The present invention provides a preventive or therapeutic agent of a new type for diabetes mellitus and diabetic complications on the basis of an adenosine A2 receptor antagonist action.
A purine compound represented by the formula (I), its pharmacologically acceptable salt or hydrates thereof has an adenosine A2 receptor antagonistic action and is useful for prevention or therapy of diabetes mellitus and diabetic complications. In addition, adenosine A2 receptor antagonists having different structures from those of the compounds described above, for example KW6002, are also effective for prevention or therapy of diabetes mellitus and diabetic complications. ##STR00001##
In the formula, W is —CH2CH2—, or —CH═CH— or —C≡C—; R1 is:
##STR00002##
(in the formula, X is hydrogen atom, hydroxyl group, a lower alkyl group, a lower alkoxy group, etc.; and R5 and R6 are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a cycloalkyl group, etc.) and the like; R2 is an amino group, etc. which maybe substituted with a lower alkyl group, etc.; R3 is a cycloalkyl group, an optionally substituted aryl group, etc.; and R4 is a lower alkyl group etc.
##STR00003##
|
wherein A and b represent halogen atoms;
R3 represents an optionally substituted c3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; and
R4 represents an optionally substituted linear or branched lower alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.
13. A method for the manufacturing of a 6-amino-2-ethynylene compound represented by the formula (V):
##STR00272##
wherein R3 represents an optionally substituted c3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; R4 represents a linear or branched alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; R1 represents:
1) formula:
##STR00273##
wherein X is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted acyloxy group or an optionally substituted amino group; and R5 and R6 are the same as or different from and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally protected carboxyl group or an optionally substituted four- to six-membered ring having at least one hetero atom; optionally, R5 and R6 is either an oxygen atom or a sulfur atom together or are a ring which may have hetero atom being formed together with a carbon atom to which they are bonded; wherein the ring may be substituted; or
2) a five- or six-membered aromatic ring which may have substituent group and hetero, to give a 2-ethynylene-6-halopurine compound represented by the formula (IV):
##STR00274##
wherein A is a halogen atom, and R1, R3 and R4 have the same meanings as defined above; and R21 and R22 are the same as or different from each other and each represents a hydrogen atom or an optionally substituted lower alkyl group or a saturated 3- or 8-membered ring being formed together with the nitrogen atom to which they are bonded and the ring containing said nitrogen atom optionally has another heteroatom of nitrogen or oxygen or is substituted; comprising the steps of:
a) reacting a 2,6-dihalo-substituted purine compound represented by the formula (II):
##STR00275##
wherein A and b represent halogen atoms, and R3 and R4 are defined as above, with an ethynylene compound represented by the formula (III):
R1C═CH (III) wherein in the formula (III) R1 is defined as above in formula (V); and
b) reacting the resulting compound with HNR21R22 to form said 6-amino-2-ethynylene compound represented by the formula (V).
14. A method for the manufacture of a 6-amino-2-ethynylene compound represented by the formula (V):
##STR00276##
wherein R3 represents an optionally substituted c3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; R4 represents a linear or branched alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; R1 represents:
1) formula:
##STR00277##
wherein X is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted acyloxy group or an optionally substituted amino group; and R5 and R6 are the same as or different from and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally protected carboxyl group or an optionally substituted four- to six-membered ring having at least one hetero atom; optionally, R5 and R6 is either an oxygen atom or a sulfur atom together or are a ring which may have hetero atom being formed together with a carbon atom to which they are bonded; wherein the ring may be substituted; or
2) a five- or six-membered aromatic ring which may have substituent group and hetero, to give a 2-ethynylene-6-halopurine compound represented by the formula (IV):
##STR00278##
wherein A is a halogen atom, and R1, R3 and R4 have the same meanings as defined above; and R21 and R22 are the same as or different from each other and each represents a hydrogen atom or an optionally substituted lower alkyl group or a saturated 3- or 8-membered ring being formed together with the nitrogen atom to which they are bonded and the ring containing said nitrogen atom optionally has another heteroatom or is substituted, comprising the steps of:
a) reacting a 2,6-dihalo-substituted purine compound represented by the formula (II):
##STR00279##
wherein A and b represent halogen atoms, and R3 and R4 are defined as above, with ammonia or a primary or secondary amine to give a 6-amino-2-halopurine compound represented by the formula (VI):
##STR00280##
wherein b, R3, R4, R21 and R22 have the same meanings as defined above; and
b) reacting the resulting compound with an ethynylene compound represented by the formula (III):
R1—C≡H (III) wherein R1 has the same meaning as defined above.
