UA82182C2 - Derivatives of benzothiazine and benzothiadiazine, process for preparation thereof and pharmaceutical composition containing thereof - Google Patents

Abstract

The present invention relates to the compounds of the formula (I):where:Ris hydrogen, halogen or alkyl,Ris hydrogen or alkyl,Ris hydrogen, halogen or hydroxyА is CRRor NR,Ris hydrogen, alkyl or cycloalkylRis hydrogen or alkyl, orА is nitrogen, and together with the near situated -СНR-group, forms a ring, where m is 1,2 or 3,Ris hydrogen or halogen, Х is as defined in the description of an invention, theirs isomers, and theirs additive salts. Medicaments.

Description

Description of the invention

This invention relates to new derivatives of benzothiazine and benzothiadiazine, to the method of their preparation and 2 pharmaceutical compositions containing them.

To date, it is known that excitatory amino acids, especially glutamate, play a key role in the physiological processes of neuronal plasticity and in the mechanisms underlying learning and memorization. Pathophysiological studies have clearly shown that a deficiency in glutamatergic neurotransmission is closely related to the development of Alzheimer's disease. hemiemov, 1992, 16, 13-24; 70 Rgodgevs ip Mepgobioiodu, 1992, 39, 517-545).

Moreover, numerous works in recent years have demonstrated the existence of subtypes of excitatory receptors of amino acids and their functional interactions.

Among such receptors, the AMPA (A-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor appears to be the receptor that is most involved in the phenomenon of physiological neuronal excitability and, 72 especially, in the phenomena that are involved in the processes memorization For example, it was found that the learning process is associated with an increase in the binding of AMPA to its receptor in the hippocampus, one of the areas of the brain important for the processes of memory and cognition. Similarly, nootropic agents such as aniracetam have recently been described as positively modulating AMPA receptors of neuronal cells (Soshigpa! Meigospetivighu, 1992, 58, 1199-1204).

In the literature, compounds with the benzamide structure have been described as having the same mechanism of action and improving the memorization process (Izuparze, 1993, 15, 326-329). Compound BA 74, in particular, is the most active of the new pharmacological agents.

Finally, the description (patent EP 692 484 | discloses a benzothiadiazine derivative that has facilitating activity against the AMPA current, and (patent application MUO 99/42456) | describes, among others, specific benzothiadiazine derivatives as modulators of AMPA receptors. ge)

Derivatives of benzothiazine and benzothiadiazine, to which the present invention refers, in addition to being new, unexpectedly reveal pharmacological activity against the current of AMP A, which is clearly more preferable than the activity of compounds having similar structures described in the previous state of the art. They are useful as AMPA modulators for the treatment or prevention of age-related memory and cognitive disorders, anxiety or depression syndromes, progressive neurodegenerative diseases,

Alzheimer's disease, Pick's disease, Huntington's chorea, schizophrenia, the consequences of acute neurodegenerative diseases, the consequences of ischemia and the consequences of epilepsy. h-

More specifically, this invention relates to compounds of formula (1): si

Zo so shk St. N "

E, in "sh7 - s a | Her "X o "" i S .

OTAT uy V.V. so i ' ko - () so

And" ko 60 where:

Ku is a hydrogen atom, a halogen atom or a linear or branched (C 1-C) alkyl group, 65 Ka is a hydrogen atom or a linear or branched (C 1-C) alkyl group,

E" represents a hydrogen atom, a halogen atom or a hydroxy group,

A represents a SEC group or MK, a group,

Ez is a hydrogen atom, a linear or branched (C.4-C) alkyl group or a (C-C7) cycloalkyl group,

KE. represents a hydrogen atom or a linear or branched (C.4-Cv)alkyl group, or

A is a nitrogen atom and, together with the -SNK z-group located near it, forms a ring, where t is 1,2 or 3, e pil t

K5 is a hydrogen or halogen atom,

X is an MKK, З(О)04Ка or ОК'v group or a heterocyclic group, where:

Ko represents a hydrogen atom, a linear or branched (С 4-Св)alkyl group, З(О)рКе, СОКе" or с 29 Р(ООВаОВо, о

K; represents a hydrogen atom or a linear or branched (C.4-C) alkyl group, or Kb and K7, together with the nitrogen atom that contains them, form a heterocyclic group,

Ka, Ke and Ko, which can be the same or different, represent a hydrogen atom; a linear or branched (Ci-Cv)alkyl group, optionally substituted by one or more halogen atoms; aryl-(C 4-Cv)alkyl c group, in which the alkyl part is linear or branched; or an aryl group, p

Kv represents a linear or branched (C 4-C) alkyl group or a linear or branched (C 4-C) acyl group, - p and p, which can be the same or different, represent 1 or 2, si to their enantiomers and diastereoisomers , as well as their addition salts with a pharmaceutically acceptable acid or base, it should be understood that: - the term "heterocyclic group" means a monocyclic or bicyclic, aromatic or non-aromatic group, which contains from one to four identical or different heteroatoms selected from nitrogen , oxygen and sulfur, "optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C.4-Cv)alkyl, linear or branched (C.i-Cv)alkyl, linear or branched o, c (C4-C) polyhaloalkyl, linear or branched (C-C) alkoxycarbonyl, oxo, thioxo, carboxy, linear

Is" or branched (Ci-Cb) acyl, linear or branched (C.4-C) polyhaloalkyl, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C 1-C) alkyl groups) , aminosulfonyl (optionally substituted by one or more linear or branched (C -C)alkyl groups) and (C4-C)alkylsulfonylamino, co - the term "aryl group", as it should be understood, means a monocyclic aromatic group or a bicyclic co group, in which at least one of the rings is aromatic, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C.i.d.-Cv)alkyl (optionally substituted by one or more hydroxy groups), linear or branched (C--Cv) alkoxy, linear or oo 20 branched (C.4-Cv) polyhaloalkyl, linear or branched (C.i-Cv) alkoxycarbonyl, oxo, thioxo, linear or branched (C.i-Cv)alkylthio , carboxy, linear or branched (C.--Cv) acyl, li ny or 05) branched (C.4-C) polyhalo alkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C.4-C) alkyl or linear or branched (C.--C )acyl groups), aminocarbonyl (optionally substituted by one or more linear or branched (C4i-C8)alkyl groups), aminosulfonyl (optionally substituted by one or more linear or

GF! branched (C.4-C) alkyl groups), mono- or di--trifluoromethylsulfonyl)amino, РО(OKAHOK,) (where Ka and K, which can be the same or different, represent a hydrogen atom or a linear or branched co ( Ci-Cv)alkyl group), benzyloxy and phenyl (optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C-i-Cv)alkyl, linear or 60 branched (C.4-Cv )perhaloalkyl, hydroxy or linear or branched (C.--C.) alkoxy).

