JPH03218378A - Xanthine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, 4-methoxybenzyl, 1-4C alkyl, etc.; (n) is 1-4; A is COCH3 or C(OR<2>)(OR<3>)CH3 (R<2> and R<3> are 1-3C alkyl or together form 2-4C polymethylene)] and its salt. EXAMPLE:3-Cyclopropyl-3,7-dihydro-7-(4-methoxybenzyl)-1-(5-oxohexyl)-1H- purine-2,6-dione. USE:A bronchodilator and cerebral function improver. PREPARATION:The objective compound of formula I can be produced by reacting a compound of formula II (R<1>' is 4-methoxybenzyl, 1-6C alkyl or 3-6C cycloalkyl) with an alkyl hallide derivative of formula III (X is halogen) in an organic solvent (e.g. methanol or ethanol) in the presence of a base as a dehydrohalogenation agent.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel xanthine derivative that has bronchodilation and brain function improving effects and is useful as a therapeutic agent for airway diseases and brain function diseases, and its pharmacological properties. Regarding acceptable salts.

Conventional technology Theophylline (The Merck Index)
kIndex), 11th edition, 9212], Benxifylline [The Merck In
dex), 11th edition, 7092] or prevententphylline [The Merck Index (The Merck In
Xanthine derivatives typified by Xanthine dex), 11th edition, 7822) are widely used clinically as therapeutic agents for respiratory tract diseases or brain function diseases.

However, a compound having a cyclopropyl group at the 3-position of the xanthine skeleton and an oxoalkyl group at the 1-position, such as the compound of the present invention, has not been known so far.

Problems to be Solved by the Invention The main disadvantage of treatments using xanthine derivatives is that the drugs often have serious side effects, namely cardiac excitatory effects such as heart palpitations and tachycardia, central effects such as spasticity and headache, Or nausea,
It causes gastrointestinal effects such as vomiting. Therefore, in the clinical setting, there is a strong desire to develop new drugs that exhibit fewer side effects.

Means for Solving the Problems The present inventors have conducted intensive research in view of the above circumstances, and have found that the novel xanthine derivative according to the present invention has bronchodilator action and brain function useful for the treatment of airway diseases and brain function diseases. The present invention was completed based on the discovery that the compound has an improving effect and has fewer side effects such as cardiac stimulation.

That is, the present invention relates to the following general formula (I) (wherein R1 is a hydrogen atom, 4-methoxybenzyl group, C
, ~C6 straight or branched alkyl group or 03
~C6 cycloalkyl group, n is an integer of 1 to 4, A
is one COCR3 group or -C (OR2)(OR3)CH
Coconi R2 and R3 each represent C1 to C3.
represents an alkyl group, or R2 and R3 together represent a 02 to C4 polymethylene group. ) and its pharmacologically acceptable salts.

In the general formula (I) of the present invention, C1 to C represented by R1
6 straight chain or branched alkyl group or 03 to C6
Examples of the cycloalkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, SeC-butyl group, tert-butyl group, cyclobutyl group, n -pentyl group, 2-methylbutyl group, cyclopentyl group, n
-Hexyl group, cyclohexyl group, etc., and the C1-C3 alkyl group represented by R2 and R3 include methyl group, ethyl group, n-propyl group, etc., and also formed by R2 and R3 together. Examples of the 02 to C4 polymethylene groups include ethylene groups and propylene groups.

Preferred compounds in the present invention include the following compounds.

