GB1567448A - Pyrazole derivatives - Google Patents
Pyrazole derivatives Download PDFInfo
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- GB1567448A GB1567448A GB9180/78A GB918078A GB1567448A GB 1567448 A GB1567448 A GB 1567448A GB 9180/78 A GB9180/78 A GB 9180/78A GB 918078 A GB918078 A GB 918078A GB 1567448 A GB1567448 A GB 1567448A
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- pyrazole
- methylethoxy
- carboxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
Abstract
The novel 3-(1-carboxyalkoxy)pyrazole derivatives of the general formula I, their salts with inorganic or organic bases and their esters and amides, strongly lower the content of cholesterol, beta -lipoprotein and triglyceride in blood serum and may therefore be used for treating hyperlipaemias. They are obtained by reacting tautomeric mixtures of 3-hydroxypyrazole derivatives and DELTA <4>-pyrazolinone-(3) derivatives with carbonyl compounds and trihalomethane or the alcohols which are formed from them. <IMAGE>
Description
(54) PYRAZOLE DERIVATIVES
(71) We, AKADEMIE DER WISSEN
SCHAFTEN DER DDR, of 5, Rudower
Chaussee, 1199 Berlin, German Democratic
Republic, a Corporation organised under the laws of the German Democratic
Republic, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention is concerned with new 3-(l-carboxyalkoxy)-pyrazole derivatives and with the preparation thereof.
The 3-(1-carboxyalkoxy)-pyrazole derivatives according to the present invention are compounds of the general formula:
in which R' is a phenyl radical, and optionally substituted benzyl radical or an optionally substituted, straight-chained or branched alkyl radical containing up to 4 carbon atoms, whereby the substituents can be 1 or 2 chlorine atoms, 1 or 2 methoxy radicals, I chlorine atom and 1 methoxy radical, I or 2 straight-chained or branched alkyl radicals containing up to 4 carbon atoms or I methylenedioxy radical; R2 is a halogen atom or a straight-chained or branched alkyl radical containing up to 4 carbon atoms; R3 and R4, which can be the same or different, are straight-chained or branched alkyl radicals containing up to 4 carbon atoms and R5 is a hydroxyl group and, when R5 is a hydroxyl group, the free carboxylic acids can also be in the form of their salts with physiologically acceptable inorganic and organic bases or can also be in the form of esters or amides.
The compounds of general formula (I) according to the present invention bring about a marked decrease of the cholesterol, p-lipoproteid and triglyceride content of the blood serum and can, therefore, be used for the treatment of hyperlipidaemias. Since an increased lipid content in the blood serum is an important risk factor for the occurrence of coronary heart diseases and, in general, for arterioscleroses, the new compounds of general formula (I) are of especial interest as heart-circulatory pharmaceuticals for the therapy of atheroscleroses and for the prophylaxis of cardiac infarcts. In contradistinction to the previously known and clinical employed hypolipaemic compounds, the 3-(l-carboxyalkoxy)pyrazole derivatives according to the present invention have the following advantages:
They do not cause liver damage and do not have an adverse influence on important enzymes, such as the transaminases and creatinine phosphokinase. They can be administered in significantly lower dosages and maintain their effectiveness even after having been used for a comparatively long time. They prolong the bleeding time, which advantageously extends their spectrum of activity for the use thereof as pharmaceuticals for the prophylaxis of atherosclerosis and infarcts. Furthermore, the new compounds according to the present invention display a very good antiphlogistic action.
Especially good pharmacological results and a very good compatibility are displayed by compounds of general formula (I) in which the substituents R' and R2 have the following meanings:
R' is a benzyl and R2 is chlorine;
R' is 4-chlorobenzyl and R2 is methyl;
R' is 4-chlorobenzyl and R2 is chlorine;
R' is benzyl and R2 is methyl; Rl is 3-chloro-4-methoxybenzyl and R2 is
methyl.
The present invention also provides a process for the preparation of the compounds of general formula (I), wherein a tautomeric mixture of a 3hydroxypyrazole derivative of the general formula:
in which R1 and R2 have the same meanings as above, and of a å4-pyrazolin-3-one derivative of the general formula:
in which R1 and R2 have the same meanings as above, is reacted with an alcohol of the general formula:
in which R3 and R4 have the same meanings as above and Z is a chlorine, bromine or iodine atom; or with at least 1 mole of a carbonyl compound of the general formula:
R3-CO-R4 (V) in which R3 and R4 have the same meanings as above, per mole of tautomeric mixture (II+III), as well as with at least 1 mole of a trihalomethane of the general formula
Z3CH, in which Z has the same meaning as above, per mole of tautomeric mixture (II+III), the reaction being carried out, in each case, with the addition of 4 to 6 moles of an alkali metal hydroxide, alcoholate, hydride or amide and in a polaraprotic solvent and in each case optimally with the addition of an alkali metal iodide.
