Pharmaceutical composition having anticonvulsive and analgesic activity

 

(57) Abstract:

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsive and analgesic activity. The invention lies in the fact that the pharmaceutical composition comprises 3-aminopyrrolo formula

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and pharmaceutical acceptable carriers and/or excipients. The invention provides a reduction in side effects. 1 C.p. f-crystals, 2 tab.

This invention relates to the field of drugs and for the application of 3-aminopyrrolo General formula I

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where

R1and R2mean methoxycarbonyl and phenyl, etoxycarbonyl and phenyl, methoxycarbonyl and para-chlorophenyl, methoxycarbonyl and para-tolyl, etoxycarbonyl and para-tolyl, and methoxycarbonyl and para-anisyl,

as a drug; these compounds are used alone or as an active ingredient in medicines, which, along with active early also contain conventional physiologically tolerated additives and carriers.

Still it was not known anticonvulsive action 3-aminopyrrolo. Described that 3-aminopyrazole with 4-position AMI is one to affect the Central nervous system. It is known that this action is a sedative and analgesic in nature, however, the test results in the literature is not published. The above six representatives 3 morpholino-4-arylpyrimidines acid obtained by cyclization of morpholino 3 alkoxycarbonylmethyl-2-aryl-tigrillos acid (see "the Chemistry of heterocyclic compounds", N 5, 1985, page 628, article A. P. the Knoll and J. Liebscher: "Synthesis of esters of substituted 3-aminopyrrolo-2-carboxylic acid from Tigrinya and esters of glycine"). About the pharmacological activity of these compounds is still not known. Also known anticonvulsive means have a common weakness - they have undesirable side effects (e.g., neurotoxicity).

The objective of the invention is the use of 3-aminopyrrolo with activity against Central nervous system, and in particular those that have anticonvulsive and analgesic activity, and are used as drugs and medicines. It should seek to minimise adverse effects, for example, to reduce neurotoxicity and make it less than that known to date eastersunday above, in testing various models of seizures showed a high anticonvulsive activity, less toxicity, and most importantly, a significantly higher protective effect than known today anticonvulsive means. Surprised by their unusually high anticonvulsive activity, as previously for 3-aminopyrrolo such action was unknown. Obtaining claimed according to the invention can be manufactured in various ways. For example, compounds of General formula I can be obtained in the course of the cyclization reactions, synthesizing them from amides aminothiazolo acid and glycerol radicals (ibid.). Next 3-aminopyrazole with the General formula I, where R1and R2have values methoxycarbonyl and phenyl, etoxycarbonyl and phenyl, methoxycarbonyl and p-chlorophenyl, methoxycarbonyl and p-tolyl, etoxycarbonyl and p-tolyl or methoxycarbonyl and p-anisil can be obtained by cyclization of salt trimethine General formula II

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where

R1and R2have the above values, and in which X1- tsepliaeva group, for example, halogen, alkoxygroup or amino group, and Z-the anion of the acid residue, such as halide, perchlorate, alkylsulfate, sulfonate, is the initial base salt trimethine with the General formula II, preferably in the presence of a base. Next for the synthesis of the present invention 3-aminopyrrolo you can use the exchange and conversion of the substituents in the pyrrole skeleton. So, for example, 3-aminopyrrolo-2-carboxylic acid with the General formula (V)

< / BR>
where

R2has the above values,

when interacting with alcohols are transformed into 3-aminopyrazole General formula I, in which R2- alkoxycarbonyl group. You can also in the 2-unsubstituted 3-aminopyrazole with the General formula VI

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in the 2-position by a known method, Vilsmeier or acylation Friedel of qualification to enter the group, formyl or acyl, resulting in the formation of 3-aminopyrrolo with the General formula I, in which R2- formyl or acyl.

These 3-aminopyrazole according to the invention are used as medicines by themselves or as the active principle in pharmaceutical preparations that contain along with the active beginning of the physiologically tolerated additives and carriers.

Medicinal product according to the invention have, in particular, activity in the Central nervous system, preferably anticonvulsive and/or analgesic activity at a dose of from 0.5 to 20 mg 3-aminopyrrolo total of four who Yu, in particular, in respect of epilepsy in different forms, in respect of nonepileptic diseases, in respect of migraines and pain of various origin. The active substance can be included in conventional dosage forms such as tablets, capsules, pills, granules or solutions, using inert, non-toxic suitable for this purpose substances-carriers or solvents.

Below the invention is illustrated in the examples.

Example 1. Synthesis of 3-aminopyrrolo General formula I.

In table. 1 shows a connection offer in accordance with this invention. They were obtained according to the method described in the article by Knol and Liebscher.

Example 2. The definition of protection against maximum elektrobudowa (MEAs).

Irritation of the front paws of electric current (pulse frequency 35 Hz, the scan pulse is 20 MS, the current rectangular pulse of 50 mA, a pulse duration of between 400 and 600 MS) cause mice weighing 18-22 g KM long spasm of the rear limbs. Anticonvulsive means protect the animals from the maximum MEAs.

