JPH05194516A - Xanthine derivative - Google Patents

Abstract

PURPOSE:To obtain a xanthine derivative having excellent alleviating activity against dementia. CONSTITUTION:A xanthine derivative of formula I [one of R<1> and R<2> is substituted or nonsubstituted (lower alkyl, alicyclic alkyl, phenyl or benzyl), lower alkenyl or lower alkynyl and the other is (CH2)mX; (m) is 2 or 3; X is group of formula II or formula III; (a) is NH, O or S; (b), (d), (e), (g) and (h) are CH or N; Q is group of formula IV to formula VII; R<3> and R<4> are substituted or nonsubstituted alicyclic alkyl; Y is single bond or alkylene; (n) is 0 or 1; L-M is CH2CH2 or CH=CH] or its pharmaceutically acceptable salt such as 3-(4-aminophenethyl)-8-(3-noradmantyl)-1-propylxanthine. The compound is produced by reacting a compound of formula VIII (R<5> and R<6> are R<1> or R<2> with the proviso that NH2 in formula II to formula III has protecting group; Hal is halogen) with a compound of the formula QCO2H or its reactive derivative, subjecting to ring closure and further deprotecting.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to xanthine derivatives. The xanthine derivative is useful as an anti-dementia drug.

[0002]

2. Description of the Related Art Conventionally, as xanthine derivatives,

[0003]

[Chemical 8]

(Wherein R ^A and R ^B represent lower alkyl, and R ^C and R ^D represent substituted or unsubstituted alicyclic alkyl), a chitin sun derivative represented by the formula: Having a vasodilatory effect, etc. (JP-A-3-173888),

[0005]

[Chemical 9]

[Wherein R ^E and R ^F represent a lower alkyl group, and Q ^A represents

[0007]

[Chemical 10]

[0008] (wherein, L ^A -M ^A is -CH ₂ -CH ₂ -
Or -CH = CH-, Y ^A represents a single bond or alkylene, and n ^a represents 0 or 1.)
The xanthine derivative represented by diuretic action, renal protective action,
Having a bronchodilation effect, etc. (JP-A-3-17388)
No. 9 bulletin),

[0009]

[Chemical 11]

Has an adenosine A ₁ antagonism [Mol. Pharmacol., 33 , 585 (1988)],

[0011]

[Chemical formula 12]

Has an adenosine A ₁ antagonism [J. Med. Chem., 31 , 745 (1988)],

[0013]

[Chemical 13]

The xanthine derivative represented by the formula (wherein Q ^B represents alkyl) has a bronchodilator effect [Eu
r. J. Med. Chem., 25 , 653 (1990)],

[0015]

[Chemical 14]

Wherein the xanthine derivative represented by the formula (wherein R ^G and R ^H represent alkyl or aralkyl, and Q ^C represents cycloalkyl) has a diuretic effect (Canadian Patent No. 724173),

[0017]

[Chemical 15]

[Wherein R ^J , R ^K and Q ^D are substituted or unsubstituted aliphatic or cycloaliphatic hydrocarbons having 1 to 8 carbon atoms (substituents are halogen, alkyl or hydroxyl group), substituted Or an insecticide (WO86 / 01724) containing a xanthine derivative represented by unsubstituted aromatic hydrocarbon (substituent is halogen, alkyl, hydroxyl group) or phenethyl],

[0019]

[Chemical 16]

[Wherein, R ^L and R ^M represent alkyl or amino-substituted aralkyl, one of R ^N and R ^P is hydrogen, and the other is —Y ^B —Z (wherein Y ^B represents alkenylene, Z represents carboxy] and the xanthine derivative having an adenosine antagonizing action (JP-A-62-
42986) and the like are known.

[0021]

DISCLOSURE OF THE INVENTION The present invention is to provide a xanthine derivative having an excellent anti-dementia action.

[0022]

The present invention has the general formula (I)

[0023]

[Chemical 17]

[Wherein ^one of R ¹ and R ² is substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted phenyl or substituted or represents unsubstituted benzyl and the other - (CH _{2) m} -X
[In the formula, m represents 2 or 3, and X represents

[0025]

[Chemical 18]

(In the formula, a represents NH, O or S, and b
And d are the same or different and represent CH or N) or

[0027]

[Chemical 19]

(Wherein, e, g and h are the same or different and represent CH or N), and Q is

[0029]

[Chemical 20]

(Wherein R ³ and R ⁴ are the same or different and each represents a substituted or unsubstituted alicyclic alkyl),

[0031]

[Chemical 21]

(In the formula, Y represents a single bond or alkylene, and n means 0 or 1),

[0033]

[Chemical formula 22]

(Wherein LM represents -CH ₂ -CH ₂ -or -CH = CH-, and Y has the same meaning as above) or

[0035]

[Chemical formula 23]

(Wherein Y is as defined above)
And a pharmacologically acceptable salt thereof. In the definition of formula (I), the substituted or unsubstituted lower alkyl has a straight chain or branched chain having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert.
-Butyl, pentyl, neopentyl, hexyl and the like, and examples of the substituent of lower alkyl include alicyclic alkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.

The lower alkenyl includes linear or branched carbon atoms having 2 to 4 carbon atoms, such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, etc., and the lower alkynyl includes linear or branched carbon atoms. Examples include 2 to 4, such as propargyl and 3-butynyl.