More particularly, the process according to the present invention can be carried out as follows: a mixture of 1 mole of the tautomeric mixture (II+III) and 0.4 to 3.2 litres of a polar-aprotic solvent, for example, acetone, methyl ethyl ketone, a cyclic ketone containing 5 to 7 carbon atoms, acetonitrile, dioxan or tetrahydrofuran, and preferably 0.6 to 1.3 litres of acetone or dioxan, are admixed with 4 to 6 mole of an alkali metal hydroxide, alcoholate, hydride or amide, preferably with 4.0 to 4.2 mole of sodium hydroxide or potassium hydroxide, while stirring mechanically at a temperature of from 5 to 45"C. and preferably of from 15 to 25"C. To this mixture is added, with stirring an optionally with simultaneous cooling with water, a solution of 1.0 to 1.3 mole and preferably of 1.0 to 1.05 mole of an alcohol of general formula (IV) in 50 to 500 ml. and preferably 80 to 160 ml. of the solvent used for the above-mentioned mixture and the temperature of the slightly exothermal reaction is thereby maintained at 16 to 70"C. and preferably at 15 to 350C.
Subsequently, the reaction mixture is heated, with mechanical stirring and under reflux, at a temperature of 60 to 150"C and preferably of 70 to 110"C. until, in a thin layer chromatogram (silica gel G: elution agent ethanol and n or isopropanol; iodine development), no more of the tautomeric mixture can be detected. The period of the reaction is from 2 to 60 hours. Subsequently, the solvent is distilled off, optionally under reduced pressure. The salt which remains behind is dissolved in water and, by the addition of an acid, the pH is adjusted to 4.0 to 6.5, the 3-(1-carboxyalkoxy)-pyrazole derivative of general formula (I)(R5=OH) thereby crystallising out or precipitating out in amorphous form. The product thus obtained is treated with an aqueous solution of 1.0 to 3.0 mole and preferably of 1.2 to 2.0 mole of an alkali metal bicarbonate, the carboxylic acid of general formula (I)(R5=OH) thereby dissolving as an alkali metal salt.
It is also possible to proceed in such a manner that the precipitated product is taken up in a water-immiscible solvent, preferably in methylene chloride, chloroform, trichloroethylene or ethyl acetate, and the solution obtained shaken out with the above-mentioned aqueous alkali metal bicarbonate solution. Upon acidification of the aqueous bicarbonate solution to a pH of 2.5 to 6.0, the O-selective carboxylic acid of general formula (I) precipitates out in a yield of 65 to 100 ' of theory, referred to the amount of tautomeric mixture used. It can be recrystallised with a loss of 4 to 10%, preferably from benzene, toluene, xylene, a lower alcohol, a mixture of an alcohol with water or from water,
A further embodimental form of the
O-selective substitution of the tautomeric mixtures (II+III) consists in that 1 mole of the tautomeric mixture is stirred in one of the above-mentioned solvents with 4 to 6 mole of an alkali metal hydroxide, alcoholate, hydride or amide, preferably with 4.0 to 4.2 mole of sodium hydroxide or potassium hydroxide, ketonic solvents of general formula (V), for example, acetone, methyl ethyl ketone, cyclopentanone or cyclohexanone, thereby simultaneously serving as a reaction component and whereby at least 1 mole of (V) must be present per mole of the tautomeric mixture (II+III). In the case of the use of nonketonic solvents, for example, dioxan or tetrahydrofuran, to the reaction mixture is added 1.0 to 1.5 mole and preferably 1.0 to 1.1 mole of a ketone of general formula (V).
Subsequently, 1.0 to 2.5 mole and preferably 1.2 to 1.4 mole of a trihalomethane, preferably chloroform, is allowed to run into the above-described reaction mixture and the reaction mixture thereafter heated under reflux, with mechanical stirring, for about 0.5 to 15 hours at a temperature of from 20 to 1500C. and preferably of 20 to 80"C. until starting material can no longer be detected in a thin layer chromatogram.
