Derivatives of pyrimidine, the method of production thereof, pharmaceutical composition based on them

 

(57) Abstract:

Derivatives of pyrimidine having the angiotensin II antagonistic activity, of General formula (I)

< / BR>
Compounds of General formula (I) in which R, R1, R2, R3X and Z groups have the meanings given in the description, and endowed with AII-antagonist properties. 4 C. and 3 h. p. F.-ly, 2 tab.

The invention relates to heterocyclic compounds having angiotensin II antagonistic activity.

System the renin-angiotensin (CPA) is a proteolytic (breaks down protein) cascade, which plays a major role in regulating blood pressure, and obviously causing the beginning and help maintain some cardiovascular pathologies such as hypertension and heart failure.

Octapeptide hormone angiotensin II (AII) is the end product of CPA is formed in the blood during decomposition of angiotensin I enzyme extract of the adrenal cortex (enzyme ACN), which is localized in the endothelium of blood vessels, lungs, kidneys and many other organs. This hormone exerts on the artery strong sosudosuzhayushcheye effect in accordance with its cooperation with the special Retz the ISM at the receptor level. Some peptide analogs of AII (for example, saralasin, carmesin) is known for a completely antagonistic interaction of the hormone, but their clinical and experimental application is limited to a partial agonistic activity and lack of oral activity.

Recently as AII-receptor antagonists have installed some 5 - or 6-membered heterocyclic compounds. Examples of these compounds are patented in EP 253310, EP 323841, EP 324377, EP 409332, EP 411507, EP A, EP A. The present invention relates to a heterocyclic derivative having AII-antagonist properties, which therefore can be used to treat various cardiovascular pathologies such as hypertension, heart failure, and intraocular hypertension. Compounds of the invention have the formula (I):

< / BR>
in which R is a linear or branched C1-4-alkyl;

R1hydrogen, linear or branched C1-4is alkyl, aryl or arylalkyl, where aryl is phenyl, naphthyl, 2-thienyl, optionally substituted by one or more halogen, C1-4-alkyl, C1-4-alkoxy, hydroxy, carboxy or a linear or branched C1-4-alkoxycarbonyl group; when N and X are connected by digitoxin, amino, aryl, where aryl, as defined above, or a group of the General formula NHA, where A C2-7-acyl, CN, NO2, CONHB or CSNHB, where B is hydrogen, linear or branched C1-4-alkyl, C3-7-cycloalkyl, aryl as defined above;

R3hydrogen or one or more halogen atoms;

X CO or C-R4group, where R4OR1(where R1should normally be present and have the above values) aryl, optionally substituted by carboxy or hydroxy group, or CH2OR5where R5hydrogen, lower alkyl, arylalkyl where allcast defined above;

-COOR6group, where R6hydrogen or linear or branched C1-4is alkyl or tetrazol-5-yl group, General formula

< / BR>
in which R7hydrogen or C1-4-alkyl, provided that when X IS CO and R1H, phenyl or phenethyl, R2is not hydrogen or alkyl.

Connection unreached represented by the formula known from EP 0435827.

Preferred compounds of General formula (I) are compounds that have

X CO;

R1preferably, hydrogen; C1-4-alkyl, phenyl, benzyl, thienyl, furanyl optionally substituted by carboxy or C1-4-alkoxycarbonyl-what about substituted by carboxy or C1-4-alkoxycarbonyl-group;

R3preferably hydrogen.

Another group of preferred compounds are compounds in which R2hydrogen or C1-4-alkyl, and R1C1-4-alkyl, phenyl, benzyl, furanyl or thienyl, optionally substituted by carboxy or alkoxycarbonyl group. Especially preferred are compounds in which R2-amino. Particularly preferred compounds are: 4-butyl-1-[(2-carboxyphenyl)methyl] -2-methyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl -4] -methyl]-pyrimidine-6-he 2-amino-6-butyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidine-4-one.

Compounds of General formula (I) is methylbiphenyl group on the carbon atom instead of a nitrogen atom, as in the known level.

The invention includes also pharmaceutically acceptable salts of the compounds of General formula (I) with organic or inorganic bases or acids. These salts include ammonium salts, alkali metal such as Na and K salts of alkaline-earth metal such as Ca, Mg, salts of organic bases, for example, dicyclohexylamine, N-methyl-D-glucamine, with amino acids such as arginine, lysine, and so on, Examples of salts with organizations Hydrobromic, sulfuric, phosphoric, methansulfonate, toluensulfonate, maleic, fumaric, camphorsulfacid etc.

The invention relates also to a method of obtaining compounds of General formula (I).

Compounds of General formula (I) in which Z-COOR6group (R6C1-4-alkyl) or substituted tetrazolyl group, produced by interaction of 1,3-dicarbonitrile or ketoconazole derivative of General formula (II).

< / BR>
in which R and R3such as defined for General formula (I);

R8and OR9group (R9methyl or ethyl) or CH2OR5group, where R5the same as defined for General formula (I);

Y COOR6group, (R6C1-4the alkyl group) or a substituted tetrazolyl-5-yl group, with compounds of General formula (III)

< / BR>
in which R1and R2such as defined for General formula (I), provided that R1at least hydrogen.

