Derivatives piperidineacetate-2-it, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new derivatives of piperidineacetate-2-it General formula I, where R1and R2each independently from each other represents an unsubstituted or once substituted phenyl residues, substituents which may be OA, Hal, NH2, OTHER3; R3denotes-CO-alkyl, where alkyl has 1 to 7 carbon atoms; And indicates WITH1-C6alkyl; Hal denotes F, CL, Br or j is a Method of obtaining derivatives of piperidineacetate-2-it General formula I by reacting the compounds of formula II, where R1above, Z1denotes Cl, Br, J, HE, alkylsulfonate with 1-6 C-atoms in the alkyl, arylsulfonate with up to 60 atoms in the aryl or another reactive functionally modified IT group, with a compound of formula III, where R2above. The pharmaceutical composition has a psychopharmacological effect and contains a compound of the formula I and the usual additives. 3 c. and 4 C.p. f-crystals, 1 PL.

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The invention relates to new derivatives of methyloxazolidine-2-it formula I

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where

R1and R2respectively independently Torah can be A, OA, aryloxy with 6-10 C atoms, aralkylated with 7-11 C atoms, -O- (CH2)nO- (directly adjacent positions or in the meta - or para-position to each other are connected to phenyl ring), -O-(CH2)nHE, Hal, CF3HE, NO2, NH2, NHA, NA2, OTHER3, NAR3, SO2NH2, SO2NHA, SO2NA2, SO2OTHER3(except for R3= SO2A), SO2N(R3)2(except for R3= SO2A) or R3,

R3means SLEEP, CO-alkyl with 1-7 C atoms in the alkyl, CO-alkyl-Ar with 8 to 12 C-atoms, GO-Ar with 7-13 C-atoms, SO2A,

And denotes an alkyl residue with 1-6 C-atoms,

n denotes 1 or 2,

Hal denotes F, Cl, Br or J,

and to their physiologically not causing fear salts. The invention relates also to receive these new compounds and to their use as a psycho-active substances.

In the application Germany 4 005 371 A1, along with a large number of possible other compounds, as is well known pharmaceutically active compounds also described piperidinecarboxylate, which is substituted on the nitrogen oxazolidinone ring in the 5th position is linked to the nitrogen replaced piperidino to the tion of action, affecting the Central nervous system.

In the application Germany 43 24 393 A1 also describes piperidinecarboxylate that have influential effect on the Central nervous system, particularly neuroleptic action, not causing significant cataleptic action. In this case we are talking about the piperidine derivatives, which are in the 4-position is replaced by aryloxy or aristokratami.

Therefore, the basis of the invention lies task is to provide new compounds that can be used for getting medicines that have however compared with known active substances pronounced action spectrum and selectively affecting the Central nervous system, have few side effects, while they may be appointed on the basis of the changed patterns in small doses and they have no or only a very small potential dependencies.

It was found that the compounds of formula I and their physiologically not cause fear salts with good endurance have valuable pharmacological properties. They have an impact especially on the Central nervous system and it is not detecting worth mentioning cataleptic action.

The subject invention are therefore new derivatives of piperidineacetate-2-she mentioned formula I and their salts and their use as pharmacologically active substances.

But the subject of the invention are also suitable methods for obtaining these compounds or their salts.

In particular, the compounds of the aforesaid formula I and their salts have a dampening effect on behavior in mice (Method, cf. Irvine, Psychopharmacology 13 8 (1968), 222-257). They inhibit in mice induced by Apomorphine state lasagna (Methodology cf. Costal and others European journal of pharmacology, 50 (1968), 39-50) or induce contralateral state of rotation in rats with Parkinson's disease (established method Ungerstedt and others, brain Res. 24 (1970), 485-493), without causing significant cataleptic side effects (Method cf. dolní Štôla, Pharmacopsychiatry 6 (1973), 189-197). These active ingredients inhibit the binding trithiolane of dopaminegeneric and deaminations with veins receptors (determined by the method of Schwartz and others, Journal of neurochemistry laboratory 34 (1980), 772-778, and Kriz and others, European Journal of pharmacology, 46 (1977), 377-381). Further, these compounds inhibit the tongue-jaw reflex at narcotize is. the European Journal of pharmacology, 33 (1975), 61-64). Along with this you can detect pain and lowering blood pressure steps, namely, the bearing catheter awake, with spontaneous hypertension rats (strain SHR/NiH-MO//CHB-EMD), directly measured arterial blood pressure after intragastric receiving active substances is reduced (Method cf. Weeks and Jones, Proc. Soc. Expti. Biol. Med. 104 (1960), 646-648.

