Xanthine derivatives

Abstract: Disclosed are xanthine derivatives represented by the following Formula (I): in which R¹, R², and R³ independently represent hydrogen or lower alkyl; Q¹, Q², and Q³ independently represent hydrogen, lower alkyl, lower alkoxy, or halogen; and X represents -COR⁴ (in which R⁴ represents hydrogen, hydroxy, lower alkyl, or lower alkoxy) or -SO₂R⁵ {in which R⁵ represents hydroxy, lower alkoxy, trifluoromethyl, in which R⁶ and R⁷ independently represent hydrogen, hydroxy-substituted or unsubstituted lower alkyl, aryl, or (in which m represents an integer of 1 to 3; and R⁸ and R⁹ independently represent hydrogen or lower alkyl), or (in which Y represents a single bond, oxygen, or N-R¹⁰ in which R¹⁰ represents hydrogen or lower alkyl; and n1 and n2 independently represent an integer of 1 to 3 )}, and pharmaceutically acceptable salts thereof.

Description: The present invention relates to novel 8-substituted xanthine derivatives and pharmaceutically acceptable salts thereof which are expected to exhibit therapeutic effects on various kinds of diseases caused by hyperergasia of adenosine A 2 receptors, for example, Parkinson's disease, senile dementia, depression, asthma, and osteoporosis. It is known that adenosine exhibits neurotransmitter depressing activity, bronchospasmic activity, bone absorption promoting activity, and the like via an A 2 receptor. Therefore, adenosine A 2 receptor antagonists (hereinafter referred to as A 2 -antagonists) are expected as therapeutic agents for various kinds of diseases caused by hyperergasia of adenosine A 2 receptors, for example, therapeutic agents for Parkinson's disease, anti-dementia agents, antidepressants, anti-asthmatic agents, and therapeutic agents for osteoporosis. It is known that adenosine antagonistic activity is found in compounds represented by Formula (A) in which R 1a and R 2a independently represent methyl or propyl, R 3a represents hydrogen, and R 4a represents substituted or unsubstituted phenyl, aromatic heterocyclic group, cycloalkyl, styryl, or phenylethyl [J. Med. Chem., 34 , 1431 (1991)]. Further, U.S.P. 3,641,010 discloses, as cerebral stimulants, compounds represented by Formula (B) in which R 1b and R 2b independently represent methyl or ethyl, R 3b represents methyl, Y 1b and Y 2b represent hydrogen, and Z b represents phenyl or 3,4,5-trimethoxyphenyl. WO92/06976 discloses, as compounds having an adenosine A 2 receptor antagonistic activity and therapeutic effects on asthma and osteoporosis, compounds represented by Formula (B) in which R 1b and R 2b independently represent hydrogen, propyl, butyl, or allyl, R 3b represents hydrogen or lower alkyl, Y 1b and Y 2b independently represent hydrogen or methyl, and Z b represents substituted or unsubstituted phenyl, pyridyl, imidazolyl, furyl, or thienyl. Furthermore, other compounds represented by Formula (B) are known. One is 8-styryl caffeine which is a compound of Formula (B) in which R 1b , R 2b , and R 3b represent methyl, Y 1b and Y 2b represent hydrogen, and Z b represents phenyl [Chem. Ber. 119 , 1525 (1986)]. Another is a compound of Formula (B) in which R 1b , R 2b , and R 3b represent methyl, Y 1b and Y 2b represent hydrogen, and Z b represents pyridyl, quinolyl, or methoxy-substituted or unsubstituted benzothiazolyl [Chem. Abst. 60 , 1741h (1964)]. However, there is no description with regard to the pharmacological activity of any of these compounds. EP-A-0 203 721 relates to certain novel 8-phenylxanthines substituted in the 3 or 4 position of the phenyl group by an alkenylene, alkenyleneoxy, alkynylene or alkynyleneoxy bearing a terminal acidic grouping, and to their use in human and veterinary therapy, particularly for conditions associated with the cell surface effects of adenosine. EP-A-0 092 398 describes substituted 8-phenylxanthines, their use as bronchodilators, processes for their preparation and use as well as pharmaceutical compositions containing them. An object of the present invention is to provide novel 8-substituted xanthine derivatives and pharmaceutically acceptable salts thereof which exhibit therapeutic effects on various kinds of diseases caused by hyperergasia of adenosine A 2 receptors, for example, Parkinson's disease, senile dementia, depression, asthma, and osteoporosis. This object has been achieved by xanthine derivatives represented by the following Formula (I): in which R 1 , R 2 , and R 3 independently represent hydrogen or lower alkyl; Q 1 , Q 2 , and Q 3 independently represent hydrogen, lower alkyl, lower alkoxy, or halogen; and X represents -COR 4 (in which R 4 represents hydrogen, hydroxy, lower alkyl, or lower alkoxy), and pharmaceutically acceptable salts thereof. The compounds represented by Formula (I) are hereinafter referred to as Compounds (I), and the same applies to the compounds of other formula numbers. In the definitions of the groups in Formula (I), the lower alkyl means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, and hexyl, and the aryl means phenyl or naphthyl. The lower alkyl moiety of the lower alkoxy has the same meaning as the lower alkyl defined above. The halogen means fluorine, chlorine, bromine, and iodine. The above-mentioned pharmaceutically acceptable salts of Compounds (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Examples of the pharmaceutically acceptable acid addition salts are inorganic acid addition salts such as hydrochloride, sulfate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, tartrate, and citrate. Examples of the pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminium salt, and zinc salt. Examples of the pharmaceutically acceptable ammonium salts are ammonium salt and tetramethyl ammonium salt. Examples of the pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of the pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine. The processes for producing Compounds (I) are described below. Process 1 Compound (Ic) [Compound (I) in which X is COR 4a (wherein R 4a represents lower alkoxy in the definition of R 4 )] and Compound (Id) [Compound (I) in which X is COOH] can be prepared by the following reaction steps. (In the formulae, R 1 , R 2 , R 3 , R 4a , Q 1 , Q 2 , and Q 3 have the same meanings as defined above; Z' represents chlorine, bromine, or iodine; and Ph represents phenyl.) (STEP 1) Compound (Ic) can be obtained by reaction of Compound (IV) obtained by a known method [Chem. Ber., 95 , 414 (1962)] with a phosphonium salt (V) in a solvent in the presence of a base. Examples of the base are alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkyl lithiums such as butyl lithium, and