RU2583158C2 - Methyl 5-(arylcarbamoyl) -1-(benzyl and phenyl)-4-cinnamoyl-1h-pyrazole-3-carboxylates, exhibiting analgesic activity and synthesis method thereof - Google Patents

Methyl 5-(arylcarbamoyl) -1-(benzyl and phenyl)-4-cinnamoyl-1h-pyrazole-3-carboxylates, exhibiting analgesic activity and synthesis method thereof Download PDF

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RU2583158C2
RU2583158C2 RU2014123249/04A RU2014123249A RU2583158C2 RU 2583158 C2 RU2583158 C2 RU 2583158C2 RU 2014123249/04 A RU2014123249/04 A RU 2014123249/04A RU 2014123249 A RU2014123249 A RU 2014123249A RU 2583158 C2 RU2583158 C2 RU 2583158C2
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ph
cinnamoyl
ar
1h
pyrazole
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RU2014123249A (en
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Павел Сергеевич Силайчев
Валерий Олегович Филимонов
Андрей Николаевич Масливец
Рамиз Рагибович Махмудов
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Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Пермский государственный национальный исследовательский университет"
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic 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
    • C07D231/14Heterocyclic 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

Abstract

FIELD: chemistry.
SUBSTANCE: invention relates to novel compounds of pyrazole class. Described are methyl 5-(arylcarbamoyl)-1-(benzyl, phenyl)-4-cinnamoyl-1H-pyrazole-3-carboxylates (IIIa-e) having formula shown below, and a method for production thereof.
EFFECT: technical result is providing novel compounds which may be used as precursors for synthesis of novel heterocyclic systems in pharmacology as having analgesic activity.
5 cl, 1 tbl, 3 ex

Description

The invention relates to the field of organic chemistry, namely to new individual compounds of the pyrazole class and to a process for their preparation, which can be used as starting materials for the synthesis of new heterocyclic systems and in pharmacology.

Known structural analogues of the claimed compounds are obtained by the recycling of 4,5-diaroyl-1H-pyrrole-2,3-dione under the action of monosubstituted hydrazines in absolute chloroform at room temperature for 15-20 minutes, followed by boiling in ethanol for 20-30 minutes 2- (1- (benzyl and phenyl) -5-aryl-3-aroyl-1H-pyrazol-4-yl) -2-oxoacetic acid N-arylamides are formed (Silaichev P.S., Kudrevatykh N.V., Maslivets A.N. // ZhORKh. 2010.V. 46, issue 10. P. 1540-1543):

Figure 00000001

Figure 00000002

The disadvantages of this method include the inability to obtain methyl 5- (arylcarbamoyl) -1- (benzyl and phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates.

The objective of the invention is to develop a simple method for the synthesis of methyl 5- (arylcarbamoyl) -1- (benzyl and phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates not described in the literature.

The task is carried out by the interaction of methyl 1-aryl-3-cinnamoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates (Silaichev P.S., Filimonov V.O., Slepukhin P.A. ., Maslivets A.N. // ZhORKh. 2012.V. 48. S. 563-567) (Ia-c) with benzylhydrazine (IIa) and phenylhydrazine (IIb) in an inert polar aprotic solvent - 1,4-dioxane according to the scheme:

Figure 00000003

The process is carried out by keeping the reagent solution in absolute 1,4-dioxane at a temperature of 100-102 ° C for 20-30 minutes.

From the patent and technical literature were not identified methods for producing methyl 5- (arylcarbamoyl) -1- (benzyl and phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates having similar characteristics with the claimed method, namely, the original products, solvents in which the reaction takes place, and the temperature range, on the basis of which we can conclude that the claimed technical solution meets the criteria of "novelty" and "inventive step".

The invention is illustrated by the following examples.

Example 1. Methyl 1-benzyl-5- (phenylcarbamoyl) -4-cinnamoyl-1H-pyrazole-3-caboxylate (IIIa).

To a solution of 1.0 mmol of compound (Ia) in 20 ml of absolute 1,4-dioxane was added a solution of 1 mmol of benzylhydrazine (IIa) in 5 ml of absolute 1,4-dioxane, boiled for 30 minutes, the solvent was distilled off, the residue was recrystallized from ethanol. Yield 83% mp. 168-170 ° C (ethanol). Compound (IIIa) C 28 H 23 N 3 O 4 .

