JPH01221381A - Pyrazolopyrimidines - Google Patents

Abstract

NEW MATERIAL:Compounds expressed by formulae I-II [R<1> is 1-4C alkyl or phenyl having substituent group such as 1-3C alkyl; R<2> is 1-20C alkyl, 1-4C alkenyl ACO2R<21>, etc.; A is (CH2)p which may be substituted by 1-3C alkyl, etc.; p is integer of 1-15; R<21> is H or 1-4C alkyl; R<3> is (CH2)n-pyridyl, wherein pyridine nucleus part may be substituted with 1-4C alkyl, etc. and/or (CH2)n part may be substituted with 1-2 numbers of 1-3C alkyls; n is integer of 1-10). EXAMPLE:Ethyl 2-methyl-3-(1'-(3''-pyridyl)ethyloxy)-pyrazolo[4,3-d]-pyrimidin-7- ylthioacetate. USE:A medicine having antihyperlipemia action as well as cardiac action. PREPARATION:Mercapto group of compound expressed by formula III is alkylated to afford a compound expressed by formula II, which is further reacted with various kind of alkylating agents to provide the compounds expressed by formula I-II.

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel pyrazolo(4,3-d) pyrimidine derivative and a method for producing the same. [Prior Art] The present inventors have already revealed in JP-A-60-231679 that pyrazolo(4,3-d) pyrimidines have excellent antihyperlipidemic effects. [Problem to be solved by the invention] This time, the novel pyrazolo of the present invention [4゜3-d
] The present inventors synthesized pyrimidine derivatives and found that they have cardiotonic effects as well as antihyperlipidemic effects, and completed the present invention. [Means for Solving the Problems] The novel pyrazolo(4,3-d)pyrimidines of the present invention are compounds represented by the following general formulas (Ia) and (Ib). (I a) (I b)

[In the formula, R1
is C3-C4 alkyl, or 01-C3 alkyl, 0
means phenyl optionally substituted with 1-C3 alkoxy, fluorine atom, chlorine atom, bromine atom or trifluoromethyl; R2 is 01-C2° alkyl,
CI''' Ca alkenyl, phenyl core part is 01-C
, alkyl, 01-C3 alkoxy, fluorine atom, chlorine atom, bromine atom or trifluoromethyl (CIlz) m Phenyl(
m means an integer of sails 1 to 3. ) or ACO□R
1+ (8 is C1-C, may be substituted by alkyl or phenyl (C11□), (p is 1-1
means an integer of 5. ), and R1' means a hydrogen atom or 01-C4 alkyl. ]; R3 means that the pyridine core moiety is C1-C4 alkyl, 01-
C, alkoxy, fluorine atom, chlorine atom, bromine atom, trifluoromethyl or CO□R31()73+ is 0
Means 1-C4 alkyl. ), the (C11□)7 portion may be replaced by one or two 01-C
(CHz) which may be substituted by 3 alkyl, Pyridyl (n means an integer of 1-10), [D means (CHz) II which may be substituted by 01 to C3. ], (R32 means C, ~C4 alkyl, fluorine atom, chlorine atom or bromine atom.), MCO□R33 (M may be substituted with self ~C3 alkyl or phenyl (Cllz)
p means R32 is a hydrogen atom, 01-C4 alkyl,
It means 1, 2 or 3-pyridylmethyl, sodium atom, potassium atom or 1/2 atom of calcium. ], the alkylene moiety is C. -C. Optionally substituted by alkyl or phenyl (CIl□) qOi+
(q means an integer from 3 to 18), or MOC
(0)R" [R34 means C, ~C4 alkyl, phenyl, or pyridyl.] -S pyrazolo (4,3-d:1
Pyrimidines are synthesized according to the reaction formula below. (
Hereinafter, blank) Sl+ (I[I) n■ (Ia) (Tb) [In the reaction formula, R1, 1172, and R3 represent the same meanings as in the explanations of general formulas (I a) and (I b) above; X and Y are chlorine, bromine, iodine, lower alkylsulfonyloxy,
It represents a leaving group such as benzenesulfonyloxy and benzenesulfonyloxy substituted with an alkyl group having 1 to 3 carbon atoms, chlorine, bromine, nitro, or an alkoxy group having 1 to 3 carbon atoms. ] Step 1 is an alkylation reaction of a mercapto group (or may be expressed as a 1,000-ion type), and is performed using water or methanol,
Sodium carbonate, in an alcoholic solvent such as ethanol, or a mixed solvent thereof, at room temperature or under heating.
