Derivatives of 1,1-dioxothiomorpholinylindolyl methanone for use as histaminase modulators

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

 

The present invention relates to new derivatives of 1,1-doctrine.reincarnation, their receipt containing their pharmaceutical compositions and their use as medicines. The active compounds according to the present invention are used in the treatment of obesity and other diseases.

In particular, the present invention relates to compounds of General formula

where

R1selected from the group including hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenated, lower cycloalkenyl, lower alkanoyl, lower alkoxycarbonyl, lower cianelli, lower alkylsulfonyl,

phenylsulfonyl, where the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl;

phenyl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl;

lowest phenylalkyl, where the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from h is schego of alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl; and

heteroaryl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, lower alkoxygroup, halogen, lower halogenoalkane, low halogenlampe and cyanopropyl;

R2denotes hydrogen or halogen;

G denotes a group selected from the

where

m denotes 0, 1 or 2;

R3selected from lower alkyl, lower halogenoalkane, cycloalkyl, halogennitroalkane, lower cycloalkenyl and lower phenylalkyl;

n denotes 0, 1 or 2;

R4denotes lower alkyl;

P denotes 0, 1 or 2;

Q denotes 0, 1 or 2;

And choose from CR10R10', O and S;

R5, R5', R6, R6', R7, R7', R10and R10'independently of each Vybrat from the group comprising hydrogen, lower alkyl, hydroxy-group, halogen and dialkylamino,or

R6and R10together form a double bond;

R8denotes lower alkyl;

R9stands With3-C6alkyl;

and their pharmaceutically acceptable salts.

The compounds of formula I are back antagonists and/or inverse agonists of the histamine 3 receptor (H3 receptor).

Histamine (2-(4-imidazolyl)ethylamine) is one of energicheskoj neurotransmitters, which are widely distributed throughout the body, for example, the gastrointestinal tract (Burks 1994 in Johnson L.R. ed., Discrimination of the Gastrointestinal Tract, Raven Press, NY, pp.211-242). Histamine regulates a number of pathophysiological cases related to digestion, such as the secretion of gastric acid, intestinal motility (Leurs et al., Br. J. Pharmacol. 1991, 102, pp 179-185), vasomotor responses, intestinal inflammatory responses and allergic reactions (Raithel et al., Int. Arch. Allergy Immunol, 1995, 108, 127-133). In the mammalian brain histamine is synthesized in histaminergic the body's cells, which are concentrated in Bagratashvili nuclei posterior basal hypothalamus. From it histaminergic cells of the organism in different parts of the brain (Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagaki et al., J. Comp. Neurol 1988, 273, 283-300).

According to these views histamine mediates all their shares in the Central nervous system and the peripheral nervous system, through the four histamine receptors, histamine H1, H2, H3 and H4 receptors.

H3 receptors are mainly localized in the Central nervous system (CNS). As autoreceptor H3 receptors significantly inhibit synthesis and secretion of histamine from histaminergic neurons (Arrang et al., Nature 1983, 302, 832-837; Arrang et al., Neuroscience 1987, 23, 149-157). In quality the ve heteroreceptors H3 receptors also modulate the release of other neurotransmitters such as acetylcholine, dopamine, serotonin and norepinephrine, along with others, in both the nervous system and the peripheral organs such as the lungs, cardiovascular system and gastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982, 107, 919-923; Blandina et al. in The Histamine H3 Receptors (Leurs R.L. and H. Timmermann, eds, 1998, p.27-40, Elsevier, Amsterdam, The Netherlands). H3 receptors show significant activity, i.e. even in the absence of exogenous histamine receptor toniceski activated. In the case of inhibitory receptor such as H3 receptor, this inherent activity causes tonic inhibition of neurotransmitter secretion. Consequently, it is important that H3R antagonist may also have activity inverse agonist as compared to the impacts of exogenous histamine and the transition of the receptor from its significantly active (inhibitory) forms in a neutral state.

Wide distribution of the H3 receptor in the CNS of mammals indicates the physiological role of this receptor, therefore it is assumed that it is therapeutically a potential target to develop new drugs for various indications.

The introduction of H3R ligands in the form of antagonists, inverse agonists, agonists or partial agonists can influence the levels of histamine or the secretion of neurotransmitters in the Central and peripheries the th nervous system and therefore can be used in the treatment of some diseases. Such diseases include obesity (Masaki et al, Endocrinol. 2003, 144, 2741-2748; Hancock et al., European J. of Pharmacol. 2004, 487, 183-197), cardiovascular diseases such as acute myocardial infarction, dementia and cognitive diseases such as hyperactive attention deficit (ADHD) and Alzheimer's disease, neurological diseases such as schizophrenia, depression, epilepsy, Parkinson's disease, and seizures or convulsions, sleep disorders, narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction such as Meniere's disease, drug abuse, and motion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-11).

Consequently, an object of the present invention is a selective, direct transformation of antagonists of the H3 receptor in inverse agonists. Such antagonists/inverse agonists are used as therapeutically active substances, especially in the treatment and/or prevention of diseases associated with the modulation of H3 receptors.

In the present description, the term "alkyl", alone or in combination with other groups, refers to a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from 1 to 20 carbon atoms, preferably from 1 to 16 carbon atoms, more preferably from 1 to 10 carbon atoms.