Found,%: C 72.22; Η 4.95; N 9.00.

Calculated,%: C 72.25; Η 4.98; N 9.03.

Compound (IIIa) is a colorless crystalline substance, readily soluble in DMF and DMSO, sparingly soluble in ordinary organic solvents, insoluble in alkanes and water.

The IR spectrum of compound (IIIa), recorded as a paste in liquid paraffin, contains valence vibration bands of the amide ΝΗ group at 3253 cm -1 , the methoxycarbonyl group at 1733 cm -1 , the amide carbonyl group at 1675 cm -1 , the ketone carbonyl group and a double bond of the cinnamoyl substituent at 1648 and 1620 cm -1 , as well as the amide II band at 1562 cm -1 .

In the 1H NMR spectrum of compound (IIIa) recorded in a solution in DMSO-d 6 , in addition to signals of protons of aromatic rings and related groups, there are a singlet of protons of a methoxycarbonyl substituent at 3.80 ppm, a singlet of a methylene group of a benzyl substituent at 5.56 ppm. , doublets of protons of the double bond of the cinnamoyl substituent at 7.26 and 7.53 ppm with spin-spin coupling constants characteristic of trans-substituted alkenes

Figure 00000004
and the proton singlet of the amide group ΝΗ at 10.87 ppm

Example 2. Methyl 1-phenyl-5- (phenylcarbamoyl) -4-cinnamoyl-1H-pyrazole-3-carboxylate (IIIb).

To a solution of 1.0 mmol of compound (Ia) in 20 ml of absolute 1,4-dioxane was added a solution of 1 mmol of phenylhydrazine (IIb) in 5 ml of absolute 1,4-dioxane, boiled for 30 minutes, the solvent was distilled off, the residue was recrystallized from ethanol. Yield 80%, mp. 209-210 ° C (ethanol). Compound (IIIb) C 27 H 21 N 3 O 4 .

Found,%: C 71.80; Η 4.66; N, 9.27.

Calculated,%: C 71.83; Η 4.69; N 9.31.

Compound (IIIb) is a colorless crystalline substance, readily soluble in DMF and DMSO, sparingly soluble in ordinary organic solvents, insoluble in alkanes and water.

The IR spectrum of compound (IIIb), recorded as a paste in liquid paraffin, contains stretching vibrations of the amide ΝΗ group at 3281 cm -1 , the methoxycarbonyl group at 1728 cm -1 , the amide carbonyl group at 1684 cm -1 , the ketone carbonyl group and a double bond of the cinnamoyl substituent at 1649 and 1621 cm -1 , as well as the strip "amide II" at 1558 cm -1 .

In the 1H NMR spectrum of compound (IIIb) recorded in a solution in DMSO-d 6 , in addition to signals of protons of aromatic rings and related groups, there are a singlet of protons of a methoxycarbonyl substituent at 3.86 ppm, doublets of protons of a double bond of a cinnamoyl substituent at 7.29 and 7.61 m .d. with spin-spin coupling constants characteristic of Airais-substituted alkenes

Figure 00000005
and a singlet of the proton of the amide group ΝΗ at 10.95 ppm

Compounds (IIIc-e) were synthesized in a similar manner.

The proposed method is simple to implement, one-step and allows to obtain methyl 5- (arylcarbamoyl) -1- (benzyl and phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates (IIIa-e) with good yields, which are not described in the literature. will find application as starting materials for the synthesis of new heterocyclic systems and in pharmacology as potential medicines.

Example 5. Pharmacological study of methyl 5- (arylcarbamoyl) -1- (benzyl and phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates (IIIa-g, e), for the presence of analgesic activity.

Evaluation of the analgesic properties of compounds (IIIa-d, e) was studied on outbred mice weighing 18-22 grams by the method of thermal stimulation "hot plate" according to Eddy and Leimbach (Eddy NB, Leimbarh DJ Pharmacol and Exper. Gher. 1953., 385-393) . Metamizole sodium was used as a reference drug.

Studies have shown (see table.) That compounds (IIIa-d, e) have a pronounced analgesic activity at or above that of the comparison drug. Data on the pharmacological activity of analogues of the claimed compounds in the available literature are not available.