1. A purine compound represented by the formula (I), or its pharmacologically acceptable salt thereof,
##STR00264##
wherein in the formula (I),
R1 represents:
1) formula:
##STR00265##
wherein X is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted acyloxy group or an optionally substituted amino group; and R5 and R6 are the same as or different from each other and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted saturated or unsaturated c3-8 cycloalkyl group, an optionally substituted c3-8 cycloalkyl-c2-6 alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally protected carboxyl group or an optionally substituted four- to six-membered ring having at least one hetero atom; optionally R5 and R6 is either an oxygen atom or a sulfur atom together, or R5 and R6 are a ring which may have a hetero atom being formed together with a carbon atom to which they are bonded; wherein said ring may be substituted; or
2) a five- or six-membered aromatic ring that may have a substituent group and a hetero atom;
W represents formula —CH2CH2—, —CH═CH— or —C≡C—;
R2 represents a hydrogen atom, an optionally substituted lower alkyl group, a hydroxyl group or a formula —NR7R8, wherein R7 and R8 are the same as or different from each other and each represents a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, and optionally substituted acyl group, an optionally substituted c3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; optionally R7 and R8 are a saturated ring which is formed together with a nitrogen atom to which they are bonded, said saturated ring is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperidine, perhydroazepine, perhydroazocine, piperazine, homopiperazine, morpholine and thiomorpholine; wherein the ring optionally has a substituent selected from the group consisting of a lower alkyl group, a halogen and an acyl group;
R3 represents an optionally substituted c3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted c2-6 alkenyl group; and
R4 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted c3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted c2-6 alkenyl group, an optionally substituted c2-6 alkynyl group or an optionally substituted cyclic ether group; wherein when W is —CH2CH2—, then X is not a hydrogen atom or an alkyl group.
2. The purine compound or its pharmacologically acceptable salt thereof as claimed in
3. The purine compound, or its pharmacologically acceptable salt thereof, as claimed in
4. The purine compound as claimed in
5. The purine compound as claimed in
6. The purine compound as claimed in
wherein X represents a hydroxyl group, an acyloxy group or an optionally substituted lower alkyl group; and
R5 and R6 are the same as or different from and each represents an optionally substituted lower alkyl group or a ring being formed together with the carbon atom to which they are bonded which may have a hetero atom and may be substituted.
7. The purine compound as claimed in
wherein X represents a hydroxyl group or a lower aliphatic acyloxy group; and R5 and R6 are the same as or different from each other and each represents an optionally substituted lower alkyl group or an optionally substituted c3-8 cycloalkyl group being formed with the carbon atom to which they are bonded; and
R2 is a formula —NR7R8, wherein R7 and R8 are the same as or different from and each represents a hydrogen atom, a lower alkyl group or an acyl group.
8. The purine compound as claimed in
wherein X represents a hydroxyl group or a lower aliphatic acyloxy group; and R5 and R6 are the same as or different from each other and each represents an optionally substituted lower alkyl group or an optionally substituted c3-8 cycloalkyl group being formed together with the carbon atom to which they are bonded; and
R2 is a formula —NR7R8, wherein both R7 and R8 represent hydrogen atoms.