The reaction is performed in proton solvent such as a lower alcohol (e.g. methanol, ethanol, isopropyl alcohol), or in water or in a mixture thereof, or in an aprotic solvent such as benzene or toluene, optionally in the presence of a base, such as an alcoholate (CHthe tour may vary from room temperature to the temperature of reflux distilled.

The formation of the heterocycle can be performed in the presence of acids, such as acetic acid or hydrochloric acid, at a temperature of from 20 to 80oC. Alternative compounds of General formula (I) are obtained from compounds of General formula (IV)

< / BR>
in which R, R1, R2, R3such as defined above;

Y COOR6group (R6C1-4-alkyl), CN, or tetrazol-5-yl group, substituted triphenylmethyl group.

When Y is alkoxycarbonyl group, the compound of General formula (IV) can be subjected to an acid (for example hydrochloric, triperoxonane, formic, acetic acids in proton solvents such as CH2Cl2, dioxane) or alkaline (potassium hydroxide in water-alcohol mixtures at temperatures from 20 to 80oC) hydrolysis.

When Y is a CN-group, it can be hydrolyzed by strong acids or bases, preferably a mixture of 1:1 hydrochloric acid and glacial acetic acid when heated in a flask with reflux condenser, or NaOH in ethanol or ethylene glycol at a temperature of 20oC to the boiling point. CN group can be converted into tetrachloropropane obrabotka trialkyl or Triaryl-channelside in solvents, such as toluene or xylene at temperatures of from 110 to 130oC.

If Y tetrazolyl group, substituted triphenylmethyl group, the latter can be removed by treatment with acetic, tetracarboxylic or hydrochloric acid or by hydrogenolysis.

Compounds of General formula (IV) in which R1is hydrogen, can be alkylated in the presence of a base, such as K2CO3, NaH, NaNH2, utility, LDA in aprotic polar solvents such as dimethylformamide, (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) at temperatures between -20oC to +30oC compounds of General formula (V)

X-CH2R1< / BR>
in which R1such as defined above, and X is leaving group such as chlorine, bromine, iodine or mesilate or tosylate group.

Compounds of General formula (IV) in which X R4where R4-CH2OCH2-phenyl, can be converted into the corresponding hydroxy catalytic hydrogenolysis in the hydroxyl solvent such as methanol, ethanol, in the presence of platinum or palladium as a catalyst.

Compounds of General formula (IV) obtained by the interaction of the compounds of General formula (II) in which Y tacos the BOM.

Compounds of General formula (II) are obtained by known alkylation-diketones or β-ketoesters, as indicated in the examples.

These compounds are antagonistic activity with AII receptor.

Were conducted in-vitro-tests (inhibition of AII-induced interaction in aorta rabbits and125I-Sar1-Ile8-ATP-substitution in the adrenal cortex of rats) and in-vivo-test (inhibition of AII-induced changes in blood pressure in rats with normal blood pressure under ganglion block).

Compounds of the invention are active in the above test, for example, in tests in vitro on aortech rats some compounds showed pA2above 6.5.

Compounds of General formula (I) or their pharmaceutically acceptable salts can be used in pharmaceutical compositions separately or in a mixture with pharmaceutically acceptable additives, for oral administration or for parenteral use. The pharmaceutical compositions can be in solid form such as tablets, capsules or suppositories, or in liquid form such as solutions, suspensions or emulsions.

In addition, in the case of parenteral p is of the formula (I) can be applied in single doses ranging from 1 to 100 mg to patients, suffering from cardiovascular pathologies such as hypertension, acute and chronic heart failure, intraocular hypertension. Can also be used in other pathologies, such as secondary giperaldosteronizm, pulmonary hypertension, renal disease (glomerulonephritis, diabetic nephropathy) or vascular disorders (migraine syndrome Ranada).

The following additional examples illustrate the invention.

Melting points are uncorrected, the structure and purity of the compounds was determined by elemental analysis (C, H, N) and UV-, IR-, NMR - and mass-spectroscopy.

Flash chromatography (PC) was performed on silica gel according to the method described by W. C. Still, J.Org. Chem. 43, 2923 (1978)

Example 1. 1 benzoxa-2-,4-octadien.

To a solution containing 4,9-methylbenzylamine in 50 ml of dehydrated toluene was added under nitrogen atmosphere 0.9 g CH3ONa and after 10 min of 2 ml of 2-hexanone. After 10 h stirring at room temperature was added 10 ml of water and acetic acid to pH 5. Toluene phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases are combined with the toluene phase, bil (dry). The residue was purified PF (eluent: a mixture of 9:1 hexane: AcOEt). There was obtained 2.5 g of pale yellow oil (yield 63%); 1H-NMR (200 MHz, CDCl3) Delta: 0,92 (so 3H), 1,22 by 1.68 (m, 4H), 2,33 (so 2N), 4,07 (s, 2H), 4,60 (S. 2N), to 5.85 (s, 1H), 7,30 was 7.45 (m, 5H).

Similarly, there were obtained the following compounds:

1-benzyloxy-2,4-heptadien

1-methoxy-2,2-octadien,

1-methoxy-2,4-heptadien;

1-[(4-ethoxycarbonylphenyl)methoxy]-2,4-octadien.

Example 2. 1-benzyloxy-3-[(2'-methoxycarbonylmethyl-4-yl)methyl]-2,4-octadien.

