Derivatives of azetidine and pyrrolidine

 

(57) Abstract:

The invention relates to new derivatives of azetidine and pyrrolidine General formula

< / BR>
where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidine. The connection I have affinity to the 5-NTS-receptor, which allows their use in pharmaceutical compositions for the treatment or prevention of serotoninovykh disorders. 2 s and 5 C.p. f-crystals, 3 tables.

The invention relates to a derivative of azetidine and pyrrolidine containing their pharmaceutical compositions, and method of production thereof, and use of derivatives of azetidine and pyrrolidine to obtain medication that acts on the Central nervous system.

In recent years, the well-documented contribution serotoninergicheskoi activity in the mechanism delouses as antidepressants. Inhibitors of serotonin reuptake (SRI) work by increasing the amount of serotonin available in the synapse. While (SRI) have less severe side effects compared to previous generations, but they have weaknesses and are retarded effect [Andrews and Nemero, "Contemporary management of depression" - the American Journal of Medicine 97(6A): 24S-32S (1994); Leonard, "The comparative pharmacology of new antidepressants" - Journal of Clinical Psychiatry 54(Suppl): 3-15 (1993)] . Moreover, the mechanism of action of SRI, although specific to serotonin, is not selective, since they affect the activity with many different subtypes of serotonin receptors. Such a wide spectrum of activity can lead to many side effects associated with (SRI), for example, nausea activating 5-NT3, headache due to activation of 5-NTV. Thus, SRI can change several subtypes of receptors 5-HT2, however, the effectiveness of these medications can be most strongly correlated with their effect on the system 5-NTS [(Broekkamp and Berendsen "The importance of 5-HT1C receptors for antidepressant effects," Polish Journal of Pharmacology and Pharmacy 44 (Suppl): 20(1992); Cesana et al. "Mesulergine antagonism towards the fluoxetine antiimmobility effect in the forced swimming test in mice", the Journal of Pharmacy and Pharmacology, 45: 473-475 (1993); Berendsen and Broekkamp "Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists Nene, which selectively activate the receptor 5-NTS will be effective in the treatment of emotional disorders and related conditions.

The present invention relates to compounds of the formula I

< / BR>
in which a represents optionally saturated 5 - or 6-membered ring which may contain heteroatom selected from N, O and S, and which may be substituted by oxo or (1-6C)alkyl; R1, R2and R3independently represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, or halogen atom; X is O or S and n = 1 or 2; or pharmaceutically acceptable salts, with the exception of 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahedronal-1-yl-oxy)-pyrrolidine. These compounds have a selective action on the receptors 5-NTS in the Central nervous system.

In U.S. patent 4452809 [filed April 22, 1983] disclosed are 3-aryloxy-4-hydroxypyrrolidine and it was found that 3-naphthyl or 3-inderalici-4-oxopyrrolidin possess antiarrhythmic activity, whereas 3-phenoxy-4-hydroxypyrrolidine have antidepressant effects. A few years earlier, in the German patent 2738477 [the priority date of 1 September 1977] have also been disclosed 3-aryloxy-4-hydroxypyrrolidine, and prepost alidina, where pyrolidine group in all compounds is N-substituted affecting the serotonin receptor, has been disclosed in European patent 0338331 [with a priority of April 19, 1988].

Suddenly, after many years of research it was found that the compounds of formula I (bicyclic aryl)oxy-substituted pyrrolidine and (bicyclic aryl)oxy-substituted azetidine, in which 5 - or 4-membered heterocycle is not substituted in any of the provisions of the rings, have a selective action on the receptors 5-NTS in the Central nervous system. It was also found that the compounds 3-(naphthas-1-yl-oxy)-pyrrolidin and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)pyrrolidin, known as intermediate compounds, but not claimed in the European patent 0338331, have this effect. Therefore, it is necessary to seek protection on the use of these compounds and containing pharmaceutical compositions. Thus, the present invention also relates to the first medical use of the compounds of formula I, i.e. including the compound 3-(naphthas-1-yl-oxy)-pyrrolidine, 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin for use as a medicine (or, in other words, for use in therapy).

Using select and the receptors 5-NTS, allowing for much more rapid growth of selective pharmacological activation than observed at SRI. Moreover, the selectivity of such compounds reduces the probability of negative effects caused by other serotonin receptors, such as nausea, headache, effects that can interfere with the detection of complications and thus have a negative impact on the effectiveness of the drug.

Compounds of the present invention act on the Central nervous system, in particular as antidepressants and against Intrusive emotional disorders, anxiety, including General anxiety, panic attacks, agoraphobia, disorders associated with eating, such as obesity, incontinence, impotence, aggression and abuse of drugs, such as addiction to alcohol or drugs.

Preferred compounds of the present invention have the formula I, in which the heteroatom radical And, if present, is an atom N or S; R1means a hydrogen atom, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl; R2means a hydrogen atom, (1-6C)alkoxy or halogen, and R3is the Sabbath.)

< / BR>
in which a represents an unsubstituted saturated 5-membered or optionally aromatic 6-membered ring which may contain a nitrogen atom adjacent to the position indicated by the asterisk; R1means a hydrogen atom or (1-6C)alkoxy; R2means a hydrogen atom, (1-6C)alkoxy or halogen atom; R3represents a hydrogen atom or a halogen atom; and n = 1 or 2. More preferred are the compounds of formula (Ia) in which a represents unsubstituted saturated 5-membered or optionally aromatic 6-membered ring; the radical R1mean (1-6C)alkoxy, and the radicals R2and R3represent a hydrogen atom. Most preferably, when a in the formula (Ia) represents a 5-membered ring and the radicals R1represents a methoxy group, especially when n = 2.

