JPH06239862A - Xanthine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as a therapeutic agent for Parkinson's disease, geriatric dementia, depression, osteoporosis, etc. CONSTITUTION:A compound of formula I {R1 to R3 are H or lower alkyl; Q1 to Q3 are H, lower alkyl, lower alkoxy or halogen; X is C0R4 (R4 is H, hydroxyl, lower alkyl, etc.) or SO2R5 [R5 is hydroxyl, lower alkoxy, group of formula II [R6 and R7 are H, (substituted) alkyl, aryl, group of formula III ((m) is 1-3; Rg and R9 are H or lower alkyl), etc.], etc.]} such as 4,5- dimethoxy-beta-(7-methyl-1,3-dipropylxanthin-8-yl)styrene-2-sulfonic acid. The compound of formula I is obtained by sulfonylating a xanthine derivative of formula IV with a sulfonylating agent (e.g. chlorosulfonic acid) by using a reaction solvent (e.g. carbon tetrachloride, etc.). The reaction is preferably carried out at -40 to 70 deg.C for 30 minutes to 3 hours.

Description

Detailed Description of the Invention

[0001]

The present invention relates to various diseases derived from hyperactivity of adenosine A2 receptor (for example, Parkinson's disease, senile dementia, depression, asthma or osteoporosis).
To a novel 8-substituted xanthine derivative or a pharmacologically acceptable salt thereof, which is expected to have a therapeutic action against

[0002]

2. Description of the Prior Art Adenosine is known to exhibit a weakened action of a neurotransmitter, a bronchospasm action, a bone resorption promoting action and the like via an A2 receptor. Therefore, adenosine A2 receptor antagonists (hereinafter referred to as A2 antagonists) are used to enhance the function of adenosine A2 receptors, such as Parkinson's disease therapeutic agents, anti-dementia agents, depression therapeutic agents, anti-asthma agents or osteoporosis therapeutic agents. It is expected as a therapeutic drug for various diseases derived from it.

[0003]

[Chemical 5]

In the formula (A), R^1aAnd R^2aAre the same
Or differently methyl or propyl, R^3aIs hydrogen, R^4a
Is a substituted or unsubstituted phenyl, aromatic heterocyclic group,
Cycloalkyl, styryl or phenylethyl
Compounds are known to have adenosine antagonism
[Journal of Medicinal Chemistry (J.
 Med. Chem.),34, 1431 (1991)]. Also,
In formula (B), R ^1bAnd R^2bAre the same or different
R represents methyl or ethyl^3bRepresents methyl, and Y^1b
And Y^2bRepresents hydrogen, Z^bIs phenyl or 3,4
A compound which is 5-trimethoxyphenyl is disclosed in Japanese Examined Patent Publication No. 47
-26516 discloses as a cerebral stimulant
It In the formula (B), R^1bAnd R^2bAre the same
Differently represent hydrogen, propyl, butyl or allyl
And R^3bRepresents hydrogen or lower alkyl, and Y^1bAnd Y
^2bAre the same or different and represent hydrogen or methyl, Z^b
Is a substituted or unsubstituted phenyl, pyridyl, imidazo
Compounds that are ril, furyl or thienyl are adenosine
It has antagonism of A2 receptor and is effective for treating asthma and osteoporosis
Having fruit is disclosed in WO92 / 06976
ing. Furthermore, in the formula (B), R^1b, R^2bAnd R^3b
Is methyl, Y^1bAnd Y^2bOf the compounds in which is hydrogen, Z
^bIs phenyl (8-styrylcaffeine)
[Chem. Ber.,119, 15
25 (1986)] and Z^bAre pyridyl and quinolyl
Or methoxy-substituted or unsubstituted benzothiazolyl
A compound [Chem. Abst.
 ),60, 1741h (1964)] is known.
There is no description about the pharmacological action of.

[0005]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel xanthine derivative having an excellent A2 antagonistic activity or a pharmacologically acceptable salt thereof.

[0006]

The present invention provides a compound of formula (I)

[0007]

[Chemical 6]

[In the formula, R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl, and Q ₁ , Q ₂ and Q ₃ are the same or different and represent hydrogen, lower alkyl, lower alkoxy or halogen. And X is —COR ⁴ (wherein R ⁴ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy) or —SO ₂ R ⁵ [wherein R ⁵
Is hydroxyl, lower alkoxy, trifluoromethyl,

[0009]

[Chemical 7]

[Wherein R ⁶ and R ⁷ are the same or different and are hydrogen, hydroxyl-substituted or unsubstituted lower alkyl, aryl or

[0011]

[Chemical 8]

(Wherein m represents an integer of 1 to 3, R ⁸ and R ⁹ are the same or different and represent hydrogen or lower alkyl)] or

[0013]

[Chemical 9]

[Wherein Y is a single bond, O or N—R]
¹⁰ (in the formula, R ¹⁰ represents hydrogen or lower alkyl), and n1 and n2 each represent an integer of 1 to 3]] or a pharmacologically acceptable derivative thereof. Regarding salt. Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers.

In the definition of each group of the formula (I), lower alkyl is linear or branched and has 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -Butyl, pentyl, neopentyl, hexyl and the like can be mentioned, and aryl can be phenyl or naphthyl. The alkyl part of lower alkoxy has the same meaning as the above lower alkyl. Halogen means each atom of fluorine, chlorine, bromine, and iodine.

The pharmaceutically acceptable salts of compound (I) are
It includes pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochlorides, sulfates and phosphates, acetates,
Examples thereof include organic acid salts such as maleate, fumarate, tartrate, and citrate. Examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, magnesium salt, calcium salt. Alkaline earth metal salts, such as
Examples thereof include aluminum salts and zinc salts. Examples of the pharmacologically acceptable ammonium salts include salts such as ammonium and tetramethylammonium. Examples of the pharmacologically acceptable organic amine addition salts include morpholine and piperidine. And the pharmacologically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.

Next, the method for producing the compound (I) will be described. Production Method 1 Compound (I) wherein X is SO ₃ H (I
a) is obtained by the following reaction step.

[0018]

[Chemical 10]

(Wherein R ¹ , R ² , R ³ , Q ¹ , Q ² and Q ³ have the same meanings as described above) Step 1: Obtained by a known method (WO92 / 06976) or a modification thereof The compound (Ia) can be obtained by sulfonylating the xanthine derivative (II).

Examples of the sulfonylating agent include chlorosulfonic acid, sulfuric acid, sulfur trioxide, sulfur trioxide pyridine complex, sodium sulfite, sulfuryl chloride and the like. Examples of the reaction solvent include halogenated hydrocarbons such as carbon tetrachloride, chloroform and dichloroethane, thionyl chloride, nitromethane and dimethylformamide. When sulfuric acid is used as the sulfonylating agent, it is carried out without a solvent. The reaction is carried out at -40 to 70 ° C and is completed in 30 minutes to 3 hours.

Production Method 2 In compound (I), X is SO ₂ R ^5a (in the formula, R ^5a is R
Compound (Ib) which is a group other than hydroxyl and trifluoromethyl in the definition of ⁵ ) is obtained by the following reaction step.

[0022]

[Chemical 11]

(Wherein R ¹ , R ² , R ³ , R ^5a , Q ¹ ,
Q ² and Q ³ have the same meanings as above, and Z represents chlorine, bromine or iodine).

Step 2: Compound (III) can be obtained by reacting compound (Ia) obtained by the production method 1 or its sodium salt with a halogenating agent. Examples of the halogenating agent include phosphorus oxyhalide such as phosphorus oxychloride and phosphorus oxybromide, phosphorus halide such as phosphorus pentachloride, halogenated sulfonic acid such as chlorosulfonic acid, and thionyl halide such as thionyl chloride. To be As the reaction solvent, carbon tetrachloride, chloroform,
Halogenated hydrocarbons such as ethane dichloride, dioxane,
Ethers such as tetrahydrofuran, dimethylformamide and the like can be mentioned. Further, the reaction may be carried out without solvent using an excessive amount of the halogenating agent. The reaction is -20 to
Perform at 200 ° C. and finish in 0.5-24 hours.

Step 3: Compound (Ib) can be obtained by reacting compound (III) with the corresponding amine or alcohol in the presence of a base. Note that step 2
The compound (III) obtained in step (1) may be used in the reaction system without isolation after being produced. Examples of the base include pyridine, 2,6-lutidine, triethylamine, 4-dimethylaminopyridine, N-methylmorpholine and the like. The reaction solvent is appropriately selected from those shown in Step 1. The reaction is carried out at -80 to 50 ° C for 0.5 to 2
It ends in 4 hours.

Production method 3: In compound (I), X is CO
(Wherein, R ^4a represents a lower alkoxy in the definition of R ⁴⁾ R ^4a compound is (Ic) and compound in (I) X
Compound (Id) in which is COOH can be obtained by the following reaction step.

[0027]

[Chemical 12]

(Wherein R ¹ , R ² , R ³ , R ^4a , Q ¹ ,
Q ² and Q ³ are as defined above, Z'represents chlorine, bromine or iodine, and Ph represents phenyl).

Step 4: The compound (IV) obtained by a known method [Chem. Ber., 95 , 414 (1962)] is reacted with a phosphonium salt (V) in the presence of a base. (Ic) can be obtained. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkyl lithium such as butyl lithium, potassium tert-butoxide, and alkali such as potassium tert-amyl alcoholate. Examples include metal alkoxides. As the reaction solvent, toluene, aromatic hydrocarbons such as xylene, dioxane, ethers such as tetrahydrofuran, dimethylformamide,
Examples include dimethyl sulfoxide and the like. The reaction is 0-1
Perform at 20 ° C. and finish in 0.5 to 24 hours.

Step 5: The ester group of compound (Ic) is hydrolyzed in the presence of a suitable additive to give compound (Ic).
d) can be obtained. As the additive, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, calcium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, lithium halides such as lithium chloride, potassium tert- Examples thereof include alkali metal alkoxides such as butoxide. As the reaction solvent, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, and optionally water are mixed and used. The reaction is carried out at 0 to 120 ° C. and is completed in 0.5 to 24 hours.

Production Method 4: In compound (I), X is CO
Compound (Iea) and compound (Id), which are CH ₃ , are
It is obtained by the following reaction step.

[0032]

[Chemical 13]

(Wherein R ¹ , R ² , R ³ , Q ¹ , Q ² and Q ³ have the same meanings as described above, R ¹¹ represents lower alkyl, and Z ″ represents bromine or iodine) R Lower alkyl in the definition of ¹¹ has the same meaning as the above lower alkyl.

Step 6: Trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, or N-phenyl-N- in the presence of a base in the compound (V) obtained according to a known method [EP565377] or its equivalent.
(Trifluoromethanesulfonyl) Compound (VI) by reacting trifluoromethanesulfonamide
Can be obtained.

As the base, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine,
Examples thereof include organic amines such as pyridine and inorganic carbonates such as potassium carbonate. As a reaction solvent, methylene chloride,
Examples thereof include halogenated hydrocarbons such as ethane dichloride. The reaction is carried out at -30 to 100 ° C and is completed in 0.5 to 10 hours.

Step 7: Compound (VI) or a known method [EP565377] or a compound (VII) obtained in accordance with it, is reacted with a tin compound (VIII) in the presence of a transition metal catalyst to give compound (IX).
Can be obtained. Examples of transition metal catalysts include palladium catalysts such as dichlorobis (triphenylphosphine) palladium and palladium acetate. Examples of the tin compound (VIII) include (1-ethoxyvinyl) tributyltin. Examples of the reaction solvent include aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane and tetrahydrofuran, dimethylformamide and dimethylsulfoxide. Depending on the reaction, lithium chloride may be added appropriately. The reaction is 0
Perform at 120 ° C. and finish in 0.5 to 24 hours.