Examples of the substituted or unsubstituted alicyclic alkyl include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The alicyclic alkyl, phenyl, and benzyl substituents may be the same or different and have 1 to 3 substituents.
, Lower alkyl, hydroxy, lower alkoxy, halogen, nitro, amino and the like. The alkyl portion of lower alkyl and lower alkoxy has the same definition as the above lower alkyl, and halogen includes each atom of fluorine, chlorine, bromine and iodine.

In the definition of Y, alkylene is as follows.
Straight-chain or branched C1-C4, for example, methylene,
Examples thereof include ethylene, trimethylene, tetramethylene, methylmethylene, propylene and ethylethylene. The pharmaceutically acceptable salt of compound (I) includes a pharmaceutically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt, amino acid addition salt and the like.

The pharmacologically acceptable acid addition salts include inorganic acid salts such as hydrochlorides, sulfates and phosphates, organic salts such as acetates, maleates, fumarates, tartrates and citrates. Acid salt; alkali metal salt such as sodium salt and potassium salt, alkaline earth metal salt such as magnesium salt and calcium salt, aluminum salt, zinc salt as metal salt; ammonium salt such as ammonium and tetramethylammonium salt; Examples of the organic amine addition salt include addition salts such as morpholine and piperidine; examples of the amino acid addition salt include addition salts such as lysine, glycine and phenylalanine.

Next, the method for producing the compound (I) will be described.

[0042]

[Chemical formula 24]

[0043]

[Chemical 25]

Wherein R ⁵ and R ⁶ are different, and one of them is substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted phenyl or substituted or represents unsubstituted benzyl and the other - (CH _{2) m} -X
^A [wherein, m has the same meaning as above, and X ^A is

[0045]

[Chemical formula 26]

(Wherein a, b, d, e, g and h have the same meanings as defined above, and P represents a protecting group for an amino group), and Hal represents halogen, R ¹ , R ² and Q have the same meanings as above} As a protecting group for the amino group, tert-butoxycarbonyl,
Examples thereof include benzyloxycarbonyl, acetyl, and formyl, and halogen has the same meaning as above.

Step 1 Compound (IV) can be prepared by a known method (for example, JP-A-59-42).
No. 383) and the compound (II) obtained according to
It can be obtained by reacting (III) or its reactive derivative. As the reactive derivative of the compound (III),
Acid halides such as acid chloride and acid bromide, active esters such as p-nitrophenyl ester and N-oxysuccinimide, commercially available acid anhydrides, 1-ethyl-3- (3-
Examples thereof include acid anhydrides produced using carbodiimides such as dimethylaminopropyl) carbodiimide, diisopropylcarbodiimide and dicyclohexylcarbodiimide, and mixed acid anhydrides with carbonic acid monoethyl ester, carbonic acid monoisobutyl ester and the like.

The compound (III) is 1 to the compound (II).
Used in 5 equivalents. When the compound (III) is used, the reaction is carried out by heating at 50 to 200 ° C. in the absence of a solvent, while when the reactive derivative is used, it is carried out according to a method commonly used in peptide chemistry. For example, as the reaction solvent, halogenated hydrocarbons such as methylene chloride, chloroform and ethane dichloride, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide and optionally water are appropriately selected, and the reaction temperature is − The reaction is carried out at 80-50 ° C and the reaction is completed in 0.5-24 hours. If necessary, an additive such as 1-hydroxybenzotriazole, pyridine, triethylamine, or 4
It can also be carried out in the coexistence of a base such as -dimethylaminopyridine and N-methylmorpholine.

Step 2 Compound (V) is the same as Compound (IV) in the presence of a base (Method A),
It can be obtained by performing a ring closure reaction by treatment with a dehydrating agent (method B) or heating (method C). Method A Compound (V) is prepared by converting Compound (IV) into a solvent in the presence of a base,
It can be obtained by reacting at 4 to 180 ° C. for 10 minutes to 6 hours.

Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. As the reaction solvent, water, lower alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like are used alone or in combination.

Method B compound (V) can be obtained by reacting compound (IV) in the presence of a dehydrating agent in a solvent or a solvent at 4 to 180 ° C. for 0.5 to 12 hours. Examples of the dehydrating agent include thionyl halide such as thionyl chloride and phosphorus oxyhalide such as phosphorus oxychloride. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and ethane dichloride, dimethylformamide, dimethylsulfoxide and the like.

Method C compound (V) is compound (IV) in a solvent at 50 to 200 ° C.
Obtained by heating for ~ 20 hours. As a solvent,
Examples thereof include dimethylformamide, dimethyl sulfoxide, Dow Thermo A (Dow Chemical Co.) and the like.

Step 3 Compound (I) can be obtained by deprotecting protecting group P of compound (V) by a conventional method in synthetic organic chemistry.
When the protecting group P is, for example, a benzyloxycarbonyl group, the catalytic hydrogenation reaction is carried out in the presence of a hydrogenation catalyst in a solvent at atmospheric pressure with hydrogen gas. Reaction is 0.5 at 4-100 ℃
~ 48 hours.

As the hydrogenation catalyst, platinum oxide, platinum-based catalyst such as activated carbon with platinum (Pt / C), activated carbon with palladium (Pd / C), palladium-based catalyst such as palladium black, nickel-based catalyst such as Raney nickel, Examples include activated carbon with rhodium. Examples of the solvent include alcohols such as methanol and ethanol, esters such as ethyl acetate, ethers such as dioxane and tetrahydrofuran, dimethylformamide, acetic acid and the like.

Step 4 Compound (VI) can be obtained by carrying out compound (IV) according to the method of Step 3. Step 5 Compound (I) can be obtained by carrying out compound (VI) according to the method of Step 2.