3-cyclopropyl-3,7-dihydro-7methyl-1
-(2-year-old xopipil)-1H-purine-2,6-di-3-cyclopropyl-7-ethyl-3,7-dihydro-
1-(2-Year-Old Kissop Pill)-1H-Purine-2,6-
Sion 3-cyclopropyl-3,7-dihydro-1 (2-year-old xopucopyl)-7-n-propyl-IH-purine-2,
6-dione 3-cyclopropyl-3,7-dihydro-7methyl=1
-(31 years old xobutyl)-1H-purine-2 6-sion 3-cyclopropyl-7-ethyl-3,7-dihydro-
1-(3-oxobutyl)-1H-purine-2,6-sion 3-cyclopropyl-3,7-dihydro-1-5 (3-year-old xobutyl)-7-n-propyl-IH purine-2,6 -Sion 3-cyclopropyl-3,7-dihydro-7methyl-l
-(41 years old xopentyl)-1H-purine-2,6-sion 3-cyclopropyl-7-ethyl-3,7-cyhydro-
1-(4-oxopentyl)-1H-purine-2,6-
Dione 3-cyclopropyl-3,7-dihydro-1(4-year-old xopentyl)-7-n-propyl-IH purine-2.6
-Sion 3-cyclopropyl-3,7-dihydro-1 (51 year old xohexyl)-18-purine-2,6 dione 3-cyclopropyl-3,7-dihydro-7methyl-1
-(5-oxohexyl)-1H-purine-2,6-dihydro-3-cyclopropyl-7-ethyl-3,7-dihydro-
1-(5-oxohexyl)-1H-purine-2,6-
Sion 6 3-cyclopropyl-3,7-dihydro-1(5-oxohexyl)-7-n-propyl-IH purine-2,6
-Sion 7-n-butyl-3-cyclopropyl-3,7dihydro-1-(5-oxohexyl) -LH purine-2,6
-di-3-cyclopropyl-3,7-dihydro-1(5-oxohexyl)-7-n-pentyl-IH-purine-2,
6-Sion 3-Cyclopropyl-7-n-hexyl-3,7dihydro-1-(51 year old xohexyl)-1H purine-2,6
-dione 3-cyclopropyl-3,7-dihydro-7(4-methoxybenzyl)-1- (51 year old xohexyl)-1H
-purine-2,6-dione 3-cyclopropyl-3,7
-cyhydro-7methyl-1-((2-methyl-1,3-
dioxolan-2-yl)methyl]-IH-purine-2
,6-dihydrogen-3-cyclopropyl-3,7-dihydro-7methyl-1
- C4- (2-methyl-1,3-dioxolane-2
[-yl)butyl]-IH-purine 2,6-dioxygen The pharmacologically acceptable salts of the compound represented by the general formula (I) of the present invention include, for example, sodium, potassium, calcium, ammonium and salts of organic bases such as ethylenediamine, ethanolamine, N,N-dialkylethanolamine, and triethanolamine.

The novel xanthine derivative represented by the general formula (I) of the present invention can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention,
In the general formula (I), R1 is a 4-methoxybenzyl group I
A Cl to C6 linear or branched alkyl group, or a C3 to C6 cycloalkyl group, and A is -C
A compound having an OCHff group has the following general formula (II) (wherein Rl' is a 4-methoxybenzyl group, Cl to C6
There is a linear or branched chain alkynole group (C) (YC, ~
C, represents a cycloalkyl group. ) has the following general formula (I[)♀CH3-C-(CH2). 1X (II[
) (In the formula, n represents the same meaning as above, and X represents a norogen atom.) A halogenated alkyl derivative represented by
It can be produced by reacting in the presence of a base as a dehydrohalogenating agent.

Examples of organic solvents used in this production method include alcoholic solvents such as methanol, ethanol, n-propanol, isoprobanol, and n-butanol, tetrahydrofuran, acetonyl, N,N-
Examples include aprotic polar solvents such as dimethylformamide, N9 methyl-2-pyrrolidone, and dimethyl sulfoxide. Examples of bases used include sodium metal, sodium hydride, sodium amide, sodium hydroxide, Examples include potassium hydroxide, sodium carbonate, potassium carbonate, etc.
The reaction is carried out at a temperature ranging from water cooling to the reflux temperature of the solvent.

The general formula (II) used as the starting material in this production method
) can be produced as follows.

(In the formula, Rl' represents the same meaning as described above, and Y represents a halogen atom.) The compound represented by the above formula (IV) is
It is a known compound disclosed in No. 57589, and can be produced by the method described therein.

According to the second mode of the method for producing a compound according to the present invention,
In the general formula (I), R1 or 4-methoxybenzyl group, C
,-C. a linear or branched alkyl group or C3
A compound in which there is a cycloalkyl group of ~C6, n is 2, and A or -C O C H 3 groups is obtained by adding methyl vinyl ketone to the xanthine derivative represented by the general formula (II) above, and adding methyl vinyl ketone to the basic It can be produced by Michael addition reaction in an organic solvent.

