CA2416199A1 - Adenosine compound and pharmaceutical composition containing the same - Google Patents
Adenosine compound and pharmaceutical composition containing the same Download PDFInfo
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Abstract
An adenosine compound having the formula (I) wherein R represents a straight or branched lower alkyl group and R1 represents a C2 to C6 lower alkylamino group or a substituent having the formula (II), (III) or (IV) wherein R2 independently represent a hydrogen group or lower alkyl group, X represnts N - R3, O or CH2, R3 represents a hydrogen atom, lower alkyl group or benzyl gro up and n represents an integer of 1 to 6, or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutical composition containing th e same. This compound have an anti-hyperlipemia, antiallergic, antidiabetes or analgesic action.
Description
DESCRIPTION
ADENOSINE COMPOUND AND PHARMACEUTICAL
COMPOSITION CONTAINING THE SAME
Technical Field The present invention relates to a novel adenosine compound. The compounds according to the present invention are effective for the treatment or alleviation of hyperlipemia, diabetes, hypertension, arrhythmia, cardiac infarction, rena failure, epilepsy, mental disorders, obesity, etc. and useful also as an anti-inf lammatory and analgesic.
Background Art In recent years, along with the aging of the population and changes in the diet, the number of persons suffering from hyperlipemia and diabetes has been increasing annually. These ailments sometimes cause arteriosclerosis and grave ischemic heart diseases etc., and therefore, have been viewed as problems worldwide.
Development of an effective method of treatment is therefore desired.
In view of this situation, efforts have been made to develop a medicine for the treatment of hyperlipemia.
Adenosine compounds having an action against hyperlipemia have been described in, for example, U.S. Patent No.
5,322,840 and W097/43300. These compounds are acid esters which leave the ribosyl portions as hydroxyl groups or protect the hydroxyl groups of the ribosyl portions with an acid chloride. _ Disclosure of Invention The object of the present invention is to provide a novel anti-hyperlipemia, anti-inflammatory, antidiabetic or analgesic drug.
The present inventors engaged in various studies to found novel adenosine compounds useful as pharmaceuticals and, as a result, found that an ether compound obtained by condensing all of the three hydroxyl groups of the ribosyl portion of an adenosine compound with alkyl groups, a different structure from the compounds described in the above publications, has a superior action against hyperlipemia, anti-inflammatory action, and action in lowering glucose, whereby the present invention was completed.
That is, in accordance with the present invention, there is provided an adenosine compound having the formula (I):
R~
I I N>
'N O N
RO ~I) RO OR
wherein R represents a straight or branched lower (e. g., a C1 - CS straight or a C3 - CS branched) alkyl group and R1 represents a C2 to C6 lower alkylamino group or a substituent having the formula (II), (III), or (IV):
2 /~
-~(CH2)n CO-N;R2 -NH(CHa)nC0- ~ -N, r--CONH2 R ~l2 (II) ' (III) ' (IV) wherein Rz independently represent a hydrogen group or lower alkyl group, X represents N-R3, 0 or CHz, R3 represents a hydrogen atom, lower alkyl group, or benzyl group, and n represents an integer of 1 to 6 or an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof suitable for use as an anti-hyperlipemia, anti-inflammatory, antidiabetic or analgesic agent.
Best Mode for Carrying out the Invention The present invention will be explained in further detail below.
The present invention is as described above, but the preferable compounds include those having the formula (I), wherein R is a C3 to CS alkyl group, in particular a propyl or pentyl group, or those having the formula (I), where R1 is a carbamoyl alkylamino group or butylamino group. Further, more preferable compounds of the present invention are those satisfying a plurality of the conditions of the substituents given above.
Specific examples of the preferable compounds of the present invention are as follows.
Compound 2: N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine Compound 6: N-6-(2-carbamoylethyl)-9-(2',3',5'-tri-O-propyl-/3-D-ribosyl)adenine Compound 7: N-6-(4-carbamoylbutyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 12: N-6-methyl-N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 14: N-6-(3-morpholinocarbonylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 15: N-6-(3-piperidinocarbonylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 18: N-6-butyl-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The adenosine compounds having the formula (I) of the present invention may be pharmaceutically acceptable salts thereof as well. Specifically, an inorganic acid salt formed from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfic acid, or~
phosphoric acid and an organic acid salt formed from, for example, formic acid, acetic acid, citric acid, fumaric acid, gluconic acid, lactic acid, malefic acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid may be mentioned. Further, the compounds of the present invention may form in some cases hydrates.
The adenosine compounds according to the present invention may be prepared by a conventional method.
Typical methods among these will be explained below.
Production Process 1 The compounds of the present invention may be synthesized in accordance with the following reaction formulae:
Cl N ~ N RO O OCH3 1 ) HMDS N' N + RO 2 ) TMSOTf ~N ~ N
N H OR RO
v RO OR
Cl R1 N ~ ~ NHZ-(CH2)n-CONH2 N\
~N O N ~N O N
RO ~ RO
RO OR RO OR
(I) In the reaction formulae, HMDS represents hexamethyldisilazane and TMSOTf represents trimethylsilyl triflate and R and R1 have the same meanings as those of formula (I).
The reactions used in this production process are known conventional methods. That is, the desired compound having the formula (I) can be obtained by reacting 6-chloropurine and the corresponding ribose derivative, followed by reacting with the corresponding amino compound.
Production Process 2 O CI O
HN N N~ N N~ N
~ ~ ~~ 3 step s ~ ~ ~~ 2 step s N N N N N I N
HO O HO O RO O
HO OH HO OH RO OR
CI R~
2 steps HN' ~ N~ NHZ-(CH2)n-CONHa HN' I N>
'N .O N 'N O N
RO RO
(I) As shown in the above reaction formulae, inosine is used as the starting substance, the three reactions of acetylation, chlorination, and then deacetylation are carried out to obtain the chlorinated compound of purine.
Then, the resultant compound was benzylated and alkylated and further debenzylated and again chlorinated to obtain a purine compound chlorinated at the 6-position followed by reacting with the corresponding amino compound to produce the desired compound having the formula (I).
The substances used in the above production processes 1 and 2 are easily synthesized using known standard methods. For example, the amino compound used for introducing R1 can be easily produced from amino acid by the following process:
NHZ-(CH2)n-COOH (~~ BocNH-{CH2)n-COOH 1) C1COOCZHS
2) NH3 BocNH--(CH2)n-CONH2 H~ NHZ-(CH2)n-CONH2 Further, the ribose compound can be produced by the following process:
HO ~/~ CH3OHlH2SO4 HO ~/~ NaH RO ~/
'-HO OH HO OH RO OR
when the present compound is used as an anti-hyperlipemia, anti-inflammatory, antidiabetic, or analgesic agent, it may be administered to the patients by a suitable method of administration such as an oral or nonoral method. As the form of oral administration, for example, tablets, granules, capsules, pills, powders, syrups, etc. and as the form of nonoral administration, for example, injections, inhalants, suppositories, liquids, etc. may be mentioned. When preparing these compositions for administration of medicines, they may be prepared by ordinary methods using the present compounds or the pharmaceutically acceptable salts thereof etc.