On the basis of these results, studies have found that the compounds of formula I and their physiologically not causing fears of salt accession can however also be used as intermediate products for other active substances of medicines.

The compounds of formula I and their salts can be obtained so that the compound of formula II

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where

R1has specified in paragraph 1 value and

Z1denotes Cl, Br, J, HE, alkylsulfonate with 1-6 C-atoms in the alkyl, arylsulfonate with the number of C-atoms to 60 aryl or another reactive functionally modified OH-group,

interacting with the compound of the formula III

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where

R2is referred to in paragraph 1

or, if

Z1obuchenie and

Z2and Z3- same or different and denote, respectively, Cl, Br, J, HE, SO3CH3or other reactive functionally modified OH-group,

that, in addition, corresponding to the formula 1 compound, which, however, instead of one or more hydrogen atoms contains one or more recoverable groups and/or one or more additional-SO2- and/or-SO-group, is treated with a reducing agent,

or that in order to obtain the compounds of formula I according to paragraph 1, the remainder R1and/or the remainder R2turn in the remainder R1and/or R2or that the compound of formula IY

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where

R1and R2are referred to in paragraph 1 values, interacting with a derivative of carbonic acid,

and/or, if necessary, the compound of formula I release from its functional derivative processing by means of solvolysis or hydrogenolysis, or the compound of formula I recovery or oxidation converted into another compound of formula I, and/or that the base of the formula I in claim 1 turn by treatment with an acid into one of its salts.

Above and below the remains of R1, R2, R3And Hal, and the parameter n them is mulah And denotes an alkyl residue with 1-6 C-atoms, preferably with 1, 2, 3 or 4 C-atoms. In particular, a represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, then also pentyl, 1-, 2-, or 3-methylbutyl, 1,1 - 1,2 - or 2,2-dimethylpropyl, hexyl, 1-, 2 - or 3-methylpentyl or 2,2 - or 2,3 - dimethylpropyl.

The remains of R1and R2may be the same or different. R1and R2mainly denote, respectively independently of one another, unsubstituted or substituted phenyl with the substituents may be ortho-, meta -, and particularly preferably in the para-position.

In particular, R1and R2denote preferably phenyl or para-position substituted stands, ethyl, tert.-bootrom, methoxy, ethoxy, fluorine, chlorine, hydroxy, nitro, amino, alkylamino, where alkyl has the meaning As, acylamino, sulfonylamino, sulfonylamino, sulphonamido or p - phenylmethoxy, p-acetamidophenyl or p-N-methylacetamide phenyl.

Then R1and R2can also designate preferably 3,4-methylendioxy, propionamido - or p-methylsulfinylphenyl.

Acyl refers especially acetyl, propionyl, but also formyl, butyryl, isobutyryl, valeryl, isovaleryl, develpement preferably substituents from the following groups: alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfonyl with 1 to 3, preferably 1 or 2 C-atoms, methylenedioxy, HE, F, Cl, Br, J, NO2, NH2alkylamino or dialkylamino respectively from 1-3, preferably 1 or 2 C atoms in the alkyl group. Preferred residues of Arola are benzoyl, o-, m - or p-toluene, o-, m-, or p-methoxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzoyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-trimethoxybenzoyl, o-, m - or p-methylsulfonylbenzoyl, 2,3 - or 3,4-methylenedioxybenzyl, 1 - or 2-naphtol. Speakers may refer to arkanoid with 1-10 C-atoms, as for example, phenylacetyl, 2 - or 3-phenylpropionyl or 2-, 3 - or 4-phenylbutyric or 2-or 3-phenylazophenyl.

In accordance with the objects of the invention are, in particular, such compounds of formula I in which at least one of these residues is one of the particularly specified values.

Some preferred groups of compounds can be expressed by the following individual formulas, which correspond to the formula I, where not indicated more residues and parameters are specified for formula I values, but the formula la R1denotes a p-methoxyphenyl or phenyl and

R2denotes p-acetamidophenyl the Le Ic R1denotes a p-methoxyphenyl and

R2denotes phenyl, m-methoxy-, p-methoxy-p-hydroxy-p-amino-, p-chloro, p-fluoro-, p-phenylmethoxy-, 3,4-methylendioxy-, p-methyl - or p-tert.-butylphenyl;

in the formula Id R1denotes a p-methoxyphenyl,

R2denotes p-methylsulfinylphenyl;

in the formula Ie R1denotes phenyl and

R2denotes phenyl, m-methoxy-, p-methoxy-p-hydroxy-p-amino-, p-chloro, p-fluoro-, p-phenylmethoxy-, 3,4-methylene - dioxy-, p-methyl, p-tert.-butyl or p-methylsulfinylphenyl.