9. The purine compound as claimed in
wherein X represents a hydroxyl group or a lower aliphatic acyloxy group; and R5 and R6 are the same as or different from and each represents a linear or branched lower alkyl group or cyclobutyl group, cyclopentyl group or cyclohexyl group being formed together with the carbon atom to which they are bonded, and the ring may be substituted with a hydroxyl group, a lower aliphatic acyloxy group, a linear or branched lower alkyl group, a lower alkoxy group or a halogen atom;
R2 is a formula —NR7R8, wherein both R7 and R8 are hydrogen atoms;
R3 is a phenyl group which may be substituted with hydroxyl group, a halogen atom, a linear or branched lower alkyl group, a lower alkoxy group, an acyl group, amino group, a mono- or di-lower alkylamino group or a cyano group; and
R4 is a lower alkyl group which may be substituted with a hydroxyl group, a halogen atom, a cyano group, an amino group, a mono- or di-lower alkylamino group, a lower alkoxy group, a carbamoyl group, a mono- or di-substituted carbamoyl group, a carboxyl group or a lower alkyloxycarboxyl group.
10. The purine compound, or its pharmacologically acceptable salt thereof, as claimed in
wherein X represents a hydroxyl group; and R5 and R6 are the same as or different from and each represents a lower alkyl group or a cyclobutyl group, a cyclopentyl group or a cyclohexyl group being formed with the carbon atom to which they are bonded;
R2 is a formula —NR7R8, wherein both R7 and R8 are hydrogen atoms;
R3 is an optionally halogen-substituted phenyl group; and
R4 is a lower alkyl group.
11. The purine compound, or its pharmacologically acceptable salt thereof, as claimed in
1) 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;
2) 1-{2-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;
3) 1-{2-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;
4) 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol;
5) 1-{2-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol;
6) 1-{2-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol;
7) 1-{2-[6-amino-9-dimethylaminophenyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol;
8) 1-{2-[6-amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;
9) 1-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-ol;
10) 4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-ol;
11) 4-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol;
12) 4-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol; and
13) 1-{2-[6-amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol.
15. A preventive or therapeutic composition comprising:
the purine compound as claimed in
a pharmaceutically acceptable carrier.
16. A method of treating a disease or condition selected from the group consisting of diabetes mellitus, diabetic complications, hypoglycemia, hyperglycemia, impaired glucose tolerance and obesity, said method comprising:
administering an effective amount of the purine compound of
17. The method according to
18. The method according to
19. The method according to
20. The method according to
21. The method according to
22. A method of potentiating insulin sensitivity, said method comprising
administering an effective amount of the purine compound of
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This application is the national phase under 35 U.S.C. §371 or PCT International Application No. PCT/JP98/05870 which has an International filing date of Dec. 24, 1998, which is designated the United States of America.
The present invention relates to a novel purine compound having an adenosine receptor antagonism and to a preventive or therapeutic agent for diabetes mellitus and diabetic complication comprising an adenosine receptor antagonist having a hypoglycemic action and a glucose tolerance improving action on the basis of an inhibiting action to Saccharogenesis
Total binding amount is a 3H-CCPA binding radioactivity in the absence of the test compound.
Non-specific binding amount is a 3H-CCPA binding radioactivity in the presence of 100 μM of RPIA.
Binding amount in the presence of drug is a 3H-CCPA binding radioactivity in the presence of the test compound of various concentrations.
The inhibition constant (Ki value) in Table was calculated from Cheng-Prusoff's expression.
The results are shown in Table 4.
A membrane specimen prepared by an over-expression of adenosine A2a receptor was purchased from Receptor Biology, Inc. and adenosine A2a receptor binding experiments were carried out using that. The purchased membrane specimen was suspended in an incubation buffer (20 mM HEPES, 10 mM MgCl2 and 100 mM NaCl; pH 7.4) to make the concentration 22.2 μg/ml. To 0.45 ml of this membrane specimen were added 0.025 ml of tritium-labeled 3H-CGS21680 (500 nM; 30 Ci/mmol) and 0.025 ml of the test compound. The solution of the test compound was prepared in such a manner that, firstly, the compound was dissolved in DMSO to make 20 mM concentration and then successively diluted each 10-fold using an incubation buffer. The mixture was allowed to stand at 25° C. for 90 minutes, subjected to a quick suction on a glass fiber filter (GF/B; manufactured by Whatman) and immediately washed with 5 ml of ice-cooled 50 mM Tris-HCl buffer twice. After that, the glass fiber filter was transferred to a vial bottle, a scintillator was added and the radioactivity on the filter was measured by a liquid scintillation counter. Calculation of the inhibition rate of the test compound to the receptor bond (3H-CGS21680) of A2a was carried out by the following expression and, based upon that, IC50 was calculated.