alkali metal alkoxides such as potassium tert-butoxide and potassium tert-amyl alcoholate. Examples of the solvent are aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane and tetrahydrofuran, dimethylformamide, and dimethylsulfoxide. The reaction is carried out at 0 to 120°C and is completed in 0.5 to 24 hours. (STEP 2) Compound (Id) can be obtained by hydrolysis of an ester group of Compound (Ic) in a solvent in the presence of a suitable additive. Examples of the additive are alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide, halogenated lithiums such as lithium chloride, and alkali metal alkoxides such as potassium tert-butoxide. As the solvent, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, and, if necessary, water or the like may be used in combination. The reaction is carried out at 0 to 120°C and is completed in 0.5 to 24 hours. Process 2 Compound (Iea) [Compound (I) in which X is COCH 3 ], and Compound (Id) can be prepared by the following reaction steps. (In the formulae, R 1 , R 2 , R 3 , Q 1 , Q 2 , and Q 3 have the same meanings as defined above; R 11 represents lower alkyl; and Z'' represents bromine or iodine.) The lower alkyl in the definition of R 11 has the same meaning as defined above. (STEP 3) Compound (VI) can be obtained by reaction of Compound (V) obtained by a known method (EP-A-0565377) or a method similar thereto with trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, or N-phenyl-N-(trifluoromethanesulfonyl)trifluoromethanesulfonamide in a solvent in the presence of a base. Examples of the base are organic amines such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and pyridine, and inorganic carbonates such as potassium carbonate. Examples of the solvent are halogenated hydrocarbons such as methylene chloride and ethylene dichloride. The reaction is carried out at -30 to 100°C and is completed in 0.5 to 10 hours. (STEP 4) Compound (IX) can be obtained by reaction of Compound (VI) or Compound (VII) obtained by a known method (EP-A-0565377) or a method similar thereto with a tin compound (VIII) in a solvent in the presence of a transition metal catalyst. Examples of the transition metal catalyst are palladium catalysts such as dichlorobis(triphenylphosphine)palladium and palladium acetate. An example of the tin compound (VIII) is (1-ethoxyvinyl)tributyltin. Examples of the solvent are aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane and tetrahydrofuran, dimethylformamide, and dimethylsulfoxide. Lithium chloride may be added, if necessary. The reaction is carried out at 0 to 120°C and is completed in 0.5 to 24 hours. (STEP 5) Compound (Iea) can be obtained by hydrolysis of a vinyl ether group of Compound (IX) in a solvent in the presence of a suitable acid. Examples of the acid are protic acids such as hydrochloric acid and p-toluenesulfonic acid. As the 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 may be used solely, or if necessary in combination. The reaction is carried out at 0 to 120°C and is completed in 0.5 to 24 hours. (STEP 6) Compound (Id) can be obtained by subjecting Compound (Iea) to a haloform reaction in a solvent in the presence of a base. Examples of the base are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples of the halogen used in the haloform reaction are bromine and iodine. As the solvent, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, water, and the like may be used solely, or if necessary in combination. The reaction is carried out at 0 to 120°C and is completed in 0.5 to 24 hours. Process 3 Compound (Ie) [Compound (I) in which X is COR 4b (wherein R 4b represents hydrogen or lower alkyl in the definition of R 4 )] can be prepared by the following reaction step. (In the formulae, R 1 , R 2 , R 3 , R 4b , Q 1 , Q 2 , and Q 3 have the same meanings as defined above; and Z''' represents chlorine, bromine, or iodine.) (STEP 7) Compound (Ie) can be obtained by reaction of Compound (II) obtained by a known method (WO92/06976) or a method similar thereto, with an equivalent amount of Compound (X) in a solvent in the presence of a Lewis acid. As the Lewis acid, 1-3 equivalents, preferably 2 equivalents of aluminum chloride, or the like is used. Examples of the solvent are 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 desired compounds in the processes described above can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various kinds of chromatography. In the case where a salt of Compound (I) is desired and it is produced in the form of the desired salt, it can be subjected to purification as such. In the case where Compound (I) is produced in the free state and its salt is desired, Compound (I) is dissolved or suspended in a suitable solvent, followed by addition of an acid or a base to form a salt. Compounds (I) can exist in the form of geometrical isomers such as an (E)-isomer and a (Z)-isomer, and the present invention covers all possible isomers including these geometrical isomers and mixtures thereof. In the case where separation between an (E)-isomer and a (Z)-isomer is desired, they can be isolated and purified by fractionation methods, for example, fractional crystallization, fractional precipitation, and fractional dissolution. Compounds (I) and pharmaceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which are also within the scope of the present invention. Examples of Compounds (I) are shown in Table 1. The pharmacological activities of Compounds (I) are shown below by test examples. Test Example 1 Acute Toxicity Test Test compounds were orally administered to groups of dd-strain male mice weighing 20 ± 1 g, each group consisting of three mice (po; 300 mg/kg). Seven days after the administration, minimum lethal dose (MLD) of each compound was determined by observing the mortality. The results of Compounds (I) are shown in Table 2. As shown in Table 2, the toxicity of Compounds (I) is weak. Therefore, these compounds can be safely used in a wide range of doses. Compound MLD (mg/kg) 2 > 300 3 > 300 Test Example 2 Adenosine Receptor Antagonistic Activity (Adenosine A 2 Receptor Binding Test) The test was conducted according to the method of Bruns et al. [Mol. Pharmacol., 29 , 331 (1986)] with slight modification. Corpus striatum of a rat was suspended in ice-cooled 50 mM Tris hydroxymethyl aminomethane hydrochloride (Tris HCl) buffer (pH 7.7) by using Polytron homogenizer (manufactured by Kinematicas Co.). The suspension was centrifuged (50,000 x g, 10 minutes), and the precipitate was suspended again in the same amount of 50 mM Tris HCl buffer. The suspension was centrifuged under the same conditions, and the