The term (1-6C)alkyl means a branched or unbranched alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl and the like. The most preferred alkyl group is methyl.

The term (1-6C)alkoxy means alkoxygroup containing 1-6 carbon atoms, alkyl residue, which has the above Sacaton fluorine, chlorine or bromine.

The compounds of formula I can be obtained by a method known to those compounds. At this stage of the compounds of General formula II, in which A, R1, R2, R3, X and n have the meanings defined above, and P is any N-protective group which is stable under alkaline conditions [suitable for use N-protective group can be found in the publication T. W. Green and P. G. M. Wuts: Protective Groups in Organic Synthesis, Second Edition (Wiley, NY, 1991)], is subjected to reaction o protective group using appropriate conditions, such as catalytic hydrogenation or the formation of an intermediate carbamate, followed by interaction with alcohols. Not necessarily at the same time, can form a salt.

< / BR>
Compounds of General formula (II) can be obtained by simple education of alleyra corresponding N-protected 3-hydroxy-azetidine or pyrrolidine, in which the protective group is a group specified above, with an appropriately substituted aromatic or heteroaromatic compounds containing acceptable tsepliaeva group. In another embodiment, the N-protected-azetidine or pyrrolidine containing the appropriate tsepliaeva gruppovushka follows substituted aromatic or heteroaromatic compounds, containing hydroxy or mercaptopropyl. Compounds of the present invention, which may be in free base form, can be isolated from the reaction mixture in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts can also be obtained by treating the free base of formula I with organic or mineral acid, such as hydrochloric, Hydrobromic, idiscovered, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonate, succinato acid, oxalic acid, citric acid, benzoic acid, ascorbic acid, and the like. Compounds of the present invention may contain one or more chiral carbon atoms and can therefore be obtained in the form of a pure enantiomer or as a mixture of enantiomers or as a mixture containing diastereomers. Methods of obtaining pure enantiomers are well known, for example, crystallization of salts, which are obtained from optically active acids and racemic mixtures, or chromatography using chiral columns.

Compounds of the present invention can be in is preferably 0.01 to 10.0 mg per 1 kg of body weight. Being mixed with a pharmaceutically acceptable ingredients, for example, as described in the standard reference, Gennaro et al. , Remington''s Pharmaceutical Sciences (18th ed. , Mack Publishing Company, 1990, Part 8: Pharmaceutical Preparations and their Manufacture), these compounds can be compressed into a solid single dose, such as pills, tablets, or may be used for the manufacture of capsules or suppositories. With the help of pharmaceutically acceptable liquids, these compounds can be introduced in the form of a solution, suspension, emulsion, for example, for use as drugs for injection, or as sprays, for example, for use as a nasal spray. For the manufacture of single doses, for example, tablets, discusses the use of conventional additives such as fillers, dyes, polymeric binder, and the like. In General, there may be used any pharmaceutically acceptable additive, which does not affect the action of active compounds.

Acceptable carriers, with which the composition can be introduced include lactose, starch, cellulose derivatives and the like, or mixtures thereof, in an appropriate amount.

Further, the present invention is illustrated by the following note the sa is to obtain acceptable N-protected-3-hydroxy-azetidine or pyrrolidine followed by the formation of simple alleyra.

Wear any protective group which is stable under alkaline reaction conditions combinations. This also applies to the ranks of pyrrolidino, where the benzyl group is the most appropriate and most convenient protecting group. As azetidinol, for easier education azetidinone ring in the synthesis process can be used bulky groups, such as triphenylmethyl, 4,4'-disubstituted diphenylmethyl-methylbenzyl and to choose diphenylmethyl. These compounds can be obtained by reaction of the corresponding primary amines with epichlorohydrin in the medium polar solvent, such as methanol or dimethylformamide, at elevated temperatures lying in the range from room temperature to the boiling temperature under reflux, usually within a few days.

N-Protected-3-hydroxy-azetidine and - pyrrolidone can be used as such in the condensation reaction with a wide range of compounds containing acceptable tsepliaeva group on an aromatic residue, to form a simple ether. When tsepliaeva group is, for example, halogen atom, the reaction may SAG is Aliya, in the presence of catalytically activated such copper at elevated temperatures ranging from room temperature to the boiling temperature under reflux.

The preferred second stage of the General process of the hydroxy-group of N-protected-3-hydroxy-azetidine and pyrrolidine transform using well known methods in reactive tsepliaeva group, such as for example, halogen atom, triplet, toilet and to choose mesilate, to carry out a subsequent condensation reaction with a wide range of compounds containing in the aromatic part of the hydroxy (or mercapto)group, to obtain a wide range of simple arolovich esters, as well as simple arolovich thioesters.

The mesylates conveniently be obtained by adding methanesulfonanilide to 3-hydroxidealuminum in the environment of a non-polar solvent, such as toluene, in the presence of organic bases such as triethylamine, at temperatures between -30oC to the boiling temperature under reflux, typically at a lower temperature.

