JPS5896087A - Novel xanthine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A xanthine derivative shown by the formulaI(R1 is 3-pyridylcarbonyl, 3-pyridylmethylcarbonyl or 3-pyridylmethylamino; R2 is H or OH). EXAMPLE:1-[2-Hydroxy-3-(3-pyridylmethylamino)propyl]-3,7-dimethylxanth ine. USE:A remedy for peripheral blood stream disorder and cerebrovascular disorder, having vasodilating action. PROCESS:Sodium salt of 3,7-dimethylxanthine shown by the formula II is reacted with a compound shown by the formula III (X is halogen; n is 0 or 1) to give a compound shown by the formula IV, which is hydrolyzed to give a compound wherein R1 in the formulaI is 3-pyridylcarbonyl or 3-pyridylmethylcarbonyl, and a compound shown by the formula V is reacted with a compound shown by the formula IV to give a compound wherein R1 in the formulaIis 3-pyridylmethylamino.

Description

[Detailed description of the invention] The present invention relates to a novel xanthine derivative and a method for producing the same.

The xanthine derivative according to the present invention has the general formula (wherein R1 is 3
-pyridylcarbonyl, 3-pyridylmethylcarbonyl, or 3-pyridylmethylamino group, and R2 means a hydrogen atom or a hydroxyl group), and all of these compounds are new compounds that have not been described in any literature. , has a vasodilating effect, and is therefore useful as a therapeutic agent for circulatory system diseases such as peripheral blood flow disorders and cerebrovascular disorders.

According to the method of the present invention, the compound represented by the general formula (1) can be obtained as shown in the following reaction formula.

(tV) Crystallization (white (in the formula, X means a halogen atom, n means 0 or 1) (V) (VI) 01 (5 (I5 In method a, shown by the formula The reaction between 3,7-dimethylxanthine sodium and the compound represented by the general formula (2) is carried out using a suitable inert solvent such as dimethylformamide,
The reaction can be carried out in dioxane, dimethyl sulfoxide, etc., and then the resulting compound of general formula (2) can be hydrolyzed using a base such as sodium hydroxide, potassium hydroxide, etc.

On the other hand, in the method, 1-(2,3
The condensation reaction between 3,7-dimethylxanthine (-epoxypropyl)-3,7-dimethylxanthine and 3-aminomethylpyridine represented by formula Vl is carried out by first dissolving compound V in anhydrous methanol by heating, and then heating and refluxing compound 1. can be

In both of these methods, the reaction temperature cannot be absolutely specified, and in particular in method a, it varies depending on the solvent and base used, but in both methods, it is usually about 80 to 120°C, and the reaction time is about 2 to 120°C. It takes about 18 hours.

Next, the present invention will be explained in more detail by way of examples.

Example 1 a) 2-(3-(3,7-dimethylxanthine-1-yl)propyl)-2-(3-pyridyl)-1,3-dioxolane 2(3-chloropropyl)-2-(3 -pyridyl)-1
, 10 tons of 3-dioxolane and 8°88 f of sodium 3,7-dimethylxanthine were mixed with 507 tons of dimethylformamide! and heat and stir at 110 to 120°C to react. After the reaction is completed, the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform made alkaline with a 5-chloride NaOH solution. The desired compound is obtained by washing the chloroform I- with water, drying it with Glauber's salt, distilling off the chloroform, and recrystallizing the obtained residue from ethanol (yield: 91.0%).

Melting point 144-145°C Elemental analysis value (C1g 121 N50q) CHN Theory 58,215.7018.86 Actual measurement 58.315.6918.73 b) 1-[4-oxo-4-(3-pyridyl)butyl]
-3,7-Simethylxanthine 8.89 g of dioxolane obtained by the method described in section a) is dissolved in 300 td of concentrated hydrochloric acid and heated under reflux.

After the reaction is completed, the mixture is made alkaline with 10% NaOHM solution, extracted with chloroform, the extract is dried with Glauber's salt, the chloroform is distilled off, and the residue is recrystallized from ethanol to obtain the desired compound. (Yield 91.8%).