final precipitate was suspended once again in 50 mM Tris HCl buffer containing 10 mM magnesium chloride and 0.02 unit/mg tissue of adenosine deaminase (manufactured by Sigma Co.) to give a tissue concentration of 5 mg (wet weight)/ml. To 1 ml of the tissue suspension thus prepared were added 50 µl of a mixture of N-ethylcarboxamidoadenosine labeled with tritium ( 3 H-NECA: 26 Ci/mmol, manufactured by Amersham Co.) (final concentration: 3.8 nM) and cyclopentyladenosine (CPA, manufactured by Sigma Co.) (final concentration: 50 nM), and 50 µl of a test compound. The resulting mixture was allowed to stand at 25°C for 120 minutes and then rapidly filtered by suction through a glass fiber filter (GF/C, manufactured by Whatman Co.). The filter was immediately washed three times with 5 ml each of ice-cooled 50 mM Tris HCl buffer, and transferred to a vial, and a scintillator (EX-H by Wako Pure Chemical Industries, Ltd.) was added thereto. The radioactivity on the filter was determined with a liquid scintillation counter (manufactured by Packard Instrument Co.). The inhibition rate of the test compound against the binding of A 2 receptors ( 3 H-NECA binding) was calculated by the following equation: Inhibition Rate (%) = 1 - [B] - [N] [T] - [N] × 100 [Notes] 1. "B" means the amount of radioactivity of 3 H-NECA bound in the presence of a test compound at a concentration shown in Table 3. 2. "T" means the amount of radioactivity of 3 H-NECA bound in the absence of a test compound. 3. "N" means the amount of radioactivity of 3 H-NECA bound in the presence of 100 µM CPA. The similar procedure as above was repeated to determine the radioactivity bound to the A 2 receptors using 50 µl of CGS 21680 labeled with tritium { 3 H-2-[p-(2-carboxyethyl)phenethylamino]-5'-(N-ethylcarboxamide)adenosine: 40 Ci/mmol, manufactured by New England Nuclear Co. [J. Pharmacol. Exp. Ther., 251 , 888 (1989)]} (final concentration: 4.0 nM) in place of 50 µl of the mixture of N-ethylcarboxamidoadenosine labeled with tritium ( 3 H-NECA: 26 Ci/mmol, manufactured by Amersham Co.) (final concentration: 3.8 nM) and cyclopentyladenosine (CPA, manufactured by Sigma Co.) (final concentration: 50 nM). The inhibition rate of the test compound against the binding of A 2 receptors ( 3 H-CGS 21680 binding) was calculated by the following equation: Inhibition Rate (%) = 1 - [B] - [N] [T] - [N] × 100 [Notes] 1. "B" means the amount of radioactivity of 3 H-CGS 21680 bound in the presence of a test compound at a concentration shown in Table 3. 2. "T" means the amount of radioactivity of 3 H-CGS 21680 bound in the absence of a test compound. 3. "N" means the amount of radioactivity of 3 H-CGS 21680 bound in the presence of 100 µM CPA. The results are shown in Table 3. The Ki values shown in the table were calculated by the following equation: Ki = IC 50 1 + L Kd + C Kc [Notes] IC 50 : Concentration at which the inhibition rate is 50% L: Concentration of 3 H-NECA or 3 H-CGS 21680 Kd: Dissociation constant of 3 H-NECA or 3 H-CGS 21680 C: Concentration of CPA Kc: Inhibition constant of CPA Compd. A 2 Receptor Inhibition Rate (%) K i (nM) 10 -7 M 10 -6 M 10 -5 M 10 -4 M 1 77 92 2 92 101 3 72 4 68 94 5 69 88 6 80 94 7 60 92 8 70 95 9 85 99 13 11 66 93 13 76 86 15 83 95 Compounds (I) and pharmaceutically acceptable salts thereof exhibit a potent adenosine A 2 receptor antagonistic activity. Thus, they are effective against various kinds of diseases caused by hyperergasia of adenosine A 2 receptors, for example, Parkinson's disease, senile dementia, depression, asthma, and osteoporosis. Test Example 3 Effect on Haloperidol-Induced Catalepsy Parkinson's disease is a clinical syndrome caused by degeneration of nigrostriatal dopaminergic neurons. Systemic administration of haloperidol (dopamine D 1 /D 2 antagonist) induces catalepsy resulting from the blockade of postsynaptic dopamine D 2 receptors. It is generally accepted that this haloperidol-induced catalepsy is a classical model of parkinsonism in humans [Eur. J. Pharmacol., 182 , 327 (1990)]. The experiment was performed by using several groups of 5-weeks-old male ddY mice (weighing 22 to 24 g, Japan SLC), each group consisting of 5 mice. Haloperidol (Janssen Pharmaceutica) suspended in 0.3% CMC was intraperitoneally administered to each mouse at a dose of 1.0 mg/kg. Test compounds were suspended in injectable distilled water (Otsuka Pharmaceutical Co., Ltd.) containing Tween 80 [polyoxyethylene (20) sorbitan monooleate]. L-DOPA (Kyowa Hakko Kogyo Co., Ltd.) and benserazide hydrochloride (Kyowa Hakko Kogyo Co., Ltd.) were suspended in 0.3% CMC. One hour after the haloperidol administration, the test compound suspensions and the control suspension [injectable distilled water (Otsuka Pharmaceutical Co., Ltd.) containing Tween 80] containing no test compound were orally administered to separate groups of the mice (0.1 ml per 10 g of body weight). One hour after the administration of the test compound, the forelimbs of each mouse and subsequently the hindlimbs of the same mouse were placed on a 4.5 cm-high, 1.0 cm-wide bar and catalepsy was estimated. All of the test compounds were orally administered at a dose of 10 mg/kg, and L-DOPA (100 mg/kg) and benserazide (25 mg/kg) were intraperitoneally administered together as a control experiment. The catalepsy score and the standard of judgment are shown below. score duration of the cataleptic posture 0: forelimbs less than 5 seconds hindlimbs less than 5 seconds 1: forelimbs from 5 (inclusive) to 10 (exclusive) seconds hindlimbs less than 5 seconds 2: forelimbs 10 seconds or more hindlimbs less than 5 seconds 3: forelimbs from 5 (inclusive) to 10 (exclusive) seconds hindlimbs from 5 (inclusive) to 10 (exclusive) seconds; or forelimbs less than 5 seconds hindlimbs 5 seconds or more 4: forelimbs 10 seconds or more hindlimbs from 5 (inclusive) to 10 (exclusive) seconds; or forelimbs from 5 (inclusive) to 10 (exclusive) seconds hindlimbs 10 seconds or more 5: forelimbs 10 seconds or more hindlimbs 10 seconds or more The effect of the compounds was evaluated by the total of the catalepsy scores of five mice in each group (25 points at the full). The groups wherein the total score was not more than 20 points were estimated to be effective. The number of the animals showing remission against catalepsy is the number of the mice for which the catalepsy score was not more than 4 points. The remission rate shows the rate of decrease in total score based on that of the control group. The results are shown in Table 4. Compound Total Score Number of the Animals Showing Remission Remission Rate (%) 0.3% Tween 80(Control) 