For example, in the case of an oral medicine, an excipient such as lactose, glucose, corn starch, or sucrose, a disintegrant such as carboxylmethyl cellulose calcium or hydroxypropyl cellulose, a lubricant such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hardened oil, a binding agent such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, and arabia gum, a humectant such as glycerol or ethylene glycol, and, optionally or if necessary, a surfactant, flavoring agent, etc. are used to prepare the desired administration preparation.
Further, in the case of a nonoral medicine, a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and tragacanth gum is used and, if necessary, a solution adjuvant, buffer agents, preservative, flavor, coloring agent, etc. may be used.
When the compound of the present invention is prepared as an anti-hyperlipemia agent, the unit of administration, in terms of the compound of the present invention, is, per adult in the case of oral administration, 1 to 1000 mg, preferably 30 to 600 mg, per day and, in the case of nonoral administration, 0.1 to 100 mg, preferably 0.5 to 30 mg per day. The desired therapeutic effect can be expected by administration one to three times a day.
EXAMPLES
Next, Examples of synthesis of the present compounds, Preparation Examples and Test Examples will now be given as Examples, but the present invention is, of course, not limited to these. Examples, further, processes for producing the starting substances are given as Preparation Examples.
Preparation Example 1 Synthesis of 2,3-5-tri-0-isobutyl-1-O-methyl-D-ribofuranose (1) D-ribose (5 g) was dissolved in methanol (100 ml), then concentrated sulfuric acid (0.6 ml) was added, under cooling at 0°C. The mixture was allowed to stand overnight at 4°C. After Amberlite IR-45~ (made by Rohm &
Hass) (4 g) was added to neutralize to this solution, the mixture was filtered and then the methanol was evaporated in vacuo to obtain a crude product of 1-O-methyl-D-ribofuranose (5 g).
(2) The 1-O-methyl-D-ribofuranose (5 g) was dissolved in tetrahydrofuran (50 ml), then sodium hydride (60%, 5.9 g) was added at 0°C, followed by stirring at room temperature for 30 minutes. After 3-chloro-2-methyl-1-propene (13.3 ml) was added to this solution, the mixture was heated for 24 hours, then cooled at 0°C.
Next, ice water was added. The solution was extracted with ether. Then the solution was dried over sodium sulfate, the solvent was concentrated to dryness. The - g -residue was purified by silica gel column chromatography to obtain 1-O-methyl-2,3,5-tri-0-(2-methyl-2-propenyl)-D-ribofuranose (6.9 g).
(3) The 1-0-methyl-2,3,5-tri-O-(2-methyl-2-propenyl)-D-ribofuranose (0.45 g) was dissolved in methanol (50 ml) and catalytically reduced using 10%
palladium-on-carbon (40 mg). The crude product was purified by silica gel column chromatography to obtain 2,3,5-tri-O-isobutyl-1-O-methyl-D-ribofuranose (0.42 g).
Preparation Example 2 Synthesis of y-aminobutyric acid amide hydrochloride (1) y-aminobutyric acid (10.3 g) was dissolved in water (120 ml), 1N sodium hydroxide solution (150 ml) and dioxan (100 ml). Di-t-butyl dicarbonate (24 g/dioxan 100 ml) was added at 5°C, then the mixture was stirred at room temperature for 12 hours. The solvent was evaporated, then the residue was diluted with water and the solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layers was concentrated to dryness obtain a residue (19.4 g).
(2) The residue (11.2 g) and triethylamine (8.5 ml) were dissolved in chloroform (125 ml), then ethyl chlorocarbonate (5.3 ml) was added at -5°C. After 10 minutes, the mixture was treated with ammonia gas, followed at -5°C for 15 minutes and at room temperature for 1 hour under stirring. The solution was then allowed to stand overnight at 4°C, then diluted with dichloromethane. The organic layers was concentrated to dryness obtain y-N-t-butoxycarbonylaminobutyric acid amide (8.1 g). The amide (8 g) was treated with formic acid (87 ml) and concentrated hydrochloric acid (2.4 ml) to obtain y-aminobutyric acid amide hydrochloride (4.8 g)~
Preparation Example 3 _ g -Synthesis of 6-chloro-9-(2',3'5'-tri-0-isobutyl-j3-D-ribosyl)purine 6-chloropurine (0.32 g) in hexamethyldisilazane (10 ml) was refluxed under a nitrogen atmosphere for 2 hours, then the mixture was evaporated in vacuo. The residue thus obtained was dissolved in acetonitrile (17 ml).
2,3,5-Tri-O-isobutyl-1-O-methyl-D-ribofuranose (0.68 g) in acetonitrile (4 ml) solution was added thereto, and .
the solution was cooled to -30°C, then trimethylsilyl triflate (0.4 ml) in acetonitrile (4 ml) solution was added and the solution stirred under a nitrogen atmosphere at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and extraction performed with ether.
The organic layers was washed with water, then dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography to obtain 6-chloro-9-(2',3',5'-tri-O-isobutyl-(3-D-ribosyl)purine (0.25 g) and its a,-isomer (0.11 g).
Example 1 Compound 1: N-~3-carbamoylpropylL 9-(2',3',5'-tri-O-isobutyl-(3-D-ribosyl)adenine The 6-chloro-9-(2',3',5'-tri-O-isobutyl-(3-D-ribosyl)purine (0.21 g) obtained in the Preparation Example, y-aminobutyric acid (GABA) amide hydrochloride (0.13 g), and triethylamine (0.21 ml) were dissolved in a mixture of ethanol (16 ml) and water (4 ml) and refluxed overnight, and then concentrated to dryness. The residue was dissolved in dichloromethane, washed with water, then the residue obtained from the organic layers was purified by silica gel chromatography to obtain the target compound (compound 1) (0.13 g) (Yield 14~).
Melting point: 64°C
Analysis values ( as C~6HqqN6O5 ) Calculated C: 59.98, H: 8.52, N: 16.14 Found C: 59.85, H: 8.37, N: 16.09 Example 2 Compound 2: N-6-l3-carbamoylpropyl~-9-(2',3',5'-tri-O-propel-I(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using 2,3,5-tri-O-propyl-l-O-methyl-D-ribofuranose, instead of 2,3,5-tri-0-isobutyl-1-0-methyl-D-ribofuranose.
Melting point: 114°C
Analysis values ( as C23HseNsOs ) Calculated C: 57.72, H: 8.00, N: 17.56 Found C: 57.81, H: 8.72, N: 17.68 Example 3 Compound 3: N-6-(3-carbamovlpropyl)-_ 9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example l, except for using 2,3,5-tri-O-pentyl-1-O-methyl-D-ribofuranose (0.48 g), instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 19%).
Melting point: 87°C
Analysis values ( as C29HSON6O5 ) Calculated C: 61.89, H: 8.95, N: 14.93 Found C: 61.94, H: 8.90, N: 14.94 Example 4 Co~ound 4: N-6-l4-carbamo~lbutyl)-9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using 8-aminovaleric acid amide (0.35 g), instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-O-pentyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 19%).
