where R3and R4are the same or different and represent H, methyl, ethyl, propyl or butyl, or R3and R4together with AENA or its pharmaceutically acceptable salt according to p. 3, where Z represents tetrazol-5-ilen radical and m = 1.

5. The compound or its pharmaceutically acceptable salt under item 1, with the indicated compound of formula (I) is one selected from the group including
2-n-butyl-5-iminodicarboxylate-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 1),
2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 2),
2-n-butyl-5-diethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 3),
2-n-butyl-5-heptanedicarboxylic-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 4),
2-n-butyl-5-dimorpholinyldiethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]pyrimidine-4(3H)-he (compound 5),
2-n-butyl-5-morpholinosydnonimine-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 6),
2-n-butyl-5-piperidinecarboxylate-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidine-4(3H)-he (compound 7),
2-n-butyl-5-pyrrolidinecarbonyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4(3H)-he (compound 8),
2-n-butyl-5-AZ is butyl-5-(2'-iminodicarboxylate)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 10),
2-n-butyl-5-(2'-dimethylaminocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 11),
2-n-butyl-5-(2'-diethylaminocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 12),
2-n-butyl-5-(2'-dimorpholinyldiethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he(compound 13) and
2-n-butyl-5-(2'-morpholinosydnonimine-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-he (compound 14).

6. Pharmaceutical composition having antagonistic activity against angiotensin II, containing a therapeutically effective amount of the compounds according to paragraphs.1-5 and a pharmaceutically inert carrier.

7. Connection PP.1-5, which has antagonistic activity against angiotensin II, applicable in cardiovascular diseases.

8. The method of obtaining the compound (I) under item 1, in which X represents S, the reaction of the compound of formula (II)

with P4S10or a reagent of Lesson in a solvent selected from benzene, dichloromethane or tetrahydrofuran:
where R1, R2, R3, R4, Z, m and n have the same values that

 

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