Step 8: Compound (Iea) can be obtained by hydrolyzing the vinyl ether group of compound (IX) in the presence of a suitable acid. As the acid, hydrochloric acid, p
-Proton acids such as toluenesulfonic acid and the like.
As the reaction solvent, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, ketones such as acetone and 2-butanone, dimethylformamide, dimethylsulfoxide, pyridine, water and the like are mixed and used as necessary. The reaction is 0-120 ℃
And finish in 0.5 to 24 hours.

Step 9: Compound (Ida) can be obtained by subjecting compound (Iea) to a haloform reaction in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples of the halogen used in the haloform reaction include bromine and iodine. As the reaction solvent, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, water and the like may be mixed and used as necessary. The reaction is carried out at 0 to 120 ° C. and is completed in 0.5 to 24 hours.

Production Method 5: In Compound (I), X is CO
(Wherein, R ^4b is hydrogen or lower alkyl in the definition of R ⁴⁾ R ^4b compound is (Ie) is obtained by the following reaction step.

[0040]

[Chemical 14]

(Wherein R ¹ , R ² , R ³ , R ^4b , Q ¹ ,
Q ² and Q ³ have the same meanings as above, and Z ′ ″ represents chlorine, bromine or iodine)

Step 10: Compound (II) can be reacted with 1 equivalent of compound (X) in the presence of a Lewis acid to give compound (Ie). 1 for Lewis acid
˜3 equivalents, preferably 2 equivalents of aluminum trichloride and the like. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane and dichloroethane.
The reaction is carried out at 0 ° C to room temperature and is completed in 1 to 24 hours.

The target compound in the above-mentioned production method can be isolated and purified by a purification method commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. it can. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is. When it is obtained in a free form, it may be dissolved in a suitable solvent or It may be suspended and added with an acid or a base to form a salt.

Compound (I) has, for example, geometric isomers of E / Z , but the present invention includes all possible isomers including these geometric isomers and mixtures thereof.
If E / Z separation is desired, it may be isolated and purified by a fractionation method such as fractional crystallization, fractional precipitation, fractional dissolution, and the like. The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

Specific examples of the compound (I) are shown in Table 1.

[0046]

[Table 1]

[0047]

[Table 2]

[0048]

[Table 3]

[0049]

[Table 4]

[0050]

[Table 5]

Next, the pharmacological action of compound (I) will be described in Test Examples. Test Example 1 Acute toxicity test A test compound was orally (po; 300 mg / kg) administered to 3 groups of 3 dd male mice each having a body weight of 20 ± 1 g. The death condition 7 days after administration was observed and the minimum lethal dose (MLD) value was calculated. The test results of the compound (I) are shown in Table 2. According to the test results,
Compound (I) has low toxicity and can be safely used in a wide dose range.

[0052]

[Table 6]

Test Example 2 Adenosine Receptor Antagonism (Adenosine A2 Receptor Binding Test) The method of Bruns et al. [Molecular Pharmacology (Mo
l. Pharmacol.), 29 , 331 (1986)] with some modifications. Rat striatum was chilled on ice
mM Trishydroxymethylaminomethane hydrochloride (TrisHCl)
Polytron homogenizer (Kinem) in buffer (pH 7.7)
atica). Centrifuge suspension (50,000 x
g, 10 minutes), and then the same amount of 50 mM TrisH was added to the obtained precipitate.
Cl buffer was added and resuspended, and the same centrifugation was performed. The final precipitate obtained was adjusted to a tissue concentration of 5 mg (wet weight) / ml with 50 mM Tris HCl buffer [10 mM magnesium chloride, adenosine deaminase 0.02 units / mg tissue].
(Manufactured by Sigma) was added thereto and suspended.

1 ml of the above-prepared tissue suspension was treated with tritium-labeled N-ethylcarboxamide adenosine ( ³ H-NEC
A: 26 curie / mmol; Amersham) (final concentration 3.8
50 μl of a mixture of nM) and cyclopentyladenosine (CPA; Sigma) (final concentration 50 nM) and 50 μl of the test compound were added. The mixture was allowed to stand at 25 ° C. for 120 minutes, then subjected to rapid suction filtration on a glass fiber filter paper (GF / C; manufactured by Whatman), and immediately washed 3 times with 5 ml of ice-cooled 50 mM TrisHCl buffer. Transfer the glass fiber filter paper to a vial and
XH; Wako Pure Chemical Industries, Ltd.) was added, and the radioactivity was measured with a liquid scintillation counter (Packard).

The inhibition rate of the test compound for A2 receptor binding ( ³ H-NECA binding) was calculated by the following formula.

[0056]

[Equation 1]

(Note) The total amount of binding is the amount of ³ H-NECA binding radioactivity in the absence of the test compound. The non-specific binding amount is the amount of ³ H-NECA binding radioactivity in the presence of 100 μM CPA. The amount of binding in the presence of a drug is the amount of ³ H-NECA binding radioactivity in the presence of various concentrations of test compounds. In addition, tritium-labeled N-ethylcarboxamide adenosine ( ³ H-
NECA: 26 curie / mmol; Amersham) (final concentration
3.8 nM) and cyclopentyladenosine (CPA; Sigma)
CGS 21680 { ³ H-2- [p- (2-carboxyethyl) phenethylamino] -5 '-(N-ethylcarboxamide) labeled with tritium instead of 50 μl mixture with (final concentration 50 nM)
Adenosine: 40 Curie / mmol; New England Nuclear
Manufactured by [The Journal of Pharmacology and Experimental Therapeutics (J. Pha
rmacol. Exp. Ther.), 251 , 888 (1989)}
The amount of radioactivity bound to the A2 receptor was measured by the same procedure as above except that 50 μl (final concentration 4.0 nM) was used.

A2 receptor binding of test compounds ( ³ H-CGS 2168
The inhibition rate for 0 binding) was calculated by the following formula.

[0059]

[Equation 2]

(Note) The total binding amount is the amount of ³ H-CGS 21680 binding radioactivity in the absence of the test compound. The non-specific binding amount is the amount of ³ H-CGS 21680 binding radioactivity in the presence of 100 μM CPA. The binding amount in the presence of a drug is the amount of ³ H-CGS 21680 binding radioactivity in the presence of various concentrations of a test compound.

The results are shown in Table 3. The Ki value in the table was calculated from the following equation.

[0062]

[Equation 3]

(Note) In the formula, IC ₅₀ is 50% inhibitory concentration and L is
Concentration of ³ H-NECA or ³ H-CGS 21680, Kd is ³ H-NECA
Alternatively, the dissociation constant of ³ H-CGS 21680, C is the concentration of CPA,
Kc represents the inhibition constant of CPA.

[0064]

[Table 7]

The compound (I) or a pharmaceutically acceptable salt thereof shows a strong anti-A2 activity. Therefore, the drug containing the compound (I) as an active ingredient is effective for various diseases derived from hyperfunction of the adenosine A2 receptor (for example, Parkinson's disease, senile dementia, depression, asthma or osteoporosis).

Test Example 3 Action on haloperidol-induced catalepsy Parkinson's disease is a disease based on degeneration and cell death of the substantia nigra-striatal dopamine nerve. Administration of haloperidol (a dopamine D ₁ / D ₂ antagonist) causes catalepsy by postsynaptic D ₂ receptor blockade. This haloperidol-induced catalepsy is known as a classic model for reproducing Parkinson's disease by drug administration [European Journal of Pharmacol., 182 , 327 (199).
0)].

An experiment was carried out using five 5-week-old male ddY mice (body weight 22 to 24 g, Japan SLC) per group. Haloperidol (Janssen) was suspended in 0.3% CMC, and 1.0 mg / kg was intraperitoneally administered to the mouse. The test compound is Tween8
After adding 0 [polyoxyethylene (20) sorbitan monooleate], it was used as a suspension with distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.). In addition, L-DOPA (L-DOPA; manufactured by Kyowa Hakko Kogyo Co., Ltd.) and benserazide hydrochloride (benserazide)
HCl; manufactured by Kyowa Hakko Kogyo Co., Ltd.) was used as a 0.3% CMC suspension. Suspension containing a test compound or a suspension containing no test compound [Tw 1 hour after intraperitoneal administration of haloperidol
Distilled water for injection with een80 added (Otsuka Pharmaceutical Co., Ltd.);
Control] orally (0.1 ml per 10 g mouse weight)
), And 1 hour after the administration of the test compound, one animal at a height of 4.5
Catalepsy was measured by sequentially suspending only both forelimbs and both hindlimbs of a mouse on a table having a width of 1.0 cm and a width of 1.0 cm. All test compounds were orally administered at 10 mg / kg, and the control drug was L-dopa 100 m
G / kg and benserazide 25 mg / kg were combined and administered intraperitoneally. The cataleptic score and criteria are shown below.

Score Duration of catalepsy 0: Both frontal and hindlimb suspensions last less than 5 seconds of posture with the pedestal hung 1: Five postures with the forelimb hung on the pedestal Holds for more than 10 seconds but less than 10 seconds, hind limbs lasts less than 5 seconds
Hind limbs last less than 5 seconds 3: Both forelimbs and hind limbs hang on the table for more than 5 seconds, less than 10 seconds Fore limbs hang on table for less than 5 seconds and hind limbs Duration of 5 seconds or more 4: Keep the posture for 10 seconds or more with the forelimbs hanging on the table,
Hind limbs last for 5 seconds or more and less than 10 seconds Hold the posture of the hind limbs for 5 seconds or more and less than 10 seconds, hind limbs last for 10 seconds or more 5: Both forelimbs and hind limbs remain on the table Duration of the posture is 10 seconds or more

The effect was judged by totaling the catalepsy scores of 5 animals per group (25 points in total). When the total score was 20 points or less, it was determined to be effective. The number of catalepsy remission reaction animals is the number of cases in which the catalepsy score was 4 or less in 5 cases. The catalepsy remission rate was shown as a percentage of the decrease in the total score of the test compound-administered group with respect to the total score of the control group.

The results are shown in Table 4.

[0071]

[Table 8]

Test Example 4 Action on Clonidine-induced Aggressive Behavior Aggressive behavior induced by intraperitoneal administration of clonidine [European Journal of Pharmacology (Eu
r. J. Pharmacol.), 29 , 374 (1968), and the enhancing effect of the test compounds was examined.
The experiment was carried out using two male mice of one strain (Japan SLC). After adding Tween80, the test compound was suspended in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.), and clonidine hydrochloride (manufactured by Sigma Co.) was dissolved in physiological saline (Otsuka Pharmaceutical Co., Ltd.). Using. Suspension containing test compound or suspension without test compound (control) was orally administered (0.1 ml per 10 g of mouse body weight) and the test compound was administered.
After 60 minutes, clonidine 20 mg / kg was intraperitoneally administered. Immediately after the administration of clonidine, the number of aggressive behaviors of the mice was measured for 30 minutes. To determine the effect, the values of the number of attacks in the control group and the test compound-administered group were compared [significant difference test: Student's t-test].

The results are shown in Table 5.

[0074]

[Table 9]

The compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention, as an active ingredient,
It can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. These pharmaceutical compositions are preferably in unit dose form suitable for oral or injection administration.

Any useful pharmacologically acceptable carrier can be used in the preparation of compositions in oral dosage form. Oral liquid preparations such as suspensions and syrups can be prepared by using water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, p. It can be produced by using antiseptics such as hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint and the like. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrating agents such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl. It can be produced by using a binder such as cellulose or gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin and the like. Tablets and capsules are the most useful oral unit dosages because they are easy to administer. Solid pharmaceutical carriers are used in the production of tablets and capsules.