Obtaining compounds of the formula I is carried out in the rest of the known methods, as are described in the literature (for example, in basic writings as Houben Weyl, Methods of Organic Chemistry, publisher George Tim; J. March, Advanced Organic Chemistry 3rd ed. (1984) or Organic Reactions, both John Wiley & Sons, Inc. New York), namely under the reaction conditions which are known and suitable for the mentioned transformations. You can also use well-known in and of themselves are not mentioned here in detail options.

Source materials for the inventive method, if necessary, can be formed in situ (in place) so that they are not isolated from the reaction mixture, and immediately turn on the laksi, arylsulfonate or other reactive functionally modified OH-group. Accordingly the compounds of formula II interact in particular with derivatives of piperine formula III to obtain the compounds of formula I. In particular, Z1if it is reactive functionally modified OH group, denotes alkylsulfonates with 1-6 C-atoms, as for example methanesulfonate, or arylsulfonate with the number of C-atoms to 60, such as benzosulfimide, p-toluensulfonate, 1 - or 2-naphthalenesulfonate.

However, it is also possible that Z1in compounds of formula II denotes NH2. The receipt of these compounds according to the invention is performed by the reaction of interaction with compounds of formula IIIa, in which Z2and Z3may be the same or different represent mainly Cl or Br, but also J or HE or reactive functionally modified OH group, as may be described above. Compounds of formulas II, III and IIIa mostly known from the literature. Hitherto unknown compounds of this structure can be obtained in a simple way, by analogy with the corresponding known soedineniya esters. Treatment of chloride tiomila, hydrogen bromide, tribromide phosphorus or similar halogen compounds gives the corresponding halides of the formula II.

Sulfonylacetanilide formula II are obtained from the corresponding alcohols by reacting with the corresponding sulfonic acid chlorides. Iodine compounds of the formula II receive, for example, by the action of potassium iodide on the corresponding esters of p-toluenesulfonic acid. Amines of formula II can benefit in particular from halides with phthalimide potassium or recovery of the corresponding NITRILES.

Piperidine formula III are well known. If desired the compounds of formula I required is not known until now piperidine, get them by analogy with the known. The compounds of formula IlIa receive, for example, the recovery of the corresponding complex diesters to diatomic alcohols and, if necessary, followed by transformation with SOCl2or PBr3.

The conversion of compounds II and III proceeds by methods which are known for the alkylation of amines from the literature. You can, for example, directly fused to each other starting compound, namely depending on their swathi neutral solvent. As solvents are used, for example, hydrocarbons like benzene, toluene, xylene; ketones, such as acetone, butanone; alcohols as methanol, ethanol, isopropanol, n-butanol; ethers, like tetrahydrofuran (THF) or dioxane; amides as dimethylformamide (DMF) or N-methyl-pyrrolidone; NITRILES like acetonitrile, if necessary, the mixture of these solvents or mixtures with water. Can be beneficial additive acid binding means, for example, hydroaxe alkaline or alkaline-earth metal, a carbonate of alkali or alkaline earth metal or alkaline bicarbonate or alkaline earth metal or of another salt of a weak acid of the alkali or alkaline earth metal, mainly potassium, sodium or calcium, or the addition of organic bases like triethylamine, dimethylamine, pyridine or quinoline, or an excess of amine components or compounds of formula III or formula IlIa. The reaction temperature is depending on the applied conditions between about 0 and 150oC, usually between 20 and 130oC. in Addition, the compounds of formula I can be obtained so that the preliminary product that instead of hydrogen atoms contains one of the recovered group, or n is ustanavlivaushee means, mainly at temperatures between 80 and 250oC in the presence of at least an inert solvent.

Recoverable (replaced by hydrogen) groups are particularly oxygen in a carbonyl group, hydroxyl, arylsulfonate (for example, toluensulfonate), N-benzene-sulfonyl, N-benzyl or O-benzyl.

In principle, compounds that contain only one group, or such compounds that contain two or more of these groups or contacts, you can restore to translate in the compound of formula I. For this purpose, mainly catalytic hydrogenation of hydrogen at the time of selection or of certain complex compounds of metal hydrides as NaBH4or LiAlH4.

For the catalytic hydrogenation are used as catalysts, for example, catalysts based on noble metal, Nickel and cobalt. Catalysts based on noble metal can be on the media (for example, platinum or palladium on charcoal, palladium on calcium carbonate or strontium carbonate), can be an oxide catalysts (e.g. platinum oxide), or may be finely dispersed metal catalysts. Catalgue or pumice as the carrier. The hydrogenation can be performed at room temperature and at normal pressure or at an elevated temperature and/or high pressure. Mainly work at pressures between 1 and 100 bar and at temperatures between 80 and +150oC, mainly between room temperature and 100oC. the Reaction interaction should be carried out in acidic, neutral or basic region and in the presence of a solvent, such as water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dioxane, acetic acid or THF, you can also use mixtures of these solvents.