Melting point: 86°C
Analysis values ( as C3oH52N6O5 ) Calculated C: 62.46, H: 9.08, N: 14.57 Found C: 62.64, H: 8.95, N: 14.62 Example 5 Compound 5: N-6-(2-carbamoylethyl)-9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using (3-aminopropionic acid amide instead of y-aminobutyric acid (GABA) amide and using 2,3,5-tri-O-pentyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 14%).
Melting point: 110°C
Analysis values ( as CZ8H48N6O5 ) Calculated C: 61.28, H: 8.81, N: 15.31 Found C: 61.55, H: 8.72, N: 15.20 Example 6 Compound 6: N-6-(2-carbamoylethyl)-9-(2',3',5'-tri-O-progyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using (3-aminopropionic acid amide, instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-O-propyl-1-0-methyl-D-ribofuranose instead of 2,3,5-tri-0-isobutyl-1-O-methyl-D-ribofuranose (Yield 18%).
Melting point: 125°C
Analysis values (as C22H3sNsOs) Calculated C: 56.87, H: 7.81, N: 18.09 Found C: 57.32, H: 7.89, N: 18.37 Example 7 Compound 7~ N-6-(4-carbamoylbutyl)-9-(2',3',5'-tri-O-propel-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using b-aminovaleric acid amide, instead of y-aminobutyric acid (GABA) amide and using 2,3,5-tri-0-propyl-1-O-methyl-D-ribofuranose instead of 2,3,5-tri-O-isobutyl-1-O-methyl-D-ribofuranose (Yield 14~).
Melting point: 119°C
Analysis values (as C~QHQON605) Calculated C: 58.51, H: 8.18, N: 17.06 Found C: 58.62, H: 7.97, N: 17.27 Example 8 Compound 8: N-6-(5-carbamoylpentyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example l, except for using e-aminocaproic acid amide, instead of Y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-0-propyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 14~).
Melting point: 99°C
Analysis values ( as C25H42N5O5 ) Calculated C: 59.26, H: 8.35, N: 16.59 Found C: 59.27, H: 8.18, N: 16.68 Example 9 Compound 9: N-6-(5-carbamoylpentyl)-9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using E-aminocaproic acid amide, instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-0-pentyl-1-O-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 17%).
Melting point: 85°C
Analysis values (as C31H5aNsOs' 1~2H20) Calculated C: 62.07, H: 9.24, N: 14.01 Found C: 61.77, H: 8.80, N: 14.50 Example 10 Compound 10: N-6-(3-N-methylcarbamoylpropyl)-9-~2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using y-aminobutyric acid N-methyl amide, instead of Y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-0-propyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-O-methyl-D-ribofuranose (Yield 18%).
Melting point: 85°C
Analysis values ( as C24H4oN6O5 ~ HC1 ) Calculated C: 54.48, H: 7.87, N: 15.88 Found C: 54.61, H: 7.92, N: 15.92 Example 11 Compound 11: N-6-(3-(N,N-dimethylcarbamoyl)propyl~-~2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example l, except for using ~y-aminobutyric acid N,N-dimethyl amide, instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-O-pentyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 17%).
MS (FAB): M++l; 591.2 (molecular weight 590.79) Example 12 Compound 12: N-6-methyl-N-6-(3-carbamoylpropyl)-9-~2',3',5'-tri-0-prowl-j3-D-ribosyl)adenine X11 Synthesis of 2',3',5'-tri-O-acetylinosine Inosine (20 g) was dissolved in a mixture of acetic anhydride (200 ml) and pyridine (240 ml). The solution was allowed to stand overnight, then concentrated to dryness. Ethanol (80 ml) was added to the residue. This was crystallized, then filtered to obtain crystals of the desired compound (26 g).
~2) Synthesis of 6-chloro-9-(2',3',5'-tri-O-acetyl-(3-D-ribofuranosyl ~purine The 2',3',5'-tri-O-acetylinosine (4 g) obtained in (1) above was added to a cooled mixture of phosphorus oxychloride (20 ml) and N,N'-diethylaniline (20 ml).
Next, the solution was heated at 120°C for 5 minutes, then the reaction solution was poured into ice and extracted with dichloromethane. The organic phase was washed with diluted hydrochloric acid, then with sufficient water. The organic phase was dried and concentrated to dryness, then the residue purified by silica gel chromatography to obtain 6-chloro-9-(2',3',5'-tri-O-acetyl-(3-D-ribofuranosyl)purine (3.7 g).
~3~ynthesis of 6-chloropurine riboside The 6-chloro-9-(2',3',5'-tri-0-acetyl-(3-D-ribofuranosyl)purine (3.6 g) obtained at (2) was dissolved in methanol (72 ml). Ammonia gas was saturated and the resultant mixture was stirred for 6 hours. The reaction solution was concentrated to dryness, then the residue was crystallized from acetone/ether to obtain 6-chloropurine riboside (2.2 g).
(4) Synthesis of 6-0-benzylinosine Metal sodium (2.9 g) was dissolved in benzyl alcohol (130 ml). The 6-chloropurine riboside (10.5 g) obtained at (3) above was added to this solution and the solution was then heated at 85°C for 1 hour. The reaction solution was dried to a solid, then the residue was dissolved in ethyl acetate and washed with water. The organic layers was concentrated to dryness and the residue was purified by silica gel chromatography to obtain (3-6-0-benzylinosine (7.2 g).
~5) Synthesis of 6-O-benzyl-2',3'5'-tri-0-allylinosine The 6-0-benzylinosine (2 g) obtained at (4) above was dissolved in tetrahydrofuran (40 ml). Sodium hydride (60%, 1.2 g) was added, then the solution stirred at room temperature for 30 minutes. Next, allyl bromide (2.1 g) was added and the resultant mixture was refluxed overnight. This was then cooled, then ice water was added and extracted with ethyl acetate. The residue obtained from the organic layers was purified by silica gel chromatography to obtain 6-0-benzyl-2',3',5'-tri-0-allylinosine (1.7 g).
!6) Synthesis of 2'.3',5'-tri-O-propylinosine The 6-O-benzyl-2',3',5'-tri-0-allylinosine (1.7 g) obtained at (5) above was dissolved in ethanol (40 ml) and the resultant mixture was reduced by hydrogenation under medium pressure in the presence of 10~ palladium-IO on-carbon (0.2 g). The catalyst was removed, then the solvent was concentrated to dryness and the residue was purified by silica gel chromatography to obtain 2',3',5'-tri-O-propylinosine (1.0 g).
l7~ynthesis of 6-chloro-9-(2',3',5'-tri-O-propyl-(3-D-ribofuranosyl)purine 2',3',5'-tri-0-propylinosine (1.0 g) obtained in (6) above, phosphorus oxychloride (5 ml) and N,N-diethylaniline (0.3 ml) were treated and purified in the same way as in (2) above to obtain 6-chloro-9-(2',3',5'-tri-O-propyl-(3-D-ribofuranosyl)purine (0.87 g).