25 0 0 L-DOPA + benserazide 18 4 28 1 11 4 56 9 7 5 72 Test Example 4 Effect on Clonidine-Induced Aggressive Behavior The effect of a test compound on the aggressive behavior induced by intraperitoneal administration of clonidine was investigated [Eur. J. Pharmacol., 29 , 374 (1968)]. The experiment was performed by using several groups of male ddY mice (weighing 20 to 25 g, Japan SLC), each group consisting of two mice. The test compound was suspended in injectable distilled water (Otsuka Pharmaceutical Co., Ltd.) containing Tween 80. Clonidine hydrochloride (Sigma Co.) was dissolved in physiological saline solution (Otsuka Pharmaceutical Co., Ltd.) The test compound suspension and the control suspension [injectable distilled water (Otsuka Pharmaceutical Co., Ltd.) containing Tween 80] were orally administered to separate groups of the mice (0.1 ml per 10 g of body weight). Sixty minutes after the oral administration of the test compound, clonidine hydrochloride (20 mg/kg) was intraperitoneally injected. The number of biting attacks during 30 minutes after clonidine treatment was counted. The effect of the compound was evaluated by comparing the average number of biting attacks of the test compound-administered groups with that of control groups (Student's t-test). The results are shown in Table 5. Compd. Dose (mg/kg,po) Number of the Biting Attacks (mean ± S.E.M.) Number of the Attacks of Test Compound-Treated Group/Number of the Attacks of Control Group Control Group (number of animals) Test Compound-Treated Group (number of animals) 9 10 6.3 ± 2.09 (15) 33.1 ± 7.16 (15) 5.3 Compounds (I) and pharmaceutically acceptable salts thereof can be administered as they are, or in the form of various pharmaceutical compositions. The pharmaceutical compositions in accordance with the present invention can be prepared by uniformly mixing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient, with a pharmaceutically acceptable carrier. It is desired that such pharmaceutical compositions are prepared in a unit dose form suitable for oral administration or administration through injection. For preparing a pharmaceutical composition for oral administration, any useful pharmaceutically acceptable carrier can be used. For example, liquid preparations for oral administration such as suspension and syrup can be prepared 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, preservatives such as p-hydroxybenzoates, flavors such as strawberry flavor and peppermint, and the like. Powders, pills, capsules, and tablets can be prepared using excipients such as lactose, glucose, sucrose, and mannitol, disintegrating agents such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, and gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, and the like. Tablets and capsules are the most useful oral unit dose forms because of the readiness of administration. For preparing tablets and capsules, solid pharmaceutical carriers are used. Injectable preparations can be prepared using a carrier such as distilled water, a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution. The preparations can be prepared in the form of solution, suspension, or dispersion according to a conventional method by using a suitable solubilizing agent or suspending agent. Compounds (I) and pharmaceutically acceptable salts thereof can be administered orally in the said dosage forms or parenterally as injections. The effective dose and the administration schedule vary depending upon the mode of administration, the age, body weight, and conditions of a patient, etc. However, generally, Compound (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of 0.01 to 25 mg/kg in 3 to 4 parts. In addition, Compounds (I) may also be administered by inhalation in the form of aerosol, fine powder, or spray solution. In the case of aerosol administration, the compound of the present invention is dissolved in an appropriate pharmaceutically acceptable solvent such as ethyl alcohol or a combination of miscible solvents, and the resulting solution is mixed with a pharmaceutically acceptable propellant. Certain embodiments of the invention are illustrated in the following examples, reference examples, and preparation examples. Example 1 (E)-β-(7-Methyl-1,3-dipropylxanthin-8-yl)styrene-4-carboxylic acid methyl ester (Compound 1) and (Z)-β-(7-methyl-1,3-dipropylxanthin-8-yl)styrene-4-carboxylic acid methyl ester (Compound 2) 60% Sodium hydride (25.9 mg, 0.648 mmol) was added to a suspension of 353 mg (0.719 mmol) of (4-methoxycarbonylbenzyl)triphenylphosphonium bromide in 3 ml of tetrahydrofuran under ice-cooling in a stream of argon. The reaction mixture was heated at 50°C for 20 minutes, and then ice-cooled, and 100 mg (0.360 mmol) of Compound c obtained in Reference Example 3 was added slowly thereto. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then poured into 10 ml of water and extracted three times with 10 ml of ether. The extract was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by column chromatography (eluent: 25% ethyl acetate/hexane) to give 40.0 mg (yield 27%) of Compound 1 and 39.5 mg (yield 27%) of Compound 2 as pale yellow powders. Compound 1 NMR (270MHz; 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 2 NMR (270MHz; 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 2 (Z)-β-(7-Methyl-1,3-dipropylxanthin-8-yl)styrene-4-carboxylic acid (Compound 3) Compound 2 (2.64 g, 6.44 mmol) obtained in Example 1 was dissolved in a solvent mixture of 60 ml of dioxane and 40 ml of water. To the solution was added 1.08 g (25.8 mmol) of lithium hydroxide monohydrate, and the resulting mixture was stirred at room temperature for one hour. After neutralization with 1N HCl, the mixture was extracted three times with ethyl acetate. The combined extract was dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The resulting crude crystals were recrystallized from toluene/cyclohexane to give 2.26 g (yield 89%) of Compound 3 as a yellow powder. Melting Point: 214.7-216.9°C Elemental Analysis: C 21 H 24 N 4 O 4 ·0.1CH 3 C 6 H 5 Calcd. (%): C, 64.25; H, 6.16; N, 13.81 Found (%): C, 64.34; H, 6.33; N, 13.91 IR (KBr) ν max (cm -1 ): 1723, 1687, 1656 NMR (270MHz; 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 3 (E)-β-(7-Methyl-1,3-dipropylxanthin-8-yl)styrene-4-carboxylic acid (Compound 4) A solution of 1.25 g (3.15 mmol) of Compound 3 obtained in Example 2 and 40 mg (0.32 mmol) of iodine in 125 ml of toluene was heated under reflux for 6.5 hours. After cooling, a 0.1M aqueous solution of sodium thiosulfate and chloroform were added thereto, followed by stirring. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 740 mg (yield 59%) of Compound 4 as ocher needles. Melting Point: 273.4-275.4°C Elemental Analysis: C 21 H 24 N 4 O 4 Calcd. (%): C, 63.62; H, 6.10; N, 14.13 Found (%): C, 63.49; H, 6.25; N, 14.12 IR (KBr) ν max (cm -1 ): 1726, 1691, 1633, 1543 NMR (270MHz; 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), 4.02(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 4 (E)-β-(1,3-Diethyl-7-methylxanthin-8-yl)-2-methoxystyrene-4-carboxylic acid methyl ester (Compound 5) A 1.65M n-butyl lithium/hexane solution (1.09 ml, 1.799 mmol) was added to a suspension of 938 mg (1.799 mmol) of (2-methoxy-4-methoxycarbonylbenzyl)triphenylphosphonium bromide in 10 ml of tetrahydrofuran under ice-cooling in an argon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, and ice-cooled, and a suspension of 300 mg (1.199 mmol) of Compound f obtained in Reference Example 6 in 1 ml of tetrahydrofuran was added slowly thereto. The resulting solution was stirred at room temperature for 2.5 hours. After ice-cooling, 1.8 ml of a 1N aqueous solution of ammonium chloride was added thereto, followed by addition of ethyl acetate . The organic layer was washed three times with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by column chromatography (eluent: hexane/ethyl acetate=3/1) to give 422 mg (yield 85%) of Compound 5, which was further recrystallized from hexane/ethyl acetate to give a yellow powder. Melting Point: 239.0-241.2°C Elemental Analysis: C 21 H 24 N 4 O 5 Calcd. (%): C, 61.16; H, 5.86; N, 13.58 Found (%): C, 61.28; H, 5.99; N, 13.62 IR (KBr) ν max (cm -1 ): 1719, 1687, 1652, 1304, 1231 NMR (270MHz; 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=7.3Hz), 4.07(3H, s), 4.01(3H, s), 3.95(3H, s), 1.39(3H, t, J=7.3Hz), 1.27(3H, t, J=7.3Hz) Example 5 (E)-2-Methoxy-β-(7-methyl-1,3-dipropylxanthin-8-yl)styrene-4-carboxylic acid methyl ester (Compound 6) Substantially the same procedure as in Example 4 was repeated using 2.81 g (5.390 mmol) of (2-methoxy-4-methoxycarbonylbenzyl)triphenylphosphonium bromide, 3.27 ml (5.396 mmol) of a 1.65M n-butyl lithium/hexane solution, and 1.00 g (3.593 mmol) of Compound c obtained in Reference Example 3. The resulting crude crystals were recrystallized from hexane/ethyl acetate to give 203 mg (yield 33%) of Compound 6 as yellow grains. Melting Point: 198.5-200.4°C Elemental Analysis: C 23 H 28 N 4 O 5 ·0.4H 2 O Calcd. (%): C, 61.70; H, 6.48; N, 12.51 Found (%): C, 61.77; H, 6.42; N, 12.45 IR (KBr) ν max (cm -1 ): 1704, 1655, 1541, 1436, 1234 NMR (270MHz; 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 6 (E)-β-(1,3-Diethyl-7-methylxanthin-8-yl)-2-methoxystyrene-4-carboxylic acid (Compound 7) Compound 20 (108 mg, 0.262 mmol) obtained in Example 4 was suspended in a solvent mixture of 2 ml of tetrahydrofuran, 2 ml of ethanol, and 1 ml of water. To the suspension was added 55 mg (1.311 mmol) of lithium hydroxide monohydrate, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was acidified with 2N HCl, and the precipitated crystals were collected by filtration. The obtained crude crystals were purified by column chromatography (eluent: chloroform/methanol/acetic acid=40/1/1) to give 25 mg (yield 24%) of Compound 7, which was further recrystallized from isopropanol to give a yellow powder. Melting Point: >280°C Elemental Analysis: C 20 H 22 N 4 O 5 ·0.6H 2 O Calcd. (%): C, 58.70; H, 5.71; N, 13.69 Found (%): C, 58.55; H, 5.66; N, 13.46 IR (KBr) ν max (cm -1 ): 1689, 1648, 1543, 1434, 1305 NMR (270MHz; DMSO-d 6 ) δ (ppm): 8.00(1H, d, J=8.3Hz), 7.94(1H, d, J=15.8Hz), 7.58(1H, d, J=8.3Hz), 7.56 (1H, s), 7.44(1H, d, J=15.8Hz), 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 7 (E)-2-Methoxy-β-(7-methyl-1,3-dipropylxanthin-8-yl)styrene-4-carboxylic acid (Compound 8) Substantially the same procedure as in Example 6 was repeated using 300 mg (0.681 mmol) of Compound 6 obtained in Example 5. The resulting crude crystals were recrystallized from isopropanol to give 203 mg (yield 70%) of Compound 8 as a yellow powder. Melting Point: 284.7-286.1°C Elemental Analysis: C 22 H 26 N 4 O 5 Calcd. (%): C, 61.96; H, 6.14; N, 13.14 Found (%): C, 61.74; H, 6.31; N, 13.12 IR (KBr) ν max (cm -1 ): 2864, 1691, 1650, 1531, 1435 NMR (270MHz; DMSO-d 6 ) δ (ppm): 13.04(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=7.3Hz), 3.96(3H, s), 3.83(2H, t, J=7.3Hz), 1.80-1.67(2H, m), 1.63-1.50 (2H, m), 0.91(3H, t, J=7.3Hz), 0.87(3H, t, J=7.3Hz) Example 8 (E)-8-(3-Acetylstyryl)-1,3-diethyl-7-methylxanthine (Compound 9) Compound h (1.00 g, 2.480 mmol) obtained in Reference Example 8 and dichlorobis(triphenylphosphine)palladium (17 mg, 0.024 mmol) were suspended in 20 ml of dimethylformamide. To the suspension was added 0.84 ml (2.486 mmol) of (1-ethoxyvinyl)tributyltin in an argon atmosphere, and the resulting mixture was stirred at 120°C for 3 hours. After ice-cooling, 2N ammonium fluoride was added to the mixture, followed by filtration. The filtrate was diluted with chloroform, and washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was suspended in a solvent mixture of 20 ml of tetrahydrofuran and 5 ml of 2N HCl, and the suspension was stirred at room temperature for 2.5 hours. After neutralization with a 2N aqueous solution of sodium hydroxide, the reaction mixture was diluted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by column chromatography (eluent: hexane/ethyl acetate=2/1), and further recrystallized from ethyl acetate to give 482 mg (yield 53%) of Compound 9 as pale yellow flocculent precipitate. Melting Point: 221.4-221.8°C Elemental Analysis: C 20 H 22 N 4 O 3 Calcd. (%): C, 65.56; H, 6.05; N, 15.29 Found (%): C, 65.23; H, 6.22; N, 15.26 IR (KBr) ν max (cm -1 ): 1679, 1650, 1542, 1441, 1276 NMR (270MHz; CDCl 3 ) δ (ppm): 8.19(1H, s), 7.93(1H, d, J=7.9Hz), 7.84(1H, d, J=15.8Hz), 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 9 (E)-β-(1,3-Diethyl-7-methylxanthin-8-yl)styrene-3-carboxylic acid (Compound 10) Sodium hydroxide (432 mg, 10.8 mmol) and bromine (0.13 ml, 2.523 mmol) were added to water (3 ml) under ice-cooling, followed by addition of dioxane (3 ml). The mixture was slowly added to a suspension of 300 mg (0.819 mmol) of Compound 9 obtained in Example 8 in 3 ml of dioxane under ice-cooling, and the resulting mixture was stirred at room temperature for 3.5 hours. After ice-cooling, a 5% aqueous solution of sodium thiosulfate was added thereto, and the mixture was acidified with 2N HCl. The precipitated crystals were collected by filtration, and recrystallized from ethanol/water to give 254 mg (yield 84%) of Compound 10 as pale yellow needles. Melting Point: 260.2-261.5°C