JP3165769B2 - Xanthine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to various diseases (eg, Parkinson's disease, senile dementia, depression, asthma or osteoporosis) caused by hyperactivity of adenosine A2 receptor.
A novel 8-substituted xanthine derivative or a pharmacologically acceptable salt thereof, which is expected to have a therapeutic effect on oxamine.

[0002]

2. Description of the Related Art Adenosine is known to exhibit attenuating effects of neurotransmitters via A2 receptor, bronchospasm or bone resorption. Therefore, an adenosine A2 receptor antagonist (hereinafter, referred to as an A2 antagonist) increases the function of adenosine A2 receptor such as a Parkinson's disease drug, an anti-dementia drug, a drug for depression, an anti-asthmatic drug or a drug for osteoporosis. It is expected as a therapeutic agent for various diseases of origin.

[0003]

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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, an aromatic heterocyclic group,
Compounds that are chloroalkyl, styryl or phenylethyl
Compounds are known to have adenosine antagonism
[Journal of Medicinal Chemistry (J.
 Med. Chem.),34, 1431 (1991)]. Also,
In the formula (B), R ^1bAnd R^2bAre the same or different
Represents methyl or ethyl;^3bRepresents methyl, Y^1b
And Y^2bRepresents hydrogen, Z^bIs phenyl or 3,4
The compound which is 5-trimethoxyphenyl is disclosed in
No. 26516 discloses a cerebral stimulant
You. In the formula (B), R^1bAnd R^2bAre the same
Differently represent hydrogen, propyl, butyl or allyl
Then R^3bRepresents hydrogen or lower alkyl;^1bAnd Y
^2bAre the same or different and represent hydrogen or methyl;^b
Is substituted or unsubstituted phenyl, pyridyl, imidazo
A compound that is ril, furyl or thienyl is adenosine
A2 receptor antagonism, therapeutic effect on asthma and osteoporosis
It is disclosed in WO 92/06976 that the
ing. Further, in the formula (B), R^1b, R^2bAnd R^3b
Is methyl, Y^1bAnd Y^2bIs a hydrogen atom, Z
^bIs phenyl (8-styrylcaffeine)
[Chemische Berchte,119, 15
25 (1986)] and Z^bIs pyridyl, quinolyl
Or methoxy-substituted or unsubstituted benzothiazolyl
Certain compounds [Chem. Abst.
 ),60, 1741h (1964)] is known.
There is no description on the pharmacological effects of.

[0005]

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

[0006]

According to the present invention, there is provided a compound of the formula (I)

[0007]

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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. represents, 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]

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

[0011]

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Wherein m is an integer of 1 to 3, and R ⁸ and R ⁹ are the same or different and each represents hydrogen or lower alkyl.

[0013]

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

In the definition of each group in the formula (I), lower alkyl includes straight-chain or branched C1-C6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. -Butyl, pentyl, neopentyl, hexyl and the like, and aryl as phenyl or naphthyl. The alkyl part of the lower alkoxy has the same meaning as the lower alkyl. Halogen means each atom of fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salt of compound (I) is
Pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like are included. Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochlorides, sulfates and phosphates, acetates,
Organic salts such as maleate, fumarate, tartrate, citrate and the like can be mentioned, and pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, magnesium salt, and calcium salt. Alkaline earth metal salts such as
Aluminum salts, zinc salts and the like can be mentioned, and pharmaceutically acceptable ammonium salts include ammonium, tetramethylammonium and the like, and pharmaceutically acceptable organic amine addition salts include morpholine, piperidine and the like. And pharmacologically acceptable amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.

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

[0018]

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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 (WO 92/06976) or a method analogous thereto. 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, dimethylformamide and the like. When sulfuric acid is used as the sulfonylating agent, the reaction is performed 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 (where R ^5a is R
Compound (Ib), which represents a group other than hydroxyl and trifluoromethyl in the definition of ⁵ , is obtained by the following reaction step.

[0022]

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Wherein R ¹ , R ² , R ³ , R ^5a , Q ¹ ,
Q ² and Q ³ are as defined above, and Z represents chlorine, bromine or iodine.

Step 2: Compound (III) can be obtained by reacting compound (Ia) obtained by Production Method 1 or its sodium salt with a halogenating agent. Examples of the halogenating agent include phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide, phosphorus halides such as phosphorus pentachloride, halogenated sulfonic acids such as chlorosulfonic acid, and thionyl halides such as thionyl chloride. Can be Reaction solvents include carbon tetrachloride, chloroform,
Halogenated hydrocarbons such as ethane dichloride, dioxane,
Ethers such as tetrahydrofuran; dimethylformamide; Further, the reaction may be carried out without using a solvent by using an excessive amount of a 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 a corresponding amine or alcohol in the presence of a base. Step 2
May be used without isolation after being produced in the reaction system. 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. and 0.5 to 2
Finish 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
Is a COOH compound (Id) is obtained by the following reaction step.