~8) Synthesis of N-6-methyl-N-6-(3-carbamoylpropyl~-9-(2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine The 6-chloro-9-(2',3',5'-tri-O-propyl-(3-D-ribofuranosyl)purine (0.45 g) obtained in (7) above, a hydrochloride of N-methyl-y-aminobutyric acid amide (0.45 g), and triethylamine (0.45 ml) were dissolved in ethanol/water (8/2) (10 ml) and refluxed overnight. Next, the reaction solution was concentrated to dryness and the residue was dissolved in ethyl acetate and washed with water. The organic layers was concentrated to dryness, then the residue was purified by silica gel chromatography to obtain N-6-methyl-N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine (0.4 g).
MS (FAB): M++1; 493.3 (molecular weight 492.62) Example 13 Compound 13: N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-O-methyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 12, except for using y-aminobutyric acid (GABA) amide, instead of the N-methyl-y-aminobutyric acid amide, and using methyl iodide, instead of allyl bromide.
MS (FAB): M~+1; 395.0 (molecular weight 394.43) Example 14 Compound 14: N-6-(3-morpholinocarbonylpropyl (2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 12, except for using y-aminobutyric acid morpholinamide, instead of the N-methyl-y-aminobutyric acid amide.
MS (FAB): M++l; 549.3 (molecular weight 548.69) Example 15 Compound 15: N-6-(3-piperidinocarbonylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 12, except for using y-aminobutyric acid piperizinamide, instead of the N-methyl-y-aminobutyric acid amide.
MS (FAB): M++1; 547.3 (molecular weight 546.71) Example 16 Compound 16: N-6-(3-(4-benzylpiperadin-1-yl-carbonylprogyl))-9-(2',3',5'-tri-0-propyl-(3-D-ribosvl)adenine The desired compound was prepared by a similar method to Example 12, except for using 'y-aminobutyric acid 4-benzylpiperizinamide, instead of the N-methyl-y-aminobutyric acid amide.
Melting point: 145°C (2~HCl~2H20) MS (FAB): M++l; 638.3 (molecular weight 637.82, free seat) Example 17 Compound 17: 6-(4-carbamoylpiperadino)-9-~2',3',5'-tri-0-propel-~3-D-ribosyl)purine The desired compound was prepared by a similar method to Example 12, except for using isonipecotic acid amide, instead of the N-methyl-y-aminobutyric acid amide.
Melting point: 104°C (1H20) MS (FAB): M++1; 505.2 (molecular weight 504.63) Example 18 Compound 18: N-6-butyl-X2',3',5'-tri-0-propel-(3-D-ribosyl~ adenine The desired compound was prepared by a similar method to Example 12, except for using butylamine, instead of the N-methyl-y-aminobutyric amide.
MS (FAB): M++l; 450.1 (molecular weight 449.59) Example 19 (Preparation of Tablets Present compound (compound 1) 250 g Lactose 620 g Corn starch 400 g Hydroxypropyl cellulose 20 g Magnesium stearate 10 g The present compound, lactose, and corn starch were mixed until becoming homogeneous, then a 5 W/V% ethanol hydroxypropyl cellulose solution was added and the mixture mixed, then granulated. The granules were passed through a 16 mesh sieve for grading, then tableted by an ordinary method to obtain tablets having a weight of 130 mg per tablet, a diameter of 7 mm, and a medicine content of 25 mg.
Test Example 1 ~Pharmacolog~ical Test in Normal Rats) Male Sprague-Dawley rats (Charles river, Japan) aged 6 weeks were used in this Experiment. Test compounds were suspended in Z% sodium CMC solution, and were given orally to rats fasted for 18 hours at the ratio of 1 mg/mL/100 g body weight. Two hours after the administration, blood was collected from abdominal aorta under ether anesthesia, and the concentration of triglycerides in the serum was measured by the L-a-glycerophosphate oxidase method and the concentration of glucose in the serum was measured by glucose oxidase method.
The action of the test compound in lowering the triglycerides was shown in Table 1 as a rate of suppression (%) against the solvent treated rats, while the action in lowering the glucose was shown in Table 2 as a rate of suppression (%) against the solvent treated rats.
Test Example 2 LPharmacoloaical Test of Hypertriglyceridemia Model) Male Sprague-Dawley rats (Charles river, Japan) aged 6 weeks were used in this Experiment. Test compounds were suspended in 1% CMC Na solution, and were given orally to rats fasted for 18 hours at the ratio of 1 mg/mL/100 g body weight. 20 minutes after the administration of Test compounds, 400 mg/kg body weight of Triton WR-1339 (Sigma) was injected to the tail vein. Two hours after the injection of the Triton WR-1339, blood was collected from abdominal aorta under ether anesthesia, and the concentration of triglycerides in the serum was measured by the L-a-glycerophosphate oxidase method.
The action of the test compound in lowering the triglycerides was shown in Table 1 as a rate of suppression (%) against the solvent treated Triton WR-1339 loaded rats.
Table 1: Action in Lowering Trialycerides in Serum Tested compound Rate of Rate of suppression for suppression for normal rats (~) Triton WR-1339 load rats (%) Table 2: Action in Lowering Glucose in Serum Rate of sup ression (~) Compound 14 26.2 Compound 15 22.4 Industrial Applicability The present compounds have action in improving hyperlipemia accompanying hypertriglyceridemia or diabetes etc., have a low toxicity, and exhibit effects in both oral and nonoral administration and, therefore, are useful as medical drugs for human use.
ADENOSINE COMPOUND AND PHARMACEUTICAL
COMPOSITION CONTAINING THE SAME
Technical Field The present invention relates to a novel adenosine compound. The compounds according to the present invention are effective for the treatment or alleviation of hyperlipemia, diabetes, hypertension, arrhythmia, cardiac infarction, rena failure, epilepsy, mental disorders, obesity, etc. and useful also as an anti-inf lammatory and analgesic.
Background Art In recent years, along with the aging of the population and changes in the diet, the number of persons suffering from hyperlipemia and diabetes has been increasing annually. These ailments sometimes cause arteriosclerosis and grave ischemic heart diseases etc., and therefore, have been viewed as problems worldwide.
Development of an effective method of treatment is therefore desired.
In view of this situation, efforts have been made to develop a medicine for the treatment of hyperlipemia.
Adenosine compounds having an action against hyperlipemia have been described in, for example, U.S. Patent No.
5,322,840 and W097/43300. These compounds are acid esters which leave the ribosyl portions as hydroxyl groups or protect the hydroxyl groups of the ribosyl portions with an acid chloride. _ Disclosure of Invention The object of the present invention is to provide a novel anti-hyperlipemia, anti-inflammatory, antidiabetic or analgesic drug.
The present inventors engaged in various studies to found novel adenosine compounds useful as pharmaceuticals and, as a result, found that an ether compound obtained by condensing all of the three hydroxyl groups of the ribosyl portion of an adenosine compound with alkyl groups, a different structure from the compounds described in the above publications, has a superior action against hyperlipemia, anti-inflammatory action, and action in lowering glucose, whereby the present invention was completed.
