3-benzylpiperidine, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new 3-benzylpiperidine F.-ly (I)

< / BR>
where R1denotes unsubstituted or substituted groups Hal, CN, AO, COOH or cooa 2 - or 3-indolyl, 5H-1,3-dioxolo [4,5-f]- indolyl, R2denotes unsubstituted or substituted by groups a, AO, Hal, or CN benzyl or phenylhydroxylamine, Hal denotes F, Cl, Br or J, And indicates WITH1-C10alkyl, k represents 0 or 1, m denotes 1, 2, 3 or 4 in the form of racemic mixtures or individual stereoisomers as well as their physiologically acceptable salts and solvate. The compounds of formula (I) have an impact on the Central nervous system, are highly effective ligands - receptors and exhibit a strong inhibitory effect on reuptake of 5-HT. 3 c. and 2 C.p. f-crystals, 1 table.

The present invention relates to compounds of the formula I

< / BR>
in which R1denotes unsubstituted or one - or twofold substituted by the groups Hal, CN, A, AO, HE CONH2, CONHA, SOMA2, COOH and/or cooa 2 - or 3-indolyl, 5H-1,3-dioxolo[4,5-f]-7-indolyl,

R2denotes unsubstituted or one-, two - or three-fold substituted by groups a, AO, HE, Hal, CN, NO2, NH2 is elgeroctober,

Hal denotes F, C1, Br or J,

And indicates premiani or branched alkyl with 1-10 C-atoms which may be substituted by 1-5 F and/or Cl atoms, or cycloalkyl with 3-10 C-atoms,

k represents 0 or 1 and

m denotes 1, 2, 3, or 4

and their physiologically acceptable salts and solvate.

Compounds such structures are known, for example, international applications WO 95/02592 or WO 95/33743.

The present invention was based on the task to obtain new compounds with valuable properties, in particular such compounds, which could be used for the manufacture of medicines.

It has been found that the compounds of formula I and their salts along with good compatibility possess particularly valuable pharmacological properties. They affect the Central nervous system and exhibit high anti-epileptic and primarily antiischemic efficacy (which was confirmed on the model of temporary (volatile) occlusion of the Central cerebral artery in rats and reducing neurological symptoms). These substances are highly effective ligand-receptor with neuroprotective properties (see M. O'neill and others, is the train effect on the NMDA ion channel where NMDA (N-methyl-D-aspartate) forms a complex with the corresponding ions (see also H. Yamamoto and others, Journ. Neuroscience (1995), 15(1), pages 731-736). The agonist-receptor additional beneficial effects on age-related memory impairment (cf. Maurice and others, Brain Research 733 (1996), pp. 219-230. Some compounds of formula I are further strong inhibitory effect on reuptake of 5-HT. From such compounds is legitimate to expect especially high antidepressant, anxiolytic effectiveness and positive impact on neurosis obsessive-compulsive disorder (obsessive-compulsive disorder (OCD), disturbances in feeding behavior, such as bulimia, on a slower dyskinesia, a disorder in the learning process, age-related memory impairment and psychotic state.

The compounds of formula I and their physiologically acceptable acid additive salt along with good compatibility possess particularly valuable pharmacological properties. These compounds can be used for the treatment of schizophrenia, disorders of cognitive abilities, state of fear, depression, nausea, slow psoriasis, disorders of the gastrointestinal tract or parkinsonism. They have vozdastsa confirm ex-vivo inhibition of serotonin reuptake is possible to use a method of inhibiting this grip on synaptic and somatic levels (see Wong and others, Neuropsychopharmacol. 8 (1993), 23-33) antagonism against p-chloroamphetamine (see Fuller and others, Journ. Pharmacol. Exp. Ther. 212 (1980), pp. 115-119).

As mentioned substance as a ligand-receptor have a neuroprotective effect, they are suitable also for use primarily as therapeutic agents for the treatment of the effects of a stroke, to treat traumatic brain injuries and spinal cord, as well as for the treatment of ischemic conditions after the heart stops.

Thus, the compounds of formula I can be used both in veterinary medicine and in medicine for the treatment of functional disorders of the Central nervous system and inflammation. They can be used for the prevention and treatment of stroke (apoplexia cerebri) such as stroke and cerebral ischemia, as well as for treatment extrapyramidal-motor side effects of antipsychotic drugs (tranquilizers) and Parkinson's disease, is an and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. Equally they are suitable for the treatment of traumatic brain injuries and spinal cord. At the same time, they can be used as an active vedicheskikh States, tranquilizers, antihypertensives and/or positive impact on neurosis obsessive-compulsive disorder, sleep disorders, slowed dyskinesia, disorders in the learning process, age-related memory disorders, disorders in feeding behavior, in particular bulimia, and/or sexual disorders.

With regard to the foregoing, an object of the invention are the compounds of formula I and their physiologically acceptable salts.