This Michael addition reaction is a method known per se, and basic organic solvents used include, for example, pyridine, 2
-picoline, 2,6-lutidine, etc., and the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.

According to the third mode of the method for producing a compound according to the present invention,
In the general formula (I), R1 is a hydrogen atom, and A or -
Compounds having a COCH3 group include R1 in the general formula (I)
is 4-methoxybenzyl group, and A is -COCH
It can be produced by treating the three compounds with an acid in the absence of a solvent or in an organic solvent in the presence of a scavenger.

Examples of organic solvents used in this production method include benzene, toluene, xylene, carbon tetrachloride,
, 2-dichloroethane, etc., as a scavenger,
Examples include anisole, thioanisole, etc., and acids include trifluoroacetic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, etc. Further, the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent or acid.

According to the fourth mode of the method for producing a compound according to the present invention,
In the general formula (I), R1 or 4-methquinbenzyl group, C
1 to C6 straight or branched alkyl group or 03
-C6 cycloalkyl group, and A or -COCH
The compound with two groups is a xanthine derivative represented by the following general formula (V) (wherein n represents the same meaning as above), and the following general formula (VI) R
A halogenated alkyl derivative represented by l-Y (VI) (wherein R1° and Y represent the same meanings as above) is reacted in an organic solvent in the presence of a base as a dehydrohalogenating agent. It can be manufactured by

Examples of organic solvents used in this production method include alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, and N-methyl-2 - Aprotic polar solvents such as pyrrolidone and dimethyl sulfoxide, etc., and bases used include, for example, metallic sodium, sodium hydride, sodium amide, sodium hydroxide, thorium, potassium hydroxide, and sodium carbonate. The reaction may be carried out at a temperature ranging from water cooling to the reflux temperature of the solvent.

According to the fifth mode of the method for producing the compound of the present invention, the compound in which 8 in the general formula (I) is one C(OR2)(OR3)CH3 group, It can be produced by ketalizing a compound in an organic solvent in the presence of an acid.

The ketalization reaction is a method known per se. Examples of the organic solvent used include benzene, 1-toluene, xylene, etc., and examples of the acid catalyst include p-
Examples include toluenesulfonic acid, pyridinium p-1' toluenesulfonate, and the reaction is carried out near the reflux temperature of the solvent.

The bronchodilator and brain function improving agent containing the novel xanthine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient of the present invention are usually prepared in the form of capsules, tablets, or thin strips. It is administered orally as granules, granules, syrups, powders, etc., or as injections and suppositories. These preparations can be manufactured by conventional methods by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral preparations and suppositories, excipients (lactose, D-mannitol, starch, crystalline cellulose, etc.), disintegrants (carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), binders (hydroxypropyl cellulose, Hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylene methylcellulose, sucrose, etc.), bases (polyethylene glycol, hard fat, etc.), etc. Preparation ingredients, or in the case of injections, solubilizers or solubilizers (distilled water for injection, physiological saline, propylene glycol, etc.) that can constitute aqueous or dissolution-type injections, pH regulators ( Inorganic acids, organic acids, or inorganic bases), stabilizers, and other formulation ingredients are used.

The dosage of this drug for treated patients depends on the patient's symptoms.
The usual daily dose for adults is 10 to 1 once per oral administration.
It is 0QOmg.

Effects As an example of the excellent effects of the compounds of the present invention, Table 1 shows the test results of isolated guinea pig tracheal relaxing effect as an indicator of bronchodilatory effect, and the test results of isolated canine mesenteric artery relaxing effect and as an indicator of brain function improving effect. The test results for the protective effect against complete cerebral ischemia in mice are shown in Tables 2 and 3, respectively.

Furthermore, Table 4 shows the test results of chronotropic effect in isolated guinea pig right atrium as an index of cardiac excitatory effect, which is a side effect.

In addition, as control drugs, theophylline and propene 1.
Filin was used.

? Experimental Example 1 Relaxation of Extracted Guinea Pig Trachea The trachea was removed from a male Hartley guinea pig (weighing around 500 g), and a chain specimen was prepared.

The specimens were suspended in a Lock-Ringer bath (37°C) through which a mixed gas of 95% 02 and 5% CO2 was aerated, and the relaxing effect of the test compound on resting tension was measured isotically. Test compounds were applied cumulatively into the bath. The effect of the test compound was to reduce the relaxation response of 10-'M isoproterenol by 10
When it is set to 0%, the concentration required for 50% relaxation (E
Dso value).

The results are shown in Table 1.

Table 1 As is clear from Table 1, the compound of the present invention exhibited superior tracheal relaxation activity compared to theophylline, a control drug.

Test Example 2 Relaxation effect on isolated canine mesenteric artery The mesenteric artery was extracted from a male and female hybrid dog (weighing around 10 kg), and a helical specimen 17 having a length of 20 mm and a width of 2 mm was prepared. The specimen was placed in a Krebsu-Henseleite liquid bath (37°C) with a gas mixture of 95% 02 and 5% C○2 aerated.
) was suspended under a load of 1,0 g, and the relaxing effect of the test compound on prostaglandin F2α (3×10 −′M) contraction was measured isometrically. Test compounds were applied cumulatively into the bath. The effect of the test compound was pavaberine 10-
When the relaxation response of 'M is taken as 100%, it is expressed as the concentration required to cause 50% relaxation (EDso value).

The results are shown in Table 2.

Table 2 Test Example 3 Protective effect against complete cerebral ischemia in mice Male ddY mice weighing approximately 25 g were used.Complete cerebral ischemia was induced by cutting the neck between the medulla oblongata and the spinal cord. Gasping time ranges from decapitation to final ga
sp). The test compounds, except for propentophylline, which was dissolved in distilled water, were suspended in a 0.5% carboxymethyl cellulose solution and administered orally 30 minutes before decapitation. Gasping time was evaluated at a dose of 50 mg/Kg.

The results are shown in Table 3.

Table 3 As is clear from Tables 2 and 3, the compound of the present invention exhibited superior brain function improving effects compared to the control drug propene 1/fillin.

Test Example 4 Chronotropic effect in isolated guinea pig right atrium The right atrium was extracted from a Hartle strain male guinea pig (weighing approximately 500 g), and a right atrium specimen was prepared.

0.5 g of the specimen was placed in a Krebs-Henseleite bath (30°C) with a gas mixture of 95% 02 and 5% CO2.
The subjects were suspended under a load of 100%, and the spontaneous heart rate of the right atrium was measured using a tachometer. Test compounds were applied cumulatively into the bath. The effect of the test compound is determined by the concentration required to increase the spontaneous beat rate by 15% (ED, 5
value).

The results are shown in Table 4.

Table 4 As is clear from Table 4, the compound of the present invention had an extremely weak cardiac excitatory effect compared to the control drugs theophylline and prevententphylline, and was found to be a highly safe compound.

Examples Hereinafter, the present invention will be explained by reference examples and examples.
The invention is not limited to the specific details of these examples.

Reference example 1 3-cyclopropyl-3,7-dihydro-7 (4-meth1
~xypenzyl)-1H-purine-2,6-sion 3-cyclopropyl-3,7-dihydro-IH brine-
4,00 g of 2,6-diamine, 3.10 mj' of 4-methoxypenzyl chloride, 2.87 g of potassium carbonate and N,
A mixture of 30 mρ of N-dimethylformamide was heated at 60°C.
The mixture was stirred for 2.5 hours. The reaction solution was poured into ice water and adjusted to pH 5 with 10% hydrochloric acid. Preparation 21 The crystals were collected by filtration and washed successively with water and isopropyl ether to obtain 5.65 g of pale yellow crystals. Recrystallized from NN-dimethylformamide ethanol, melting point 224.5
Colorless needles at ~226°C were obtained.

Elemental analysis value C+cHIeN40, theoretical value C, 61.53; H, 5.16・N, 17
．． 94 experimental value C. 61.48; H, 5.36N,
17.85 Compounds of Reference Examples 2 to 7 were obtained according to the method of Reference Example 1.

Reference example 2 3-cyclopropyl-3,7-dihydro-7methyl-I
H-purine-2,6-dione Properties Pale brown needle crystals (D
MF) Melting point 288-290°C Elemental analysis value C9H, oN402 Theoretical value C, 52.42; H, 4.89. N, 2
7.17 Experimental value C. 52.19: H. 4.98N
．． 26.9822 Reference Example 3 3-cyclopropyl-7-ethyl-3,7-dihydro-
IH-Purine-2.6-Diane Properties: Colorless needle crystals (E
tOH) Melting point 227.5-228.5°C Elemental analysis value C 1o H 1 2 N 40 2 Theoretical value C. 54.54;H. 5.49・N, 25
．． 44 Experimental value C. 54.61. H. 5.60・
N. 25. 48 Reference Example 4 3-Cyclopropyl-3,7-dihydro-7n-propyl-IH-purine-2,6-sion Properties Colorless needle crystals
(EtOH) Melting point 165-166°C Elemental analysis value C,,H,4N402 Theoretical value C, 56.40; H. 6.02: N. 2
3.92 Experimental value C, 56.28. H. 6.07・
N 23.96 Reference example 5 n-butyl-3-cyclopropyl-3, dihydro-IH
-Purine-2 6-Sion Properties Pale yellow needle crystals (Et
OH) Melting point: 154-155.5°C Elemental analysis value: C1. H,. N402 Theoretical value C, 58.05. H. 6.50. Experimental value
C. 57.81;H. 6.50N 22.57 7N. 22.37 7? Example 6 3-Cyclopropyl-3,7-dihydro n-pentyl-IH-purine-2,6-sion Properties Pale yellow prismatic crystals (is■-PrOH) Melting point 128-129.5°C Elemental analysis value C13Hl8N402 Theoretical value C. 59.53: H, 6.92: Experimental value
C. 59.60. H. 6.77. N, 21.36 N. 21.33 7-Reference Example 7 3-Cyclopropyl-7-n-hexyl-3,7dihydro-IH-purine-2,6-sion Properties Pale yellow platelet crystals (EtOH) Melting point 130.5-131. 5℃ Elemental analysis value C14H2oN402 Theoretical value C. 60.85. H. 7.29; N, 2
0.27 experimental value C. 60.87. H. 7.24:
N, 20.01 Example 1 3-Cyclopropyl-3,7-dihydro-7(4-methoxybenzyl)-1-(51 year old xohexyl)-1H-
Purine-2,6-dione 3-cyclopropyl-3,7-
A mixture of 4.00 g of dihydro-7(4-methoxybenzyl)-LH-purine-26-diamine, 2.75 g of 5-year-old xohexyl bromide, 2.13 g of potassium carbonate, and 26 mj of N,N-dimethylformamide was added to 60 9 at °C.
Stirred for 5 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue. The precipitated crystals were collected by filtration and washed successively with water and n-hexane to obtain 5.00 g of colorless crystals. Ethyl acetate -■-
Recrystallization from hexane gave colorless needles with a melting point of 113-114.5°C.

25 Elemental analysis value C22H26N404 Theoretical value C, 64.38. H. 6.38N, 13.
65 Experimental value C. 64.24. H. 6.26: N
．． 13.47 Example 2 3-cyclopropyl-3,7-dihydro-1(5-oxohexyl)-1H-purine-2,6dione 3-cyclopropyl-3,7-dihydro-7-(4-methoxy) benzyl)-1-(5-oxohexyl)-1H
-Purine-2,6-jisai 4.50g, Anisole 16
To a mixture of 7 ml and 20 mj of trifluoroacetic acid was added 0.20 ml of concentrated sulfuric acid while stirring at room temperature, and the mixture was heated under reflux for 10 hours. After evaporating the solvent and adding water and isopropyl ether to the residue, it was diluted with 10% sodium hydroxide aqueous solution.
It was set as H6. The precipitated crystals were collected by filtration and washed successively with water and n-hexane to obtain 2.55 g of slightly brown crystals. Recrystallization from ethanol gave colorless crystals with a melting point of 203-205°C.

26 Elemental analysis value C14H+sN403 Theoretical value C. 57.92. H, 6.25; N, 1
9.30 Experimental value C. 57.97; H, 6.19.
N, 19.19 Example 3 3-cyclopropyl-3,7-dihydro-7methyl-1
-(2-oxopropyl)-1H-purine-2,6-dione 3-cyclopropyl-3,7-dihydro-7methyl-I
H-purine-2 6-dione 3 80g, potassium carbonate 3.06g and N,N-dimethylformamide 38m
Add 1.85 ml of promoacetone to the mixture of j under stirring under water cooling.
was added dropwise, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The precipitated crystals were collected by filtration, and water and n
-Hexane to obtain 3.18 g of light brown crystals. Recrystallized from ethyl acetate, melting point 183-185°C
A light brown prism product was obtained.

Elemental analysis value C 12H 14N40 2 Theoretical value C.
54.96; H, 5.38; N. 21.36 Experimental value C. 54.85 H, 5.66 N 21.35 Based on the method of Example 3, a compound was obtained.

Examples 4 to 1 Example 4 3-Cyclopropyl-3,7-dihydro-7methyl-1
-(3-year-old xobutyl)-1H-purine-2,6-sion Properties Colorless crystals (AcOEt) Melting point 145-147°C Elemental analysis value C13H16N403 Theoretical value C, 56.51: H, 5.84; N, 2
0, 28 experimental value C, 56.43: H. 5.79;
N, 20.31 Example 5 3-cyclopropyl-3,7-dihydromethyl-1-(
AcOEt-n-Hexane
)7 Melting point 86.5-88°C Elemental analysis value C zH,sN40s Theoretical value C, 57.92; H. 6.25 Experimental value C
, 57.95: H. 6.29. N. 19.30 N 19.24 Example 6 3-cyclopropyl-3,7-dihydro-7methyl-l
-(5-oxohexyl)-1H-purine-2,6-dione Properties Colorless columnar crystals (iso-PrOH) Melting point 89
~90'C Elemental analysis value C,. H2. N403 Theoretical value C. 59.20; H, 6.62; N. 1
8.41 Experimental value C. 59. l6; H, 6.66:
N. 18.46 Example 7 3-cyclopropyl-7-ethyl-3,7-dihydro-
1-(21-year-old kissop mouth pill)-lH-purine-2,6-
ion properties Brown columnar crystals (iso-PrOH-iso-P
r20) 29 Melting point 163-165°C Elemental analysis value C 13 H + @N 40 3 Theoretical value C, 56.51; H, 5, 84: Experimental value C. 5
6.27. H. 5.83N, 20.28N, 20.23 Example 8 3-Cyclopropyl-7-ethyl-3,7-dihydro-
1-(31-year-old xobutyl)-1H-purine-2,6-sion Properties Light brown crystals (AcOEt) Melting point 130-132°C Elemental analysis values C. 4H. ．． N403 Theoretical value C. 57.92+H. 6.25;N. 1
9.30 Experimental value C, 57.85: H, 6.22;
N. 19.29 Example 9 3-Cyclopropyl-7-ethyl-3,7hydro-1-(4-oxopentyl)-1H phosphorus-2,6-sion Properties Pale yellow needle crystals (iso-Pr20) 30 Zip melting point 91~93°C Elemental analysis value C I5H20N40s Theoretical value C,
59. 20・H. 6.62 Experimental value C. 59.0
3: H, 6.47N N 18.41 18. 20 Example 10 3-cyclopropyl-7-ethyl-3,7-dihydro-
l-(5-oxohexyll)-1H-purine-2,6
-Gold properties Colorless needle crystals (iso-PrOH) Melting point 98
~101'C Elemental analysis value C16H22N403 Theoretical value C, 60.36; H, 6.96N. 17.
60 Experimental value C, 60. 19・H. 6.77N
17.60 Example 11 3-cyclopropyl-3,7-dihydro-1 (2-oxopyl)-7-n-propyl-1 purine-2 6-
Acion properties Pale yellow plate-like crystals (AcOEt-iso-Pr2
0)H Melting point 123-125°C Elemental analysis value C, 4H 18N 40, Theoretical value C.
57.92. H. 6.25・N. 19.30 Experimental value C. 57.95. H. 6.13;N. 19.5
8 Example 12 3-Cyclopropyl-3,7-dihydro-1-(3-year-old xobutyl)-7-n-propyl-IH purine-2 6
-Sion properties Colorless needle crystals (iso-Pr20) Melting point 83
~85°C Elemental analysis value C + s H 2 0 N 40 s Theoretical value C. 59.20;H. 6.62;N. 18
, 41 experimental value C, 59.28: H. 6.61N1
8.52 Example 13 3-Cyclopropyl-3,7-dihydro(41-year-old xopentyl)-7-n-probylpurine-2,6-dientyl Properties Colorless plate-like crystals (iso-Pr20) 1 IH Melting point 65-66°C Elemental analysis value C, 6 H22N 40 3 Theoretical value C, 60.36. H, 6.96; N. 17.6
0 experimental value C. 60.28H, 6.96. N. 17
．． 48? Example 14 3-cyclopropyl-3,7-dihydro-1=(51 year old xohexyl)-7-n-propyl-IH purine-2,
6-Dione Properties Colorless crystal (iso-PrOH) Melting point 84~
86°C Elemental analysis value C1 H 2 4N 4 0 3 Theoretical value
C. 61.43;H. 7.28;N. 16, 86
Experimental value C. 61.26;H. 7.22: N. 1
6.74 Example 15 7-n-Butyl-3-cyclopropyl-3,7dihydro-1-(5-oxohexyl)-LH purine-2,6-
Characteristics Colorless needle crystals (iso-PrOH - iso
-Pr20)33 Melting point 54-56°C Elemental analysis value C + 8H 26N 4 0, l Theoretical value C, 62. 41・H, 7.56: N, 1
6.17 Experimental value C, 62.32; H. 7.54:
N. 16.08 Example 16 3-cyclopropyl-3,7-dihydro-1=(51 year old xohexyl)-7-n-pentyl-IH purine-2,
6-Dione Properties Colorless needle crystals (iso-PrOH - iso
-Pr20) Melting point 51-53°C Elemental analysis value C, 9H28N40, theoretical value C, 63.31; H. 7.83;N. 1
5.54 Experimental value C. 63.30; H, 7.88;
N, 15.29 Example 17 3-cyclopropyl-7-n-hexyldihyde-1
-(5-oxohexyl)-purine-2,6-sion Properties Colorless needle crystals (iso-Pr20) 34 37 1 H Melting point 49-51°C Elemental analysis value C 2 0 H 3 o N 4 0 s
Theoretical value C, 64.15. H, 8.07. N,1
4.96 Experimental value C. 64.21;H. 8.15;
N, 14.63 Example 18 3-cyclopropyl-3,7-dihydro-7methyl-1
((2-Methyl-1,3-dioxolan-2-yl)methyl]-IH-purine-2,6-dione 3-cyclopropyl-3,7-dihydro-7methyl-1
-(2-year-old kissop pill) -1H-purine-2,6-di-saiken 1.60g, ethylene glycol 3.40mj',
A mixture of 1.16 g of p-toluenesulfonic acid l hydrate and 160 ml of benzene was added to a Dean-Stark t
Heat to reflux for 43.5 hours using a rap apparatus (occasionally removing the resulting water). The reaction solution was washed successively with an aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain colorless crystals. 186g of melting point was obtained. A colorless prism product was obtained which was recrystallized from ethyl acetate at 30-135°C.