The term "lower alkyl" or "C1-C8alkyl" alone or in combination with other groups, means a linear or branched alkyl group containing from 1 to 8 carbon atoms, preferably a linear or branched alkyl group containing from 1 to 6 carbon atoms, and particularly preferably a linear or branched alkyl group containing from 1 to 4 carbon atoms. Examples of linear and branched C1-C8the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily, isomeric Gately, the isomeric octile, preferably methyl and ethyl and most preferably methyl.

The term "lower alkenyl" or "C2-8alkenyl", alone or in combination with other groups, means a linear or branched hydrocarbon radical comprising olefinic bond and up to 8, preferably up to 6, especially preferably up to 4 carbon atoms. Examples alkenyl groups are ethynyl, 1-propenyl, 2-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and Isobutanol. Preferred is 2-propenyl.

The term "lower quinil" or "C2-8quinil", alone or in combination with other groups, means a linear or branched hydrocarbon radical with up to 8, preferably up to 6, especially preferably up to 4 carbon atoms. Examples etkinlik groups are ethinyl, 1-PROPYNYL or 2-PROPYNYL. Pre is respectful is 2-PROPYNYL.

The term "cycloalkyl" or "C3-7cycloalkyl" means a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Especially preferred are cyclopropyl, cyclopentyl and cyclohexyl.

The term "lower cycloalkenyl" or "C3-7cycloalkyl1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted by cycloalkyl. It is preferable to cyclopropylmethyl.

The term "alkoxygroup" refers to the group R'-O-, where R' is lower alkyl in the definition above. Examples of the lower alkoxygroup are, for example, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan and tert-butoxypropan, preferably the methoxy group and ethoxypropan, most preferably the methoxy group.

The term "lower alkoxyalkyl" or "C1-8alkoxyl1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted by alkoxygroup, preferably a methoxy group or ethoxypropane. Among lower alkoxyalkyl groups, preferred are 2-methoxyethyl or 3-methoxy who repel.

The term "alkylsulfonyl" or "C1-8alkylsulfanyl" refers to the group R'-S-, where R' represents lower alkyl and the term "lower alkyl" has the value. Examples alkylsulfanyl groups are, for example, methylsulfanyl or ethylsulfonyl.

The term "lower alkylsulfonyl" or "C1-8alkylsulfanyl1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted alkylsulfanyl group, preferably methylsulfonyl. An example of a preferred lower alkylsulfanyl group is 2-methylsulfonylmethyl.

The term "alkylsulfonyl" or "lower alkylsulfonyl" refers to the group R'-S(O)2-, where R' denotes a lower alkyl having this earlier value. Examples alkylsulfonyl groups are, for example, methylsulphonyl or ethylsulfonyl.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine are preferred.

The term "lower halogenated" or "Halogens1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Preferred halogenerator the e lower alkyl groups include triptoreline, deformational, formeterol and chloromethylene groups and triptorelin group is particularly preferred.

The term "lower halogenlampe" or "Halogens1-8alkoxygroup" refers to the lower alkoxygroup by definition above, where at least one of the hydrogen atoms of the lower alkoxygroup substituted by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. The preferred halogenated lower alkyl groups include cryptometer, dipterocarp, formatexpr and chlorotoxin, tripterocarpa is especially preferred.

The term "lower hydroxyalkyl" or "hydraxis1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl group substituted by a hydroxy-group. Examples of lower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.

The term "dialkylamino" refers to the group-NR'r R”, where R' and R” represent lower alkyl, and the term "lower alkyl" has the value. The preferred dialkylamino is dimethylaminopropyl.

The term "lower dialkylaminoalkyl" or "C1-8dialkylamino1-8alkyl" refers to lower alkyl groups defined above, where Raina least one of the hydrogen atoms of the lower alkyl groups substituted by dialkylamino, preferably by dimethylaminopropoxy. Preferred lower dialkylaminoalkyl group is a 3-dimethylaminopropyl.

The term "lower alkanoyl" refers to the group-CO-R', where R' represents lower alkyl and the term "lower alkyl" has the value. Preferred is the group-CO-R', where R' denotes methyl, namely acetyl group.

The term "lower alkoxycarbonyl" or "C1-8alkoxycarbonyl" refers to the group-COOR', where R' represents lower alkyl and the term "lower alkyl" has the value. Preferred is a group-COOR', where R' denotes methyl.

The term "carbarnoyl" refers to the group-CO-NH2.

The term "dialkylamino" or "C1-8-dialkylamino" refers to a group

-CO-NR'r R", where R' and R” represent lower alkyl, and the term "lower alkyl" has the value. Preferred dialkylanilines group is dimethylcarbamoyl.

The term "lower diallylbarbituric" or "C1-8dialkylamino-C1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted by dialkylamino by definition above. Preferred lower dialkylanilines group are the two who is dimethylcarbamoyl.

The term "lower phenylalkyl" or "panels1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl group substituted phenyl group. Preferred lower phenylalaninol group is benzyl or phenethyl.

The term "heteroaryl" refers to aromatic, 5 - or 6-membered ring system which may comprise one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Examples of heteroaryl groups are, for example, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolin, oxazolyl, imidazolyl or pyrrolyl. Especially preferred are furyl and pyridyl.

The term "lower heteroaromatic" or "heteroaryl1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted heteroaryl group defined above.

The term "heterocyclyl" refers to saturated or partially unsaturated 5 - or 6-membered ring which may contain one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Examples heterocyclyl rings include piperidinyl, piperazinil, azepine, pyrrolidinyl, pyrazolidine, imidazoline, imidazolidine, pyridinyl, pyridazinyl, pyrimidine is l, oxazolidinyl, isooxazolyl, morpholinyl, diazolidinyl, isothiazolinones, thiadiazolidine, trihydrogen, tetrahydrofuryl, trihydroxyphenyl, tetrahydropyranyl and trimorphodon. Preferred heterocyclyl group is piperidinyl.