The object of the invention is first of all the compounds of formula I, selected from the group including

a) 3- [4-(3-benzylpiperidine-1-yl)butyl]indole;

b) 3- [4-(3-phenylhydroxylamine-1-yl)butyl] indole;

C) 3- [4-(3-benzylpiperidine-1-yl)butyl] -5-Florinda;

g) 3-benzyl-1- [4-(5-Florinda-3-yl)butanoyl] piperidine;

d) 3-benzyl-1-14-(5-Clorinda-3-yl)butanoyl] piperidine;

e) 3- [4-(3-benzylpiperidine-1-yl)butyl] -5-carboxyla;

f) methyl ester 3-[4-(3-benzylpiperidine-1-yl)butyl]indole-5-carboxylic acid;

C) methyl ester(-)-3-{4-[3-(3R')-benzylpiperidine-1-yl]butyl}indole-5-carboxylic acid;

and) methyl ester(+)-3-{ 4-[3-(3S')-benzylpiperidine-1-yl] butyl} indole-5-carboxylic acid;

to) 3-{4- [3-(3R')-benzylpiperidine-1-yl]butyl]-6-methoxyindole;

l) 3- {4- [3-(3S')sulpiride-1-yl)butyl]indole;

o) 3- [4-(3-benzylpiperidine-1-yl)butyl]-5-chlorinda;

p) 3- [4-(3-benzylpiperidine-1-yl)butyl]-5-methoxyindol;

p) 3- [4- [3-(4-terbisil) piperidine-1-yl]butyl]-5-Florinda;

C) 7-{4-[(3R)-3-benzylpiperidine-1-yl]butyl]-5H-1,3-dioxolo[4,5

f] indole;

t) 7- {4-[(35)-3-benzylpiperidine-1-yl]butyl]-5H-1,3-dioxolo[4,5 - indole;

I) 3- [4-[(3R)-3-benzylpiperidine-1-yl]butyl] -5-Florinda;

f) 3- {4- [(3S)-3-benzylpiperidine-1-yl]butyl]-5-Florinda;

x) 3-{4-[(3R)-3-benzylpiperidine-1-yl]butyl}indole-5-carbonitrile;

C) 3-{4-[(3S)-3-benzylpiperidine-1-yl]butyl}indole-5-carbonitrile;

h) 3- [4- [3-(4-florfenicol)piperidine-1-yl] butyl] indole-5-carbonitrile;

as well as their salts and solvate.

Compounds (d), (e) and (f) serve as intermediate products.

About all residues present in the compounds, as for example, specify that their values do not depend on each other.

The solvate represent, for example, semi-, mono - or dihydrate or, for example, the addition products with alcohols.

Balance And represents the alkyl has 1-10, preferably 1, 2, 3, 4, 5 or 6 and especially 1 or 2 C-atoms, so its main value is, for example, methyl, additionally, it signifies ethyl, n-propyl, and who, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl, also referred to as vermeil, deformity, trifluoromethyl, 1,1,1-trichloroethyl or pentafluoroethyl.

Cycloalkyl is a first, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-substituted.

OA represents preferably methoxy, and ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is a preferred methylamino, then ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA2means preferably dimethylamino, then N-ethyl-N-methylamino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino. On this basis, CO-NHA preferably denotes N-methylcarbamoyl or N-ethylcarbamate; a CO-NA2means preferably N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.

Hal represents fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, k represents 0 or 1, preferably 0. If k denotes 1, the mean intermediate products for IC R1represents preferably unsubstituted or one - or twofold substituted, but first of all, once substituted by a group of Hal, CN, A, AO, HE CONH2, CONHA, CONA2, COOH and/or cooa 2 - or 3-indolyl, and 5H-1,3-dioxolo[4,5-P-7-indolyl, which may be unsubstituted, single or twofold substituted by a group of Hal, CN, A, AO, or HE, but primarily this residue is unsubstituted. The preferred values of R1are therefore the following: 2 - or 3-indolyl, 5 - or 6-methylindol-2-yl, 5 - or 6-methylindol-3-yl, 5 - or 6-methoxyindol-2-yl, 5 - or 6-methoxyindol-3-yl, 5 - or 6-hydroxyindole-2-yl, 5 - or 6-hydroxyindole-3-yl, 5 - or 6-Florinda-2-yl, 5 - or 6-Florinda-3-yl, 5 - or 6-laninga-2-yl, 5 - or 6-laninga-3-yl, 5 - or 6-Clorinda-2-yl, 5 - or 6-Clorinda-3-yl, 5 - or 6-carboxybenzoyl-2-yl, 5 - or 6-carboxybenzoyl-3-yl, 5 - or 6-methoxycarbonyl-2-yl, 5 - or 6-methoxycarbonylmethyl-3-yl, 5H-1,3-dioxolo[4,5-f] indol-7-yl, 5-or 6-bromoindole-2-yl, 5 - or 6-bromoindole-3-yl, 5 - or 6-ethylindole-2-yl, 5 - or 6-ethylindole-3-yl, 5 - or 6-cryptomaterial-2-yl, 5 - or 6-cryptomaterial-3-yl, 5 - or 6-isopropylindole-2-yl, 5 - or 6-isopropylindole-3-yl, 5 - or 6-dimethylaminoethyl-3-yl or 5 - or 6-dimethylaminoethyl-2-yl, 5 - or 6-acetamidine either one, two - or three-fold substituted by a group of Hal, HE, OA, A, NH2, NHA, NA2, CONH2, CONHA, CONA2, COOH, COA, CF3CN, OSO2A, OSO2CF3and/or NO2benzyl or phenylhydroxylamine. In accordance with this R2stands above all preferably benzyl, phenylhydroxylamine and once substituted by a group Hal benzyl or phenylhydroxylamine, i.e., for example, p-terbisil or p-florfenicol, p-methylbenzyl or p-methylphenylhydrazine, p-Chlorobenzyl or p-chlorophenylhydrazone. The preferred values of R2are next p-aminobenzyl, p-methylaminophenol, p-dimethylaminophenyl, p-ethylaminomethyl, p-cyanobenzyl, m-tormentil, m-methylbenzyl or m-methylphenylhydrazine, p-nitrobenzyl or p-nitrophenylhydrazine.

