CA1152074A - Pyrimidyl thioureas - Google Patents
Pyrimidyl thioureasInfo
- Publication number
- CA1152074A CA1152074A CA000376557A CA376557A CA1152074A CA 1152074 A CA1152074 A CA 1152074A CA 000376557 A CA000376557 A CA 000376557A CA 376557 A CA376557 A CA 376557A CA 1152074 A CA1152074 A CA 1152074A
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- methoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
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- Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF DISCLOSURE
Pyrimidyl thioureas of the formula (I) wherein R1, R2, and R3 individually represent hydrogen, halogen, a linear or branched alkoxy group, or a linear or branched alkyl group, said groups having 1 to 8 carbon atoms, and their pharmaceutically acceptable salts. These compounds are useful for the treatment of hyperlipidemia and hypertension.
Compositions containing these compounds as well as methods of use and preparation thereof are also disclosed.
Pyrimidyl thioureas of the formula (I) wherein R1, R2, and R3 individually represent hydrogen, halogen, a linear or branched alkoxy group, or a linear or branched alkyl group, said groups having 1 to 8 carbon atoms, and their pharmaceutically acceptable salts. These compounds are useful for the treatment of hyperlipidemia and hypertension.
Compositions containing these compounds as well as methods of use and preparation thereof are also disclosed.
Description
~LS;2(~'74 ; The present application is directed to certain thioureas, their use as pharmaceuticals, and methods of preparation thereof. More specifically, it has been found that certain compounds falling within the foregoing class possess excellent hypolipidemic and hypotensive characteristics.
I
The compounds of the present invention are represented by the formula ~ (I) ~3 ~ ~-C~
wherein Rl, R2, and R3 are individually hydrogen, halogen, linear or branched alkoxy groups, or linear or branched alkyl groups. The alkoxy and alkyl groups, in the broadest scope of the invention, have 1 to 8 carbon atoms. In a more preferred form c,f the invention, each of these groups contains 1 to 4 carbon atoms. Pharmaceutically acceptable salts of these basic compounds are also suitable.
Preferred are compounds of Eormula I, wherein R , R and R3 are alkoxy groups and/or alkyl groups, especially preferred alkoxy groups are methoxy groups and ethoxy groups, especially methoxy groups. Especially preferred alkyl groups are methyl groups and ethyl groups, especially methyl groups. Preferably two of the substituents are alkoxy groups and the third substituent is hydrogen or an alkoxy group.
It has been found that the cholesterol lowering and tri-glyceride reducing effects in hyperlipidemic mice can be achieved in a dosage range of 1 to 300 mg/kg of body weight.
It has been found that the new compounds possess both stronger
I
The compounds of the present invention are represented by the formula ~ (I) ~3 ~ ~-C~
wherein Rl, R2, and R3 are individually hydrogen, halogen, linear or branched alkoxy groups, or linear or branched alkyl groups. The alkoxy and alkyl groups, in the broadest scope of the invention, have 1 to 8 carbon atoms. In a more preferred form c,f the invention, each of these groups contains 1 to 4 carbon atoms. Pharmaceutically acceptable salts of these basic compounds are also suitable.
Preferred are compounds of Eormula I, wherein R , R and R3 are alkoxy groups and/or alkyl groups, especially preferred alkoxy groups are methoxy groups and ethoxy groups, especially methoxy groups. Especially preferred alkyl groups are methyl groups and ethyl groups, especially methyl groups. Preferably two of the substituents are alkoxy groups and the third substituent is hydrogen or an alkoxy group.
It has been found that the cholesterol lowering and tri-glyceride reducing effects in hyperlipidemic mice can be achieved in a dosage range of 1 to 300 mg/kg of body weight.
It has been found that the new compounds possess both stronger
- 2 - ~r~
" ~ s2(~
hypolipidemic effects and reduced toxicity, especially when compared with such known drugs as clofibrate. This is particularly true for those compounds wherein Kl and R~ are alkoxy and R3 is hydrogen.
In addition to the foregoing, these compounds exhibit valuable anti-hypertensive properties. In hypertensive rats, ' a dose of 1 to 30 mg/kg p~oduced these therapeutlc effects and no central side efEects. Similarly, the alpha-receptor bloc~ade, which is undesirable because of annoying accompany-ing effects, was also absent.
Hence, the compounds of the present invention are suitable for humans for the treatment of hyperlipidemia and/or diseases of the cardiac-circulatory system, especially hypertension.
The daily dose is between 10 and 1000 mg/person and it is preferab y given two to four times a day in amounts of 5 to 1 500 mg/person. Alternatively, it can be given with advantage ! once a day in a time-release form. The preferred daily dose is from 50 to 300 mg per person.
- By a suitable selection of Rl, R2, and R3, the therapeutic effect can be influenced so that either the hypolipidemic or hypotensive property predominates. The 'O following are examples of compounds according to the presentinvention which exhibit the desirable therapeutic effects:
N-(4,6-dimethoxy-5-pyrimidyl)-thiourea N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea N-(4-isopropoxy-6-methoxy-5-pyrimidyl)-thiourea N-(4-butoxy-6-methoxy-5-pyrimidyl)-thiourea N-(4,6-diethoxy-5-pyrimidyl)-thiourea N-(4,6-dibutoxy-5-pyrimidyl)-thiourea N-(4-methoxy-6-methyl-5-pyrimidyl)-thiourea i2U7~
N-(4,6-dimethyl-5-pyrimidyl)-thi~urea N-t2,4-dimethoxy-5-pyrimidyl)-thiourea N-(2-chloro-4-methyl-5-pyrimidyl)-thiourea N-(2-ethoxy-4-methoxy-5-pyrimidyl)-thiourea N-(2,4-diethoxy-5-pyrimidyl)-thiourea N-(2,4-diisopropoxy-5-pyrimidyl)-thiourea N-(4-methoxy-2-methyl-5-pyrimidyl)-thiourea N-(2-methyl-4-propoxy-5-pyrimidyl)-thiourea N-(2-methyl-5-pyrimidyl)-thiourea N-(2-isopropyl-5-pyrimidy:L)-thiourea N-(4-methyl-5-pyrimidyl3-lhiourea N-(4-ethyl-5-pyrimidyl)-thiourea N-(4-butyl-5-pyrimidyl)-thiourea N-(2-methoxy-5-pyrimidyl)--thiourea N-(4-methoxy-5-pyrimidyl)-thiourea N-(4-ethoxy-5-pyrimidyl)-thiourea N-(4-propoxy-5-pyrimidyl)-thiourea N-(4-isopropoxy-5-pyrimidyl)-thiourea N-(4-butoxy-5-pyrimidyl)-t:hiourea N-(5-pyrimidyl)-thiourea N-(2,4,6-trimethoxy-5-pyri.midyl)-thiourea N-(2,4,6-trimethyl-5-pyrimidyl)-thiourea N-(2,4-dimethoxy-6-methyl--5-pyrimidyl)-thiourea N-(2,4-diethoxy-6-methyl-S-pyrimidyl)-thiourea N-(4,6-dimethoxy-2-methyl--5-pyrimidyl)-thiourea N-(4,6-dimethoxy-2-isopropyl-5-pyrimidyl)-thiourea N-(4-ethoxy-6-methoxy-2-methyl-5-pyrimidyl)-thiourea N-(4-ethoxy-2-ethyl-6-methoxy-5-pyrimidyl)-thiourea N-(2-butyl-4-methoxy-6-propoxy-5-pyrimidyl)-thiourea __ .