Melting point 143-145°C Elemental analysis value (C16H17N5) CHN Theory 58°70 5.23 21.40 Actual measurement 58.
fi8 5.21 21.29 Example 2 a) 5-chloro-1-(3-pyridyl)-2-pentanone 3-pyridyl acetic acid ethyl ester 5°Ov, γ-butyro2 lactone 3.91 and sodium methylate 4. 86r and 50ml of completely dry dioxane and heated under reflux for 3 hours. After the reaction is completed, salt #150me is added and heated under reflux again for 18 hours. After cooling the reaction mixture, add sodium carbonate to adjust the pH to 7.6, extract with ethyl acetate, wash the extract with water, and dry with Glauber's salt.

Chromatography of the residue on silica gel using a mixture of chloroform and methanol (volume ratio 200:1) gives the desired substance as a pale yellow oil (yield 56. 6%
).

1R spectrum: 1720 (C=O) NMR spectrum: 1.80-2.22 (2H, mX-CH2CH2Ct
)2.69(2H,t,J='lHz,-COCJ(2
CH2) 3.50 (2H, t, J=7IIz, -C
H2C1) 3.70 (2H,s, -CH2COCH2C
H2) 7.05-7.60 (28, m, Ar-H) 8.
25-8.60(2H,m,Ar-H)b)2-(3-
chloropropyl)-2-(3-pyridylmethyl)-1,
3-dioxolane Pentanone 15.32 obtained by the method described in item a) above and ethylene glycol 15Fz+l
: Add 19.6 f of p-toluenesulfone &lk salt and 410 g of gold-dried benzene, and heat under reflux while removing water. After the reaction is completed, the mixture is made alkaline with a 3% NaOH solution, the organic layer is separated, dried over Glauber's salt, and the benzene is then distilled off. Chromatography of the residue on silica gel using a mixture of chloroform and methanol (volume ratio 200:1) gives the desired compound as a pale yellow oil (yield 54.2%).

NMR spectrum: 1.70-2.05 (4H, m, -CH2CH2C
H2Ct) 7.02-7.35 (IH, m, Ar-H
) 7.40-7.75 (IH, m, Ar-H) 8.30
-8.60(2H,mXAr-H)a) 2- (3
-(3,7-Simethylxanthine-1-yl)propyl)-2(3-pyridylmethyl)-1,3-dioxolane 2-(3-chloropropyl) obtained by the method described in item b) above -2-(3-pyridylmethyl)-1,3-dioxolane 9°Of and 7.7f of the sodium salt of 3,7-dimethylxanthine were dissolved in dimethyl sulfoxide 6°-
and heat under reflux. After the reaction is completed, the solvent is distilled off under reduced pressure, water is added to the residue, made alkaline with 5% NaOH solution, and extracted with chloroform. The chloroform extract was washed with water, dried with Glauber's salt, and the chloroform was distilled off.
The desired compound is obtained by recrystallizing the obtained residue from inpropyl alcohol (yield: 91.4%).

Melting point 140-145°C Elemental analysis value (C19H23N50q)CHN Theory 59.21 6.02 18.17 Actual measurement 59.
08 6.11 18.23d) 1-(4-oxo-5
-(3-pyridyl)pentyl)-3,7-dimethylxanthine 4°7f of dioxolane obtained by the method described in section C) above is dissolved in 152ml of concentrated hydrochloric acid and heated under reflux for 2 hours. After the reaction is completed, the mixture is made alkaline by adding 10% NaOHm solution, extracted with chloroform, and the extract is dried with Glauber's salt. Then, chloroform was distilled off,
The target compound is obtained by recrystallizing the residue t-1 from sopropyl alcohol (yield: 86.3%).

