JPS6140266A - Pyrazole derivative - Google Patents

Abstract

NEW MATERIAL:The pyrazole derivative of formula I (R<1> is H, alkyl, alkylcarboxylic acid residue, its ester, phenyl or benzyl; R<2> is carboxylic acid residue, its ester, carbamoyl, or alkyl; R<3> is alkyl or benzyl). EXAMPLE:Ethyl 5-[4-(4-chlorobenzyloxy)phenyl]pyrazole-3-carboxylate. USE:A drug having lipid-level lowering activity. It remarkably increases the HDL- cholesterol level, and has low toxicity. PREPARATION:The compound of formula I wherein R<2> is CO2C2H5, i.e. the compound of formula III can be prepared e.g. by alkylating or benzylating acetophenone in DMF in the presence of potassium carbonate, subjecting the reaction product to Claisen condensation with diethyl oxalate in the presence of an alkali, and heating and refluxing the resultant enolate sodium salt of formula IIin acetic acid in the presence of hydrazine.

Description

Detailed Description of the Invention The present invention is based on the general formula [wherein R+ is a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid group, a lower alkyl carboxylic acid ester group,
Phenyl group or benzyl group, R2 is carboxylic acid group,
a carboxylic acid ester group, a carbamoyl group with or without a substituent on N, or a lower alkyl group with or without a substituent; R3 is a straight-chain alkyl group;
or a benzyl group with or without a substituent at the 4-position of the benzene nucleus or the α-position of the benzyl group]
Regarding the pyrazole derivative CI) represented by

The pyrazole derivative of the present invention, represented by CI) above, is a novel compound that exhibits an excellent lipid-lowering effect, that is, an effect that significantly lowers serum lipids (triglycerides, total cholesterol, and phospholipids) in patients with hypertriglyceridemia. This compound is useful as a pharmaceutical because it significantly increases HDL-cholesterol and has low toxicity.

The flower compound ('f,) of this crystallization can be produced by various methods. For example, acetophenone is alkylated or benzylated in the presence of potassium carbonate in DMF,
Then, the enolate sodium salt represented by the general formula (R5 represents the same as above) obtained by Claisen condensation of diethyloxalic acid in the presence of alkali was treated with hydrazine hydrate, phenylhydrazine sulfate, or methylhydrazine in acetic acid. By heating under reflux for 6 hours, the general formula (,
III) [In the formula, R1 represents a hydrogen atom, a methyl group, or a phenyl group, and R5 represents a straight-chain alkyl group, or a benzyl group with or without a substituent at the 4-position of the benzene nucleus or the α-position of the benzyl group. ] to obtain a pyrazole derivative.

In the general formula [■], when R1 is a lower alkyl group, a lower alkylcarboxylic acid group, a lower alkylcarboxylic acid ester group, or a benzyl group, the corresponding halide and R1 in the general formula [■] are a urea atom. Compound, DM
It can be produced by alkylation or benzylation in F in the presence of potassium carbonate.

In the general formula [■], R2 is a carboxylic acid group, which is produced by reacting the corresponding ester synthesized above with sodium hydroxide in an aqueous lower alkanol solution at about 80°C.

In addition, in the case of a compound in which R2 is a carbamoyl group in general formula [I], the carboxylic acid obtained by the above production method is converted into an acid chloride, and then the compound is reacted with various amines in the presence of a Lewis base. be done.

Among the carboxylic acid esters in the general formula CI), those in which R2 is a carboxylic acid ester other than ethyl ester are produced by reacting the acid chloride obtained by the above production method with various alcohols in benzene.

Next, the present invention will be explained in detail by giving examples.

Example 1 Ethyl 5-L: 4-(4-chlorobenzyloxy)phenyl]pyrazole-6-carboxylate sodium 1-
Ethoxycarbonyl-6-(4-chlorobenzyloxy)
Phenyl-6-oxitubrovanate 2142 is dissolved in ethanol + 0 [am], and hydrazine hydrate is added dropwise under stirring at room temperature.