Step 6 Compound (VIII) can be obtained by reacting compound (II) with compound (VII) in a solvent at −20 to 100 ° C. for 10 minutes to 5 hours. Compound (VII) is used in the amount of 1 to 2 equivalents based on compound (II). Examples of the solvent include mixed solvents of acetic acid and lower alcohols such as methanol and ethanol.

Step 7 Compound (V) can be obtained by treating Compound (VIII) in the presence of an oxidizing agent in a solvent at 4 to 180 ° C. for 30 minutes to 10 hours. Examples of the oxidizing agent include oxygen, ferric chloride, cerium (IV) ammonium nitrate, diethyl azodicarboxylate and the like. As the solvent, methanol,
Examples thereof include lower alcohols such as ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, xylene and nitrobenzene.

Step 8 Compound (XI) can be obtained by reacting compound (IX) with compound (X) in a solvent at 50 to 150 ° C. for 30 minutes to 10 hours. Compound (X) is used in the amount of 1 to 2 equivalents based on compound (IX). Examples of the solvent include lower alcohols such as methanol and ethanol, dimethylformamide, dimethylsulfoxide and the like.

Step 9 Compound (V) can be obtained by reacting compound (XI) with a nitrosating agent in the presence of an acid in a solvent at 4 ° C. to the boiling point of the solvent for 30 minutes to 10 hours. The nitrosating agent is a compound (X
It is used in 1 to 3 equivalents relative to I). Examples of the nitrosating agent include nitrite derivatives such as sodium nitrite and isoamyl nitrite, examples of the acids include acetic acid, dilute hydrochloric acid and the like, and examples of the solvent include lower alcohols such as methanol and ethanol.

Step 10 Compound (I) can be obtained by carrying out compound (V) according to the method of Step 3. The target compound in each of the above steps can be isolated and purified by a purification method commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like.

When it is desired to obtain the salt of compound (I), a conventional method of organic synthetic chemistry may be used. For example, when the compound (I) is obtained in the form of a salt, it may be purified as it is. When it is obtained in a free form, it is dissolved or suspended in an appropriate solvent and then an acid or a base is added. A salt may be formed. The compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

Although some compound (I) may have optical isomers, the present invention includes all possible stereoisomers including optical isomers and mixtures thereof. Table 1 shows specific examples of the compound (I).

[0063]

[Table 1]

Next, the pharmacological activity of compound (I) is shown in Test Examples.

Test Example 1 Effect on Amnesia Induced by Scopolamine The anti-dementia effect of compound (I) was measured in a scopolamine-induced dementia model system [Basic, Clinical, and Therapeutic].
Aspects of Alzheimers and Perkinsons Diseases; Vol
2; T. Nagatsu et al. Edt; pp449; Plenum Press New Yor
k; 1990]. As test animals, 12 to 15 male Wistar rats (body weight 220 to 280 g, supplied by Charles River)
Was used. The test was performed using a step-through passive avoidance device (light and dark box). This light and dark box device consists of a 25 x 25 x 25 cm bright room and a 25 x 25 x 25 cm dark room illuminated by a 4 W white fluorescent lamp. The floors of the two rooms are made of stainless steel grid floor, and a weak current (2 mA; 2 seconds) can be applied only to the floor grid of the dark room. Both rooms are separated by a 9x9 cm guillotine door. There is.

The test compound was suspended in 0.3% carboxymethylcellulose (CMC) and orally administered 60 minutes before the acquisition test described below (normal control group and amnestic control group to be subjected to amnestic treatment below were treated with 0. Only 3% CMC was administered). Thirty minutes after administration of the test compound, 1 mg / kg of scopolamine was intraperitoneally administered as amnestic treatment (no scopolamine was administered to the normal control group).

Next, training (acquisition trial) for acquiring learning was performed. The rat was placed in the light room and the guillotine door was opened after 5-10 seconds. The rat placed in the light room moves to the dark room promptly, but the whole body of the rat is completely in the dark room, and at the same time, the guillotine door is closed and 2mA is applied to the floor grid.
Was applied for 2 seconds (foot shock). After receiving the foot shock, the rat was immediately removed from the dark room.

On the day after the acquisition trial, a test (recollection trial) for examining memory retention / recollection was conducted as follows. Put the rat in the light room 24 hours after the acquisition trial, and the time from the opening of the guillotine door until the rat completely enters the dark room (latency).
Was measured. The maximum measurement time was 600 seconds, and the latency of 600 seconds or more was recorded as 600 seconds.

The anti-dementia effect was judged by whether or not the reaction latency of the test compound administration group was significantly increased compared to the reaction latency of the amnestic control group. The significant difference test was judged by the Mann Whitney U-test. The results are shown in Table 2.

[0070]

[Table 2]

Test Example 2 Acute Toxicity Test Test compounds 1, 2, 3 and 4 were orally administered to 3 male dd strain mice (body weight 20 ± 1 g) per group. The minimum mortality (MLD value) of each compound obtained by observing the mortality status 7 days after administration was> 300 mg / kg.

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

In preparing the composition in oral dosage form, any useful pharmacologically acceptable carrier can be used. For example, suspensions and syrups include water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, p-hydroxybenzoic acid esters and the like. Preservatives, strawberry flavors, flavors such as peppermint and the like can be used for production. Dusts, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrating agents such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl. It can be produced using a binder such as cellulose or gelatin, a surface active agent such as fatty acid ester, a plasticizer such as glycerin and the like. Tablets and capsules are the most useful oral unit dosages because they are easy to administer.