Although it can be used with all common reactions of formation of simple arylalkyl esters known from the literature, but most compounds asprihanal to obtain, consists of a heterogeneous two-phase reaction between mesilate and the appropriate nucleophile, preferably a bicyclic compound containing an aromatic hydroxy or mercaptopropyl. Two-phase system consisting of an aqueous solution of an inorganic base such as sodium hydroxide, and an organic layer, preferably 4-methyl-2-pentanone. The reaction is carried out at a temperature of 25oC to the boiling temperature under reflux, preferably at elevated temperature.

(ii) a Second receiving method consists in the condensation reaction of both substrates, nelfinavir and the nucleophile, in the environment of the polar organic solvent, such as tert-butanol or dimethyl sulfoxide, or mixtures thereof, and the appropriate base, such tert-piperonyl potassium, usually at elevated temperatures lying in the range 25 - 100oC.

(iii) the Third method of obtaining is the formation of anion-like base sodium hydride and subsequent reaction with mesilate in the environment of the polar organic solvent, such as dimethylformamide, typically at elevated temperatures lying in the range 25oWith up to boiling under reflux.

The third stage of secondary amines. Consideration should be involved in all the traditional methods relating to the selected protective group. As for Uralkalij groups, is widely used in the present invention, preferred are methods of removal of the protective groups of the two types. The first method is to remove the protective group using catalytic hydrogenation at pressures varying from atmospheric to 420 kPa in the medium polar solvent, such as ethanol or methanol, in the presence of a widely used catalyst, such as palladium on activated carbon or palladium hydroxide on carbon, at 25-60oC. the Second method is to replace the original protective group on the intermediate urethane functional group, which is then removed. Suitable for use reagents are, for example, 1-chloroethyl chloroformate or vinylchloride in an aprotic solvent such as 1,2-dichloroethane, at a temperature of from -15oC to the boiling temperature under reflux and subsequent reaction with an alcohol, such as methanol or ethanol at a temperature of from -15oC to the boiling temperature under reflux.

The fourth stage of the overall process is concerned with the obtaining or the x centers of chirality.

Enantioselective methods of production can be carried out, starting with enantioface (R) and (S)of substrates, such as for example, (R)- or (S)-1-benzyl-3-pyridinol.

Of a mixture of stereoisomers can also be obtained from the individual enantiomers using well-known methods of separation of these isomers on the components of this mixture of enantiomers. For example, using the methods described in Stereochemistry of Organic compounds, E. L. Eliel and S. H. Wilen, chapter 7, 1994. In particular, methods such as the formation of salts with optically active acids and subsequent fractional crystallization or differential absorption using columns filled with a chiral material, for example, chiral liquid or gas chromatography.

The fifth stage of the overall process includes the conversion of secondary or tertiary amines obtained in the synthesis process, in any salt or solvate form, preferably pharmaceutically acceptable salt or a solvate, such as hydrochloride, namely, obtained by adding the selected acid to the free base in a solvent such as ethanol, and the allocation in the form of a solid substance.

Obtaining raw materials (azetidinone substrates)

Reliable methods(modification of U.S. patent 4183923, E. H. Gold et al., January 1980):

1-(Diphenylmethyl)-3-azetidinol.

To a solution of epichlorohydrin (34,7 ml) in 1 l of anhydrous dimethylformamide under a nitrogen atmosphere add diphenylethylamine (34,5 ml). The reaction mixture is heated at 95oC for 64 hours After it is cooled to 5oC and added dropwise a mixture of 20 ml of an aqueous solution of concentrated hydrochloric acid and 20 ml of water. After evaporation under vacuum, the residue is stirred with diethyl ether and filtered. The solid residue was washed with diethyl ether and then divide between diethyl ether and 2n. aqueous solution of sodium hydroxide. The organic layer is dried with sodium sulfate, filtered and concentrated under vacuum. The residue is crystallized from a mixture of toluene and petroleum ether, resulting in a gain of 36.3 g of 1-(diphenylmethyl)-3-azetidinol, so pl. 107oC.

1-(Diphenylmethyl)-3-methanesulfonate-azetidin

To a suspension of 1-(diphenylmethyl)-3-azetidinol (29.3 g) and triethylamine (14 ml) in 220 ml of dry toluene under 15oC and under a nitrogen atmosphere is added dropwise slowly add methanesulfonanilide (7.8 ml). The temperature is slowly increased to room temperature and the reaction mixture is stirred throwaway and washed with a mixture of diethyl ether/dichloromethane (4: 1). The organic layer was washed with 100 ml of a 1.1 M solution of sodium bicarbonate, and then a strong solution of salt. It is dried with sodium sulfate, filtered and evaporated under vacuum, resulting in a gain of 29.4 g of 1-(diphenylmethyl)-3-methanesulfonanilide, M. S. (C. I.) (M/Z): 318 [M+H]+.

For other raw materials.

5-Chloro-2,3-dihydro-1H-inden-4-ol (Stages a, b, C)

a) Complex 2-hlorfenilovy ether 3-chloro-propanoic acid

To 2-chlorophenol (18,18 g) add 3-chloropropionitrile (14 ml) and the mixture is stirred and heated at 60oC for 1 h, at 75oC for 1 h and left at room temperature at the end of the week. Connection purified by distillation under vacuum and get to 19.7 g (because 91-94oS, 0.08 mm RT.St) complex 2-Hohenlohe ether 3-chloro-propanoic acid.

b) 6-Chloro-2,3-dihydro-7-hydroxy-1H-inden-1-it.

