JPS633876B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel N ²
- Substituted phenyl-2,6-diaminonebularin. More specifically, the present invention provides a general formula that has an excellent coronary artery dilating effect. [In the formula, either R ¹ or R ² is −COR ³
(R ³ is a lower alkyl group, and the other is a hydrogen atom, a halogen atom, or a lower alkoxyl group) and salts thereof. Regarding the above general formula (), either R ¹ or R ² is a lower alkanoyl group represented by -COR ³ () (R ³ represents a lower alkyl group). The lower alkyl group as R ³ in this general formula () is linear
Any branched form may be used, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
Examples include t-butyl and hexyl, and those having 3 or less carbon atoms are particularly advantageous. The other of R ¹ and R ² in the general formula () is a hydrogen atom, a halogen atom, or a lower alkoxyl group, and the halogen atom may be chlorine, bromine, fluorine, etc., and the lower alkoxyl group may be methoxy, ethoxy, etc. , n-propoxy, isopropoxy, etc., and those having 3 or less carbon atoms are particularly preferred. The above compound () can be easily produced, for example, by Process A or Process B below. Process A General formula [In the formula, R ¹ and R ² have the same meanings as above,
R ⁴ , R ⁵ and R ⁶ each represent a hydroxyl group that may be protected, and A represents an active group that can react with ammonia to form an amino group] with ammonia, and the protecting group is removed as necessary. By subjecting it to treatment, compound () is obtained. Examples of protecting groups for the protected hydroxyl groups as R ⁴ , R ⁵ , and R ⁶ in the above general formula () include acyl groups derived from carboxylic acids (acetyl, propionyl, caproyl, palmitoyl, benzoyl, toluoyl, furoyl, etc.). aliphatic, aromatic, heterocyclic, saturated or unsaturated acyl group), nitro group, sulfonyl group,
Examples include an isopropylidene group and an alkoxyalkylidene group, and in particular, an acyl group derived from an aliphatic or aromatic carboxylic acid having 7 or less carbon atoms is preferably used. All of R ⁴ , R ⁵ and R ⁶ may be protected, only a part of them, for example R ⁴ and R ⁵ may be protected, or all of R ⁴ , R ⁵ and R ⁶ may be protected. It may be a hydroxyl group that is not These protected hydroxyl groups are usually eliminated when the compound () is reacted with ammonia, but benzoyl, toluoyl, nitro, sulfonyl, isopropylidene, etc. For groups that are difficult to separate,
If necessary, in the case of benzoyl and toluoyl groups, for example, by treatment with an alkali metal, in the case of nitro groups, for example, by catalytic reduction, and in the case of isopropylidene groups, for example, by treatment with an acid (formic acid, acetic acid, hydrochloric acid, etc.). It can be easily removed by methods known per se, such as treatment with. The active group A may be any group as long as it can react with ammonia to form an amino group, such as halogen atoms such as chlorine, bromine, and fluorine, and mercapto, alkylthio, aralkylthio, alkylsulfinyl, etc. General formula -SO _o R such as alkylsulfonyl (R represents a hydrogen atom, an alkyl group or an aralkyl group, n is 0,
Groups represented by 1 or 2) are conveniently used. When reacting ammonia with the compound represented by the general formula () in this process A, generally the ammonia is dissolved in a solvent and used in an amount equal to or more than the mole of the compound (), preferably about 2 to 5 times the mole. Good. As the solvent, for example, lower alcohols (methanol, ethanol, etc.), methyl cellosolve, water, or a mixed solvent thereof can be conveniently used. This reaction generally proceeds advantageously by heating to about 100-200°C, particularly preferably in a gas-tight reactor. The above raw material compound () can be produced by the method described in US Pat. No. 3,936,439 or a method analogous thereto. Process B General formula [In the formula, R ⁷ , R ⁸ and R ⁹ each represent an optionally protected hydroxyl group] [In the formula, R ¹ and R ² have the same meanings as above. ]
Compound () is obtained by reacting with a compound represented by and optionally subjected to a protective group removal treatment. In the above general formula (), R ⁷ , R ⁸ , and R ⁹ are protected as hydroxyl protecting groups such as R ⁴ , R ⁵ ,
Mention may be made of the protecting groups mentioned above for R ⁶ , among which propionyl is most advantageously used.
All of R ⁷ , R ⁸ , and R ⁹ may be protected, some of them, for example, only R ⁷ and R ⁸ may be protected, or all of R ⁷ , R ⁸ , and R ⁹ may be protected. may be an unprotected hydroxyl group. The protecting group for these protected hydroxyl groups is usually removed when compound () is reacted with compound (), but if necessary, in the case of an acyl group derived from a carboxylic acid, for example, a base (ammonia water, alkaline In the case of nitro groups, for example by catalytic reduction; in the case of isopropylidene groups, for example by treatment with acids (formic acid, acetic acid, hydrochloric acid, etc.), by methods known per se. Can be easily removed. The cyanamide compound represented by the above general formula () is described, for example, in "Berichte der Deutschen Hemitschen Gesellschaft" Volume 18.
It can be easily obtained by the method described on pages 3217-3234 (1885) or a method analogous thereto. When reacting the compound () with the compound () in this process B, it is generally preferable to use at least the same mole or more preferably about 2 to 5 times the mole of the compound () per 1 mole of the compound (). . This reaction is generally preferably carried out in the presence of a base. As the base, ammonia, primary to tertiary amines (low boiling point ones including cyclic amines are preferable, such as n-propylamine, isopropylamine, n-butylamine, triethylamine,
pyridine, picoline, 2,6-lutidine, etc.)
Mention may be made of sodium or potassium alcoholates (eg sodium methylate, sodium ethylate, sodium methoxyethylate, potassium tert-butylate, etc.), among others ammonia is advantageously used. These bases are usually used in an amount of about 10 to 100 times the molar amount of compound (). This reaction is generally preferably carried out in the presence of a solvent. As the solvent, any organic solvent that does not inhibit this reaction may be used; for example, lower alkanols (methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane, dimethylformamide, or a mixed solvent thereof are conveniently used. Generally, this reaction is about 100~
The reaction proceeds advantageously by heating to 200°C and is preferably carried out in an airtight container. If a protecting group remains on the hydroxyl group of the compound thus produced, it can be easily removed by carrying out the above-described protecting group removal treatment to obtain the compound (). The above raw material compound () is, for example,
No. 44-4225 (Patent No. 552745) or "Method for producing N ² -substituted 2,6-diaminoneblarin" filed by the applicant as Japanese Patent Application No. 127147 on October 21, 1972. 5-amino-1- which can be obtained at low cost as a fermentation product by the method described in the application specification or a method similar thereto.
Good yields can be obtained from β-D-ribofuranosylimidazole-4-carboxamide in two or three steps. The thus produced N ² -substituted phenyl-2,
6-Diaminonebularin () can be easily collected from the reaction solution by means known per se.
For example, the compound () can be purified by distilling off excess reactants and solvents from the reaction solution, washing the residue with lower alkanol, etc., and recrystallizing it with water, lower alkanol, or a mixture thereof. The compounds () can also be obtained as salts, such as physiologically acceptable acid addition salts, such as mineral salts (hydrochlorides, sulfates, etc.), by means known per se. The ^N2 -substituted phenyl-2,6-diaminonebularine () and its salts of the present invention are novel compounds that have not been described in any literature, and have excellent coronary artery dilator action.
In addition, it has few side effects such as antihypertensive effects and low toxicity, such as coronary insufficiency, angina pectoris, and myocardial disease in mammals (humans; pet animals such as dogs and cats; laboratory animals such as rats and mice). It is useful as a therapeutic agent for ischemic heart diseases such as infarction. When the target compound of the present invention is used as these pharmaceuticals, it can be used as such or mixed with appropriate pharmaceutically acceptable carriers, excipients, and diluents in the form of powder, granules, tablets, capsules, injections, etc. It can be administered orally or parenterally. The dosage varies depending on the target disease and administration route, but
For example, when administered to adults for the purpose of treating coronary insufficiency, dosages of about 1 to 10 mg/day for oral administration and about 0.05 to 0.5 mg/day for intravenous injection are advantageous. The present invention will be explained in more detail below using Examples, Reference Examples, and Experimental Examples, but these are not intended to limit the scope of the present invention. Reference example 1 3-acetyl-4-ethoxyaniline hydrochloride 6
g was dissolved in 100 ml of water, 5 g of rhodan potassium was added, and the mixture was heated at 100° C. for 4 hours. After cooling, collect the precipitated crystals and add them to a 10% potassium hydroxide aqueous solution.
Dissolved in 130 ml, added 19 g of lead acetate, and stirred at 80°C for 20 minutes. The precipitated lead sulfide was removed and the liquid was neutralized with acetic acid to obtain 1.9 g of 3-acetyl-4-ethoxyphenyl cyanamide. Melting point 138-139℃. Reference example 2 13g of 3-acetylaniline was mixed with ethyl ether
The mixture was dissolved in 100 ml, 20 g of cyanogen bromide was added, and the mixture was stirred for 3 hours. The precipitate was removed and the liquid was concentrated to dryness to give an oily substance, which gradually crystallized on standing. Water was added to crush the crystals and then collected to obtain 6 g of 3-acetylphenyl cyanamide. Melting point 79−81
℃. N-substituted phenyl cyanamides shown in Table 1 were obtained in the same manner as above.