Melting point 104-105℃ Elemental analysis value (C1r f■19N50) CHN Theory 59,81 5.61 20.52 Actual measurement 59.
68 5゜5320.60 Example 3 1-[2-hydroxy-3-(3-pyridylmethylamino)propyl)-3,7-dimethylxanthine 1-(2,3-epoxypropyl)-3,7-dimethyl Xanthine 3. Of? 3-Aminomethylpyridine 1 was heated and dissolved in anhydrous methanol.
Add 37t and heat to reflux for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel using a mixture of chloroform and methanol (volume ratio 40:1) to obtain the desired compound.

Melting point: Can be measured due to hygroscopicity IR spectrum: 3450.3300.1700.1655α-1HMR
Spectrum 2.65-2.73 (I H, m, -NH-)3.
25 3.43(2H,m, -NHCH2CH(OH
)) 3.49- (3H, tsl, >N-CH5)
>N-CH2+>CH(OH)) 4.75 (IH, a, -0H) 7.20 7
．． 55(IHXm, Ar-H)N 7.708.05(2H,m, Ar-Ij+-N'H
) 8.30 8.70 (2H, m, Ar-H) Patent applicant Sanoro Kagaku Kenkyusho Co., Ltd. Shiratori Pharmaceutical Co., Ltd. as company president, ・1 14- Hand H Amendment (Spontaneous 1, 1987, 6 Monday/ρday Director General of the Patent Office Shima 1) Haruki Tono 1. Showing 11 items % Gansho F16-1917! IF1,
Name of the invention: New xanthine derivatives and their relationship with the person who corrects the manufacturing process Patent applicant: 35 Higashi Sotobori-cho, Higashi-ku, Nagoya City, Shimi Shikisha, Representative: Sanwa Kagaku Kenken Center, Tetsuji Suzu Suzu a ((ゝ Rijin 〒 105 Higashido Miyako 1
Nutora] Mon 1-11-7-@Full text of the specification 6, Ai 1 contents The full text has been amended as per the attached appendix to the specification of the present application 11.1.

l Attachment - l = needle tl + full text amended specification 1 Specification 1 Title of the invention Novel xanthine derivatives and process for producing the same 2 Claims (1) General formula (in the formula Ruj3-pyridylcarbonyl, 3 A novel xanthine derivative represented by -pyridylmethylcarbonyl or 3-pyridylmethylamine base, ft2t; !means a hydrogen atom or a hydroxyl group).

The sodium salt of 3,7-dimethylxanthine represented by CH is reacted with a compound represented by the general formula (wherein X means a halogen atom and n means O or l). A novel xanthine spinner represented by the general formula (in which n has the above meaning), characterized by hydrolyzing a 1,3-dioxolane compound represented by aa.

1-(2,3-epoxy)propyl-3,
1. A method for producing a novel xanthine enzyme derivative represented by the formula, which comprises reacting 7-dimethylxanthine with 3-aminomethylpyridine represented by the formula.

-1 Detailed Description of the Invention The present invention relates to a novel xanthine 111I conductor and its manufacturing method.

The xanthine enzyme conductor according to the present invention has the general formula (wherein R1t1
3-pyridylcarbonyl, 3-pyridylmethylcarbonyl, or 3-pyridylmethylamino group, and R2 means a hydrogen atom or a hydroxyl group), and all of these compounds are new compounds not described in literature. , has a vasodilating effect, and is therefore useful as a therapeutic agent for circulatory system diseases such as peripheral blood flow disorders, cerebrovascular disorders, etc.

According to the method of the present invention, the compound represented by the general formula 1 can be obtained as shown in the following reaction formula.

(1') (In the formula, X means a halogen atom, n means 0 or 1) The reaction with the compound represented by I) can be carried out in a suitable inert solvent such as dimethylformamide, dioxane, dimethyl sulfoxide, etc., and then the resulting general formula (fV
) The hydrolysis of the compound of formula (V) can be carried out using an acid such as hydrochloric acid, acidic acid, etc. On the other hand, in the method, 1-(2
, 3-Epoxypropyl)-3,7-dimethylxanthine and 3-aminomethylpyridine represented by the formula (Vl) can be carried out by first dissolving the compound (V) in anhydrous methanol by heating, and then dissolving the compound (V) in anhydrous methanol. 9 can be carried out by heating Vl) to reflux.

In both of these methods, the reaction temperature cannot be absolutely regulated, and it varies depending on the solvent and acid used, especially in method a, but in both methods, the reaction temperature is usually about 80-120°C, and the reaction time is 2-18°C. It takes about an hour.

Next, the present invention will be explained in more detail by way of examples.

Fl! 1 a) 2-(3-(3,7-dimethylxanthine-1-yl)propyl]-2-(3-pyridyl)-1,3
-Dioxolane 2-(3-chloropropyl)-2-(3-pyridyl)-
10F of 1,3-dioquinrane and 18.88F of sodium 3,7-dimethylxanthine are added to 50 g of dimethylformamide, and the mixture is heated and stirred at 110 to 120°C to react. After the reaction was completed, the solvent was distilled off under reduced pressure.
Water is added to the residue, made alkaline with 5% NaOHfR solution, and extracted with chloroform. The chloroform layer was washed with water, dried with Glauber's salt, and the chloroform was distilled off. ! If 4tIi is recrystallized from ethanol, the desired compound can be obtained (yield 91.0%).

Melting point 144-145℃ Elemental analysis 1+K CC15k421N5011) CHN Science 1ifi& 58.21 5.70 18.8
6 Actual measurement 58.31 5.69 18
．． 73b) 1-(4-oxo-4-(3-pyridyl)butyl]-3.7-dimethylxanthine 8.8 t of dioquinrane obtained by the method described in section a) was dissolved in 300 ml of hydrochloric acid. Dissolve and heat to reflux.

After the reaction is completed, the reaction is made alkaline with 10% NaOH# solution, extracted with chloroform, the extract is dried with Glauber's salt, the chloroform is distilled off, and the residue is recrystallized from ethanol to obtain the desired compound. obtained (yield 91.8%)
.

Melting point 143-145℃ Elemental analysis value (C16H17N505) CHN Theory 58.70 5.23 21.40
Actual measurement 58.68 5.21 21.2
9 Example 2 a) 5-chloro-1-(3-pyridyl)-2-pentanone 3-pyridyl acetic acid ethyl ester5. Of, 3.92 tons of r-butyrolactone and 4.86 tons of sodium methylate are added to 50 tons of dry dioxane and heated in a cross-flow for 3 hours = 7 hours. After the reaction is completed, Danshi [50-] is added and the mixture is heated under reflux for 18 hours. After the reaction mixture has cooled down, sodium carbonate is added to adjust the pH to 7.6, extracted with acetic acid ethyl ester, the extract is washed with water and dried over Glauber's salt. Ethyl acetate is distilled off and the residue is chromatographed on silica gel using a mixture of chloroform and methanol (volume ratio 200:1) to obtain the desired product as a pale yellow oil (yield 56.6). %).

IR spectrum: 1720. z (C-0)NMR
Spectrum: 1.80-2.22 (2B%m, -CH20H2C
t) 2.69 (2B, t, J=7Hz, -CO
CH2C112) 3.50 (28%t, J-7Hz,
-CH2C4)3.7 (] (2H,s, -CH2
COCH2CH2) 7.05-7.60 (2B2m%
Ar-H) 8.25-8.60 (2H, m, Ar-H)
b) 2-(3-chloropropyl)-2-(3-pyridylmethyl)-1,3-dioquinrane Pentanone 15.38-f obtained by the method described in item a) above, ethylene glycol 155d and p- 19.6 grams of toluenesulfonic acid monohydrate were added to 410 grams of dry benzene, and the mixture was heated under reflux while removing water. After the reaction is completed, the mixture is made alkaline with a 3% NaOH solution, the organic 1- is separated and dried over Glauber's salt, and then Tehenzen is distilled off. Residue/I! on silica gel using a mixture of chloroform and methanol (volume ratio 200:1). Chromatography of L gives the desired compound as a pale yellow oil (yield 54.2%).