The reaction mixture is then worked up in the manner described above.
The compounds of general formula (I) in which R2 is a halogen atom can also be prepared, according to the present invention, by reacting a carboxyalkoxy)-pyrazole derivative of general formula (I), in which R2 is a hydrogen atom, in an inert solvent, for example a chlorinated hydrocarbon, a dialkyl ether, tetrahydrofuran, dioxan, acetic acid or water, with a halogenation agent, for example, chlorine, sulphuryl chloride, tert.-butyl hypochlorite, bromine,
N-chloramide or N-bromamide, optionally with the addition of a hydrohalic acid acceptor, for example an alkali metal carbonate, an alkaline earth metal carbonate or an alkali metal bicarbonate, with the addition of a catalytic amount of a radical former and preferably of a,a'- azoisobutyric acid dinitrile or dimethyl ester.
More particularly, it is possible to proceed in the following manner: to a mixture of 1 mole of a 3-( I-carboxyalkoxy)- pyrazole derivative of general formula (I) (R2=H) and of an inert solvent, for example a chlorinated hydrocarbon, a dialkyl ether, tetrahydrofuran, dioxan, acetic acid or water, preferably carbon tetrachloride or methylene chloride, optionally with the addition of 0.5 to 0.8 mole of anhydrous calcium, potassium or sodium carbonate or of 0.95 to 1.5 mole of potassium or sodium bicarbonate, there is added the radical
former, preferably 0.02 to 0.0001 mole of a,a'-azoisobutyric acid dinitrile or dimethyl ester, and then the halogenation agent, preferably in an amount of from 0.95 to 1.15 mole, is added as such or dissolved in an inert solvent, with mechanical stirring at a temperature of from -5 to 800 C. and preferably of from 0 to 350C. The reaction time is from 10 to 180 minutes, the course of the reaction being monitored with the help of thin layer chromatography, preferably by means of very small plates of microsope slide size (silica gel G: elution agent ethanol/carbon tetrachloride=3:2 v/v: iodine development). Subsequently, the solvent is distilled off. The residue remaining behind consists, possibly besides the corresponding alkali metal or alkaline earth metal halides, of up to 80 to 100% of a 4-halogen-substituted 3-( 1 -carboxyalkoxy)- pyrazole derivative of general formula (I).
When, in general formula (I), R5 is a hydroxyl group, then, according to the present invention, the product can be purified by dissolving it in an aqueous solution of an alkali metal hydroxide or carbonate.
This solution is treated with an appropriate water-immiscible solvent, for example ethyl acetate, by shaking out and/or treated with active charcoal and thereafter the compound of general formula (I)(R5=OH) precipitated out by acidification. According to the present invention, the purification of the compounds of general formula (I) can also take place by dissolving the crude compound of general formula (I) in an organic solvent and preferably in a halogenated hydrocarbon, whereafter this solution is passed through a colum of preferably silica gel.
This process according to the present invention gives the 4-halogen-substituted compounds of general formula (I) in a yield of from 80 to 96 Mn of theory.
The resultant O-selective carboxylic acids of general formula (I)(R5=OH) can be converted into their salts with physiologically acceptable inorganic or organic bases or can be converted in known manner into esters or amides.
The esterification can be carried out according to the conventional known processes directly with the corresponding alcohols or by reaction of the carboxylic acid chlorides of general formula (I)(R5=CI), which can be prepared in the usual manner, for example, by reaction with thionyl chloride with the addition of an inert solvent.
Amides of the carboxylic acids of general formula (I) can be obtained in conventional and known manner by reaction of the above-mentioned carboxylic acid esters or carboxylic acid chlorides with appropriate amines, optionally in the presence of a hydrogen chloride acceptor, for example of an alkali metal carbonate or of a tertiary amine. Preferred salts of the carboxylic acids of the general formula (I) include the sodium, potassium magnesium and ammonium salts.
The new compounds of general formula (I) and the salts, esters and amides thereof can be used as such or in admixture with solid, liquid or semi-liquid pharmaceutical diluents or carriers. The diluents or carriers can be, for example, inert organic and/or inorganic materials, for example, water, isotonic aqueous solutions, polyethylene glycols, gelatine, lactose, cellulose or starch or derivatives thereof, talc, magnesium stearate. To the pharmaceutical compositions can be added adjuvants, for
example, preserving, stabilising and wetting
agents, flavouring agents and/or aroma
materials. They can also contain one or more known active materials, for example, -adrenolytic compounds or derivatives of nicotinic acid. For enteral administration, there can be used, for
example, tablets, capsules, syrups or dragees, whereby the latter can also be produced in the form of multi-layer dragees.