[Table] Example 1 5-amino-1-β-D-ribofuranosyl-4
- 2.4 g of cyanoimidazole was added to 2.6 g of 3-propionyl phenyl cyanamide and 30 ml of 20% methanolic ammonia and reacted in an autoclave at 180°C for 5 hours. The reaction solution was concentrated to dryness, the residue was extracted with 700 ml of hot water, and when the extract was cooled, brown crystals were precipitated. This was recrystallized in 300 ml of boiling water to form colorless needle-like N ² -(3-propionyl phenyl)-2,
350 mg of 6-diaminonebularin was obtained. Melting point 148−
150℃. Elemental analysis _value C(%) H(%) N(%) Calculated value (as _C19H22O5N6・1/ _4H2O ): 54.47 _5.41 20.06 Actual value 54.36 5.22 20.15 Example 2 5 _- amino- 4-cyano-1-(2,3,5-
2.5 g of tri-O-propionyl-β-D-ribofuranosyl)imidazole, 2.3 g of 3-acetylphenyl cyanamide, 20% methanolic ammonia
30 ml was subjected to post-reaction treatment in the same manner as in Example 1 to obtain N ² -(3
0.4 g of -acetylphenyl)-2,6-diaminonebralin was obtained. Melting point 142-143℃. Elemental analysis value C (%) H (%) N (%) Calculated value (as C ₁₈ H ₂₀ O ₅ N ₆ ) 53.99 5.04 20.99 Actual value 53.23 5.19 19.75 Example 3 2-bromuinosine ammonium salt 3 g, 3
- A mixture of 5 g of acetylaniline and 50 ml of 60% aqueous methanol was boiled for 10 hours, and after cooling, the crystals formed were collected and 2-(3-acetylphenylamino) was obtained.
2.2 g of inosine was obtained. This was dissolved in 30 ml of pyridine, 15 ml of acetic anhydride was added, and the mixture was allowed to stand at room temperature for 2 hours, and then concentrated to dryness under reduced pressure. The resulting candy-like substance was dissolved in 70 ml of chloroform, and anhydrous sodium sulfate was added to dry it. Add 2 ml of dimethylformamide and 2 ml of phosphorus oxychloride to the chloroform solution under ice cooling.
ml and boiled for 1 hour. After concentrating the reaction solution and decomposing the remaining substances with ice water, chloroform
The extract was extracted with 100 ml, washed with water, and concentrated to dryness to obtain oily 2-(3-acetylphenylamino)-6-chloro-2',3',5'-tri-O-acetylnebularin. Add this to 50ml of 20% methanolic ammonia.
After heating in an autoclave at 120°C for 5 hours, it was concentrated to dryness, and the resulting residue was recrystallized from hot water to obtain N ² -(3-acetylphenyl)-2,
0.32 g of crystals of 6-diaminonebularin were obtained. Melting point 142-143℃. Examples 4 to 8 Compounds () shown in Table 2 were obtained by performing the same reaction operations and purification treatments as in Examples 1 to 3 above.