If reducing agents are used, the hydrogen at the time of allocation, the latter can be obtained, for example, processing of metals with weak acids or bases. Thus, it is possible to apply, for example, a mixture of zinc and caustic liquor or of iron and acetic acid. Also suitable application of sodium or other alkali metal in alcohol, as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. Further, it is possible to use an alloy of aluminum-Nickel in aqueous-alkaline solution, if necessary with the addition of ethanol. For hydrogen at the time of allocation of suitable sodium amalgam or aluminum amalgam is advisable to apply the aqueous phase and phase benzene or toluene.

Further, as reducing agents, you can apply complex compounds of metal hydrides as NaBH4the hydride diisobutylaluminum or NaAl(OCH2CH2OCH3)2H2and DIBORANE, if desirable, with the addition of catalysts, as BF3, AlCl3or LiBr. As solvents for this purpose are suitable especially ethers as simple diethyl ether, simple di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, as well as hydrocarbons like benzene. To restore using NaBH4suitable primary alcohols as methanol or ethanol, then water and water-alcohol solutions as solvents. According to these methods, the recovery is made mainly at temperatures between -80 and +150oC, especially between 0 and about 100oC.

The compounds of formula I are also due to the fact that the aromatic residue R1and/or R2turn, for example, electrophilic substitution in the remainder R1and/or R2.

The compounds of formula I receive, in addition, the transformation of the aminoalcohols of formula IV with a reactive derivative of carbonic acid. As such preferably used diallylmalonate as dimethy the ether of Harborview acid, N,N'-carbonyldiimidazole or phosgene. The interaction should be carried out in the presence of an inert solvent, mainly halogenated hydrocarbons like chloroform, hydrocarbons like toluene or amide as dimethylformamide at temperatures between about 20 and 200oC, preferably between 100 and 150oC. Derivatives of carbonic acid should be used in excess.

The compounds of formula I can also be obtained, liberating them from their functional derivatives by solvolysis, especially hydrolysis, or by hydrogenolysis.

The preferred initial agents for the solvolysis or hydrogenolysis are those which generally correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxy-group, preferably such that instead of H-atom with a N-atom, are a protective amino group, especially those who instead of HN-groups are1-N-group, where R1denotes a protective amino group, and/or such that instead of the H atom of the hydroxy-group are protective hydroxy-group.

In the molecule of the original substance can also contain several identical or different is in many cases to selectively split.

The terms "protected amino group" is generally known and relates to groups which are suitable to protect the amino group prior to chemical reactions, but which are easily removed after the desired reaction has occurred on the other side of the molecule. Typical of such groups are especially unsubstituted or substituted acyl, aryl (e.g., 2,4-dinitrophenol), Alcoceber(e.g., benzyloxyethyl) or Uralkaliy (for example, benzyl, 4-nitrobenzyl, triphenylmethyl). So as a protected amino group after the desired reaction or sequence of reactions is removed, their type and size is not critical; however prefer such groups with 1 to 20, especially 1 to 8 C-atoms. The expression "acyl group" in connection with this method should be understood in its broadest sense. It includes formed from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulphonic acids of accelgroup, but especially alkoxycarbonyl, aryloxyalkyl and alcoxycarbenium. Examples for such accelgroup are alkenyl as acetyl, propionyl, butyryl; arcanol as phenacetin; aroyl as benzoyl or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl the sludge; artkoktebel as benzyloxycarbonyl, 4-methoxybenzenesulfonyl, 9-fluorenylmethoxycarbonyl. Preferred protected amino groups are tert.-butoxycarbonyl, 2,4-dinitrophenol, benzoyloxymethyl, benzyloxycarbonyl, benzyl and acetyl.

The expression "protected hydroxy-group" is also generally known and relates to groups which are suitable for protecting a hydroxy-group before chemical reactions, but which are easily removed after the desired reaction takes place at a different location of the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl-, aralkyl or acyl group, and altergroup. And in this case, the nature and size of the protected hydroxyl groups are not critical, because after the desired reaction or sequence of reactions again removed. However, the preferred protective group with 1-20, especially with 1-10 C - atoms. Examples for such protected hydroxy groups are, in particular, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluensulfonyl and acetyl, and especially prefer benzyl and acetyl.