After completion of the dropwise addition, the mixture was heated under reflux for 1 hour while stirring. The reaction solution is concentrated to dryness under reduced pressure, chloroform and water are added to the resulting solid residue, and the organic layer is thoroughly washed with water. After drying the organic layer with Glauber's salt, it was concentrated to dryness under reduced pressure, and the resulting crude crystals were
When recrystallized from HF, the desired product 14y (yield: 70%) is obtained as white needle-like crystals having a melting point of +98-200°C.

ENGRJ/nuj0'am': '3270(
NH), +695 (c=o).

NMR (DMSO-R6) δ: hydrogen at position 4 of pyrazole ring.

7.13 (iHs singlet).

Ma8s m/e: 556 (M) - elemental analysis value (
C+9H+7CIN206) Theoretical value (%l):
c, 63.96; H, 4,80; IJ, 7.85 actual measurement value ((a): C, 64,13p H, 4,76; N
, 7.99゜Example 2 Ethyl 1-phenyl-5-C1-(4-chlorobenzyloxy)phenyl]pyrazole-6-carboxylate sodium 1-ethoxycarbonyl-6-(4-chlorobenzyloxy)phenyl-3 -Oxoprobane-)10
．． 7y was dissolved in a mixture of ethanol +00+++j' and concentrated hydrochloric acid 2-, and phenylhydrazine sulfate 6y was added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture was heated under reflux for 6 hours while stirring. The reaction solution is concentrated to dryness under reduced pressure, chloroform and water are added to the resulting solid residue, and the organic layer is thoroughly washed with water. After drying the organic layer with Glauber's salt, it was concentrated to dryness under reduced pressure.
The obtained crude crystals were placed in a chloroform-methanol mixed bath I.
Recrystallization with K gives the desired product 91y (75% yield) as white needles with a melting point of +42-141°C.

Engineering RyW Tomoe 01cm’: +710 (C!=O).

NMR (DMSO-C6)li: Hydrogen at the 4-position of the virazole ring.

716 (IH, singlet).

Mass m/e: 452 (M”).

Elemental analysis value (as 025H2I CIN2O3) Theoretical value (%): C, 69, Ro6:H, 4,87iN,
6.47 Actual value ((6): c, 69.02; H, 4
,59;N, 6.67゜Example 5-[:'4-(4-chlorobenzyloxy)phenyl]
Pyrazole-6-carboxylic acid Ethyl 5-(:,4-(chlorobenzyloxy)phenyl)pyrazole-local boxylate 10y synthesized according to Example 1 was dissolved in 50me of 4% sodium hydroxide-ethanol solution and stirred for 2 hours. Heating to reflux.Cold welding,
The reaction solution was made acidic with acetic acid and concentrated to dryness under reduced pressure. When the obtained crude crystals are recrystallized with a mixed solvent of DMF=-water, the melting point is 2.
Object 8.52 (white plate-like crystals exhibiting a temperature of 265°C)
Yield: 89%).

nujol -1.

Engineering Rνmax Cm, 3+80 (NH), +
610 (c=o).

NMR (DMSO-C6) δ: hydrogen at the 4-position of the virazole ring.

6.82 (I HXsinglet).

Hass m/e: 329 (M+).

Elemental analysis value (as C17H15CIN205) Theoretical value ((6): C) 62. +0;H,5,99;N%
8.52 real value (@: C,, 6189; H, 4, 13
iN, 886° Example 4 5-(4-(4-chlorobenzyloxy)phenyl]pyrazole-6-carpamide 5-111:1-(4-chlorobenzyloxy)phenyl]pyrazole-6-carvone synthesized according to Example B Acid 33y to benzene I 5ome, DMF + 0rn
15.62 of thionyl chloride was added dropwise while stirring at room temperature. After completion of the dropwise addition, the mixture was heated and stirred at 80°C for 4 hours. After cold welding, the reaction solution was concentrated to dryness under reduced pressure to obtain 5-C4-(4-chlorobenzyloxy)phenyl]pyrazole-6-carpoyl chloride as a pale yellow oil (2e,6y (yield: 82%) )obtain. Next, 5-C
4-C4-chlorobenzyloxy)phenyl]pyrazole-6-carpoyl chloride 279y is dissolved in dichloroethane 200me. After adding 162 y of triethylamine while stirring at room temperature, ammonia gas was blown in for 1 hour. After blowing, the reaction solution was concentrated to dryness under reduced pressure, and the resulting crude crystals were re-crystallized from DMF to give a melting point of 289°C (de
The desired product 75y (yield 29%) is obtained as white plate-like crystals exhibiting comp, ).