Pharmaceutically acceptable acids may include, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc.

Pharmaceutically acceptable bases may include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.

Group | is mainly located in position B of phenyl, which is in

B nn you

Xx contains

Preference is given to K.4 and Ko groups, which are hydrogen atoms. 75 Group B is mainly located in the meta- or para-position of the phenoxy structure

And and

What is the ring that contains it.

X is preferably an MCC; or a 5(O)OKa group or a heterocyclic group. high school

More specifically, group X is mainly an MCC"; a group where Co represents a hydrogen atom or a З(О) Co group and K7 represents a hydrogen atom, such as, for example, the groups МНЗОоМе, МНЗО»иРГ, МНЗО»СЕ», МН». Gee)

The preferred compounds of the invention are compounds where A is a nitrogen atom and, together with the adjacent -СНК3 group, forms a ring -, where т is (he) h-

YOU Ge so 1, 2 or 3, preferably 1.

Preferred compounds of the invention are: 13-(5,5-dioxido-2,3,3,3,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|benzothiadiazin-7-yl)oxy|phenyl )methanamine, "

IM-3-((5,5-dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,benzothiadiazin-7-yl)-oxy|Ibenzylimethanesulfonamide, shi c M-(4-((5,5-dioxido-2,3,Za,4-tetrahydro-1H-haroloi|2,1-c1(1,2,4benzothiadiazin-7-yl)-oxy|Ibenzylimethanesulfonamide) The invention also relates to methods of preparing compounds of formula (1).

The method of preparation of compounds of formula (I), where A represents the MKA group or A represents a nitrogen atom and, together with the SNK" group located next to it, forms a ring; (ee) rent ko - so 50 tp

Oh, we! where t represents 1, 2 or 3, which differs in that the compound of formula (I) is used as a starting material: (1) o KE, o "ZO, MH , 60 ; (1) in chn, b5 where:

KU is a linear or branched (C 41-C) alkoxy group, Ko is a hydrogen atom, a halogen atom or a linear or branched (C.i-C) alkoxy group, which: (a) is either reacted with an acid chloride of the formula (PP) in the presence of a base, in the environment of tetrahydrofuran or acetonitrile:

СССНо-(СНо)т-СНо-СОСИ СП) where t is as defined for formula (I) to obtain the compound of formula (IM): (M

EE

And 50, MN, iv ' with U)

Mi-сSOo-сСн.(СН,), - СН, - SI t 1 Ge! 1. 2 where Ki and Ka" are as defined above, which is then cyclized in the medium of a base to obtain a compound of formula (M):

And about

I"u "Y sch to 1 5 th so

Her h with (y) with 3o; | (ge) "E" - s vo;

And where K", EK. and t are as defined above, and which is optionally subjected to reduction, in the medium of alcohol or dimethylformamide, in the presence of sodium borohydride, to obtain the compound of the formula (MI):

M oo (M) - so MN

And"; (M) 25 IM M; o 2 u ) in 60 where KU, K" and t are as defined above, where the compound of the formula (M) or (MI) is subjected to the action of boron tribromide to obtain the compound of the formula (MI): b5 o, ,0 and no td and | "ak:

AN). 4 , (UP) y M Mid where K" is as defined for formula (I), and t is as defined above, (B) or cyclized: - in the presence of an amidine of the formula (MIP): (mM) you -th SUPIV) sch

MH, where Kz is as defined for formula (I), to obtain the compound of formula (IX): с (ге) гу (х) «-- ; ХХ) 3o and (ge)

KE ME, « | - c h» where KU, K» and Kz are as defined above, which: " - or reduced, using a metal hydride, to obtain a compound of the formula (X): b bo KE, Ye t : 2 o Mn C) i : Same with in "'""N NE, 2

HF) where KU, K" and Kz are as defined above, t - or alkylate by the action of a strong base in the presence of an alkylating agent K'AH, where K'; represents a linear or branched (C.4-C) alkyl group and X represents a halogen atom, and then is reduced to obtain a compound of the formula (XII): b5

(Hee)

KE

1 ZO, many os) ' and 70 Kk 7 | Kk,

Ks 4 where KU, K", Kz and K. are as defined above - in the presence of aldehyde of the formula (XII): (х1) ю о и (ХП)

KI, whether

H is where K" is as defined for formula (1), to obtain a compound of formula (X) described above, where the compound of formula (X) or (XI) is a Ki group, when the group K'" represents a linear or a branched (C.4-C) alkoxy group, the Co group is converted into a hydroxy group to obtain a compound of the formula (ХП):

Both "

M; - ;" p

E, so where Co, Kz and K. are as defined for the formula (I), where the compound of the formula (MII) or (XIII) is subjected to reaction with the boronic acid of the compound of the formula (XIM): - (khm) and Kk"

PO) And with ; СХИУ) ю В(ООН), 60 and where K" represents a cyano group or a K.KaHSO-group as defined for formula (I), to obtain (after an optional transformation of the K" 4 group, when the latter represents a cyano group , in

MKeK; group as defined for formula (I)) compound of formula (I/a 4) or (I/a2), specific variants of compound of formula (1): b5

(ma

M) x

Kk-s Ya

NA o 5O, o chi ; a/ai)) and | ts 4 de KU, Ka; Ko, Ku, K. and X are as defined for formula (1), (ma 2) , ih c . (8)

K,-- . "/ at 5; 2 sc

H m so ' MN ; (/az) "--

Wu M cm | so )" where Ki, Ka, Ko, t and X are as defined for formula (1), 40 . - c where the compounds of the formulas (I/a.) and (I/a"): are purified, if necessary, according to the usual purification technique, separated, if desired, into their :z" isomers according to the usual separation technique and converted, if preferably, in addition salts thereof with a pharmaceutically acceptable acid or base. 415 The method of preparation of compounds of the formula (I), where A represents the SK AK» group, which differs in that the compound of the formula (XM) is used as the starting material:

Kk so | --50,

Te M

And and oh more; 60 where:

K is a linear or branched (C.4-C) alkoxy group,

K" represents a hydrogen atom, a halogen atom or a linear or branched (C -C) alkoxy group, which is subjected to the action of chloroacetone in the presence of dimethylformamide to obtain a compound of the formula (KMI): b5

(HM)

EE. those "50,

M; SM) in y y y o o where Ki Ka" are as defined above, which is subjected to rearrangement in the medium of a base to obtain a compound of the formula (ХМИЙ): (ХМ)