Elemental analysis value C, 4H, 8N404 Theoretical value C, 54.89; H, 5.92. N. 1
8.29 Experimental value C, 54.97. H, 5.88:
N. 18.59 According to the method of Example 18, Example l
9 compounds were obtained.

Example 19 3-cyclopropyl-3,7-dihydro-7methyl-1
- (4- (2-methyl-1,3-dioxolane-2
-yl)butyl]-IH-purine 2,6-dione Properties Pale yellow plate (AcOEt) Melting point 134-135.5°C Elemental analysis value C17H24N404 Theoretical value C, 58. 61・H, 6.94; N
．． 16.08 Experimental value C. 58.51; H, 6.9
5: N. 15.93 Effects of the Invention The novel xanthine derivative represented by the general formula (I) and its pharmacologically acceptable salts produced in this way have a bronchodilatory effect and a brain function improving effect, It is extremely useful as a medicine.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a hydrogen atom, a 4-methoxybenzyl group,
C_1 to C_6 linear or branched alkyl group or C_3 to C_6 cycloalkyl group, n is an integer of 1 to 4, A is -COCH_3 group or -C(OR^2)(
OR^3) represents CH_3 group, where R^2 and R^3
each represents an alkyl group of C_1 to C_3, or R^2 and R^3 together represent a polymethylene group of C_2 to C_4. ) A xanthine derivative and a pharmacologically acceptable salt thereof.