In a suspension containing 0.16 g of 80% NaH in 15 ml of anhydrous DMF, was added in nitrogen atmosphere of 1.3 g of 1-benzyloxy-2,4-octadiene dissolved in 5 ml of anhydrous DMF. After the rapid allocation of gas bubbles was added 2 g of cylindrical form, and then to the mixture was added dropwise 1.6 g of 4-methyl bromide-2'-ethoxycarbonylphenyl dissolved in 5 ml of anhydrous DMF. After stirring for 6 h at room temperature and for 6 hours at 70oC the solvent was evaporated and the residue was treated with water and extracted Et2O. the Organic phase was washed with saturated solution of NaCl, dried over Na2SO4and evaporated to remove the solvent (dry). The residue was purified PF (eluent: hexane: AcOEt=75:25).,17 (dt. 1H), 2,47 (dt. 1H), 3,03 (DD, 1H), up 3.22 (DD, 1H), 3,62 (s, 3H), 3,99 (s, 2H), 4,19 (t, 1H), 4,48 (s, 2H), 7,10-of 7.55 (m, N), of 7.82 (DD, 1H).

Similarly, there were obtained the following compounds:

-1-benzyloxy-3-[(2'-methoxycarbonylmethyl-4-yl)methyl]-2,4-heptadien;

-1-methoxy-3-[(2'-methoxycarbonylmethyl-4-yl)methyl]-2,4-octadien;

-1-[(4-ethoxycarbonylphenyl)methoxy]-3-[(2'-methoxycarbonylmethyl-4-yl) methyl]-2,4-octadien;

1-benzyloxy-3-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-octadien,

1-benzyloxy-3-[(2'-[N-triphenylmethyl(1H-tetrazol-5-yl)] biphenyl-4-yl] -methyl]-2,4-octadien.

Example 3. Methyl-3-oxogedunin.

59 ml utility 1.6 M in hexane was added under nitrogen atmosphere at 0oC to a solution containing 14 ml of Diisopropylamine in 200 ml of dehydrated THF.

After 20 min stirring was added dropwise to 9.3 ml of methylacetoacetate, stirring was continued for 30 min at 0oC, after which it was added dropwise 54 ml utility 1.6 M in hexane. After another 30 min to dark orange solution was added dropwise to 8.4 ml propyliodide. The temperature of the reaction mixture reached room temperature, and after 30 min was added dropwise, with the temperature maintained at 15oC, 50 ml of 37% HCl, razbam is NaCl, dried over Na2SO4and evaporated to remove the solvent (dry). The residue was purified PF (eluent: AcOEt hexane 1:9). Received of 8.3 g of pure oil (yield 61% );1H-NMR (200 MHz, CDCl3) Delta: from 0.90 (t, 3H), 1,22-of 1.65 (m,4H), of 2.53 (t,2H), 3,44 (s,2H), of 3.73 (s,3H).

Similarly, there was obtained methyl-3-oxohexanoate.

Example 4. Methyl-2-[(2'-methoxycarbonylmethyl-4-yl)methyl]-3-oxogedunin.

2.3 g of methyl-3-acceptance dissolved in 10 ml of dehydrated THF was added dropwise to a suspension containing 0,22 g of 80% NaH in 30 ml of dehydrated THF. After the rapid allocation of gas bubbles 2,22 g of 4-methyl bromide-2'-ethoxycarbonylphenyl dissolved in 10 ml of dehydrated THF was slowly added dropwise to the clear solution. After 15 min was added water, and was added acetic acid until acidic pH. The reaction mixture was extracted AcOEt. The organic phase was washed with saturated solution of NaCl, dried over Na2SO4and evaporated to remove the solvent (dry). The residue was purified PF (eluent: hexane: AcOEt 8:2). There was obtained 2.6 g of pure oil (yield 93%);1H-NMR (200 MHz, CDCl3d 0,86 (t, 3H), 1,15-of 1.62 (m, 3H), 2,25-to 2.65 (m, 2H), 3,20 (d, 2H), 3,63 (s, 3H), 3,71 (s, 3H), of 3.84 (t, 1H), 7,12-7,58 (m, 7H),]-3-oxogedunin;

1H-NMR (CDCl3d of 0.85 (t, 3H), 1,15-to 1.63 (m, 4H), 2,27-to 2.67 (m, 2H), up 3.22 (d, 2H), 3,71 (s, 3H), 3,85 (t, 1H), 7.23 percent-7,79 (m, 84),

-methyl-2-[[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl] -methyl] -3-oxogedunin;1H-NMR (CDCl3d is 0.84 (t, 3H), 1,12-to 1.61 (m, 4H), 2,18-2,62 (m, 2H), 3,06 (d, 2H), 3,66 (s, 3H), of 3.69 (t, 1H), for 6.81-7,52 (m, 22N), of 7.90 (DD, 1H),

-methyl-2-[(2'-methoxycarbonylmethyl-4-yl)methyl]-3-oxohexanoate.

-methyl-2-[(5'-chloro-2'-methoxycarbonylmethyl-4-yl)methyl] -3-oxogedunin;

-methyl-2-[(2'-tertbutoxycarbonyl-4-yl)methyl]-3-oxogedunin.

Example 5. 6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-one.