[0027]

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(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 to give the compound. (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 butyllithium; and alkali metals such as potassium tert-butoxide and potassium tert-amyl alcoholate. Metal alkoxide and the like can be mentioned. As the reaction solvent, toluene, aromatic hydrocarbons such as xylene, dioxane, ethers such as tetrahydrofuran, dimethylformamide,
Dimethyl sulfoxide and the like. Reaction is 0-1
Perform at 20 ° C. and finish in 0.5-24 hours.

Step 5: Compound (Ic) is hydrolyzed in the presence of a suitable additive to give compound (Ic).
d) can be obtained. Examples of the additives include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; lithium halides such as lithium chloride; And 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, if necessary, water are used in combination. 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) that are CH ₃ are
Obtained by the following reaction steps.

[0032]

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Wherein R ¹ , R ² , R ³ , Q ¹ , Q ² and Q ³ are as defined above, R ¹¹ represents lower alkyl, and Z ″ represents bromine or iodine. The lower alkyl in the definition of ^{11 has} the same meaning as the lower alkyl.

Step 6: A compound (V) obtained according to a known method [EP 565377] or a compound obtained according to the method, in the presence of a base, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride or N-phenyl-N-
(Trifluoromethanesulfonyl) compound (VI) by the action of trifluoromethanesulfonamide
Can be obtained.

As the base, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine,
Organic amines such as pyridine; inorganic carbonates such as potassium carbonate; As the reaction solvent, methylene chloride,
And 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 (IX) obtained by reacting compound (VI) or a known method [EP 565377] or compound (VII) obtained according to the method with tin compound (VIII) in the presence of a transition metal catalyst.
Can be obtained. Examples of the transition metal catalyst 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, dimethyl sulfoxide and the like. Lithium chloride may be appropriately added according to the reaction. The reaction is 0-
Perform at 120 ° C. and finish in 0.5-24 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
-Protonic acids such as toluenesulfonic acid.
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 used as needed. Reaction is 0-120 ° C
And ends in 0.5 to 24 hours.

Step 9: Compound (Id) 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 used as needed. 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]

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(Where R ¹ , R ² , R ³ , R ^4b , Q ¹ ,
Q ² and Q ³ are as defined above, and Z ′ ″ represents chlorine, bromine or iodine.

Step 10: Compound (Ie) can be obtained by reacting compound (II) with 1 equivalent of compound (X) in the presence of a Lewis acid. As the Lewis acid, 1
３3 equivalents, preferably 2 equivalents of aluminum trichloride. 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 organic synthetic 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), if compound (I) is obtained in the form of a salt, it may be purified as it is, or if it is obtained in a free form, it may be dissolved in an appropriate solvent or What is necessary is just to suspend, add an acid or a base, and form a salt.

Compound (I) includes, for example, geometric isomers of E / Z , and the present invention also 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, or fractional dissolution. The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Table 1 shows specific examples of the compound (I).

[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 with reference to test examples. Test Example 1 Acute toxicity test A test compound was orally administered (po; 300 mg / kg) using three dd male mice weighing 20 ± 1 g per group. Seven days after administration, the state of death was observed, and the minimum lethal dose (MLD) value was determined. Table 2 shows the test results of compound (I). According to the test results,
Compound (I) has low toxicity and can be used safely 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 ice-cold 50
mM Tris (hydroxymethyl) aminomethane hydrochloride (Tri
sHCl) buffer (pH 7.7) in a Polytron homogenizer.
(Kinematica). Centrifuge the suspension (50,00
(0 × g, 10 minutes), and the same amount of 50 mM Tr
An isHCl buffer was added and resuspended, and the same centrifugation was performed. A 50 mM TrisHCl buffer solution (containing 10 mM magnesium chloride, adenosine deaminase 0.02 unit / mg tissue (Sigma)) was added to the final precipitate to obtain a tissue concentration of 5 mg (wet weight) / ml, and suspended. did.

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

[0055] Calculation of percentage inhibition against A2 receptor binding of the test compound ⁽³ H-NECA binding) was calculated by the following equation.

[0056]

(Equation 1)

(Note) The total binding amount is the amount of ³ H-NECA binding radioactivity in the absence of the test compound. The non-specific binding amount is the ³ H-NECA binding radioactivity in the presence of 100 μM CPA. The amount of binding in the presence of the drug is the amount of ³ H-NECA binding radioactivity in the presence of various concentrations of the test compound. Moreover, labeled with tritium N- ethyl carboxamide adenosine ⁽³ H-
NECA: 26 Curie / mmol; Amersham) (final concentration
3.8 nM) and cyclopentyl adenosine (CPA; manufactured by Sigma)
CGS 21680 labeled with tritium instead of 50 μl of the mixture with (final concentration 50 nM) ｛ ³ H-2- [p- (2-carboxyethyl) phenethylamino] -5 ′-(N-ethylcarboxamide)
Adenosine: 40 Curie / mmol; New England Nuclear
[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 Compound ( ³ H-CGS 2168
(0 binding) was calculated by the following equation.