The results:

methyl ester of 4-(4-chlorophenyl)-3-morpholinopropan-2-carboxylic acid (compound a)):

intraperitoneal the e/kg

Other research results see table. 2.

Comparative values for "carbamazepine": oral introduction: ED50= 4,310-5mol/kg

Example 3. The determination of the activity of cramps caused by pentetrazole.

When administered intravenously in the coccygeal vein of mice (18-22 g KM) certain dose of the drug was noted extensor spasms of the hind limbs of the animals. Removing clinical seizures were considered as the criterion of anticonvulsive effect of the investigated substances.

The results:

methyl ester of 4-(4-chlorophenyl)-3-morpholinopropan-2-carboxylic acid (compound a)):

intraperitoneal injection: ED50= 4.5 to 10-5mol/kg,

when introduced through the mouth: ED50= 1,5 10-4mol/kg

Example 4. The determination of the threshold of seizures.

By infusion of 100 mg/kg of pentetrazole (rate of infusion of 36 ml/h) via the tail vein, there is the first clonic seizures (myoclonic seizures) in mice (18-22 g KM). The increased duration of infusion (in seconds) until seizures compared with the control individuals is seen as raising the threshold for convulsions caused by pentetrazole and the self-morpholinopropan-2-carboxylic acid (compound b)):

intraperitoneal injection 1 10-4mol/kg:

raising the threshold of seizures in 80%,

Example 5. Approximate determination of the lethal dose.

Experimental animals received the test substance in the number of 510-4, 10-3and 510-3mol/kg body weight of the mouse (weight 18-22 g). After 24 h was determined mortality of animals.

The research results are summarized in table. 2.

Example 6. Determination of analgesic activity in experiments on heated panel.

Mice weighing 18-22 g after 30 min after injection of the analyte was placed on the panel, heated to 56oC.

The aim of the research is determination of the time response to painful thermal stimulation. The increase in reaction time for animals receiving the test substance, in comparison with the control group was estimated as analgesic effect.

The results:

methyl ester of 4-phenyl-3-morpholinopropan-2 carboxylic acid (compound b)):

when oral administration of 10-3mol/kg: 90% (30 min).

Comparative data:

analgin: 55% inhibition.

Example 7. Determination of analgesic activity of the test substances for their ability near the red acid to mice with a body weight of 18-22 g u last mentioned twitching abdominal wall. A measure of the activity of the substance was the reduction of the number of reactions twitching in treated animals compared with the control group. Along with substances with analgesic activity, ability to remove or significantly reduce the effects of jitter are also compounds affecting the Central nervous system.

The results:

methyl ester of 4-phenyl-3-morpholinopropan-2-carboxylic acid (compound b)):

when oral administration of 10-3mol/kg 71,3% inhibition.

Comparative results:

analgin: oral introduction 10-4mol/kg 50% inhibition.

Example 8. The definition of neurotoxicity in experiments on models with rotating wand.

Prepared accordingly mice with body weight of 18-22 g after administration of the substance by 1 min landed on a rotating plate (5 rpm for 1 min). A measure of the activity of the substance was the fact premature slipping off from the plates. "Protective measure" was represented by the quotient of the values DT50/ED50MEK-unit standardization by the action of the mice.

The results:

methyl ester-4-(4-chlorophenyl)-3-morpholinopropan-2-carboxylic what additional information:

"carbamazepine": GD50= 2,2 10-4mol/kg,

"protective measure" = 5,1.

In table. 2 shows the anticonvulsive effect and toxicity of 3-aminopyrrolo General formula I.

Comparative data:

"carbamazepine": ED50= 4,3 (3,2-5,8)10-5< / BR>
OLD > 110-3<510-5< / BR>
OLD 510-4C. B.

"phenytoin": ED50= 2,4(1,5-3,9)10-5< / BR>
OLD > 110-3<5

where R1and R2denote methoxycarbonyl and phenyl, etoxycarbonyl and phenyl, methoxycarbonyl and p-chlorophenyl, methoxycarbonyl and p-tolyl, etoxycarbonyl and p-tolyl, methoxycarbonyl and p-anisil,

when one dose of 0.5 - 20 mg/kg of body weight.

2. The composition according to p. 1, characterized in that it further comprises a diluent.

 

Same patents:

The invention relates to new chemical substances possessing valuable properties, in particular derivatives pyridyl General formula (I)

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where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts

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The invention relates to medicine, specifically to medicines used in the treatment of ischemic heart disease, and arrhythmias complicating it

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

The invention relates to the field of medicine, particularly, to a method of prolonging the therapeutic effect of timolol drug belonging to the group nekardioselektivnym beta - blockers used to reduce intraocular pressure and treating glaucoma

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to medicine, in particular to rheumatology, and for the treatment of arthritis

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts
The invention relates to medicine, namely, pulmonology, and can be used for treatment of pulmonary hypertension in patients with chronic non-specific lung diseases

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

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