This is carried out in the presence of a deoxidizing agent such as potassium carbonate or lithium carbonate. It can also be carried out in ammonia water at room temperature. Step 2 is a reaction between the compound (1) synthesized in Step 1 and various alkylating agents, such as various organic solvents such as benzene, toluene, xylene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, methanol, and ethanol. in solvent,
At room temperature or under heating, potassium carbonate, sodium carbonate,
This can be carried out in the presence of a deoxidizing agent such as lithium carbonate, tertiary amine, or pyridine. Also, chloroform. In a mixed solvent of water and an immiscible organic solvent such as methylene chloride, benzene, and toluene, a deoxidizing agent such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydroxide, and sodium hydroxide, and 18-crown-6. It can also be carried out in the presence of a phase transfer catalyst such as. The product obtained by the reaction operation in step 2 is usually obtained as a mixture of compounds 1a and Ib, and the production ratio changes by changing the reaction conditions. Compounds Ia and Ib thus obtained can each be obtained as a single substance usually by column chromatography using silica gel. The compounds of the present invention can suppress or reduce the amount of cholesterol in the blood as shown by the test results described below. Therefore, it is useful as an active ingredient in therapeutic agents for hyperlipidemia, hyperlipoproteinemia, and atherosclerosis. It also has the effect of strengthening the contractile force of myocardium, so it is useful as an active ingredient in cardiotonic drugs. The active ingredient can be formulated into various types depending on the route of administration. If the compound is the free acid, it can be administered in the form of a pharmaceutically acceptable salt (eg, sodium salt). The pharmaceutical composition according to the present invention may contain the compound of the present invention itself, an appropriate pharmacologically acceptable binder (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, cornstarch, etc.). , calcium phosphate, sorbitol, glycine, etc.),
It can be mixed with lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.) and disintegrants (potato starch, etc.) and taken in the form of powder, granules, tablets, or capsules, and is administered orally. This is desirable. However, it is of course not limited to this, and parenteral administration is also possible. For example, there is also the possibility of administration as a suppository using an oily base such as cocoa butter, polyethylene glycol, lanolin, or fatty acid triglyceride. The dosage when treating adults is -0,1 m per day
g~2.0g, preferably 1~180g, -day 1~
The drug is administered three times, but the dose may vary depending on age, body weight, symptoms, purpose of administration, etc. [Examples (test examples, toxicity test examples, formulation examples)] Below,
Examples of biological activity evaluation tests, synthesis examples, and formulation examples of the compounds of the present invention have been described. Note that the present invention is not limited to these. Test example I. The CMC suspension of the specimen was orally administered to ddY mice (5 mice in the − group), and the acute toxicity value of the specimen was determined by whether the specimen was alive or dead after 3 days. Compound numbers 1a-1, Ia-3, Ia-8, ra-12
゜The compounds of the present invention of I b-12 and I b-13 are 3
No deaths were observed at a dose of 0.00 μg/kg. Test example 2. Antihyperlipidemic effect Male ddY mice were fed a high-cholesterol diet supplemented with cholesterol and cholic acid for 7 days to achieve a hypercholesterolemic state. CMC suspension of drug was orally administered on the 6th and 7th day. - After an overnight fast, serum cholesterol was measured. ” Bezafibrate: 2- (4-(2
-((4-chlorohendiyl)amino]ethyl]-phenoxy]-2-methylpropanoic acid Test Example 2 Measurement of cardiac activity Male guinea pigs were sacrificed by exsanguination, the heart was removed, and a nutrient solution (NaCl 135. OmM, KCl 5.Om
M. MgCj! z 1. OmM, CaC1z 2. OmM
, Na1lCO:+15.0mM. The left atrium was immediately isolated in Glucose 5.5mM). The left atrium specimen was kept at 31°C and oxygenated (carbon dioxide 5χ
including. ) filled with an aerated nutrient solution (
A tension of 500 cm was applied to the electric stimulation device (Nihon Kohden 5
Rectangular wave electrical stimulation (voltage = 2 (V
) 1 width: 3 (msec), frequency: 1 (Hz)) and the generated tension is picked up by FD pickup (Nihon Kohden 611T)
, was recorded on a recorder (Nihon Kohden) via a strain pressure amplifier (Nihon Kohden AP-600G). After stabilizing the contractile force by replacing the nutrient solution several times, the left atrial specimen was replaced with a 1mM nutrient solution (NaCj213).