[0059]

(Equation 2)

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

The results are shown in Table 3. The Ki values in the table were determined by 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 indicates the inhibition constant of CPA.

[0064]

[Table 7]

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

Test Example 3 Effect 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 (dopamine D ₁ / D ₂ antagonists), catalepsy is induced by D ₂ receptor blockade postsynaptic. This haloperidol-induced catalepsy is known as a classical model for reproducing Parkinson's disease by drug administration [Eur. J. Pharmacol., 182 , 327 (199)
0)].

The experiment was carried out using 5-week-old male ddY mice (body weight: 22 to 24 g, SLC Japan) with 5 animals per group. Haloperidol (manufactured by Janssen) was suspended in 0.3% CMC, and 1.0 mg / kg was intraperitoneally administered to the mouse. The test compound was Tween8
After adding 0 [polyoxyethylene (20) sorbitan monooleate], the mixture was used as a suspension in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.). In addition, L-DOPA (L-DOPA; manufactured by Kyowa Hakko Kogyo KK) and benserazide hydrochloride (benserazide)
HCl (manufactured by Kyowa Hakko Kogyo KK) was used as a 0.3% CMC suspension. One hour after intraperitoneal administration of haloperidol, a suspension containing the test compound or a suspension containing no test compound [Tw
distilled water for injection to which een80 is added (manufactured by Otsuka Pharmaceutical Co., Ltd.);
Control] was orally administered (0.1 ml per 10 g of mouse body weight)
1 hour after the administration of the test compound, one animal at a height of 4.5
The catalepsy was measured by suspending only both forelimbs and only both hindlimbs of the mouse on a table having a width of 1.0 cm2 and a width of 1.0 cm2. All test compounds were orally administered at 10 mg / kg, and the control drug was L-dopa 100m
g / kg and benserazide 25 mg / kg were administered intraperitoneally. The catalepsy score and criteria are shown below.

Score Duration of catalepsy 0: When the forelimb is hung and the hindlimb is hung, the duration of the posture is less than 5 seconds while being hung on the table 1: The posture is 5 while the forelimb is hung on the table Hold for more than 10 seconds, less than 10 seconds, hind limb lasts less than 5 seconds 2: Keep the posture for more than 10 seconds with the forelimb hanging on the table,
The hind limb has a duration of less than 5 seconds. 3: The fore limb and the hind limb are hung on a table and the duration of the posture is 5 seconds or more and less than 10 seconds. Duration: 5 seconds or more 4: Keep your posture for 10 seconds or more with your forelimb hanging on the table,
The hind limb has a duration of 5 seconds or more and less than 10 seconds. The posture is maintained for 5 or more and less than 10 seconds while the forelimb is hung on the table. The hind limb has a duration of 10 seconds or more. Duration of the posture is 10 seconds or more

[0069] determination of the effect was performed the sum of the five of catalepsy score 1 group (25 points). When the total score was 20 points or less, it was determined that there was an effect. The number of catalepsy remission animals was the number of catalepsy score of 4 or less out of 5 animals. The catalepsy remission rate indicated the percentage reduction of the total score of the test compound administration group relative to the total score of the control group.

The results are shown in Table 4.

[0071]

[Table 8]

Test Example 4 Effect on clonidine-induced aggressive behavior Aggressive behavior induced by intraperitoneal administration of clonidine [European Journal of Pharmacology (Eu
r. J. Pharmacol.), 29 , 374 (1968 ) ]. DdY weighing 20-25g
The experiment was performed using two male mice of each strain (Japan SLC). The test compound was suspended in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) after adding Tween 80, and clonidine hydrochloride (manufactured by Sigma) was dissolved in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.). Using. A suspension containing the test compound or a suspension containing no test compound (control) was orally administered (0.1 ml per 10 g of mouse body weight), and the test compound was administered.
0 minutes later, clonidine 20 mg / kg was intraperitoneally administered. The number of aggressive behaviors of the mice was measured for 30 minutes immediately after the administration of clonidine. Determination of the effect was done by comparing the number of attacks level in the control group and test compound-administered group [significance test: Student's t-test (Student's t-test)] .

Table 5 shows the results.

[0074]

[Table 9]

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. Desirably, these pharmaceutical compositions are in unit dosage form suitable for administration orally or by injection.