[Table] *: The numbers in the upper row show calculated values, and the numbers in the lower row show actual measured values.
Example 9 When the compound () of the present invention is used as a therapeutic agent for ischemic heart diseases such as coronary insufficiency, angina pectoris, and myocardial infarction, it can be used, for example, in the following formulation. 1 tablet (1) N ² -(4-acetylphenyl)-2,6-diaminonebularin 1 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 221mg After mixing (1), (2), (3) with 2/3 of (4) and 1/2 of (5),
Granulate. The remaining (4) and (5) are added to the granules and pressure molded into tablets. 2 Capsules (1) N ² -(3-acetylphenyl)-2,6-diaminonebularin 1mg (2) Lactose 100mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10mg 1 capsule 181mg (1) , (2), (3) and 1/2 of (4) are mixed and then granulated. Thereafter, the remaining (4) is added to the granules, and the whole is encapsulated in a gelatin capsule. 3 Injection (1) N ² -(4-acetylphenyl)-2,6-diaminonebularine hydrochloride 0.1mg (2) Inosyt 100mg (3) Benzyl alcohol 20mg (1), (2), (3) ) in distilled water for injection to a total volume of 2 ml, sealed in a brown ampoule, and purged with nitrogen gas. All steps are performed under sterile conditions. Experimental example A dog weighing 7-12 kg was anesthetized with pentobarbital sodium (30 mg/Kg, intravenous injection), and under artificial respiration, an incision was made in the left 5th intercostal space to expose the heart, and polyethylene was injected from the femoral artery into the left circumflex coronary artery. It was refluxed with blood directed through the tube. Coronary blood flow was measured by installing an electromagnetic flowmeter (MF-2, manufactured by Nihon Kohden) in the middle of the extracorporeal circulation circuit. The test compound is directly introduced into the coronary artery via a polyethylene tube as a 1 μg/ml physiological saline solution.
0.1μg/dog administered, 30 seconds, 1 minute, 2 minutes, 3 minutes after administration
minutes, and the rate of increase in coronary blood flow 5 minutes later was measured. The results were as shown in Table 3. Incidentally, the rate of increase in coronary blood flow was calculated by the following formula. (Coronary artery blood flow measured after administration - Coronary artery blood flow before administration / Coronary artery blood flow before administration) x 100 = Coronary artery blood flow increase rate (%)

【table】

Claims (1)

[Claims] 1. General formula [In the formula, either R ¹ or R ² is −COR ³
(R ³ is a lower alkyl group, and the other is a hydrogen atom, a halogen atom, or a lower alkoxyl group) or a salt thereof.