For the invention is generally true that all residues, which can repeatedly be present in the molecule may be identical or different values, i.e., independently from each other.

In accordance with this object of the invention are such compounds of formula I in which at least one of these residues has one of the abovementioned preferred meanings. Some preferred grimbane more residues have the same value, as in the formula I, but there are some differences, namely:

in 1A R1denotes unsubstituted 3-indolyl;

in Ib R1in position 5 denotes a substituted 3-indolyl;

in 1C K stands for 0, a m is 4;

in Id K stands for 1, and m is 3;

in Ie R1has the meaning specified in Ib, and the Deputy is Hal, and also indicates methoxycarbonyl, CN or carboxypropyl;

If R1indicates 5H-1,3-dioxolo[4,5-g]indol-7-yl;

in Ig R2denotes unsubstituted benzyl;

in Ih R2has the value shown in Ig, but benzyl ring is substituted once;

in Ii R2has the meaning specified in Ih, and the Deputy is Hal;

in Ij R2represents an unsubstituted or substituted once phenylhydroxylamine;

in Ik R2has the meaning specified in Ij, and the Deputy is Hal.

The object of the invention is further a method of producing compounds of the formula I and their salts and solvate. The method differs in that the compound of formula II

< / BR>
in which R2has the above meaning, is subjected to the interaction with the compound of the formula III

R1-(CH2)m-(CO)k-L (III)

in oznachaet alkyl, or any other reactionsare esterified HE group, or easily nucleophile substitutable leaving group, and R1, m and k have the meanings specified in paragraph 1 of the formula, or by reductive amination of the compound of formula IV

R1-(CH2)m-1-CHO (IV)

in which R1and m have the meanings specified in paragraph 1 of the formula, is subjected to the interaction with the compound of the formula II, or that any compound falling within formula I, but instead of containing one or more hydrogen atoms of one or more recoverable groups such as C=O, and/or one or more additional C-C and/or C-N-bonds is treated with a reducing agent, or that any compound falling within formula I, but instead of containing one or more hydrogen atoms of one or more solvolysis groups, process by means of solvolysis, and/or that under certain conditions the remainder R1and/or R2turn in the remainder R1and/or R2for example, by splitting OA-group with the formation of Oh-groups and/or by derivatization CN-, COOH-, cooa groups and/or by alkylation, for example, primary or secondary N-atom and/or obtained by transformation axle obtain compounds of the formula I is carried out in principle by known methods, described in the literature (for example, in a seminal publications such as Houben-Weyl, Methods der Organischen Chemie, published by Georg Thieme Verlag, Stuttgart; Organic Reactions, published by John Wiley & Sons, Inc. , New York; DE-OS 4101686), namely, when the conditions are known and suitable for the above exchange reactions. You can use these options, which in the present description are not mentioned in more detail.

Source materials required for carrying out the method, if necessary, can also be obtained in situ, that is, without separating them from the reaction mixture, and directly using the subsequent conversion into the compounds of formula I.

The compounds of formula I are preferably obtained by interaction of the compounds of the formula II with compounds of formula III. Source materials of formulas II and III, generally known; no known compounds of formulas II and III can be easily obtained analogously to known compounds.

Derivatives of piperidine of formula II for the most part known. If they cannot be purchased commercially or if they are not known, they can be obtained using known methods.

Derivatives of indole of formula III is mostly known and partly also reveal who eat electrophilic, and in certain cases also by nucleophilic aromatic substitution. As a starting substance is used preferably corresponding indole-3-alanovoy acid (obtained analogously to the synthesis of indole Fisher (the type of the Japp-Klingemann), cf. Bttcher and others, Journ. Med. Chem. 1992, 35, pp. 4020-4026 or Iyer and others, Journ. Chem. Soc. Perkin Trans. II, 1973, pp. 872-878). Acid group and then by introducing a reactive leaving groups L, optionally after preliminary reduction of the acid group by known methods, for example, by using hydride layalina in tetrahydrofuran, to the Oh-group, prepare to interact with the derivatives of piperidine.

The interaction of the compounds of formulas II and III are carried out by known literature methods used for alkylation, respectively acylation of amines. Components can be fused together in the absence of solvent, under certain conditions in the tube or in an autoclave. But you can also make connections in the presence of a neutral solvent. As solvents are suitable, among others, for example, hydrocarbons, such as benzene, toluene, xylene; ketones, such as acetone, butanone; alcohols such as methanol, ethanol, isoprop the f) or N-organic (N-MP); NITRILES, such as acetonitrile, under certain conditions it is possible to use mixtures of these solvents among themselves or mixed with water. It may be appropriate to add acid binding agent, such as hydroxide, carbonate or bicarbonate of an alkaline or alkaline-earth metal or any other salt of a weak acid of the alkali or alkaline-earth metals, preferably of potassium, sodium or calcium, or the addition of organic bases such as triethylamine, dimethylaniline, pyridine or quinoline, or the addition of excess piperidine derivative of formula II. Duration of response depending on the environment ranges from a few minutes up to 14 days, and the reaction temperature is in the range from approximately 0 to 150, usually from 20 to 130oC.

Under certain conditions prior to the implementation of this reaction is necessary before the process of alkylation or acylation to protect others contained amino groups, by introducing appropriate protective group. The concept of "aminosidine group" is well known and refers to groups that are capable of protecting the amino group from chemical reactions, but can be easily removed upon completion required the and off, in principle known to the person skilled in the technical field of the numerous literary sources and textbooks, the need for a more detailed explanation disappears.