Kk tudi 80, 7 IR and re;(KHUP) u s 4 o s de Ki Ka" are as defined above, which is de-ethylated by heating under reflux in a benzene medium in the presence of an excess of ethylene glycol and a catalytic amount of p-toluenesulfonic acid to obtain a compound of the formula -- (CHMII): si (XM) (ge)

V.; that 50, and whether ; SHUPI) Z s g» KE, ; о со ко - where Ки Ка" are as defined above, оо 20 which is subjected to hydrolysis in an acid environment to obtain a compound of the formula (хХихХа): о) (Хиха) ,' в КЕ, 5о, о | I am s (XIX) 60 '

EE b5 where Ki Ka» are as defined above, the nitrogen atom of which is optionally, depending on the nature of the K z group, which is desired, protected by a protecting group and which is then, after treatment with a strong base, treated with a compound of the formula K'3 -P" where Kz represents a linear or branched (C 1-Cv)alkyl group or a (C3-SU)cycloalkyl group and P is a leaving group, to obtain, after deprotection of the nitrogen atom, the compound of the formula (XIX a): ( xih a) 70 E; 5. 1 rij

We'. In (heh a)

Kk KE with Z where KU, K» and Kz are as defined above, where the compound of the formula (XixXa) or (XIX'a) represented by the formula (XIX): (xx) cm and Kk, 5

Miracle,

МИ ОО СХ) sch ' o so

In the name of - 2 c ze o so de Ki K" are as defined above, and Kz is as defined for formula (1): - or subject to catalytic reduction to obtain a compound of formula (XX): "0) n- я B from ;" 1: with IR in b) so iia de і

Oh

And where Ki Ka" are as defined above, or are converted by the action of a hydride into an alcohol, the hydroxy group of which is converted into a halogen atom by the action of a suitable reagent to obtain a compound of the formula (XXI):

F) ko 60 b5 g. (XXI)

KE'

And 50, ; many o bOo) i . 70 KE 2 V,

EE where K", EK. and Kz are as defined above, and K'5 represents a halogen atom, - or is subjected to the action of an organomagnesium compound K; AMOoVg, where Ku; represents a linear or branched (C4-Cv) alkyl group , to obtain a compound of the formula (ХХБ): (ХХБ)

EE

! ZO,

And MN; ОХХ) сч (8)

KS B, "В с » ии он со "-- where KU, K", Kz and K are as defined above, where the compound of the formula (XIX B) - or is subjected to catalytic reduction to obtain the compound of the formula (XXI): se co (XX)

EE at 50, . "40. - I'm sorry. " » and at Mon I

I: КЕ, 2 that их т 4 - со 20 where KU, K", Kz and K. are as defined above, - or its hydroxy group is converted into a halogen atom by the action of the appropriate reagent

From to obtain the compound of the formula (XXII): (XX) z» I:5 5 "I

F, 2nd MN (xxh) 60; ,

EE KE

' In 4 ' 65 Kk 1 !

where K, KE", Kz and K'; are as defined above, and K'5 represents a halogen atom, where compounds of the formulas (XX) - (XXI), the KU group and, when the Ko group represents a linear or branched (C4-C8)alkyl group, the K» group is converted in the hydroxy group to obtain the compound of the formula (XXIM): but What " and XXIM)

MnO,o i5 B. m Z where K»o, Kz, K. and K»5 are as defined for the formula (I), where the compound of the formula (XXIM) is reacted with the boronic acid of the compound of the formula (XIM): ( ХМ) with (8)

E" with (XI M): 1 cm and

В(ОН) о 2 - s where K"1 represents a cyano group or K.KaHS-group as defined for formula (1), s to obtain (after optional transformation of the K" 4 group, when the latter represents a cyano group , in

MAK" group as defined for the formula (I)) of the compound of the formula (1/5), a specific variant of the compound of the formula (1): "

K.-s "I: » and 2-9 50, so X | me DV - 50 . with (1/5) 9 V io in E, 4 KE,

F) ko 60 b5

(c) where KU, Ka; Co, Kz, Ka, Kb and X are as defined for formula (I), wherein the compound of formula (1/5) is purified, if necessary, according to conventional purification techniques, separated, if desired, into its isomers according to conventional separation techniques and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base.

The invention also relates to pharmaceutical compositions that contain, as an active ingredient, a compound of formula (I) with one or more suitable, inert, non-toxic excipients. Among the pharmaceutical C compositions according to the invention, those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, cakes, suppositories, creams, ointments, dermal gels, injectable drugs, drinkable suspensions, etc.

The acceptable dosage can vary depending on the nature and complexity of the disease, the route of He administration, the age and weight of the patient and is in the range from 1 to 50 Ωg per day for one or more administrations.

The following examples demonstrate the present invention and do not limit its scope in any way. co

Products that are known or manufactured according to known cooking methods are used as raw materials.

The structures of the compounds described in the Examples were determined according to conventional spectrophotometric techniques (infrared radiation, NMR, mass spectrometry...). with

Example 1: 13-(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c)(1,2,4|-benzothiadiazin-7-yl)oxy|phenyl) methanamine hydrochloride

Stage A: 2,3-Dihydro-1H-pyrrolo|2,1-c1(1,2,benzothiadiazin-7-ol 5,5-dioxide

A solution of VVgz (68.75 mmol) in 25 ml of methylene chloride was added dropwise to the solution cooled to 02°C, 27.5 mmol of 7-methoxy-2,3-dihydro-1H-pyrrolo|2,1-c1-(1,2,4benzothiadiazine 5 ,5-dioxide in ZB5BOml of methylene chloride. - s Stirring was carried out at ambient temperature for 24 hours. The reaction mixture was poured into a mixture of ice and water, and the suspension was stirred for 30 minutes. The precipitate was filtered off, washed -" several times with water, filtered with suction and dried in a vacuum to obtain the expected product.

Melting point: 3002 °C 111 °C

Stage B: 3-((5,5-Dioxido-2,3-dihydro-1H-pyrrolo|2,1-siI(1,2,benzothiadiazin-7-yl)oxy)|benzonitrile with a suspension consisting of 7 ,0bmmol of the product obtained in the Stage above, 3-cyanophenylboronic acid

Iz (11.02 mmol), copper(II) acetate (11.02 mmol), pyridine (22.0 mmol) and about 5000 mg of 4A molecular sieves in 200 ml of methylene chloride were stirred for 24 hours. The reaction mixture was diluted by adding another 100 ml of methylene chloride and the suspension was filtered. The filtrate was concentrated and then applied directly to a silica gel column eluted with a methylene chloride/methanol 95/5 system. Fractions containing the expected product were combined and evaporated, and the residue was added to a small amount of ethyl ether. After filtering (F), the solid, expected product was recovered in the form of a white powder. ka Melting point: 229-233

Elemental microanalysis: 60 111 m in 65 Stage p. 13-(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c)(1,2,4|-benzothiadiazin-7-yl)oxy|phenyl)methanamine hydrochloride

112 mg (2.95 mmol) HYAIN); was added, in small portions, to a solution of O0.58 mmol of the product obtained at

Stages above, in 20 ml of anhydrous THF and the mixture was stirred at ambient temperature for an hour. The excess hydride was hydrolyzed by successive dropwise addition of 1.5 ml of isopropanol and 1.5 ml of a saturated aqueous solution of MaSi. Aluminum salts were filtered off and the filtrate was evaporated to dryness.