For complex 2-chlorpheniramine ether 3-chloro-propanoic acid (19.6 g) was added 1 equivalent of aluminum chloride (11,93 g) and the mixture is stirred under nitrogen atmosphere for 2.5 h at 100oC, cooled, add the second portion of aluminum chloride (14 g) and heated at 170oC for 2 h, the Reaction mixture was cooled to 70-80oWith and carefully doba is an ode, dried magnesium sulfate, filtered and concentrated under vacuum. The precipitation is filtered off, and the remaining filtrate is evaporated to dryness. The residue is passed through a chromatographic column filled with silica using as eluent toluene, and obtain 3.2 g of 6-chloro-2,3-dihydro-7-hydroxy-1H-inden-1-it. M. S. (C. I.) (M/Z): 183 [M+H]+.

C) 5-Chloro-2,3-dihydro-1H-inden-4-ol.

3.2 g of 6-Chloro-7-hydroxy-1H-inden-1-she 16.8 ml of water and 67.2 per ml of concentrated aqueous hydrochloric acid is stirred and heated with a freshly prepared amalgam of zinc (26,88 g of zinc wool) on an oil bath at 120oC for 16 h, the Reaction mixture was cooled, decanted and treated with ethyl acetate and dichloromethane. The organic layer is evaporated under vacuum. The residue is purified by the method of acid-base separation and gain of 2.08 g of 5-chloro-2,3-dihydro-1H-inden-4-ol, M. S. (C. I.) (M/Z): 169 [M+H]+.

Similarly obtained 2,3-dihydro-5-methyl-1H-inden-4-ol, M. S. (C. I. ) (M/Z): 149 [M+H]+using as starting compound complex 2-methylphenylene ether 3-chloro-propanoic acid.

2,3-Dihydro-5-methoxy-1H-inden-4-ol (stages a, b, C, d).

a) 3-(2,3-Acid)-propanoic acid.

+.

b) 2,3-Dihydro-4,5-dimethoxy-1H-inden-1-it.

A solution of 3-(2,3-acid)-propanoic acid (2 g) in 50 ml methanesulfonic acid under a nitrogen atmosphere, heated to 60oWith and maintain it at this temperature for 2 hours, the Reaction mixture was cooled to room temperature and poured into ice water. After extraction with ethyl acetate the organic layer was washed with 1N. aqueous sodium hydroxide solution, dried with magnesium sulfate, filtered and evaporated under vacuum, resulting in a gain of 1.2 g of 2,3-dihydro-4,5-dimethoxy-1H-inden-1-she, M. S. (C. I.) (M/Z): 193 [M+H]+.

C) 2,3-Dihydro-4-hydroxy-5-methoxy-1H-inden-1-it.

Under a nitrogen atmosphere 2,3-dihydro-4,5-dimethoxy-1H-inden-1-he (and 31.7 g) dissolved in 600 ml of anhydrous 1,2-dichloroethane and cooled to 0oC. Parts added aluminium chloride (44 g) and the reaction mixture heated to 60oC for 17 h, cooled to kerevat. The residue is recrystallized from ethyl acetate and get to 20.5 g of 2,3-dihydro-4-hydroxy-5-methoxy-1H-inden-1-she, M. S. (C. I.) (M/Z): 179 [M+H]+.

g) 2,3-Dihydro-5-methoxy-1H-inden-4-ol.

20.5 g of 2,3-Dihydro-4-hydroxy-5-methoxy-1H-inden-1-it is suspended in a mixture of 310 ml of concentrated aqueous hydrochloric acid and 53 ml of water. To the mixture is added a freshly prepared zinc amalgam (87 g of zinc wool) and the mixture stirred for 3 h at ambient temperature. After decanting the remaining zinc amalgam three times washed with diethyl ether and the acidic aqueous solution is extracted with diethyl ether. The combined ethereal solutions are washed with 1N. aqueous solution of hydrochloric acid, dried with magnesium sulfate, filtered and evaporated under vacuum, resulting in a gain of 15.0 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol, M. S. (C. I.) (M/Z): 165 [M+H]+.

6-Fluoro-1-methyl-1H-inden-4-ol (stages a, b, C).

a) Complex 3-forfinally ether 4-chloro-butane acid

4-Chlorobutyrate (35,3 g) are added to 3-terfenol (25 g). This mixture is stirred for 48 h at room temperature. After completion of the reaction, the target product is purified by vacuum distillation. Output: 35,3 g (because 106< the) 5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-it.

After heating the obtained complex 3-fortunelounge ether 4-chloro-butane acid (35,33 g) up to 80oWith added aluminium chloride (24,0 g). The reaction mixture begins to foam. After foaming the mixture is stirred for 2 h at 100oC. After the addition the cooling water and ethyl acetate, the mixture is heated on the steam bath. After dissolution of all oil organic layer is separated and washed with water and a strong brine. The solvent is removed and the residue is recrystallized from 2-propanol, resulting in a gain of 21.2 g of 5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-it. M. S. (C. I.) (M/Z): 181 [M+H]+.

b) 6-Fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol.

5 g of 5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-it is heated at 80oWith up to full melting solids. After adding to this melt of aluminum chloride (9.3 g) the reaction mixture is heated to 170oWith over 17 hours After the addition of cooling water and ethyl acetate, the mixture is heated on a steam bath until complete dissolution of the content. The organic layer is separated and washed with water and brine. After removal of solvent the compound purified through column chromatography using heptane/ethyl acetate (9: 1) result

WAYS TO GET

Example 1.