In preparing the compositions in oral dosage form, any useful pharmaceutically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, p -Can be produced using preservatives such as hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint and the like. Powders, pills, capsules and tablets include lactose, glucose, sucrose, mannitol and other excipients, starch, disintegrants such as sodium alginate, magnesium stearate, lubricants such as talc, polyvinyl alcohol, hydroxypropyl It can be produced using a binder such as cellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. When manufacturing tablets and capsules, a solid pharmaceutical carrier is used.

The injection can be prepared using a carrier comprising distilled water, salt solution, glucose solution or a mixture of salt water and glucose solution. At this time, it is prepared as a solution, suspension or dispersion using a suitable solubilizing agent and a suspending agent according to a conventional method. Compound (I) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an injection in the above-mentioned pharmaceutical form. , Weight, symptoms, etc., but usually from 0.01 to
25 mg / kg is administered in 3 to 4 divided doses.

In addition, compound (I) can be administered by inhalation in the form of an aerosol, finely divided powder or spray solution. For aerosol administration, the compounds can 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. .

Hereinafter, embodiments of the present invention will be described with reference to Examples, Reference Examples and Formulation 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)
No. 976) 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 was carefully poured into ice water. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 1.77 g (yield 93%) of a compound as yellow powder.

Melting point: 191.5-193.5 ° C. Elemental analysis: 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) 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 was added to 20 ml of dimethylformamide. And 0.29 ml (3.92 mmol) of thionyl chloride under ice-cooling
Was added dropwise. After stirring at room temperature for 10 minutes, ice-cool again,
1.02 ml (9.80 mmol) of diethylamine were added dropwise. After stirring at room temperature for 1 hour, the reaction solution was added to 50 ml of water.
Was injected. The mixture was extracted three times with 20 ml of chloroform, and the extract was washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by column chromatography (elution solvent: 65% ethyl acetate / hexane), and then recrystallized from cyclohexane / toluene to obtain 2,320 mg (yield 30%) of the compound as a pale yellow powder.

Melting point: 227.1-227.7 ° C. Elemental analysis: C ₂₆ H ₃₇ N ₅ O ₆ S Theoretical value (%): C 57.02, H 6.81, N 12.79 Observed 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-
Il) Styrene-2-sulfonamide (Compound 3) 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 2.68 ml of dipropylamine (19.6)
Mmol) and the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from cyclohexane / toluene to obtain 3,450 mg (yield: 40%) of the compound as a pale yellow powder.

Melting point: 207.8-208.5 ° C. Elemental analysis: 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
Hz). FAB-MS: 576 (M + H) ⁺ .

Example 4 (E) -4,5-Dimethoxy-β- (7-methyl-1,
3-Dipropylxanthin-8-yl) -2-piperidinosulfonylstyrene (compound 4) 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 1.93 ml of piperidine (19.6) Mmol) and the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from dimethyl sulfoxide / water,
4,600 mg (yield 55%) of the compound was obtained as a pale yellow powder.

Melting point: 266.5-268.2 ° C. Elemental analysis: 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 of 3-dipropylxanthin-8-yl) -2- (4-methylpiperazin-1-ylsulfonyl) styrene (Compound 5) 1,1.00 g of the compound obtained in Example 1 (1.96) Mmol) and 1.08 ml of 4-methylpiperazine (9.
8 mmol) and the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from ethanol to obtain 5,390 mg (0.679 mmol; yield 35%) of a compound as a pale yellow powder. This is isopropanol 15m
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 a fumarate 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 (270 MHz; 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 in 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 needles.

Melting point: 199.1-199.7 ° C. Elemental analysis: 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 (1
H, d, J = 15.8Hz), 7.55 (1H, s), 7.15 (1H, s), 6.74 (1
H, 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 (2H,
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). FAB-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 an argon stream under ice-cooling, 60% sodium hydride (25.9 mg,
(0.648 mmol) and heated at 50 ° C. for 20 minutes. After ice cooling, 100 mg of compound c obtained in Reference Example 3
(0.360 mmol) was added slowly, 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.
Extracted three times with 0 ml. After washing the extract with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was separated and purified by column chromatography (eluent: 25% ethyl acetate / hexane) to give Compounds 7 and 4.
0.0 mg (27% yield) and 8,39.5 mg of compound
(Yield 27%) were obtained as pale yellow powders.

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) The same operation as in Example 2 was performed using 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 0.6 ml of concentrated aqueous ammonia. The obtained crude crystals were recrystallized from dioxane / water to give 9,670 mg of compound (yield 7).
0%) as yellow needles.

Melting point: 266.1-267.8 ° C. Elemental analysis: As 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 Example 2 using 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 1.85 ml (20.3 mmol) of aniline. The operation was performed. The obtained crude crystals were recrystallized from toluene to give Compounds 10, 26
1 mg (23% yield) was obtained as a pale yellow powder.

Melting point: 247.4-249.1 ° C. Elemental analysis: 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,
JB = 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) ) -7-Methyl-1,3-dipropyl-8- (3,
4,5-trimethoxystyryl) xanthine (WO92
/ 06976 publication) 10.0 g (22.6 mmol)
And the same operation as in Example 1 was performed. The obtained crude crystals 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: 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) Compound obtained in 10 (1.80 g, 3.4)
5 mmol) and 1.0 ml of concentrated aqueous ammonia, and the same operation as in Example 2 was performed. The obtained crude crystals were recrystallized from acetonitrile to obtain 12,200 mg of a compound.
(11% yield) as yellow needles.

Melting point: 242.9-244.7 ° C. Elemental analysis: 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 of methyl-β- (7-methyl-1,3-dipropylxanthin-8-yl) -3,4,5-trimethoxystyrene-2-sulfonamide (Compound 13) Obtained in Example 10. Compound 11,11.40 g (2.6
8 mmol) and 0.39 ml (5.36 mmol) of N, N, N'-trimethylethylenediamine, and substantially the same operation as in Example 2 was performed. The obtained crude crystal 670
mg of fumaric acid in 10 ml of isopropanol.
7 mg (0.84 mmol) were added. The precipitated crystals were collected by filtration and dried, and 550 mg of the fumarate of compound 13 was obtained.
(Yield 28%) as a yellow powder.

Melting point: 191.6-192.9 ° C. Elemental analysis: 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) Almost the same operation as in Example 2 was performed using 1,1.00 g (1.96 mmol) of the compound obtained in Example 1 and 1.2 ml (20.3 mmol) of ethanolamine.
The obtained crude crystals were recrystallized from toluene to give Compound 14,
600 mg (55% yield) were obtained as yellow platelets.

Melting point: 213.4-215.0 ° C. Elemental analysis: 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) were used, and substantially the same operation as in Example 1 was performed. The obtained crude crystals were recrystallized from ethanol to give Compound 15,3.09 g (yield 67%) as a pale yellow powder.

Melting point:> 280 ° C. Elemental analysis: 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 (3H
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), and substantially the same operation as in Example 1 was performed.
The obtained crude crystals were recrystallized from dioxane / water to give Compound (16.3.27 g, yield 34%) as pale yellow plate-like crystals. Melting point: 208.9-210.5 ° C Elemental analysis: as C ₁₉ H ₂₂ N ₄ O ₆ S.H ₂ O Theoretical value (%): C 50.43, H 5.35, N 12.38 Actual 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, and substantially the same operation as in Example 2 was performed. The obtained crude crystals are subjected to high performance liquid chromatography (column: YMC-pac
k, SH-365-10, 30 i.d. × 500 mm, elution solvent: 40% acetonitrile / water, flow rate: 40 ml / min) to obtain 17,55 mg of compound (6% yield) as a pale yellow powder. Was.

Melting point: 236.5-237.2 ° C. Elemental analysis: 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) 2.64 g (6.44 mmol) of the compound obtained in Example 7 was dissolved in a mixed solvent of 60 ml of dioxane and 40 ml of water, and 1.08 g of lithium hydroxide monohydrate (2
(5.8 mmol) and stirred at room temperature for 1 hour. 1N
After neutralization with hydrochloric acid, the mixture was extracted three times with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from toluene / cyclohexane to obtain 2.26 g (yield 89%) of compound 18 as yellow powder.

Melting point: 214.7-216.9 ° C. Elemental analysis: 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 1.25 g (3.1 g) obtained in Example 17
5 mmol) and 40 mg of iodine (0.32 mmol)
Was heated and refluxed for 6.5 hours.
After cooling, a 0.1 M aqueous solution of sodium thiosulfate and chloroform were added and stirred. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 19,740 mg of compound (yield 5
9%) as ocher needles.

Melting point: 273.4-275.4 ° C. Elemental analysis: 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 Methyl (E) -β- (1,3-diethyl-7-methylxanthin-8-yl) -2-methoxystyrene-4-carboxylate (Compound 20) -Methoxycarbonylbenzyl) triphenylphosphonium bromide 938 mg (1.7
1.99 ml (1.799 mmol) of a 1.65 M n-butyllithium / hexane solution was added to 10 ml of a suspension of tetrahydrofuran (99 mmol) under ice-cooling and argon replacement, followed by stirring at room temperature for 30 minutes. After cooling with ice, 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, followed by stirring at room temperature for 2 hours and 30 minutes. After cooling with ice, 1.8 ml of a 1N aqueous ammonium chloride solution was added. Ethyl acetate was added to the reaction solution, and the mixture was washed three times with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give Compound 20,422.
mg (yield: 85%) and further recrystallized from hexane / ethyl acetate to obtain a yellow powder.