To a solution containing 0,37 g CH3ONa in 8 ml of absolute methyl alcohol was added in a nitrogen atmosphere while cooling 0.18 g of pharmamedstore followed was added 0.87 g of methyl 2-[(2'-methoxycarbonylmethyl-4-yl)methyl] -3-exagerate dissolved in 2 ml of absolute methyl alcohol. After stirring for 20 h at room temperature the solvent was evaporated, the residue was regenerated H2O and the pH was brought to 5 with diluted HCl. The aqueous phase was extracted Et2O, and a white solid, which was highlighted on the phase boundary, was filtered. recommended reading:

5-[(2'-methoxycarbonylmethyl-4-yl)methyl]-6-propylpyrimidine-4-one;

6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]-2-methylpyrimidin-4-one (so pl. 144-147oC);

4-benzoyloxymethyl-6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -methylpyrimidin;

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -6-methoxymethyl-2-methylpyrimidin;

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -6-[(4 - ethoxycarbonylphenyl)methoxymethyl]-2-methylpyrimidin;

6-butyl-5-[(2'-cyanobiphenyl-4-yl)methyl]-pyrimidine-4-one;

6-butyl-5-[[(2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl-4-yl]methyl] pyrimidine-4-it;

2-amino-6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-one (so pl. 252-254oC).

6-butyl-2-hikkoshi-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-one;

6-butyl-[(5'-chloro-2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-one;

6-butyl-2-cyanoimino-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] pyrimidine-4-one (so pl. 222-224oC);

6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]-2 - nitroanilide-4-one;

6-butyl-2-methyl-5-[[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4 - yl] methyl]pyrimidine-4-one (so pl. 98-100oC);

2-amino-6-butyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] pyrimidine-4-one (so pl. 234-236oC">

A solution containing 0.5 g of 4-benzoyloxymethyl-6-butyl-2-methyl-5-[(2' -methoxycarbonylmethyl-4-yl)methyl] pyrimidine in 50 ml of ethanol was gidrirovanny in the presence of 0.1 g of 10% palladium on coal at atmospheric pressure and room temperature. After theoretical vodorodovorot the reaction mixture was filtered on celite, and the solvent was evaporated to obtain 0,38 g light oil, which was used directly without further purification (yield 95%).

Example 7. 6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]pyrimidine-4-one.

of 0.13 g of NaOH dissolved in 2 ml of water was added to the solution containing 0.42 g of 6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-it in 10 ml of methanol. After boiling for 24 h with stirring, the solvent was evaporated. The residue was regenerated with water and extracted Et2O. the Aqueous phase was acidified to pH 3. Thus obtained waxy substance was treated with a mixture of H2O:Et2O. After filtration there was obtained 0.35 g of a white solid substance (yield 88% so pl. 197-200oC).

Similarly, there were obtained the following compounds:

5-[(2 carboxyphenyl-4-yl)methyl]-6-propylpyrimidine-4-one;

6-butyl-5-[(2'-carboxamidine ethyl-2-methylpyrimidin;

- 4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -2-methyl-6-ethoxymethyleneamino;

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -6-[(4-carboxyphenyl) methoxymethyl]pyrimidine;

2-amino-6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] pyrimidine-4-one (so pl. 190-195oC);

6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-2-hydroxypyrimidine-4-one;

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -1-[(4-carboxyphenyl) methyl]pyrimidine-6-he (I. pl. 141-144oC);

1-benzyl-4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] pyrimidine-6-he (I. pl. 198-200oC);

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -1-[(4-hydroxyphenyl) methyl]pyrimidine-6-he;

6-butyl-5-[(2'-carboxy-5-chlorobiphenyl-4-yl)methyl]pyrimidine-4-one;

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -6-[(3-carboximide-2-yl)methoxy]-2-methylpyrimidin (so pl. 180-185oC, with decomposition);

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-6-[(3-carboxyphenyl-2-yl)methyl] -2-methylpyrimidin (so pl. 149-152oC)

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-1-[(2-carboxyphenyl) methyl]pyrimidine-6-he (I. pl. 185-187oC).

4-butyl-5-[(2-carboxyphenyl-4-yl)methyl] -1-[(3-carboximide-2-yl) methyl] -2-methylpyrimidin-6-he (I. pl. 175-178oC, with decomposition);

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-1-[(3-carboxyphenyl-2-yl) methyl] -2-meth is l] pyrimidine-6-he (I. pl. 205-208oC);

6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-2 - cyanoaniline-4-one (so pl. 230-232oC);

6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-2-nitroanilide-4-one;

6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -2 - phenylaminopyrimidine-4-one (so pl. 229-231oC);

6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -2 - cyclohexylcarbodiimide-4-one (so pl. 234-236oC).

6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] -2 - methylenedioxyethylamphetamine-4-one (so pl. 179-181oC)

2 aminocarbonyl-6-butyl-5-[(2'-carboxyphenyl-4-yl)methyl] pyrimidine-4-one;

4-butyl-1-[(3-carboximide-2-yl)methyl]-5-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]pyrimidine-6-he (I. pl. 154-156oC);

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

4-butyl-5-[(2'-carboxyphenyl-4-yl)methyl]-6-[[4-carboxyphenyl) methyl]pyrimidine (so pl. 208-211oC)

Example 8. 4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]-1-[(4-ethoxycarbonylphenyl)methyl]pyrimidine-6-he.