3-[(5-Chloro-2, 3-dihydro-1H-inden-4-yl) oxy]-1-(diphenylmethyl)-azetidin.

a) 2 g of 5-Chloro-2,3-dihydro-1H-inden-4-ol is stirred in 75 ml of 2n. the sodium hydroxide solution for 1 h To a transparent solution was added 75 ml of 4-methyl-2-pentanone and 3.76 g of 1-(diphenylmethyl)-3-methanesulfonanilide and the mixture is heated on an oil bath at 120oWith over 3.5 hours Then add 2 g of nelfinavir and heating continued for 64 hours, the Upper layer is separated and washed with water. After evaporation under vacuum and chromatography with toluene/ethyl acetate (95: 5) receive 4,22 g of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy] -1-(diphenylmethyl)-azetidine in the form of a clear oil which spontaneously cures. M. S. (C. I.) (M/Z): 391 [M+H]+.

In a similar manner there were obtained the following compounds:

b) 3-[(2,4-dichloro-1-naphthalenyl)oxy]-1-(diphenylmethyl)-azetidin, M. S. (C. I.) (M/Z): 435 [M+H]+on the basis of 2, 4-dichloro-1-naphthol,

C) 1-(diphenylmethyl)-3-[(4-methyl-1-naphthalenyl)oxy]-azetidine, M. S. (C. I.) (M/Z): 380 [M+H]+on the basis of 4-methyl-1-naphthol,

g) 1-(diphenylmethyl)-3-[(2-methoxy-1-naphthalenyl)oxy]-azetidine, M. S. (C. I.) (M/Z): 393 [M+H]+on the basis of 2-methoxy-1-naphthol,

d) 1-(diphenylmethyl)-3-[(5,6,7,8-lettermail)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy] -azetidine, M. S. (C. I.) (M/Z): 386 [M+H]+on the basis of 2,3-dihydro-5-methoxy-1H-inden-4-ol,

g) 3-[(7-bromo-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidin, M. S. (C. I.) (M/Z): 435 [M+H]+on the basis of 7-bromo-2,3-dihydro-1H-inden-4-ol,

C) 1-(diphenylmethyl)-3-[(6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-yl)oxy] -azetidine, M. S. (C. I.) (M/Z): 388 [M+H]+on the basis of 6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol,

3-[(2,3-dihydro-5-methyl-1H-inden-4-yl)oxy] -1-(diphenylmethyl)-azetidin, M. S. (C. I.) (M/Z): 370 [M+H]+on the basis of 2,3-dihydro-5-methyl-1H-inden-4-ol,

K) 1-(diphenylmethyl)-3-[(2,3-dihydro-1H-inden-4-yl)oxy] azetidin, M. S. (C. I.) (M/Z): 356 [M+H]+on the basis of 2,3-dihydro-1H-inden-4-ol,

l) 3-[(benzo(b)Tien-4-yl)-1-(diphenylmethyl)-azetidin, M. S. (C. I.) (M/Z): 372 [M+H]+based on benzo (b) thiophene-4-ol,

m) 5-(3-azetidinone)-1-(diphenylmethyl)-isoquinoline, M. S. (C. I.) (M/Z): 367 [M+H]+on the basis of 5-hydroxyisoquinoline,

n) 8-(3-azetidinone)-1-(diphenylmethyl)-quinoline, M. S. (C. I.) (M/Z): 371 [M+H]+based on 8-oksihinolina.

Example 2.

1-(Diphenylmethyl)-3-(1-naphthalenyloxy)-azetidine hydrochloride.

a) To a solution 3,37 g of tert-butoxide potassium in 71 ml of tert-butanol under a nitrogen atmosphere add 1.44 g of 1-naphthol. After stirring for half an hour add to 4.33 g is small the l of dimethyl sulfoxide. The mixture is heated on an oil bath at 80oWith over 40 hours of t-Butanol is distilled off under vacuum and the residue partitioned between water and ethyl acetate. An ethyl acetate extracts are washed with water, dried with magnesium sulfate, filtered and evaporated under vacuum. The residue is passed through a chromatographic column using toluene and obtain 2.7 g of the target product. It is treated with hydrochloric acid in methanol, evaporated under vacuum and recrystallized from absolute ethanol, resulting in a gain of 2.09 g of the hydrochloride of 1-(diphenylmethyl)-3-(1-naphthalenyloxy)-azetidine, so pl. 182oC.

In a similar manner there were obtained the following compounds:

b) 1-(diphenylmethyl)-3-[(2-methyl-1-naphthalenyl)oxy]-azetidine, M. S. (C. I.) (M/Z): 380 [M+H]+on the basis of 2-methyl-1-naphthol,

C) 1-(diphenylmethyl)-3-[(4-methoxy-1-naphthalenyl)oxy]-azetidine, M. S. (C. I.) (M/Z): 396 [M+H]+on the basis of 4-methoxy-1-naphthol,

g) 1-(diphenylmethyl)-3-(1-naphthalenethiol)-azetidin, M. S. (C. I.) (M/Z): 382 [M+H]+on the basis of 1-naphthalenethiol,

d) 1-(diphenylmethyl)-3-(2-naphthalenyloxy)-azetidin, M. S. (C. I.) (M/Z): 366 [M+H]+on the basis of 2-naphthol.

Example 3.