The compounds of formula I can be obtained by reductive amination of compounds of the formula IV with compounds of the formula II. Educt of formula IV and II partially known. If they are not known, they can be obtained using known methods. Reductive amination can be performed in the presence of a reducing agent such as NaBH3CN and N(SLA)3.

Another possibility of obtaining the compounds of formula I is that forproduct that instead of hydrogen atoms contains one or more recoverable groups and/or one or more additional C-C and/or C-N-bonds is treated with a reducing agent, preferably at temperatures in the range from -80 to +250oWith the presence of at least one inert solvent. Recoverable (replaced by hydrogen) groups are primarily oxygen in a carbonyl group, hydroxyl, arylsulfonate (for example, p-toluensulfonate), N-benzazolyl, N-benzyl or O-benzyl.

When the sustained fashion ties, you can translate by recovering the compound of formula I; at the same time can recover the substituents in the group I contained in the initial connection. It is preferable to use the evolving hydrogen or complex hydrides of metals, in addition it is possible to restore the wolf-Kishner, as well as using gaseous hydrogen in the catalysis by transition metals.

If the reductant is planned to use the evolving hydrogen, the latter can be formed, for example, by treating metals with weak acids or bases. For example, you can use a mixture of zinc with caustic lye or iron with acetic acid. Acceptable to use the sodium or other alkali metal dissolved in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. In addition, there may be used aluminum alloy with Nickel in alkaline-aqueous solution, optionally with the addition of ethanol. For the formation of hydrogen is also suitable sodium amalgam or aluminum in hydroalcoholic or aqueous solution. The reaction can also be performed in a heterogeneous phase, while CE is preferably used as reducing agents are complex metal hydrides, such as LiAlH4, NaBH4the hydride diisobutylaluminum or NaAl(OCH2CH2OCH3)2H2and DIBORANE, if necessary with the addition of catalysts such as BF3, ll3or LiBr. As solvents suitable for these purposes are primarily ethers, in particular diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, as well as hydrocarbons, in particular benzene. When restoring using NaBH4preferred as solvents in the first place alcohols, such as methanol or ethanol, then water, and aqueous solutions of alcohols. The restoration of these methods is conducted preferably at temperatures in the range from -80 to +150, especially from about 0 to about 100oC. Particularly preferably able to recover-CO-group in amido acid to SN2groups using LiAlH4in THF at temperatures in the range of from about 0 to 66oC.

Another possibility is that one or more carbonyl groups to restore according to the method of wolf-Kishner to CH2groups, for example, by treatment with anhydrous hydrazine in absolute ethanol under their sodium alcoholate. Possible recovery by the method of Huang-Minlon, which is that the reaction is carried out using hydrazine hydrate in a high-boiling, mixed with water, a solvent such as diethylene glycol or triethylene glycol, in the presence of alkali, in particular sodium hydroxide. The reaction mixture is boiled at the same time, usually for about 3-4 hours. Then the water is distilled off and the resulting hydrazone decompose at temperatures up to about 200oC. Recovery of the wolf-Kishner can be performed at room temperature in dimethyl sulfoxide using hydrazine.

In addition, some of the reactions on the restoration can be carried out using gaseous N2when catalysis by transition metals, such as Raney Nickel or Pd. With this technology, for example, Cl, Br, I, SH, and in certain cases, and the Oh-group can be replaced by hydrogen. Equally the nitro group by catalytic hydrogenation using Pd/H2in methanol to turn in NH2group.

Compounds falling within the principle under formula I, but instead of containing one or more H atoms of one or more solvolysis groups may be subjected to solvolysis and preid the uly I by known methods can be transformed into any other compound of formula I.

The compounds of formula I in which R1denotes the residue, substituted CONH2, CONHA or CONA2can be obtained by derivatization of the corresponding substituted compounds of formula I by the partial hydrolysis. Another possibility is that lanzamiento the compounds of formula I first hydrolyzing to acids, which are then lidiruyut primary or secondary amines. Preferably the free carboxylic acid to expose the interaction with the amine under the conditions of peptide synthesis. This reaction is expedient to carry out preferably in the presence of a dehydration agent, such as carbodiimide, such as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; these may also be used anhydride papapostolou acid (compare Angew. Chem. 92, 129 (1980)), diphenylphosphoryl or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline in an inert solvent, for example in a halogenated hydrocarbon, such as dichloromethane, in a simple ether, such as THF or dioxane, in amide, such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures in the range of from approximately -10 to +40, preferably from 0 to 30oC. But it is particularly preferable to work ewu of trichloroacetamide /Et3[see Synthesis (2), 184 (1985)] or l3(see Journ. Org. Chem. 26. 1003 (1961)).

Received under formula I, can be translated using acid to the corresponding acid additive salt. For the implementation of this reaction is suitable acids forming physiologically acceptable salt. Thus, in particular, it is possible to use inorganic acids, for example sulfuric acid, halogen acids such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, Sultanova acid, and also organic acids, specifically aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic with one or mnogotonnye carbon, sulfo or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - libcelt, naphthalenamine and dissolvability, louisanna acid.

Free base of formula I can be liberated from their salts by treatment strong bases such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium, in cases where the molecule in the absence of other acid groups. In those cases, when the compounds of formula I have free acid groups, by treatment with bases also can be used to form salts. As such grounds are suitable hydroxides of alkali and alkali-earth metals or organic bases as primary, secondary or tertiary amines.

The compounds of formula I according to the invention due to their molecular structure can be chiral and in accordance with this can be presented in two enantiomeric or several diastereoisomeric forms. Therefore, due to the presence of one or more chiral centers, they can be represented in racemic or in optically active form.