That is, in accordance with the present invention, there is provided an adenosine compound having the formula (I):
R~
I I N>
'N O N
RO ~I) RO OR
wherein R represents a straight or branched lower (e. g., a C1 - CS straight or a C3 - CS branched) alkyl group and R1 represents a C2 to C6 lower alkylamino group or a substituent having the formula (II), (III), or (IV):
2 /~
-~(CH2)n CO-N;R2 -NH(CHa)nC0- ~ -N, r--CONH2 R ~l2 (II) ' (III) ' (IV) wherein Rz independently represent a hydrogen group or lower alkyl group, X represents N-R3, 0 or CHz, R3 represents a hydrogen atom, lower alkyl group, or benzyl group, and n represents an integer of 1 to 6 or an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof suitable for use as an anti-hyperlipemia, anti-inflammatory, antidiabetic or analgesic agent.
Best Mode for Carrying out the Invention The present invention will be explained in further detail below.
The present invention is as described above, but the preferable compounds include those having the formula (I), wherein R is a C3 to CS alkyl group, in particular a propyl or pentyl group, or those having the formula (I), where R1 is a carbamoyl alkylamino group or butylamino group. Further, more preferable compounds of the present invention are those satisfying a plurality of the conditions of the substituents given above.
Specific examples of the preferable compounds of the present invention are as follows.
Compound 2: N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine Compound 6: N-6-(2-carbamoylethyl)-9-(2',3',5'-tri-O-propyl-/3-D-ribosyl)adenine Compound 7: N-6-(4-carbamoylbutyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 12: N-6-methyl-N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 14: N-6-(3-morpholinocarbonylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 15: N-6-(3-piperidinocarbonylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine Compound 18: N-6-butyl-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The adenosine compounds having the formula (I) of the present invention may be pharmaceutically acceptable salts thereof as well. Specifically, an inorganic acid salt formed from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfic acid, or~
phosphoric acid and an organic acid salt formed from, for example, formic acid, acetic acid, citric acid, fumaric acid, gluconic acid, lactic acid, malefic acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid may be mentioned. Further, the compounds of the present invention may form in some cases hydrates.
The adenosine compounds according to the present invention may be prepared by a conventional method.
Typical methods among these will be explained below.
Production Process 1 The compounds of the present invention may be synthesized in accordance with the following reaction formulae:
Cl N ~ N RO O OCH3 1 ) HMDS N' N + RO 2 ) TMSOTf ~N ~ N
N H OR RO
v RO OR
Cl R1 N ~ ~ NHZ-(CH2)n-CONH2 N\
~N O N ~N O N
RO ~ RO
RO OR RO OR
(I) In the reaction formulae, HMDS represents hexamethyldisilazane and TMSOTf represents trimethylsilyl triflate and R and R1 have the same meanings as those of formula (I).
The reactions used in this production process are known conventional methods. That is, the desired compound having the formula (I) can be obtained by reacting 6-chloropurine and the corresponding ribose derivative, followed by reacting with the corresponding amino compound.
Production Process 2 O CI O
HN N N~ N N~ N
~ ~ ~~ 3 step s ~ ~ ~~ 2 step s N N N N N I N
HO O HO O RO O
HO OH HO OH RO OR
CI R~
2 steps HN' ~ N~ NHZ-(CH2)n-CONHa HN' I N>
'N .O N 'N O N
RO RO
(I) As shown in the above reaction formulae, inosine is used as the starting substance, the three reactions of acetylation, chlorination, and then deacetylation are carried out to obtain the chlorinated compound of purine.
Then, the resultant compound was benzylated and alkylated and further debenzylated and again chlorinated to obtain a purine compound chlorinated at the 6-position followed by reacting with the corresponding amino compound to produce the desired compound having the formula (I).
The substances used in the above production processes 1 and 2 are easily synthesized using known standard methods. For example, the amino compound used for introducing R1 can be easily produced from amino acid by the following process:
NHZ-(CH2)n-COOH (~~ BocNH-{CH2)n-COOH 1) C1COOCZHS
2) NH3 BocNH--(CH2)n-CONH2 H~ NHZ-(CH2)n-CONH2 Further, the ribose compound can be produced by the following process:
HO ~/~ CH3OHlH2SO4 HO ~/~ NaH RO ~/
'-HO OH HO OH RO OR
when the present compound is used as an anti-hyperlipemia, anti-inflammatory, antidiabetic, or analgesic agent, it may be administered to the patients by a suitable method of administration such as an oral or nonoral method. As the form of oral administration, for example, tablets, granules, capsules, pills, powders, syrups, etc. and as the form of nonoral administration, for example, injections, inhalants, suppositories, liquids, etc. may be mentioned. When preparing these compositions for administration of medicines, they may be prepared by ordinary methods using the present compounds or the pharmaceutically acceptable salts thereof etc.
For example, in the case of an oral medicine, an excipient such as lactose, glucose, corn starch, or sucrose, a disintegrant such as carboxylmethyl cellulose calcium or hydroxypropyl cellulose, a lubricant such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hardened oil, a binding agent such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, and arabia gum, a humectant such as glycerol or ethylene glycol, and, optionally or if necessary, a surfactant, flavoring agent, etc. are used to prepare the desired administration preparation.
Further, in the case of a nonoral medicine, a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and tragacanth gum is used and, if necessary, a solution adjuvant, buffer agents, preservative, flavor, coloring agent, etc. may be used.
When the compound of the present invention is prepared as an anti-hyperlipemia agent, the unit of administration, in terms of the compound of the present invention, is, per adult in the case of oral administration, 1 to 1000 mg, preferably 30 to 600 mg, per day and, in the case of nonoral administration, 0.1 to 100 mg, preferably 0.5 to 30 mg per day. The desired therapeutic effect can be expected by administration one to three times a day.
EXAMPLES
Next, Examples of synthesis of the present compounds, Preparation Examples and Test Examples will now be given as Examples, but the present invention is, of course, not limited to these. Examples, further, processes for producing the starting substances are given as Preparation Examples.
Preparation Example 1 Synthesis of 2,3-5-tri-0-isobutyl-1-O-methyl-D-ribofuranose (1) D-ribose (5 g) was dissolved in methanol (100 ml), then concentrated sulfuric acid (0.6 ml) was added, under cooling at 0°C. The mixture was allowed to stand overnight at 4°C. After Amberlite IR-45~ (made by Rohm &
Hass) (4 g) was added to neutralize to this solution, the mixture was filtered and then the methanol was evaporated in vacuo to obtain a crude product of 1-O-methyl-D-ribofuranose (5 g).
(2) The 1-O-methyl-D-ribofuranose (5 g) was dissolved in tetrahydrofuran (50 ml), then sodium hydride (60%, 5.9 g) was added at 0°C, followed by stirring at room temperature for 30 minutes. After 3-chloro-2-methyl-1-propene (13.3 ml) was added to this solution, the mixture was heated for 24 hours, then cooled at 0°C.
Next, ice water was added. The solution was extracted with ether. Then the solution was dried over sodium sulfate, the solvent was concentrated to dryness. The - g -residue was purified by silica gel column chromatography to obtain 1-O-methyl-2,3,5-tri-0-(2-methyl-2-propenyl)-D-ribofuranose (6.9 g).