1-(Diphenylmethyl)-3-[(2-methoxy-1-naphthalenyl)oxy]-azetidine hydrochloric 1-bromo-2-methoxynaphthalene and 200 mg activated copper heated with stirring for 40 h at an oil bath at 170oC. the Reaction mixture was separated between water and toluene. A mixture of the crude product from the organic extracts are passed through a chromatographic column, using toluene and toluene/ethyl acetate (95:5). The target product is dissolved in simple diethyl ether and purified by adding hydrochloric acid in methanol. Output: a 1.96 g of the hydrochloride of 1 - diphenylmethyl)-3-[(2-methoxy-1-naphthalenyl)oxy] -azetidine, M. S. (C. I.) (M/Z: 400 [M+H]+.

A similar method was obtained following connection;

b) 1-(diphenylmethyl)-3-[(2-methoxymethyl)-1-naphthalenyl)oxy]-azetidine hydrochloride, M. S. (C. I.) (M/Z): 410 [M+H]+on the basis of 1-bromo-2-(methoxymethyl)-naphthalene.

Example 4.

3-[(2,3-Dihydro-1H-inden-4-yl)oxy]azetidine hydrochloride.

a) To a suspension of 3 g of 3-[(2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine hydrochloride in 250 ml ethanol add 600 mg of palladium hydroxide on powdered carbon and the mixture hydronaut on installing Parra at a pressure of 420 kPa for 16 hours After removal of the catalyst and evaporation of the solvent under vacuum, the residue is washed several times with diethyl ether and decanted to remove the formed difenilmetana. The remaining solid substances is ihydro-1H-inden-4-yl)oxy]azetidine, so pl. 65oC.

In a similar way we obtain the following connections:

b) hydrochloride of 3-[(2-methyl-1-naphthalenyl)oxy] -azetidine, so pl. 171oWith on the basis of 1-(diphenylmethyl)-3-[(2-methyl-1-naphthalenyl)oxy]-azetidine,

b) hydrochloride of 3-(1-naphthalenyloxy)-azetidine, so pl. 292oWith on the basis of 1-(diphenylmethyl)-3-[(1-naphthalenyl)oxy]-azetidine,

g) of the hydrochloride of 3-[(4-methoxy-1-naphthalenyl)oxy]-azetidine, so pl. 198oWith on the basis of 1-(diphenylmethyl)-3-[(4-methoxy-1-naphthalenyl)oxy]-azetidine,

d) of the hydrochloride of 3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-azetidine, so pl. 187oWith on the basis of 1-(diphenylmethyl)-3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-azetidine,

e) of the hydrochloride of 3-[(5,6,7,8-tetrahydro-2-methoxy-1-naphthalenyl) oxy]-azetidine, so pl. 164oWith on the basis of 1-(diphenylmethyl)-3-[(2-methoxy-1-naphthalenyl)oxy]-azetidine,

g) of the hydrochloride of 3-(2-naphthalenyloxy)-azetidine, so pl. 168oWith on the basis of 1-(diphenylmethyl)-3-(2-naphthalenyloxy)-azetidine,

C) the hydrochloride of 8-(3-azetidinone)-1,2,3,4-tetrahydroquinoline, so pl. >250oWith on the basis of 8-(3-azetidinone)-1-(diphenylmethyl)-quinoline.

Example 5.

Hydrochloride 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine.

a) 4,22 g of 3-[(5-Chloro-2,3-dihydro-1H-in the and. The mixture is refluxed on an oil bath at 120oWith within 2.5 hours After evaporation under vacuum, the residue is refluxed in 71 ml of anhydrous methanol for 2 hours After evaporation under vacuum semi-solid residue is mixed with diethyl ether and filtered. The residue is recrystallized from ethanol/diethyl ether and gain of 1.57 g of the hydrochloride of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine, so pl. 188oC.

In a similar way we obtain the following connections:

b) hydrochloride of 3-[(2,4-dichloro-1-naphthalenyl)oxy]-azetidine, so pl. 187oWith on the basis of 3-[(2,4-dichloro-1-naphthalenyl)oxy]-1-(diphenylmethyl)-azetidine

b) hydrochloride of 3-[(4-methyl-1-naphthalenyl)oxy] -azetidine, so pl. 180oWith on the basis of 1-(diphenylmethyl)-3-[(4-methyl-1-naphthalenyl)oxy]-azetidine,

g) of the hydrochloride of 3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-azetidine, so pl. 166oWith on the basis of 1-(diphenylmethyl)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-azetidine,

d) of the hydrochloride of 3-[(7-bromo-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine, so pl. 203oWith on the basis of 3-[(7-bromo-2,3-dihydro-1H-inden-4-yl)oxy] -1-(diphenylmethyl)-azetidine,

g) of the hydrochloride of 3-[(6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-yl)oxy]-azetidine, so pl. 170(2,3-dihydro-5-methyl-1H-inden-4-yl)oxy]azetidine, so pl. 184oWith on the basis of 1-(diphenylmethyl)-3-[(2,3-dihydro-5-methyl-1H-inden-4-yl)oxy]-azetidine,

and) of the hydrochloride of 3-[(benzo[b]Tien-4-yl)oxy]-azetidine, so pl. 203oWith on the basis of 3-[(benzo[b]Tien-4-yl)oxy]-1-(diphenylmethyl)-azetidine,

K) of the dihydrochloride of 5-(3-azetidinone)-isoquinoline, so pl. 198oWith, starting from 5-(3-azetidinone)-1-(diphenylmethyl)-isoquinoline.

Example 6.