The injection can be prepared using a carrier made of 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 auxiliary 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, and its effective dose and frequency of administration are the administration form, the age of the patient. Usually, 0.02 to 50 mg / kg is administered in 3 to 4 divided doses per day, though it depends on the body weight, symptoms, etc.

[0075]

EXAMPLES Examples and reference examples will be shown below. Example 1.3 3-noradamantanecarboxylic acid 2.79 g (16.8
Mmol) was dissolved in 50 ml of tetrahydrofuran and 50 ml of methylene chloride. To this was added at 0 ° C. 2.57 g (16.8 mmol) of 1-hydroxybenzotriazole and 3.22 g (16.8 mmol) of 1-ethyl-3- (3-dimethylamino) propylcarbodiimide hydrochloride. After reacting at room temperature for 4 hours, 170 mg (1.4 mmol) of 4-dimethylaminopyridine was added to the resulting solution, and Reference Example 1 was further added.
5,6-Diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in
A solution obtained by dissolving 6.12 g (14.0 mmol) in 20 ml of N, N-dimethylformamide and 40 ml of tetrahydrofuran was added. After reacting for 1 hour, the reaction solution was concentrated to about half. After adding 100 ml of water to the concentrated solution, the solution was extracted three times with chloroform. After combining the organic layers and washing with saturated saline,
It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: 2% methanol / 98% chloroform), 6-amino-5- (3-noradamantane) carbonylamino-1- (4-benzyloxycarbonylaminophenethyl). 6.95 g of -3-propyluracil (yield 85%) was obtained.

NMR (90 MHz; CDCl ₃ ) δ (ppm): 7.99 (1
H, brs), 7.50-7.25 (7H, m), 7.12 (2H, d, J = 7.8Hz), 6.
89 (1H, brs), 5.20 (2H, s), 4.25-3.65 (6H, m), 3.05-
2.75 (3H, m), 2.45-1.45 (14H, m), 0.90 (3H, t, J = 7.0H
z)

6.81 g (11.6 mmol) of the obtained compound was dissolved in 200 ml of ethanol, and then 10% Pd / C 600 m was added thereto.
g was added, and the mixture was stirred for 15 hours under a hydrogen stream. The catalyst was removed by filtration, washed with ethanol, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (elution solvent: 5% methanol / 95% chloroform), triturated with diethyl ether / hexane = 3/1 (v / v), and 6-amino-1- 3.63 g (yield 69%) of (4-aminophenethyl) -5- (3-noradamantane) carbonylamino-3-propyluracil was obtained.

NMR (90 MHz; CDCl ₃ ) δ (ppm): 7.32 (1
H, brs), 6.97 (2H, d, J = 8.5Hz), 6.60 (2H, d, J = 8.5H
z), 5.28 (2H, brs), 4.20-3.75 (4H, m), 3.27 (2H, br
s), 3.00-2.75 (3H, m), 2.45-1.45 (14H, m), 0.96 (3H,
(t, J = 7.0Hz)

3.50 g (7.75 mmol) of the obtained compound was dissolved in 80 ml of dioxane. To this, 240 ml of a 1N sodium hydroxide aqueous solution was added, and the mixture was heated under reflux for 1 hour. After cooling, the crystals precipitated by neutralization with concentrated hydrochloric acid were collected by filtration, dried under reduced pressure, and recrystallized from tetrahydrofuran.
1.33 g (yield 40%) of (4-aminophenethyl) -8- (3-noradamantyl) -1-propylxanthine (Compound 1) was obtained.

Melting point: 283.7-285.2 ° C. Elemental analysis value: C ₂₅ H ₃₁ N ₅ O ₂ calculated value (%); C 69.25, H 7.20, N 16.15 measured value (%); C 69.38, H 7.48, N 16.17 IR (KBr) ν _max (cm ^-1 ): 1694, 1644, 1554, 1519, 1
494 NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 13.0 (1H, brs), 6.8
3 (2H, d, J = 8.4Hz), 6.46 (2H, d, J = 8.4Hz), 4.86 (2H,
brs), 4.10 (2H, t, J = 7.4Hz), 3.83 (2H, t, J = 7.4Hz),
2.78 (2H, t, J = 7.4Hz), 2.61 (1H, t, J = 6.5Hz), 2.35-
2.25 (2H, m), 2.20-2.10 (2H, m), 2.00-1.85 (4H, m),
1.70-1.50 (6H, m), 0.86 (3H, t, J = 8.0Hz), MS (m / e): 433 (M ⁺ )

Example 2. In Example 1, 2.79 g (16.8 mmol) of 3-noradamantanecarboxylic acid and 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -obtained in Reference Example 1 were used. Instead of 6.12 g (14.0 mmol) of 3-propyluracil, 0.40 g (2.41 mmol) of 3-noradamantanecarboxylic acid and 5,6-diamino-3- (4-benzyloxycarbonylaminophenethyl) obtained in Reference Example 2 were obtained. According to the method of Example 1, except that 0.87 g (2.01 mmol) of -1-propyluracil was used, 3- (4-aminophenethyl) -8- (3-
0.32 g (yield 37%) of noradamantyl) -1-propylxanthine (Compound 2) was obtained.