Because the pharmaceutical effectiveness of the racemates, respectively stereoisomers of the compounds according to the invention, can be different, it may be appropriate to apply it Vastu well-known specialist chemical or physical operations can be divided into enantiomeric compounds either directly apply them as such for the synthesis.

In the case of racemic amines of the mixture by reacting with an optically active separating agent can be used to form diastereomers. As such separating agents are suitable, in particular, optically active acids, such as R - and S-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid, acceptable and N-protected amino acid or the various optically active camphorsulfonic acid. Preferably also the chromatographic separation of the enantiomers with an optically active separating agent (as, for example, dinitrobenzonitrile, cellulose triacetate or other derivatives of hydrocarbons or fixed on silica gel chiral derivateservlet metacrilate polymers). As eluents suitable for these purposes are water or alcohol solvent mixture.

In the case of racemic acids in a similar way can be used optically active base, such as R - and S-form of 1-phenethylamine, 1-naphthylethylene, dehydroabietylamine, cinchonine or cinchonidine.

When specific conditions are already in the process of synthesis is also possible skin is different ways. This chirality is preserved during the subsequent stages of the synthesis.

The object of the invention is further the use of compounds of the formula I and their physiologically acceptable salts for pharmaceutical compositions, primarily non-chemical way. While one together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance and optionally in combination with one or more other active substances can be made appropriate dosage form.

Another object of the invention is the means, especially a pharmaceutical composition, containing in its composition at least one compound of the formula I and/or one of its physiologically acceptable salts. These compositions can be used as drugs in medicine and in veterinary medicine. As substances vehicles in them acceptable organic or inorganic substances suitable for enteral (for example oral), parenteral or local administration and not reacts with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates shall be primarily tablets, tablets, capsules, syrups, tinctures, drops or suppositories, for parenteral administration are solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application can be assigned ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilizate be used, for example, for the manufacture of drugs for injection. These compositions can be sterilized and/or can contain such auxiliary substances as oil, preservatives, stabilizers and/or wetting, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, colorants, flavorings and/or flavorings. Optionally, the composition can include several other active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used in therapeutic applications for the treatment of humans and animals and to fight disease. They are suitable for the treatment of diseases of the Central nervous system, such as a state of tension, depression, fear, schizophrenia, disorders of the gastro-kicheche the treatment of hypertension (for example, -methyldopamine). In addition, the proposed connection can be used in endocrinology and gynaecology, for example for the treatment of acromegaly, hypogonadism, secondary amenorea, premenstrual syndrome, undesired puerperal (postpartum) lactation, in addition to the prevention and treatment of disorders associated with cerebral blood vessels (e.g., migraine headaches), primarily in geriatrics, like some ergotalkaloids.

Especially preferably, they can also be used as therapeutic agents to combat the effects of a stroke (apoplexia cerebri), in particular stroke and cerebral ischemia, and for the treatment of traumatic brain injuries and spinal cord.

Proposed in the invention substance prescribed as a rule, similar to well-known drugs with similar action, preferably in dosages of from about 0.1 to 500 mg, especially from 0.2 to 300 mg per uniform dose. The daily dose is preferably from about 0.001 to 250 mg/kg of body weight of the patient. However, assigned to a particular patient dose depends on a number of factors, in particular the effectiveness of the applied compound, the patient's age, weight, speed selection, the combination of drugs and the severity of the corresponding disease, treatment is therapy. Preferably oral administration.

Above and beyond all temperatures are in degrees Celsius. Under used in the following examples, the term "normal processing" we mean the following: if necessary, water is added, if necessary, depending on the structural characteristics of the final product set pH values from 2 to 10, extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel, but the following isomers, and/or by crystallization. Values of Rfwere determined using thin-layer chromatography on silica gel. The values of M++1 was identified by FAB-mass spectrometry (FAB - bombardment with accelerated atoms). These values of specific rotation of optically active compounds was measured in each case on the solutions of the free bases.

Example 1

a) a Solution of 4-(5-Florinda-3-yl)butane acid [obtained, for example, by diazotization of sauvetat method Japp-Klingemann obtaining in the corresponding 4-(5-fluoro-2-ethoxy-carbanilide-3-yl)butane acid and subsequent saponification and decarboxylation ethoxycarbonyl group] in THF subjected to restore using hydride layalina. After the usual processing receive 4-(5-Florinda-3-yl)butanol, which then interact with the acid chloride of methansulfonate transferred to the reactive 4-(5-Florinda-3-yl)butyl ether methanesulfonate.

b) a Mixture of 2,80 g (0,0098 mole) of 4-(5-Florinda-3-yl)butyl ether methanesulfonate, 3,20 g (0,0097 mol) of (S)-(+)-(almond acid/3-benzylpiperidine), 3.80 g (0,0294 mole) of ethyldiethanolamine heated in 100 ml of acetonitrile for about 96 hours on the steam bath. Then the reaction mixture was filtered and concentrated, the residue is dissolved in ethyl acetate and extracted with water. The organic phase is processed and the remainder chromatographic in ethyl acetate at silicagel column. Fraction is concentrated and the residue is dissolved in ethyl acetate and with Hcl in ethanol precipitated hydrochloride 3- {4-[(38)-3-benzylpiperidine-1-yl]butyl} -5-farindola, which is subjected to further processing, tPLto 152.0-153,0oC,20D(+) 9,7o(1.0, dimethylsulfoxide).