The residue was chromatographed on a silica gel column, eluting with a mixture of СНоСИЛ/ЕУН/aq. MNaz 95/5/0.5. After evaporation of the amine-containing fractions, the meringue was added to ethereal NSI. The solution was evaporated to dryness and the residue redissolved in a minimum amount of isopropanol. The expected product was crystallized and recovered by filtration. 70 Melting point: 14590

Elemental microanalysis: 111 Gezhine | me the whole 'v

Example 2:

M-(3-((5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrroloi|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|Ibenzyl )methanesulfonamide

Methanesulfonic anhydride (0.20 mmol) dissolved in 2 ml of СНоSiO» was added dropwise to a solution, cooled in an ice bath, of the compound obtained in Example 1 (0.13 mmol) in tTOml of СНСи», containing

O, 34mmol of EBM. The reaction mixture was stirred at ambient temperature for 3 hours.

The reaction solution was washed with water and then saturated with Masi and dried over M950,u. After evaporation in vacuo, the residue was solidified by trituration in ethyl ether to give the title product after filtration.

Melting point: 1833-1902. see what and

Elemental microanalysis: Fr

Owl NU MU; 895

Calculated 51.06 5.00 9.92 15.14

Found 51.09 5.33 9.58 15.55

The following Examples were prepared according to the methods described in Examples 1 or 2, starting from the appropriate starting materials. h-

Example 3: si

IM-(3-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,41-benzothiadiazin-7-yl)oxy|Ibenzylacetamide

Zo Melting point: 5820. so

Elemental microanalysis: 11 F (ezhine meuve « to 8 s h Example 4: I M-(1-73-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1- c)(1,2,4|benzothiadiazin-7-yl)oxy|phenyl)ethyl)acetamide

Example 5:

M-(1-43-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrroloi|2,1-c1(/1,2,benzothiadiazin-7-yl)oxy|phenyl) -1-fluoroethyl)a (ee)cetamide from Example 6: 3-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4| -benzothiadiazin-7-yl)oxy|benzyl isopropyl sulfone - Example 7: 20 1-13-I(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1 ,2,41-benzothiadiazin-7-yl)oxy|phenyl)ethyl isopropyl co sulfone

Also) Example 8: 1-3-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|-benzothiadiazin-7-yl)oxy |phenyl)-1-fluoroethylisopropylsulfone 52 Example 9:

IM-3-((5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|benzyl Utrifluoro) methane and) sulfonamide ke Melting point: 104-113260,

Elemental microanalysis: 60 11 (ezhine me vy) 65 Example 10:

M-(1-73-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-s)(1,2,4|benzothiadiazin-7-yl)oxy| phenylethyl trifluoro

)methanesulfonamide

Example 11:

M-(1-73-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-s)(1,2,4|benzothiadiazin-7-yl)oxy| phenyl)-1-fluoroethyl trifluoro)methanesulfonamide

Example 12:

IM-(3-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrroloi|2,1-c1(1,2,benzothiadiazin-7-yl)/oxy|Ibenzyl)-M -methylbenzamide

Example 13:

M-(1-73-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-cI(1,2,4benzothiadiazin-7-yl)oxy|phenyl)ethyl )-M-methyl 70 benzamide

Example 14:

M-(1-73-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-s)(1,2,4|benzothiadiazin-7-yl)oxy| phenyl)-1-fluoroethyl)-

M-methylbenzamide

Example 15: 7-13-(1H-Imidazol-4-yl)umethyl|phenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,benzothiadiazine 5,5- dioxide

Example 16: 7-13-I11-(1H-Imidazol-4-yl)ethyl|phenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|benzothiadiazine 5,5-dioxide

Example 17: 7-13-(1-Fluoro-1-(1H-imidazol-4-ylethyl|phenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2, 4benzothiadiazine 5,5-dioxide

Example 18:

IM-3-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4benzothiadiazin-7-yl)uoxy|Ibenzylpropane-2-sulfo intention

Melting point: 112-11826. with

Elemental microanalysis: (8) 7 (blue) sch

Example 19: 7-IZ-1H-Pyrrol-1-ylmethyl)phenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-cI(1,2,|benzothiadiazine 0 5,5-dioxide 200 mg (0.58 mmol) of the product obtained in Example 71, in the form of a free amine, and 105 mL (0.81 mmol) of 2,5-dimethoxytetrahydrofuran were added to a two-phase mixture of 2.0 mL of water, 0 mL of AcOH, and 285 mL of DMSO dichloro- 1,2-ethane. The mixture was stirred at 8092 for 2 hours, allowed to cool to ambient temperature, and extracted with SiOCl." The organic phase was washed with saturated aqueous Mass solution and dried over Ma 5 O. The expected product was purified on a silica gel column (CH 2 SiO/heptane 75 /25).

Melting point: 150-15296,

Elemental microanalysis: « ten kv, Z p

From

Example 20: 15 1-4-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl) oxy|phenyl)methanaminehydrochloride Use the same procedure as for Example 1, substituting the 3-cyanophenylboronic acid in Step B as the 4-cyanophenylboronic acid isomer.M.P.: 165-17296.

Example 21: 25 M-4-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c111,2,4|-benzothiadiazin-7-yl)oxy|benzyl )methanesulfonamide

The same procedure as for Example 2 is used, starting with the compound obtained in Example 20. o Melting point: 165-17296, ko Elemental microanalysis: bo 7 (blue in)

The two enantiomers of Example 21 were separated by chiral chromatography on a Spigairak OR Eluent: 65 SNZSM/LRTN/OEA 1000/2/1. The two enantiomers are listed in Examples 22 and 23 in the order in which they were eluted according to the above conditions.

