Method of obtaining activated esters

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining activated ester of formula (I): where R stands for C1-C6 alkyl, linear or branched, 6-membered heteroaryl with one nitrogen atom as heteroatom; Alk stands for C1-C6 alkyl, linear or branched, consisting in interaction of dicyclohexylamine salt P1 and disuccinimidylcarbonate (DSC) in solvent which represents ketone, in which salt of dicyclohexylamine and N-hydroxycuccinimide P2 precipitates.

EFFECT: method makes it possible to obtain target product with high output and good degree of purity.

10 cl, 1 dwg, 2 ex

 

The present invention relates to the preparation of activated esters of the formula (I):

in which R denotes a (C1-C6) alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci and Alk represents (C1-C6)alkylenes group. These activated esters can be used to obtain conjugates, i.e. antibodies that through covalent bonds attached to biologically active chemical compounds, such as cytotoxic compounds. More details about the chemistry of the conjugates can be found, for example, Birch and Lennox, Monoclonal Antibodies: principles and Applications, Chap. 4, Wiley-Liss, New York, N.Y. (1995).

Prior art

In WO 2004/016801 described activated esters containing nitrosalicylanilide link. The syntheses of these compounds are depicted in Fig. 1-6, based on the reactions other than the reaction of the present invention.

InJ. Med. Chem.2006,49(14), 4392-4408 described the synthesis of activated esters, in particular, N-Succinimidyl-[4-methyl-4-(matildico)]pentanoate according to scheme 6 by reactions other than the reaction of the present invention.

InLangmuir, 2000, 16(1), 81-86 described for scheme 1 Succinimidyl-3-(2-pyridyldithio)butyrate (spdb) (SPDB) a combination of the corresponding acid with N-hydroxysuccinimide.

In America nski patents US 6407263, US 5872261, US 5892057 and US 5942628 described activated esters and the way they are received.

InCan. J. Chem.1982,60, 976 describes the synthesis of salts dicyclohexylamine and N-hydroxysuccinimide (P2) by the reaction between dicyclohexylamine and N-hydroxysuccinimide in acetone. This connection has no CAS 82911-72-6.

InCan. J. Chem.1986,64(11), 2097-2102; J. Chem. Soc., Perkin Trans. 1, 1985,4, 765-8; Bull. Soc. Chem. Jpn., 1986,59(8), 2505-8; Coll. Czech. Chem. Comm., 1985,50(12), 2925-2936 described the synthesis of esters of succinimide on the basis of salts of dicyclohexylamine, but without the use of disuccinimidyl.

InTetrahedron Letters1979,49, 4745-4746 described DSK and its involvement in the synthesis (see scheme 2).

InBiochem. J.,1978,173, 723-737 described the synthesis of activated esters in the presence of N-hydroxysuccinimide and dicyclohexylcarbodiimide.

InJACS2003,125(30), 8994-8995 revealed shortcomings of the technological plan.

Brief description of the invention

The invention relates to a method for producing an activated complex ester of the formula (I):

in which R denotes a (C1-C6) alkyl, linear or branched, aryl, heteroaryl, cycloalkyl, heteroseksualci and Alk represents (C1-C6)alkylenes group, linear or branched, which consists in the introduction into the reaction salts dicyclohexylamine P1

and disuccinimidyl (DSC) (DSC) in a solvent in which the salt of dicyclohexylamine and N-hydroxysuccinimide P2

precipitates.

The invention relates also to the products of formula R1:

in particular the products of formula:

Description of the invention

Definition

• an alkyl group: a saturated aliphatic hydrocarbon group, linear or branched, obtained by removal of a hydrogen atom from an alkane; it is possible, in particular, to include the following groups: methyl, ethyl, through bucilina, pentilla, hexeline, 2-methylbutyl, 2-methylpentyl, 1-methylpentyl;

• Allenova group: divalent group derived by removal of two hydrogen atoms from an alkane; it is possible, in particular, to include the following groups: methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-);

• cycloalkyl group: a cyclic alkyl group containing 3 to 10 carbon atoms involved in a cyclic structure; can be called, in particular, the following groups: cyclopropyl, cyclopentamine, tsiklogeksilnogo;

• aryl group: aromatic group, the content is Ada from 6 to 10 carbon atoms; can be called, in particular, the following groups: phenyl, naftalina, angenlina, fluoroaniline;

• the heteroaryl group is an aromatic group containing from 5 to 10 parts, having in its composition as atoms forming cycle, one or more heteroatoms selected among O, S or N;

• heterocytolysine group: cycloalkyl group as defined before containing, in addition, as the atom(s)constituting () loop, one or more heteroatoms selected among O, S or N.