IRv product':, Tip 010m': 3280 (NH)
, 1610 (c=o).

NMR (DMSO-d6) δ: hydrogen at position 4 of pyrazole ring.

7.08 (IH,s inlet).

1Vlass m/e: 327 (M) - Elemental analysis value (as C17H14CIN303) Theoretical value (%)
: c, 62.29; H, 4, 3+; N, +2
．． 82 Actual value (%): 0M6211; H, 4,26+
Ni2.61゜Example 5 Cyclohexyl 5-C4-(4-chlorobenzyloxy)
Phenyl]pyrazole-5-carboxylate When synthesized as an intermediate according to Example 4, -[4-(4-
5 g of 10 lobenzyloxy) phenyl] virazole-local boil chloride is suspended in 100 yne of benzene, and 46 y of cyclohexanol is added dropwise while stirring at room temperature.

After completion of the dropwise addition, the mixture was heated under reflux for 1 hour while stirring. After cooling, the reaction solution was concentrated to dryness under reduced pressure, and the resulting crude crystals were recrystallized from methanol to obtain the desired product 28y (yield: 48%) in the form of white plate-like crystals with a melting point of 215-217°C.

Engineering R, nuJO1+.

max Crrl, 3215 (NH), +66
5 (c=o).

NMR (DMS 0-C6) δ: Hydrogen at the 4-position of the virazole ring.

7.12 (1HXsinglet).

Mass m/e: 409 (M).

Elemental analysis value (as C25H22CIN2 paste) theoretical value (
%): c, 67.40; H, 5,37; N
, 6.84 Actual value (%): C, 67, +2; H, 5
, 39iN, 6.72° Example 6 Ethyl 1-benzyl-5-C4-(4-chlorobenzyloxy)phenyl]virazole-6-carboxylate 5-[4,(4-chlorobenzyloxy) synthesized according to Example B ) phenyl]pyrazole-3-carboxylic acid 10y
300ml of DMF! and add 58y of potassium carbonate while stirring at room temperature. While heating and stirring at 40°C, benzyl bromide 6ii7 is added dropwise.

After the dropwise addition is completed, the reaction solution is heated and stirred for 5 hours. Cold welding, the reaction solution was concentrated to dryness under reduced pressure, and the resulting crude crystals were reconsolidated with a mixed solvent of chloroform-methanol to give a melting point of 126-12.
Target product 552 (yield 44%) as white plate crystals showing 7°C
get.

IRvnuJolam': +700 (C=0)
-NMR (DMSO-d6) δ: hydrogen at the 4-position of the pyrazole ring.

7ro I (I HXsing), etc.

Mass m/e: 446 (M).

Elemental analysis value (as C26H2sC1, N2O3) Theoretical value (%): C, 69,87; H, 519; N,
627 actual measurement value (@: c, 70.16; H, 5
28; N, 6.03° Examples 7 to 0 The pyrazole derivatives listed in Table 1 are obtained by performing the reaction and post-treatment according to Examples 1 to 6 above.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. R^2 is a carboxylic acid group, a carboxylic acid ester group, a carbamoyl group with or without a substituent on N, or a lower alkyl group with or without a substituent, R^3 is a linear alkyl group, or benzene α of the 4-position of the nucleus or the benzyl group
A pyrazole derivative represented by a benzyl group with or without a substituent at that position.