Example 22:

MM-4-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|benzyl) methanesulfonamide, enantiomer 1

Elemental microanalysis: 7 (blue)

Example 23:

MM-4-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|benzyl) methanesulfonamide, enantiomer 2

Elemental microanalysis: 5 7 (blue)

Example 24: 20. M-(4-(5,5-Duxido-2,3,3Za,4-tetrahydro-1H-pyrrolo-(2,1-c1(1,2,4|-benzothiadiazin-7-yl) )oxy|benzyl)acetamide

The same technique as for Example 2 is used, replacing methanesulfonic anhydride with acetyl chloride and using the amine obtained in Example 20 as a starting material.

Melting point: 1158-1612

Elemental microanalysis: se tek o p

Example 25:

M-4-((5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|benzyl) -2,2,2-trifluoroacetamide h:

The same technique is used as for Example 2, replacing methanesulfonic anhydride with trifluoroacetic anhydride and using as a starting material the amine obtained in Example 20.

Melting point: 136-1382С so

Elemental microanalysis: genes) h 2 s Example 26: ; » M-13-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-si(1,2,41-benzothiadiazin-7-yl)oxy|benzyl)- 4-fluorobenzamide

The same technique is used as for Example 2, replacing methanesulfonic anhydride with 4-fluorobenzoyl chloride and using as a starting material the amine obtained in Example 20. oo Melting point: 104-1082С

Elemental microanalysis: number of genes) o so (empirically 6 | in yav v.g,

I" Example 27: 7-I4-"1nH-Tetrazol-5-ylmethyl)phenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4benzothiadiazine 5,5- dioxide

Stage A:

TA-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|-benzothiadiazin-7-yl)oxy|phenyl)acetonitrile

GF) A suspension containing 1.15 g (4.77 mmol) of 2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1-(1,2,4benzothiadiazin-7-ol 5,5-dioxide, 1.00 g (6.21 mmol) (|4-(cyanomethyl)phenyl|-boronic acid, 1.3 g (7.15 mmol) copper acetate), about 1.16 ml (14.31 mmol) of pyridine and about 500 mg of 4A molecular sieves in 200 ml of methylene chloride, stirred overnight.The reaction mixture was diluted by adding another 100 ml of methylene chloride and the suspension was filtered.

The filtrate was concentrated and then placed directly on a silica gel column eluted with a methylene chloride/methanol 99/1 system. Fractions containing the expected product were combined and evaporated, and the residue was added to a small amount of ethyl ether. After filtration, the solid title product was obtained as a beige powder. ve Melting point: 156-15820

Stage B: 0 7-I(4-(1n-Tetrazol-5-ylmethyl)phenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-cI(1,2,4benzothiadiazine

5,5-dioxide

A suspension of 300mg (0.844mmol) of the product obtained in Stage A, 16b4mg (2.53mmol) of sodium azide and 113mg (2.11mmol) of MNACI in 3ml of OME was stirred at 11023 for 24 hours. The reaction mixture was allowed to cool to ambient temperature and poured into 200 ml of 1M HCl. Extraction (AsOE), drying (Mo95O) and evaporation to dryness were carried out. The residue was pulverized in ESO and the precipitate was filtered to give the title product.

Melting point: 209-21296

Elemental microanalysis: pi SNY ISNSYA

Example 28: 3-4-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1I(1,2,4|-benzothiadiazin-7-yl)oxy|benzyl )-1,2,4-oxadiazol-5(4H)-thione

Stage A: 2-TA-I(5,5-Dioxido-2,3-dihydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|phenyl)- M'-hydroxyethaneimidamide 2.51 ml (18.0 mmol) of triethylamine was added to a solution of 1.25 g (18.0 mmol) of hydroxylamine hydrochloride in 4 ml

OM5O and the suspension were stirred for 1 hour. The precipitate was filtered off and the filtrate was concentrated. 992 mg (3.00 mmol) of the product of Stage A of Example 27 was added to the filtrate and the solution was stirred at 7593 for 1 hour ЗОхв. The solution was allowed to cool to ambient temperature, and the sediment of the reaction mixture was replaced using water. The precipitate was filtered to give the title product. with

Stage B: 3-4-(5,5-Dioxido-2,3-dihydro-1H-pyrrolo|2,1-c1(1,2,41-benzothiadiazin-7-yl)uoxy|benzyl)-1,2 ,4-oxadiazole-5(4H)-thione (o) 348mg (1.95mmol) of 1,1'-thiocarbonylimidazole and then 530ml (3.51bmmol) of DBU were added to a suspension of the product obtained in Stage A (33Omg, 0.8bmmol) at the University of the SnaUSM. The reaction solution was stirred at ambient temperature overnight. 20 ml of 1M NSI was added; were extracted with zo (СНСІ), washing (saturated Masi), drying (МоЗО)) and evaporation to dryness. The title product was obtained in the form of a yellow wax, which was used in the crude form in the next Stage. (heh)

Stage C: 0/0 3-(A-I(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrroloi|2,1-c1(1,2,4|-benzothiadiazine-7- yl)oxy|benzyl "- 1-1,2,4-oxadiazole-5(4H)-thione

The product obtained in Stage B (290 mg, 0.68 mmol) in ethanol (12 ml) in the presence of MavVN. (77 mg, 20 Zmmol) "EM was stirred at ambient temperature for an hour. 1 Oml of 1M NOI was added and co-extraction was carried out (СНоСи»). The title product was purified by chromatography on a silica gel column (snosi./meon 99/1).

Melting point: 124-1262С

Elemental microanalysis: « 7 streams

AND"

Example 29: 15 M-(1-44-K(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4benzothiadiazin-7-yl)oxy) |phenyl)ethyl)methanesulfonamide

Kz Stage A: 1-4-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl) oxy|phenyl)ethanone-3 A suspension containing 3.0 g (12.48 mmol) of 2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1-(1,2,4benzothiadiazin-7-ol) 5 ,5-dioxide, 3.18g (18.7mmol) (4-acetylphenyl)boronic acid, 3.42g (18.82mmol) copper(I) acetate, 3.OZml about 50 (37.15mmol) pyridine and about 5x00mg 4A of molecular sieves in 150 ml of methylene chloride was stirred overnight. The reaction mixture was diluted by adding another 100 ml of methylene chloride and the suspension was filtered. The filtrate

I" was concentrated and then placed directly on a silica gel column, which was eluted with the system CH OSidl/acetone 99/1.

Fractions containing the expected product were combined and evaporated, and the residue was added to ethyl ether.

After filtration, the solid title product was recovered as a white powder. 59 Melting point: 152-15490

HF) Stage B: (1--4-I(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-troloi|2,1-c1(1,2,4|-benzothiadiazine-7- yl)oxy|phenyl)ethyl)amine dni 1.65 ml (5.633 mmol) of titanium isopropoxide (M) was added dropwise to a solution of 1.0 g (2.80 mmol) of the product obtained in Stage A in 5 ml of 7/M ammonia methanol. Stirring was carried out at ambient temperature overnight, 424 mg (11.20 mmol) of Mavn was added, and stirring was continued for another 2 hours. Precipitation of the reaction mixture was carried out by adding water (2-Zml); the white precipitate was filtered off.