Melting point: 244.6-245.1 ° C. Elemental analysis value: C ₂₅ H ₃₁ N ₅ O ₂ calculated value (%); C 69.25, H 7.20, N 16.15 measured value (%); C 69.06, H 7.26, N 15.95 IR (KBr) ν _max (cm ^-1 ): 1694, 1657, 1645, 1547, 1
518, 1493 NMR (270MHz; DMSO-d ₆ ) δ (ppm): 12.92 (1H, brs), 6.
87 (2H, d, J = 7.9Hz), 6.48 (2H, d, J = 7.9Hz), 4.87 (2H,
brs), 3.99 (2H, t, J = 7.9Hz), 3.95 (2H, t, J = 7.4Hz),
2.65-2.55 (3H, m), 2.30-2.25 (2H, m), 2.20-2.10 (2H, m
m), 2.00-1.85 (4H, m), 1.75-1.55 (6H, m), 0.87 (3H,
t, J = 7.4Hz) MS (m / e): 433 (M ⁺ )

Example 3. In Example 1, 2.79 g (16.8 mmol) of 3-noradamantanecarboxylic acid and 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -obtained in Reference Example 1 1.12 g (8.0 mmol) of dicyclopropylacetic acid instead of 6.12 g (14.0 mmol) of 3-propyluracil and 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3 obtained in Reference Example 1 -Propyluracil 2.93g
0.28 g of 3- (4-aminophenethyl) -8-dicyclopropylmethyl-1-propylxanthine (Compound 3) according to the method of Example 1 except that (8.0 mmol) is used.
(Yield 13%) was obtained.

Melting point: 184.7-184.9 ° C. Elemental analysis value: C ₂₃ H ₂₉ N ₅ O ₂ calculated value (%); C 67.78, H 7.17, N 17.19 measured value (%); C 67.95, H 7.37, N 16.97 IR (KBr) ν _max (cm ^-1 ): 1693, 1646, 1552, 1517, 1
495 NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 13.06 (1H, brs), 6.
83 (2H, d, J = 8.3Hz), 6.46 (2H, d, J = 8.3Hz), 4.84 (2H,
brs), 4.11 (2H, t, J = 7.1Hz), 3.83 (2H, t, J = 6.9Hz),
2.79 (2H, t, J = 7.9Hz), 1.60-1.45 (3H, m), 1.30-1.15
(2H, m), 0.86 (3H, t, J = 7.4Hz), 0.65-0.50 (2H, m),
0.40-0.25 (4H, m), 0.25-0.10 (2H, m) MS (m / e): 407 (M ⁺ )

Example 4. 2.79 g (16.8 mmol) of 2,3-noradamantanecarboxylic acid in Example 1 and 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) obtained in Reference Example 1 In place of 6.12 g (14.0 mmol) of 3-propyluracil, 0.73 g (5.2 mmol) of dicyclopropylacetic acid and 5,6-diamino-3- (4-benzyloxycarbonylaminophenethyl) -obtained in Reference Example 2 1-Propyluracil 1.71g
0.25 g of 1- (4-aminophenethyl) -8-dicyclopropylmethyl-3-propylxanthine (Compound 4) according to the method of Example 1 except that (4.67 mmol) is used.
(Yield 20%) was obtained.

Melting point: 190.7-193.2 ° C. Elemental analysis value: C ₂₃ H ₂₉ N ₅ O ₂ calculated value (%); C 67.78, H 7.17, N 17.19 measured value (%); C 67.67, H 7.35, N 16.93 IR (KBr) ν _max (cm ^-1 ): 1694, 1652, 1532, 1516, 1
496 NMR (270 MHz; DMSO-d ₆ ) δ (ppm): 13.08 (1H, brs), 6.
87 (2H, d, J = 8.5Hz), 6.48 (2H, d, J = 8.5Hz), 4.86 (2H,
brs), 4.10-3.90 (4H, m), 2.64 (2H, t, J = 7.9Hz), 1.7
5-1.50 (3H, m), 1.30-1.15 (2H, m), 0.87 (3H, t, J = 7.4
Hz), 0.60-0.50 (2H, m), 0.40-0.25 (4H, m), 0.20-0.10
(2H, m) MS (m / e): 407 (M ⁺ )

Example 5 3-noradamantanecarboxylic acid 2.79 in Example 1
g (16.8 mmol) and 6.12 g (14.0 mmol) of 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in Reference Example 1 in place of bicyclo [3.3]. .0] octane-2
-Using 1.70 g (11.0 mmol) of carboxylic acid and 4.00 g (9.14 mmol) of 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in Reference Example 1. Otherwise, according to the method of Example 1, 3- (4-aminophenethyl) -8-
[(1R ^* , 2R ^* , 5R ^* )-bicyclo [3.3.
0] octane-2-yl] -1,3-dipropylxanthine (Compound 5) 1.48 g (yield 25%) was obtained.

Melting point: 237.1-238.1 ° C. Elemental analysis value: C ₂₄ H ₃₁ N ₅ O ₂ calculated value (%); C 68.38, H 7.41, N 16.61 measured value (%); C 68.09, H 7.67 , N 16.58 IR (KBr) ν _max (cm ⁻¹ ): 1700, 1641, 1554, 1505 NMR (270MHz; CDCl ₃ ) δ (ppm): 12.27 (1H, brs), 7.08 (2H,
d, J = 8.4Hz), 6.61 (2H, d, J = 8.4Hz), 4.31 (2H, t, J = 7.9Hz),
4.01 (2H, t, J = 7.8Hz), 3.57 (2H, brs), 2.97 (2H, t, J = 7.9H
z), 2.90-2.65 (3H, m), 2.20-1.25 (12H, m), 0.97 (3H, t, J = 7.
3Hz) .MS (m / e): 421 (M ⁺ )

Example 6 In Example 1, 3-noradamantanecarboxylic acid 2.
79 g (16.8 mmol) and 5,6-obtained in Reference Example 1
Instead of 6.12 g (14.0 mmol) of diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil, bicyclo [2.2.1] heptane-
1.54 g (11.0 mmol) of 2-carboxylic acid and 4.00 g (9.14 mmol) of 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in Reference Example 1 were obtained. Example 1 except using
In accordance with the method of 3- (4-aminophenethyl) -8-
[(1R ^* , 2R ^* , 5R ^* )-bicyclo [2.2.
1] Heptan-2-yl] -3-propylxanthine (about 1: 1 mixture with 1R ^* , 2R ^* , 5S ^* ) (Compound 6) 1.47 g (yield 40%) was obtained.