The injection can be prepared by using a carrier made of distilled water, salt solution, glucose solution or a mixture of salt water and glucose solution. At this time, according to a conventional method, it is prepared as a solution, suspension or dispersion using an appropriate solubilizing agent and suspending agent. The compound (I) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an injection in the above-mentioned pharmaceutical form, and its effective dose and frequency of administration are the administration form, the age of the patient. , Usually from 0.01 to
25 mg / kg is administered in 3 to 4 divided doses.

In addition, compound (I) can also be administered by inhalation in the form of an aerosol, a finely divided powder or a spray solution. For aerosol administration, the compounds may be dissolved in a suitable pharmaceutically acceptable solvent such as ethyl alcohol or a combination of miscible solvents and used in admixture with a pharmaceutically acceptable spray base. .

The embodiments of the present invention will be described below with reference to Examples, Reference Examples and Preparation Examples.

[0080]

【Example】

Example 1 (E) -4,5-dimethoxy-β- (7-methyl-1,
3-dipropylxanthin-8-yl) styrene-2-
Sulfonic acid (Compound 1) (E) -8- (3,4-dimethoxystyryl) -7-methyl-1,3-dipropylxanthine (WO92 / 06
976 gazette) 2.41 g (5.84 mmol) was dissolved in 11 ml of thionyl chloride, and 1.17 ml (17.53 mmol) of chlorosulfonic acid was added dropwise at 0 ° C. After stirring at room temperature for 30 minutes, the reaction solution was carefully poured into ice water. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 1,2.77 g (yield 93%) of a compound as a yellow powder.

Melting point: 191.5-193.5 ° C. Elemental analysis value: C ₂₂ H ₂₈ N ₄ O ₇ S.H ₂ O theoretical value (%): C 51.76, H 5.92, N 10.97 Actual value (%): C 51.71, H 6.01, N 10.75 IR (KBr) ν _max (cm ^-1 ): 3750 (br), 1716, 1681, 15
42, 1507.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
63 (1H, d, J = 16.3Hz), 7.42 (1H, s), 7.37 (1H, s), 7.05
(1H, d, J = 16.3Hz), 4.04 (3H, s), 4.00 (2H, t, J = 7.4H
z), 3.87 (3H, s), 3.84 (2H, t, J = 7.4Hz), 3.79 (3H,
s), 1.90-1.55 (4H, m), 0.92-0.84 (6H, m). FAB-MS: 493 (M + H) ⁺ .

Example 2 (E) -N, N-diethyl-4,5-dimethoxy-β-
(7-Methyl-1,3-dipropylxanthin-8-yl) styrene-2-sulfonamide (Compound 2) The compound 1 obtained in Example 1 (1.00 g, 1.96 mmol) was added to dimethylformamide (20 ml). And thionyl chloride 0.29 ml (3.92 mmol) under ice cooling.
Was dripped. After stirring at room temperature for 10 minutes, ice-cooling again,
1.02 ml (9.80 mmol) of diethylamine was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was mixed with 50 ml of water.
Injected. The mixture was extracted 3 times with 20 ml of chloroform, the extract was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by column chromatography (eluting solvent: 65% ethyl acetate / hexane) and then recrystallized from cyclohexane / toluene to obtain 2,320 mg of compound (yield 30%) as a pale yellow powder.

Melting point: 227.1-227.7 ° C. Elemental analysis value: C ₂₆ H ₃₇ N ₅ O ₆ S Theoretical value (%): C 57.02, H 6.81, N 12.79 Actual value (%): C 56.94, H 6.86, N 12.87 IR (KBr) ν _max (cm ^-1 ): 2962, 1696, 1658, 1595,
1543, 1510, 1440.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.46
(1H, d, J = 15.5Hz), 7.58 (1H, s), 7.14 (1H, s), 6.73 (1
H, d, J = 15.5Hz), 4.08 (3H, s), 4.02 (3H, s), 3.98 (3H,
s), 4.15-3.94 (4H, m), 3.32 (4H, q, J = 7.3Hz), 1.88-
1.60 (4H, m), 1.12 (6H, t, J = 7.3Hz), 1.00-0.87 (6H,
m). FAB-MS: 548 (M + H) ⁺ .

Example 3 (E) -N, N-dipropyl-4,5-dimethoxy-β
-(7-Methyl-1,3-dipropylxanthine-8-
Yl) Styrene-2-sulfonamide (Compound 3) 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 2.68 ml (19.6 ml) of dipropylamine.
Was used in the same manner as in Example 2. The obtained crude crystals were recrystallized from cyclohexane / toluene to obtain the compound 3,450 mg (yield 40%) as a pale yellow powder.

Melting point: 207.8-208.5 ° C. Elemental analysis value: C ₂₈ H ₄₁ N ₅ O ₆ S Theoretical value (%): C 58.41, H 7.18, N 12.16 Actual value (%): C 58.34, H 7.45, N 12.14 IR (KBr) ν _max (cm ^-1 ): 2874, 1699, 1656, 1560,
1509.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.47
(1H, d, J = 15.8Hz), 7.57 (1H, s), 7.13 (1H, s), 6.73
(1H, d, J = 15.8Hz), 4.08 (3H, s), 4.02 (3H, s), 3.98 (3
H, s), 4.11-3.90 (4H, m), 3.19 (4H, t, J = 7.9Hz), 1.9
0-1.45 (8H, m), 1.00-0.90 (6H, m), 0.81 (6H, t, J = 7.3
FAB-MS: 576 (M + H) ⁺ .

Example 4 (E) -4,5-Dimethoxy-β- (7-methyl-1,
3-dipropylxanthin-8-yl) -2-piperidinosulfonyl styrene (Compound 4) Compound 1, 1.00 g (1.96 mmol) obtained in Example 1 and piperidine 1.93 ml (19.6). Was used in the same manner as in Example 2. The obtained crude crystals were recrystallized from dimethyl sulfoxide / water,
Compound 4,600 mg (yield 55%) was obtained as a pale yellow powder.

Melting point: 266.5-268.2 ° C. Elemental analysis value: C ₂₇ H ₃₇ N ₅ O ₆ S Theoretical value (%): C 57.94, H 6.66, N 12.51 Actual value (%): C 57.64, H 6.84, N 12.14 IR (KBr) ν _max (cm ^-1 ): 1696, 1656, 1508.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.53
(1H, d, J = 15.8Hz), 7.53 (1H, s), 7.17 (1H, s), 6.77
(1H, d, J = 15.8Hz), 4.10 (3H, s), 4.02 (3H, s), 3.97
(3H, s), 4.11-3.90 (4H, m), 3.20-3.10 (4H, m), 1.90-
1.40 (10H, m), 1.00-0.90 (6H, m). FAB-MS: 560 (M + H) ⁺ .

Example 5 (E) -4,5-dimethoxy-β- (7-methyl-1,
Fumarate salt of 3-dipropylxanthin-8-yl) -2- (4-methylpiperazin-1-ylsulfonyl) styrene (Compound 5) Compound 1 obtained in Example 1, 1.00 g (1.96) 1.08 ml (9. mmol) and 4-methylpiperazine (9.
(8 mmol) was used and the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from ethanol to obtain the compound 5,390 mg (0.679 mmol; yield 35%) as a pale yellow powder. Isopropanol 15m
It was dissolved in 1 and a solution of fumaric acid (79 mg, 0.679 mmol) in isopropanol was added. The precipitated crystals were collected by filtration and dried to obtain 329 mg of the fumarate salt of compound 5 as a pale yellow powder.

Melting point: 248.8-250.0 ° C (decomposition) IR (KBr) ν _max (cm ^-1 ): 3450 (br), 1695, 1654, 15
45, 1508. NMR (270MHz; DMSO-d ₆ ) δ (ppm): 8.39 (1H, d, J =
15.8Hz), 7.65 (1H, s), 7.340 (1H, s), 7.37 (1H, d, J = 1
5.8Hz), 4.07 (3H, s), 4.00 (3H, s), 3.99 (2H, t, J = 7.4
Hz), 3.89 (3H, s), 3.85 (2H, t, J = 7.6Hz), 3.45-2.30
(11H, m), 1.75-1.50 (4H, m), 0.90-0.80 (6H, m). FAB-MS: 575 (M + H) ⁺ .

Example 6 (E) -N- [2- (dimethylamino) ethyl] -N-
Methyl-4,5-dimethoxy-β- (7-methyl-1,
3-dipropylxanthin-8-yl) styrene-2-
Sulfonamide (Compound 6) Using 1,500 mg (0.98 mmol) of the compound obtained in Example 1 and 0.62 ml (4.9 mmol) of N, N, N'-trimethylethylenediamine, almost the same as Example 2. The same operation was performed. The obtained crude crystals were recrystallized from cyclohexane / toluene to give compound 6,280 mg
(Yield 48%) was obtained as yellow needle crystals.

Melting point: 199.1-199.7 ° C. Elemental analysis value: C ₂₇ H ₄₀ N ₆ O ₆ S Theoretical value (%): C 56.23, H 6.99, N 14.57 Actual value (%): C 55.82, H 7.14, N 14.19 IR (KBr) ν _max (cm ^-1 ): 1696, 1657, 1511, 1441.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.50
(1H, d, J = 15.8Hz), 7.55 (1H, s), 7.15 (1H, s), 6.74
(1H, d, J = 15.8Hz), 4.09 (3H, s), 4.02 (3H, s), 4.15-
4.05 (2H, m), 3.97 (3H, s), 4.00-3.90 (2H, m), 3.23 (2
H, t, J = 7.0Hz), 2.89 (3H, s), 2.47 (2H, t, J = 7.0Hz),
2.19 (6H, s), 1.85-1.50 (4H, m), 1.00-0.90 (6H, m) .FA
B-MS: 577 (M + H) ⁺ .

Example 7 (E) -β- (7-Methyl-1,3-dipropylxanthin-8-yl) styrene-4-carboxylic acid methyl ester (Compound 7) and (Z) -β- (7 -Methyl-1,
3-dipropylxanthin-8-yl) styrene-4-
Carboxylic acid methyl ester (Compound 8) (4-methoxycarbonylbenzyl) triphenylphosphonium bromide 353 mg (0.719 mmol)
In a 3 ml suspension of tetrahydrofuran in 60% sodium hydride (25.9 mg,
0.648 mmol) was added and the mixture was heated at 50 ° C. for 20 minutes. After ice cooling, the compound c obtained in Reference Example 3, 100 mg
(0.360 mmol) was slowly added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into 10 ml of water, and ether 1 was added.
Extract 3 times with 0 ml. After washing the extract with saturated saline,
It was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was separated and purified by column chromatography (eluting solvent: 25% ethyl acetate / hexane) to give compound 7,4
0.0 mg (yield 27%) and compound 8,39.5 mg
(Yield 27%) was obtained as a light yellow powder.

Compound 7: NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.07 (2H, d, J = 8.
4Hz), 7.82 (1H, d, J = 15.8Hz), 7.67 (2H, d, J = 8.4Hz),
7.01 (1H, d, J = 15.8Hz), 4.11 (2H, t, J = 7.4Hz), 4.09
(3H, s), 3.95 (2H, t, J = 7.1Hz), 3.94 (3H, s), 1.91-
1.60 (4H, m), 1.00-0.90 (6H, m). EI-MS: 410 (M) ⁺

Compound 8: NMR (270 MHz; CDCl ₃ ) δ (ppm): 7.97 (2H, d, J = 8.
4Hz), 7.54 (2H, d, J = 8.4Hz), 7.03 (1H, d, J = 12.4Hz),
6.47 (1H, d, J = 12.4Hz), 4.05-3.90 (4H, m), 3.92 (3H,
s), 3.78 (3H, s), 1.85-1.60 (4H, m), 1.05-0.90 (6H,
m) .EI-MS: 410 (M) ⁺

Example 8 (E) -4,5-Dimethoxy-β- (7-methyl-1,
3-dipropylxanthin-8-yl) styrene-2-
Sulfonamide (Compound 9) Using the compound 1 obtained in Example 1, 1.00 g (1.96 mmol) and concentrated ammonia water 0.6 ml, substantially the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from dioxane / water to give compound 9,670 mg (yield 7
0%) was obtained as yellow needles.