Inhibition Rate (%)=[1−{(Binding amount in the presence of drug-Non-specific binding amount)/(Total binding amount amount-Non-specific binding amount)}]×100
Total binding amount is a 3H-CGS21680 binding radioactivity in the absence of the test compound.
Non-specific binding amount is a 3H-CGS21680 binding radioactivity in the presence of 100 μM of RPIA.
Binding amount in the presence of drug is a 3H-CGS21680 binding radioactivity in the presence of the test compound of various concentrations.
The inhibition constant (Ki value) in Table was calculated from Cheng-Prusoff's expression.
The results are shown in Table 4.
TABLE 4
Human adenosine A1, A2a receptor binding test
A1 receptor
A2a receptor
Receptor Test Compound
Ki (μM)
Ki (μM)
##STR00259##
0.024
0.002
##STR00260##
0.019
0.0014
##STR00261##
0.054
0.75
##STR00262##
10<
0.052
##STR00263##
10<
0.047
Human adenosine A2b receptor cDNA was over-expressed in CHOK1 cells. The cells were uniformly placed on a 24-well plate at the rate of 1.5×105 cells/well, incubated for one night and then used for the experiments. Affinity of the test compound to the A2b receptor was evaluated in which the index used was the degree of suppression of the amount of cAMP produced by stimulation of NECA (30 nM) which was an adenosine agonist in the presence of the test compound. Thus, after washing with 2 ml/well of an incubation buffer (Krebs solution; pH7.4) twice, a pre-incubation was carried out at 0.5 ml/well for 30 minutes. After that, 100 μl/well of a mixed solution containing 600 μM of Ro-20-1724 (phosphodiesterase inhibitor), 180 nM of NECA and a test compound which was 6-fold concentrated in a reaction solution were added. After 15 minutes, the reaction was stopped by substituting 0.1N HCl (300 μl/well) for the reaction solution. Measurement of cAMP was carried out using an Amersham cAMP EIA Kit.
Calculation of the suppression rate of the test compound to the NECA-stimulated cAMP production was done by the following expression.
Inhibition Rate (%)=[1−{(cAMP amount in the presence of NECA and test compound-cAMP amount in the case of incubation buffer only)/(cAMP amount stimulated only by NECA-cAMP amount in the case of incubation buffer only)}]×100.
IC50 (3-fluorophenyl) was calculated from the above.
The result is shown in Table 5.
TABLE 5
suppressing action to NECA-stimulated cAMP production
in adenosine A2b receptor expressed cells
Receptor
A2b receptor
Compound
IC50 (μM)
Compound A
0.028
Compound B
0.070
Compound C
0.10
KW6002
2.85
KF17837
1.36
The result is shown in Tables 6-1 to 6-4 for each experiment.
The result is shown in terms of “(% ratio of the blood sugar after 5 hours from the administration to the blood sugar before the administration)±(standard error)”. The data were subjected to a one-way layout analysis of variance and then subjected to a multiple comparison of Dunnett type. The case where p<0.05 was judged that a significant difference was available.
TABLE 6-1
Action of spontaneous diabetic mice (KK-A7/Ta Jcl)
to hyperglycemia
Test Compound
Dose (mg/kg)
Sig- nificance
Solvent
72.4 ± 4.4
Compound
10
47.8 ± 4.8
**
A
Compound
10
51.8 ± 2.9
**
B
Compounds A and B are administered in a form of sulfate.