The synthesis is based on the reaction between salt dicyclohexylamine P1and disuccinimidylsulfite (DSC) in a solvent in which the salt of dicyclohexylamine and N-hydroxysuccinimide P2precipitate (Scheme I).

Scheme 1

where R denotes a group:

• (C1-C6)alkyl: for example, methyl, ethyl, through boutelou or pentelow possibly branched;

• (C3-C7)cycloalkyl: for example, cyclopropyl;

• aryl, for example: phenyl;

• heteroaryl: for example, 2-pyridinyl group ();

• geterotsyklicescoe: for example, piperidinyloxy group.

Alk denotes (C1-C6)alkylenes group, for example, propylene, butylene or Panteleeva, prob is tenderly, branched; in particular, represents a group (CH2)nwhere n denotes an integer variable in the range from 1 to 6.

The role of dicyclohexylamine is to carry out the reaction and to make insoluble the N-hydroxysuccinimide. This reaction provides the following benefits:

• ease of implementation: the interaction takes place without heating slowly and in a controlled manner is allocated WITH2;

• because the connection P1is in the form of a carboxylate, there is no need to add more base to activate the reaction.

• connection R2that separated from the reaction mixture, it is very poorly soluble in the used solvent and it precipitates; therefore, a large part of the P2can be easily separated by simple mechanical separation, for example, by filtration;

• reaction makes it easy to get activated ester in good yield and good purity.

P2produced by neutralizing the corresponding acid dicyclohexylamine. DSK is a commercial product.

Preferably, the solvent is a ketone, which is less Toxicological problems than the solvents normally used for reactions of this type (dichloro is an or dimethylformamide). The ketone may represent, for example, acetone or methyl isobutyl ketone (MIBK) (MIBK). MILK is preferred because, being poorly miscible with water (1,55% wt./mass. at 20°C), it allows rinse water to the product and thereby facilitate separation of residual P2. Equally, it allows you to remove residual water by azeotropic distillation. Finally, MILK is a good solvent of ester activated, but not compounds P2, R1and DSC, which enables the exercise slow and controlled reaction between P1and DSK: thus, the reactants may be initially completely safe mixed (without rapid reaction with uncontrolled release CO2).

The reaction is carried out at room temperature (about 20°C). Some solvents P2can spontaneously precipitate. To facilitate the deposition of P2, after introduction into the reaction P1and DSC cooling the reaction mixture (for example, to a temperature close to 0°C).

This reaction allows, in particular, to synthesize the following activated esters: N-Succinimidyl-3-(2-pyridyldithio)propionate (people) (SPDP), N-Succinimidyl-3-(2-pyridyldithio)butyrate (spdb) (SPDB) or N-Succinimidyl-[4-methyl-4-(metallicity)]pentanoate on the basis of salts of the respective keys is from, namely, respectively:

EXAMPLES

Example 1: synthesis of N-Succinimidyl-[4-methyl-4-(metallicity)]pentanoate

The reaction is as follows:

Suspension dicyclohexylamine salt of 4-methyl-4-(metallicity)pentanol acid (23 g) and DSC (18.2 g, 1.1 EQ.) in 161 ml MIBK was stirred at approximately 20°C for 5 hours Then the suspension was cooled to approximately 0°C., stirred 1 h at this temperature, then was filtered.

The solid is washed 2×23 ml MIBK. The organic phases were combined, washed 2×58 ml of aqueous 6N HCl, then 92 ml of demineralized water. Then the organic phase is concentrated to dryness in vacuo. The obtained solid substance was dissolved in 230 ml of dichloromethane (DHM) (DCM) and the resulting solution was treated with 46 g of silicon dioxide, stirred 10 min, then the silica was filtered and washed 2×69 ml DHM. This operation is repeated a second time. Then the organic phase was concentrated to approximately half volume, then, approximately at 20°C, was added 391 ml of n-heptane for about 30 minutes the Obtained white suspension was stirred at this temperature approximately for 1 h, cooled, up to -10°C for approximately 1 h, and then stirred at this temperature approximately within 1 hour have a look at the solid was filtered, washed 2×23 ml of n-heptane. Cooled to -10°C., then dried in vacuum at 40°C for 15 h 4-N-Hydroxysuccinimidyl-[4-methyl-4-(matildico)]pentanoate were isolated output 70,6%. Its degree of purity, determined by HPLC (HPLC)was 99,65% (excluding the solvent).