The daily dosage of the new compounds according to the present invention can be from 10 to 1 mg./kg. of body weight.
The following Examples are given for the purpose of illustrating the present invention: Example 1
With vigorous stirring and cooling, to a mixture of 9.2 g. (44 mMol) l-benzyl-4- chloro-3-hydroxypyrazole, 100 ml. acetone and 7.05 g. sodium hydroxide, there is added a solution of 8.22 g. (44 mMol) 1,1,1- trichloro-tert.-butanol hemihydrate in 50 ml.
acetone. After stirring for about 40 hours, the solvent is distilled off. The residue is dissolved in water, the aqueous solution is shaken out two or three times with 8 ml.
amounts of ethyl acetate and the aqueous phase then adjusted to a pH of 4 to 5 with a mineral acid. The precipitated crude 1benzyl-3-( 1 -carboxy- 1 -methylethoxy) - 4 - chloropyrazole is filtered off and recrystallised from toluene. The yield is 7.7 g. (59 /n of theory): after recrystallisation from toluene, the product melts at 125.5 to 126"C.
Example 2
Analogously to Example 1, from 4-chloro I - (4 - isopropylbenzyl) - 3 - hydroxy- pyrazole there is prepared, in a yield of 57% of theory, 3 - (1 - carboxy - 1 methylethoxy) - 4 - chloro - I - (4 - isopropylbenzyl - pyrazole which, after recrystallisation from cyclohexane, melts at
102 to 103"C.
Example 3
Analogously to Example I, from l-benzyl4-bromo-3-hydroxypyrazole, there is prepared, in a yield of 58% of theory, 1benzyl - 4 - bromo - 3 - (1 - carboxy - 1 - methylethoxy) - pyrazole which, after recrystallisation from xylene, melts at 1320C.
Example 4
Analogously to Example 1, from 1 - (4 chlorobenzyl) - 4 - chloro - 3 - hydroxypyrazole, there is prepared, in a yield of 57% of theory, 3 - (1 - carboxy - 1 - methylethoxy) - 4 - chloro - 1 - (4 - chlorobenzyl) pyrazole which, after recrystallisation from xylene, melts at 1390C.
Example 5
Analogously to Example 1, from 4-chloro
I-isopropyl-3-hydroxypyrazole. there is prepared, in a yield of 58% of theory, 3 - ( I carboxy - 1 - methylethoxy) - 4 - chloro - 1 - isopropylpyrazole which, after recrystallisation from cyclohexane, melts at 81 to 820C.
Example 6
Analogously to Example 1, from 4bromo - 3 - hydroxy - 1 - (4 - isopropylbenzyl) - pyrazole, there is prepared, in a yield of 58 z of theory, 4 - bromo - 3 - (1
carboxy - 1 - methyl - ethoxy) - 1 - (4 - isopropylbenzyl)pyrazole which, after recrystallisation from toluene, melts at 97 to 98"C.
Example 7
Analogously to Example I, from 4bromo-3-hydroxy-l-phenylpyrazole, there is prepared, in a yield of 56 /n of theory, 4 bromo - 3 - (1 - carboxy - 1 - methylethoxy) -
1 - phenylpyrazole which, after recrystallisa- tion from toluene, melts at 166 to 1670C
Example 8
Analogously to Example 1, from 4
chloro - 3 - hydroxy - 1 - phenylpyrazole,
there is prepared, in a yield of 59% of
theory, 3 - (1 - carboxy - 1 - methylethoxy)
4 - chloro - 1 - phenylpyrazole which, after
recrystallisation from toluene, melts at 152
to 1530C.