The release of the compounds of the formula I from their functional derivatives, depending on the use of protective groups, ozuluama, as trichloroacetic acid or sulfonic acids, as benzene - or p - toluensulfonate. This can be done, if required, in the presence of an additional solvent.

As inert solvents for this purpose are used most organic solvents, namely carboxylic acids, as acetic acid, ethers, like tetrahydrofuran, amides, as dimethylformamide, halogenated hydrocarbons like dichloromethane, then also alcohols as methanol, ethanol or isopropanol, and also water. However, apply also mixtures of these solvents. For this purpose, choose preferably physiologically tolerated inert solvents or those solvents in which case very little rest should remain in the resulting product and which do not pose health risks.

Triperoxonane acid is preferably used in excess without the addition of another solvent. On the contrary, perchloric acid is used in a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. Cleavage of the protective groups is useful to temperatures of about 0-50oC, preferably at 15-30oC or at room temperature.

Tert. - butoxycarboxim another, approximately 3-5 N. HCl in dioxane at 15-60oC. Group fluorenylmethoxycarbonyl otscheplaut approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50oC. Cleavage of 2,4-dinitrophenyl spend approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15-30oC.

Removed by hydrogenolysis of the protective group, as benzoyloxymethyl, benzyloxycarbonyl or benzyl, can be split by treatment with hydrogen in the presence of a catalyst (for example, a catalyst based on a noble metal, such as palladium, usually on the media as coal). As solvents for this purpose apply the above solvents, especially alcohols, like methanol or ethanol, or amides as dimethylformamide. The hydrogenolysis is carried out, as a rule, at temperatures between 0 and 100oC and at pressures between 1 and 200 bar, preferably at 20 to 30oC and at 1 to 10 bar. Hydrogenolysis of benzyloxycarbonyl good, for example, on 5-10% Pd-C in methanol at 20 - 30oC.

Further, the compound of formula I, if necessary, known methods can be converted into another compound of formula I.

So, you can split the corresponding ethers, and form the compound dimethyl sulfide-trichromate boron in the solvent, as toluene, 1,2-dichloroethane, THF or dimethyl sulfoxide, or by fusing with hydrohloride pyridine or aniline. This reaction pyridinecarboxamide preferably carried out at approximately 150-250oC, with HBr/acetic acid or with Al-trigliceride in chlorinated hydrocarbons as 1,2-dichloroethane.

The compounds of formula I can have a center of asymmetry. Therefore, they can be as racemates or, if using optically active starting compound, also in optically active form. Resulting racemates, if required, can be separated by known physical or chemical methods. From racemates by chemical transformation of optically active separating means are formed preferably diastereoisomers. As the separation means are used for example, optically active acids, such as D - or L-forms of tartaric acid, dibenzoyltartaric acid, diatsetilvinny acid, camphoric acid, mandelic acid, malic acid or lactic acid. Various forms of the diastereomers can be divided in a known manner, for example by fractional crystallization, and optically active compounds of formula I release known way of diastereomers.

ü. For this purpose, in particular acids, which give physiologically not causing fears of salt. As inorganic acids for this purpose it is possible to use sulfuric acid, kaleidostone acid as HCl, HBr, phosphoric acid, like phosphoric acid, nitric acid, sulfamic acid, then the organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic with one or polybasic carboxylic acids, sulfonic or sulfuric acids, as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinoyl acid, methane - or econsultation, ethicalfashion, 2-oxetanemethanol, benzosulfimide, p-toluensulfonate, naphthalene-mono - and - disulfonate, louisanna acid, the acid additive salts that are physiologically not cause fear, and which can be used for isolation and purification of the bases of formula I.

Free base of formula I, if desired, can be released from their deleitosa compounds of General formula I and their physiologically not cause fear salts can be used for the manufacture of pharmaceutical preparations and from them receive the relevant dosage form together with at least a substance carrier or auxiliary substance and, if desired, with one or more other active ingredients.

Thus obtained pharmaceutical form can be used as drugs in medicine or in veterinary medicine.

As a matter-carriers take into account organic or inorganic substances which are suitable for intestinal (e.g., oral or rectal), parenteral or local purposes and which do not enter into reaction with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates as lactose or starch, cellulose, magnesium stearate, talc or vaseline, glyceryltrinitrate and other glycerides of fatty acids, soy lecithin.

For oral administration are especially tablets, coated tablets, capsules, syrups, juices or drops. Interest special lacquer tablets and capsules resistant to gastric juice coating or capsule shell. For rectal use suppositories, for parenteral destination are solutions, preferably maslany or powder.

Claimed according to the invention the active substance can also be lyophilized and the resulting products lyophilization to apply, for example, for the manufacture of drugs for injection.