NMR spectrum 1.70-2.05 (4H, m, -CH20H2Ct
p, C1) 7.02-7.35 (IH, m, Ar −
H) 7.40-7.75 (IH, m, Ar-H)8.
30-8.60(,2H,m, Ar-H)a) 2
- (3-(3,7-cymethylxanthine-1-yl)
10 Biru)-2-(3-pyridylmethyl)-1,3-dioxolane 2-(3-chloropropyl)-2-(3-pyridylmethyl)-1,3 obtained by the method described in item b) above. - Add 9.02 grams of dioxolane, 17.7 grams of sodium 3,7-dimethylxanthine, and 60 grams of poppy methylformamide, and heat in a boiling water stream.

After the reaction is completed, the solvent is distilled off under reduced pressure, the residue is immediately cooled with water, made alkaline with 5% NaOH solution, and extracted with chloroform. The desired compound can be obtained by washing the chloroform extract with water, drying with Glauber's salt, distilling off the chloroform, and recrystallizing the resulting residue from inpropyl alcohol (
Yield 91.4'%).

Melting point 140-145℃ Elemental analysis 1 [(C19f(2uN5011)C+4
N Ri stripe 59.21 6.02 18.
17 measurement 594) 8 6.11 1
8.23d) l-(4-oxo-5-(3-pyridyl)
Pentyl]-3+7-dimethelxanthine 4.7f of dioxolane prepared by the method described in C) above is a salt +
1152 rrt and heated to reflux for 2 hours. After the reaction is completed, the mixture is made alkaline by adding 10% NaOH solution, extracted with chloroform, washed with water, and the extract is dried with Glauber's salt. Next, chloroform is distilled off, and the residue is recrystallized from inpropyl alcohol to obtain the target compound (yield: 86.3%).

Melting point 104-105℃ Elemental analysis value (C17H19N505) CHN Theory 59.81 5.61 20.5
2 fruit ri 4 li 59.68 5.5
3 20.60 Example 3 1-[2-hydroxy-3-(3-pyridylmethylamino)propyl]-3,7-dimethylxanthine 1-(2,3-epoxypropyl)-3,7-dimethyl Xanthine 3. Of is heated and dissolved in anhydrous methanol (45-), and the ? ′? Add 1.37 F of 3-aminomethylpyridine to the mixture and heat under reflux for 5 hours. The reaction mixture is condensed under reduced pressure and the residue is chromatographed on silica gel using a mixture of chloroform and methanol (volume ratio 40:1) to yield the desired compound.

Melting point: Can be measured due to hygroscopicity IR spectrum: 3450.3300.1700.1655 polarization -1NMR
Spectrum 2.65-2.73 (l)i, m, -NH-)
3-25-3.43 (2H1m, -N) (CH2CH
(OH)-)3.49 (3H,a,)N-C
H3)) N-CH2+>CH(OH)) 4.75 (1 positive 1.s, -OH)N 7.70-8.05 (,2H,m, Ar〉〉〉〉8.30 -8.70 (2H, m, Ar-flea ■) Patent applicant: Sanwa Kagaku Kenkyusho Co., Ltd. Shiratori Pharmaceutical Co., Ltd. 12-

Claims (1)

[Claims] (1) In the general formula (wherein R1 means 3-pyridylcarbonyl, 3-pyridylmethylcarbonyl or 3-pyridylmethylamine group, and R2U means a hydrogen atom or a hydroxyl group) n
A new xanthine derivative. Obtained by reacting the sodium salt of 3,7-dimethylxanthine represented by CH with a compound represented by the general formula (wherein X means a halogen atom and n means O or 1t-). 1,3- represented by the general formula (in which n has the above meaning)
1. A method for producing a novel xanthine derivative represented by the general formula (wherein n has the above-mentioned meaning), which comprises hydrolyzing a dioxolane compound. 1-(2,3-epoxy)propyl-3,
A method for producing a novel xanthine derivative represented by the formula, which comprises reacting 7-dimethylxanthine with 3-aminomethylpyridine represented by the formula.