30 . N-(2-chloro-4-methyl-6-melhoxy-5-pyrimidyl)-thiourea N-(2-chloro-4-propyl-6-isopropoxy-5-pyrimidyl)-thiourea ~:lSZ0~4 N-(4-chloro-6-methoxy-2-methyl-5-pyrimidyl)-thiourea N-(4-chloro-6-ethoxy-2-isopropyl-5--pyrimidyl)-thiourea N-(4-methoxy-6-pentyloxy-5-pyrimidyl)-thiourea N-(4-methoxy-2-t.-pentyl-5-pyrimidyl)-thiourea N-(2-methoxy-4-penty]oxy-5-pyrimidyl)-thiourea N-(4,6-dihexyloxy-5-pyrimidyl)-thiourea N-(2-heptyl-4-methoxy-5-pyrimidyl)-thiourea N-(4-heptyloxy-2-pentyl-5-pyrimidyl)-thiourea N-(2-chloro-4-methyl-6-octyloxy-5-pyrimidyl)-thiourea lû N-(2-octyl-4-methyl-6-heptoxy-5-pyrimidyl)-thiourea N-(2-bromo-4-methyl-6-methoxy-5-pyrimidyl)-thiourea Especially suitable compounds are N-(4,6-dimethoxy-5-pyrimidyl)-thiourea; N-(2,4-dimethoxy-5-pyrimidyl)-thiourea;
N-(4,6-dimethoxy-2-methyl-5-pyrimidyl)-thiourea, and N-(4,6-diethoxy-5-pyrimidyl)-thiourea. These compounds exhibit both desirable effects.
The use of the usual derivatives, as well as suitable diluents, adjuvants, or vehicles is also contemplated.
Administration can be oral or parenteral. The compounds can take the form of tablets, pillr,, syrups, suspensions, and liquids for oral adminstration. When administered parenterally, they should be provided as solutions or suspensions.
. .
The tablets may contain additives, adjuvants, granulating agents, aids to disintegration, binders, lubricants, etc. The nature of these materials is generally known and need not be expressly set forth here.
~152U7~
The tablets can also be coated in order to delay disintegration and absorption in the gastro-intestinal tract.
In this manner, the effectiveness of the active ingredient can be extended over a long period of time. The pharmaceutical preparations can advantageously contain the active ingredient in an amount of 0.1 to 90/0, preferably l.O to 90~/0. The balance being usually a vehicle or adjuvant. For ease of manufacture and administration, the solid forms (such as tablets and capsules) are preferred. Such preparations can contain the active substance in an amount of 50 to 300 mg, corresponding to the preferred daily dose.
The compounds of the present invention can be prepared from aminopyrimidines of the formula (II) ~2 .. .. .. . .
by reaction with benzoylisothiocyanate, whereby the corresponding benzoylthioureas are obtained which are then hydrolized to produce the desired compound. The benzoylisothiocyanate can be obtained from ammonium thiocyanate and benzoyl chloride.
~lsza74 - In a preferred method of preparing the com~ounds of the present invention, the ammonium thiocyanate, benzoyl chloride, and aminopyrimidine are reacted together in an organic solvent under heating. The solvent is preferably boiling acetone. It is preferred to carry out the reaction from ambient temperature to the boilin~ point of the solvent over a period of 30 minutes to 3 hours, preferably 30 minutes to 1 hour. The reaction mixture is then introduced into water and the reaction product is extracted with a solvent which is immiscible with water, preferably chloroform. The thiourea derivatives obtained are then hydrolized, e.g. in the presence of bases and, if necessary, with heating in order to separate the benzoyl radical. Suitable bases are dilute lye and sodium methylate solution.
The aminopyrimidines used as starting materials are either known or obtainable in a known manner from available starting materials (see D. J. Brown, "The Pyrimidines", 1962 Interscience Publishers).
In the thioureas of the present invention wherein Rl and R2 are alkoxy (preferably methoxy), and R3 has the usual meaning, a new alkoxy radical can be introduced by reacting with a corresponding alcoholate. This reaction is preferably carried out with equimolar amounts of sodium alcoholate in an alcohol which corresponds to the alcoholate. It is desirable to carry out the reaction at an elevated temperature, preferably at the boiling temperature of the alcohol. In this manner the compounds of the present invention wherein Rl and R are alkoxy radicals which may be different from each other can be formed.
~15Z(~7~
Alkoxypyrimidines can be obtained from halopyrimidines by reaction with alcoholate in a suitable solvent. It is preEerred that the solvent be an alcohol correspondinK to the alcoholate. If a plurality of halogen atoms is present on the nucleus, either one or more can be substituted by the corresponding alkoxy groups by a suitable selection of reaction conditions, particularly the concentration of alcoholate and reaction temperature. The process is most suitable for those compounds wherein the halogen is chlorine. It is also possible to introduce different alkoxy groups successively and the reactions can generally be carried out with both the halo-5-nitropyrimidines and with halo-5-aminopyrimidines.
The chlorine atoms which are linked to the pyrimidine ring can be separated by catalytic hydration in the presence of a base. The removal of such atoms can also be effected by reacting corresponding chloropyrimidines with hydrazine, followed by separation of the hydrazine group with silver (I) oxide. The hydrazine reaction is preferably carried out in a suitable solvent tespecially methanol or ethanol~, at temperatures between 0C and the boiling point of the solvent.