These dosage forms can be sterilized and/or may contain auxiliary substances, such as lubricants, preservatives, stabilizers and/or substances with a high surface activity, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and/or aromatic substances. They can, if desired, also contain one or more other active substances, for example one or more vitamins, diuretics, anti-inflammatory agents.

The compounds of formula I and their physiologically not cause fear salts can be used for therapeutic treatment of the human or animal, in particular for disease control. They are effective in the treatment of schizophrenia, mental disorders and psychopathy, depression, severe chronic pain and diseases, followed by high blood pressure. These compounds can also be used in the treatment of extrapyramidal disorders. Connection to izopet is such a significant cataleptic side effects.

Compounds according to the invention of the formula I and their physiologically not causing fears of salt, as a rule, by analogy with other, well-known for the claimed indications, commercially available drugs (Thioridazine, Haloperidol), is prescribed mainly in doses of between approximately 0.1 and 500 mg, in particular between 0.2 and 50 mg per unit dosage. The daily dosage is preferably approximately between 0,002 and 20 mg/kg, especially 0.2 and 0.4 mg/kg body weight.

However, the specific dose for each patient depends on various factors such as the efficiency of the applied compound, the age, body weight, General health, sex, diet, time and method of assignment, rate allocation, from a combination of medicinal substances and the severity of the relevant disease for which treatment acts. Prefer oral assignment.

Below are examples that serve to illustrate the invention but do not limit the invention to these examples.

In the following examples, "conventional" processing refers to:

add if you want water, extracted with dichloromethane, separated, dried with organizacia (all temperatures are listed inoC and []Dvalue measured at 20oC in dimethyl sulfoxide).

Example 1

A solution consisting of 4,92 g (5R)-(-)-5-(methanesulfonylaminoethyl) 3-p-forfinal-oxazolidin-2-it, 65 ml of acetonitrile, 4,70 g of 4-(4-aminobenzyl)-piperidine [obtained from 4-(4-nitrobenzyl)-pyridine by hydrogenation of the nitro group to the NH2and the pyridine ring to piperidino rings in the presence of a catalyst based on palladium in glacial acetic acid] and 4,43 g of sodium bicarbonate, stirred for 26 h in terms of phlegmy. Then the reaction mixture is diluted with 100 ml of dichloromethane, extracted several times with small amounts of water and dried. After drying, the solvent is distilled off and purify the product by chromatography on a column of silica gel. Thus obtained reaction product as a colourless resin, which vykristallizovyvalas.

Output: 3,18 g (5S)-(-)-5-[4-(4-aminobenzyl)- 1-piperidinylmethyl]-3-(4-forfinal)-oxazolidin-2-it (48.8% of theory)

The melting point 95-99oC

[]D20= -24,5(dimethylsulfoxide)

Similarly, you can get:

from 4-(4-acetylaminobenzoic)-piperidine [obtained from 4-(4-nitrobenzyl)-pyridine by hydrogenation of the nitro group to the NH2in the reed acetic acid/triethylamine to 4-(acetylaminobenzoic)-pyridine and subsequent hydrogenation of the pyridine ring in the presence of a catalyst based on palladium in glacial acetic acid]

and (5R)-(-)-5-(methanesulfonylaminoethyl)-3-(p-forfinal)-oxazolidin-2-it

(5S)- (-)-5- [4-(4-acetylaminobenzoic)-1-piperidinylmethyl]-3-(4-forfinal)- oxazolidin-2-it.

The melting point of 177-179oC

[]D20= -23,6(dimethylsulfoxide);

from 4-(4-terbisil)-piperidine and

(5R)-(-)-5- (methanesulfonylaminoethyl)-3-(4-methoxyphenyl)- oxazolidin - 2-it

(5S)-(-)-5- [4-(4-terbisil)-piperidinylmethyl-3-(4-methoxyphenyl)- oxazolidin-2-it.

The melting point of 203-205oC

[]D20= -27,7(dimethylsulfoxide);

from 4-(4-acetylaminobenzoic)-piperidine and (5R)-(-)-5- (methanesulfonylaminoethyl)-3-(4-methoxyphenyl)-oxazolidin-2-it

(5S)-(-)-5- [4- (4-acetylaminobenzoic)-1-piperidinylmethyl] -3-(4-methoxyphenyl)- oxazolidin-2-it.

The melting point 204-206oC

[]D20= -25,8(dimethylsulfoxide);

from 4-(4-aminobenzyl)-piperidine

and (5R)-(-)-5-(methanesulfonylaminoethyl)-3-(4-methoxyphenyl)- oxazolidin-2-it

(5S)-(-)-5-[4-(4-aminobenzyl)-1-piperidinylmethyl]-3-(4 - methoxyphenyl)-oxazolidin-2-it.