The term "lower geterotsiklicheskikh" or "heterocyclic1-8alkyl" refers to lower alkyl groups defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted heterocyclyl group defined above.

The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids and which are not undesirable neither biological, nor with any other points of view. Salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably with hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic sour is a, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, N-acetylcysteine and the like. In addition, salts may be obtained by attaching an inorganic or organic base to the free acid. Salts derived from inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from inorganic base include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymeric resins and the like. The compounds of formula I can be in the form of zwitter ions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are hydrochloric salt.

The compounds of formula I may also be solvated, for example gidratirovana. Solutionone may be in the process of receiving, for example, due to the hygroscopic properties of the original anhydrous compounds of formula I (hydration). The term "pharmaceutically acceptable salt" also includes a physiologically acceptable with livity.

The term "isomer" refers to compounds that have identical molecular formulas but differ in the nature or sequence of bonding of atoms or the arrangement of atoms in space. Isomers that differ by the arrangement of atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other are indicated by the term "diastereoisomer, and stereoisomers, mirroring which are not compatible, denoted by the term "enantiomers", or, sometimes, optical isomers. The carbon atom that is linked to four non-identical substituents, denoted by the term "chiral center".

Specifically, the present invention relates to compounds of General formula

,

where

R1selected from the group including hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenated, lower cycloalkenyl, lower alkanoyl, lower alkoxycarbonyl, lower cianelli, lower alkylsulfonyl,

phenylsulfonyl, where the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl;

phenyl, unsubstituted or substituted the first one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl;

lowest phenylalkyl, where the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl; and

heteroaryl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, lower alkoxygroup, halogen, lower halogenoalkane, low halogenlampe and cyanopropyl;

R2denotes hydrogen or halogen;

G denotes a group selected from the

where m denotes 0, 1 or 2;

R3selected from lower alkyl, lower halogenoalkane, cycloalkyl, halogennitroalkane, lower cycloalkenyl and lower phenylalkyl;

n denotes 0, 1 or 2;

R4denotes lower alkyl;

p denotes 0, 1 or 2;

Q denotes 0, 1 or 2;

And choose from CR10R10', O and S;

R5, R5', R6, R6', R7, R7', R10and R10'independently from each other selected from the group including hydrogen, lower alkyl, hydroxy-group, halogen and dialkylamino is, or

R6and R10together form a double bond;

R8denotes lower alkyl;

R9stands With3-C6alkyl;

and their pharmaceutically acceptable salts.

In addition, preferred compounds of formula I of the present invention are those where R1selected from the group including

hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenated, lower cycloalkenyl, lower cianelli,

lower alkylsulfonyl and

phenyl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl.

More preferred are such compounds of formula I, where R1selected from the group including hydrogen, lower alkyl and lower halogenated, especially preferred are such compounds where R1denotes hydrogen, or such compounds, where R1indicates the lowest halogenated. Most preferably, when R1denotes triptorelin.

In addition, preferred compounds of formula I are those compounds where R1indicates the lowest cianelli. Particularly preferred is 1-cyanoethyl (propionitrile).

Also preferred compounds of formula I of the present invention are such compounds, where R1indicates the lowest hydroxyalkyl or lower alkoxyalkyl. More preferably, R1selected from the group comprising 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl and 3-methoxypropyl.

In addition, compounds of formula I of the present invention are preferably compounds where R1denotes heteroaryl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, lower alkoxygroup, halogen, lower halogenoalkane, low halogenlampe and ceanography. Most preferably, heteroaryl is pyridyl or pyrimidinyl.

R2denotes a hydrogen or halogen. The compounds of formula I, where R2selected from the group comprising hydrogen, chlorine and bromine are preferred.

Especially preferred compounds of formula I according to the invention are such link, where R2denotes hydrogen.

In addition, preferred compounds of formula I of the present invention are such compounds where G denotes

where m denotes 0, 1 or 2, and R3selected from lower alkyl, lower halogenoalkane, cycloalkyl, halogennitroalkane, lower cycloalkenyl and lower phenylalkyl.

Within this group, preferred are such compounds of formulas is I, where R3denotes lower alkyl. Most preferably, R3represents isopropyl.

Preferred are such compounds of formula I, where m denotes 1, which implies a connection, where G1 is piperidinyl.

Also preferred are the compounds of formula I, where m denotes 0, which implies connection, where G1 is pyrrolidinyl.

Also preferred are the compounds of formula I of the present invention, where G is a

where n denotes 0, 1 or 2 and R4denotes lower alkyl.

Also preferred are the compounds of formula I of the present invention, where G is a

where p denotes 0, 1 or 2, q represents 0, 1 or 2; And selected from CR10R10', O and S; and R5, R5', R6, R6', R7, R7', R10and R10'independently from each other selected from the group including hydrogen, lower alkyl, hydroxy-group, halogen and dialkylamino, or R6and R10together form a double bond.

Also preferred are the compounds of formula I of the present invention, where G is a

where q denotes 0, 1 or 2, R8denotes lower alkyl and R denotes lower alkyl.