Melting point: 258.3-260.2 ° C. IR (KBr) ν _max (cm ⁻¹ ): 1704, 1649, 1520, 1496 NMR (270 MHz; DMSO) δ (ppm): 12.29 (1H, brs), 6.83 (2 ×
1 / 2H, d, J = 8.4Hz), 6.82 (2 × 1 / 2H, d, J = 8.4Hz), 6.45 (2H,
d, J = 8.4Hz), 4.86 (2H, brs), 4.11 (2 × 1 / 2H, t, J = 7.4Hz),
4.09 (2 × 1 / 2H, t, J = 7.4Hz), 3.81 (2H, t, J = 7.0Hz), 3.25-3.
15 (1 / 2H, m), 2.80-2.70 (1 / 2H + 2H, m), 2.60-2.25 (2H, m), 2.
10-1.10 (10H, m), 0.85 (3H, t, J = 7.4Hz) MS (m / e): 407 (M ⁺ )

Reference Example 1.4-Nitrophenethylamine 127
After dissolving g (0.767 mol) [J. Org. Chem., 43 , 31 (1978)] in 2.5 liters of toluene, 72 ml (0.764 mol) of propyl isocyanate was slowly added dropwise thereto at room temperature. After stirring for 2 hours, the precipitated crystals were collected by filtration and dried under reduced pressure to give 1- (4-nitrophenethyl) -3-propylurea (compound a) (171.5 g, yield 89.8%). IR (KBr) ν _max (cm ^-1 ): 3322, 2870, 1620, 1578, 1
516 NMR (90MHz; CDCl ₃ ) δ (ppm): 8.10 (2H, d. J = 8.8H
z), 7.35 (2H, d, J = 8.8Hz), 4.95-4.50 (2H, m), 3.70-
3.30 (2H, m), 3.25-2.75 (6H, m), 1.70-1.30 (2H, m),
0.90 (3H, t, J = 7.0Hz)

170 g (0.677 mol) of compound a and 63.3 g (0.744 mol) of cyanoacetic acid were dissolved in 196 ml of acetic anhydride and then reacted at 75 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, 200 ml of water was added thereto, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were recrystallized twice from ethyl acetate to obtain 42.9 g (yield 19.9%) of 1-cyanoacetyl-3- (4-nitrophenyl) -1-propylurea (Compound b). At the time of recrystallization, the obtained filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: 2% methanol / 98% chloroform) to give compound b (62.2 g).
(Yield 29%) and 1-cyanoacetyl-1- (4-nitrophenyl) -3-propylurea (compound c) 45.0 g
(Yield 21%) was obtained.

Compound b: IR (KBr) ν _max (cm ^-1 ): 3386, 2876, 2260, 1693, 1
678, 1518, 1503 NMR (90MHz; CDCl ₃ ) δ (ppm): 8.55 (1H, brs), 8.16
(2H, d, J = 8.7Hz), 7.38 (2H, d, J = 8.7Hz), 3.78 (2H,
s), 3.80-3.45 (4H, m), 3.01 (2H, t, J = 7.0Hz), 1.80-
1.40 (2H, m), 0.99 (3H, t, J = 7.0Hz) MS (m / e): 318 (M ⁺ )

Compound c: NMR (90MHz; CDCl ₃ ) δ (ppm): 8.17 (2H, d, J = 8.5H
z), 7.36 (2H, d, J = 8.5Hz), 3.90 (2H, t, J = 7.5Hz), 3.
63 (2H, s), 3.40-3.00 (4H, m), 1.61 (2H, s), 1.80-1.4
0 (2H, m), 0.96 (3H, t, J = 7.0Hz) To the obtained compound b (57.5 g, 0.181 mol) was added 680 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at 75 ° C for 30 minutes. After cooling this liquid and collecting the resulting crystals by filtration and washing with water,
After drying under reduced pressure, 51.7 g of 6-amino-1- (4-nitrophenethyl) -3-propyluracil (compound d) (yield
89.7%).

IR (KBr) ν _max (cm ^-1 ): 1658, 1639, 1
611, 1518, 1492 NMR (90MHz; DMSO-d ₆ ) δ (ppm): 8.10 (2H, d. J = 8.5
Hz), 7.47 (2H, d, J = 8.5Hz), 6.82 (2H, brs), 4.78 (1H,
s), 4.08 (2H, t, J = 7.2Hz), 1.65-1.15 (2H, m), 0.77 (3
H, t, J = 7Hz) MS (m / e): 318 (M ⁺ )

Compound d 20 g (62.8 mmol) 100 ml
After dissolving in acetic acid of 10%, add 1 g of 10% Pd / C to this and add 8
The mixture was stirred under hydrogen flow for an hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and made alkaline with a 1N aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure to obtain 15.6 g (yield 86.5%) of 6-amino-1- (4-aminophenethyl) -3-propyluracil (compound e).