(3) The 1-0-methyl-2,3,5-tri-O-(2-methyl-2-propenyl)-D-ribofuranose (0.45 g) was dissolved in methanol (50 ml) and catalytically reduced using 10%
palladium-on-carbon (40 mg). The crude product was purified by silica gel column chromatography to obtain 2,3,5-tri-O-isobutyl-1-O-methyl-D-ribofuranose (0.42 g).
Preparation Example 2 Synthesis of y-aminobutyric acid amide hydrochloride (1) y-aminobutyric acid (10.3 g) was dissolved in water (120 ml), 1N sodium hydroxide solution (150 ml) and dioxan (100 ml). Di-t-butyl dicarbonate (24 g/dioxan 100 ml) was added at 5°C, then the mixture was stirred at room temperature for 12 hours. The solvent was evaporated, then the residue was diluted with water and the solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layers was concentrated to dryness obtain a residue (19.4 g).
(2) The residue (11.2 g) and triethylamine (8.5 ml) were dissolved in chloroform (125 ml), then ethyl chlorocarbonate (5.3 ml) was added at -5°C. After 10 minutes, the mixture was treated with ammonia gas, followed at -5°C for 15 minutes and at room temperature for 1 hour under stirring. The solution was then allowed to stand overnight at 4°C, then diluted with dichloromethane. The organic layers was concentrated to dryness obtain y-N-t-butoxycarbonylaminobutyric acid amide (8.1 g). The amide (8 g) was treated with formic acid (87 ml) and concentrated hydrochloric acid (2.4 ml) to obtain y-aminobutyric acid amide hydrochloride (4.8 g)~
Preparation Example 3 _ g -Synthesis of 6-chloro-9-(2',3'5'-tri-0-isobutyl-j3-D-ribosyl)purine 6-chloropurine (0.32 g) in hexamethyldisilazane (10 ml) was refluxed under a nitrogen atmosphere for 2 hours, then the mixture was evaporated in vacuo. The residue thus obtained was dissolved in acetonitrile (17 ml).
2,3,5-Tri-O-isobutyl-1-O-methyl-D-ribofuranose (0.68 g) in acetonitrile (4 ml) solution was added thereto, and .
the solution was cooled to -30°C, then trimethylsilyl triflate (0.4 ml) in acetonitrile (4 ml) solution was added and the solution stirred under a nitrogen atmosphere at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and extraction performed with ether.
The organic layers was washed with water, then dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography to obtain 6-chloro-9-(2',3',5'-tri-O-isobutyl-(3-D-ribosyl)purine (0.25 g) and its a,-isomer (0.11 g).
Example 1 Compound 1: N-~3-carbamoylpropylL 9-(2',3',5'-tri-O-isobutyl-(3-D-ribosyl)adenine The 6-chloro-9-(2',3',5'-tri-O-isobutyl-(3-D-ribosyl)purine (0.21 g) obtained in the Preparation Example, y-aminobutyric acid (GABA) amide hydrochloride (0.13 g), and triethylamine (0.21 ml) were dissolved in a mixture of ethanol (16 ml) and water (4 ml) and refluxed overnight, and then concentrated to dryness. The residue was dissolved in dichloromethane, washed with water, then the residue obtained from the organic layers was purified by silica gel chromatography to obtain the target compound (compound 1) (0.13 g) (Yield 14~).
Melting point: 64°C
Analysis values ( as C~6HqqN6O5 ) Calculated C: 59.98, H: 8.52, N: 16.14 Found C: 59.85, H: 8.37, N: 16.09 Example 2 Compound 2: N-6-l3-carbamoylpropyl~-9-(2',3',5'-tri-O-propel-I(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using 2,3,5-tri-O-propyl-l-O-methyl-D-ribofuranose, instead of 2,3,5-tri-0-isobutyl-1-0-methyl-D-ribofuranose.
Melting point: 114°C
Analysis values ( as C23HseNsOs ) Calculated C: 57.72, H: 8.00, N: 17.56 Found C: 57.81, H: 8.72, N: 17.68 Example 3 Compound 3: N-6-(3-carbamovlpropyl)-_ 9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example l, except for using 2,3,5-tri-O-pentyl-1-O-methyl-D-ribofuranose (0.48 g), instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 19%).
Melting point: 87°C
Analysis values ( as C29HSON6O5 ) Calculated C: 61.89, H: 8.95, N: 14.93 Found C: 61.94, H: 8.90, N: 14.94 Example 4 Co~ound 4: N-6-l4-carbamo~lbutyl)-9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using 8-aminovaleric acid amide (0.35 g), instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-O-pentyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 19%).
Melting point: 86°C
Analysis values ( as C3oH52N6O5 ) Calculated C: 62.46, H: 9.08, N: 14.57 Found C: 62.64, H: 8.95, N: 14.62 Example 5 Compound 5: N-6-(2-carbamoylethyl)-9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using (3-aminopropionic acid amide instead of y-aminobutyric acid (GABA) amide and using 2,3,5-tri-O-pentyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 14%).
Melting point: 110°C
Analysis values ( as CZ8H48N6O5 ) Calculated C: 61.28, H: 8.81, N: 15.31 Found C: 61.55, H: 8.72, N: 15.20 Example 6 Compound 6: N-6-(2-carbamoylethyl)-9-(2',3',5'-tri-O-progyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using (3-aminopropionic acid amide, instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-O-propyl-1-0-methyl-D-ribofuranose instead of 2,3,5-tri-0-isobutyl-1-O-methyl-D-ribofuranose (Yield 18%).
Melting point: 125°C
Analysis values (as C22H3sNsOs) Calculated C: 56.87, H: 7.81, N: 18.09 Found C: 57.32, H: 7.89, N: 18.37 Example 7 Compound 7~ N-6-(4-carbamoylbutyl)-9-(2',3',5'-tri-O-propel-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using b-aminovaleric acid amide, instead of y-aminobutyric acid (GABA) amide and using 2,3,5-tri-0-propyl-1-O-methyl-D-ribofuranose instead of 2,3,5-tri-O-isobutyl-1-O-methyl-D-ribofuranose (Yield 14~).
Melting point: 119°C
Analysis values (as C~QHQON605) Calculated C: 58.51, H: 8.18, N: 17.06 Found C: 58.62, H: 7.97, N: 17.27 Example 8 Compound 8: N-6-(5-carbamoylpentyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example l, except for using e-aminocaproic acid amide, instead of Y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-0-propyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 14~).
Melting point: 99°C
Analysis values ( as C25H42N5O5 ) Calculated C: 59.26, H: 8.35, N: 16.59 Found C: 59.27, H: 8.18, N: 16.68 Example 9 Compound 9: N-6-(5-carbamoylpentyl)-9-(2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using E-aminocaproic acid amide, instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-0-pentyl-1-O-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 17%).
Melting point: 85°C
Analysis values (as C31H5aNsOs' 1~2H20) Calculated C: 62.07, H: 9.24, N: 14.01 Found C: 61.77, H: 8.80, N: 14.50 Example 10 Compound 10: N-6-(3-N-methylcarbamoylpropyl)-9-~2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 1, except for using y-aminobutyric acid N-methyl amide, instead of Y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-0-propyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-O-methyl-D-ribofuranose (Yield 18%).