Example 9
18.8 g. (0.1 Mol) l-Benzyl-4-methyl-3
hydroxy-pyrazole, 16.0 g. (0.4 Mol) sodium hydroxide and 130 ml. acetone are mixed,
with vigorous stirring. Then, with cooling, a
solution of 19.55 g. (0.1 Mol) I,l,l-trichloro- tert.-butanol monohydrate in 45 ml. acetone is added dropwise thereto and the reaction mixture heated under reflux, with stirring, for about 60 hours The solvent is distilled
off, the residue is dissolved in water and
acidified with a mineral acid to a pH of 4 to
5, crude 1 - benzyl - 3 - (1 - carboxy - 1
methylethoxy) - 4 - methylpyrazole thereby precipitating out. It is filtered off, washed with water, when treated with 210 ml. of a 0.5 N aqueous solution of potassium or sodium bicarbonate and the solution clarified with active charcoal and filtered, whereafter it is acidified with a mineral acid.
In this way, there are obtained 26 g. of pure product (95 /n of theory) which, after recrystallisation from toluene, melts at 1 15 C.
Example 10
With methanical stirring, a mixture of 25.3 g. (100 mMol) 1 - (3-chloro-4methoxybenzyl) - 4-methyl-3hydroxypyrazole, 16.0 g. (400 mMol) sodium hydroxide and 100 ml. acetone is heated to 53 to 58"C. Then, while stirring, there is added dropwise, within the course of 10 minutes, 23.9 g. (200 mMol) chloroform and the reaction temperature kept to this value by gentle cooling. 4.0 g.
sodium hydroxide are then added thereto and the reaction allowed to continue until I - (3-chloro-4-methoxybenzyl) - 4-methyl- 3-hydroxypyrazole can no longer be detected, this taking about 1 to 3 hours.
After distilling off the solvent, the residue is dissolved in water, filtered and the aquedus solution adjusted to pH 5.0 by the addition of an acid. The precipitated crude product is washed with water and then treated with 100 ml. of an aqueous solution of sodium or potassium bicarbonate. The solution, after filtration and clarification with active charcoal, is acidified with a mineral acid to a pH of 5, 3 - (I - carboxy - 1 - methylethoxy) - t - (3 - chloro - 4 - methoxybenzyl) - 4 - methylpyrazole thereby precipitating out. The yield is 27 to 31 g. (80 to 92 /" of theory) and the product, after recrystallisation from toluene, melts at 123 to 124 C.
Example 11
While stirring, to a solution of 8.92 g.
(29.5 mMol) 3 - (1 - carboxy - 1 - methylethoxy) - 1 - (4 - isopropylbenzyl) pyrazole in 70 ml. methylene chloride there
Is added dropwise at 5 to 80 C., within the course of 15 minutes, a solution of 4.22 g.
(30 mMol) sulphuryl chloride in 15 ml.
methylene chloride. Before commencement of the dropwise addition, 9.8 mg. (0.06 mol) a,a'-azoisobutyric acid dinitrile is added to the solution. The reaction mixture is further stirred for 25 minutes at 50C. and then the solvent is distilled off under reduced pressure. The residue is dissolved in methylene chloride or in chloroform and the solution passed through a column of silica gel (0.02 to 0.6 mm.). After evaporation of the eluate, there are obtained 9.47 g. 3 - (1 - carboxy - 1 methylethoxy) - 4 - chloro - 1 - (4 - isopropylbenzyl) - pyrazole, the yield being 95.3% of theory. After recrystallisation from cyclohexane, the product melts at 102 to 103"C.
Example 12
A solution of 6.55 g. (25.1 mMol) 1 benzyl - 3 - (I - carboxy - 1 - methylethoxy) - pyrazole in 75 ml. methylene chloride is admixed with 4.1 g. (0.0025 mMol) a,a'-azo- isobutyric acid dinitrile and cooled to 0 to -3"C. While stirring, there is added dropwise at 0 to 4"C., within the course of 30 minutes, a solution of 3.38 g. (25.1 mMol) sulphuryl chloride in 14 ml. methylene chloride, whereafter stirring is continued for
15 minutes. The residue obtained after distilling off the solvent is recrystallised from toluene, with the addition of a little active charcoal, to give 6.78 g. 1 - benzyl 3 - (I - carboxy - 1 - methylethoxy) - 4 chloropyrazole, the yield being 92% of theory. The compound melts at 125.5 to 126"C.
Example 13
Analogously to Examples 11 and 12, from 3 - (l-carboxy-l-methylethoxy) - I - (4- chlorobenzyl) - pyrazole, there is prepared, in a yield of 93% of theory, 3 - (1 - carboxy - - methylethoxy) - 4 - chloro - 1 - (4 - chlorobenzyl) - pyrazole. After recrystallisation from xylene, the product melts at 139"C.