Melting point: 266.1-267.8 ° C. Elemental analysis value: C ₂₂ H ₂₉ N ₅ O ₆ S.H ₂ O theoretical value (%): C 51.85, H 6.13, N 13.74 Actual value (%): C 51.99, H 6.10, N 13.48 IR (KBr) ν _max (cm ^-1 ): 1695, 1654, 1510.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
40 (1H, d, J = 15.8Hz), 7.50 (1H, s), 7.48 (1H, s), 7.45
(2H, s), 7.23 (1H, d, J = 15.8Hz), 4.05 (3H, s), 3.95
(3H, s), 3.85 (3H, s), 4.10-3.80 (4H, m), 1.75-1.51
(4H, m), 0.89 (3H, t, J = 7.3Hz), 0.87 (3H, t, J = 7.3H
z). FAB-MS: 492 (M + H) ⁺ .

Example 9 (E) -N-phenyl-4,5-dimethoxy-β- (7
-Methyl-1,3-dipropylxanthin-8-yl)
Styrene-2-sulfonamide (Compound 10) Almost the same as in Example 2 except that 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 1.85 ml (20.3 mmol) of aniline were used. The operation was performed. The crude crystals obtained were recrystallized from toluene to give compound 10,26
1 mg (23% yield) was obtained as a pale yellow powder.

Melting point: 247.4-249.1 ° C. Elemental analysis value: C ₂₈ H ₃₃ N ₅ O ₆ S Theoretical value (%): C 59.24, H 5.86, N 12.34 Actual value (%): C 59.17, H 5.88, N 12.18 IR (KBr) ν _max (cm ^-1 ): 1695, 1657, 1509.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
0.25 (1H, brs), 8.34 (1H, d, J = 15.5Hz), 7.39 (2H, s),
7.18-7.05 (5H, m), 6.98-6.93 (1H, m), 4.04 (2H, t, J
= 7.0Hz), 4.00 (3H, s), 3.92 (3H, s), 3.86 (2H, t, J =
7.3Hz), 3.77 (3H, s), 1.81-1.52 (4H, m), 0.92 (3H, t,
J = 7.3Hz), 0.88 (3H, t, J = 7.3Hz). FAB-MS: 568 (M + H) ⁺ .

Example 10 (E) -β- (7-Methyl-1,3-dipropylxanthin-8-yl) -3,4,5-trimethoxystyrene-2-sulfonic acid (Compound 11) (E ) -7-Methyl-1,3-dipropyl-8- (3,3
4,5-Trimethoxystyryl) xanthine (WO92
/ 06976 gazette) 10.0 g (22.6 mmol)
Using, the same operation as in Example 1 was performed. The crude crystals obtained were recrystallized from acetonitrile to give compound 11,
3.83 g (yield 32%) was obtained as a pale yellow powder.

Melting point: 247.9-249.6 ° C. Elemental analysis value: C ₂₃ H ₃₀ N ₄ O ₈ S.1.5 H ₂ O theoretical value (%): C 50.26, H 6.05, N 10.19 actual value (%): C 50.53 , H 6.06, N 10.32 IR (KBr) ν _max (cm ^-1 ): 1719, 1681.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
80 (1H, d, J = 15.8Hz), 7.03 (1H, s), 6.84 (1H, d, J = 15.
8Hz), 4.02 (3H, s), 3.89 (3H, s), 3.76 (3H, s), 3.74
(3H, s), 4.05-3.90 (2H, m), 3.86-3.73 (2H, m), 1.79-
1.53 (4H, m), 0.91-0.84 (6H, m). FAB-MS: 523 (M + H) ⁺ .

Example 11 (E) -β- (7-Methyl-1,3-dipropylxanthin-8-yl) -3,4,5-trimethoxystyrene-2-sulfonamide (Compound 12) Example The compound 11 obtained in 10 was 1.80 g (3.4
(5 mmol) and 1.0 ml of concentrated aqueous ammonia were used, and substantially the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from acetonitrile to give a compound 12,200 mg.
(Yield 11%) was obtained as yellow needle crystals.

Melting point: 242.9-244.7 ° C. Elemental analysis value: C ₂₃ H ₃₁ N ₅ O ₇ S Theoretical value (%): C 52.96, H 5.99, N 13.43 Actual value (%): C 52.89, H 5.86, N 13.11 IR (KBr) ν _max (cm ^-1 ): 1692, 1648, 1496.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
59 (1H, d, J = 15.5Hz), 7.16 (2H, s), 7.14 (1H, s), 7.02
(1H, d, J = 15.5Hz), 4.03 (3H, s), 3.98 (3H, s), 3.91
(3H, s), 3.83 (3H, s), 4.05-3.90 (2H, m), 3.85-3.70
(2H, m), 1.79-1.50 (4H, m), 0.91-0.84 (6H, m). FAB-MS: 522 (M + H) ⁺ .

Example 12 (E) -N- [2- (dimethylamino) ethyl] -N-
Fumarate salt of methyl-β- (7-methyl-1,3-dipropylxanthin-8-yl) -3,4,5-trimethoxystyrene-2-sulfonamide (Compound 13) Obtained in Example 10. Compound 1.1.40 g (2.6
(8 mmol) and 0.39 ml (5.36 mmol) of N, N, N'-trimethylethylenediamine were used, and the same operation as in Example 2 was performed. Crude crystals obtained 670
mg was dissolved in 10 ml of isopropanol, and fumaric acid 9 was added.
7 mg (0.84 mmol) was added. The precipitated crystals were collected by filtration and dried to give 550 mg of fumarate of compound 13.
(Yield 28%) was obtained as a yellow powder.

Melting point: 191.6-192.9 ° C. Elemental analysis value: C ₂₈ H ₄₂ N ₆ O ₇ S.C ₄ H ₄ O ₄ Theoretical value (%): C 53.17, H 6.41, N 11.63 Actual value (%): C 53.43, H 6.34, N 11.64 IR (KBr) ν _max (cm ^-1 ): 1695, 1650.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
44 (1H, d, J = 15.5Hz), 7.17 (1H, s), 7.03 (1H, d, J = 15.
5Hz), 6.59 (2H, s), 4.03 (3H, s), 3.99 (3H, s), 3.88
(3H, s), 3.83 (3H, s), 4.05-3.90 (2H, m), 3.85-3.70
(2H, m), 3.21 (2H, t, J = 6.6Hz), 2.80 (3H, s), 2.47 (2
H, t, J = 6.6Hz), 2.19 (6H, s), 1.80-1.48 (4H, m), 0.9
1-0.84 (6H, m). FAB-MS: 607 (M + H) ⁺ .

Example 13 (E) -N- (2-hydroxyethyl) -4,5-dimethoxy-β- (7-methyl-1,3-dipropylxanthin-8-yl) styrene-2-sulfonamide (Compound 14) Using compound 1,1.00 g (1.96 mmol) obtained in Example 1 and 1.2 ml (20.3 mmol) of ethanolamine, substantially the same operation as in Example 2 was performed.
The crude crystals obtained were recrystallized from toluene to give compound 14,
600 mg (yield 55%) was obtained as yellow plate crystals.

Melting point: 213.4-215.0 ° C. Elemental analysis value: C ₂₄ H ₃₃ N ₅ O ₇ S Theoretical value (%): C 53.82, H 6.21, N 13.08 Actual value (%): C 54.03, H 6.31, N 12.89 IR (KBr) ν _max (cm ^-1 ): 1700, 1655, 1510.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
45 (1H, d, J = 15.5Hz), 7.60 (1H, brs), 7.53 (1H, s),
7.44 (1H, s), 7.25 (1H, d, J = 15.5Hz), 4.70 (1H, t, J =
5.2Hz), 4.05 (3H, s), 3.96 (3H, s), 3.86 (3H, s), 4.10
-3.80 (4H, m), 3.40-3.32 (1H, m), 2.95 (1H, t, J = 6.0H
z), 1.78-1.50 (4H, m), 0.92-0.84 (6H, m). FAB-MS: 536 (M + H) ⁺ .

Example 14 (E) -4,5-Dimethyl-β- (7-methyl-1,3)
-Dipropylxanthin-8-yl) styrene-2-sulfonic acid (Compound 15) (E) -8- (3,4-Dimethylstyryl) -7-methyl-1,3-dipropylxanthine (WO92 / 069
No. 76), 4.9 g (12.9 mmol) was used, and the substantially same operation as in Example 1 was performed. The obtained crude crystals were recrystallized from ethanol to obtain 15,3.09 g of the compound (yield 67%) as a pale yellow powder.

Melting point:> 280 ° C. Elemental analysis value: C ₂₂ H ₂₈ N ₄ O ₅ S.H ₂ O theoretical value (%): C 55.22, H 6.32, N 11.71 Actual value (%): C 55.37, H 6.42, N 11.76 IR (KBr) ν _max (cm ^-1 ): 1719, 1679.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
61 (1H, d, J = 15.8Hz), 7.67 (1H, s), 7.59 (1H, s), 7.07
(1H, d, J = 15.8Hz), 4.03 (3H, s), 4.00 (2H, t, J = 7.2H
z), 3.85 (2H, t, J = 7.0Hz), 2.27 (3H, s), 2.24 (3H,
s), 1.80-1.50 (4H, m), 0.89 (3H, t, J = 7.3Hz), 0.87 (3
H, t, J = 7.2Hz). FAB-MS: 461 (M + H) ⁺ .

Example 15 (E) -β- (1,3-Diethyl-7-methylxanthin-8-yl) -5-methoxystyrene-2-sulfonic acid (Compound 16) Compound s obtained in Reference Example 18 , 4.0 g (11.3 mmol) were used, and an operation similar to that of Example 1 was performed.
The obtained crude crystals were recrystallized from dioxane / water to obtain 3.27 g (yield 34%) of compound 16 as light yellow plate crystals. Melting point: 208.9-210.5 ° C Elemental analysis value: C ₁₉ H ₂₂ N ₄ O ₆ S · H ₂ O theoretical value (%): C 50.43, H 5.35, N 12.38 actual measurement value (%): C 50.13, H 5.36, N 12.34 IR (KBr) ν _max (cm ^-1 ): 1714, 1673, 1652, 1560.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
65 (1H, d, J = 15.8Hz), 7.77 (1H, d, J = 8.6Hz), 7.37 (1
H, d, J = 2.6Hz), 7.14 (1H, d, J = 15.8Hz), 6.87 (1H, d
d, J = 8.6, 2.6Hz), 4.08 (2H, q, J = 6.9Hz), 3.93 (2H,
q, J = 7.2Hz), 3.84 (3H, s), 1.27 (3H, t, J = 6.9Hz), 1.
14 (3H, t, J = 7.2Hz) .EI-MS: 434 (M) ⁺ .

Example 16 (E) -β- (1,3-Diethyl-7-methylxanthin-8-yl) -5-methoxystyrene-2-sulfonamide (Compound 17) The compound obtained in Example 15 16,1.00 g (2.3
(0 mmol) and 0.7 ml of concentrated aqueous ammonia were used, and the same operation as in Example 2 was performed. The obtained crude crystals were subjected to high performance liquid chromatography (column: YMC-pac
k, SH-365-10, 30i.d. × 500 mm, elution solvent: 40% acetonitrile / water, flow rate: 40 ml / min) to obtain 17,55 mg (yield 6%) of compound as a pale yellow powder. It was

Melting point: 236.5-237.2 ° C. Elemental analysis value: C ₁₉ H ₂₃ N ₅ O ₅ S.0.5 H ₂ O Theoretical value (%): C 51.57, H 5.47, N 15.83 Actual value (%): C 51.86 , H 5.30, N 15.76 IR (KBr) ν _max (cm ^-1 ): 1700, 1659.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
41 (1H, d, J = 15.5Hz), 7.87 (1H, d, J = 8.6Hz), 7.53 (1
H, d, J = 2.3Hz), 7.44 (2H, brs), 7.31 (1H, d, J = 15.8H
z), 7.10 (1H, dd, J = 8.6, 2.3Hz), 4.06 (3H, s), 4.10-
4.00 (2H, m), 3.95-3.85 (2H, m), 3.91 (3H, s), 1.27 (3
H, t, J = 6.9Hz), 1.14 (3H, t, J = 7.2Hz). FAB-MS: 434 (M + H) ⁺ .