The melting point of 126-128oC

[]D20= -27,8(dimethylsulfoxide);

from 4-(4-acetylaminobenzoic)-piperidine

and (5R)-Tyl]-3-phenyloxazolidine-2-it.

The melting point 199-201oC

[]D20= -24,3(dimethylsulfoxide);

from 4-(4-acetylaminobenzoic)-piperidine

and (5R)-(-)-5-(methanesulfonylaminoethyl)-3-(4-chlorophenyl)- oxazolidin-2-it

(5S)-(-)-5-[4-(4-acetylaminobenzoic)-1-piperidinylmethyl]-3- (4-chlorophenyl)-oxazolidin-2-it.

The melting point 221-223oC

[]D20= -27,4(dimethylsulfoxide);

from 4-(4-aminobenzyl)-piperidine

and (5R)-(-)-5-(methanesulfonylaminoethyl)-3-(4-chlorophenyl)- oxazolidin-2-it

(5S)-(-)-5-[4-(4-aminobenzyl)-1 - piperidinylmethyl] -3-(4-chlorophenyl)-oxazolidin-2-it.

The melting point 146-149oC

[]D20= -29,8(dimethylsulfoxide);

from 4-(4-aminobenzyl)-piperidine

and (5R)-(-)-5-(methanesulfonylaminoethyl)-3-phenyloxazolidine-2-it

(5S)-(-)-5-[4-(4-aminobenzyl)-1-piperidinylmethyl] -3-phenyloxazolidine-2-it.

The melting point 148-150oC

[]D20= -28,5(dimethylsulfoxide).

The following examples relate to pharmaceutical dosage forms:

Example: ampoules for injection

A solution of 100 g of the active substance of the formula I and 5 g of dinitrigenoxide in 3 l of double distilled water adjusted with pee in sterile conditions and closed under sterile conditions. Each ampoule for injection contains 5 mg of active substance.

Example: candles

A mixture of 20 g of the active substance of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and cooled. Each suppository contains 20 mg of active substance.

Example: solution

Prepare a solution of 1 g of the active substance of the formula I 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g benzalkonium chloride in 940 ml of double distilled water. Establish a pH value of 6.8, the complement to 1 l and sterilized by irradiation.

Example D: ointment

Mix 500 mg of active substance of formula 1 with 99.5 g of vaseline under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate in the usual way pressed into tablets such that each tablet contains 10 mg of active substance.

Example F: bean

Analogously to example E is pressed tablets, which are then the usual way is covered with a shell of sucrose, potato starch, talc, tragant and dye.

Example G: capsules

2 kg of active substance form of the substance.

Example H: ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double distilled water, filtered under sterile conditions, poured into vials are lyophilized under sterile conditions and closed under sterile conditions. Each ampoule contains 10 mg of active substance.

Report on pharmacological tests (see table).

The compound of General formula I

< / BR>
The test procedure is similar to that described in the publication "Century Costall and others ". The ability for climbing in mice induced by apomorphine; potential model to determine the neuroleptic activity. European journal of pharmacology, 50, 39-50(1978).

1. Derivatives piperidineacetate-2-it formula I

< / BR>
where R1and R2each independently from each other represents an unsubstituted or once substituted phenyl residues, substituents which may be OA, Hal, NH2, OTHER3;

R3denotes-CO-alkyl, where alkyl has 1 to 7 carbon atoms;

And indicates WITH1-C6alkyl;

Hal denotes F, Cl, Br or j

2. Derivatives piperidineacetate-2 on p. 1, representing

(5S)-(-)-5-[4-(4-Chlorobenzyl)-1-piperidine Catholicon-2-he;

(5S)-(-)-5-[4-(4-aminobenzyl)-1-piperidinyl] -3-(4-methoxyphenyl)-oxazolidin-2-he;

(5S)-(-)-5-[4-(4-acetylaminobenzoic)-1-piperidinyl] -3-phenyl-oxazolidin-2-he;

(5S)-(-)-5-[4-(4-aminobenzyl)-piperidinyl] -3-(4-forfinal)-oxazolidin-2-he;

(5S)-(-)-5-[4-(4-acetylaminobenzoic)-1-piperidinyl] -3-(4-forfinal)-oxazolidin-2-he;

(5S)-(-)-5-[4-acetylaminobenzoic)-1-piperidinyl] -3-(4-chlorophenyl)-oxazolidin-2-he;

(5S)-(-)-5-[4-(4-aminobenzyl)-1-piperidinylmethyl] -3-(4-chlorophenyl)-oxazolidin-2-he;

(5S)-(-)-5-[-(4-aminobenzyl)-1-piperidinylmethyl] -3-phenyloxazolidine-2-it.