The filtrate was deposited. The garden was suspended in ASOEI, stirring was carried out for 30 minutes and filtration was carried out. The filtrate was combined with the first filtrate and the extraction of AsSOEL was continued. The organic phases in 5 were combined, washed (saturated Mass), dried (Mo950O) and evaporated in vacuo to give the title product.

Stage C.

M-(1--4-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-c1I(1,2,4|-benzothiadiazin-7-yl)oxy |phenyl)ethyl)methanesulfonamide

The same technique is used as for Example 2, using the product from the stage as the starting material

In above.

Melting point: 122-12726

Elemental microanalysis: I hetnic v

Theoretically, from B2iv 530 950 1455.

Example 30: 75 M-(1-73-K(5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-cI(1,2,4|benzothiadiazin-7-yl )oxy|phenyl)ethyl)methanesulfonamide

Use the same technique as for Stages A, B and C of Example 29, substituting (4-acetylphenyl)boronic acid in Stage A with (3-acetylphenyl)boronic acid.

Melting point: 83-842С 20 Elemental microanalysis: terfnukmi in

Theoretically with|B216 520 950 1455 s 29 Example 31: ge)

M-(4-((5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4|-benzothiadiazin-7-yl)oxy|benzyl )-M-methylmethanesulfonamide

A suspension containing 5.74 mg (3.37 mmol) of 2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,benzothiadiazine-7-ol 5,5-dioxide, 92 bmg ( 4.04 mmol) (4-Pmethyl(methyl-sulfonyl)amino|methylphenyl)boronic acid, 920 mg s 30 (B. Obmmol) of copper(I) acetate, 817 ml (10.10 mmol) of pyridine and about 4 g of 4AA molecular sieves in BOml. The CHCl was stirred overnight. The reaction mixture was filtered, washing with CH5Cl2/Meon (1/1). The filtrate was concentrated and then placed directly on a silica gel crown, which was eluted with the CHClO/MeonN 95/5 system. 7

Fractions containing the expected product were combined and evaporated, and the residue was added to ethyl ether. si

After filtration, the solid title product was recovered as a white powder.

Z Melting point: 142-1442С so

Elemental microanalysis: 7 (blue)

Theoretically, they were reduced to 8 hours Example 32: I 13-(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,4| -benzothiadiazin-7-yl)oxy|Ibenzyl) and dimethylamine

Stage A: Methyl 3-(5,5-Dioxido-2,3-dihydro-1H-pyrrolo|2,1-c1I(1,2,4|-benzothiadiazin-7-yl)oxy|benzoate

The same procedure is used as for Stage B of Example 1, using as starting materials the compound O obtained in Stage A of Example 1 and (3-(methoxycarbonyl)phenyl|boronic acid. z) Melting point: 2211-2149

Elemental microanalysis: - from genes) co

That

Stage B: 3-3-Aminosulfonyl)-4-(2-oxopyrrolidin-1-ylphenoxy|benzoic acid

A suspension of the product obtained at Stage A (1.1 g, 2.55 mmol) in 1 mL of 1 M NaOH was heated at 9590 until a solution was obtained. The solution was allowed to cool to ambient temperature, acylated with 1 M NaCl and extracted (CH2Cl). The organic phases were combined, washed (saturated Massi), dried (Mo5O)) and

Go) evaporated. The rest of the powder in EBO; the title product precipitated and was recovered by filtration. 6o0 Stage C: 3-(2,3-Dihydro-5,5-dioxido-1H-pyrrolo|2,1-c|(1,2,4benzothiadiazin-7-yl)ioxy|benzoic acid

A suspension of the product obtained at Stage B (850 mg, 2.2 mmol) in 25 ml of THF in the presence of 675 ml (4.52 mmol)

DBU was heated with reflux for an hour. It was allowed to cool to ambient temperature and acylated with 1M NOSI, and the white precipitate corresponding to the title product was filtered off.

Elemental microanalysis: b5 sin miv

Stage 0: 3-(5,5-Dioxido-2,3-dihydro-1H-pyrrolo|2,1-cI(1,2,benzothiadiazin-7-yl)oxy|-M,M-dimethylbenzamide

2 drops of OME were added to a suspension of the product obtained at Stage C (1.40 g, 3.91 mmol) in 200 ml of CHClCl, and then, dropwise, 684 ml (7.81 mmol) of oxalyl chloride, diluted with 2 ml of CHClCl. Stirring was carried out at ambient temperature for 2 hours. ЗОХв.; carried out evaporation to dryness; the residue was added to 15 ml of SiO2"; added 1.1 ml (7.81 mmol) of EBM and then 2.94 ml (5.87 mmol) of a 2 M solution of dimethylamine in

THF. Stirring was carried out at ambient temperature for an hour. The reaction mixture was acylated with 0.5 M NaCl and extracted (СНоСи2). The organic phases were combined, washed (saturated Mass), dried (Mo50) and evaporated. The residue was powdered in EBO; the title product precipitated and was recovered by filtration.

Elemental microanalysis: and 7 (seni mvi

Stage E: 13-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|-benzothiadiazin-7-yl)oxy|Ibenzylidemethylamine

3.72 ml (3.72 mmol) of a 1M solution of HyAIN; in THF was added dropwise to the suspension of 57 7 mg (1.49 mmol) obtained at

Stages of the product in 20 ml of THF. The reaction mixture was observed to turn into a solution, and stirring was carried out at ambient temperature for 10 minutes. Excess hydride was hydrolyzed by adding water dropwise until gas evolution ceased. The suspension was stirred for 1 hour, 20 ml of water was added at 29, and ASOEI was extracted. The organic phases were combined, washed (saturated g) mass), dried (Ma 5 O,) and evaporated, and the residue was chromatographed on a silica gel column (SNOSI./mMeon 95/5) to give the title product.

Melting point: 122920 зо Elemental microanalysis: с tetu о - сч

Pharmacological studies of products according to this invention p

Study of excitatory currents caused by AMPA in Heporiz a oocytes - Method:

mRNA was obtained from the cerebral cortex of male Uu/iziag rats by the guanidine thiocyanate/phenol/chloroform method. "

Poly (A") mRNA was separated by chromatography on oligo-4T cellulose and injected at a level of 5 ng per oocyte. Oocytes were incubated for 2-3 days at 182C to allow receptor expression, and then stored at 8-102C. - s Electrophysiological registration in the RiekhidiazvF chamber at 20-242С7 in the environment OK2 | U. Exhr.