Example 17 (Z) -β- (7-Methyl-1,3-dipropylxanthin-8-yl) styrene-4-carboxylic acid (Compound 1
8) The compound 8, 2.64 g (6.44 mmol) obtained in Example 7 was dissolved in a mixed solvent of 60 ml of dioxane and 40 ml of water to obtain 1.08 g (2) of lithium hydroxide monohydrate.
5.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. 1N
After neutralization with hydrochloric acid, extraction was performed 3 times with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from toluene / cyclohexane to obtain the compound 18, 2.26 g (yield 89%) as a yellow powder.

Melting point: 214.7-216.9 ° C. Elemental analysis value: C ₂₁ H ₂₄ N ₄ O ₄ .0.1 CH ₃ C ₆ H ₅ Theoretical value (%): C 64.25, H 6.16, N 13.81 Actual value (%): C 64.34, H 6.33, N 13.91 IR (KBr) ν _max (cm ^-1 ): 1723, 1687, 1656.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 7.
87 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz), 7.08 (1H,
d, J = 12.5Hz), 6.70 (1H, d, J = 12.5Hz), 3.87 (3H, s),
3.90-3.77 (4H, m), 1.66-1.49 (4H, m), 0.86 (3H, t, J
= 7.6Hz), 0.79 (3H, t, J = 7.6Hz). EI-MS: 396 (M) ⁺ .

Example 18 (E) -β- (7-Methyl-1,3-dipropylxanthin-8-yl) styrene-4-carboxylic acid (Compound 1
9) Compound 18 obtained in Example 17, 1.25 g (3.1
5 mmol) and iodine 40 mg (0.32 mmol)
125 ml of toluene solution of was heated under reflux for 6.5 hours.
After cooling, 0.1 M sodium thiosulfate aqueous solution and chloroform were added and stirred. The precipitated crystals were collected by filtration and recrystallized from ethanol to give the compound (19,740 mg, yield 5
9%) as ocher needles.

Melting point: 273.4-275.4 ° C. Elemental analysis value: C ₂₁ H ₂₄ N ₄ O ₄ Theoretical value (%): C 63.62, H 6.10, N 14.13 Actual value (%): C 63.49, H 6.25, N 14.12 IR (KBr) ν _max (cm ^-1 ): 1726, 1691, 1633, 1543.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 7.
96 (2H, d, J = 8.2Hz), 7.90 (2H, d, J = 8.2Hz), 7.70 (1H,
d, J = 15.5Hz), 7.47 (1H, d, J = 15.5Hz), 4.06 (3H, s),
4.00 (2H, t, J = 6.8Hz), 3.84 (2H, t, J = 7.0Hz), 1.81-
1.49 (4H, m), 0.92-0.80 (6H, m). EI-MS: 396 (M) ⁺ .

Example 19 (E) -β- (1,3-Diethyl-7-methylxanthin-8-yl) -2-methoxystyrene-4-carboxylic acid methyl ester (Compound 20) (2-methoxy-4 -Methoxycarbonylbenzyl) triphenylphosphonium bromide 938 mg (1.7
To a suspension of 99 mmol) in tetrahydrofuran (10 ml) was added 1.09 ml (1.799 mmol) of a 1.65M n-butyllithium / hexane solution under ice cooling and replacement with argon, and the mixture was stirred at room temperature for 30 minutes. After ice-cooling, a suspension of 300 mg (1.199 mmol) of the compound f obtained in Reference Example 6 in 1 ml of tetrahydrofuran was slowly added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. After cooling with ice, 1.8 ml of a 1N ammonium chloride aqueous solution was added. Ethyl acetate was added to the reaction solution, washed with saturated saline three times, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give compound 20,422.
mg (yield 85%) was obtained and further recrystallized from hexane / ethyl acetate to obtain a yellow powder.

Melting point: 239.0-241.2 ° C. Elemental analysis value: C ₂₁ H ₂₄ N ₄ O ₅ Theoretical value (%): C 61.16, H 5.86, N 13.58 Actual value (%): C 61.28, H 5.99, N 13.62 IR (KBr) ν _max (cm ^-1 ): 1719, 1687, 1652, 1304,
1231.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.02
(1H, d, J = 15.8Hz), 7.69-7.59 (3H, m), 7.18 (1H, d, J
= 15.8Hz), 4.23 (2H, q, J = 7.3Hz), 4.09 (2H, q, J = 7.3H)
z), 4.07 (3H, s), 4.01 (3H, s), 3.95 (3H, s), 1.39 (3
H, t, J = 7.3Hz), 1.27 (3H, t, J = 7.3Hz).

Example 20 (E) -2-Methoxy-β- (7-methyl-1,3-dipropylxanthin-8-yl) styrene-4-carboxylic acid methyl ester (Compound 21) (2-methoxy- 4-methoxycarbonylbenzyl) triphenylphosphonium bromide 2.81 g (5.3
90 mmol), 1.65 M n-butyllithium / hexane solution 3.27 ml (5.396 mmol), and the compound c obtained in Reference Example 3, 1.00 g (3.593 mmol), were used as in Example 19. Almost the same operation was performed. The obtained crude crystals were recrystallized from hexane / ethyl acetate to obtain 21,203 mg (yield 33%) of compound as yellow granular crystals.

Melting point: 198.5-200.4 ° C. Elemental analysis value: C ₂₃ H ₂₈ N ₄ O ₅ .0.4 H ₂ O theoretical value (%): C 61.70, H 6.48, N 12.51 Actual value (%): C 61.77, H 6.42, N 12.45 IR (KBr) ν _max (cm ^-1 ): 1704, 1655, 1541, 1436,
1234.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.00
(1H, d, J = 15.8Hz), 7.69-7.59 (3H, m), 7.19 (1H, d, J =
15.8Hz), 4.15-3.98 (4H, m), 4.06 (3H, s), 4.01 (3H,
s), 3.94 (3H, s), 1.88-1.65 (4H, m), 1.00 (3H, t, J = 7.
6Hz), 0.97 (3H, t, J = 7.6Hz).

Example 21 (E) -β- (1,3-Diethyl-7-methylxanthin-8-yl) -2-methoxystyrene-4-carboxylic acid (Compound 22) Compound 20 obtained in Example 19 , 108 mg (0.2
(62 mmol) was suspended in a mixed solvent of 2 ml of tetrahydrofuran, 2 ml of ethanol and 1 ml of water, 55 mg (1.311 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at room temperature overnight. 2N Hydrochloric acid was added to the reaction solution to make it acidic, and the obtained crystals were collected by filtration. The crude crystals were separated and purified by column chromatography (eluting solvent: chloroform / methanol / acetic acid = 40/1/1) to give compound 2
2,25 mg (24% yield) was obtained and further recrystallized from isopropanol to obtain a yellow powder.

Melting point:> 280 ° C. Elemental analysis value: C ₂₀ H ₂₂ N ₄ O ₅ .0.6 H ₂ O theoretical value (%): C 58.70, H 5.71, N 13.69 Actual value (%): C 58.55, H 5.66, N 13.46 IR (KBr) ν _max (cm ^-1 ): 1689, 1648, 1543, 1434,
1305.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
00 (1H, d, J = 8.3Hz), 7.94 (1H, d, J = 15.8Hz), 7.58 (1
H, d, J = 8.3Hz), 7.56 (1H, s), 7.44 (1H, d, J = 15.8H
z), 4.07 (2H, q, J = 6.9Hz), 4.04 (3H, s), 3.96 (3H,
s), 3.92 (2H, q, J = 6.9Hz), 1.27 (3H, t, J = 6.9Hz), 1.
13 (3H, t, J = 6.9Hz).

Example 22 (E) -2-Methoxy-β- (7-methyl-1,3-dipropylxanthin-8-yl) styrene-4-carboxylic acid (Compound 23) Obtained in Example 20. Compound 21,300 mg (0.6
(81 mmol) was used and the substantially same operation as in Example 21 was performed. The obtained crude crystals were recrystallized from isopropanol to obtain 23,203 mg of compound (yield 70%) as a yellow powder.

Melting point: 284.7-286.1 ° C. Elemental analysis value: C ₂₂ H ₂₆ N ₄ O ₅ Theoretical value (%): C 61.96, H 6.14, N 13.14 Actual value (%): C 61.74, H 6.31, N 13.12 IR (KBr) ν _max (cm ^-1 ): 2864, 1691, 1650, 1531,
1435.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
3.04 (1H, brs), 7.98 (1H, d, J = 7.9Hz), 7.91 (1H, d, J
= 15.8Hz), 7.57 (1H, d, J = 7.9Hz), 7.56 (1H, s), 7.42
(1H, d, J = 15.8Hz), 4.03 (3H, s), 4.00 (2H, t, J = 7.3H
z), 3.96 (3H, s), 3.83 (2H, t, J = 7.3Hz), 1.80-1.67 (2
H, m), 1.63-1.50 (2H, m), 0.91 (3H, t, J = 7.3Hz), 0.8
7 (3H, t, J = 7.3Hz).

Example 23 (E) -8- (3-Acetylstyryl) -1,3-diethyl-7-methylxanthine (Compound 24) Compound h obtained in Reference Example 8, 1.00 g (2.480)
Mmol) and 17 mg (0.024 mmol) of dichlorobis (triphenylphosphine) palladium were suspended in 20 ml of dimethylformamide, and the atmosphere was replaced with argon.
(1-Ethoxyvinyl) tributyltin 0.84 ml
(2.486 mmol) was added, and the mixture was stirred at 120 ° C. for 3 hours. After cooling with ice, 2N ammonium fluoride was added and the mixture was filtered. The filtrate was diluted with chloroform, washed with saturated saline, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was treated with 20 ml of tetrahydrofuran and 2 ml of tetrahydrofuran.
It was suspended in a mixed solvent of 5 ml of N hydrochloric acid and stirred at room temperature for 2 hours and 30 minutes. The reaction solution was neutralized with 2N sodium hydroxide and diluted with chloroform. The organic layer was washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.
The residue was separated and purified by column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) and then recrystallized from ethyl acetate to obtain 24,482 mg of compound (yield 53%) as pale yellow flocculent crystals. .

Melting point: 221.4-221.8 ° C. Elemental analysis value: C ₂₀ H ₂₂ N ₄ O ₃ Theoretical value (%): C 65.56, H 6.05, N 15.29 Actual value (%): C 65.23, H 6.22, N 15.26 IR (KBr) ν _max (cm ^-1 ): 1679, 1650, 1542, 1441,
1276.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.19
(1H, s), 7.93 (1H, d, J = 7.9Hz), 7.84 (1H, d, J = 15.8H
z), 7.77 (1H, d, J = 7.9Hz), 7.52 (1H, t, J = 7.9Hz), 7.
01 (1H, d, J = 15.8Hz), 4.22 (2H, q, J = 6.9Hz), 4.10 (2H,
q, J = 6.9Hz), 4.09 (3H, s), 2.66 (3H, s), 1.39 (3H, t,
J = 6.9Hz), 1.27 (3H, t, J = 6.9Hz).

Example 24 (E) -β- (1,3-diethyl-7-methylxanthin-8-yl) styrene-3-carboxylic acid (Compound 2
5) 24,300 mg (0.8%) of the compound obtained in Example 23
19 mmol) in 3 ml of dioxane, 3 ml of water
432 mg (10.8 mmol) of sodium hydroxide and 0.13 ml (2.523 mmol) of bromine were added under ice-cooling, and then a solution of 3 ml of dioxane was slowly added under ice-cooling, followed by room temperature for 3 hours and 30 minutes. It was stirred. 5% after ice cooling
An aqueous sodium thiosulfate solution was added, and the mixture was acidified with 2N hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethanol / water to give compound 25,254 mg
(Yield 84%) was obtained as pale yellow needle crystals.

[0148] mp: 260.2-261.5 ° C. Elemental analysis: Calculated as _{C 19 H 20 N 4 O 4} · 0.3 H 2 0 (%): C 61.05, H 5.55, N 14.99 Found (%): C 60.99, H 5.49, N 14.89 IR (KBr) ν _max (cm ^-1 ): 1688, 1652, 1541, 1436,
1281, 1258.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
3.09 (1H, brs), 8.32 (1H, s), 8.03 (1H, d, J = 7.9Hz),
7.92 (1H, d, J = 7.6Hz), 7.73 (1H, d, J = 15.8Hz), 7.55
(1H, dd, J = 7.9, 7.6Hz), 7.45 (1H, d, J = 15.8Hz), 4.08
(2H, q, J = 6.9Hz), 4.06 (3H, s), 3.92 (2H, q, J = 6.9H
z), 1.27 (3H, t, J = 6.9Hz), 1.13 (3H, t, J = 6.9Hz).

Example 25 (E) -8- (3-Acetyl-4-methoxystyryl)
-7-Methyl-1,3-dipropylxanthine (Compound 26) Compound j obtained in Reference Example 10, 1.00 g (2.16)
8 mmol), 15 mg (0.021 mmol) of dichlorobis (triphenylphosphine) palladium and 0.74 ml of (1-ethoxyvinyl) tributyltin.
Using (2.190 mmol), substantially the same operation as in Example 23 was performed. The obtained crude crystals were recrystallized from ethyl acetate to obtain the compound 26,407 mg (yield 44%) as pale yellow needle crystals.

Melting point: 193.9-194.7 ° C. Elemental analysis value: C ₂₃ H ₂₈ N ₄ O ₄ Theoretical value (%): C 65.08, H 6.64, N 13.20 Actual value (%): C 65.11, H 6.71, N 13.23 IR (KBr) ν _max (cm ^-1 ): 1694, 1657, 1501, 1439,
1267.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.02
(1H, d, J = 2.3Hz), 7.75 (1H, d, J = 15.8Hz), 7.66 (1H,
dd, J = 8.6, 2.3Hz), 7.01 (1H, d, J = 8.6Hz), 6.85 (1H,
d, J = 15.8Hz), 4.13-3.95 (4H, m), 4.05 (3H, s), 3.97
(3H, s), 2.65 (3H, s), 1.90-1.65 (4H, m), 1.00 (3H,
t, J = 7.6Hz), 0.97 (3H, t, J = 7.6Hz).

Example 26 (E) -4-Methoxy-β- (7-methyl-1,3-dipropylxanthin-8-yl) styrene-3-carboxylic acid (Compound 27) Obtained in Example 25. Compound 26,200 mg (0.4
(71 mmol) was used, and an operation similar to that of Example 24 was performed. The obtained crude crystals were recrystallized from dioxane / water to obtain 27,190 mg (yield 95%) of compound 27 as a yellow powder.

Melting point: 209 ° C. (decomposition) IR (KBr) ν _max (cm ⁻¹ ): 1687, 1657, 1543, 1503,
1262. NMR (270MHz; DMSO-d ₆ ) δ (ppm): 12.78 (1H, br
s), 8.05 (1H, d, J = 2.3Hz), 7.89 (1H, dd, J = 8.6, 2.3H
z), 7.62 (1H, d, J = 15.8Hz), 7.26 (1H, d, J = 15.8Hz),
7.17 (1H, d, J = 8.6Hz), 4.02 (3H, s), 3.99 (2H, t, J =
7.3Hz), 3.87 (3H, s), 3.83 (2H, t, J = 7.3Hz), 1.77-1.
53 (4H, m), 0.90 (3H, t, J = 7.3Hz), 0.87 (3H, t, J = 7.3H
z). FAB-MS: 427 (M + H) ⁺ .

Example 27 (E) -8- (3-Acetyl-4-fluorostyryl)
-1,3-diethyl-7-methylxanthine (Compound 2
8) Compound m obtained in Reference Example 12, 500 mg (1.18
7 mmol), dichlorobis (triphenylphosphine) palladium 10 mg (0.014 mmol) and (1-ethoxyvinyl) tributyltin 0.41 ml.
Using (1.214 mmol), substantially the same operation as in Example 23 was performed. The obtained crude crystals were recrystallized from ethyl acetate to obtain 28,174 mg (yield 61%) of compound as yellow needle crystals.

Melting point: 238.1-239.3 ° C. Elemental analysis value: C ₂₀ H ₂₁ FN ₄ O ₃ .0.6 H ₂ O theoretical value (%): C 60.78, H 5.66, N 14.18 Actual value (%): C 60.50, H 5.42, N 14.31 IR (KBr) ν _max (cm ^-1 ): 1684, 1657, 1652, 1541,
1437.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 8.13
(1H, dd, J = 6.9, 2.3Hz), 7.78 (1H, d, J = 15.8Hz), 7.7
4-7.68 (1H, m), 7.20 (1H, dd, J = 10.6, 8.6Hz), 6.92 (1
H, d, J = 15.8Hz), 4.21 (2H, q, J = 6.9Hz), 4.09 (2H, q,
J = 6.9Hz), 4.08 (3H, s), 2.69 (3H, d, J = 5.0Hz), 1.38
(3H, t, J = 6.9Hz), 1.27 (3H, t, J = 6.9Hz).

Example 28 (E) -β- (1,3-Diethyl-7-methylxanthin-8-yl) -4-fluorostyrene-3-carboxylic acid (Compound 29) The compound obtained in Example 27. 28,450 mg (1.1
(65 mmol) was used, and an operation similar to that of Example 24 was performed. The obtained crude crystals were recrystallized from ethanol to obtain 29,187 mg (yield 41%) of compound as a light brown powder.

Melting point: 247 ° C. (decomposition) IR (KBr) ν _max (cm ⁻¹ ): 1695, 1658, 1547, 1538,
1440. NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.18-8.15 (1H,
m), 8.00-7.90 (1H, m), 7.67 (1H, d, J = 15.8Hz), 7.35-
7.28 (1H, m), 7.33 (1H, d, J = 15.8Hz), 4.06 (2H, q, J =
6.9Hz), 4.02 (3H, s), 3.91 (2H, q, J = 6.9Hz), 1.25 (3
H, t, J = 6.9Hz), 1.13 (3H, t, J = 6.9Hz) FAB-MS: 387 (M + H) ⁺ .

Example 29 (E) -8- (4-Acetyl-3-methoxystyryl)
-1,3-diethyl-7-methylxanthine (Compound 3
0) 200 mg of crude crystals of the compound q obtained in Reference Example 16, 6 m of dichlorobis (triphenylphosphine) palladium
g (0.009 mmol) and (1-ethoxyvinyl)
Using tributyltin (0.27 ml, 0.799 mmol), the substantially same operation as in Example 23 was performed to obtain compound 3
0.50 mg (yield 32%) was obtained and recrystallized from ethyl acetate to give yellow needle crystals.

Melting point: 236.1-237.2 ° C. Elemental analysis value: C ₂₁ H ₂₄ N ₄ O ₄ .0.3 H ₂ O theoretical value (%): C 62.77, H 6.17, N 13.94 measured value (%): C 62.90, H 6.16, N 13.79 IR (KBr) ν _max (cm ^-1 ): 1697, 1655, 1594, 1543,
1409.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 7.80
(1H, d, J = 8.3Hz), 7.78 (1H, d, J = 15.8Hz), 7.26 (1H,
d, J = 8.3Hz), 7.10 (1H, s), 6.99 (1H, d, J = 15.8Hz),
4.22 (2H, q, J = 6.9Hz), 4.09 (2H, q, J = 6.9Hz), 4.09 (3
H, s), 3.99 (3H, s), 2.63 (3H, s), 1.39 (3H, t, J = 6.9H
z), 1.27 (3H, t, J = 6.9Hz).

Example 30 (E) -β- (7-Methyl-1,3-dipropylxanthin-8-yl) styrene-4-sulfonic acid (Compound 3
1) (E) -7-methyl-1,3-dipropyl-8-styrylxanthine (WO92 / 06976) 500 m
g (1.42 mmol) was dissolved in 5 ml of chloroform, and 0.28 ml (4.26 mmol) of chlorosulfonic acid was added dropwise at 0 ° C. After heating under reflux for 3 hours, the reaction solution was poured into 20 ml of ice water. After separating the chloroform layer, the aqueous layer was extracted 5 times with tetrahydrofuran. Combine the organic layers,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
Compound 31,240 mg (yield 39%) was obtained as a pale yellow powder.

Melting point:> 270 ° C. IR (KBr) ν _max (cm ⁻¹ ): 3400 (br), 1676, 1543. NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 7.77 (2H, d, J =
8.4Hz), 7.66 (1H, d, J = 15.8Hz), 7.65 (2H, d, J = 8.4H
z), 7.38 (1H, d, J = 15.8Hz), 4.04 (3H, s), 4.00 (2H,
t, J = 7.9Hz), 3.84 (2H, t, J = 7.9Hz), 1.80-1.50 (4H,
m), 0.91 (3H, t, J = 7.5Hz), 0.87 (3H, t, J = 7.4Hz).

Reference Example 1 8-Hydroxymethyl-1,3-dipropylxanthine (Compound a) 5,6-Diamino-1,3-dipropyluracil [Journal of Medicinal Chemistry (J. Med. Ch.
em.), 28 , 487 (1985)] 10.0 g (44.
A mixture of 2 mmol) and 16.8 g (221 mmol) glycolic acid was heated at 110 ° C. for 15 minutes. After cooling, 60 ml of dioxane and 100 ml of water were added, and then sodium hydroxide was added to adjust the pH to 14. Three
After heating under reflux for 0 minutes, the mixture was cooled, and concentrated hydrochloric acid was added to neutralize it.
The precipitated crystals were collected by filtration and dried to give compound a, 10.6 g
(Yield 90%) was obtained as a white powder.

Melting point: 220.1-221.0 ° C. Elemental analysis value: C ₁₂ H ₁₈ N ₄ O ₃ Theoretical value (%): C 54.12, H 6.81, N 21.04 Actual value (%): C 53.94, H 6.97, N 20.85 IR (KBr) ν _max (cm ^-1 ): 3300 (br), 1703, 1632, 15
56, 1510.

NMR (90 MHz; DMSO-d ₆ ) δ (ppm): 4.
50 (2H, s), 4.15-3.80 (4H, m), 3.65-2.80 (2H, brs),
1.90-1.45 (4H, m), 1.10-0.80 (6H, m). EI-MS: 266 (M) ⁺ .

Reference Example 2 8-Hydroxymethyl-7-methyl-1,3-dipropylxanthine (Compound b) 1.00 g (3.76 mmol) of compound a obtained in Reference Example 1 was added to 30 ml of dimethylformamide. Dissolve and add 1.30 g (9.40 mmol) potassium carbonate, then 0.47 ml (7.52 mmol) methyl iodide,
The mixture was stirred at 50 ° C for 1 hour. Insoluble matter is filtered off and water 60 ml
Was added, and the mixture was extracted 3 times with 25 ml of chloroform. The extract was washed twice with water and then twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from cyclohexane to obtain 735 mg (yield 70%) of compound b as yellow needle crystals.

Melting point: 111.4-111.8 ° C. Elemental analysis value: C ₁₃ H ₂₀ N ₄ O ₃ Theoretical value (%): C 55.70, H 7.19, N 19.99 Actual value (%): C 55.73, H 7.45, N 19.64 IR (KBr) ν _max (cm ^-1 ): 3300 (br), 1706, 1665, 15
41.

NMR (90 MHz; CDCl ₃ ) δ (ppm): 4.76
(2H, s), 4.20-3.90 (4H, m), 4.02 (3H, s), 2.40 (1H, b
rs), 1.90-1.50 (4H, m), 1.05-0.80 (6H, m). EI-MS: 280 (M) ⁺ .

Reference Example 3 7-Methyl-1,3-dipropyl-8-xanthinecarbaldehyde (Compound c) Manganese dioxide 2 was added to a solution of the compound b obtained in Reference Example 2 (800 mg, 2.85 mmol) in 80 ml of chloroform. 0.48 g (28.5 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue is separated and purified by column chromatography (elution solvent: 1% methanol / chloroform),
Compound c, 440 mg (yield 56%), was obtained as a pale yellow powder.

Melting point: 129.8-130.4 ° C. IR (KBr) ν _max (cm ⁻¹ ): 1716, 1694, 1664, 1591,
1543. NMR (90MHz; CDCl ₃ ) δ (ppm): 9.95 (1H, s), 4.3
3 (2H, s), 4.15-3.90 (4H, m), 2.00-1.50 (4H, m), 1.05
-0.80 (6H, m). EI-MS: 278 (M) ⁺ .

Reference Example 4 1,3-Diethyl-8-hydroxymethylxanthine (Compound d) 5,6-Diamino-1,3-diethyluracil [Journal of American Chemical Society (J.
Am. Chem. Soc.), 75 , 114 (1953)] 5.
0 g (25.2 mmol) and 8.4 g glycolic acid
Using (111 mmol), substantially the same operation as in Reference Example 1 was performed. The obtained crude crystals are recrystallized from methanol,
Compound d (3.56 g, yield 60%) was obtained as white needle crystals.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
3.26 (1H, brs), 5.50 (1H, brs), 4.51 (2H, s), 4.02 (2
H, q, J = 6.9Hz), 3.93 (2H, q, J = 6.9Hz), 1.22 (3H, t,
J = 6.9Hz), 1.12 (3H, t, J = 6.9Hz). EI-MS: 238 (M) ⁺ .

Reference Example 5 1,3-Diethyl-8-hydroxymethyl-7-methylxanthine (Compound e) Using the compound d obtained in Reference Example 4, 2.00 g (8.40 mmol), Reference Example 2 Almost the same operation was performed.
The obtained crude crystals were recrystallized from hexane / ethyl acetate,
Compound e (1.88 g, yield 89%) was obtained as white needle crystals.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 5.
54 (1H, t, J = 5.9Hz), 4.58 (2H, d, J = 5.9HZ), 4.01 (2H,
q, J = 6.9Hz), 3.92 (2H, q, J = 6.9Hz), 3.91 (3H, s),
1.21 (3H, t, J = 6.9Hz), 1.12 (3H, t, J = 6.9Hz). EI-MS: 252 (M) ⁺ .

Reference Example 6 1,3-Diethyl-7-methyl-8-xanthinecarbaldehyde (Compound f) Using the compound e obtained in Reference Example 5, 1.00 g (3.96 mmol), Reference Example 3 Almost the same operation was performed.
The obtained crude crystals were recrystallized from hexane / ethyl acetate,
Compound f (404 mg, yield 41%) was obtained as pale yellow plate crystals.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 9.93
(1H, s), 4.35 (3H, s), 4.20 (2H, q, J = 6.9Hz), 4.10 (2
H, q, J = 6.9Hz), 1.37 (3H, t, J = 6.9Hz), 1.26 (3H, t,
J = 6.9Hz) .EI-MS: 250 (M) ⁺ .

Reference Example 7 (E) -8- (3-Bromostyryl) -1,3-diethylxanthine (Compound g) 5,6-Diamino-1,3-diethyluracil 2.0 g
(10.1 mmol) dioxane 34 ml-water 68 m
2.51 g of 3-bromocinnamic acid (11.1
Mmol) and 3- (3-diethylaminopropyl)-
1.90 g of 1-ethylcarbodiimide hydrochloride (15.2 g)
4) at room temperature while adjusting the pH to 5.5.
Stir for 0 minutes. After adding 4N sodium hydroxide to the reaction solution to adjust the pH to> 14, the mixture was heated under reflux for 20 minutes. After cooling, it was neutralized, and the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran / water to obtain 2.01 g of compound g (yield 37%) as light green plate crystals.

Melting point:> 270 ° C. Elemental analysis value: C ₁₇ H ₁₇ BrN ₄ O ₂ Theoretical value (%): C 52.46, H 4.40, N 14.39 Actual value (%): C 52.54, H 4.44, N 14.37 IR (KBr) ν _max (cm ^-1 ): 1683, 1636, 1492.

NMR (270 MHz; CF ₃ COOD) δ (ppm): 7.
99 (1H, d, J = 16.6Hz), 7.84 (1H, s), 7.70 (1H, d, J = 7.9
Hz), 7.62 (1H, d, J = 7.9Hz), 7.40 (1H, t, J = 7.9Hz),
7.19 (1H, d, J = 16.6Hz), 4.40-4.30 (4H, m), 1.53 (3H,
t, J = 7.2Hz), 1.41 (3H, t, J = 7.2Hz).

Reference Example 8 (E) -8- (3-Bromostyryl) -1,3-diethyl-7-methylxanthine (Compound h) Compound g, 2.5 g (6.43) obtained in Reference Example 7 50 mmol) was dissolved in 20 ml of dimethylformamide, and 2.22 g (16.1 mmol) of potassium carbonate was added, followed by 0.8 ml (12.9 mmol) of methyl iodide,
Stir at 70 ° C. for 70 minutes. After cooling, the insoluble material was filtered off, and water was added to the filtrate. After extraction with chloroform three times, the extract was washed with water three times and then with saturated saline twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 2.37 g (yield 92%) of crude crystals of compound h as a yellow solid, which was recrystallized from cyclohexane / toluene to give compound h.
Was obtained as a yellow powder.

Melting point: 187.3-188.2 ° C. Elemental analysis value: C ₁₈ H ₁₉ BrN ₄ O ₂ Theoretical value (%): C 53.61, H 4.75, N 13.89 Actual value (%): C 53.83, H 4.63, N 13.70 IR (KBr) ν _max (cm ^-1 ): 1694, 1654.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 8.
13 (1H, s), 7.76 (1H, d, J = 7.6Hz), 7.63 (1H, d, J = 15.
8Hz), 7.54 (1H, d, J = 8.9Hz), 7.46 (1H, d, J = 15.8Hz),
7.37 (1H, t, J = 8.2Hz), 4.11-4.03 (2H, m), 4.05 (3H,
s), 3.92 (2H, q, J = 6.9Hz), 1.26 (3H, t, J = 6,9Hz), 1.
13 (3H, t, J = 6.9Hz).

Reference Example 9 (E) -8- (3-Bromo-4-methoxystyryl)-
1,3-Dipropylxanthine (Compound i) 5,6-Diamino-1,3-dipropyluracil 3.0
Using g (13.3 mmol) and 3-bromo-4-methoxycinnamic acid (3.75 g, 14.6 mmol), substantially the same operation as in Reference Example 7 was performed. The obtained crude crystals were recrystallized from dioxane to give compound i (3.43 g, yield 58).
%) As yellow needles.

Melting point: 279.8-280.6 ° C. Elemental analysis value: C ₂₀ H ₂₃ BrN ₄ O ₃ Theoretical value (%): C 53.70, H 5.18, N 12.52 Actual value (%): C 53.77, H 5.20, N 12.49 IR (KBr) ν _max (cm ^-1 ): 1685, 1633, 1599, 1503,
1279.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
3.42 (1H, brs), 7.85 (1H, d, J = 2.0Hz), 7.61 (1H, dd,
J = 8.4, 2.0Hz), 7.55 (1H, d, J = 16.3Hz), 7.15 (1H, d,
J = 8.4Hz), 6.94 (1H, d, J = 16.3Hz), 3.98 (2H, t, J = 7.4
Hz), 3.89 (3H, s), 3.86 (2H, t, J = 7.4Hz), 1.80-1.52 (4
H, m), 0.89 (6H, t, J = 7.4Hz).

Reference Example 10 (E) -8- (3-Bromo-4-methoxystyryl)-
7-Methyl-1,3-dipropylxanthine (Compound j) Using the compound i obtained in Reference Example 9, 750 mg (1.68 mmol), substantially the same operation as in Reference Example 8 was performed.
The obtained crude crystals were recrystallized from hexane / ethyl acetate,
Compound j (588 mg, yield 76%) was obtained as pale yellow needle crystals.

Melting point: 209.4-210.8 ° C. Elemental analysis value: C ₂₁ H ₂₅ BrN ₄ O ₃ Theoretical value (%): C 54.67, H 5.46, N 12.14 Actual value (%): C 54.47, H 5.51, N 11.91 IR (KBr) ν _max (cm ^-1 ): 1693, 1656, 1542, 1500,
1264.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 7.83
(1H, d, J = 2.0Hz), 7.68 (1H, d, J = 15.8Hz), 7.48 (1H,
dd, J = 8.4, 2.0Hz), 6.92 (1H, d, J = 8.4Hz), 6.78 (1H,
d, J = 15.8Hz), 4.13-4.07 (2H, m), 4.06 (3H, s), 4.01-
3.97 (2H, m), 3.95 (3H, s), 1.90-1.65 (4H, m), 1.00 (3
H, t, J = 7.4Hz), 0.97 (3H, t, J = 7.4Hz).

Reference Example 11 (E) -8- (3-Bromo-4-fluorostyryl)-
1,3-Diethylxanthine (Compound k) 5,6-Diamino-1,3-diethyluracil 3.00
Using g (15.1 mmol) and 3-bromo-4-fluorocinnamic acid (4.08 g, 16.7 mmol), substantially the same operation as in Reference Example 7 was performed. The obtained crude crystals were recrystallized from dioxane to give compound k (2.90 g, yield 47).
%) As a pale yellow powder.

Melting point:> 300 ° C. Elemental analysis value: C ₁₇ H ₁₆ BrFN ₄ O ₂ Theoretical value (%): C 50.14, H 3.96, N 13.76 Actual value (%): C 50.27, H 3.80, N 13.66 IR (KBr) ν _max (cm ^-1 ): 1688, 1637, 1501, 1248.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
3.64 (1H, brs), 8.02 (1H, dd, J = 6.9,2.0Hz), 7.73-7.6
8 (1H, m), 7.60 (1H, d, J = 16.2Hz), 7.42 (1H, t, J = 8.6
Hz), 7.07 (1H, d, J = 16.2Hz), 4.06 (2H, q, J = 6.9Hz),
3.94 (2H, q, J = 6.9Hz), 1.26 (3H, t, J = 6.9Hz), 1.14 (3
H, t, J = 6.9Hz).

Reference Example 12 (E) -8- (3-Bromo-4-fluorostyryl)-
1,3-Diethyl-7-methylxanthine (Compound m) Compound k obtained in Reference Example 11, 2.50 g (6.14)
The same operation as in Reference Example 8 was performed. The obtained crude crystals were recrystallized from ethyl acetate to obtain 2.41 g (yield 93%) of compound m as yellow needle crystals.