Example 2: synthesis of N-Succinimidyl-3-(2-pyridyldithio)butyrate (spdb) (SPDB)

The reaction is as follows:

Salt dicyclohexylamine (40 g, 1 EQ.) and DSK (28,7 g, 1.1 EQ.) suspended in 280 ml MIBK. The mixture was stirred for 4 h at 20±3°C. the Suspension was cooled to 0±3°C, kept for 30 min at this temperature, was filtered and the obtained solid is washed with ice MILK (120 ml). Royal solutions were washed with water (I ml) and evaporated to dryness under reduced pressure in a rotary evaporator at a bath temperature of 50°C to get the number of MIBK ≤2,5%. Untreated spdb received in the form of a yellow oil.

Then spdb (32,5 g) was dissolved in ethanol (455 l) at 35±2°C. the resulting solution was cooled to 18±2°C: clear spdb began to crystallize. Within 10 min was added 90 ml of n-heptane, crystallization intensified. The mixture was cooled to 0±3°C and for 20 min was added 820 ml of n-heptane. The mixture was stirred for 1 h at 0±3°C. Pure spdb was isolated by filtration, washed with 2×90 ml of ice-cold n-heptane and dried in an oven (30°C, 50 the bar). Yield: 84.8%, and the purity determined by HPLC: 98.7 per cent.

1. The method of obtaining the activated complex ester of the formula (I):

in which R denotes a (C1-C6) alkyl, linear or branched, or 6-membered heteroaryl with one nitrogen atom as heteroatom,Alk denotes a (C1-C6)alkylenes group, linear or branched,
which consists in the interaction of salt dicyclohexylamine P1

and disuccinimidyl (DSC) (DSC) in a solvent, which is a ketone, and in which salt dicyclohexylamine and N-hydroxysuccinimide P2

precipitates.

2. The method according to claim 1, in which R denotes a methyl, ethyl, propyl, butyl or pentyl, possibly branched, or 2-pyridinyl.

3. The method according to claim 1 or 2, in which Alk denotes a propylene, butylene or Panteleeva group, possibly branched.

4. The method according to claim 1 or 2, in which Alk denotes a group
(CH2)nwhere n denotes an integer variable in the range from 1 to 6.

5. The method according to claim 1, wherein the ketone is MIBK (MIBK)

6. The method according to claim 1 or 2, in which after the introduction into the reaction P1and DSK reaction mixture is cooled to facilitate precipitation of P2.

7. The method according to the .1 or 2, where P2allocate mechanical separation.

8. The method according to claim 7, in which the mechanical separation is a filter.

9. The product formula P1

in which R and Alk are as defined in one of claims 1 to 4.

10. The product according to claim 9 of the formula:



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: agriculture.

SUBSTANCE: agent for control of plant diseases comprises: at least one compound chosen from tetrazolyl oxime derivatives represented by the formula , and their salts: in the formula (I) X is C1-6-alkyl group, C1-6-alkoxy group, halogen atom, nitro group, cyano group, C6-10-aryl group or C1-6-alkyl-sulfonyl group; n is an integer from 0 to 5; Y is C1-6 alkyl group; Z is a hydrogen atom, an amino group or a group represented by the formula NHC(-O)-Q; Q is a hydrogen atom, C1-8-alkyl group, C1-6-haloalkyl group, C3-6-cycloalkyl group, C1-8-alkoxy group, C3-6-cycloalkoxy group, C7-20-aralkoxy group, C1-4-alkylthio-C1-8 alkyl group, C1-4-alkoxy-C1-2-alkyl group, C1-4-acylamino-C1-6-alkyl group, C1-4-acylamino-C1-6-alkoxy group, C1-8-alkylamino group, C2-6-alkenyl group, C7-20-aralkyl group or C6-10-aryl group; R is an halogen atom; m is an integer from 0 to 3; and at least one compound selected from the group consisting of triflumizole, hydroxyisoxazole, acetamiprid and their salts.

EFFECT: invention enables to improve the efficiency of disease control.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel indole derivatives containing a carbamoyl group, a ureide group and a substituted oxy group or to pharmaceutically acceptable salts, having general formula

,

where values of R1-R3, m are given in claim 1.

EFFECT: compounds exhibit inhibiting activity on IKKβ, which enables use thereof as a preventive or therapeutic agent for treating several diseases associated with IKKβ.

25 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted indole derivatives of formula , where A and B are independently CH2 or C=O, X is indolyl, unsubstituted or mono- or polysubstituted; T is (CR5a-cR6a-c)n, n=1 or 2. Q is (CR7a-cR8a-c)m, m=0, 1 or 2, the values of the rest of the radicals are given in claim 1, which act on the ORL1 receptor.

EFFECT: improved method.