Figure 00000006

Figure 00000007

Claims (5)

1. Methyl 5- (arylcarbamoyl) -1- (benzyl or phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates of the formula
Figure 00000008

where III, Ar = Ph, R = CH 2 Ph (a), Ph (b); Ar = C 6 H 4 Me-4, R = CH 2 Ph (c), Ph
(g); Ar = C 6 H 4 OMe-4, R = CH 2 Ph (d), Ph (e).
2. Methyl 5- (arylcarbamoyl) -1- (benzyl or phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates of the formula
Figure 00000009

where III, Ar = Ph, R = CH 2 Ph (a), Ph (b); Ar = C 6 H 4 Me-4, R = CH 2 Ph (c), Ph
(g); Ar = C 6 H 4 OMe-4, R = CH 2 Ph (d), Ph (e) possessing analgesic activity.
3. The method of obtaining methyl 5- (arylcarbamoyl) -1- (benzyl or phenyl) -4-cinnamoyl-1H-pyrazole-3-carboxylates of the formula
Figure 00000010

where III, Ar = Ph, R = CH 2 Ph (a), Ph (b); Ar = C 6 H 4 Me-4, R = CH 2 Ph (c), Ph
(g); Ar = C 6 H 4 OMe-4, R = CH 2 Ph (d), Ph (e),
characterized in that methyl 1-aryl-3-cinnamoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates (Ia-b) of the formula
Figure 00000011

where I, Ar = Ph (a), C 6 H 4 Me-4 (b); Ar = C 6 H 4 OMe-4 (c),
subjected to interaction with benzylhydrazine (IIa) or phenylhydrazine (IIb) in an inert polar aprotic solvent, 1,4-dioxane, at a temperature of 100-102 ° C for 20-30 minutes.
4. The method according to p. 3, characterized in that the process is carried out at a temperature of 100-102 ° C - the boiling point of 1,4-dioxane.
5. The method according to one of paragraphs. 3 or 4, characterized in that absolute 1,4-dioxane is used as the solvent.
RU2014123249/04A 2014-06-06 2014-06-06 Methyl 5-(arylcarbamoyl) -1-(benzyl and phenyl)-4-cinnamoyl-1h-pyrazole-3-carboxylates, exhibiting analgesic activity and synthesis method thereof RU2583158C2 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2342365C2 (en) * 2003-05-01 2008-12-27 Бристол-Маерс Сквибб Компани Arylsubstituted pyrazolamides as kinases inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2342365C2 (en) * 2003-05-01 2008-12-27 Бристол-Маерс Сквибб Компани Arylsubstituted pyrazolamides as kinases inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
СИЛАЙЧЕВ П.С. И ДР. "Рециклизация 4,5-диароилзамещенных 1-Н-пиррол-2.3-дионов под действием бензилгидразина", ЖоргХ, 2009,т.45, 8, с.1276-77. СИЛАЙЧЕВ П.С. И ДР. "Рециклизация 4,5-диароилзамещенных 1-Н-пиррол-2.3-дионов под действием бензилгидразина", ЖоргХ, 2009,т.45, 8, с.1276-77;СИЛАЙЧЕВ П.С. И ДР. "Пятичленные 2,3-диоксогетероциклы. LXXXII. Рециклизация 4,5-бис(метоксикарбонил)-1Н-пиррол-2,3-дионов под действием монозамещенных гидразинов. Кристаллическая и молекулярная структура диметил 1-бензил-5-[(4-метилфенил)карбамоил]-1Н-пиразол-3,4-дикарбоксилата", ЖоргХ, 2012, т.48, 1, с.114-117. СИЛАЙЧЕВ П.С. И ДР. "Пятичленные 2,3-диоксогетероциклы. LXXXV. Синтез 5-метоксикарбонил-4-циннамоил-1Н-пиррол-2,3-дионов и их взаимодействие с 3-амино-5,5-диметилциклогекс-2-ен-1-онами. Кристаллическая и молекулярная структура 4'-гидрокси-6,6-диметил-1'-(4-метоксифенил)-1-фенил-3'-циннамоил-6,7-дигидроспиро[индол3,2'-пиррол]2,4,5'(1Н,1Н',5Н)триона", ЖоргХ, 2012, т.48, 4 с.563-567. *

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