Melting point: 239.0-241.2 ° C. Elemental analysis: C ₂₁ H ₂₄ N ₄ O ₅ Theoretical value (%): C 61.16, H 5.86, N 13.58 Observed 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) 2.81 g of 4-methoxycarbonylbenzyl) triphenylphosphonium bromide (5.3
Example 19 using 3.27 ml (5.396 mmol) of a 1.65 M n-butyllithium / hexane solution and 1.00 g (3.593 mmol) of compound c obtained in Reference Example 3. Almost the same operation was performed. The obtained crude crystals were recrystallized from hexane / ethyl acetate to obtain 21,203 mg (yield 33%) of a compound as yellow granular crystals.

Melting point: 198.5-200.4 ° C. Elemental analysis: 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. The reaction solution was acidified by adding 2N hydrochloric acid, and the obtained crystals were collected by filtration. The crude crystals were separated and purified by column chromatography (elution solvent: chloroform / methanol / acetic acid = 40/1/1) to give Compound 2
225 mg (yield: 24%) was obtained, and recrystallized from isopropanol to obtain a yellow powder.

Melting point:> 280 ° C. Elemental analysis: 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) and the same operation as in Example 21 was performed. The obtained crude crystals were recrystallized from isopropanol to obtain 23,203 mg (yield: 70%) of a compound as yellow powder.

Melting point: 284.7-286.1 ° C. Elemental analysis: as 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 suspension was replaced with argon.
0.84 ml of (1-ethoxyvinyl) tributyltin
(2.486 mmol) and stirred at 120 ° C. for 3 hours. After cooling on 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. After evaporating the solvent under reduced pressure, the residue was washed with 20 ml of tetrahydrofuran and 2 ml of
The mixture 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 was neutralized with 2N sodium hydroxide and diluted with chloroform. Wash the organic layer with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was separated and purified by column chromatography (elution solvent: hexane / ethyl acetate = 2/1), and recrystallized from ethyl acetate to obtain 24,482 mg (yield 53%) of the compound as pale yellow floc. .

Melting point: 221.4-221.8 ° C. Elemental analysis: 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 of the compound obtained in Example 23 (0.8
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 to the mixture under ice-cooling, and then a solution of 3 ml of dioxane was slowly added thereto under ice-cooling, followed by 3 hours 30 minutes at room temperature. Stirred. After ice cooling, 5%
An aqueous sodium thiosulfate solution was added, 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 25,254 mg of a compound.
(84% yield) as pale yellow needles.

[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
(2.190 mmol) and substantially the same operation as in Example 23 was performed. The obtained crude crystals were recrystallized from ethyl acetate to obtain 26,407 mg of the compound (44% yield) as pale yellow needles.

Melting point: 193.9-194.7 ° C. Elemental analysis: 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 26,200 mg of compound (0.4
71 mmol), and the same operation as in Example 24 was performed. The obtained crude crystals were recrystallized from dioxane / water to obtain 27,190 mg (yield 95%) of a compound as yellow powder.

Melting point: 209 ° C. (decomposition) IR (KBr) ν _max (cm ⁻¹ ): 1687, 1657, 1543, 1503,
1262. NMR (270 MHz; 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, 500 mg (1.18) obtained in Reference Example 12.
7 mmol), 10 mg (0.014 mmol) of dichlorobis (triphenylphosphine) palladium and 0.41 ml of (1-ethoxyvinyl) tributyltin
(1.214 mmol), and substantially the same operation as in Example 23 was performed. The obtained crude crystals were recrystallized from ethyl acetate to obtain 28,174 mg of the compound (61% yield) as yellow needles.

Melting point: 238.1-239.3 ° C. Elemental analysis: 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) Compound obtained in Example 27 28,450 mg (1.1
65 mmol) and the same operation as in Example 24 was performed. The obtained crude crystals were recrystallized from ethanol to obtain 29,187 mg (yield 41%) of the 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 (3H
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 compound q obtained in Reference Example 16, 6 m of dichlorobis (triphenylphosphine) palladium
g (0.009 mmol) and (1-ethoxyvinyl)
Using 0.27 ml (0.799 mmol) of tributyltin, substantially the same operation as in Example 23 was carried out to obtain Compound 3.
0.50 mg (yield 32%) was obtained and further recrystallized from ethyl acetate to obtain yellow needles.

Melting point: 236.1-237.2 ° C. Elemental analysis: C ₂₁ H ₂₄ N ₄ O ₄ .0.3 H ₂ O Theoretical value (%): C 62.77, H 6.17, N 13.94 Actual 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) 500 m of (E) -7-methyl-1,3-dipropyl-8-styrylxanthine (WO92 / 06976)
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 five times with tetrahydrofuran. Combine the organic layers,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
Compound 31 and 240 mg (yield 39%) were 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) of 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. 3
After heating under reflux for 0 minutes, the mixture was cooled, and concentrated hydrochloric acid was added for neutralization.
The precipitated crystals were collected by filtration and dried to give Compound a, 10.6 g.
(90% yield) as a white powder.