0.6 g of 6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-she dissolved in 3 ml of anhydrous DMF, was added to the suspension containing 0.05 g of 80% NaH in 5 ml of anhydrous DMF at paramasivan-4-bromobutyrate, dissolved in 2 ml of anhydrous DMF. After 3 h stirring, the solvent was evaporated and the residue was purified PF (eluent: AcOEt: hexane: 1: 1). There was obtained 0.7 g of light oil (yield 85%);1H-NMR (200 MHz, CDCl3d of 0.91 (t, 3H), 1,15-of 1.65 (m, 4H), 2,62 (t, 2H), 3,62 (s, 3H), 3,91 (s, 3H), of 3.97 (s, 2H), further 5.15 (s, 2H), 7,12-7,52 (m, N), 7,78 (DD, 1H), 7,98-8,10 (m, 2H), 8,07 (s, 1H).

Similarly, there were obtained the following compounds:

1-benzyl-4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-6-he;1H-NMR (CDCl3d of 0.91 (t, 3H), 1,20-of 1.65 (m, 4H), 2,61 (t, 2H), 3,61 (s, 3H), 3,98 (s, 2H), 5,10 (s, 2H), 7,15-7,52 (m, N), 7,78 (DD, 1H), with 8.05 (s, 1H).

4-butyl-1-[(4-hydroxyphenyl)methyl] -5-[(2'-methoxycarbonylmethyl-4-yl)methyl]pyrimidine-6-he,

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -1- [(2-ethoxycarbonylphenyl)methyl] pyrimidine-6-he.1H-NMR (CDCl3d of 0.91 (t, 3H), 1,25-of 1.65 (m, 4H), 2.63 in (t, 2H), 3,61 (s, 3H), 3,91 (s, 3H), of 3.97 (s, 2H), of 5.55 (s, 2H), 7,12-EUR 7.57 (m, 10H), 7,78 (DD, 1H), 8,03 (DD, 1H), 8,15 (s, 1H);

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -1- [(Tien-2-yl)methyl] pyrimidine-6-he;1H-NMR (CDCl3d of 0.96 (t, 3H), 1,15-of 1.65 (m, 4H), 2,60 (t, 2H), 3,62 (s, 3H), 3,98 (s, 2H), 5.25 in (s, 2H), 6.89 in (DD, 1H), 7,08-7,53 (m, N), 7,78 (DD, 1H), 8,08 (s, 1H),

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl]-1-[(3 - methoxycarbonylamino-2-yl)methyl] -2-methylpyrimidin-6-N), for 7.78 (DD, 1H);

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -1- [(3-methoxycarbonylamino-2-yl)methyl] -2-methylpyrimidin-6-he; 1H-NMR (CDCl3d of 0.90 (t, 3H), 1,15-of 1.65 (m, 4H), 2,47 (s, 3H), 2.57 m (t, 2H), 3,61 (s, 3H), 3,88 (s, 3H), 3,98 (s, 2H), 5,69 (s, 2H), 6,9 (d, 1H), 7,12-of 7.55 (m, 8H), 7,78 (DD, 1H);

4-butyl-1-[(2-methoxycarbonylbenzyl)methyl]-2-methyl-5- [[(2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl] methyl]pyrimidine-6-he; 1H-NMR (CDCl3d of 0.91 (t, 3H), 1,15-of 1.65 (m, 4H), of 2.36 (s, 3H), of 2.53 (t, 2H), 3,85 (s, 2H), 3,93 (s, 3H), 5,73 (s, 2H), 6.75 in (DD, 1H), 6,82-7,10 (m, 8H), 7.18 in-of 7.48 (m, N), of 7.75 (DD, 1H), 8,08 (DD, 1H);

4-butyl-1-[(3-methoxycarbonylamino-2-yl)methyl]-2-methyl-5- [[2'-[N-triphenylmethyl-(1-tetrazol-5-yl)] biphenyl-4-yl] methyl]pyrimidine-6-he; 1H-NMR (CDCl3d to 0.88 (t, 3H), 1,20-of 1.65 (m, 4H), to 2.46 (s, 3H), of 2.50 (t, 2H), 3,86 (s, 2H), 3,90 (s, 3H), by 5.87 (s, 2H), 6,80-of 7.55 (m, 24N), 7,88 (DD, 1H),

4-butyl-1-[(3-methoxycarbonylamino-2-yl)methyl] -2-methyl-5- [[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl] methyl] pyrimidine-6-he;1H-NMR (CDCl3d of 0.90 (t, 3H), 1,15-of 1.65 (m, 4H), to 2.46 (s, 3H), of 2.50 (t, 2H),3,86 (s, 2H), 3,88 (s, 3H), to 5.66 (s, 2H), 6,69 (d, 1H), 6,80-of 7.55 (m, N), 7,88 (DD, 1H);

4-butyl-1-[(4-ethoxycarbonylphenyl)methyl] -2-methyl-5-[[2'- [N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-ml] methyl]pyrimidine-6-he;1H-NMR (CDCl3d of 0.91 (t, 3H), 1,15-of 1.65 (m, 4H), of 2.36 (s, 3H), of 2.53 (t, 2H), 3,85 (s, 2H), 3,93 (C,l)methyl]-6-[(4 - ethoxycarbonylphenyl)methoxy]pyrimidine;1H-NMR (CDCl3d of 0.91 (t,3H), 1,20-1,70 (m, 4H), 2,77 (t, 2H), 3,61 (s, 3H), 3,90 (s, 3H), 4,08 (s, 2H), 5,48 (s, 2H), 7,05-of 7.55 (m, N), 8,81 (DD, 1H), 7,93 shed 8.01 (m, 2H), 8,63 (s, 1H);