13 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula l , where a and b are independently equal to 0-5; R1 and R2 independently denote -C1-4alkyl, CN, halogen, -ORa, -CH2OH, Ra independently denotes H, C1-4alkyl; R3 denotes -C(O)NR3aR3b, -CN; R3a and R3b denote H; R5 denotes -C1-6alkyl; Q denotes -C0-5-alkylene-Q'-C0-1alkylene-, Q' denotes -CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -OC(O)-, -C(O)O-, -NRQ1C(O)-, -C(O)NRQ1-, -NRQ2-C(O)-NRQ3-, -C=N-O-, -S-S- and -C(=N-O-RQ4)-, RQ1 denotes H; RQ2 and RQ3 denote H; RQ4 denotes -C1-4alkyl, benzyl; e equals 0-5; R6 independently denotes halogen, -C1-4alkyl, -C0-4alkylene-OH, CN, -C (O)O-C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl, -NH-C(O)-C1-4alkyl, -N (C1-4alkyl)2 and -N+(O)O; where the alkyl group in R6 is optionally substituted with 1-5 F atoms; one -CH2- group in Q is optionally substituted with one -OH; or a pharmaceutically acceptable salt or zwitterion form thereof.

EFFECT: compounds exhibit antagonistic activity towards muscarinic receptors, which enables their use to produce pharmaceutical compositions for treating lung diseases such as chronic obstructive pulmonary disease and asthma.

32 cl, 16 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-pyrrolidone of the formula (I): wherein Q means -CH2-, -O-; B means -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-CH2 under condition that if B means -CH=CH-, -CH=CH-CH2- then Q means -CH2-; X means -O-, -S-, -SO- or -SO2- or a simple bond under condition that if X meana simple bond then Q means oxygen atom; J means -(CRbRc)n- wherein n means a whole number from 1 to 4; both Rb and Rc mean hydrogen atom, or both Rb and Rc mean (C1-C4)-alkyl and one of them means hydrogen atom (H), or Rb and Rc in common with carbon atom to which they are bound form (C2-C5)-polymethylene group or -CH2-CH=CH-; A means -CH2-CH2-, -CH=CH- or -C≡C-; Z means -C(O)OR' wherein R' means H, (C1-C6)-alkyl; n means 1, 2, 3 or 4; R1 means -(CH2)pR7 wherein R7 means (C1-C)-alkyl, (C3-C8)-cycloalkyl, furanyl substituted with trifluoromethyl, phenyl or phenyl-Y-phenyl wherein Y means oxygen atom (O), a simple chemical bond and phenyl is optionally substituted with 1, 2 or three substitutes chosen independently from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, halogen-(C1-C6)-alkyl; p means 0, 1, 2, 3, 4, 5; R2 means H, (C1-C6)-alkyl; R3, R4, R5 and R6 mean H, or their pharmaceutically acceptable salts or solvates, individual isomers or racemic or nonracemic mixture of isomers. Compounds of the formula (I) elicit competitive affinity in binding EP2, EP3 and EP4 that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

11 cl, 11 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-pyrrolidone of the formula (I): wherein Q means -CH2-, -O-; B means -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-CH2 under condition that if B means -CH=CH-, -CH=CH-CH2- then Q means -CH2-; X means -O-, -S-, -SO- or -SO2- or a simple bond under condition that if X meana simple bond then Q means oxygen atom; J means -(CRbRc)n- wherein n means a whole number from 1 to 4; both Rb and Rc mean hydrogen atom, or both Rb and Rc mean (C1-C4)-alkyl and one of them means hydrogen atom (H), or Rb and Rc in common with carbon atom to which they are bound form (C2-C5)-polymethylene group or -CH2-CH=CH-; A means -CH2-CH2-, -CH=CH- or -C≡C-; Z means -C(O)OR' wherein R' means H, (C1-C6)-alkyl; n means 1, 2, 3 or 4; R1 means -(CH2)pR7 wherein R7 means (C1-C)-alkyl, (C3-C8)-cycloalkyl, furanyl substituted with trifluoromethyl, phenyl or phenyl-Y-phenyl wherein Y means oxygen atom (O), a simple chemical bond and phenyl is optionally substituted with 1, 2 or three substitutes chosen independently from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, halogen-(C1-C6)-alkyl; p means 0, 1, 2, 3, 4, 5; R2 means H, (C1-C6)-alkyl; R3, R4, R5 and R6 mean H, or their pharmaceutically acceptable salts or solvates, individual isomers or racemic or nonracemic mixture of isomers. Compounds of the formula (I) elicit competitive affinity in binding EP2, EP3 and EP4 that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