Example 14
Analogously to Examples 11 and 12, from
3 - (l-carboxy-l-methylethoxy) - 1- phenylpyrazole, there is prepared, in a yield
of 90.7% of theory, 3 - (I-carboxy-lmethylethoxy) - 4 - chloro - 1 - phenylpyrazole which, after recrystallisation from toluene, melts at 152 to 1530C.
Example 15
To a solution of 4.66 g. (17.7 mMol) 1 benzyl - 3 - (1 - carboxy - 1 - methylethoxy) - pyrazole in o 45 ml. methylene chloride there are added 2.9 mg. (0.017 mMol) a,a'-azo-isobutyric acid dinitrile and then, while stirring at 4"C., a solution of 2.87 g. (18 mMol) bromine in 20 ml.
methylene chloride added dropwise thereto within the course of 65 minutes. Stirring is continued for 20 minutes, without cooling and then the solvent is distilled off. The residue is treated with 15 ml. 0.4N aqueous potassium bicarbonate solution, the undissolved product is filtered off with suction and washed with water. After drying, there are obtained 5.88 g. I-benzyl- 4-bromo-3 - ( I -carboxy- I pyrazole (98% of theory). For the purpose of high purification, the crude product is dissolved in 36 ml. 0.5N aqueous sodium carbonate solution, with gentle warming and then precipitated out again with the equivalent amount of a mineral acid. After recrystallisation from toluene, the product melts at 1320C.
Example 16
Analogously to Example 15, 3 - (1carboxy - 1 - methyl - ethoxy) 1 phenylpyrazole is brominated. A further purification variation consists in dissolving the product remaining after distilling off the methylene chloride in chloroform and then passing it through a column of silica gel (0.02 to 0.6 mm.). There is obtained, in a yield of 879 of theory, 4-bromo-3 - (1carboxy - 1 - methylethoxy) - 1 - phenyl- pyrazole which, after iicrystallisation from toluene, melts at 166 to 167"C.
Example 17
Analogously to Example 15, 3 - (1carboxy - 1 - methylethoxy) - 1 - (4 isopropylbenzyl)- pyrazole is brominated to give, in a yield of 86% of theory, 4-bromo3 - (l-carboxy-l-methylethoxy) - I - (4- isopropylbenzyl)- pyrazole which, after recrystallisation from toluene, melts at 97 to 98"C.
WHAT WE CLAIM IS:
1. 3 - (1 - Carboxyalkoxy) - pyrazole derivatives of the general formula:
wherein R' is a phenyl radical, an optionally substituted benzyl radical or an optionally substituted, straight-chained or branched alkyl radical containing up to 4 carbon atoms, the substituents being 1 or 2 chlorine atoms, 1 or 2 methoxy radicals, 1 chlorine atom and 1 methoxy radical, 1 or 2 straightchained or branched alkyl radicals containing up to 4 carbon atoms or 1 methylenedioxy radical, R2 is a halogen atom or a straight-chained or branched alkyl radical containing up to 4 carbon atoms, R3 and R4, which can be the same or different, are straight-chained or branched alkyl radicals containing up to 4 carbon atoms and R5 is a hydroxyl group, whereby, when R5 is a hydroxyl group, the free carboxylic acids can also be present in the form of their salts with physiologically acceptable inorganic or organic bases or can be in the form of esters or amides.
2. 1 - Benzyl - 3 - (1 - carboxy - 1 - methylethoxy) - 4 - chloro - pyrazole.
3. 3 - (1 - Carboxy - 1 - methylethoxy) 4 - chloro - 1 - (4 - isopropylbenzyl) pyrazole.
4. 1 - Benzyl - 4 - bromo - 3 - (I carboxy - 1 - methyl - ethoxy) - pyrazole.
5. 3 - (I - Carboxy - 1 - methylethoxy) 4- chloro - I - (4 - chlorobenzyl)pyrazole.
6. 3 - (I - Carboxy - 1 - methylethoxy) - 4 - chloro - 1 - isopropylpyrazole.
7. 4 - Bromo 3 - (1 - carboxy - 1 methylethoxy) - 1 - (4 - isopropylbenzyl) pyrazole.
8. 4 - Bromo - 3 - (1 - carboxy - 1 methylethoxy) - 1 - phenyl - pyrazole.
9. 3 - (1 - Carboxy - 1 - methylethoxy) - 4 - chloro - 1 - phenyl - pyrazole.