In a similar way interactions 4-(5-Florinda-3-yl)butyl ether methanesulfonate with (R)-(-)-(3-benzylpiperidine)Mandelstam receive the corresponding hydrochloride 3- {4- [(3R)-3-benzylpiperidine-1-yl] butyl] -5-farindola with t
(+)-3-[4-(3-benzylpiperidine-1-yl)butyl] indole, tPL74-75o,20D(+) 22,1o(1.0, dimethylsulfoxide);

(-)-3-[4-(3-benzylpiperidine-1-yl)butyl] indole, tPL73-74o,20D(-) 22,8o(1.0, dimethylsulfoxide);

methyl ester(+)-3- {4- [3-(3S')-benzylpiperidine-1-yl]butyl}indole-5-carboxylic acid, 20D(+) 6,0o(1.0, dimethylsulfoxide);

methyl ester(-)-3- {4-[3-(3R')-benzylpiperidine-1-yl}butyl]indole-5-carboxylic acid, 20D(-) 8,1o(1.0, dimethylsulfoxide);

3-{ 4-[(3R')-3-benzylpiperidine-1-yl] butyl}-6-methoxyindol, hydrochloride, tPL218 to 221o,20D(-) 7,3o(1.0, dimethylsulfoxide);

3-{ 4- [(3S')-3-benzylpiperidine-1-yl}butyl]-6-methoxyindole, hydrochloride, tPL217 to 220o,20D(+) 7,5o(1.0, dimethylsulfoxide).

Example 2

Analogously to example 1A) and b), but without the addition envisaged at the stage b) almond acid, from 4-(5-Florinda-3-yl)butane acid 4-(5-Florinda-3-yl)butyl ether methanesulfonate interaction with 3-benzylpiperidine receive 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-Florinda, hydrochloride, tPL163-165oC.

Similar by saidin-1-yl) butyl] indole, hydrochloride, tPL134-136oC;

the interaction of 4-(5-Clorinda-3-yl)butyl ether methanesulfonate with 3-benzylpiperidine receive 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-chlorinda, malonate, tPL127-129oC;

the interaction of 4-(5-Florinda-3-yl)butyl ether methanesulfonate with 3-(4-forensic) piperidine get 3-[4-[3-(4-terbisil)piperidine-1-yl] butyl}-5-Florinda.

Example 3

The solution of equivalent amounts of 3-benzylpiperidine and 3-(4-chlorobutyl)-5-caninde (obtained, for example, gorodilova corresponding alcohol compounds, which can be obtained analogously to example 1A) recovery of 4-(5-laninga-3-yl)butane acid) in acetonitrile was stirred at room temperature for about 6 hours. After the usual processing and separation of chiral compounds obtained 3- {4- [(3S)-3-benzylpiperidine-3-yl]butyl}-5-laninga,20D(+) 8,9o(1,0, dimethyl sulfoxide), in the form of hydrochloride, tPL65-67o(Amorphous); or the corresponding 3- {4- [(3R)-3-benzylpiperidine-3-yl] butyl}-5-laninga,20D(-)10,4o(c1,0 sulfoxide), in the form of hydrochloride, tPL65-75o(Amorphous).

Similar by mo Meon 95:5);

7- {4-[(3S)-3-benzylpiperidine-1-yl]butyl]-5H-1,3-dioxolo[4,5-f] indole, Rf0,4 (l3: Meon 95:5).

Example 4

Equimolar quantities of 3-benzylpiperidine and 4-(5-methoxyindol-3-yl)butane acid (getting analogously to example 1A) is subjected in THF at room temperature the interaction between them, adding 2-chloro-1-methylpyridinium. After the usual processing gain 3-benzyl-1-[4-(5-methoxyindol-3-yl)butanoyl] piperidine.

In a similar way get:

3-benzyl-1-[4-(5-Florinda-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(5-Clorinda-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-Clorinda-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-Florinda-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-methoxyindol-3-yl) butanoyl]piperidine;

3-benzyl-1-[4-(6-taxiing-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(5-taxiing-3-yl) butanoyl]piperidine;

3-benzyl-1-[4-(5-laninga-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-laninga-3-yl)butanoyl]piperidine;

3-benzyl-1-[4-(5-Florinda-2-yl)butanoyl]piperidine;

3-benzyl-1-[4-(5-Clorinda-2-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-Clorinda-2-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-Florinda-2-yl)butanoyl]piperidine;

3-benzyl-1-[41-[4-(5-taxiing-2-yl)butanoyl]piperidine;

3-benzyl-1-[4-(5-laninga-2-yl)butanoyl]piperidine;

3-benzyl-1-[4-(6-laninga-2-yl)butanoyl]piperidine.

Example 5

3-benzyl-1- [4- (5-methoxyindol-3-yl)butanoyl]piperidine put in THF interaction with hydride layalina. After the usual processing gain 3- [4-(3-benzylpiperidine-1-yl)butyl-5-methoxyindol, hydrochloride, tPL222-224oC.

In a similar way can be obtained:

3- [4-(3-benzylpiperidine-1-yl)butyl]-5-Florinda;

3- [4-(3-benzylpiperidine-1-yl)butyl]-5-chlorinda;

3- [4-(3-benzylpiperidine-1-yl)butyl]-6-chlorinda;

3- [4-(3-benzylpiperidine-1-yl)butyl]-6-Florinda;

3- [4-(3-benzylpiperidine-1-yl)butyl]-6-methoxyindole;

3- [4-(3-benzylpiperidine-1-yl)butyl]-6-taxiing;

3- [4-(3-benzylpiperidine-1-yl)butyl]-5-taxiing;

3-[4-(3-benzylpiperidine-1-yl)butyl]-5-tsianina;

3-[4-(3-benzylpiperidine-1-yl)butyl]-6-tsianina;

2-[4-(3-benzylpiperidine-1-yl)butyl]-5-Florinda;

2-[4-(3-benzylpiperidine-1-yl)butyl]-5-chlorinda;

2-[4-(3-benzylpiperidine-1-yl)butyl]-6-chlorinda;

2-[4-(3-benzylpiperidine-1-yl)butyl]-6-Florinda;

2-[4-(3-benzylpiperidine-1-yl)butyl]-6-methoxyindole;

2-[4-(3-benzylpiperidine-1-yl)butyl]-6-taxiing;

2-[4-(3-benzylpiperidine-1l]-6-laninga.