Especially preferred compounds of formula I of the present invention are the following:

(1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]metano,

(1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano,

(1,1-diocletianopolis-4-yl)-[1-isopropyl-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano,

(1,1-diocletianopolis-4-yl)-[5-(1-isopropylpyrimidine-3S-yloxy)-1H-indol-2-yl]metano,

5-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]pyridine-2-carbonitrile,

[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

[6-bromo-1-isopropyl-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

[6-bromo-1-(2-chloropyridin-4-yl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

(1,1-dioxo-1λ6-thiomorpholine-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(3-triptoreline)-1H-indol-2-yl]metano,

[1-(2-chloropyridin-4-yl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

2-[2-(1,1-dioxo-1λ6-imartin-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile,

(1,1-dioxo-1λ6-thiomorpholine-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-pyrimidine-5-yl-1H-indol-2-yl]metano,

[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(2-methoxyethyl)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(3-methoxypropyl)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

[6-bromo-1-(2-hydroxyethyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

[6-bromo-1-(3-hydroxypropyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

(S)-2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile,

(R)-2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile,

[5-(1-cyclobutylmethyl-4-yloxy)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,

and their pharmaceutically acceptable salts.

In addition, pharmaceutically acceptable salts of compounds of formula I and pharmaceutically acceptable esters of compounds of formula I are separately preferred variants of the present invention.

The compounds of formula I can form acid additive salts with acids such as standard pharmaceutically acceptable acid, for example, hydrochlor the water, hydrobromide, phosphates, acetates, fumarate, maleate, salicylates, sulphates, privacy, citrates, lactates, mandelate, tartratami and methansulfonate. Preferred are hydrochloride. The solvate and hydrates of the compounds of formula I and their salts are also included in the present invention.

The compounds of formula I may have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, a mixture of diastereoisomers, diastereoisomeric of racemates or mixtures diastereoisomeric racemate. Optically active forms may be obtained, for example, by separation of racemates using asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or allanton). The invention includes all these forms.

It should be understood that compounds of General formula I according to the present invention can be derivationally functional groups with obtaining derivatives which are capable of developing in the original compound in vivo. Physiologically acceptable and metabolically labile derivatives capable of producing the starting compounds of General formula I in vivo, are also included in the scope of the present invention.

The next aspect of the present the invention is a method of preparing compounds of the formula I according to the definition above, namely, that

a) compound of formula II

or its salt,

where R1and R2defined above, is introduced into reaction with the amine of formula III

obtaining compounds of General formula I

where R1, R2and G defined above, and

b) if necessary, allocate the compound obtained in the form of a pharmaceutically acceptable acid additive salt.

The term "salt of the compounds of General formula II includes all of the acid additive salts with acids, such as hydrochloride, hydrobromide, phosphates, acetates, fumarate, maleate, salicylates, sulphates, privacy, citrates, lactates, mandelate, tartratami and methansulfonate. Preferred are hydrochloride. In addition, these cleaners containing hydrochloride salt may contain the equivalent of alkali-chloride salt such as lithium chloride, sodium chloride or potassium chloride.

More specifically, the compounds of formula I can be obtained using the methods described below in the examples or similar methods. Obtaining compounds of the formula I according to the present invention can be implemented by means of a separate ongoing reactions or by United in one synthetic scheme. The syntheses of the compounds according to the invention is represented in the following diagrams. Methods of carrying out the reaction, the purification of the products obtained well-known specialists in this field of technology. The substituents and indices used in this description of the methods have the meanings given above unless otherwise specified.

Scheme 1

Compounds of General formula I can be obtained according to scheme 1 as follows:

a) Synthesis of esters are widely described in the literature, and methods known from the art (for example, the reaction conditions for such reactions are described in the literature: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C.Larock. John Wiley & Sons, New York, NY. 1999). While effective is the use of reaction conditions, which in General are used in so-called "reaction Mitsunobu", which is known from the field of engineering and is described (Hughes, David L. The Mitsunobu reaction. Organic Reactions, New York, 1992 42 335-656)/ We have used the condensation of phenolic alcohol (IV) with alcohols HO-G (VI) (either commercially available or successfully received by methods described in references or by methods known from the technical field) with the use of a phosphine such as tributylphosphine or triphenylphosphine and the like, and diazocompounds type diethylazodicarboxylate, diisopropylcarbodiimide (not necessarily related to the polymer), di-tert-utilisationbased, tetramethyldisiloxane and the like, in solvents commonly used in such reactions, the type face is hydrofuran, toluene, dichloromethane and the like. There are no limitations regarding the nature of the employed solvent, provided that it has no adverse effect on the reaction or input reagents, and that he dissolve the reagents, at least to a sufficient degree. The reaction may proceed in a wide range of temperatures and the precise temperature is not critical for the invention. It was found that the reaction progressing in the range from room temperature to the boiling temperature of the solvent. The time required for the reaction may vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. In addition, the time interval from 0.5 h to several days is usually sufficient to obtain the compounds of formula VII.