Elemental Analysis: C 19 H 20 N 4 O 4 ·0.3H 2 O Calcd. (%): 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 (270MHz; DMSO-d 6 ) δ (ppm): 13.09(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, d, 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=6.9Hz), 1.27 (3H, t, J=6.9Hz), 1.13(3H, t, J=6.9Hz) Example 10 (E)-8-(3-Acetyl-4-methoxystyryl)-7-methyl-1,3-dipropylxanthine (Compound 11) Substantially the same procedure as in Example 8 was repeated using 1.00 g (2.168 mmol) of Compound j obtained in Reference Example 10, 15 mg (0.021 mmol) of dichlorobis(triphenylphosphine)palladium, and 0.74 ml (2.190 mmol) of (1-ethoxyvinyl)tributyltin. The resulting crude crystals were recrystallized from ethyl acetate to give 407 mg (yield 44%) of Compound 11 as pale yellow needles. Melting Point: 193.9-194.7°C Elemental Analysis: C 23 H 28 N 4 O 4 Calcd. (%): C, 65.08; H, 6.64; N, 13.20 Found (%): C, 65.11; H, 6.71; N, 13.23 IR (KBr) ν max (cm -1 ): 1694, 1657, 1501, 1439, 1267 NMR (270MHz; 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 11 (E)-4-Methoxy-β-(7-methyl-1,3-dipropylxanthin-8-yl)styrene-3-carboxylic acid (Compound 12) Substantially the same procedure as in Example 9 was repeated using 200 mg (0.471 mmol) of Compound 11 obtained in Example 10. The resulting crude crystals were recrystallized from dioxane/water to give 190 mg (yield 95%) of Compound 12 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, brs), 8.05 (1H, d, J=2.3Hz), 7.89(1H, dd, J=8.6, 2.3Hz), 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=7.3Hz) FAB-MS: 427 (M+H) + Example 12 (E)-8-(3-Acetyl-4-fluorostyryl)-1,3-diethyl-7-methylxanthine (Compound 13) Substantially the same procedure as in Example 8 was repeated using 500 mg (1.187 mmol) of Compound m obtained in Reference Example 12, 10 mg (0.014 mmol) of dichlorobis(triphenylphosphine)palladium, and 0.41 ml (1.214 mmol) of (1-ethoxyvinyl)tributyltin. The resulting crude crystals were recrystallized from ethyl acetate to give 174 mg (yield 61%) of Compound 13 as yellow needles. Melting Point: 238.1-239.3°C Elemental Analysis: C 20 H 21 FN 4 O 3 ·0.6H 2 O Calcd. (%): C, 60.78; H, 5.66; N, 14.18 Found (%): C, 60.50; H, 5.42; N, 14.31 IR (KBr) ν max (cm -1 ): 1684, 1657, 1652, 1541, 1437 NMR (270MHz; CDCl 3 ) δ (ppm): 8.13(1H, dd, J=6.9, 2.3Hz), 7.78(1H, d, J=15.8Hz), 7.74-7.68(1H, m), 7.20(1H, dd, J=10.6, 8.6Hz), 6.92(1H, 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 13 (E)-β-(1,3-Diethyl-7-methylxanthin-8-yl)-4-fluorostyrene-3-carboxylic acid (Compound 14) Substantially the same procedure as in Example 9 was repeated using 450 mg (1.165 mmol) of Compound 13 obtained in Example 12. The resulting crude crystals were recrystallized from ethanol to give 187 mg (yield 41%) of Compound 14 as a pale brown powder. Melting Point: 247°C (decomposition) IR (KBr) ν max (cm -1 ): 1695, 1658, 1547, 1538, 1440 NMR (270MHz; 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, t, J=6.9Hz), 1.13(3H, t, J=6.9Hz) FAB-MS: 387 (M+H) + Example 14 (E)-8-(4-Acetyl-3-methoxystyryl)-1,3-diethyl-7-methylxanthine (Compound 15) Substantially the same procedure as in Example 8 was repeated using 200 mg of crude Compound q obtained in Reference Example 16, 6 mg (0.009 mmol) of dichlorobis(triphenylphosphine)palladium, and 0.27 ml (0.799 mmol) of (1-ethoxyvinyl)tributyltin to give 50 mg (yield 32%) of Compound 15, which was further recrystallized from ethyl acetate to give yellow needles. Melting Point: 236.1-237.2°C Elemental Analysis: C 21 H 24 N 4 O 4 ·0.3H 2 O Calcd. (%): C, 62.77; H, 6.17; N, 13.94 Found (%): C, 62.90; H, 6.16; N, 13.79 IR (KBr) ν max (cm -1 ): 1697, 1655, 1594, 1543, 1409 NMR (270MHz; 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(3H, s), 3.99 (3H, s), 2.63(3H, s), 1.39(3H, t, J=6.9Hz), 1.27 (3H, t, J=6.9Hz) Reference Example 1 8-Hydroxymethyl-1,3-dipropylxanthine (Compound a) A mixture of 5,6-diamino-1,3-dipropyluracil [J. Med. Chem., 28 , 487 (1985)] (10.0 g, 44.2 mmol) and glycolic acid (16.8 g, 221 mmol) was heated at 110°C for 15 minutes. After cooling, 60 ml of dioxane and 100 ml of water were added thereto, followed by addition of sodium hydroxide to adjust the pH of the solution to 14. The resulting solution was heated under reflux for 30 minutes, cooled, and neutralized by addition of concentrated hydrochloric acid. The precipitated crystals were collected by filtration and dried to give 10.6 g (yield 90%) of Compound a as a white powder. Melting Point: 220.1-221.0°C Elemental Analysis: C 12 H 18 N 4 O 3 Calcd. (%): C, 54.12; H, 6.81; N, 21.04 Found (%): C, 53.94; H, 6.97; N, 20.85 IR (KBr) ν max (cm -1 ): 3300 (br), 1703, 1632, 1556, 1510 NMR (90MHz; 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) Compound a (1.00 g, 3.76 mmol) obtained in Reference Example 1 was dissolved in 30 ml of dimethylformamide. To the solution were added 1.30 g (9.40 mmol) of potassium carbonate and subsequently 0.47 ml (7.52 mmol) of methyl iodide, and the resulting mixture was stirred at 50°C for one hour. Insoluble matters were filtered off and 60 ml of water was added to the filtrate. The mixture was extracted three times with 25 ml of chloroform. The extract was washed twice with water and twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from cyclohexane to give 735 mg (yield 70%) of Compound b as yellow needles. Melting Point: 111.4-111.8°C Elemental Analysis: C 13 H 20 N 4 O 3 Calcd. (%): C, 55.70; H, 7.19; N, 19.99 Found (%): C, 55.73; H, 7.45; N, 19.64 IR (KBr) ν max (cm -1 ): 3300 (br), 1706, 1665, 1541 NMR (90MHz; CDCl 3 ) δ (ppm): 4.76(2H, s), 4.20-3.90 (4H, m), 4.02(3H, s), 2.40(1H, brs), 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 (2.48 g, 28.5 mmol) was added to a solution of 800 mg (2.85 mmol) of Compound b obtained in Reference Example 2 in 80 ml of chloroform, and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 1% methanol/ chloroform) to give 440 mg (yield 56%) of Compound c 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), 4.33(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) Substantially the same procedure as in Reference Example 1 was repeated using 5.0 g (25.2 mmol) of 5,6-diamino-1,3-diethyluracil [J. Am. Chem. Soc., 75 , 114 (1953)] and 8.4 g (111 mmol) of glycolic acid. The resulting crude crystals were recrystallized from methanol to give 3.56 g (yield 60%) of Compound d as white needles. NMR (270MHz; DMSO-d 6 ) δ (ppm): 13.26(1H, brs), 5.50 (1H, brs), 4.51(2H, s), 4.02(2H, 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) Substantially the same procedure as in Reference Example 2 was repeated using 2.00 g (8.40 mmol) of Compound d