Example 6

3-[4-(3-benzoylpiperidine-1-yl)butyl] indole interaction in THF with sodium borohydride is subjected to reaction recovery. After the usual processing gain 3-[4-(3-phenylhydroxylamine-1-yl) butyl] indole, hydrochloride, tPL181-183oC.

In a similar way get:

3-[4-(3-phenylhydroxylamine-1-yl)butyl]-5-Florinda;

3-{4-[3-(3R)-phenylhydroxylamine-1-yl]butyl]-6-methoxyindole;

3-t4-13-(3S')-phenylhydroxylamine-1-yl]butyl]-6-methoxyindole;

3-[4-(3-phenylhydroxylamine-1-yl)butyl]-5-chlorinda;

3-[4-(3-phenylhydroxylamine-1-yl)butyl]-5-methoxyindol;

3-{4-[3-(4-florfenicol)piperidine-1-yl]butyl]-5-Florinda;

3-{4-[(3R)-3-phenylhydroxylamine-1-yl]butyl]-5-Florinda;

3-{4-[(3S)-3-phenylhydroxylamine-1-yl]butyl}-5-Florinda;

3-{ 4-[(3R)-3-phenylhydroxylamine-1-yl] butyl}-indol-5-carbonitrile;

3-{ 4-[(3S)-3-phenylhydroxylamine-1-yl] butyl]-indole-5-carbonitrile;

3-{ 4-[3-(4-florfenicol)piperidine-1-yl] butyl]-indole-5-carbonitrile, tPL157-159o.

Example 7

A mixture of 0,0098 mole of 4-(methyl ester 5-carboxylic acid indol-3-yl) butyl ether metaspatial for approximately 96 hours on the steam bath. Then the reaction mixture as described in the example of process technology and clean. The result is the methyl ester of 3-[4-(3-benzylpiperidine-1-yl)butyl]indole-5-carboxylic acid, hydrochloride, tPL181-183oC.

In a similar way can be obtained:

methyl ester 3-{4-[3-(4-terbisil)piperidine-1-yl]butyl]indole-5-carboxylic acid;

methyl ester of 3-{4-13-(4-tenbensel)piperidine-1-yl]butyl}indole-5-carboxylic acid;

methyl ester 3-{4-[3-(4-the active compounds)piperidine-1-yl]butyl}indole-5-carboxylic acid;

methyl ester 3-{4-[3-(4-methylbenzyl)piperidine-1-yl]butyl]indole-5-carboxylic acid;

methyl ester 3-{4-[3-(4-methoxybenzyl)piperidine-1-yl]butyl]indole-5-carboxylic acid;

methyl ester 3-{4-[3-(4-terbisil)piperidine-1-yl]butyl]indole-6-carboxylic acid;

methyl ester 3-{4-[3-(4-terbisil)piperidine-1-yl]butyl}indole-5-carboxylic acid;

methyl ester of 3-[4-(3-benzylpiperidine-1-yl)butyl]indole-6-carboxylic acid;

methyl ester 3-{4-[3-(4-tenbensel)piperidine-1-yl]butyl}indole-6-carboxylic acid;

methyl ester 3-{4-[3-(4-methylbenzyl)piperidine-1-yl]butyl}indole-6-carboxylic acid.

Example 8

A mixture of methyl ester of 3-[4-(3-be the normal processing gain 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-carboxyla, hydrate, tPL144-147oC.

Example: Vials for injection solutions

A solution of 100 g of the active substance of the formula I and 5 g of disodium hydrogen phosphate in C l double-distilled water using 2 N. hydrochloric acid set at pH 6.5, sterile filtered, filled flask, lyophilized in sterile sterile conditions and sealed. Each vial contains 5 mg of active substance.

Example B: Suppositories

A mixture of 20 g of the active substance of the formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to harden. 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 of benzalkonium chloride in 940 ml of double-distilled water. Then set to pH 6.8, adjusted to a volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

When observing aseptic conditions prepare a mixture of 500 mg of the active substance of the formula I with 99.5 g of petroleum jelly.

Example D: Tablets

A mixture of 1 kg of active substance of pharmaology, receiving tablets, each containing 10 mg of active substance.

Example E: Bean

Analogously to example D is pressed tablets, which then according to standard technology is covered by a shell of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of active substance of the formula I according to standard technology to produce capsules with terrorisation coating, each of which contains 20 mg of active substance.

Example C: Ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double-distilled water is sterile filtered, dispensed into ampoules under sterile conditions lyophilized sealed and sterile. Each ampoule contains 10 m g of the active substance.

REPORT ON PHARMACOLOGICAL TRIALS

In the statement of pharmacological tests described test compounds, their melting temperature, the values of IC50or Ki for these compounds, tested in three different tests, and the number of the example, the page and line numbers (see Russian translation of the description), where these compounds are described.