Alternatively, the reaction can be used the compounds of formula IV, in which phenolic HE substituted for G-X (V) (either commercially available or successfully received by methods described in references or by methods known from the field of technology). Conditions for such reactions are widely described in literature and known from the technical field. The leaving group X can be any halogen or pseudohalogen group (for example, trifloromethyl, p-toluensulfonyl, methanesulfonyl and the like is). The reaction may proceed in the presence or absence of a solvent and preferably in the presence of a base. The solvents of the type N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dietrologia ether, dioxane, acetonitrile, butanone and the like have been used successfully. There are no limitations regarding the nature of the employed solvent, provided that it has no adverse effect on the reaction or input reagents and that he dissolve the reagents, at least to a sufficient degree. Usually, the reaction is carried out in the presence of a base. Suitable bases include sodium hydride, N-ethyldiethanolamine, carbonates of sodium and cesium, and the like. The reaction may proceed in a wide temperature range, with the exact temperature is not critical for the invention. The time required for the reaction may vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. In addition, the time interval from 0.5 h to several days is usually sufficient to obtain the compounds of formula VII.

b) In the reaction can be used compounds of the compounds of formula VII, in which the indole NH may be substituted by lower alkyl, benzyl, alkyl, alkanoyl and sulfonium, for example, through reaction with alkali the existing, allermuir or sulfonylureas agent (either commercially available or successfully received by methods described in references or by methods known from the field of technology). Typical examples of alkylating or Alliluyeva agent VIII are methyliodide, 2-bromopropane, 2,2,2-cryptreleasecontext, methansulfonate or phenylsulfonyl. Conditions for such reactions, in General, are widely described in literature and known from the technical field. X denotes a leaving group such as any halogen (chlorine, bromine, iodine) or pseudohalogen group (for example, trifloromethyl, p-toluensulfonyl, methanesulfonyl and the like). The reaction may proceed in the presence or absence of a solvent and preferably in the presence of a base. Have been successfully used solvents of the type N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, butanone and the like. There are no limitations regarding the nature of the employed solvent, provided that it has no adverse effect on the reaction or input reagents and that he dissolve the reagents, at least to a sufficient degree. Usually, the reaction is carried out in the presence of a base. Suitable bases include sodium hydride, N-ethyldiethanolamine, carbonates of sodium and purpose of the Oia and the like. The reaction may proceed in a wide temperature range, with the exact temperature is not critical for the invention. The time required for the reaction may vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. In addition, the time interval from 0.5 h to several days is usually sufficient to obtain the compounds of formula IX.

C) the compounds of formula IX are transferred into the free acid under alkaline conditions, for example, using the monohydrate of lithium hydroxide as the base. Free acid or any suitable salt condense with thiomorpholine-1,1-dioxide (proposed Syntec, ref M1201) using a method known from the technical field, the reaction conditions for such reactions, for example, described in the literature: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found that the use of tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium and isopropylethylene in dimethylformamide, successfully leads to compounds of General formula Ia.

g) Indoles (IB) may be required products, but they may not necessarily be used in the subsequent alkylation reaction, as described above, according to paragraph (b) to obtain the desired compound (Ia).

Alternate the VNO, compound (IB) can be alkylated or allerban using Bronevoy acid or a complex ester Bronevoy acid of the formula X (either commercially available or successfully received by methods described in references or by methods known from the field of technology). Conditions for such reactions are widely described in literature and known from the art (see, for example, Mederski, W. W. K. R.; Lefort, M.; Germann, M. Kux, D. TeTpahedron, 1999, 55, 12757). R1may designate any aryl, cycloalkyl or heteroaryl connection.

Alternatively, the compounds (IB) can be allerban compounds of the General formula R1-X (either commercially available or successfully received by methods described in references or by methods known from the field of technology). Conditions for such reactions are widely described in literature and known from the art (see, for example, Watanabe, M; Nishiyama, M.; Yamamoto, T.; Koie, Y, Tetrahedron Letters, 2000, 41, 481; Old, D.W.; Harris. M.C.; Buchwald, S. L 2000, 2, 10, 1403; Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc., 2001, 123, 7727). The leaving group X can be any halogen (chlorine, bromine, iodine) or pseudohalogen group (for example, trifloromethyl, p-toluensulfonyl, methanesulfonyl and the like) and R1may designate any aryl or heteroaryl group.

As described above, the compounds of formula I of the present invention can be PR is changed as medicines for the treatment and/or prevention of diseases, associated with the modulation of H3 receptors.

In this context, the term "disease associated with the modulation of H3 receptors" means an illness, treatment and/or prevention of which can be achieved through modulation of H3 receptors. Such diseases include, but are not limited to, obesity, metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, geriatric memory dysfunction, average cognitive impairment, cognitive deficit, hyperactive attention deficit disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorder, narcolepsy and other diseases, including asthma, Allergy induced allergic responses in the respiratory tract, congestion, chronic obstructive pulmonary disease and gastrointestinal disease.

In a preferred aspect, the term "disease associated with the modulation of H3 receptors" refers to obesity, metabolic syndrome (syndrome X) and other diseases related to nutrition, while obesity is particularly preferred.

The invention, furthermore, relates also to pharmaceutical compositions comprising compounds according to the definition above, and pharmaceutically PR is acceptable carrier and/or excipient.

In addition, the invention relates to compounds defined above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of diseases associated with the modulation of H3 receptors.

In another embodiment, the invention relates to a method of treatment and/or prevention of diseases associated with the modulation of H3 receptors, which consists in the introduction of therapeutically effective amounts of compounds of General formula I to a human or animal. The method of treatment and/or prevention of obesity is preferred.

The invention further relates to the use of compounds of the formula I defined above for the treatment and/or prevention of diseases associated with the modulation of H3 receptors.

The invention also relates to the use of compounds of the formula I according to the definition above when getting medicines for the treatment and/or prevention of diseases associated with the modulation of H3 receptors. The use of compounds of the formula I according to the definition above to obtain drugs for the treatment and/or prevention of obesity is preferred.

In addition, the present invention relates to the use of compounds of formula I to obtain a medicinal medium spans the VA for treatment and/or prevention of obesity in a patient, who takes treatment of the lipase inhibitor and, especially when the lipase inhibitor is orlistat.