Melting point: 85°C
Analysis values ( as C24H4oN6O5 ~ HC1 ) Calculated C: 54.48, H: 7.87, N: 15.88 Found C: 54.61, H: 7.92, N: 15.92 Example 11 Compound 11: N-6-(3-(N,N-dimethylcarbamoyl)propyl~-~2',3',5'-tri-O-pentyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example l, except for using ~y-aminobutyric acid N,N-dimethyl amide, instead of y-aminobutyric acid (GABA) amide, and using 2,3,5-tri-O-pentyl-1-0-methyl-D-ribofuranose, instead of 2,3,5-tri-O-isobutyl-1-0-methyl-D-ribofuranose (Yield 17%).
MS (FAB): M++l; 591.2 (molecular weight 590.79) Example 12 Compound 12: N-6-methyl-N-6-(3-carbamoylpropyl)-9-~2',3',5'-tri-0-prowl-j3-D-ribosyl)adenine X11 Synthesis of 2',3',5'-tri-O-acetylinosine Inosine (20 g) was dissolved in a mixture of acetic anhydride (200 ml) and pyridine (240 ml). The solution was allowed to stand overnight, then concentrated to dryness. Ethanol (80 ml) was added to the residue. This was crystallized, then filtered to obtain crystals of the desired compound (26 g).
~2) Synthesis of 6-chloro-9-(2',3',5'-tri-O-acetyl-(3-D-ribofuranosyl ~purine The 2',3',5'-tri-O-acetylinosine (4 g) obtained in (1) above was added to a cooled mixture of phosphorus oxychloride (20 ml) and N,N'-diethylaniline (20 ml).
Next, the solution was heated at 120°C for 5 minutes, then the reaction solution was poured into ice and extracted with dichloromethane. The organic phase was washed with diluted hydrochloric acid, then with sufficient water. The organic phase was dried and concentrated to dryness, then the residue purified by silica gel chromatography to obtain 6-chloro-9-(2',3',5'-tri-O-acetyl-(3-D-ribofuranosyl)purine (3.7 g).
~3~ynthesis of 6-chloropurine riboside The 6-chloro-9-(2',3',5'-tri-0-acetyl-(3-D-ribofuranosyl)purine (3.6 g) obtained at (2) was dissolved in methanol (72 ml). Ammonia gas was saturated and the resultant mixture was stirred for 6 hours. The reaction solution was concentrated to dryness, then the residue was crystallized from acetone/ether to obtain 6-chloropurine riboside (2.2 g).
(4) Synthesis of 6-0-benzylinosine Metal sodium (2.9 g) was dissolved in benzyl alcohol (130 ml). The 6-chloropurine riboside (10.5 g) obtained at (3) above was added to this solution and the solution was then heated at 85°C for 1 hour. The reaction solution was dried to a solid, then the residue was dissolved in ethyl acetate and washed with water. The organic layers was concentrated to dryness and the residue was purified by silica gel chromatography to obtain (3-6-0-benzylinosine (7.2 g).
~5) Synthesis of 6-O-benzyl-2',3'5'-tri-0-allylinosine The 6-0-benzylinosine (2 g) obtained at (4) above was dissolved in tetrahydrofuran (40 ml). Sodium hydride (60%, 1.2 g) was added, then the solution stirred at room temperature for 30 minutes. Next, allyl bromide (2.1 g) was added and the resultant mixture was refluxed overnight. This was then cooled, then ice water was added and extracted with ethyl acetate. The residue obtained from the organic layers was purified by silica gel chromatography to obtain 6-0-benzyl-2',3',5'-tri-0-allylinosine (1.7 g).
!6) Synthesis of 2'.3',5'-tri-O-propylinosine The 6-O-benzyl-2',3',5'-tri-0-allylinosine (1.7 g) obtained at (5) above was dissolved in ethanol (40 ml) and the resultant mixture was reduced by hydrogenation under medium pressure in the presence of 10~ palladium-IO on-carbon (0.2 g). The catalyst was removed, then the solvent was concentrated to dryness and the residue was purified by silica gel chromatography to obtain 2',3',5'-tri-O-propylinosine (1.0 g).
l7~ynthesis of 6-chloro-9-(2',3',5'-tri-O-propyl-(3-D-ribofuranosyl)purine 2',3',5'-tri-0-propylinosine (1.0 g) obtained in (6) above, phosphorus oxychloride (5 ml) and N,N-diethylaniline (0.3 ml) were treated and purified in the same way as in (2) above to obtain 6-chloro-9-(2',3',5'-tri-O-propyl-(3-D-ribofuranosyl)purine (0.87 g).
~8) Synthesis of N-6-methyl-N-6-(3-carbamoylpropyl~-9-(2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine The 6-chloro-9-(2',3',5'-tri-O-propyl-(3-D-ribofuranosyl)purine (0.45 g) obtained in (7) above, a hydrochloride of N-methyl-y-aminobutyric acid amide (0.45 g), and triethylamine (0.45 ml) were dissolved in ethanol/water (8/2) (10 ml) and refluxed overnight. Next, the reaction solution was concentrated to dryness and the residue was dissolved in ethyl acetate and washed with water. The organic layers was concentrated to dryness, then the residue was purified by silica gel chromatography to obtain N-6-methyl-N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-O-propyl-(3-D-ribosyl)adenine (0.4 g).
MS (FAB): M++1; 493.3 (molecular weight 492.62) Example 13 Compound 13: N-6-(3-carbamoylpropyl)-9-(2',3',5'-tri-O-methyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 12, except for using y-aminobutyric acid (GABA) amide, instead of the N-methyl-y-aminobutyric acid amide, and using methyl iodide, instead of allyl bromide.
MS (FAB): M~+1; 395.0 (molecular weight 394.43) Example 14 Compound 14: N-6-(3-morpholinocarbonylpropyl (2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 12, except for using y-aminobutyric acid morpholinamide, instead of the N-methyl-y-aminobutyric acid amide.
MS (FAB): M++l; 549.3 (molecular weight 548.69) Example 15 Compound 15: N-6-(3-piperidinocarbonylpropyl)-9-(2',3',5'-tri-0-propyl-(3-D-ribosyl)adenine The desired compound was prepared by a similar method to Example 12, except for using y-aminobutyric acid piperizinamide, instead of the N-methyl-y-aminobutyric acid amide.
MS (FAB): M++1; 547.3 (molecular weight 546.71) Example 16 Compound 16: N-6-(3-(4-benzylpiperadin-1-yl-carbonylprogyl))-9-(2',3',5'-tri-0-propyl-(3-D-ribosvl)adenine The desired compound was prepared by a similar method to Example 12, except for using 'y-aminobutyric acid 4-benzylpiperizinamide, instead of the N-methyl-y-aminobutyric acid amide.
Melting point: 145°C (2~HCl~2H20) MS (FAB): M++l; 638.3 (molecular weight 637.82, free seat) Example 17 Compound 17: 6-(4-carbamoylpiperadino)-9-~2',3',5'-tri-0-propel-~3-D-ribosyl)purine The desired compound was prepared by a similar method to Example 12, except for using isonipecotic acid amide, instead of the N-methyl-y-aminobutyric acid amide.