(**; p < 0.01 vs. Solvent)
TABLE 6-2
Action of spontaneous diabetic mice (KK-A7/Ta Jcl)
to hyperglycemia
Test Compound
Dose (mg/kg)
Sig- nificance
Solvent
69.8 ± 2.3
Compound
30
48.5 ± 3.4
**
C
(**; p < 0.01 vs. Solvent)
TABLE 6-3
Action of spontaneous diabetic mice (KK-A7/Ta Jcl)
to hyperglycemia
Test Compound
Dose (mg/kg)
Sig- nificance
Solvent
76.6 ± 3.9
KW6002
100
57.6 ± 5.6
*
(*; p < 0.05 vs. Solvent)
TABLE 6-4
Action of spontaneous diabetic mice (KK-A7/Ta Jcl)
to hyperglycemia
Test Compound
Dose (mg/kg)
Sig- nificance
Solvent
80.7 ± 2.3
KF17837
100
62.0 ± 2.8
*
(*; p < 0.05 vs. Solvent)
As such, adenosine A2 receptor antagonist showed a clear hypoglycemic action in spontaneous diabetic models.
In the experiments for the NECA-stimulated glucose production in hepatic cells, the antagonist which was specific to adenosine A2a receptor did not show a saccharogenesis glucose production suppressing action and only the compound showing a strong suppressing action of A2b affinity to A2b receptor showed a saccharogenesis glucose production suppressing action. In addition, a glucose tolerance improving action in glucose tolerance test which is an index for sugar glucose utilization in peripheral tissues was noted both in antagonists which were specific to adenosine A2a and in compounds having a strong antagonistic action to A2b receptor.
On the other hand, no hypoglycemic action was noted for FK453 (European Journal of Pharmacology, 279, 217-225, 1995.) known as an antagonist specific to adenosine A1 receptor even at the dose of 100 mg/kg in the present diabetic models. In addition, no glucose tolerance improving action was noted in glucose tolerance test as well.
From the above, it is clear that the effect in the present diabetic models is due to an antagonistic action of adenosine A2 (A2a and/or A2b) receptor.
N2-(4-Pyridyl)-2,3-pyridinediamine was dissolved in 20 ml of methanol, 1 ml of acetic acid and 745 mg of 3-fluorobenzaldehyde were added and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to an azeotropy with toluene for three times. The resulting residue after concentration was suspended in 30 ml of ethanol, 1.5 g of anhydrous iron chloride were added thereto and the mixture was heated under reflux for 5 hours. The reaction solution was returned to room temperature, concentrated to dryness, diluted with 100 ml of ethyl acetate and washed with 50 ml of water and 20 ml of brine. The organic layer was concentrated to dryness and the residue was purified by a silica gel column chromatography (eluted with ethyl acetate:n-hexane=3:1) to give 0.36 g of a free compound. The free compound was dissolved in 20 ml of methanol, 6.5 ml of 1N hydrochloric acid were added thereto and the mixture was concentrated to dryness. Ethanol was added to the residue, the mixture was subjected to an azeotropy, suspended in 10 ml ethyl acetate and 0.45 g of the title compound was obtained by collecting by filtration. The overall yield was 46%.
NMR (400 MHz, δ, δ, DMSO-d6); 7.35-7.55 (m, 5H), 7.88 (d, J=6.4 Hz, 2H), 8.33 (dd, J=1.6 Hz, 8.0 Hz, 1H), 8.45 (dd, J=1.6 Hz, 4.8 Hz, 1H), 8.94 (d, J=6.4 Hz, 2H). 7.88 (d, J=6.4 Hz, 2H), 8.33(dd, J=1.6 Hz, 8.0 Hz, 1H), 8.45(dd, J=1.6 Hz, 4.8 Hz, 1H), 8.94(d, J=6.4 Hz, 2H).
The purine compound and the adenosine A2 receptor antagonists which are the compounds of the present invention show a clear hypoglycemic action in spontaneous diabetic models and also have an action of improving an impaired glucose tolerance, whereby they are useful as a preventive or therapeutic agent for diabetes mellitus and diabetic complications.
Asano, Osamu, Harada, Hitoshi, Yoshikawa, Seiji, Inoue, Takashi, Horizoe, Tatsuo, Yasuda, Nobuyuki, Ohashi, Kaya, Nagaoka, Junsaku, Murakami, Manabu, Kobayashi, Seiichi, Hoshino, Yorihisa
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