6. OmM, KCI 5. OmM, MgCfz 1
．． OmM. CaC1z 1. OmM, NaHCO315, OmM
, Glucose 5.5mM). After the contraction stabilized, 3 Xl0-5M of the test compound (prepared in talemophor solution) was applied and the contraction reaction was observed. The effect of the compound on myocardial contractile force was expressed as an enhancement rate (χ) from the contractile force before application, and cases where the increase rate was 40% or more were marked as (+). (Hereafter, margin) 9△CFs (enhancement factor) 4
0% or more is (+) Judgment Example 1 Ethyl 2-methyl-3-(1'-(3"-pyridyl)ethyloxy)-pyrazolo(4,3-d)pyrimidin-7-ylthioacetate-)(Ia- 1) and ethyl 2-methyl-1-(1'-(3'-pyridyl)
Ethyl)-3-oxo-pyrazolo[4゜3-d]pyrimidin-7-ylthioacetate (Ib-1) (Hereafter, blank space) Ethyl 3-hydroxy-2-methyl-pyrazolo(4,
3-d) Pyrimidin-7-ylthioacetate (II-
1) 1.34g was dissolved in molecular sieve dehydrated dimethylformamide 15. Furthermore, anhydrous potassium carbonate 1.
73 g and α-bromo-3-ethylpyridine hydrochloride 1.
34 g was added and stirred on an oil bath at 60°C for 2 hours. After confirming the completion of the reaction by thin layer chromatography, the solvent was distilled off under reduced pressure using a vacuum pump. The residue was extracted with chloroform, washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was completely distilled off and the resulting residue was subjected to silica gel chromatography. The first two fractions obtained using ethyl acetate/benzene as an eluent were dried under reduced pressure to obtain I a-1 as a light brown powder. Pure RA-1 recrystallized from hexane/acetone
I got it. Yield 1.12 g (60.1%), colorless powder. Melting point: io1-102°C. Exhibits bright blue fluorescence. PNMR (in CDCj23) δppm: 1.26 (
t, 3H, J=7Hz), 1.82 (d, 3H, J=
6.4Lz), 3.95 (s, 3H). 4.11 (s, 2H), 4.21 (q,
2H, J=7Hz), 6.77 ((1,I H,J
=6.4Hz), 7.1~8.8 (m, 4H
), 8.50 (s, LH) MS (m/e): 3
73 (M"), 268, 195, 1. Both the obtained fractions were further evaporated with chloroform/methanol as an eluent, and the obtained two fractions were dried under reduced pressure to obtain Ib-1 in the form of a light brown powder. Re-mixed from hexane/acetone Crystallized to obtain pure Ib-1. Yield: 0.16 g (8.6%), pale brown needle crystals. Melting point: 119.5-122°C with dark green fluorescence. PNMR (in CDCZ 2) δppnt :1.31
(t, 3H, J=711z), 1.49 (
d, 3H, J=6.9112), 3.40 (
s, 3H), 4.21 (s, 2H), 4.
24 (q, 2H, J=7tlz). 5.90 (q, IH, J=6.9Hz),
7.2-8.9 (m, 4H), 8.90 (s, LH
) MS (m/e): 373 (M'), 268, 195
, 1 Compound Ia shown in the table below was prepared by the same method as in Example 1.
-2-31 and Ib-2-31 were synthesized. In addition, in the table, Me means methyl, Et means ethyl, Pr means propyl, ph means phenyl, and i- means iso. (Hereinafter, blank spaces) Next, examples of formulations containing the compound of the present invention will be shown. Formulation Examples 1 to 4 are formulation examples of antihyperlipidemic agents, and Formulation Examples 5 to 9 are formulation examples of cardiotonic agents. Formulation example 1! Tablet ingredients (4,000 tablets) Composition Weight Compound 1a
-12500 (g) Potato starch 334 Carboxymethylcellulose 87.5 Polyvinyl alcohol 61 Magnesium stearate 17.5 Total
Amount 1. 000Measure the amount of the above ingredients,■
The mixture was placed in a mold mixer and mixed uniformly. This mixed powder was made into tablets by direct compression. -The weight per tablet was 250 . Formulation Example 2: Soft capsule ingredients (1,000 capsules) Composition Weight Compound I
a-12250 (g) Olive oil 250 total amount 500 The above ingredients were measured, mixed uniformly, filled into soft capsules of 500 square centimeters, and dried. Formulation example 3! Granule ingredients (1,000 packets) Composition Weight Compound 1a
-1210100 (silicic anhydride 80 crystalline cellulose 180 milk 1!