Melting point: 104°C (1H20) MS (FAB): M++1; 505.2 (molecular weight 504.63) Example 18 Compound 18: N-6-butyl-X2',3',5'-tri-0-propel-(3-D-ribosyl~ adenine The desired compound was prepared by a similar method to Example 12, except for using butylamine, instead of the N-methyl-y-aminobutyric amide.
MS (FAB): M++l; 450.1 (molecular weight 449.59) Example 19 (Preparation of Tablets Present compound (compound 1) 250 g Lactose 620 g Corn starch 400 g Hydroxypropyl cellulose 20 g Magnesium stearate 10 g The present compound, lactose, and corn starch were mixed until becoming homogeneous, then a 5 W/V% ethanol hydroxypropyl cellulose solution was added and the mixture mixed, then granulated. The granules were passed through a 16 mesh sieve for grading, then tableted by an ordinary method to obtain tablets having a weight of 130 mg per tablet, a diameter of 7 mm, and a medicine content of 25 mg.
Test Example 1 ~Pharmacolog~ical Test in Normal Rats) Male Sprague-Dawley rats (Charles river, Japan) aged 6 weeks were used in this Experiment. Test compounds were suspended in Z% sodium CMC solution, and were given orally to rats fasted for 18 hours at the ratio of 1 mg/mL/100 g body weight. Two hours after the administration, blood was collected from abdominal aorta under ether anesthesia, and the concentration of triglycerides in the serum was measured by the L-a-glycerophosphate oxidase method and the concentration of glucose in the serum was measured by glucose oxidase method.
The action of the test compound in lowering the triglycerides was shown in Table 1 as a rate of suppression (%) against the solvent treated rats, while the action in lowering the glucose was shown in Table 2 as a rate of suppression (%) against the solvent treated rats.
Test Example 2 LPharmacoloaical Test of Hypertriglyceridemia Model) Male Sprague-Dawley rats (Charles river, Japan) aged 6 weeks were used in this Experiment. Test compounds were suspended in 1% CMC Na solution, and were given orally to rats fasted for 18 hours at the ratio of 1 mg/mL/100 g body weight. 20 minutes after the administration of Test compounds, 400 mg/kg body weight of Triton WR-1339 (Sigma) was injected to the tail vein. Two hours after the injection of the Triton WR-1339, blood was collected from abdominal aorta under ether anesthesia, and the concentration of triglycerides in the serum was measured by the L-a-glycerophosphate oxidase method.
The action of the test compound in lowering the triglycerides was shown in Table 1 as a rate of suppression (%) against the solvent treated Triton WR-1339 loaded rats.
Table 1: Action in Lowering Trialycerides in Serum Tested compound Rate of Rate of suppression for suppression for normal rats (~) Triton WR-1339 load rats (%) Table 2: Action in Lowering Glucose in Serum Rate of sup ression (~) Compound 14 26.2 Compound 15 22.4 Industrial Applicability The present compounds have action in improving hyperlipemia accompanying hypertriglyceridemia or diabetes etc., have a low toxicity, and exhibit effects in both oral and nonoral administration and, therefore, are useful as medical drugs for human use.
Claims (6)
1. An adenosine compound having the formula (I):
wherein R represents a straight or branched lower alkyl group and R1 represents a C2 to C6 lower alkylamino group or a substituent having the formula (II), (III) or (IV):
wherein R2 independently represent a hydrogen atom or lower alkyl group, X represents N-R3, O or CH2, R3 represents a hydrogen atom, lower alkyl group or benzyl group and n represents an integer of 1 to 6.
wherein R represents a straight or branched lower alkyl group and R1 represents a C2 to C6 lower alkylamino group or a substituent having the formula (II), (III) or (IV):
wherein R2 independently represent a hydrogen atom or lower alkyl group, X represents N-R3, O or CH2, R3 represents a hydrogen atom, lower alkyl group or benzyl group and n represents an integer of 1 to 6.
2. An adenosine compound as claimed in claim 1, wherein R represents a C3 to C5 lower alkyl group and n of the formula (II) or (III) for R1 represents an integer of 2 to 5.
3. An adenosine compound as claimed in claim 1, wherein R represents a propyl group and R1 represents a C2 to C6 lower alkylamino group or a substituent having the formula (II), wherein R2 independently represent a hydrogen atom or methyl group and n represents an integer of 2 to 4.
4. An adenosine compound as claimed in claim 1, wherein R represents a propyl group and R1 represents a substituent having the formula (III), wherein X
represents O or CH2 and n represents an integer of 2 to 4.
represents O or CH2 and n represents an integer of 2 to 4.
5. A pharmaceutical composition comprising an adenosine compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a hydrate and a pharmaceutically acceptable carrier.
6. A drug for the treatment of hyperlipemia or diabetes having, as an active ingredient, an adenosine compound according to any one of claims 1 to 4 or an optical isomer thereof, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2000/006958 WO2002004474A1 (en) | 2000-07-12 | 2000-07-12 | Adenosine compound and pharmaceutical composition containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2416199A1 true CA2416199A1 (en) | 2002-01-17 |
Family
ID=8164030
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002416199A Abandoned CA2416199A1 (en) | 2000-07-12 | 2000-07-12 | Adenosine compound and pharmaceutical composition containing the same |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1303528A1 (en) |
| JP (1) | JP2004502780A (en) |
| CA (1) | CA2416199A1 (en) |
| WO (1) | WO2002004474A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101712709A (en) * | 2008-10-06 | 2010-05-26 | 中国医学科学院药物研究所 | Tifluoroacetyl-3-hydroxyphenyl adenosine and use thereof in blood fat regulation |
| CA2773773C (en) * | 2009-09-21 | 2019-04-23 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1'-substituted carba-nucleoside analogs |
| WO2017000125A1 (en) | 2015-06-29 | 2017-01-05 | Merck Sharp & Dohme Corp. | Purine inhibitors of human phosphatidylinositol 3-kinase delta |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1955387A1 (en) * | 1969-10-29 | 1971-05-06 | Schering Ag | 9-beta-d-arabinofuranosyl-n6-isopentenyla - denine |
| FR2665362B1 (en) * | 1990-08-03 | 1994-12-09 | Cepbepe | SUBSTANCE CONTAINING, AS ACTIVE INGREDIENT, A N6 SUBSTITUTED ADENOSINE AND ITS APPLICATION. |
| GB9610031D0 (en) * | 1996-05-14 | 1996-07-17 | Glaxo Group Ltd | Chemical compounds |
-
2000
- 2000-07-12 EP EP00945940A patent/EP1303528A1/en not_active Withdrawn
- 2000-07-12 JP JP2002509337A patent/JP2004502780A/en active Pending
- 2000-07-12 CA CA002416199A patent/CA2416199A1/en not_active Abandoned
- 2000-07-12 WO PCT/EP2000/006958 patent/WO2002004474A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002004474A1 (en) | 2002-01-17 |
| JP2004502780A (en) | 2004-01-29 |
| EP1303528A1 (en) | 2003-04-23 |
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