IR (KBr) ν _max (cm ^-1 ): 1658, 1613, 1
517 NMR (90MHz; CDCl ₃ ) δ (ppm): 7.00 (2H, d. J = 8.0H
z), 6.67 (2H, d, J = 8.0Hz), 4.82 (1H, s), 4.20-3.70 (6
H, m), 2.90 (2H, t, J = 7.5Hz), 1.80-1.50 (4H, m), 0.9
5 (3H, t, J = 7.2Hz) MS (m / e): 288 (M ⁺ )

After dissolving 7 g (24.3 mmol) of compound e in 180 ml of tetrahydrofuran, 120 ml of water and 4.13 g (49.2 mmol) of sodium hydrogencarbonate were added thereto.
This solution was cooled to 5-10 ° C, and while maintaining the pH at 8-9 with a 2N sodium hydroxide aqueous solution, 11.9 g (20.8 mmol) of a 30% toluene solution of benzyloxycarbonyl chloride.
Was dripped. After dropwise addition, the mixture was stirred for 30 minutes, and concentrated under reduced pressure. Water was added to this and the precipitated insoluble material was collected by filtration. This was dissolved in 500 ml of ethyl acetate by heating, dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure.
-Amino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil (Compound f) 10 g
(Yield 98%) was obtained.

IR (KBr) ν _max (cm ^-1 ): 1706, 1660, 1
606, 1527, 1511 NMR (90MHz; DMSO-d ₆ ) δ (ppm): 8.63 (1H, brs), 7.
65-7.20 (7H, m), 7.11 (2H, d, J = 8.5Hz), 5.15 (2H, s),
4.67 (1H, s), 3.99 (2H, t, J = 7.0Hz), 3.62 (2H, t, J =
7.5Hz), 2.73 (2H, t, J = 7.0Hz), 1.55-1.25 (2H, m), 0.
78 (3H, t, J = 7.5Hz) MS (m / e): 422 (M ⁺ )

6.3 g (14.0 mmol) of compound f was dissolved in 120 ml of ethanol and 40 ml of water. Concentrated hydrochloric acid 2.87 ml was added to this at 30 ° C, and then sodium nitrite 1.82 g (26.4
Mmol) was added. After stirring for about 30 minutes, the precipitated reddish purple crystals were collected by filtration, washed with water, and then dried under reduced pressure to give 6-amino-1- (4-benzyloxycarbonylaminophenethyl) -5-nitroso-3-propyluracil (compound g) 8.66 g (yield 82.3%) was obtained.

Melting point: 192.5-194.5 ° C IR (KBr) ν _max (cm ^-1 ): 1730, 1670, 1642, 1527, 1
515 NMR (90MHz; DMSO-d ₆ ) δ (ppm): 9.62 (1H, brs), 7.
45-7.20 (7H, m), 7.08 (2H, d, J = 8.8Hz), 5.12 (2H, s),
4.06 (2H, t, J = 7.5Hz), 3.79 (2H, t, J = 7.0Hz), 2.75 (2
H, t, J = 7.5Hz), 1.70-1.25 (2H, m), 0.84 (3H, t, J = 7.
0Hz) MS (m / e): 451 (M ⁺ )

6.3 g (14.0 mmol) of compound g was suspended in 280 ml of 50% ethanol aqueous solution, and 9.7 g (55.7 mmol) of sodium hydrosulfite was slowly added over 30 minutes while stirring. After removing the insoluble matter by filtration,
The crystals obtained by concentrating the filtrate under reduced pressure were collected by filtration, washed with water and dried under reduced pressure to give 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil.
5.23 g (yield 85.7%) was obtained. MS (m / e): 437 (M ⁺ )

Reference Example 2. 680 ml of 2N sodium hydroxide aqueous solution was added to 25.3 g (79.6 mmol) of compound c, and then
The mixture was stirred at 75 ° C for 30 minutes. The liquid was cooled, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 6-amino-3-
20.0 g (yield 70%) of (4-nitrophenethyl) -1-propyluracil (compound h) was obtained.

IR (KBr) ν _max (cm ^-1 ): 1658, 1643, 1
608, 1585, 1516, 1344 NMR (90MHz; DMSO-d ₆ ) δ (ppm): 8.50 (2H, d, J = 8.5
Hz), 7.48 (2H, d, J = 8.5Hz), 6.81 (2H, brs), 4.67 (1H,
s), 4.00 (2H, t, J = 7.3Hz), 3.72 (2H, t, J = 7.5Hz),
2.93 (2H, t, J = 7.5Hz), 1.70-1.20 (2H, m), 0.81 (3H,
t, J = 7.0Hz) MS (m / e): 318 (M ⁺ )

6-Amino-3- (4-aminophenethyl)-was prepared according to the method of obtaining Compound e from Compound d of Reference Example 1 using 10.8 g (32.9 mmol) of Compound h.
9.78 g of 1-propyluracil (compound i) (yield 100
%) Was obtained. IR (KBr) ν _max (cm ^-1 ): 1686, 1608, 1516, 1494 NMR (90MHz; DMSO-d ₆ ) δ (ppm): 6.78 (2H, d, J = 8.0
Hz), 6.78 (2H, brs), 6.45 (2H, d, J = 8.0Hz), 4.78 (2H,
brs), 3.93-3.50 (4H, m), 2.65-2.40 (2H, m), 1.70-1.
20 (2H, m), 0.86 (3H, t, J = 7.0Hz) MS (m / e): 288 (M ⁺ )