The reaction with silver (I) oxi~e is also carried out under the same general conditions.
Chloronitropyrimidines of the formula Cl Rc- ~ ~ No2 (III) ~ ~ .
:
li52(~7~
can be obtained from hydroxypyrimidines of the fornlula C~
~ (IV) wherein Rl and R2 are hydrogen, halogen, hydroxy, or alkyl or alkoxy groups with l to 8 carbon atoms each, by reaction with a suitable chlorinating agent. The most preferred process uses phosphoroxy trichloride in the presence of a tertiary amine, such as diethylene aniline. These reactions are most preferably carried out without solvents at an elevated temperature.
The substituted nitropyrimidines can be converted to the aminopyrimidines of Formula II by catalytic hydration in the presence of Raney nickel at a pressure of 1 to lO bar.
Alcohols can be used as the solvent, and methanol is preferable. The reaction temperature is from room temperature to approximately 50C.
The following examples are intended to illustrate the preparation of compounds according to the present invention.
llS2(~74 Preparation Example 1 ~-(4,6-dimethoxy-5-pyrimidyl)-thiourea.
(a) 200 g 4,6-dihydroxypyrimidine are introduced at 15 to 20C into a mixture of 720 ml glacial acetic acid and 230 ml nitric acid (96%). The mixture is stirred for 30 minutes, after which it is poured over ice. The precipitate formed is removed, washed with ice water, and subsequently dried at 80C. Yield: 254 g 4,6-dihydroxy-5-nitropyrimidine.
M.P. > 300C.
(b) 135 g of the product of (a) are stirrèd into 440 ml phosphoroxy-trichloride. Then 160 ml N,N-diethylaniline are added slowly over a period of 1 hour at 120C. Subsequently, the excess phosphoroxy-trichloride is distilled off, the residue is poured over ice, and the precipitate obtained is filtered of~. The precipitate is taken up in some water and stirred, after which it is neutralized with soaium bicarbonate. The residue is filtered off and it is boiled with 500 ml cyclohexane. The clear solution obtained is poured off from the undissolved residue to isolate the reaction product, and evaporated. After drying, 131 g 4,6-dichloro-5-nitropyrimidine are obtained. M.P. 103C.
(c) Into a solution of 62lg NaOH in 1200 ml methanol are introduced 120 g of the product of (b). After heating under reflux for 1 hour, the reaction product is cooled and placed in '5 3 liters of water. The crystals obtained are filtered off and dried. 87 g 4,6-dimethoxy-5-nitropyrimidine having a melting point of 168 to 170C is obtained.
_J
llSZ(~7~
(d) 125 g of the product of (c) are dissolved in 1.5 liters ethanol and hydrated in a refined steel autoclave for 5 hours in the presence of 40 g Raney nickel at 2.5 bar. lhe catalyst is filtered off and the filtrate concentrated. 88 g 5-amino-4,6-dimethoxy-pyrimidine are obtained. I~.P. 94 to 96C.
(e) To a solution of 12.9 g ammonium thiocyanate in 120 ml anhydrous acetone are added slowly in drops 25.3 g benzoyl chloride. The mixture is heated for 5 minutes under reflux, and 27 g 5-amino-4,6-dimethoxy-pyrimidine, dissolved in 50 ml acetone, are added in drops. The boiling is continued for another hour under reflux. The mixture is then cooled and placed in 1.5 liters water. Subsequently, it is extracted with chloroform, and dried over magnesium sulfate. After distilling off the chloroform, the residue is triturated with ether and vacuum tleated. Yield: 34 g (61~/o) N-benzoyl-N'-(4,6-dimethoxy-5-pyrimidyl)-thiourea. ~I.P. 193C.
(f) 34 g of the N-benzoyl thiourea derivative thus obtained are boiled for 5 minutes in 30 ml of ~0% NaOH. After cooling, the mixture is acidified with concentrated HCl and adjusted to a pH of 9 with 15% aqueous ammonia solution. The precipitated crystals are vacuum treated and washed with water. 16 g (70%) N-(4,6-dimethoxy-5-pyrimidyl)-thiourea are obtained. M.P. 214C.
-. .
- l~SZ(~7~
.
Preparation Example 2 N-(4-methoxy-5-pyrimidyl)-thiourea.
(a) 100 g 5-nitro 4,6-dichloropyrimidine are heated in 1000 ml sodium ethylate solution (16.8 g sodium) for 10 hours to 50C. Then the reaction mixture is evaporated under vacuum and the residue is stirred with water and vacuum treated.
Subsequently, it is extracted several times with hot petroleum ether (boiling range 40 to 60C). After cooling, the crystals are vacuum treated and dried. 46 g 4-chloro-6-methoxy-5-nitro-pyrimidine are obtained having a melting point of 65C.
(b) 15 g 4-chloro-6-methoxy-5-nitropyrimidine are dissolved in 600 ml ethanol. Then 8.1 ml hydrazine hydrate in 150 ml ethanol are added in drops at -8C. After one hour the crystals obtained are vacuum treated and dried.
Yield: 14.5 g 4-hydrazino-6-methoxy-5-nitropyrimidine, M.P. 155C.
(c) 14 g 4-hydrazino-6-methoxy-5-nitropyrimidine are dissolved in 3.6 liters of methanol and stirred for 10 hours at 40C with 61.9 g of freshly prepared silver (I) oxide. Then the mixture is filtered and the solution evaporated. 10.5 g 4-methoxy-5-nitropyrimidine with a melting point of 193 to 195C is obtained.
1~52(~74 (d) lO g 4-methoxy-5-nitropyrimidine in 5U0 ml meLhanol are hydrated for 2.5 hours at 2 bar in the presence of 4.5 g Raney nickel. After filtration, the solution is concentrate~.
8.0 g 5-amino-4-methoxypyrimidine havin~ a melting point of 71 to 74C are obtained.
(e) Similar to Example l, N-benzoyl-N'-(4-methoxy-5-pyrimidyl)-thiourea is prepared from 5-amino-4-methoxypyrimidine.
(f) 6.0 g N-benzoyl-Nl-(4-methoxy-5-pyrimidyl)-thiourea are dissolved in 120 ml sodium ethylate solution (0.8 g sodium). After 1 hour, the solution is neutralized with diluted hydrochloric acid. The mixture is concentrated and the residue is washed with water and recrystallized from a methanol/water mixture. 2.3 g N-(4-methoxy-5-pyrimidyl)-thiourea having a melting point of 18~ to 183C (decomp.) are obtained.