Melting point: 220.1-221.0 ° C. Elemental analysis: 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 the compound a obtained in Reference Example 1 was added to 30 ml of dimethylformamide. After dissolution, 1.30 g (9.40 mmol) of potassium carbonate and then 0.47 ml (7.52 mmol) of methyl iodide were added,
Stirred at 50 ° C. for 1 hour. The insolubles are filtered off, and water 60 ml
, And extracted three times with 25 ml of chloroform. The extract was washed twice with water and then twice with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from cyclohexane to obtain Compound 735 mg (yield 70%) as yellow needles.

Melting point: 111.4-111.8 ° C. Elemental analysis: 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-xanthine carbaldehyde (Compound c) Manganese dioxide 2 was added to a solution of 800 mg (2.85 mmol) of the compound b obtained in Reference Example 2 in 80 ml of chloroform. .48 g (28.5 mmol) were 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 was separated and purified by column chromatography (elution solvent: 1% methanol / chloroform).
Compound 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 (90 MHz; 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)].
0 g (25.2 mmol) and 8.4 g of glycolic acid
(111 mmol), and the same operation as in Reference Example 1 was performed. The obtained crude crystals were recrystallized from methanol,
3.56 g (yield 60%) of compound d was obtained as white needles.

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) The compound d obtained in Reference Example 4, 2.00 g (8.40 mmol) was used, and Reference Example 2 was used. Almost the same operation was performed.
The obtained crude crystals were recrystallized from hexane / ethyl acetate,
1.88 g (yield 89%) of compound e were obtained as white needles.

NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 5.54
(1H, t, J = 5.9Hz ), 4.58 (2H, d, J = 5.9H z), 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-xanthine carbaldehyde (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 404 mg (yield 41%) was obtained as pale yellow plate-like 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) 34 ml of dioxane-68 m of water
l 2.52 g of 3-bromocinnamic acid (11.1
Mmol) and 3- (3-diethylaminopropyl)-
2.90 g of 1-ethylcarbodiimide hydrochloride (15.2
Mmol) and adjust the pH to 5.5 at room temperature.
Stirred for 0 minutes. The reaction mixture was adjusted to pH> 14 with 4N sodium hydroxide and then heated under reflux for 20 minutes. After cooling, the mixture was neutralized and the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran / water to obtain 2.01 g (yield 37%) of Compound g as pale green plate-like crystals.

Melting point:> 270 ° C. Elemental analysis: 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) The compound g obtained in Reference Example 7, 2.5 g (6.43) Was dissolved in 20 ml of dimethylformamide, and 2.22 g (16.1 mmol) of potassium carbonate and 0.8 ml (12.9 mmol) of methyl iodide were added thereto.
Stirred at 70 ° C. for 70 minutes. After cooling, insolubles were removed by filtration, and water was added to the filtrate. After extracting three times with chloroform, the extract was washed three times with water and then twice with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.37 g (yield 92%) of crude crystals of compound h as a yellow solid, which was further recrystallized from cyclohexane / toluene to give compound h.
Was obtained as a yellow powder.

Melting point: 187.3-188.2 ° C. Elemental analysis: as C ₁₈ H ₁₉ BrN ₄ O ₂ Theoretical value (%): C 53.61, H 4.75, N 13.89 Observed 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
g (13.3 mmol) and 3.75 g (14.6 mmol) of 3-bromo-4-methoxycinnamic acid, and the same operation as in Reference Example 7 was performed. The obtained crude crystals were recrystallized from dioxane to obtain 3.43 g of Compound i (yield 58).
%) Were obtained as yellow needles.

Melting point: 279.8-280.6 ° C. Elemental analysis: 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 Compound 750 mg (1.68 mmol) obtained in Reference Example 9, substantially the same operation as in Reference Example 8 was performed.
The obtained crude crystals were recrystallized from hexane / ethyl acetate,
Compound 588 mg (yield 76%) was obtained as pale yellow needles.

Melting point: 209.4-210.8 ° C. Elemental analysis: 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 (3H
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
g (15.1 mmol) and 4.08 g (16.7 mmol) of 3-bromo-4-fluorocinnamic acid were subjected to substantially the same operation as in Reference Example 7. The obtained crude crystals were recrystallized from dioxane to give 2.90 g of compound k (yield 47).
%) As a pale yellow powder.

Melting point:> 300 ° C. Elemental analysis: 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) 2.50 g of the compound k obtained in Reference Example 11 (6.14)
Mmol) and 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 needles.

Melting point: 217.6-219.2 ° C. Elemental analysis: as C ₁₈ H ₁₈ BrFN ₄ O ₂ Theoretical value (%): C 51.32, H 4.30, N 13.30 Observed 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 subjected to substantially the same operation as in Reference Example 7. The obtained crude crystals were recrystallized from dioxane to give Compound n (2.93 g).
(36% yield) as pale yellow needles.