Hydrochloride 3-[(2-methoxy-1-naphthalenyl)oxy]-azetidine.

a) To a solution 2,07 g of 1-(diphenylmethyl)-3-[(2-methoxy-1-naphthalenyl)oxy] -azetidine in the form of the free base in 20 ml of 1,2-dichloroethane at -15oWith added dropwise a solution of 0.58 ml of vinyloxycarbonyloxy in 20 ml of 1,2-dichloroethane for 15 min and the reaction mixture is support at this temperature for half an hour. After 16 h at ambient temperature from a dropping funnel to add the ethanol. The reaction mixture is evaporated under vacuum and the residue purified through column chromatography using toluene/ethyl acetate (95: 5), resulting in a gain of 1.55 g of solid, which is dissolved in 25 ml of 2M hydrochloric acid in methanol. After maturation at ambient temperature for 16 h, the solution is evaporated under vacuum, and so is l)oxy]-azetidine, so pl. 187oC.

In a similar way we obtain the following connections:

b) hydrochloride of 3-(1-naphthalenethiol)-azetidine, so pl. 159oWith on the basis of 1-(diphenylmethyl)-3-(1-naphthalenethiol)-azetidine,

b) hydrochloride of 3-[(2-methoxymethyl)-1-naphthalenyl)oxy] -azetidine, so pl. 127oWith on the basis of 1-(diphenylmethyl)-3-[(2-(methoxymethyl)-1-naphthalenyl) oxy] -azetidine.

Example 7.

(R)-3-Methanesulfonate-1-(phenylmethyl)-pyrrolidine.

a) 10 g of (R)-1-(Phenylmethyl)-3-pyrrolidine dissolved in 160 ml of anhydrous toluene. The solution is stirred under a stream of nitrogen, cooled in ethanole-ice bath and add to 8.7 ml of triethylamine. At a temperature of -5oC for 1.5 h added dropwise to 4.9 ml of methanesulfonamide in 110 ml of anhydrous toluene, and the reaction mixture stirred for 1 h at 0oC. the Precipitate is filtered and washed with ethyl acetate. The filtrate is washed with water, dried and evaporated under vacuum, resulting in a gain of 13.9 g (R)-3-methanesulfonate-1-(phenylmethyl)-pyrrolidine in the form of almost colorless oil. M. S. (C. I.) (M/Z): 256 [M+H]+.

In a similar way we obtain the following connections:

b) (S)-3-methanesulfonate-1-(phenylmethyl)-pyrrolidin, M. S. (C. I. ) (M/Z)Raiden, M. S. (C. I.) (M/Z): 256 [M+H]+on the basis of (rat)-1-(phenylmethyl)-3-pyrrolidinone.

Example 8.

(S) -3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy] -1-(phenylmethyl)-pyrrolidine.

a) In 540 ml of anhydrous dimethylformamide was dissolved 5 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol. The solution is stirred, placed in a stream of nitrogen and add 1.5 g of 60% dispersion of sodium hydride in oil. The reaction mixture was stirred at room temperature for half an hour. The temperature was raised to 100oAnd dropwise within 1 h add a solution of 7.78 g (R)-3-methanesulfonate-1-(phenylmethyl)-pyrrolidine in 78 ml of anhydrous dimethylformamide. Dropwise over 0.5 h add 3.0 g of nelfinavir in 30 ml of anhydrous dimethylformamide and the reaction continued for another 1.5 h at 100oC. After evaporation under vacuum, get a semi-solid substance that is distributed between water and ethyl acetate. An ethyl acetate extract is dried and evaporated under vacuum. The product distinguish chromatography over silica using as eluent toluene/ethanol, resulting in a gain of 9.45 g (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy] -1-(phenylmethyl)-pyrrolidine in the form of oil. M. S. (C. I.) (M/Z): 324 [M+H]+.

Similar slidin, M. S. (C. I.) (M/Z): 324 [M+H]+on the basis of 2,3-dihydro-5-methoxy-1H-inden-4-ol and (S)-3-methanesulfonate-1-(phenylmethyl)-pyrrolidine,

in) (rat)-3-[(2, 3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl-pyrrolidin M. S. (C. I.) (M/Z): 324 [M+H]+on the basis of 2,3-dihydro-5-methoxy-1H-inden-4-ol and (rat)-3-methanesulfonate-1-(phenylmethyl)-pyrrolidine,

g) 3-(1-naphthalenyloxy)-1-(phenylmethyl)-pyrrolidin M. S. (C. I.) (M/Z): 304 [M+H]+based on 1-naphthol,

e) 3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidin, M. S. (C. I.) (M/Z): 308 [M+H]+based on 5,6, 7,8-tetrahydro-1-naphthol.

Example 9.

(S)-(+)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy]pyrrolidine hydrochloride.

a) 9.4 g (S)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine dissolved in 300 ml of anhydrous methanol and add 2.0 g of palladium hydroxide on carbon. The mixture hydronaut installation Parra for 16 h at a pressure of 350 kPa. The catalyst is filtered off through dicalite and washed with methanol. The filtrate is concentrated to its original volume and add 1 g of fresh palladium hydroxide on carbon. The hydrogenation continued for 3 hours

The catalyst was again filtered, and the filtrate is treated with excess 1M solution HLA/diethyl ether get colored crystals, which is washed with acetone and diethyl ether, resulting in a gain of 3.95 g of the hydrochloride of (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrrolidine, so pl. 176oC.