Preparation Example 3 N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea.
" ~ s2(~
hypolipidemic effects and reduced toxicity, especially when compared with such known drugs as clofibrate. This is particularly true for those compounds wherein Kl and R~ are alkoxy and R3 is hydrogen.
In addition to the foregoing, these compounds exhibit valuable anti-hypertensive properties. In hypertensive rats, ' a dose of 1 to 30 mg/kg p~oduced these therapeutlc effects and no central side efEects. Similarly, the alpha-receptor bloc~ade, which is undesirable because of annoying accompany-ing effects, was also absent.
Hence, the compounds of the present invention are suitable for humans for the treatment of hyperlipidemia and/or diseases of the cardiac-circulatory system, especially hypertension.
The daily dose is between 10 and 1000 mg/person and it is preferab y given two to four times a day in amounts of 5 to 1 500 mg/person. Alternatively, it can be given with advantage ! once a day in a time-release form. The preferred daily dose is from 50 to 300 mg per person.
- By a suitable selection of Rl, R2, and R3, the therapeutic effect can be influenced so that either the hypolipidemic or hypotensive property predominates. The 'O following are examples of compounds according to the presentinvention which exhibit the desirable therapeutic effects:
N-(4,6-dimethoxy-5-pyrimidyl)-thiourea N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea N-(4-isopropoxy-6-methoxy-5-pyrimidyl)-thiourea N-(4-butoxy-6-methoxy-5-pyrimidyl)-thiourea N-(4,6-diethoxy-5-pyrimidyl)-thiourea N-(4,6-dibutoxy-5-pyrimidyl)-thiourea N-(4-methoxy-6-methyl-5-pyrimidyl)-thiourea i2U7~
N-(4,6-dimethyl-5-pyrimidyl)-thi~urea N-t2,4-dimethoxy-5-pyrimidyl)-thiourea N-(2-chloro-4-methyl-5-pyrimidyl)-thiourea N-(2-ethoxy-4-methoxy-5-pyrimidyl)-thiourea N-(2,4-diethoxy-5-pyrimidyl)-thiourea N-(2,4-diisopropoxy-5-pyrimidyl)-thiourea N-(4-methoxy-2-methyl-5-pyrimidyl)-thiourea N-(2-methyl-4-propoxy-5-pyrimidyl)-thiourea N-(2-methyl-5-pyrimidyl)-thiourea N-(2-isopropyl-5-pyrimidy:L)-thiourea N-(4-methyl-5-pyrimidyl3-lhiourea N-(4-ethyl-5-pyrimidyl)-thiourea N-(4-butyl-5-pyrimidyl)-thiourea N-(2-methoxy-5-pyrimidyl)--thiourea N-(4-methoxy-5-pyrimidyl)-thiourea N-(4-ethoxy-5-pyrimidyl)-thiourea N-(4-propoxy-5-pyrimidyl)-thiourea N-(4-isopropoxy-5-pyrimidyl)-thiourea N-(4-butoxy-5-pyrimidyl)-t:hiourea N-(5-pyrimidyl)-thiourea N-(2,4,6-trimethoxy-5-pyri.midyl)-thiourea N-(2,4,6-trimethyl-5-pyrimidyl)-thiourea N-(2,4-dimethoxy-6-methyl--5-pyrimidyl)-thiourea N-(2,4-diethoxy-6-methyl-S-pyrimidyl)-thiourea N-(4,6-dimethoxy-2-methyl--5-pyrimidyl)-thiourea N-(4,6-dimethoxy-2-isopropyl-5-pyrimidyl)-thiourea N-(4-ethoxy-6-methoxy-2-methyl-5-pyrimidyl)-thiourea N-(4-ethoxy-2-ethyl-6-methoxy-5-pyrimidyl)-thiourea N-(2-butyl-4-methoxy-6-propoxy-5-pyrimidyl)-thiourea __ .
30 . N-(2-chloro-4-methyl-6-melhoxy-5-pyrimidyl)-thiourea N-(2-chloro-4-propyl-6-isopropoxy-5-pyrimidyl)-thiourea ~:lSZ0~4 N-(4-chloro-6-methoxy-2-methyl-5-pyrimidyl)-thiourea N-(4-chloro-6-ethoxy-2-isopropyl-5--pyrimidyl)-thiourea N-(4-methoxy-6-pentyloxy-5-pyrimidyl)-thiourea N-(4-methoxy-2-t.-pentyl-5-pyrimidyl)-thiourea N-(2-methoxy-4-penty]oxy-5-pyrimidyl)-thiourea N-(4,6-dihexyloxy-5-pyrimidyl)-thiourea N-(2-heptyl-4-methoxy-5-pyrimidyl)-thiourea N-(4-heptyloxy-2-pentyl-5-pyrimidyl)-thiourea N-(2-chloro-4-methyl-6-octyloxy-5-pyrimidyl)-thiourea lû N-(2-octyl-4-methyl-6-heptoxy-5-pyrimidyl)-thiourea N-(2-bromo-4-methyl-6-methoxy-5-pyrimidyl)-thiourea Especially suitable compounds are N-(4,6-dimethoxy-5-pyrimidyl)-thiourea; N-(2,4-dimethoxy-5-pyrimidyl)-thiourea;
N-(4,6-dimethoxy-2-methyl-5-pyrimidyl)-thiourea, and N-(4,6-diethoxy-5-pyrimidyl)-thiourea. These compounds exhibit both desirable effects.
The use of the usual derivatives, as well as suitable diluents, adjuvants, or vehicles is also contemplated.
Administration can be oral or parenteral. The compounds can take the form of tablets, pillr,, syrups, suspensions, and liquids for oral adminstration. When administered parenterally, they should be provided as solutions or suspensions.
. .
The tablets may contain additives, adjuvants, granulating agents, aids to disintegration, binders, lubricants, etc. The nature of these materials is generally known and need not be expressly set forth here.
~152U7~
The tablets can also be coated in order to delay disintegration and absorption in the gastro-intestinal tract.