10. 1 - Benzyl - 3 - (I - carboxy - 1 methylethoxy) - 4 - methyl - pyrazole.
11. 3 - (1 - Carboxy - 1 - methylethoxy)- - 1 - (3 - chloro - 4 -.
methoxybenzyl) - 4 - methylpyrazole.
12. Process for the preparation of compounds according to claim 1, wherein a tautomeric mixture of a 3-hydroxypyrazole derivative of the general formula:
and a A4-pyrazolin-3-one derivative of the general formula:
in which R1 and R2 have the same meanings as in claim 1, is reacted with an alcohol of the general formula:
in which R3 and R4 have the same meanings as in claim 1 and Z is a chlorine, bromine or iodine atom; or with at least 1 mole of a carbonyl compound of the general formula: R3-CO-R4 in which R3 and R4 have the same meanings as in claim 1, per mole of the tautomeric mixture, as well as with at least one mole of a trihalomethane of the general formula
Z3CH, in which Z has the same meaning as above, per mole of the said tautomeric mixture, tne reaction being carried out, in each case, with the addition of 4 to 6 moles of an alkali metal hydroxide, alcoholate, hydride or amide and in a polar-aprotic solvent and in each case optionally with the addition of a catalytic amount of an alkali metal iodide.
13. Process according to claim 12, wherein the resultant O-selective carboxylic acid in which R5 is a hydroxyl group, is converted into a salt by reaction with a physiologically acceptable inorganic or organic base or is converted in known manner into an ester or amide.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (21)
1. 3 - (1 - Carboxyalkoxy) - pyrazole derivatives of the general formula:
wherein R' is a phenyl radical, an optionally substituted benzyl radical or an optionally substituted, straight-chained or branched alkyl radical containing up to 4 carbon atoms, the substituents being 1 or 2 chlorine atoms, 1 or 2 methoxy radicals, 1 chlorine atom and 1 methoxy radical, 1 or 2 straightchained or branched alkyl radicals containing up to 4 carbon atoms or 1 methylenedioxy radical, R2 is a halogen atom or a straight-chained or branched alkyl radical containing up to 4 carbon atoms, R3 and R4, which can be the same or different, are straight-chained or branched alkyl radicals containing up to 4 carbon atoms and R5 is a hydroxyl group, whereby, when R5 is a hydroxyl group, the free carboxylic acids can also be present in the form of their salts with physiologically acceptable inorganic or organic bases or can be in the form of esters or amides.
2. 1 - Benzyl - 3 - (1 - carboxy - 1 - methylethoxy) - 4 - chloro - pyrazole.
3. 3 - (1 - Carboxy - 1 - methylethoxy) 4 - chloro - 1 - (4 - isopropylbenzyl) pyrazole.
4. 1 - Benzyl - 4 - bromo - 3 - (I carboxy - 1 - methyl - ethoxy) - pyrazole.
5. 3 - (I - Carboxy - 1 - methylethoxy) 4- chloro - I - (4 - chlorobenzyl)pyrazole.
6. 3 - (I - Carboxy - 1 - methylethoxy) - 4 - chloro - 1 - isopropylpyrazole.
7. 4 - Bromo 3 - (1 - carboxy - 1 methylethoxy) - 1 - (4 - isopropylbenzyl) pyrazole.
8. 4 - Bromo - 3 - (1 - carboxy - 1 methylethoxy) - 1 - phenyl - pyrazole.
9. 3 - (1 - Carboxy - 1 - methylethoxy) - 4 - chloro - 1 - phenyl - pyrazole.
10. 1 - Benzyl - 3 - (I - carboxy - 1 methylethoxy) - 4 - methyl - pyrazole.
11. 3 - (1 - Carboxy - 1 - methylethoxy)- - 1 - (3 - chloro - 4 -.
methoxybenzyl) - 4 - methylpyrazole.
12. Process for the preparation of compounds according to claim 1, wherein a tautomeric mixture of a 3-hydroxypyrazole derivative of the general formula:
and a A4-pyrazolin-3-one derivative of the general formula:
in which R1 and R2 have the same meanings as in claim 1, is reacted with an alcohol of the general formula:
in which R3 and R4 have the same meanings as in claim 1 and Z is a chlorine, bromine or iodine atom; or with at least 1 mole of a carbonyl compound of the general formula: R3-CO-R4 in which R3 and R4 have the same meanings as in claim 1, per mole of the tautomeric mixture, as well as with at least one mole of a trihalomethane of the general formula
Z3CH, in which Z has the same meaning as above, per mole of the said tautomeric mixture, tne reaction being carried out, in each case, with the addition of 4 to 6 moles of an alkali metal hydroxide, alcoholate, hydride or amide and in a polar-aprotic solvent and in each case optionally with the addition of a catalytic amount of an alkali metal iodide.