obtained in Reference Example 4. The resulting crude crystals were recrystallized from hexane/ethyl acetate to give 1.88 g (yield 89%) of Compound e as white needles. NMR (270MHz; 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) Substantially the same procedure as in Reference Example 3 was repeated using 1.00 g (3.96 mmol) of Compound e obtained in Reference Example 5. The resulting crude crystals were recrystallized from hexane/ethyl acetate to give 404 mg (yield 41%) of Compound f as pale yellow plates. NMR (270MHz; CDCl 3 ) δ (ppm): 9.93(1H, s), 4.35(3H, s), 4.20(2H, q, J=6.9Hz), 4.10(2H, 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) 3-Bromocinnamic acid (2.52 g, 11.1 mmol) and 3-(3-diethylaminopropyl)-1-ethylcarbodiimide hydrochloride (2.90 g, 15.2 mmol) were added to a solution of 5,6-diamino-1,3-diethyluracil (2.0 g, 10.1 mmol) in a dioxane (34 ml)-water (68 ml) mixture, and the resulting mixture was stirred at room temperature for 40 minutes while keeping the pH at 5.5. A 4N aqueous solution of sodium hydroxide was added thereto to adjust the pH to >14, and the mixture was heated under reflux for 20 minutes. After cooling, the mixture was neutralized and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from tetrahydrofuran/water to give 2.01 g (yield 37%) of Compound g as pale green plates. Melting Point: >270°C Elemental Analysis: C 17 H 17 BrN 4 O 2 Calcd. (%): C, 52.46; H, 4.40; N, 14.39 Found (%): C, 52.54; H, 4.44; N, 14.37 IR (KBr) ν max (cm -1 ): 1683, 1636, 1492 NMR (270MHz; CF 3 COOD) δ (ppm): 7.99(1H, d, J=16.6Hz), 7.84(1H, s), 7.70(1H, d, J=7.9Hz), 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 mmol) obtained in Reference Example 7 was dissolved in 20 ml of dimethylformamide. To the solution were added 2.22 g (16.1 mmol) of potassium carbonate and subsequently 0.8 ml (12.9 mmol) of methyl iodide, and the resulting mixture was stirred at 50°C for 70 minutes. After cooling, insoluble matters were filtered off and water was added to the filtrate. The mixture was extracted three times with chloroform. The extract was washed three times with water and subsequently twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave 2.37 g (yield 92%) of crude Compound h as a yellow solid, which was further recrystallized from cyclohexane/toluene to give Compound h as a yellow powder. Melting Point: 187.3-188.2°C Elemental Analysis: C 18 H 19 BrN 4 O 2 Calcd. (%): C, 53.61; H, 4.75; N, 13.89 Found (%): C, 53.83; H, 4.63; N, 13.70 IR (KBr) ν max (cm -1 ): 1694, 1654 NMR (270MHz; 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) Substantially the same procedure as in Reference Example 7 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.75 g (14.6 mmol) of 3-bromo-4-methoxycinnamic acid. The resulting crude crystals were recrystallized from dioxane to give 3.43 g (yield 58%) of Compound i as yellow needles. Melting Point: 279.8-280.6°C Elemental Analysis: C 20 H 23 BrN 4 O 3 Calcd. (%): C, 53.70; H, 5.18; N, 12.52 Found (%): C, 53.77; H, 5.20; N, 12.49 IR (KBr) ν max (cm -1 ): 1685, 1633, 1599, 1503, 1279 NMR (270MHz; DMSO-d 6 ) δ (ppm): 13.42(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=7.4Hz), 3.89(3H, s), 3.86(2H, t, J=7.4Hz), 1.80-1.52(4H, m), 0.89(6H, t, J=7.4Hz) Reference Example 10 (E)-8-(3-Bromo-4-methoxystyryl)-7-methyl-1,3-dipropylxanthine (Compound j) Substantially the same procedure as in Reference Example 8 was repeated using 750 mg (1.68 mmol) of Compound i obtained in Reference Example 9. The resulting crude crystals were recrystallized from hexane/ethyl acetate to give 588 mg (yield 76%) of Compound j as pale yellow needles. Melting Point: 209.4-210.8°C Elemental Analysis: C 21 H 25 BrN 4 O 3 Calcd. (%): C, 54.67; H, 5.46; N, 12.14 Found (%): C, 54.47; H, 5.51; N, 11.91 IR (KBr) ν max (cm -1 ): 1693, 1656, 1542, 1500, 1264 NMR (270MHz; 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, 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) Substantially the same procedure as in Reference Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.08 g (16.7 mmol) of 3-bromo-4-fluorocinnamic acid. The resulting crude crystals were recrystallized from dioxane to give 2.90 g (yield 47%) of Compound k as a pale yellow powder. Melting Point: >300°C Elemental Analysis: C 17 H 16 BrFN 4 O 2 Calcd. (%): C, 50.14; H, 3.96; N, 13.76 Found (%): C, 50.27; H, 3.80; N, 13.66 IR (KBr) ν max (cm -1 ): 1688, 1637, 1501, 1248 NMR (270MHz; DMSO-d 6 ) δ (ppm): 13.64(1H, brs), 8.02 (1H, dd, J=6.9, 2.0Hz), 7.73-7.68(1H, m), 7.60 (1H, d, J=16.2Hz), 7.42(1H, t, J=8.6Hz), 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(3H, t, J=6.9Hz) Reference Example 12 (E)-8-(3-Bromo-4-fluorostyryl)-1,3-diethyl-7-methylxanthine (Compound m) Substantially the same procedure as in Reference Example 8 was repeated using 2.50 g (6.14 mmol) of Compound k obtained in Reference Example 11. The resulting crude crystals were recrystallized from ethyl acetate to give 2.41 g (yield 93%) of Compound m as yellow needles. Melting Point: 217.6-219.2°C Elemental Analysis: C 18 H 18 BrFN 4 O 2 Calcd. (%): C, 51.32; H, 4.30; N, 13.30 Found (%): C, 51.52; H, 4.20; N, 13.34 IR (KBr) ν max (cm -1 ): 1692, 1649, 1543, 1504, 1439 NMR (270MHz; CDCl 3 ) δ (ppm): 7.80(1H, dd, J=6.6, 2.0Hz), 7.70(1H, d, J=15.8Hz), 7.52-7.46(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=6.9Hz), 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) Substantially the same procedure as in Reference Example 7 was repeated using 4.0 g (20.2 mmol) of 5,6-diamino-1,3-diethyluracil and 5.29 g (22.2 mmol) of 3-methoxy-4-methoxymethoxycinnamic acid. The resulting crude crystals were recrystallized from dioxane to give 2.93 g (yield 36%) of Compound n as pale yellow needles. Melting Point: 223.4-224.3°C Elemental Analysis: C 20 H 24 N 4 O 5 Calcd. (%): C, 59.99; H, 6.04; N, 13.99 Found (%): C, 59.99; H, 6.11; N, 13.93 IR (KBr) ν max (cm -1 ): 1698, 1640, 1512, 1258 NMR (270MHz; DMSO-d 6 ) δ (ppm): 13.46(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(3H, 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) Substantially the same procedure as in Reference Example 8 was repeated using 2.0 g (5.00 mmol) of Compound n obtained in Reference Example 13. The resulting crude crystals were recrystallized from ethyl acetate to give 1.77 g (yield 85%) of Compound o as yellow plates. Melting Point: 179.4-180.6°C Elemental Analysis: C 21 H 26 N 4 O 5 Calcd. (%): C, 60.86; H, 6.32; N, 13.52 Found (%): C, 61.02; H, 6.46; N, 13.43 IR (KBr) ν max (cm -1 ): 1687, 1651, 1515, 1437, 1258 NMR (270MHz; 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=6.9Hz), 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 (1.50 g, 3.62 mmol) obtained in Reference Example 14 was suspended in tetrahydrofuran (30 ml), and 2N HCl (9 ml) was added thereto, followed by heating under reflux for one hour. The reaction mixture was neutralized with a 2N aqueous solution of sodium hydroxide under ice-cooling, and water was added thereto. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 1.08 g (yield 81%) of Compound p as yellow plates. Melting Point: 185.3-186.5°C Elemental Analysis: C 19 H 22 N 4 O 4 ·H 2 O Calcd. (%): C, 58.75; H, 6.23; N, 14.42 Found (%): C, 59.13; H, 6.21; N, 14.39 IR (KBr) ν max (cm -1 ): 1687, 1657, 1650, 1515, 1276 NMR (270MHz; 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=6.9Hz), 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 (371 mg, 1.002 mmol) obtained in Reference Example 15 was dissolved in pyridine (7 ml), and 0.34 ml (2.021 mmol) of trifluoromethanesulfonic anhydride was added thereto under ice-cooling. The resulting mixture was stirred for 2 hours under ice-cooling, and ice was added to the reaction mixture. The precipitated crystals were collected by filtration to give 523 mg (quantitative yield) of crude Compound q 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=15.8Hz), 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(3H, 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) 3-Methoxycinnamic acid (2.48 g, 13.9 mmol) and 3-(3-diethylaminopropyl)-1-ethylcarbodiimide hydrochloride (3.62 g, 18.9 mmol) were added to a mixture of dioxane (80 ml) and water (40 ml) containing 5,6-diamino-1,3-diethyluracil [J. Am. Chem. Soc., 75 , 114 (1953)] (2.5 g, 12.6 mmol). The resulting solution was stirred at room temperature for 2 hours at pH 5.5. After a 4N aqueous solution of sodium hydroxide was added thereto to adjust the pH to >14, 40 ml of water was added and the mixture was heated under reflux for 20 minutes. After cooling, the mixture was neutralized and 50 ml of chloroform was added thereto. The organic layer was separated and the aqueous layer was extracted twice with 50 ml of chloroform. The combined extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from dimethylformamide/water to give 2.10 g (yield 49%) of Compound r as a white powder. Melting Point: 270.6-272.5°C Elemental Analysis: C 18 H 20 N 4 O 3 Calcd. (%): C, 63.52; H, 5.92; N, 16.46 Found (%): C, 63.20; H, 6.01; N, 16.34 IR (KBr) ν max (cm -1 ): 1686, 1634, 1500 NMR (270MHz; 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) Compound r (1.70 g, 5.0 mmol) obtained in Reference Example 17 was dissolved in 40 ml of dimethylformamide. To the solution were added 1.73 g (12.5 mmol) of potassium carbonate and subsequently 0.62 ml (10.0 mmol) of methyl iodide, and the resulting mixture was stirred at 50°C for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 1.10 g (yield 62%) of Compound s as pale yellow needles. Melting Point: 153.4-154.8°C Elemental Analysis: C 19 H 22 N 4 O 3 Calcd. (%): C, 64.39; H, 6.26; N, 15.81 Found (%): C, 64.34; H, 6.38; N, 15.82 IR (KBr) ν max (cm -1 ): 1692, 1656, 1541 NMR (270MHz; DMSO-d 6 ) δ (ppm): 7.64(1H, d, J=15.8Hz), 7.40-7.30(4H, m), 6.97-6.92(1H, 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) Preparation Example 1 Tablets Tablets having the following composition were prepared in a conventional manner. Composition of One Tablet Compound 24 20 mg Lactose 143.4mg Potato Starch 30 mg Hydroxypropylcellulose 6 mg Magnesium Stearate 0.6mg 200 mg Preparation Example 2 Fine Granules Fine granules having the following composition were prepared in a conventional manner. Composition of One Pack of Fine Granules Compound 28 20 mg Lactose 655 mg Corn Starch 285 mg Hydroxypropylcellulose 40 mg 1,000 mg Preparation Example 3 Capsules Capsules having the following composition were prepared in a conventional manner. Composition of One Capsule Compound 30 20 mg Avicel 99.5mg Magnesium Stearate 0.5mg 120 mg Preparation Example 4 (Reference) Injections Injections having the following composition were prepared in a conventional manner. Composition of One Injection Vial Compound 1 2 mg Purified Soybean Oil 200 mg Purified Egg Yolk Lecithin 24 mg Glycerine for Injection 50 mg Distilled Water for Injection 1.72 ml 2.00 ml (Compound 1: (E)-4,5-Dimethoxy-β-(7-methyl-1,3-dipropylxanthin-8-yl)styrene-2-sulfonic acid) Preparation Example 5 Syrup Preparations Syrup Preparations having the following composition were prepared in a conventional manner. Composition of One Syrup Preparation Compound 21 20 mg Refined Sugar 30 mg Ethyl p-Hydroxybenzoate 40 mg Propyl p-Hydroxybenzoate 10 mg Strawberry Flavor 0.1 ml Water 99.8 ml 100 ml

Claims: A xanthine derivative represented by the following Formula (I): in which R 1 , R 2 , and R 3 independently represent hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms; Q 1 , Q 2 , and Q 3 independently represent hydrogen, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, or halogen; and X represents -COR 4 (in which R 4 represents hydrogen, hydroxy, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a straight-chain or branched alkoxy group having 1 to 6 carbon atoms), or a pharmaceutically acceptable salt thereof. A xanthine derivative according to claim 1, in which R 1 , R 2 , and R 3 independently represent a straight-chain or branched alkyl group having 1 to 6 carbon atoms. A xanthine derivative according to claim 2, in which R 3 is methyl. A xanthine derivative according to claim 3, in which R 1 and R 2 are independently ethyl or propyl. A xanthine derivative according to any of claims 1 to 4, in which the configuration at the position 8 of the xanthine ring is (E) form. A xanthine derivative according to claim 5, in which X is acetyl. A xanthine derivative according to claim 6, in which said derivative is (E)-8-(3-acetylstyryl)-1,3-diethyl-7-methyl-xanthine, (E)-8-(3-acetyl-4-fluorostyryl)-1,3-diethyl-7-methylxanthine, or (E)-8-(4-acetyl-3-methoxystyryl)-1,3-diethyl-7-methylxanthine. A pharmaceutical composition comprising a compound as defined by any of claims 1 to 7 and optionally a pharmaceutical carrier and/or diluent. Use of a compound as defined by any of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment of diseases caused by hyperergasia of adenosine A 2 receptors.

Inventors: KASE HIROSHI, KOIKE NOBUAKI, NAKAMURA JOJI, NONAKA HIROMI, SHIMADA JUNICHI, SHIOZAKI SHIZUO, SUZUKI FUMIO, KASE, HIROSHI, KOIKE, NOBUAKI, NAKAMURA, JOJI, NONAKA, HIROMI, SHIMADA, JUNICHI, SHIOZAKI, SHIZUO, SUZUKI, FUMIO
Applicants: KYOWA HAKKO KOGYO KK, KYOWA HAKKO KOGYO CO., LTD.
Application year: 1993
Main classification: C07D473
IPC codes: C07D473