In this manner, the effectiveness of the active ingredient can be extended over a long period of time. The pharmaceutical preparations can advantageously contain the active ingredient in an amount of 0.1 to 90/0, preferably l.O to 90~/0. The balance being usually a vehicle or adjuvant. For ease of manufacture and administration, the solid forms (such as tablets and capsules) are preferred. Such preparations can contain the active substance in an amount of 50 to 300 mg, corresponding to the preferred daily dose.
The compounds of the present invention can be prepared from aminopyrimidines of the formula (II) ~2 .. .. .. . .
by reaction with benzoylisothiocyanate, whereby the corresponding benzoylthioureas are obtained which are then hydrolized to produce the desired compound. The benzoylisothiocyanate can be obtained from ammonium thiocyanate and benzoyl chloride.
~lsza74 - In a preferred method of preparing the com~ounds of the present invention, the ammonium thiocyanate, benzoyl chloride, and aminopyrimidine are reacted together in an organic solvent under heating. The solvent is preferably boiling acetone. It is preferred to carry out the reaction from ambient temperature to the boilin~ point of the solvent over a period of 30 minutes to 3 hours, preferably 30 minutes to 1 hour. The reaction mixture is then introduced into water and the reaction product is extracted with a solvent which is immiscible with water, preferably chloroform. The thiourea derivatives obtained are then hydrolized, e.g. in the presence of bases and, if necessary, with heating in order to separate the benzoyl radical. Suitable bases are dilute lye and sodium methylate solution.
The aminopyrimidines used as starting materials are either known or obtainable in a known manner from available starting materials (see D. J. Brown, "The Pyrimidines", 1962 Interscience Publishers).
In the thioureas of the present invention wherein Rl and R2 are alkoxy (preferably methoxy), and R3 has the usual meaning, a new alkoxy radical can be introduced by reacting with a corresponding alcoholate. This reaction is preferably carried out with equimolar amounts of sodium alcoholate in an alcohol which corresponds to the alcoholate. It is desirable to carry out the reaction at an elevated temperature, preferably at the boiling temperature of the alcohol. In this manner the compounds of the present invention wherein Rl and R are alkoxy radicals which may be different from each other can be formed.
~15Z(~7~
Alkoxypyrimidines can be obtained from halopyrimidines by reaction with alcoholate in a suitable solvent. It is preEerred that the solvent be an alcohol correspondinK to the alcoholate. If a plurality of halogen atoms is present on the nucleus, either one or more can be substituted by the corresponding alkoxy groups by a suitable selection of reaction conditions, particularly the concentration of alcoholate and reaction temperature. The process is most suitable for those compounds wherein the halogen is chlorine. It is also possible to introduce different alkoxy groups successively and the reactions can generally be carried out with both the halo-5-nitropyrimidines and with halo-5-aminopyrimidines.
The chlorine atoms which are linked to the pyrimidine ring can be separated by catalytic hydration in the presence of a base. The removal of such atoms can also be effected by reacting corresponding chloropyrimidines with hydrazine, followed by separation of the hydrazine group with silver (I) oxide. The hydrazine reaction is preferably carried out in a suitable solvent tespecially methanol or ethanol~, at temperatures between 0C and the boiling point of the solvent.
The reaction with silver (I) oxi~e is also carried out under the same general conditions.
Chloronitropyrimidines of the formula Cl Rc- ~ ~ No2 (III) ~ ~ .
:
li52(~7~
can be obtained from hydroxypyrimidines of the fornlula C~
~ (IV) wherein Rl and R2 are hydrogen, halogen, hydroxy, or alkyl or alkoxy groups with l to 8 carbon atoms each, by reaction with a suitable chlorinating agent. The most preferred process uses phosphoroxy trichloride in the presence of a tertiary amine, such as diethylene aniline. These reactions are most preferably carried out without solvents at an elevated temperature.
The substituted nitropyrimidines can be converted to the aminopyrimidines of Formula II by catalytic hydration in the presence of Raney nickel at a pressure of 1 to lO bar.
Alcohols can be used as the solvent, and methanol is preferable. The reaction temperature is from room temperature to approximately 50C.
The following examples are intended to illustrate the preparation of compounds according to the present invention.
llS2(~74 Preparation Example 1 ~-(4,6-dimethoxy-5-pyrimidyl)-thiourea.
(a) 200 g 4,6-dihydroxypyrimidine are introduced at 15 to 20C into a mixture of 720 ml glacial acetic acid and 230 ml nitric acid (96%). The mixture is stirred for 30 minutes, after which it is poured over ice. The precipitate formed is removed, washed with ice water, and subsequently dried at 80C. Yield: 254 g 4,6-dihydroxy-5-nitropyrimidine.
M.P. > 300C.
(b) 135 g of the product of (a) are stirrèd into 440 ml phosphoroxy-trichloride. Then 160 ml N,N-diethylaniline are added slowly over a period of 1 hour at 120C. Subsequently, the excess phosphoroxy-trichloride is distilled off, the residue is poured over ice, and the precipitate obtained is filtered of~. The precipitate is taken up in some water and stirred, after which it is neutralized with soaium bicarbonate. The residue is filtered off and it is boiled with 500 ml cyclohexane. The clear solution obtained is poured off from the undissolved residue to isolate the reaction product, and evaporated. After drying, 131 g 4,6-dichloro-5-nitropyrimidine are obtained. M.P. 103C.
(c) Into a solution of 62lg NaOH in 1200 ml methanol are introduced 120 g of the product of (b). After heating under reflux for 1 hour, the reaction product is cooled and placed in '5 3 liters of water. The crystals obtained are filtered off and dried. 87 g 4,6-dimethoxy-5-nitropyrimidine having a melting point of 168 to 170C is obtained.
_J
llSZ(~7~
(d) 125 g of the product of (c) are dissolved in 1.5 liters ethanol and hydrated in a refined steel autoclave for 5 hours in the presence of 40 g Raney nickel at 2.5 bar. lhe catalyst is filtered off and the filtrate concentrated. 88 g 5-amino-4,6-dimethoxy-pyrimidine are obtained. I~.P. 94 to 96C.
(e) To a solution of 12.9 g ammonium thiocyanate in 120 ml anhydrous acetone are added slowly in drops 25.3 g benzoyl chloride. The mixture is heated for 5 minutes under reflux, and 27 g 5-amino-4,6-dimethoxy-pyrimidine, dissolved in 50 ml acetone, are added in drops. The boiling is continued for another hour under reflux. The mixture is then cooled and placed in 1.5 liters water. Subsequently, it is extracted with chloroform, and dried over magnesium sulfate. After distilling off the chloroform, the residue is triturated with ether and vacuum tleated. Yield: 34 g (61~/o) N-benzoyl-N'-(4,6-dimethoxy-5-pyrimidyl)-thiourea. ~I.P. 193C.