In a similar way we obtain the following connection:

b) hydrochloride of 3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-pyrrolidine, so pl. 207oWith on the basis of 3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine

Example 10

(R)-(-)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy] -pyrrolidine hydrochloride

a) 800 mg (R)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy] -1-(phenylmethyl)-pyrrolidine dissolved in 150 ml of anhydrous methanol and added 1.5 equivalent of hydrochloric acid, dissolved in ethyl acetate. Add approximately 80 mg of palladium on carbon 10% and through the mixture with stirring miss a stream of hydrogen. After 24 hours add a new catalyst and the hydrogenation continued for 17 hours the Catalyst is filtered off, the filtrate is evaporated under vacuum and the product is recrystallized from ethanol/ethyl acetate/diethyl ether, resulting in a gain of 360 mg of the hydrochloride of (R)-(-)-3-[(2, 3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrrolidine, so pl. 174oC.

In a similar way we obtain the following connections:<-3-[ (2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine,

in) (rat)-3-[(1-naphthalenyl)oxy] pyrrolidine hydrochloride, T. pl. 222oSince, from (rat)-3-[(1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine.

Example 11

(+)-3-[(1-Naphthalenyl)oxy]-pyrrolidine hydrochloride.

(-)-3-[(1-Naphthalenyl)oxy]pyrrolidine hydrochloride.

3-[(1-Naphthalenyl)oxy] -pyrrolidine (80 mg) divided by the method of preparative chiral WJHL to separate the enantiomers. The separation is carried out at room temperature on column Chiracel OD size 2404,6 mm using hexane/ethanol (80:20) and 0.15% of diethylamine, flow rate 1 ml/min

(+)-3-[(1-Naphthalenyl)oxy]-pyrrolidin gathered at tRof 7.4 min,

(-)-3-[(1-naphthalenyl)oxy]-pyrrolidin gathered at tR9,8 minutes

Solutions immediately evaporated under vacuum and turn in their hydrochloride, resulting in a gain of 10 mg each. Some inarticulate for both enantiomers was >99.5% pure.

TEST

The activity of the compounds of the present invention in relation to the Central nervous system was confirmed using the following pharmacological tests; these tests showed serotoninergicescuu activity and effects similar to antidepressants is but using cloned receptors person, expressed in ZTZ cells, in accordance with the protocols described in the publication Stam et al. "Genomic organization, coding sequence and functional expression of human 5-HT2 and 5-HT1A receptor genes" - European Journal of Pharmacology - Molecular Pharmacology Section 227: 153-162 (1993) and Stam et al. "Genomic organization and functional expression of the gene encoding the human serotonin 5-HT2C receptors", European Journal of Pharmacology - Molecular Pharmacology Section 269: 339-348 (1994). The similarity to 5-NTA and 5-HT2C receptors determined by the ability of the compounds of the present invention to displace [3H]-ketanserin and [3H]-mesulergine from the corresponding receptor, PL. 1, 2.

RECTALLY TEST

This test, conducted in accordance with the Protocol Beredsen et al. ["In volment of 5-HT1C receptors in drug-induced penile erection in rats" - Psychopharmacology 101: 57-61 (1990)] provides an indication of the potential activity similar to that of antidepressants.

The results obtained show that the compounds of the present invention have greater affinity for 5-NTS receptors man than to 5-NTA receptors man: and this affinity correlates with agonist activity in vivo, as well as with activity similar to that of antidepressants, live models for the effectiveness of antidepressant.

1. Derivatives of azetidine or pyrrolidine General formula 1

< / BR>
where a is optionally unsaturated 5 - or 6-membered Kohl is R>
R1, R2and R3independently of each atom N, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom;

X is an atom of O or S;

n = 1 or 2

or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidine.

2. Connection on p. 1, wherein the heteroatom And, if present, is an atom N or S;1- atom N, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl; R2- atom N, (1-6C)alkoxy or halogen atom, and R3- atom N, (1-6C)alkyl, (1-6C)alkoxy or halogen atom.

3. Connection on p. 2, wherein the compound has the formula (Ia)

< / BR>
where a is unsubstituted saturated 5-membered or optionally aromatic 6-membered ring which may contain a nitrogen atom adjacent to the position indicated by the asterisk;

R1atom H or (1-6C)alkoxy;

R2- atom N, (1-6C)alkoxy or halogen;

R3atom H or halogen;

n = 1 or 2;

4. Connection on p. 3, characterized in that the A - unsubstituted saturated 5-membered or optionally aromatic 6-membered ring, R1- (1-6C) alkoxy and R2and R3- atom N.

5. Soy p. 5, characterized in that n = 2.

7. Pharmaceutical composition having affinity to 5-NTS-receptor containing the compound 3-(naphthas-1-yl-oxy)-pyrrolidin, or 3-(5,6,1,6-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin, or any connection at one PM.1-6 and a pharmaceutically acceptable additive.

 

Same patents:

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to the field of organic chemistry, and in particular to an improved process for the preparation of omeprazole, which is the first drug from the group of drugs to regulate the secretion of gastric acid

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

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 derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to a sodium salt of omeprazole form B, which can be used as a proton pump inhibitor, i.e

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to a method for obtaining compounds of formula III or its salt

< / BR>
(where R1is tertbutoxycarbonyl, benzyl; R3represents C1-C6alkyl interaction of the compounds of formula I

< / BR>
(where R1shall have the meaning given above and R2is methanesulfonyl group or p-toluensulfonyl group) with a compound of formula II

< / BR>
in the presence of a base
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