3. The method of obtaining derivatives of piperidineacetate-2-it formula I under item 1, characterized in that the compound of formula II

< / BR>
where R1has the data in paragraph (1 value;

Z1denotes Cl, Br, J, OH, alkylsulfonate with 1-6 C-atoms in the alkyl, arylsulfonate with the number of C-atoms to 60 aryl or another reactive functionally modified IT group

enter into interaction with the compound of the formula III

< / BR>
where R2has specified in paragraph (1 value.

4. The compound of formula I under item 1 for the preparation of pharmaceutical compositions.

5. The compound of formula I under item 1 for the preparation of farmaceutiske pharmaceutical compositions with atypical antipsychotic action.

7. Pharmaceutical composition having psychopharmacological effect, containing activetestsuite substance and conventional additives, characterized in that as activitiesthese substances it contains at least compounds of General formula I on p. 1 in an effective amount.

 

Same patents:

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to an improved process for the preparation of substituted indole derivatives useful in the treatment and prevention of migraine

The invention relates to a derivative of oxazolidin-2-it General formula (I):

< / BR>
where X is O,

Y denotesor

< / BR>
R1indicatesor< / BR>
R2and R3each, independently of one another, denotes H, A or benzyl;

A denotes alkyl with 1-6 C-atoms;

D denotes amidinopropane, aminomethyl, aminohydrocinnamic, 5-methyl-1,2,4-oxadiazolidine-3-yl or guanidinate;

r and s independently of one another denote 0, 1, 2, 3 or 4;

however, if necessary, free amino - or amidinopropane can be protected partially or fully protective for the amino function groups, as well as their enantiomers, diastereomers and physiologically acceptable salts

The invention relates to new derivatives of benzylpiperidine formula I, where R1denotes H or Hal, R2is unsubstituted or substituted Gal in the aromatic ring of the benzyl group in the 2 -, 3-or 4-position piperidino ring, provided that R2doesn't mean 4-benzyl when X represents-CO-, Y -, and Z represent CH2and R1- N; R3denotes H or A , X IS-CO-, Y is --CH2-, -NH - or-O-, Z is-CH2- or connection, And - alkyl WITH1-6In - OH, H+, HE, Hal Is F, Cl, Br or I, and their salts

The invention relates to new derivatives of phenyloxazolidine that have a relationship with a 4-8-membered heterocyclic rings of formula I and their pharmaceutically acceptable salts, where X represents NR1, S(O)gor Oh, R1represents H, C1-6alkyl, optionally zamesheny one or more CN or halogen, -(CH2)h-phenyl, -COR1-1, -СООR1-2, -CO-(CH2)h-COR1-1, -SO2- C1-6alkyl or -(CO)i-Het, R2represents H, -CO-(C1-6)alkyl or fluorine, R3and R4are the same or different and represent H or halogen, R5is1-6alkyl and C3-6cycloalkyl, optionally substituted by one or more halogen, g=0, 1, or 2, h=1 or 2, i=0 or 1, m=0, 1, 2, 3, n= 0, 1, 2, 3, provided that m and n taken together, is equal to 1, 2, 3, 4 or 5

The invention relates to new hydrochloridum substituted acetylene aminoalcohols of General formula I R1R2C(OH)CH2CCCH2AmHCl, which have low toxicity and have properties antagonists haloperidol, thanks to which can find application in medicine for the treatment and prevention of Parkinson's disease

The invention relates to a new compound is 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine (compound a) and its salts accession acid, the method of their derivation (options) and pharmaceutical compositions

The invention relates to new pyrimidine derivative or its pharmaceutically acceptable salts, pharmaceutical composition having the effect of inhibitor endothelin and method of prevention and treatment of diseases induced endothelium, particularly diseases associated with circulatory disorders such as hypertension, hypertension, asthma, angina, etc

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action

The invention relates to new naphtylpropionate F.-ly (I), where R1and R2- N, -HE or-O(C1-C4-alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholinyl, dialkylamino - or 1-hexamethylen-aminogroup; n = 2 or 3, or pharmaceutically acceptable salts

The invention relates to new derivatives of naphthalene or dihydronaphthalene formula I, where R1means-HE or-O(C1-C4-alkyl), R2- C1-C6-alkyl or C5-C7-cycloalkyl, X represents-CH(OH)-, or-CH2-, M represents-CH2-CH2- or-CH=CH-, n is 2 or 3, R3denotes 1-piperidinyl or 1-pyrrolidinyl, or their pharmaceutically acceptable salts

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts
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