Using compound i 9.78 g (33.9 mmol), and then 6-amino-3- (4-benzyloxycarbonylaminophenethyl) -1-propyl according to the method of obtaining compound f from compound e of Reference Example 1. 13.25 g (yield 95%) of uracil (compound j) was obtained. IR (KBr) ν _max (cm ^-1 ): 1722, 1689, 1657, 1651, 1
614, 1525 NMR (90MHz; DMSO-d ₆ ) δ (ppm): 9.62 (1H, s), 7.50
-7.15 (7H, m), 7.00 (2H, d, J = 9Hz), 6.63 (2H, brs), 5.
08 (2H, s), 3.95-3.50 (4H, m), 2.65 (2H, t, J = 7.5Hz),
1.70-1.20 (2H, m), 0.86 (3H, t, J = 7.0Hz) MS (m / e): 422 (M ⁺ )

Using 13.2 g (31.1 mmol) of compound j, 6-amino-3- (4-benzyloxycarbonylaminophenethyl) -5-nitroso was prepared according to the method of obtaining compound g from compound f of Reference Example 1. 12.2 g (yield 87%) of -1-propyluracil (compound k) was obtained. IR (KBr) ν _max (cm ^-1 ): 1720, 1704, 1650, 1640, 1
542, 1527 MS (m / e): 451 (M ⁺ )

Using 1 g (2.21 mmol) of compound k,
According to the method of obtaining the target compound of Reference Example 1 from Compound g in Reference Example 1, 0.8 g (yield 83%) of 5,6-diamino-3- (4-benzyloxycarbonylaminophenethyl) -1-propyluracil was obtained. Obtained. MS (m / e): 437 (M ⁺ )

[0109]

The xanthine derivative of the present invention has an excellent anti-dementia action.

[Procedure amendment]

[Submission date] December 28, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0063

[Correction method] Change

[Correction content]

[0063]

[Table 1]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0081

[Correction method] Change

[Correction content]

Example 2. In Example 1, 2.79 g (16.8 mmol) of 3-noradamantanecarboxylic acid and 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -obtained in Reference Example 1 were used. Instead of 6.12 g (14.0 mmol) of 3-propyluracil, 0.40 g (2.41 mmol) of 3-noradamantanecarboxylic acid and 5,6-diamino-3- (4-benzyloxycarbonylaminophenethyl) obtained in Reference Example 2 were obtained. 1- (4-Aminophenethyl) -8- (3- according to the method of Example 1 except that 0.87 g (2.01 mmol) of -1-propyluracil was used.
0.32 g (yield 37%) of noradamantyl) -3-propylxanthine (Compound 2) was obtained.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0085

[Correction method] Change

[Correction content]

Example 4. 2.79 g (16.8 mmol) of 3-noradamantanecarboxylic acid in Example 1 and 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3 obtained in Reference Example 1 -Propyluracil was obtained in Reference Example 2 with 0.73 g (5.2 mmol) of dicyclopropylacetic acid instead of 6.12 g (14.0 mmol).
1.76-g of 5,6-diamino-3- (4-benzyloxycarbonylaminophenethyl) -1-propyluracil (4.
1 mmol according to the method of Example 1 except that 67 mmol) is used.
0.25 g (yield 20%) of-(4-aminophenethyl) -8-dicyclopropylmethyl-3-propylxanthine (Compound 4) was obtained.

[Procedure correction 4]

[Document name to be amended] Statement

[Correction target item name] 0087

[Correction method] Change

[Correction content]

Example 5 3-noradamantanecarboxylic acid 2.79 in Example 1
g (16.8 mmol) and 6.12 g (14.0 mmol) of 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in Reference Example 1 in place of bicyclo [3.3]. .0] octane-2
-Using 1.70 g (11.0 mmol) of carboxylic acid and 4.00 g (9.14 mmol) of 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in Reference Example 1. Otherwise, according to the method of Example 1, 3- (4-aminophenethyl) -8-
[(1R ^* , 2R ^* , 5R ^* )-bicyclo [3.3.
0] octane-2-yl] -1-propylxanthine (Compound 5) (1.48 g, yield 25%) was obtained.

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0089

[Correction method] Change

[Correction content]

Example 6 In Example 1, 3-noradamantanecarboxylic acid 2.
79 g (16.8 mmol) and 5,6-obtained in Reference Example 1
Instead of 6.12 g (14.0 mmol) of diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil, bicyclo [2.2.1] heptane-
1.54 g (11.0 mmol) of 2-carboxylic acid and 4.00 g (9.14 mmol) of 5,6-diamino-1- (4-benzyloxycarbonylaminophenethyl) -3-propyluracil obtained in Reference Example 1 were obtained. Example 1 except using
In accordance with the method of 3- (4-aminophenethyl) -8-
[(1R ^* , 2R ^* , 5R ^* )-bicyclo [2.2.
1] Heptan-2-yl] -1-propylxanthine (about 1: 1 mixture with 1R ^* , 2R ^* , 5S ^* ) (Compound 6) 1.47 g (yield 40%) was obtained.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): {Wherein ^one of R ¹ and R ² is substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted of a benzyl, and the other - (CH _{2) m} -X wherein, m is 2
Or 3 and X is (Wherein a represents NH, O or S, and b and d are the same or different and represent CH or N) or (Wherein, e, g and h are the same or different and represent CH or N), and Q is (Wherein R ³ and R ⁴ are the same or different and each represents a substituted or unsubstituted alicyclic alkyl), (In the formula, Y represents a single bond or alkylene, and n represents 0 or 1.) (Wherein, L-M is -CH ₂ -CH ₂ - or -CH = C
H-, Y is as defined above) or (Wherein Y has the same meaning as defined above), or a pharmacologically acceptable salt thereof.