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -6- [(2-ethoxycarbonylphenyl)methoxy] pyrimidine;1H-NMR (CDCl3d of 0.91 (t, 3H), 1,20-1,70 (m, 4H), 2,77 (t, 2H), to 3.58 (s, 3H), 3,86 (s, 3H), 4.09 to (s, 2H), 5,86 (s, 2H), 7,06-7,56 (m, 10H), 7,78 (DD, 1H), 7,98 (DD, 1H), 8,63 (s, 1H);

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -6- [(3-methoxycarbonylamino-2-yl)methoxy] -2-methylpyrimidin; 1H-NMR (CDCL3d to 0.89 (t, 3H), 1,20-of 1.65 (m, 4H), at 2.59 (s, 3H), 2,71 (t, 2H) and 3.59 (s, 3H), a 3.87 (s, 3H), 4,06 (s, 2H), 5,96 (s, 2H), 7,12-7,52 (m, N), 7,78 (DD, 1H);

4-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -6- [(3-methoxycarbonylamino-2-yl)methoxy] -2-methylpyrimidin; 1-H-NMR (CDCl3d to 0.88 (t, 3H), 1,20-of 1.65 (m, 4H), 2,58 (s, 3H), 2,65 (t, 2H), 3,60 (s, 3H), 3,81 (s, 3H), of 3.96 (s, 2H), 5,71 (s, 2H), 6,72 (d, 1H), 7,02-of 7.55 (m, 8H), 7,78 (DD, 1H);

4-butyl-6-[(4-ethoxycarbonylphenyl)methoxy]-2-methyl-5- [[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl] methyl] pyrimidine;1H-NMR (CDCl3d 0,86 (t, 3H), 1,20-1,70 (m, 4H), of 2.56 (s, 3H), 2,62 (t, 2H), 3,88 (s, 3H), 3,90 (s, 2H), 5,42 (s, 2H), 6,82-7,03 (m, 8H), 7,15-7,52 (m, 17H), a 7.85-of 8.00 (m, 2H);

4-butyl-6-[(2-ethoxycarbonylphenyl)methoxy]-2-methyl-5- [[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl] methyl] pyrimidine;1N-AMRN);

4-butyl-6-[(3-methoxycarbonylamino-2-yl)methoxy] -2-methyl-5- [[2'-[N-triphenylmethyl-(1H-terazol-5-yl)] biphenyl-4-yl] methyl]pyrimidine;1H-NMR (CDCl3d 0,86 (t, 3H), 1,20-1,60 (m, 4H), at 2.59 (s, 3H), 2,61 (t, 2H), 3,85 (s, 3H), 3,93 (s, 2H), to 5.93 (s, 2H), 6,82-of 7.48 (m, 24N), 7,87 (DD, 1H);

4-butyl-6-[(3-methoxycarbonylamino-2-yl)methoxy]-2-methyl-5- [[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl] methyl]pyrimidine; 1H-NMR (CDCl3d 0,86 (t, 3H), 1,20-1,60 (m, 4H), to 2.55 (s, 2H), 2,59 (s, 3H), of 3.80 (s, 3H), 3,85 (s, 2H), 5,69 (s, 2H), 6,70 (d, 1H), 6,80 is 7.50 (m, N), 7,87 (DD, 1H).

Example 9. 6-butyl-5-[(2'(1H-tetrazol-5-yl)biphenyl-4-yl] methyl]pyrimidine-4-one.

Method A.

0.11 g of sodium azide and 0.09 g of ammonium chloride was added under nitrogen atmosphere to a solution containing 0.2 g of di-6-butyl-5-[(2'-cyanobiphenyl-4-yl)methyl] pyrimidine-4-it is in 2 ml of anhydrous DMF. After the interaction for 16 h at 100oC and 60 h at 120oC the reaction mixture was cooled and to it was added the same amount as originally taken the amount of sodium azide and ammonium chloride. Even after 50 h at 120oC solid component was filtered and the solvent was distilled under vacuum. The residue was regenerated with water and extracted AcOEt, the organic phase was dried over Na2SO4

The way Century.

1 ml triperoxonane acid and 1 ml of water were added to the solution containing 0.3 g of 6-butyl-5-[[2'-[N-triphenylmethyl- (1H-tetrazol-5-yl)]biphenyl-4-yl] -methyl] pyrimidine-4-one in 5 ml of THF. After stirring for 24 h at room temperature the reaction mixture was treated with NaOH to neutral, and the solvent was evaporated. The residue was purified PF according to method A. there Was obtained 0.11 g of a white solid substance (yield 60%).

Similarly, there were obtained the following compounds:

- 6-butyl-2-methyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl]-pyrimidine-4-one; (so pl. 238-240oC, with decomposition);

- 1-benzyl-4-butyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-6-he;

4-butyl-1-[(2-carboxyphenyl)methyl] -2-methyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-6-he (I. pl. 193-196oC).

4-butyl-6-[(2-ethoxycarbonylphenyl)methoxy]-2-methyl-5-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine (so pl. 103-105oC);

4-butyl-1-[(3-mykonicaminolta-2-yl)methyl] -2-methyl-5-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidine-6-he (I. pl. 100-105oC);

4-butyl-6-[(3-methoxycarbonylamino-2-yl)methoxy]-2-methyl-5-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine (so pl. 100-105oC);

4-butyl-1-[(3-metaxia reniform-2-yl)methoxy]-2-methyl-5-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine;

4-butyl-1-[(4-carboxyphenyl)methyl] -2-methyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-6-he;

4-butyl-6-[(4-ethoxycarbonylphenyl)methoxy]-2-methyl-5- [[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidine.

Example 10. 6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -2-phenylaminopyrimidine-4-one.

0.27 g of phenylisocyanate was added at 0oC to a solution containing 0.3 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)-methyl]pyrimidine-4-it in 6 ml of dry DMF. After stirring at room temperature for 30 min the mixture was evaporated to dryness and the residue was recrystallized from DMF was obtained 0,22 g of white solid (yield 56% so pl. 217-219oC).

Similarly, there were obtained the following compounds:

6-butyl-2-cyclohexylcarbodiimide-5-[(2'- methoxycarbonylmethyl-4-yl)methyl]pyrimidine-4-one (so pl. 220-222oC)

6-butyl-5-[(2'-methoxycarbonylmethyl-4-yl)methyl] -2 - methylenedioxyethylamphetamine-4-one (so pl. 186-188oC)

2 aminocarbonyl-6-butyl-[(2'-methoxycarbonylmethyl-4-yl) methyl]pyrimidine-4-one.

Example 11. 2-acetylamino-butyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl]pyrimidine-4-one.

10 ml Ac2O was dobavleni Ac2O the solution was evaporated to dryness. The residue was purified PF (eluent: a mixture of CH2Cl2: MeOH: AcOH=89,9:10:10). Received 15 mg of a white solid (yield 32% so pl. 205-208oC).

To illustrate the pharmaceutical compositions of the applicant cites the following examples of specific formulations. In these examples, as the active component used connection on p. 2 formulas, called LR-B/081.

Recipe 1.

Getting pills.

For one portion in 625.0 g to obtain tablets LR-B/081 5 mg, LR-B/081 10 mg, LR-B/081 25 mg, LR-B/081 50 mg, LR-B/081 100 mg or LR-B/081 placebo, you need the following amounts of the ingredients shown in table.1.

These dosage forms get direct pelletizing.

Pharmaceutically active ingredient is pounded into powder with highly dispersed silicon dioxide and lactosaminated and then mixed with other listed ingredients. Tableting is carried out using a Cam for pressing tablets.

In table.2 presents the results of the biological activity of the claimed compounds.

1. Derivatives of pyrimidine of the General formula I

< / BR>
where R is a linear or branched C1Cenil, 2-thienyl, 2-furanyl, optionally substituted C1C4-alkyl, C1C4-alkoxy-, carboxy -, or linear or branched C1- C4-alkoxycarbonyl, where N and X are connected by a double bond, R1not present;

R2H, C1C4-linear or branched alkyl, amino, aryl, where aryl has the specified value, or a group of the General formula NHA, where A C2C7-acyl, CN, NO2, CONHB or CSNHB, where B is H, C1C4-linear or branched alkyl, C3C7-cycloalkyl, aryl as defined above;

R3H;

X WITH or CR4group, where R4may be OR1( where R1must be present and have the values indicated above), aryl, optionally substituted carboxy-, or CH2OR5where R5- H, lower alkyl, arylalkyl, where the aryl part is as defined above;

Z group COOR6-, where R6H or linear or branched C1C4-alkyl, or tetrazol-5-yl General formula

< / BR>
or

< / BR>
where R7H, provided that when X and R1H or phenyl, R2is not H or alkyl,

and farmatsevticheskii acceptable salt.

2. Derived under item 1, differently is kidin-6-it and its pharmaceutically acceptable salts.

3. Derived under item 1, characterized in that a represents a 2-amino-6-butyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4-one and its pharmaceutically acceptable salts.

4. Derived under item 1, characterized in that it is a compound selected from the group of 4-butyl-1-[(3-carboximide-2-yl)methyl]-2-methyl-5-[[2'-(1H-tetrazol-5 - yl)-biphenyl-4-yl] methyl] pyrimidine-6-he; 4-butyl-1-[3-methoxycarbonylamino-2-yl)methyl]-2-methyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl] pyrimidine-6-he, 4-butyl-1-[(3-carboxyphenyl-2-yl)methyl] -2-methyl-5-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl] methyl]pyrimidine-6-he, 4-butyl-1-[(3-methoxycarbonylamino-2-yl)methyl]-2-methyl-5[[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-6-he.

5. Way to obtain the pyrimidine derivatives of General formula 1, characterized in that the compound of General formula II

< / BR>
where R and R3such as defined for General formula I;

R8represents a group OR9(R9methyl or ethyl) or CH2OR5group, where R5is as defined for General formula I;

Y COOR group6(R6C1C4-alkyl) or substituted tetrazol-5-yl group, is subjected to the interaction with the compound of General formula III

< / BR>
where R1and R2as openig pyrimidine of the General formula I, characterized in that the compound of General formula II

< / BR>
where R and R3as defined for General formula I;

R8OR9group (R9methyl or ethyl) or CH2OR5group, where R5as defined for General formula I;

Y COOR group6(R6C1C4-alkyl), CN-group, tetrazol-5-yl group, substituted triphenylmethyl,

subjected to interaction with the compound of General formula III

< / BR>
where R1and R2as defined for General formula I, provided that R1at least N,

obtaining compounds of General formula IV

< / BR>
where R, R1R3as defined above;

Y COOR6group (R6C1C4-alkyl), CN-group,

moreover, the compound of General formula IV is subsequently converted into a compound of General formula I.

7. The pharmaceutical composition exhibiting angiotensin II antagonistic activity, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of the pyrimidine derivative of formula 1 in PP.1 4.

 

Same patents:

The invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to imidazo - annelirovaniya ISO - and heterocyclic compounds, method of their production and to the tools based on them

The invention relates to indole derivative of General formula (l):

(I)

where R and R1such that:

or R and R1the same or different hydrogen atom, a straight or branched lower alkyl, cycloalkyl to 6 carbon atoms;

or R and R1together with the nitrogen atom to which they are bound, form a piperazinil, substituted lower alkyl,

A -:

or chain /CH2/n, where n can take the values 2 or 3,

or circuit< / BR>
X and Y or each a hydrogen atom,

or one hydrogen atom and the other is a hydroxy radical or1-C4-alkyl,

or X and Y together form an oxo radical, a radical alkyltin with 1-4 carbon atoms or a radical N-OR5where R5a hydrogen atom or an alkyl radical with 1-4 carbon atoms, the substituents a, b, c, d such that:

either each hydrogen atom,

or a and b together form a function oxo and C and d are each a hydrogen atom;

Z -:

or a hydrogen atom,

or a moiety of the lower alkyl or the group aminoalkyl formula:

R2NH2,

where R2lowest alkylen;

moreover, these compounds of formula (I) can nachtergaele or organic acids

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to new imidazole derivative of General formula I

where R1-COOH or the group< / BR>
R2=H-C3H7or n-C4H9;

R3-Cl, CF3C2F5C6H5or COOH;

R4-COOH, CHO, or CH2HE, provided that

a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,

b) when R3-COOH, R4also is COOH,

b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine

The invention relates to a method for producing 5-[3(4)-R-1-substituted]pyrimidines of General formula:

< / BR>
where R1, R2= H, lower alkyl, phenyl, substituted SN3, CF3, Cl-group; R3, R4, R5= N, hydroxyalkyl - or amino-group;

which can find wide application in the synthesis of biological active substances in medicine

The invention relates to the field of chemistry and technology of heterocyclic compounds, in particular 2,4,6-triamino-5-nitrosopyrimidine (TAP), which is used as intermediate in obtaining triamterena [1]

The number of known ways to get TARP, which can be divided into two groups

The invention relates to the derivatives of uracil and their use in agriculture, namely use as herbicides

The invention relates to new biologically active compounds derived from 4-oxo-1,4-dihydropyrimidin having antiallergic activity, which can find application in pharmaceutical industry and medicine

-hydroxyethyl)-4,6 - dimethylpyrimidine-2" target="_blank">

The invention relates to chemistry and technology of heterocyclic compounds, pyrimidine series, namely 4,6-dimethyl-N-(-oxyethyl)-2-oxo-1,2-dihydropyrimidine, which is called ksimedon recommended for use in medicine as a burn-drug immune action [1]

A known method of producing Ximena [2] consisting in the conversion of the hydrochloride of 2-hydroxy-4,6-dimethylpyrimidine sodium salt of 2-hydroxy-4,6-dimethylpyrimidine, when heated, which ethylenchlorhydrine received ksimedon

The invention relates to an improved method of producing chlorinol containing o-hydroxyphenyl group, of General formula I-III I

< / BR>
where Ia 4-CL; 2-o-HOC6H6; R = 6-CH3< / BR>
IB 4-CL; 2-o-HOC6H4; R = 6-CF3< / BR>
IB 4-Cl; 2-o-HOC6H4; R = 6-C6H5< / BR>
Iك 4-Cl; 2-o-HOC6H4; R = 5-CN

Ia 4-Cl; 2-o-HOC6H4; R = 5-COOC2H5< / BR>
Ie 4-Cl; 2-o-HOC6H4; R = 5-C6H5< / BR>
If 4-Cl; 2-o-HOC6H4; R = H

Z 4-Cl; 6-o-HOC6H4; R = H

AI 2-Cl; 4-o-HOC6H4; R = H

IC 2-Cl; 4-o-HOC6H4; R = 6-C6H5< / BR>
IIa R = H

IIb R = 4' -OC3H7< / BR>
IIb R = 5' -Br

G R = 5' -NO2< / BR>
D R = 3' , 5' -Cl2< / BR>
IIIa R = H is used as intermediate products in the synthesis of universal stabilizers for polyethylene, i.e

The invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to new biologically active compounds derived amide alanovoy acid, three different methods for their preparation, herbicide composition and method for killing weeds that may find application in agriculture

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

The invention relates to optically active compounds as components of ferroelectric liquid crystal materials (LCD monitor) recording devices for optical display of information, and modulation of radiation
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