Iz» 7001., 1973, 184, 321-334) by the "voltage-fixation" method using two electrodes, with the third electrode placed in a bath that serves as a sample.

All compounds were injected through the incubation medium and the electrical current was measured at the end of the injection period.

AMPA was used in the concentration of LOMM. For each tested compound, the concentration that doubles (EC2X) or increases by five times (EC5X) the strength of the current caused by AMPA itself (from 5 to BONA) was determined. ka b - Results:

The compounds of the present invention enhance the excitatory effects of AMPA to very significant levels and their activity is very superior compared to the compounds referred to. The compound of Example 1, in particular, has an OO 20 ESOIX value of 3.65 MM and an EC5BX value of 9.2MM, the compound of Example 2 has an EC2X value of 0.35MM and an EC5BX value of 2.6MM and the compound of Example 21 has ES2X is at the level of 0.1MM and the value of ES5X is at the level of 0.56MM.

Pharmacological composition: oo Formula for the preparation of 1000 tablets, each of which contains 100 mg of 1004 -13-K(5,5-dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo(|2,1-c1(1, 2,4benzothiadiazin-7-yl)oxy|Ibenzylumatensulfronamide (Example 2)

F) hydroxypropyldelulose 24 ko wheat starch 104 lactose 1004 bo magnesium stearate Za talc Za. in

Claims (1)