13. Process according to claim 12, wherein the resultant O-selective carboxylic acid in which R5 is a hydroxyl group, is converted into a salt by reaction with a physiologically acceptable inorganic or organic base or is converted in known manner into an ester or amide.
14. Process for the preparation of
compounds according to claim 1, in which
R2 is a halogen atom, wherein a carboxyalkoxy)-pyrazole derivative of the general formula given in claim 1, in which
R2 is a hydrogen atom, is reacted in an inert solvent with a halogenation agent, optionally with the addition of a hydrogen halide acceptor and with the addition of a catalytic amount of a radical former.
15. Process according to claim 14, wherein the inert solvent is a chlorinated hydrocarbon, a dialkyl ether, tetrahydrofuran, dioxan, acetic acid or water.
16. Process according to claim 14 or 15, wherein the halogenation agent is chlorine, sulphuryl chloride, tert.-butyl hypochlorite, bromine, N-chloroamide or N-bromoamide.
17. Process according to any of claims 14 to 16, wherein the hydrogen halide acceptor is an alkali metal carbonate, an alkaline earth metal carbonate or an alkali metal bicarbonate.
18. Process according to any of claims 14 to 17, wherein the radical former is a,ct'- azoisobutyric acid dinitrile or dimethyl ester.
19. Process for the preparation of compounds according to claim 1, substantially as hereinbefore described and exemplified.
20. Compounds according to claim 1, whenever prepared by the process according to any one of claims 12 to 19.
21. Pharmaceutical compositions, comprising at least one compound according to claim 1, in admixture with a solid, liquid or semi-liquid pharmaceutical diluent or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD19782077A DD135487A2 (en) | 1977-03-14 | 1977-03-14 | METHOD FOR PRODUCING NEW 3- (1-CARBOXY-ALKOXY) -PYRAZOLE DERIVATIVES |
| DD19781977 | 1977-03-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1567448A true GB1567448A (en) | 1980-05-14 |
Family
ID=25747584
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9180/78A Expired GB1567448A (en) | 1977-03-14 | 1978-03-08 | Pyrazole derivatives |
Country Status (5)
| Country | Link |
|---|---|
| CH (1) | CH640514A5 (en) |
| DE (1) | DE2809183C2 (en) |
| FI (1) | FI69065C (en) |
| GB (1) | GB1567448A (en) |
| SE (1) | SE446531B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695566A (en) * | 1984-07-04 | 1987-09-22 | Kali-Chemie Pharma Gmbh | 3-aminocarbonylmethoxy-5-phenylpyrazole compounds, antiarrythmic compositions containing them, and intermediates in their preparation |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2828529A1 (en) * | 1978-06-29 | 1980-01-17 | Kali Chemie Pharma Gmbh | NEW 5-PHENYLPYRAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD118638A1 (en) * | 1975-04-10 | 1976-03-12 |
-
1978
- 1978-03-03 DE DE2809183A patent/DE2809183C2/en not_active Expired
- 1978-03-08 GB GB9180/78A patent/GB1567448A/en not_active Expired
- 1978-03-10 SE SE7802797A patent/SE446531B/en not_active IP Right Cessation
- 1978-03-13 FI FI780791A patent/FI69065C/en not_active IP Right Cessation
- 1978-03-13 CH CH270278A patent/CH640514A5/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695566A (en) * | 1984-07-04 | 1987-09-22 | Kali-Chemie Pharma Gmbh | 3-aminocarbonylmethoxy-5-phenylpyrazole compounds, antiarrythmic compositions containing them, and intermediates in their preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| FI69065B (en) | 1985-08-30 |
| CH640514A5 (en) | 1984-01-13 |
| FI780791A (en) | 1978-09-15 |
| SE7802797L (en) | 1978-09-15 |
| SE446531B (en) | 1986-09-22 |
| DE2809183C2 (en) | 1984-12-06 |
| DE2809183A1 (en) | 1978-09-28 |
| FI69065C (en) | 1985-12-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |