JPH029592B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 8-substituted-7-phenyl-1,2,4
-Relating to triazolo[1,5-C]pyrimidine-5-amines and 5-amides and diuretics containing them as active ingredients. More specifically, the invention relates to the formula (wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or alkoxyalkyl, alkenyl, or alkynyl of 2 to 4 carbon atoms; R ₁ is hydrogen or 1 or 2 carbon atoms;
1-oxoalkyl). Compounds of the invention are useful as diuretics.

Examples of alkyl groups of 1 to 4 carbon atoms represented by R include methyl, ethyl, propyl and butyl and the corresponding branched isomeric groups.

Examples of alkoxyalkyl groups of 2 to 4 carbon atoms represented by R include methoxymethyl, methoxyethyl, 2-methoxypropyl, 3
-Methoxypropyl, ethoxymethyl, 1-ethoxyethyl, 2-ethoxyethyl, propoxymethyl and 1-methylethoxyethyl may be mentioned.

Examples of alkenyl and alkynyl groups of 2 to 4 carbon atoms represented by R are ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, ethynyl,
Mention may be made of 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl and the corresponding branched isomeric groups.

1- or 2 carbon atoms represented by R ₁
In compounds of the invention where the oxoalkyl group is formyl and acetyl, the formula Compounds represented by the formula (wherein R is the same as defined above) are preferred. In this formula, R is 1 carbon atom
Particularly preferred are compounds which are alkyl of 2 to 4 carbon atoms or alkoxyalkyl of 2 to 4 carbon atoms.

The compounds of this invention are useful because of their valuable pharmacological properties. For example, compounds of the invention are potent diuretics. Lipschitz the ability to increase urine output
Finney et al.: J. Pharmacol. Exp. Ther. 79 , 97 (1943).
Statistical Method in Biological Assay, 2nd
ed., Charles Griffin & Company, Limited.
According to London (1964), 8-methyl-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidine-5-amine and 8-(2- Ethoxyethyl)-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidine-5-amine is 1.2 times and
It showed 2.7 times more activity. Typical doses of hydrochlorothiazide as a diuretic are for human oral administration.
It is 25-50 mg.

For therapeutic purposes, the compounds of the invention are usually used in combination with one or more suitable adjuvants, depending on the route of administration. For oral administration, the compounds of the present invention may contain lactose, sucrose, powdered starch, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, It is mixed with gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol and filled into tablets or capsules for convenient administration. It may also be dissolved in water or similar non-toxic liquid. Parenteral administration is carried out in sterile liquid mixtures with water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, saline, and/or various buffers. Other adjuvants and methods of administration are well known in the pharmaceutical arts (eg, FW Martin et al.: Remington's
Pharmaceutical Sciences, 14th ed., Merck
Publishing Co., Eaton, Pa., 1965).

The appropriate dose in a particular case will, of course, vary depending on the condition of the mammal being treated, its severity, the route of administration, and the species of the mammal, including its size and responsiveness to the particular drug.

The amine of the present invention has the formula It can be produced by reacting 4-chloro-6-phenylpyrimidin-2-amine represented by the formula (wherein R is the same as defined above) with formylhydrazine in dimethylformamide. The amine produced can be crystallized from water and recrystallized from methanol.

Amides of the invention can be prepared by reacting the corresponding amines of the invention with formic or acetic anhydride, depending on the desired amide.

An alternative method of making the amides of the invention includes the formula A _suitable N-(4-chloro-6-phenylpyrimidine-
There is a method by reacting the 2-yl)amide with formylhydrazine in dimethylformamide. Addition of water forms a solid product.

The following examples illustrate details of the compounds of the present invention and methods for their preparation. However, the invention is not limited to this example.
It will be apparent to those skilled in the art of organic synthesis that many modifications, both to materials and methods, may be practiced without departing from the purpose and spirit of the invention. In the examples, temperatures are expressed in degrees Celsius and relative amounts of substances are expressed in parts by weight unless otherwise indicated.

Example 1 5.5 parts of 4-chloro-5-methyl-6-phenylpyrimidine-2-amine and 3.0 parts of formylhydrazine were added to 50 parts by volume of dimethylformylamide containing 5.0 parts of 3A molecular sieves, and the mixture was added under a nitrogen stream. Reflux for 2 hours. After standing at room temperature for 16 hours, the solution is poured into cold water. The yellow crystalline product is filtered, washed with water and dried. Recrystallizing the product from methanol gives the formula 8-methyl-7-phenyl-1,2,
4-triazolo[1,5-C]pyrimidine-5-
The amine is obtained as bright yellow needles with a melting point of 258°-260°C.

Example 2 4-chloro-5-(2-ethoxyethyl)-6
10.0 parts of -phenylpyrimidine-2-amine and 3.0 parts of formylhydrazine are added to 80 parts by volume of dimethylformamide containing 3 Å 8.0 parts of molecular sieves, and the mixture is refluxed for 2 hours under a nitrogen stream. to room temperature
After standing for 16 hours, pour the solution into cold water.
The crystalline product is filtered, washed with water and dried. Recrystallizing the product from methanol gives the formula 8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[1,5-C]
Pyrimidine-5-amine, melting point 162°C, is obtained.

Example 3 1.7 parts of 4-chloro-6-phenyl-5-(2-propynyl)pyrimidine-2-amine and 0.84 parts of formylhydrazine were mixed with 3 parts of molecular sieve.
Add 20 parts by volume of dimethylformamide containing 2.0 parts of Å, and reflux for 2 hours under a nitrogen stream. Allow the solution to cool and pour into cold water. filter the crystalline product;
Wash with water and dry. Recrystallizing the product from methanol gives the formula 7-phenyl-8-(2
-propynyl)-1,2,4-triazolo[1,
5-C]pyrimidine-5-amine is obtained.

Example 4 6.6 parts of 8-methyl-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidine-5-amine (Example 1) was mixed with 50 parts by volume of pyridine and acetic anhydride.
Suspend in 10 parts by volume. The solution is stirred at room temperature for about 18 hours until a clear solution forms. After about 21 hours, it becomes cloudy and solids gradually form. about
After standing for 40 hours, most of the solvent is removed under reduced pressure. The residue is stirred in water, filtered, washed with water,
dry. Recrystallizing the product from methanol gives the formula N-(8-methyl-7-
Phenyl-1,2,4-triazolo[1,5-
C] pyrimidin-5-yl)acetamide is obtained.

Example 5 An alternative preparation of the product N-(8-methyl-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidin-5-yl)acetamide of Example 4 starts from the appropriate chlorinated pyrimidine. do. formula N-(4-chloro-5-methyl-6-
Phenylpyrimidin-2-yl)acetamide
Add 7.85 parts to 6.0 parts of formylhydrazine and 60 parts by volume of dimethylformamide. The solution is heated to reflux under nitrogen for 2.5 hours. Let this solution cool,
Leave at room temperature for 16 hours. Pour the clear solution into cold water under stirring. A bright yellow crystalline substance forms. This material is filtered, washed with water, dried, and recrystallized from methanol to yield the desired product.

Example 6 6.4 parts of N-[4-chloro-5-(2-ethoxyethyl)-6-phenylpyrimidin-2-yl]acetamide and 2.4 parts of formylhydrazine in dimethylformamide containing 6.0 parts of 3 Å molecular sieves. Add 60 parts by volume and reflux for 1 hour under nitrogen. The golden solution is then allowed to cool and poured into water. The pale yellow substance produced is filtered and washed with water.
When dry, the formula N-[8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidin-2-yl]acetamide having a melting point of 75 to 76°C is obtained.

A pharmaceutical composition was manufactured by the following method. Amounts are expressed as relative amounts per tablet, capsule, suppository or unit of parenteral preparation.

Tablets 25 mg of a typical compound such as 8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidin-5-amine is dissolved in isopropyl alcohol, and 191.2 mg of lactose is added. It was dispersed into The mixture was air dried and passed through a 40 mesh sieve. 25 mg of corn starch and 7.5 mg of polyvinylpyrrolidone were added to the drug lactose mixture, mixed thoroughly and passed through a 40 mesh sieve.
The mixture was then granulated with isopropyl alcohol, spread on a tray, and dried at 120°C for 16 hours.
The dried granules were then sieved. The granules were thoroughly mixed with 1.3 mg of magnesium stearate and the mixture was compressed into tablets of appropriate size. Thus, tablets with an active ingredient content of 25 mg per tablet were obtained.

Capsules 8-(2-ethoxyethyl)-7-phenyl-
25 mg of 1,2,4-triazolo[1,5-C]pyrimidine-5-amine was added to corn starch.
177.5 mg of lactose and 177.5 mg of lactose, passed through a 40 mesh sieve and remixed.

20 mg of talc was added and the mixture was mixed thoroughly and filled into suitable hard gelatin capsules by hand or machine at a rate of 400 mg per capsule. Capsules with an active ingredient content of 25 mg/capsule were thus obtained.

Various excipients can be used in preparing tablets and capsules from the compounds of the present invention. For example, sugars such as lactose, sucrose, mannitol or sorbitol; starches such as corn starch, tapioca starch or potato starch; cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose or methylcellulose; gelatin; calcium phosphates such as dicalcium or tricalcium phosphate; sulfuric acid. Sodium; calcium sulfate, polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate;
Vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, anionic) ethylene glycol polymers; β-cyclodextrin; fatty alcohols, hydrolyzed grain solids; and other non- Adjuvants commonly used in pharmaceutical formulations can be used, such as toxic, compatible fillers, binders, disintegrants and lubricants.

Preparation for parenteral administration 8-(2-ethoxyethyl)-7-phenyl-
10 mg of 1,2,4-triazolo[1,5-C]pyrimidine-5-amine was dissolved in 2 ml of ethanol and 5 ml of sesame oil, filtered, filled into ampoules and sealed. The ampoules were then sterilized by any suitable method. The active ingredient content of the ampoule thus obtained is
It was 10mg/5ml.

A variety of vehicles and solubilizing agents can be used in preparing parenteral preparations from the compounds of the present invention. For example, vegetable oils such as peanut oil, corn oil, cottonseed oil, sesame oil; benzyl alcohol, saline, phosphate buffer, water, ethylene glycol polymers, urea, dimethylacetamide, Triton, dioxolane, ethyl carbonate, ethyl lactate, glycerol formal, myristic Acid isopropyl ester, surfactant (nonionic, cationic, anionic) polyalcohol,
Ethanol can be used.

Suppositories 975 mg of cocoa butter are melted, preferably on a water or steam bath to avoid overheating, and 8-(2-ethoxyethyl)-7-phenyl-
25 mg of 1,2,4-triazolo[1,5-C]pyrimidine-5-amine was emulsified or suspended. Finally, the mixture is poured into a cold chrome-lined metal mold.
The suppository solidified immediately. The total weight of the suppository was 1000 mg.

A variety of vehicles and suppository bases can be used in preparing suppositories from the compounds of this invention. For example, triglycerides of oleic, palmitic and stearic acids (cocoa butter),
Partially hydrogenated cottonseed oil, branched saturated fatty alcohols such as suppository base G, hydrogenated coconut oil, triglycerides of _C12 - _C18 fatty acids, water-dispersible vehicles such as polyethylene glycol, glycerin, gelatin, polyoxyl 40 stearate and polyethylene- 4-sorbitan monostearate, as well as substances capable of raising the melting point of the suppository base, such as beeswax, spermaceti, and the like.

Claims (1)

[Claims] 1 formula (wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or alkoxyalkyl, alkenyl, or alkynyl of 2 to 4 carbon atoms; R ₁ is hydrogen or 1 or 2 carbon atoms;
1-oxoalkyl). 2 N-[8-methyl-7-phenyl-1,2,
4-triazolo[1,5-C]pyrimidine-5-
The compound according to claim 1, which is [yl]acetamide. 3 formulas (wherein R' is alkylene of 1 or 2 carbon atoms, R'' is alkyl of 1 or 2 carbon atoms, and R ₁ is hydrogen or 1-oxoalkyl of 1 or 2 carbon atoms. The compound according to claim 1, which is represented by the following formula: (wherein R' is alkylene having 1 or 2 carbon atoms, and R'' is alkyl having 1 or 2 carbon atoms.) 5 8- (2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidine-5-amine according to any one of claims 3 or 4. A compound of 6 formula 2. A compound according to claim 1, wherein R is hydrogen, methyl, ethyl, ethenyl or ethynyl. 7. The compound according to claim 6, which is 8-methyl-7-phenyl-1,2,4-triazolo[1,5-C]pyrimidine-5-amine. 8 formula (wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or alkoxyalkyl, alkenyl, or alkynyl of 2 to 4 carbon atoms; R ₁ is hydrogen or 1 or 2 carbon atoms;
A diuretic containing a compound represented by the formula (1-oxoalkyl) as an active ingredient and a pharmaceutical carrier. 9 The active ingredient is 8-(2-ethoxyethyl)-7
-Phenyl-1,2,4-triazolo[1,5-
C] The diuretic according to claim 8, which is pyrimidine-5-amine. 10 formula (wherein R is hydrogen, alkyl of 1 to 4 carbon atoms or alkoxyalkyl, alkenyl or alkynyl of 2 to 4 carbon atoms, and R ₁ ' is formyl or acetyl group) The formula consists of treating N-(4-chloro-6-phenylpyrimidin-2-yl)amide with formylhydrazine and then isolating the compound obtained. (wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or alkoxyalkyl, alkenyl, or alkynyl of 2 to 4 carbon atoms; R ₁ is hydrogen or 1 or 2 carbon atoms;
1-oxoalkyl).