Melting point: 217.6-219.2 ° C. Elemental analysis value: C ₁₈ H ₁₈ BrFN ₄ O ₂ Theoretical value (%): C 51.32, H 4.30, N 13.30 Actual value (%): C 51.52, H 4.20, N 13.34 IR (KBr) ν _max (cm ^-1 ): 1692, 1649, 1543, 1504,
1439.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 7.80
(1H, dd, J = 6.6, 2.0Hz), 7.70 (1H, d, J = 15.8Hz), 7.5
2-7.46 (1H, m), 7.16 (1H, t, J = 8.3Hz), 6.84 (1H, d, J
= 15.8Hz), 4.21 (2H, q, J = 6.9Hz), 4.09 (2H, q, J = 6.9H)
z), 4.07 (3H, s), 1.38 (3H, t, J = 6.9Hz), 1.26 (3H, t,
J = 6.9Hz).

Reference Example 13 (E) -1,3-diethyl-8- (3-methoxy-4-)
Methoxymethoxystyryl) xanthine (Compound n) 5,6-diamino-1,3-diethyluracil 4.0 g
(20.2 mmol) and 5.29 g (22.2 mmol) of 3-methoxy-4-methoxymethoxycinnamic acid were used, and an operation similar to that of Reference Example 7 was performed. The obtained crude crystals were recrystallized from dioxane to give compound n, 2.93 g
(Yield 36%) was obtained as pale yellow needle crystals.

Melting point: 223.4-224.3 ° C. Elemental analysis value: C ₂₀ H ₂₄ N ₄ O ₅ Theoretical value (%): C 59.99, H 6.04, N 13.99 Actual value (%): C 59.99, H 6.11, N 13.93 IR (KBr) ν _max (cm ^-1 ): 1698, 1640, 1512, 1258.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 1
3.46 (1H, brs), 7.60 (1H, d, J = 16.2Hz), 7.30 (1H, s),
7.10 (2H, m), 6.99 (1H, d, J = 16.2Hz), 5.19 (2H, s),
4.06 (2H, q, J = 6.9Hz), 3.94 (2H, q, J = 6.9Hz), 3.85 (3
H, s), 3.40 (3H, s), 1.26 (3H, t, J = 6.9Hz), 1.14 (3H,
t, J = 6.9Hz).

Reference Example 14 (E) -1,3-Diethyl-8- (3-methoxy-4-)
Methoxymethoxystyryl) -7-methylxanthine (Compound o) Using the compound n (2.0 g, 5.00 mmol) obtained in Reference Example 13, the substantially same operation as in Reference Example 8 was performed.
The obtained crude crystals were recrystallized from ethyl acetate to give compound o,
1.77 g (yield 85%) was obtained as yellow plate crystals.

Melting point: 179.4-180.6 ° C. Elemental analysis value: C ₂₁ H ₂₆ N ₄ O ₅ theoretical value (%): C 60.86, H 6.32, N 13.52 Actual value (%): C 61.02, H 6.46, N 13.43 IR (KBr) ν _max (cm ^-1 ): 1687, 1651, 1515, 1437,
1258.

NMR (270 MHz; CDCl ₃ ) δ (ppm): 7.74
(1H, d, J = 15.8Hz), 7.17 (2H, m), 7.10 (1H, s), 6.78
(1H, d, J = 15.8Hz), 5.28 (2H, s), 4.22 (2H, q, J = 6.9H
z), 4.09 (2H, q, J = 6.9Hz), 4.07 (3H, s), 3.96 (3H,
s), 3.54 (3H, s), 1.39 (3H, t, J = 6.9Hz), 1.27 (3H, t,
J = 6.9Hz).

Reference Example 15 (E) -1,3-diethyl-8- (4-hydroxy-3)
-Methoxystyryl) -7-methylxanthine (Compound p) Compound o obtained in Reference Example 14, 1.50 g (3.62)
(Mmol) was suspended in 30 ml of tetrahydrofuran, 9 ml of 2N hydrochloric acid was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution was neutralized with 2N sodium hydroxide under ice cooling, water was further added, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate to give compound p, 1.08 g (yield 8
1%) as yellow plate crystals.

Melting point: 185.3-186.5 ° C. Elemental analysis value: C ₁₉ H ₂₂ N ₄ O ₄ .H ₂ O theoretical value (%): C 58.75, H 6.23, N 14.42 Actual value (%): C 59.13, H 6.21, N 14.39 IR (KBr) ν _max (cm ^-1 ): 1687, 1657, 1650, 1515,
1276.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 9.
45 (1H, brs), 7.59 (1H, d, J = 15.8Hz), 7.39 (1H, d, J =
2.0Hz), 7.19 (1H, dd, J = 7.9, 2.0Hz), 7.14 (1H, d, J =
15.8Hz), 6.81 (1H, d, J = 7.9Hz), 4.06 (2H, q, J = 6.9H
z), 4.02 (3H, s), 3.91 (2H, q, J = 6.9Hz), 3.86 (3H, s),
1.26 (3H, t, J = 6.9Hz), 1.13 (3H, t, J = 6.9Hz).

Reference Example 16 (E) -1,3-diethyl-8- (3-methoxy-4-)
Trifluoromethanesulfonyloxystyryl) -7-
Methylxanthine (Compound q) Compound p obtained in Reference Example 15, 371 mg (1.00
2 mmol) was dissolved in 7 ml of pyridine, and 0.34 ml (2.021 ml) of anhydrous trifluoromethanesulfonic acid was added under ice cooling.
Was added and the mixture was stirred for 2 hours under ice cooling. Ice was added to the reaction solution, and the precipitated crystals were collected by filtration to give crude crystals of compound q 5
Obtained 23 mg (quantitative) as a yellow solid.

Melting point: 249.7-251.3 ° C. IR (KBr) ν _max (cm ⁻¹ ): 1694, 1651, 1543, 1419,
1209. NMR (270MHz; CDCl ₃ ) δ (ppm): 7.75 (1H, d, J = 1
5.8Hz), 7.27-7.18 (3H, m), 6.89 (1H, d, J = 15.8Hz),
4.21 (2H, q, J = 6.9Hz), 4.09 (2H, q, J = 6.9Hz), 4.09 (3
H, s), 3.99 (3H, s), 1.38 (3H, t, J = 6.9Hz), 1.27 (3H,
t, J = 6.9Hz) .EI-MS: 502 (M) ⁺ .

Reference Example 17 (E) -1,3-Diethyl-8- (3-methoxystyryl) xanthine (Compound r) 5,6-Diamino-1,3-diethyluracil [Journal of American Chemical Society (J.
Am. Chem. Soc.), 75 , 114 (1953)] 2.
5 g (12.6 mmol) dioxane 80 ml-water 4
2.48 g of 3-methoxycinnamic acid (1
3.9 mmol) and 3.62 g of 3- (3-diethylaminopropyl) -1-ethylcarbodiimide hydrochloride (1
8.9 mmol) was added and the solution was stirred at room temperature for 2 hours while adjusting the pH to 5.5. After adding 4N sodium hydroxide to the reaction solution to adjust the pH to> 14, add 40 ml of water to this.
Was added and the mixture was heated under reflux for 20 minutes. After cooling, it was neutralized and 50 ml of chloroform was added. After separating the organic layer, the aqueous layer was further extracted twice with 50 ml of chloroform. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. By recrystallizing the residue from dimethylformamide / water, 2.10 g (yield 49%) of (E) -1,3-diethyl-8- (3-methoxystyryl) xanthine (compound r) was obtained as a white powder. It was

Melting point: 270.6-272.5 ° C. Elemental analysis value: C ₁₈ H ₂₀ N ₄ O ₃ Theoretical value (%): C 63.52, H 5.92, N 16.46 Actual value (%): C 63.20, H 6.01, N 16.34 IR (KBr) ν _max (cm ^-1 ): 1686, 1634, 1500.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 7.
61 (1H, d, J = 16.4Hz), 7.34 (1H, t, J = 7.9Hz), 7.20-7.
18 (2H, m), 7.07 (1H, d, J = 16.4Hz), 6.92 (1H, d, J = 8.
6Hz), 4.06 (2H, q, J = 7.0Hz), 3.94 (2H, q, J = 6.8Hz),
3.81 (3H, s), 1.26 (3H, t, J = 7.0Hz), 1.14 (3H, t, J =
6.8Hz).

Reference Example 18 (E) -1,3-Diethyl-8- (3-methoxystyryl) -7-methylxanthine (Compound s) The compound r obtained in Reference Example 17, 1.70 g (5.0 (3 mmol) was dissolved in 40 ml of dimethylformamide, 1.73 g (12.5 mmol) of potassium carbonate and 0.62 ml (10.0 mmol) of methyl iodide were added thereto, and the mixture was stirred at 50 ° C for 30 minutes. After cooling, the insoluble matter was removed by filtration, and 100 ml of water was added to the filtrate. After extraction with 50 ml of chloroform three times, the extract was washed twice with water and then once with saturated saline, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The obtained crude crystals were separated and purified by silica gel column chromatography (eluting solvent: 40% ethyl acetate / hexane), and cyclohexane /
By recrystallizing from toluene, compound s, 1.1
0 g (yield 62%) was obtained as pale yellow needle crystals.

Melting point: 153.4-154.8 ° C. Elemental analysis value: C ₁₉ H ₂₂ N ₄ O ₃ Theoretical value (%): C 64.39, H 6.26, N 15.81 Actual value (%): C 64.34, H 6.38, N 15.82 IR (KBr) ν _max (cm ^-1 ): 1692, 1656, 1541.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 7.
64 (1H, d, J = 15.8Hz), 7.40-7.30 (4H, m), 6.97-6.92 (1
H, m), 4.31-4.05 (2H, m), 4.05 (3H, s), 3.92 (2H, q,
J = 7.0Hz), 3.82 (3H, s), 1.26 (3H, t, J = 7.1Hz), 1.13
(3H, t, J = 7.0Hz).

Formulation Example 1 Tablet A tablet having the following composition was prepared by a conventional method.

[0215]

[Table 10]

Formulation Example 2 Fine Granule A fine granule having the following composition was prepared by a conventional method.

[0217]

[Table 11]

Formulation Example 3 Capsule A capsule having the following composition was prepared by a conventional method.

[0219]

[Table 12]

Formulation Example 4 Injectable Solution An injectable solution having the following composition was prepared by a conventional method.

[0221]

[Table 13]

Formulation Example 5 Syrup Agent A syrup agent having the following composition was prepared by a conventional method.

[0223]

[Table 14]

[0224]

INDUSTRIAL APPLICABILITY The present invention provides a xanthine derivative having an excellent anti-and anti-adenosine A2 activity or a pharmacologically acceptable salt thereof.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/52 ADD 7431-4C (72) Inventor Shizuo Shiozaki 2162-9 Harada, Fuji City, Shizuoka Prefecture (72) ) Hiromi Nonaka 580-71 Tokukura, Shimizu-cho, Sunto-gun, Shizuoka Prefecture

Claims (1)

[Claims] 1. Formula (I): {Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl, and Q ₁ , Q ₂ and Q ₃ are the same or different and represent hydrogen, lower alkyl, lower alkoxy or halogen, X Is -COR ⁴ (in the formula, R ⁴ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy) or -SO ₂ R ⁵ [wherein R ⁵ is hydroxyl, lower alkoxy, trifluoromethyl, or [Wherein R ⁶ and R ⁷ are the same or different and each is hydrogen, hydroxyl-substituted or unsubstituted lower alkyl, aryl or (In the formula, m represents an integer of 1 to 3, R ⁸ and R ⁹ are the same or different and represent hydrogen or lower alkyl)] or [In the formula, Y represents a single bond, O or NR ¹⁰ (in the formula, R ¹⁰ represents hydrogen or lower alkyl), and n1 and n2.
Represents an integer of 1 to 3]]] or a pharmacologically acceptable salt thereof.