11 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula l , where a and b are independently equal to 0-5; R1 and R2 independently denote -C1-4alkyl, CN, halogen, -ORa, -CH2OH, Ra independently denotes H, C1-4alkyl; R3 denotes -C(O)NR3aR3b, -CN; R3a and R3b denote H; R5 denotes -C1-6alkyl; Q denotes -C0-5-alkylene-Q'-C0-1alkylene-, Q' denotes -CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -OC(O)-, -C(O)O-, -NRQ1C(O)-, -C(O)NRQ1-, -NRQ2-C(O)-NRQ3-, -C=N-O-, -S-S- and -C(=N-O-RQ4)-, RQ1 denotes H; RQ2 and RQ3 denote H; RQ4 denotes -C1-4alkyl, benzyl; e equals 0-5; R6 independently denotes halogen, -C1-4alkyl, -C0-4alkylene-OH, CN, -C (O)O-C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl, -NH-C(O)-C1-4alkyl, -N (C1-4alkyl)2 and -N+(O)O; where the alkyl group in R6 is optionally substituted with 1-5 F atoms; one -CH2- group in Q is optionally substituted with one -OH; or a pharmaceutically acceptable salt or zwitterion form thereof.

EFFECT: compounds exhibit antagonistic activity towards muscarinic receptors, which enables their use to produce pharmaceutical compositions for treating lung diseases such as chronic obstructive pulmonary disease and asthma.

32 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining activated ester of formula (I): where R stands for C1-C6 alkyl, linear or branched, 6-membered heteroaryl with one nitrogen atom as heteroatom; Alk stands for C1-C6 alkyl, linear or branched, consisting in interaction of dicyclohexylamine salt P1 and disuccinimidylcarbonate (DSC) in solvent which represents ketone, in which salt of dicyclohexylamine and N-hydroxycuccinimide P2 precipitates.

EFFECT: method makes it possible to obtain target product with high output and good degree of purity.

10 cl, 1 dwg, 2 ex

FIELD: pharmaceutics.

SUBSTANCE: invention provides multifunctional nitric oxide derivatives of formula I: I, where Y is N, CH or N(→O), or its enantiomer, diastereomers, racemic mixture or its pharmaceutically acceptable salt or solvate, where A is a fragment of general formula II connected through its terminal -NH group with any atom of carbon of pyridine, phenyl or pyridine-oxide ring: II; X is absent or is -(CR2R2)n-; R1 is absent or is represented by from 1 to 5 substituents, each of which is independently selected from a halogen, -CN, -OH, -NO2, -N(R6)2, -OCF3, -CF3, -OR6, -COR6, -COOR6, -CON(R6)2, -OCOOR6, -OCON(R6)2, -(C1-C8)alkyl, -(C1-C8)alkylen-COOR6, -SR6, -SO2R6, -SO2N(R6)2 or -S(=O)R6; R2 is H; R3 each independently represents a (C1-C8)alkyl; R4 is selected from H or -(C1-C8)alkyl; R5 is selected from H or -CN; R6 each is independently selected from H or (C1-C8)alkyl and n is an integer equal to 1 or 2.

EFFECT: said compounds contain a potassium channels opener and a catalyst for degradation of reactive forms of oxygen (RFO), which can act as an antioxidant; also proposed are pharmaceutical compositions containing the said compounds, which can be used for treating diseases, disorders or conditions related to oxidative stress or endothelial dysfunction.

19 cl, 9 dwg, 5 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for prostaglandin amides preparation by general formula (I)

compounds of general formula (V)

a method for preparation of compounds of general formula (IIA)

via an intermediate lactone triol of general formula (XIII)

.

EFFECT: activated carboxylic acid derivatives of the present invention can be easily purified by crystallization to remove impurities and may also be easily converted to the desired amide final product under mild reaction conditions with high yields.

14 cl, 12 dwg

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention proposes two variants of the improved method for preparing anti-ulcerous therapeutic agents of the formula (I): wherein radicals R1-R6 have values given in cl. 1 and cl. 2 of the invention claim. Method involves interaction of corresponding sulfides with m-chloroperoxybenzoic acid in acetone or a mixture acetone/water as a solvent. According to the first variant pH value of the reaction mixture is increased to the value above 7 after the reaction interaction and solvent is removed and crystals of compound of the formula (I) are separated. According to the second variant the interaction is carried out at pH ≥ 7.0 followed by addition of water if necessary and compound of the formula (I) crystals are separated. Invention is directed for preparing omeprazole or pantoprazole preferably. Invention provides preparing the end products of high purity and with high yield.

EFFECT: improved preparing method.

9 cl, 3 ex

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