(f) 34 g of the N-benzoyl thiourea derivative thus obtained are boiled for 5 minutes in 30 ml of ~0% NaOH. After cooling, the mixture is acidified with concentrated HCl and adjusted to a pH of 9 with 15% aqueous ammonia solution. The precipitated crystals are vacuum treated and washed with water. 16 g (70%) N-(4,6-dimethoxy-5-pyrimidyl)-thiourea are obtained. M.P. 214C.
-. .
- l~SZ(~7~
.
Preparation Example 2 N-(4-methoxy-5-pyrimidyl)-thiourea.
(a) 100 g 5-nitro 4,6-dichloropyrimidine are heated in 1000 ml sodium ethylate solution (16.8 g sodium) for 10 hours to 50C. Then the reaction mixture is evaporated under vacuum and the residue is stirred with water and vacuum treated.
Subsequently, it is extracted several times with hot petroleum ether (boiling range 40 to 60C). After cooling, the crystals are vacuum treated and dried. 46 g 4-chloro-6-methoxy-5-nitro-pyrimidine are obtained having a melting point of 65C.
(b) 15 g 4-chloro-6-methoxy-5-nitropyrimidine are dissolved in 600 ml ethanol. Then 8.1 ml hydrazine hydrate in 150 ml ethanol are added in drops at -8C. After one hour the crystals obtained are vacuum treated and dried.
Yield: 14.5 g 4-hydrazino-6-methoxy-5-nitropyrimidine, M.P. 155C.
(c) 14 g 4-hydrazino-6-methoxy-5-nitropyrimidine are dissolved in 3.6 liters of methanol and stirred for 10 hours at 40C with 61.9 g of freshly prepared silver (I) oxide. Then the mixture is filtered and the solution evaporated. 10.5 g 4-methoxy-5-nitropyrimidine with a melting point of 193 to 195C is obtained.
1~52(~74 (d) lO g 4-methoxy-5-nitropyrimidine in 5U0 ml meLhanol are hydrated for 2.5 hours at 2 bar in the presence of 4.5 g Raney nickel. After filtration, the solution is concentrate~.
8.0 g 5-amino-4-methoxypyrimidine havin~ a melting point of 71 to 74C are obtained.
(e) Similar to Example l, N-benzoyl-N'-(4-methoxy-5-pyrimidyl)-thiourea is prepared from 5-amino-4-methoxypyrimidine.
(f) 6.0 g N-benzoyl-Nl-(4-methoxy-5-pyrimidyl)-thiourea are dissolved in 120 ml sodium ethylate solution (0.8 g sodium). After 1 hour, the solution is neutralized with diluted hydrochloric acid. The mixture is concentrated and the residue is washed with water and recrystallized from a methanol/water mixture. 2.3 g N-(4-methoxy-5-pyrimidyl)-thiourea having a melting point of 18~ to 183C (decomp.) are obtained.
Preparation Example 3 N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea.
3.0 g N-(4,6-dimethoxy-5-pyrimidyl)-thiourea are mixed with a sodium-ethylate solution (0.317 g sodium in 30 ml absolute ethanol) and heated for 3 hours under reflux. After cooling the mixture is neutralized. The reaction product is vacuum treated and purified chromatographically on silica gel (developer; chloroform/methanol 95:5). 0.6 g N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea having a melting point of 186 to 187C are obtained.
_, .
1 152~)7 4 The compounds l;sted in the following table were synthetized in analogy to the foregoing preparation examples.
Preparation Example Rl R2 R3 Mp.deg.C.
6 OC4Hg OC4Hg H 105-106(hydrate) CH3 OCH3 Cl 1~6 (decomp.) 11 OCH3 Cl CH3 from 190(decomp.) The production of pharmaceuticals using compounds of the present invention is illustrated by the following examples.
Example 1 Production of tablets and capsules.
Tablets and capsules which contain the components indicated below are produced according to known methods. They are suitable for the treatment of hyperlipidemia in doses of one tablet or capsule two ~o four times daily.
~52(~74 Components Weight (mg) TabletCapsule N-(4,6-dimethoxy-5-pyrimidyl)-thiourea 100 100 Tragacanth 10 --Lactose 247.5300 Corn Starch 25 --Talcum 15 --Magnesium stearate 2.5 --Example 2 The lipid-reducing action of N-(4,6-dimethoxy-5-pyrimidyl)-thiourea is tested on hyperlipidemic mice in analogy to a testing method indicated in "~creening Methods in Pharmacology", Robert A. Turner, 1965, Academic Press, New York and London; and Garattine et al, Arzneimittelforschung 5,206, (1959). The compound is administered perorally at a dosage level of 10 mg/kg. The cholesterol level is reduced by 25%, and the triglyceride level by 27%.
Example 3 The antilipidemic and antihypertensive action of N-(2,4-dimethoxy-5-pyrimidyl)-thiourea is tested on hyperlipidemic mice and spontaneously hypertensive rats.
1~52~74 The mice are given a dose of 100 mg/kg perorally, and a reduction of the cholesterol level by 38% and of the triglyceride level by 49% is achieved.
The rats are given a dose of 30 mg/kg perorally and the blood pressure is reduced by 30%.
Example 4 The antihypertensive action of N-(4,6-dimethoxy-2-methyl-5-pyrimidyl)-thiourea is tested on spontaneously hypertensive rats. The compound is administered perorally in a dose of 30 mg/kg. The blood pressure is reduced by 30/0.
Although only a limited r.umber of specific embodiments of this invention have been expressly disclosed, it is, nonetheless, to be broadly construed and not to be limited except by the character of the claims appended hereto.
~ .
-~15Z(~4 Example 5 Production of tablets and capsules Tablets and capsules which contain the components indicated below are proau-ed according to known methods. They are suitable for the treatment of hypertension in doses of one tablet or capsule two to four times daily.
Weight (mg) Components TabletCapsule N-(2,4-dimethoxy-5-pyrimidyl)-thiourea 50 50 Tragaeanth 10 --Laetose 297.5 350 Corn Stareh 25 --Talcum 15 --Magnesium Stearate 2.5 --
_, .
1 152~)7 4 The compounds l;sted in the following table were synthetized in analogy to the foregoing preparation examples.
Preparation Example Rl R2 R3 Mp.deg.C.
6 OC4Hg OC4Hg H 105-106(hydrate) CH3 OCH3 Cl 1~6 (decomp.) 11 OCH3 Cl CH3 from 190(decomp.) The production of pharmaceuticals using compounds of the present invention is illustrated by the following examples.
Example 1 Production of tablets and capsules.
Tablets and capsules which contain the components indicated below are produced according to known methods. They are suitable for the treatment of hyperlipidemia in doses of one tablet or capsule two ~o four times daily.
~52(~74 Components Weight (mg) TabletCapsule N-(4,6-dimethoxy-5-pyrimidyl)-thiourea 100 100 Tragacanth 10 --Lactose 247.5300 Corn Starch 25 --Talcum 15 --Magnesium stearate 2.5 --Example 2 The lipid-reducing action of N-(4,6-dimethoxy-5-pyrimidyl)-thiourea is tested on hyperlipidemic mice in analogy to a testing method indicated in "~creening Methods in Pharmacology", Robert A. Turner, 1965, Academic Press, New York and London; and Garattine et al, Arzneimittelforschung 5,206, (1959). The compound is administered perorally at a dosage level of 10 mg/kg. The cholesterol level is reduced by 25%, and the triglyceride level by 27%.
Example 3 The antilipidemic and antihypertensive action of N-(2,4-dimethoxy-5-pyrimidyl)-thiourea is tested on hyperlipidemic mice and spontaneously hypertensive rats.
1~52~74 The mice are given a dose of 100 mg/kg perorally, and a reduction of the cholesterol level by 38% and of the triglyceride level by 49% is achieved.
The rats are given a dose of 30 mg/kg perorally and the blood pressure is reduced by 30%.
Example 4 The antihypertensive action of N-(4,6-dimethoxy-2-methyl-5-pyrimidyl)-thiourea is tested on spontaneously hypertensive rats. The compound is administered perorally in a dose of 30 mg/kg. The blood pressure is reduced by 30/0.
Although only a limited r.umber of specific embodiments of this invention have been expressly disclosed, it is, nonetheless, to be broadly construed and not to be limited except by the character of the claims appended hereto.
~ .
-~15Z(~4 Example 5 Production of tablets and capsules Tablets and capsules which contain the components indicated below are proau-ed according to known methods. They are suitable for the treatment of hypertension in doses of one tablet or capsule two to four times daily.
Weight (mg) Components TabletCapsule N-(2,4-dimethoxy-5-pyrimidyl)-thiourea 50 50 Tragaeanth 10 --Laetose 297.5 350 Corn Stareh 25 --Talcum 15 --Magnesium Stearate 2.5 --
Claims (29)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a pyrimidyl thiourea of the general formula (I) (I) wherein R1 is hydrogen, methoxy, ethoxy, butoxy, or methyl, R2 is R1 ox chloro, and R3 is hydrogen, methoxy, ethoxy, methyl, isopropyl or chloro, and the pharmaceutically acceptable salts thereof, which comprises conducting one of the following reactions:
reacting a substituted 5-aminopyrimidine of the general formula (II) (II) wherein R1, R2 and R3 are as defined above, with benzoylisothio-cyanate, whereby the corresponding benzoylthiourea is obtained, hydrolizing said benzoylthiourea to produce the desired compound of the formula (I) and optionally forming a physiologically accep-table acid addition salt of the compound of the formula (I);
where a compound of the general formula (I) is desired wherein at least one of R1 or R2 is an alkoxy group and R3 has the usual meaning, reacting a compound of the formula (I) which contains at least one alkoxy group with a corresponding alcoholate, whereby one or two of the alkoxy substituents are replaced by new alkoxy groups;
where a compound of the general formula (I) is desired wherein at least one of the substituents R1, R2 or R3 is an alkoxy group, reacting a compound of the formula (I) which contains at least one halogen atom with an alcoholate, whereby one or more of the halogen substituents are replaced by alkoxy groups;
where a compound of the general formula (I) is desired wherein at least one of the substituents R1, R2 or R3 is hydrogen, a compound of the formula (I) which contains at least one halogen atom is catalytically hydrogenated whereby one or more of the halogen substituents are replaced by hydrogen; and where a compound of the general formula (I) is desired wherein at least one of the substituents R1, R2 or R3 is hydrogen, reacting a compound of said formula (I) which contains at least one halogen atom with hydrazine and silver oxide, whereby one or more of the halogen substituents are replaced by hydrogen.
reacting a substituted 5-aminopyrimidine of the general formula (II) (II) wherein R1, R2 and R3 are as defined above, with benzoylisothio-cyanate, whereby the corresponding benzoylthiourea is obtained, hydrolizing said benzoylthiourea to produce the desired compound of the formula (I) and optionally forming a physiologically accep-table acid addition salt of the compound of the formula (I);
where a compound of the general formula (I) is desired wherein at least one of R1 or R2 is an alkoxy group and R3 has the usual meaning, reacting a compound of the formula (I) which contains at least one alkoxy group with a corresponding alcoholate, whereby one or two of the alkoxy substituents are replaced by new alkoxy groups;
where a compound of the general formula (I) is desired wherein at least one of the substituents R1, R2 or R3 is an alkoxy group, reacting a compound of the formula (I) which contains at least one halogen atom with an alcoholate, whereby one or more of the halogen substituents are replaced by alkoxy groups;
where a compound of the general formula (I) is desired wherein at least one of the substituents R1, R2 or R3 is hydrogen, a compound of the formula (I) which contains at least one halogen atom is catalytically hydrogenated whereby one or more of the halogen substituents are replaced by hydrogen; and where a compound of the general formula (I) is desired wherein at least one of the substituents R1, R2 or R3 is hydrogen, reacting a compound of said formula (I) which contains at least one halogen atom with hydrazine and silver oxide, whereby one or more of the halogen substituents are replaced by hydrogen.
2. A process as claimed in claim 1 wherein said aminopyridine, ammonium thiocyanate, and benzoyl chloride are reacted in acetone as a solvent at a temperature between ambient temperature and the boiling point of the solvent for a period of 30 minutes to 3 hours to form a reaction mixture, introducing said mixture into water, contacting said mixture with a solvent immiscible with water, hydrolyzing said thiourea with heating if necessary, whereby the benzoyl radical is separated.
3. A pyrimidyl thiourea of the formula I as defined in claim 1 and the pharmaceutically acceptable salts thereof, whenever obtained according to a process as claimed in claim 1 or claim 2 or by an obvious chemical equivalent thereof.
4. A process as claimed in claim 1 wherein R and R are each methoxy and R3 is hydrogen.
5. A compound of the formula I as set forth in claim 1 wherein R and R are methoxy and R is hydrogen, whenever obtained according to a process as claimed in claim 4 or by an obvious chemical equivalent thereof.
6. A process as claimed in claim 1 wherein R1 and R3 are each methoxy and R2 is hydrogen.
7. A compound of the formula I as set forth in claim 1 wherein R1 and R3 are each methoxy and R2 is hydrogen, whenever obtained according to a process as claimed in claim 6 or by an obvious chemical equivalent thereof.
8. A process as claimed in claim 1 wherein R1 and R2 are each ethoxy and R3 is hydrogen.
9. A compound of the formula I as set forth in claim 1 wherein R1 and R2 are each ethoxy and R3 is hydrogen, whenever obtained according to a process as claimed in claim 8 or by an obvious chemical equivalent thereof.
10. A process as claimed in claim 1 wherein R1 is methoxy and R2 and R3 are each hydrogen.
11. A compound of the formula I as set forth in claim 1 wherein R1 is methoxy and R2 and R3 are each hydrogen, whenever obtained according to a process as claimed in claim 10 or by an obvious chemical equivalent thereof.
12. A process as claimed in claim 1 wherein R1 and R2 are each butoxy and R3 is hydrogen.
13. A compound of the formula I as set forth in claim 1 wherein R1 and R2 are each butoxy and R3 is hydrogen, whenever obtained according to a process as claimed in claim 12 or by an obvious chemical equivalent thereof.
14. A process as claim 1 wherein R1 is methoxy and R2 and R3 are each methyl.
15. A compound of the formula I as set forth in claim 1 wherein R1 is methoxy and R2 and R3 are each methyl, whenever obtained according to a process as claimed in claim 14 or by an obvious chemical equivalent thereof.
16. A process as claimed in claim 1 wherein R and R2 are each methoxy and R3 is methyl.
17. A compound of the formula I as set forth in claim 1 wherein R1 and R2 are each methoxy and R3 is methyl, whenever obtained according to a process as claimed in claim 16 or by an obvious chemical equivalent thereof.
18. A process as claimed in claim 1 wherein R1 and R3 are each methoxy and R2 is hydrogen.
19. A compound of the formula I as set forth in claim 1 wherein R1 and R3 are each methoxy and R2 is hydrogen, whenever obtained according to a process as claimed in claim 18 or by an obvious chemical equivalent thereof.
20. A process as claimed in claim 1 wherein R1 is methyl, R2 is methoxy and R3 is chloro.
21. A compound of the formula I as set forth in claim 1, wherein R1 is methyl, R2 is methoxy and R3 is chloro, whenever obtained according to a process as claimed in claim 20 or by an obvious chemical equivalent thereof.
22. A process as claimed in claim 1 wherein R1 is methoxy, R2 is chloro and R3 is methyl.
23. A compound of the formula I as set forth in claim 1, wherein R1 is methoxy, R2 is chloro and R3 is methyl, whenever obtained according to a process as claimed in claim 22 or by an obvious chemical equivalent thereof.
24. A process as claimed in claim 1 wherein R1 and R3 are each methoxy and R2 is methyl.
25. A compound of the formula I as set forth in claim 1, wherein R1 and R3 are each methoxy and R2 is methyl, whenever obtained according to a process as claimed in claim 24 or by an obvious chemical equivalent thereof.
26. A process as claimed in claim 1 wherein R1 and R3 are each ethoxy and R2 is methyl.
27. A compound of the formula I as set forth in claim 1 wherein R1 and R3 are each ethoxy and R2 is methyl, whenever obtained according to a process as claimed in claim 26 or by an obvious chemical equivalent thereof.
28. A process as claimed in claim 1 wherein R1 and R2 are each methoxy and R3 is isopropyl.
29. A compound of the formula I as set forth in claim 1, wherein R1 and R3 are each methoxy and R3 is isopropyl, whenever obtained according to a process as claimed in claim 28 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3016767.0 | 1980-04-30 | ||
| DE19803016767 DE3016767A1 (en) | 1980-04-30 | 1980-04-30 | PYRIMIDYLTHIOUROSES, THE MEDICINES CONTAINING THEM AND THEIR USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1152074A true CA1152074A (en) | 1983-08-16 |
Family
ID=6101393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000376557A Expired CA1152074A (en) | 1980-04-30 | 1981-04-29 | Pyrimidyl thioureas |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0039037B1 (en) |
| JP (1) | JPS56169677A (en) |
| AT (1) | ATE11285T1 (en) |
| CA (1) | CA1152074A (en) |
| DE (2) | DE3016767A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2642053A1 (en) * | 1989-01-24 | 1990-07-27 | Pilard Annick | RECEPTION DOCK AND EXPEDITION OF BULK PRODUCT IN "WEIGHING AND MIXING" |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2849537C2 (en) * | 1978-11-15 | 1983-03-17 | Beiersdorf Ag, 2000 Hamburg | Substituted 5- (2-imidazolin-2-yl) aminopyrimidines, processes for their preparation and pharmaceuticals containing them |
-
1980
- 1980-04-30 DE DE19803016767 patent/DE3016767A1/en not_active Withdrawn
-
1981
- 1981-04-18 DE DE8181102997T patent/DE3168252D1/en not_active Expired
- 1981-04-18 AT AT81102997T patent/ATE11285T1/en not_active IP Right Cessation
- 1981-04-18 EP EP81102997A patent/EP0039037B1/en not_active Expired
- 1981-04-21 JP JP5934081A patent/JPS56169677A/en active Pending
- 1981-04-29 CA CA000376557A patent/CA1152074A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATE11285T1 (en) | 1985-02-15 |
| JPS56169677A (en) | 1981-12-26 |
| DE3016767A1 (en) | 1981-11-05 |
| DE3168252D1 (en) | 1985-02-28 |
| EP0039037A1 (en) | 1981-11-04 |
| EP0039037B1 (en) | 1985-01-16 |
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