Table 1 shows the inhibition constants for a number of typical compounds;

value floors I

< / BR>
in which R1denotes unsubstituted or substituted groups Hal, CN, AB, COOH or cooa 2 - or 3-indolyl, 5H-1,3-dioxolo[4,5-f]-7-indolyl;

R2denotes unsubstituted or substituted by groups a, AO, Hal, or CN benzyl or phenylhydroxylamine;

Hal denotes F, Cl, Br or J;

And denotes alkyl with 1-10 C-atoms;

k represents 0 or 1;

m denotes 1, 2, 3, or 4

in the form of racemic mixtures or individual stereoisomers as well as their physiologically acceptable salt and solvate.

2. The stereoisomers of the compounds of formula I under item 1.

3. Connection under item 1 or 2, selected from the group including

a) 3-[4-(3-benzylpiperidine-1-yl)butyl]indole;

b) 3-[4-(3-phenylhydroxylamine-1-yl)butyl]indole;

C) 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-Florinda;

g) 3-benzyl-1-[4-(5-Florinda-z-yl)butanoyl]piperidine;

d) 3-benzyl-1-[4-(5-Clorinda-3-yl)butanoyl]piperidine;

e) 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-carboxyla;

f) methyl ester 3-[4-(3-benzylpiperidine-1-yl)butyl]indole-5-carboxylic acid;

C) methyl ester(-)-3-{4-[3-(3R')-benzylpiperidine-1-yl]butyl}indole-5-carboxylic acid;

and) methyl ester(+)-3-{4-[3-(3S')-benzylpiperidine-1-yl]butyl}indole-5-carboxylic acid;
m) (+)-3-[4-(3-benzylpiperidine-1-yl)butyl]indole;

n) (-)-3-[4-(3-benzylpiperidine-1-yl)butyl]indole;

o) 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-chlorinda;

p) 3-[4-(3-benzylpiperidine-1-yl)butyl]-5-methoxyindol;

p) 3-{4-[3-(4-terbisil)piperidine-1-yl]butyl}-5-Florinda;

C) 7-{4-[(3R)-3-benzylpiperidine-1-yl]butyl}-5H-1,3-dioxolo[4,5-f]indole;

t) 7-{4-[(3S)-3-benzylpiperidine-1-yl]butyl}-5H-1,3-dioxolo[4,5-f]indole;

I) 3-{4-[(3R)-3-benzylpiperidine-1-yl]butyl}-5-Florinda;

f) 3-{4-[(3S)-3-benzylpiperidine-1-yl]butyl}-5-Florinda;

x) 3-{4-[(3R)-3-benzylpiperidine-1-yl]butyl}indole-5-carbonitrile;

C) 3-{4-[(3S)-3-benzylpiperidine-1-yl]butyl}indole-5-carbonitrile;

h) 3-{ 4-[3-(4-florfenicol)piperidine-1-yl]butyl}indole-5-carbonitrile,

as well as their salts and solvate.

4. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula II

< / BR>
in which R has the meaning specified in paragraph 1, is subjected to the interaction with the compound of the formula III

R1-(CH2)m-(CO)k-L, (III)

in which L denotes Cl, Br, I, HE, OSOA, OCOPh, OSO2A, OSO2Ar, where Ar represents a phenyl or tolyl and a denotes alkyl, or any other reactive esterified HE is the group or is the divergence of the compound obtained of the formula I, contains instead of one or more hydrogen atoms of one or more recoverable groups, is treated with a reducing agent, to obtain the compounds of formula I containing one or more hydrogen atoms; and/or residue R1and/or R2in the resulting compound of the formula I is converted into another residue R1and/or R2by splitting OA-group with the formation of the Oh-group, and/or the resulting compound of formula I is transferred into one of its salts by treatment with acid or base.

5. The pharmaceutical composition intended for use as an inhibitor of reuptake 5H-T, containing in its composition at least one compound of General formula I and/or one of its physiologically acceptable salts.

 

Same patents:

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to compounds which inhibit the protease encoded by human immunodeficiency virus, or their pharmaceutically acceptable salts, and such compounds are used for the prevention of infection by HIV, treating infection by HIV and the treatment of acquired as a result immunodeficiency syndrome (AIDS)

The invention relates to new derivatives of pyrrolidine or piperidine F.-ly (I), their enantiomers and pharmaceutically acceptable salts

< / BR>
where R10- H or C(O)N(R1)YZ, R1- N, Y - (CH2)p, (CH2)qCH(R3) or CH(R3)(CH2)q, R3- aryl, aralkyl or heteroaryl, q = 1-3, p = 2 or 3, Z - CO2H, CO2-alkyl or 5-tetrazol, X-S(O) M-(CH2)nor piperidine-1-yl, m = 2, n = 2, R5Mr. And selected from piperidine-2-yl, piperidine-3-yl, piperidine-4-yl or N-substituted piperidine

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to pharmaceutical compositions containing two or more compounds having anti-HIV activity

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

The invention relates to methods of reducing the level of TNFin mammals and connections that are applicable for this purpose

The invention relates to new derivatives of chloropyridinyl formula I where Het is a group of formula a, b, C, d or e, R1is hydrogen, unsubstituted or substituted C1- C6alkyl, and the substituents selected from the group comprising halogen, phenyl, cyano, C1- C4alkoxy, C1- C4alkylthio,1- C4alkylsulphonyl; C2- C4alkenyl, unsubstituted or substituted C1- C4alkoxygroup; phenyl or unsubstituted or substituted 1 or 21- C4alkoxygroup, n = 1 or 2, and their acid additive salts

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity

The invention relates to new triazinyl compounds of formulas Ia and Ib:

< / BR>
or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment
Up!