A preferred object of the present invention is a method of treatment or prevention of obesity obesity and related diseases, which consists in the introduction of therapeutically effective amounts of compounds of General formula I in combination or conjunction with a therapeutically effective amount of other drugs for the treatment of obesity and diseases related to nutrition, so that together they give effective attenuation of the disease. Other suitable drugs include, but are not limited to, reducing appetite agents, inhibitors, lipase inhibitors selective capture of a serotonin (SSRI), and agents that stimulate the metabolism of fat in the body. Combination or combinations of the aforementioned agents may be introduced separately, sequentially or simultaneously.

The term "lipase inhibitor" refers to compounds that can inhibit the action of lipases, such as gastric and pancreatic lipases, such as orlistat and lipstatin, which are described in US 4598089 and are potential inhibitors of lipases. Lipstatin is a natural product of microbiological origin, and orlistat is a product of hydrogenation of lipstatin. Other lipase inhibitors include the class of compounds, the total related to anglicanum, which are analogues of orlistat (Mutoh et al, 1994). The term "lipase inhibitor " refers to a polymer-bound lipase, e.g. as described in WO 99/34786 (Geltex Pharmaceuticals Inc.). Such polymers are characterized by the fact that they substituted by one or more groups which inhibit the lipase. The term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably refers to tetrahydrolipstatin. The introduction of a therapeutically effective amount of a compound according to formula I in combination or conjunction with a therapeutically effective amount of tetrahydrolipstatin is especially preferred.

Tetrahydrolipstatin (orlistat) is a known compound used for the control or prevention of obesity and hyperlipidemia. For example, in US 4598089, published July 1, 1986, reveals the processes of obtaining orlistat and US 6004996, reveals the corresponding pharmaceutical compositions. In addition, corresponding pharmaceutical compositions are described, for example, in the publications WO 00/09122 and WO 00/09123. Additionally, the ways to get orlistat disclosed in European patent applications 0185359, 0189577, 0443449 and 0524495.

Suitable anorexicskin agents used in combination with the compound of the present invention, include, but are not limited to, APD356, Aminorex, AMF is chloral, amphetamine, axokine, benzphetamine, bupropion, chlorphentermine, clobenzorex, klotrix, glominerals, clortermine, SR, cilexetil, CYT009-GhrQb, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, penetrex, fenproporex, Fluarix, luminares, furfurylmercaptan, levamfetamine, levorotatory, mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin, norpseudoephedrine, phenterex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, pierrex, rimonabant, sibutramine, SLV319, SNAP 7941, SRI 47778 (surinabant), steroid plant extracts (for example, P57) and TM and their pharmaceutically acceptable salts.

The most preferred anorectics agents are sibutramine, rimonabant and phentermine.

Suitable selective inhibitors of serotonin reuptake, used in combination with the compound of the present invention, include uoxetine, fluvoxamine, paroxetine, tetralin and their pharmaceutically acceptable salts.

Suitable agents which stimulate the fat metabolism of the body include, but are not limited to, agonists of growth hormone (e.g., AOD-9604).

The use of compounds of General formula I when getting medicines for the treatment and prevention of obesity in a patient who also takes treatment of compounds is s, selected from the group comprising a lipase inhibitor, anorectics agent, inhibitor selective serotonin reuptake and the agent that stimulates metabolism of body fat, also is an object of the present invention.

The use of compounds of General formula I when getting medicines for the treatment and prevention of obesity in a patient who takes treatment of the lipase inhibitor, preferably tetrahydrolipstatin, also is an object of the present invention.

In addition, a preferred object of the invention is a method of treatment or prophylaxis of type II diabetes (insulin-dependent diabetes mellitus (NIDDM)) in humans, including the introduction of a therapeutically effective amount of the compounds of formula I in combination or conjunction with a therapeutically effective amount of a lipase inhibitor, particularly where the lipase inhibitor is tetrahydrolipstatin. It is also an object of the invention is the method described above for the joint, separate or sequential introduction of the compounds of formula I and of the lipase inhibitor, particularly tetrahydrolipstatin.

In addition, a preferred object of the invention is a method of treatment or prophylaxis of type II diabetes (insulin-dependent diabetes mellitus (NIDDM)) in humans, including introduced the e therapeutically effective amount of the compounds of formula I in combination or conjunction with a therapeutically effective amount of an anti-diabetic agent.

The term "anti-diabetic agent" refers to compounds selected from the group including 1) PPARγ agonists such as palpitation (actos) or rosiglitazone (avandia) and the like; 2) biguanides such as Metformin (glucophage) and the like; 3) sulfonylureas such as glibenclamide, glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta) and the like; 4) nonsulfonylurea such as nateglinide (starlix), Repaglinide (prandin) and the like; 5) PPARα/γ agonists such as GW-2331 and the like; 6) DPP-IV - inhibitors such as LAF-237 (vildagliptin), MK-0431, BMS-477118 (saxagliptin) or GSK23A and the like; 7) glucokinase activators such as the compounds disclosed, for example, in WO 00/58293 A1, and the like; 8) inhibitors of α-glucosidase such as acarbose (precose) or miglitol (glyset) and the like.

It is also an object of the invention is the method described above for joint, separate or sequential introduction of the compounds of formula I and a therapeutically effective amount of an anti-diabetic agent.

The use of compounds of General formula I when getting medicines for the treatment and prevention of type II diabetes in a patient who is also receiving treatment with antidiabetic agent, is also an object of the present invention.