130 Magnesium stearate 10 Total amount 500 Measure the above ingredients, mix uniformly, make granules, - 50 per package
It was divided into packages so that the amount was 0. Formulation example 4: Suppository component (1,000 units) Composition Weight Compound Ia
-12200 (g) Cocoa butter 1.000 Total amount 1. 200 The above ingredients were measured, uniformly melted at 38°C, and poured into suppository molds that had been slightly cooled beforehand. The weight of each suppository was 1.2 g. Formulation Example 5 Tablet Compound 1b-121! Breasts 1! 20
g Starch 4 g Starch (for glue) 1 g Magnesium stearate 100 ■ Carboxymethyl 7 g Total amount of cellulose calcium 33.1 g
The above ingredients were mixed in a conventional manner to form sugar-coated tablets each containing 5 mg of the active ingredient. Formulation Example 6 Capsule Compound 1 b-121 g Lactose 20 g Microcrystalline cellulose Log The above ingredients were mixed in a conventional manner and then filled into gelatin capsules to form capsules containing 5 μm of active ingredient per capsule. Formulation Example 7 Soft capsule Compound I b-121g Total amount 36g After mixing the above ingredients, a soft capsule containing 5 ml of active ingredient per capsule was prepared by a conventional method. Formulation Example 8 Ointment Compound 1b-121.0g Olive oil 20g White petrolatum 79g Total amount
Mix 100g of the above ingredients in a conventional manner,
It was made into a 1% ointment. Formulation Example 9 Aerosol Suspension (A) Compound 1b-120, 25C%) Isopropyl myristate 0.10 Ethanol 26.40 (B) The above composition (A) was mixed, and the resulting mixture was prepared with pulp. The propellant (B) was heated at 20°C for about 2.
An aerosol suspension was press-injected through a pulp nozzle to a cage pressure of 46 to 2.81 .mu./C. [Effect] As mentioned above, the compound of the present invention exhibits antihyperlipidemic and cardiotonic effects and is useful as an active ingredient of pharmaceuticals.

Claims (1)

[Claims] (1) General formula ( I a) or ( I b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) ▲ Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (I b) [In the formula, R^1 is C_1 to C_4 alkyl, or C_
R^2 means C_1-C_2_0 alkyl, C_1-C_4
Alkenyl, phenyl core part is C_1-C_3 alkyl, C_1-C_3 alkoxy, fluorine atom, chlorine atom,
(CH_2)_mPhenyl (m is 0,
means an integer from 1 to 3. ) or ACO_2R^2
^1 [A may be substituted by C_1 to C_3 alkyl or phenyl (CH_2)_p (p is 1
means an integer from 15 to 15. ), and R^2^1 means a hydrogen atom or C_1 to C_4 alkyl. ]
R^3 means that the pyridine core moiety is C_1-C_4 alkyl,
C_1-C_3 alkoxy, fluorine atom, chlorine atom, bromine atom, trifluoromethyl or CO_2R^3^
1 (R^3^1 means C_1-C_4 alkyl), and the (CH_2)_n portion may be substituted with 1 to 2 C_1-C_3 alkyl (CH_2) __nPyridyl (n means an integer from 1 to 10), ▲Mathematical formulas, chemical formulas, tables, etc.▼ [D may be substituted with C_1 to C_3 (C
H_2) means _m. ], ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^3^2 is C_1 to C_4 alkyl, fluorine atom,
Means a chlorine atom or a bromine atom. ), ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ MCO_3R^3^3 [M may be substituted with C_1 to C_3 alkyl or phenyl (CH
_2) means _p, R^3^3 is a hydrogen atom, C_1~
C_4 alkyl, 1, 2 or 3-pyridylmethyl, sodium atom, potassium atom or 1/2 atom of calcium. ], the alkylene moiety may be substituted with C_1-C_3 alkyl or phenyl (CH_2)_qO
H (q means an integer from 3 to 18), or MOC(O)R^3^4 [R^3^4 is C_1
~C_4 means alkyl, phenyl, or pyridyl. ] means. ] A compound represented by.