Melting point: 223.4-224.3 ° C. Elemental analysis: 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) The same operation as in Reference Example 8 was performed using 2.0 g (5.00 mmol) of the compound n obtained in Reference Example 13.
The obtained crude crystals were recrystallized from ethyl acetate to give compound o,
1.77 g (yield 85%) were obtained as yellow plate-like crystals.

Melting point: 179.4-180.6 ° C. Elemental analysis: C ₂₁ H ₂₆ N ₄ O ₅ Theoretical value (%): C 60.86, H 6.32, N 13.52 Observed 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, and 9 ml of 2N hydrochloric acid was added thereto, followed by heating under reflux for 1 hour. Under ice cooling, the reaction solution was neutralized with 2N sodium hydroxide, water was further added, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate to give 1.08 g of compound p (yield 8).
1%) as yellow platelets.

Melting point: 185.3-186.5 ° C. Elemental analysis: 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 mg)
2 mmol) was dissolved in 7 ml of pyridine, and 0.34 ml (2.021 ml) of trifluoromethanesulfonic anhydride was dissolved under ice cooling.
Mmol), and the mixture was stirred under ice cooling for 2 hours. Ice was added to the reaction solution, and the precipitated crystals were collected by filtration.
23 mg (quantitative) were obtained as a yellow solid.

Melting point: 249.7-251.3 ° C. IR (KBr) ν _max (cm ⁻¹ ): 1694, 1651, 1543, 1419,
1209. NMR (270 MHz; 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)].
5 g (12.6 mmol) of dioxane 80 ml-water 4
To a 0 ml mixed solution, 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) 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 mixture to adjust the pH to> 14, 40 ml of water was added thereto.
Was added and heated under reflux for 20 minutes. After cooling, the mixture 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 saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from dimethylformamide / water to give 2.10 g (yield 49%) of (E) -1,3-diethyl-8- (3-methoxystyryl) xanthine (compound r) as a white powder. Was.

Melting point: 270.6-272.5 ° C. Elemental analysis: as 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) (Mmol) was dissolved in 40 ml of dimethylformamide, and thereto were added 1.73 g (12.5 mmol) of potassium carbonate and then 0.62 ml (10.0 mmol) of methyl iodide, followed by stirring at 50 ° C. for 30 minutes. After cooling, insolubles were removed by filtration, and 100 ml of water was added to the filtrate. After extracting three times with 50 ml of chloroform, the extract is washed twice with water and then once with a saturated saline solution, 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 (elution solvent: 40% ethyl acetate / hexane), and further purified with cyclohexane / hexane.
By recrystallization from toluene, compound s, 1.1
0 g (62% yield) were obtained as pale yellow needles.

Melting point: 153.4-154.8 ° C. Elemental analysis: As 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 Tablets Tablets having the following composition were prepared by a conventional method.

[0215]

[Table 10]

Formulation Example 2 Fine Granules Fine granules having the following composition were prepared by a conventional method.

[0217]

[Table 11]

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

[0219]

[Table 12]

Formulation Example 4 Injection An injection having the following composition was prepared by a conventional method.

[0221]

[Table 13]

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

[0223]

[Table 14]

[0224]

According to the present invention, an excellent anti-adenosine A2
A xanthine derivative having an action or a pharmaceutically acceptable salt thereof is provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 25/24 A61P 25/24 25/28 25/28 43/00 111 43/00 111 Examiner Aki Nakagi (56) References International Publication 92/6976 (WO, A1) Med. Chem. 34, no. 4 (1991) p. 1431-1435 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 473/04-473/12 A61K 31/522 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the formula (I) Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl; Q ₁ , Q ₂ and Q ₃ are the same or different and represent hydrogen, lower alkyl, lower alkoxy or halogen; 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, Wherein R ⁶ and R ⁷ are the same or different and are hydrogen, hydroxyl-substituted or unsubstituted lower alkyl, aryl or (Wherein m represents an integer of 1 to 3, and R ⁸ and R ⁹ are the same or different and represent hydrogen or lower alkyl).
Or Wherein Y represents a single bond, O or N—R ¹⁰ (wherein R ¹⁰ represents hydrogen or lower alkyl), and n1 and n2
Represents an integer of 1 to 3], and represents a xanthine derivative represented by ま た は or a pharmaceutically acceptable salt thereof. 2. The xanthine derivative or the pharmaceutically acceptable salt thereof according to claim ¹ , wherein R ¹ , R ² and R ³ are the same or different and are lower alkyl. 3. An adenosine A2 receptor antagonist comprising the xanthine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. A therapeutic agent for Parkinson's disease comprising the xanthine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. A therapeutic agent for depression, comprising the xanthine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.