In addition, according to preferred object of the invention predlagaetsya treatment or prevention of dyslipidemia in humans, involving the introduction of a therapeutically effective amount of the compounds of formula I in combination or conjunction with a therapeutically effective amount of a lipid-lowering agent.

The term "lipid-lowering agent" refers to compounds selected from the group including 1) sequestrator bile acids such as cholestyramine (questran), cholesterol (colestid) and the like; 2) inhibitors of HMG-CoA reductase such as atorvastin (lipitor), cerivastatin (baycol), fluvastatin (lescol), pravastatin (pravachol), simvastatin (zocor) and the like; (3) inhibitors of cholesterol absorption such as ezetimibe and the like; 4) SETR inhibitors such as torcetrapib, JTT 705 and similar; 5) PPARα agonists such as clofibrate, gemfibrozil (lopid), fenofibrate (lipidil), bezafibrate (bezalip) and the like; 6) inhibitors urine synthesis such as Niacin and the like; and (7) receptor agonists Niacin such as nicotinic acid and the like.

It is also an object of the invention is the method described above for joint, separate or sequential introduction of the compounds of formula I and a therapeutically effective amount of a lipid-lowering agent.

The use of compounds of General formula I when getting medicines for the treatment and prevention of lipidemia the patient, which also receives lachenalii-lowering agent, also an object of the present invention.

In addition, in the preferred embodiment, the invention features a method of treating or preventing hypertension in humans, including the introduction of a therapeutically effective amount of the compounds of formula I in combination or conjunction with a therapeutically effective amount of an antihypertensive agent.

The term "antihypertensive agent" or "agent that lowers blood pressure" refers to compounds selected from the group including 1) inhibitors angiotensin-converting enzyme (ACE), including benazepril (lotensin), captopril (capoten), enalapril (vasotec), fosinopril (monopril), lisinopril (prinivil, zestril), moexipril (univasc), perindopril (coversum), quinapril (accupril), ramipril (Altec), trancopal (mavik) and the like; 2) antagonists angiotensin II receptor comprising candesartan (atacand), eprosartan (Teveten), irbesartan (avapro), losartan (cozaar), telmisartan (megadisc), valsartan (diovan) and the like; 3) adrenergicheskie blockers (peripheral and Central) such as β-adrenergicheskie blockers, including acebutolol (sectral), atenolol (tenormin), betaxolol (kerlone), bisoprolol (zebeta), carteolol (cartrol), metoprolol (lopressor; toprol-XL), nadolol (corgard), penbutolol (levatol), pindolol (visken), propranolol (ind the RAF), timolol (blocadren) and the like; α/β-adrenergicheskie blockers, including carvedilol (coreg), labetalol (normodyne) and the like; α-1-adrenergicheskie blockers, including prazosin (minipress), doxazosin (xatral), terazosin (hytrin), phenoxybenzamine (dibenzyline) and the like; peripheral adrenergicheskie-neuronal blockers, including guanadrel (hylorel), guanethidine (ismelin), reserpine (serpasil) and the like; α-2-adrenergicheskie blockers, including α-methyldopa (aldomet), clonidin (catapres), guanabenz (wytensin), guanfacine (TENEX) and the like; 4) means that widen blood vessels (vasodilators), including hydralazine (apresoline), Minoxidil (loniten), clonidine (catapres) and the like; 5) calcium channel blockers, including amlodipine (norvasc), felodipine (plendil), isradipine (dynacirc), nicardipine (Cardin sr), nifedipine (procardia, adalat), nisoldipine (sular), diltiazem (cardizem), verapamil (isoptin) and similar; 6) diuretics such as thiazides and teased-like agents, including hydrochlorothiazide (hydrodiuril, microzide), chlorthiazide (diuril), chlorthalidone (hydrate), indapamide (lozol), metolazone (mikros) and the like; looped (loop) diuretics such as bumetanide (Bumex) and furosemide (lasix), ethacrynic acid (edecrin), torsemide (demadex) and the like; potassium-saving diuretics, including amiloride (m is Damar), triamteren (dyrenium), spironolactone (aldactone) and thiamine (simcor) and the like; 7) inhibitors of tyrosine hydroxylase, including metyrosine (demser) and the like; 8) inhibitors of neutral endopeptidase, including BMS-186716 (omapatrilat), UK-79300 (candoxatril), ecadotril (sinehan), BP-1137 (fasidotril), UK-79300 (sampatrilat) and the like; and 9) endothelin antagonists, including tezosentan (RO0610612), A and the like.

It is also an object of the invention is the method described above for joint, separate or sequential introduction of the compounds of formula I and a therapeutically effective amount of an antihypertensive agent.

The use of compounds of General formula I when getting medicines for the treatment and prevention of hypertension in a patient who is also receiving treatment antihypertensive agent, is also an object of the present invention.

As described above, the compounds of formula I and their pharmaceutically acceptable salts possess various pharmacological properties. In particular, it was found that the compounds of the present invention are good antagonists and/or inverse agonists of the histamine 3 receptor (H3R).

The following test was conducted to determine the activity of compounds of the formula (I).

Analysis of the binding3N-(R)-α-methylhistamine

The experiments on which ysenia binding was performed using HR3-CHO membranes, obtained as described in Takahashi, K, Tokita, S., Kotani, N. (2003) J. Pharmacol. Exp. Therapeutics, 307, 213-218.