The formula of the invention 1. The compound of formula (1): и ши - "у -о т и СН (Ф), В/ ASV, where: hl is a hydrogen atom, a halogen atom or a linear or branched (C.4-Cv)alkyl group, Ka represents a hydrogen atom or a linear or branched (C.-Cv)alkyl group, E" represents a hydrogen atom, A represents a nitrogen atom and, together with the adjacent -SNK z-group, forms a ring, where t is 1, 2 or 3, -M c t (8) Ez represents a hydrogen atom, a linear or branched (C.4-C) alkyl group or a (C-C7) cycloalkyl group, X represents MKK, З(О)ОРа or heterocyclic group, where: Ke represents a hydrogen atom, a linear or branched (C.4-C) alkyl group, З(О)рК»о or СОК», with K; represents a hydrogen atom, a linear or branched (C.4- An alkyl group, or Kb and K7, together with the nitrogen atom that contains them, forms a pyrrole group, with Ka, Ke and Ko, which can be the same or different, represent a hydrogen atom; linear or branched "-- (Si -Cv)alkyl group, optionally substituted by one or more halogen atoms; aryl-(C 4-Cv)alkyl lin group, in which the alkyl part is linear or branched; or an aryl group, c p and p, which may be the same or different, represent 1 or 2, and heterocyclic group means an imidazole, pyrrole, tetrazole or oxadiazole group, its enantiomers and diastereoisomers, as well as its addition salts with a pharmaceutically acceptable acid or base. 2. The compound of formula (I) according to claim 1, where group B is located. in « z ОХ 2 с Кк ХХЖЗ-В2 m ota i І» x - about the position b of the phenyl containing it. - A compound of the formula according to any of claims 1 or 2, where X represents 6; or pa group, or so 3. s f () b 1 or 2 x b MAK vk; or 5(O)E. b with a heterocyclic group. 4. The compound of formula (I) according to any of clauses 1, 2 or 3, where X represents the MKK" group. 5. The compound of formula (I) according to any of items 1-4, where VE is in the meta-position of Go! those x X structures of the phenoxy ring that contains it. 6. The compound of formula (I) according to any of clauses 1-4, where I is in the para-position of the structure of the phenoxy ring that contains it. 65 7. The compound of formula (I) according to any of clauses 1-6, where A is a nitrogen atom and, together with the adjacent -SNKz group, forms a ring, where t is 1, 2 or 3, preferably 1 . t 8. The compound of formula () according to claim 1, which is 13-(5,5-dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|benzothiadiazine- 7-yl)oxy|phenyl)imethanamine, as well as its additive salts. 9. The compound of formula () according to claim 1, which is IM-(3-((5,5-dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2, 4benzothiadiazin-7-yl)oxy|benzyl)-methanesulfonam 75 id, as well as its additive salts. 10. The compound of formula () according to claim 1, which is M-(4-((5,5-dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2, 4benzothiadiazine-7-yl)oxy|benzyl)-methanesulfonamide, as well as its additive salts. 11. The method of obtaining compounds of formula (I) according to claim 1, where A is MK. group or A is a nitrogen atom and, together with the adjacent -SNK group, forms a ring, where t is 1, 2 or -M' s o t З, which differs in that the compound of the formula (I ): V c Tu ""5О МН со 2 2 "-- (10), с со EE ІМ в 2 7 where: "K is a linear or branched (C.4-Cv)alkyl group, - с K" is a hydrogen atom, a halogen atom or a linear or branched (C -C) alkoxy group, which: with (a) or is subjected to a reaction with an acid chloride of the formula (I) in the presence of a base, in the environment of tetrahydrofuran or acetonitrile: nat. ; - (СНи) в - СН» - СОСИ (n), where t is as defined for formula (I), - and with obtaining the compound of formula (IM): o EE . and ! 5О, MchN, ! (IM), o , МН-СО-СН.-СН,), - СН. - SI V. m 2 2 t 2 z 2 60 where EK" and B" are as defined above, which is then cyclized in the medium of a base to obtain a compound of formula (M): b5 In M And 2. also (U I M 2 p where KU, K" and t are as defined above, which is optionally subjected to reduction, in the medium of alcohol or dimethylformamide, in the presence of sodium borohydride, to obtain the compound of the formula (MI): ВЕ te 1 5 (U), ts B! В / y 2 da sch de K", K" and t are as defined above, c where the compound of the formula (M) or (MI) is subjected to the action of boron tribromide "- z obtaining a compound of the formula (MY): o,.,0 y » no tv so o") " ' ' (UP z y ) -o still M z 1554 ; | ) t so where K" is as defined for formula (I), and t is such , as defined above, ke (B) or cyclize: -3 - in the presence of an amidine of the formula (MI): ИЙ со Pe Кк; (UP), in МН, ГФ) where Kz is as defined for formula (1), Ф to obtain a compound of the formula (IX): in t Ka 5, X ikh), in Mn k 2 Z where KU, K'" and gz are as defined above, which: - or reduced, using a metal hydride, to obtain compounds of the formula (X): I 1 50 ШЧИ ю со with v. MN Kk, 2 where KU, K" and Kz are as defined above - or alkylated by the action of a strong base in the presence of an alkylating agent K'/X, where K' represents a linear or branched (C.4-C) alkyl group and X represents a halogen atom, and then is reduced to obtain a compound of the formula (XII): Kk, o 2 KE where KE, B», Vaz and K4 are as defined above, so - in the presence of an aldehyde of the formula (XII): o t schi sch with K--C (ХП), so x where K» is as defined for formula (I), "from unit of the compound of the formula (X) described above, where the compound of the formula (X) or (XI) has a K'4 group and when the K'' group is a linear or branched (C.4-C.sub.1) alkoxy group, » the Ko group is converted into a hydroxy group to obtain a compound of the formula (XIII): no so 5O, t a a MH (ХП), (se) А И» 35 Te | KE, VE, F! where Ko, Kz and K. are as defined for the formula (1), where the compound of the formula (MIII) or (XIII) is subjected to reaction with the boronic acid of the compound of the formula (XIM): B" I 60 (ХУ), вв В(ОН), where K"1 represents a cyano group or a K.KaHS-group as defined for formula (I), with the result (after optional transformation of the group K", when the latter is a cyano group, in MKK"; a group as defined for the formula (I)) compounds of the formula (I/ai) or (I/ag), specific variants of the compound of the formula (1): 9. oh zh MH (Ma,), and V. MV, 4 where Ki, Ka, Ko, Kz, K. and X are as defined for formula (1), 1 Ж с ! IN; 76 o "o | o X this I MN (Ia,), сч (ге) В M - с : ) с п where Ki, Ka, Ko, t and X are as defined for formula (I), where the compounds of formulas (I/a .) and (I/a") " purified, if necessary, according to conventional purification techniques, separated, if desired, into their isomers according to conventional separation techniques and converted, if desired, into their addition salts with a pharmaceutically acceptable acid or basis. "» 12. The method of obtaining compounds of the formula (I) according to claim 1, where A represents the SK Kb group, which differs in that "as a starting material, a compound of the formula (ХМ): в: со 50 кох 2 мно (ХУ) - and ВЕ we are where: K represents a linear or branched (C.4-C) alkoxy group, (F, K" represents a hydrogen atom, a halogen atom or a linear or branched (C -C) alkoxy group, Ho) which is subjected to the action of chloroacetone in the presence of dimethylformamide to obtain a compound of the formula (KMI): 60 b5 And / oti -5О0 12 M (ХУ», EE 2 to o o where Ki Ka» are as defined above, which are subjected to rearrangement in the medium of a base to obtain a compound of the formula (ХМИЙ): в В, св о, (ХУ ), ; I KE 2. . but o shch be de Ki K" are as defined above, Ge) which is de-ethylated by heating under reflux in a benzene environment in the presence of an excess of ethylene glycol and a catalytic amount of p-toluenesulfonic acid to obtain a compound of the formula XM): (Х сч ; 12 Квій (ХУ), сч в (ге) ВЕ оо иш - s de Ki Ka" are as defined above, from which they are subjected to hydrolysis in an acid environment to obtain a compound of the formula (хиХа): КЕ "и 18 1 -о more with MN about (HiIHha) co. : z ' so EE, z o where Ki Ka" are as defined above, the 59 nitrogen atom of which is optionally, depending on the nature of the K z group, which is desired, protected by a protective o group and which then, after treatment with a strong base, treated with a compound of the formula K'5-P, where Kz is a linear or branched (C 1-Cv)alkyl group or a (C3-SU)cycloalkyl group and P is a leaving group, with the result that after deprotection of the nitrogen atom , compounds of formula (XIX'a) 60 b5 With ! Я80, МН , (XIX a), V I 24. . x КИ and о where K", K'" and K'z are as defined above, where the compound of formula (XixXa) or (XIX'a) represented by formula (XIX): with B. 1 50 and 2 sp, ; Y KE B, 2 o sh where Ki K" are as defined above, and Kz is as defined for formula (1): (8) - or subjected to catalytic reduction to obtain a compound of formula (XX): B, сс И 5О, сч - МН (ХХ) со : з І ч- и с KE K, 2 со de Ki Ka" are as defined above, - or are converted by the action of a hydride into an alcohol, the hydroxy group of which is converted into a halogen atom by the action of "the corresponding of the reagent to obtain the compound of the formula (XXI): shsh s V i sh 1 5O, i che y (XXI), (ee) 7 a m V K, as 2 'so KE. iv: where K", EK. and Kz are as defined above, and K'5 represents a halogen atom, - or is subjected to the action of an organomagnesium compound K/MaoVg, where KK; represents a linear or branched (C4-Cv)alkyl group, 59 to obtain a compound of the formula (XIXB): above, where the compound of the formula (XIX B) is either subjected to catalytic reduction to obtain the compound of the formula (XXII): I I 5 ! I. (ХХХ), Il ШХХ 2 Z EE 4 where KU, K", Kz and K. are as defined above, - or its hydroxy group is converted into a halogen atom by the action of the appropriate reagent to obtain the compound of the formula (ХХХХ): » В 1 50 s (XX), sch o KE KE VE 4 E.. sch 5 so de K, KE», Kz and K'; are as defined above, and K'5 represents a halogen atom, where the compounds of the formulas (XX) - (XXI), the KU group and, when the Ko group represents a linear or branched - (C4-Cv)alkyl group, the K» group are converted into hydroxy groups with obtaining a compound of the formula (XXIM): " no 7 -50, МН (ХХ), « | - с | « i 2 v 3 Kk, 24 s 5 t where Ko, KU, K, and K5 are such as defined for the formula (I), where the compound of the formula (XX/IM) is subjected to a reaction with the boronic acid of the compound of the formula (XIM): - so "zo"; (XIM), zv B(OH), (F, where K "1 represents a cyano group or a K./KAaXsO group as defined for formula (1), Go) with the result (after optional transformation of the K group). 4, when the latter represents a cyano group, in MKeK7 a group as defined for the formula ( I)) of the compound of the formula (1/5), a specific variant of the compound of the formula (1): 60 b5 B, x; W, WHAT at 50, . X | M I " sn (plo), 4 rya where KU, Ka, Ko, Kz, Ka, Kb and X are as defined for formula (I), where the compound of formula (1/5) is purified, if necessary, according to conventional purification techniques, separated, if desired, into its isomers according to conventional separation techniques and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base. 13. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1-10 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 14. A pharmaceutical composition according to claim 13, which contains as an active ingredient a compound according to any one of claims 1-10, for use as medicinal products as AMPA modulators. si 7 o Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 06, 25.03.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s (ge) «-- s Zo so - with . and? so ko - so I» F) ko 60 b5