The appropriate amount of membrane (60 to 80 µg protein/cell) were incubated with increasing concentrations dihydrochloride3H(R)-α-methylhistamine (from 0.10 to 10 nm). Nonspecific binding was determined using 200-fold excess of trihydrobromide (R)-α-methylhistamine (500 nm final concentration). Incubation was carried out at room temperature (shaking for 3 h in deep-honeycomb tablets). The final volume in each cell was 250 μl. After incubation was followed by rapid filtration on GF/B filters (pre-soaking 100 µl of 0.5% PEI in Tris 50 mm, shaking at 200 rpm for 3 h). Filtration was carried out using a cell harvester, and filter plates then were washed five times with cold buffer for washing, containing 0.5 M NaCl. After harvestore tablets were dried at a temperature of 55°C for 60 min, and then thereto were added to scintillation fluid (Microscint 40, 40 microl in each cell) and the amount of radioactivity on the filter was determined on a Packard top-of-the device after shaking tablets for 2 h at 200 rpm at room temperature.

Buffer for binding: 50 mm Tris-HCl pH 7.4, 5 mm MgCl2×6H2O pH 7.4.

Buffer for washing: 50 mm Tris-HCl pH 7.4 and 5 mm MgCl2×6H2and 0.5 M NaCl pH 7.4.

Indirect measurement of affinity H3R inverse agonists: 12 selected compounds at increasing concentrations (in the range from 10 μm to 0.3 nm) was continuously tested in competitive binding experiments using membranes of human HR3-CHO cell line. The appropriate amount of protein, for example, approximately 500 imp./min binding RAMAH when Kd, were incubated for 1 h at room temperature with a final volume of 250 μl in 96-honeycomb tablets in the presence of3N(R)-α-methylhistamine (1 nm final concentration = Kd). Nonspecific binding was determined using 200-fold excess of cold trihydrobromide (R)-α-methylhistamine.

All compounds were tested at each concentration in a double loop. Compounds that showed inhibition of [3H]-RAMH more than 50%were tested again to determine the IC50in the experiment serial dilution. Ki was calculated from the IC50on the basis of the equation of Cheng-Prusoff (Cheng, Y., Prusoff, W.H. (1973) Biochem. Pharmacol., 22, 3099-3108).

Compounds of the present invention showed Kivalues in the range from 0.1 nm to approximately 1000 nm, preferably from about 0.1 nm to 300 nm and more preferably from about 0.1 nm to 100 nm.

The following table shows the measured values for some selected compounds p the present invention.

ExampleKi (nm)
13
449

Demonstration of the activity of a biological binding compounds of the present invention can be conducted in vitro, ex vivo and in vivo, which are well known from the technical field. For example, to demonstrate the efficacy of the pharmaceutical agent in the treatment of obesity-related diseases such as diabetes, syndrome X, or atherosclerotic disease, and related diseases such as hypertriglyceridemia and hypercholesteremia, can be applied the following tests.

Method of measuring glucose levels in the blood

db/db Mice (obtained from Jackson Laboratories, Bar Harbor, ME) bleed (through eye or tail vein) and grouped according to the equivalent value of the glucose levels in the blood. Then oral route is injected dose (by sensing in a pharmaceutically acceptable solvent) test compound once daily for 7 to 14 days. After that, the animals again obeskrovlivaya through eye or tail vein, and blood is determined glucose levels.

Method of measuring levels of triglycerides

hApoAl mice (obtained Jackson Laboratories, Bar Harbor, ME) bleed (through eye or tail vein) and grouped according to the equivalent value of serum levels of triglycerides. Then oral route is injected dose (by sensing in a pharmaceutically acceptable solvent) test compound once daily for 7 to 14 days. After that, the animals again obeskrovlivaya through eye or tail vein, and blood is determined serum levels of triglycerides.

Method of measuring levels of cholesterol, high-density

To determine the levels of plasma cholesterol, high-density (HDL) hApoAl mice bleed (through eye or tail vein) and grouped according to the equivalent value of plasma levels of cholesterin high density. Then oral route to mice injected dose (by sensing in a pharmaceutically acceptable solvent) test compound once daily for 7 to 14 days, and the next day after that, the animals again obeskrovlivaya. The plasma is analyzed for HDL-cholesterol.

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be entered n the example, orally, for example in the form of tablets, pills in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection or infusion solutions, or tapicerki, for example, in the form of ointments, creams or oils.

The pharmaceutical preparation may be carried out using techniques well known to experts in the field of engineering, and lies in making the described compounds of formula (I) and their pharmaceutically acceptable derivatives medicines prepared according to the officially approved recipe, along with a suitable, inert, therapeutically compatible solid or liquid carriers and, optionally, conventional pharmaceutical excipients.

As suitable materials for the media can be used as inorganic and organic materials. So, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carriers for tablets, pellets in the shell, coated tablets and hard gelatin capsules. Suitable carriers for soft gelatin capsules can be, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols (depending on the nature of the active ing is edient non-native). Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural and hydrogenated oils, waxes, fats and semi-solid or liquid polyols. Suitable carriers for topical drugs are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, wetting agents and emulsion that improves the consistency agents, flavoring agents, salts for installation osmotic pressure, buffer substances, soljubilizatory, dyes, masking agents and oxidants are considered as pharmaceutical excipients.

The dosage of the compounds of formula (I) can vary within wide limits depending on subject to the control of the disease, age and individual condition of the patient and the route of administration and should, of course, be adjusted to the individual requirements in each particular case. For adult patients, the recommended daily dose ranges from 1 mg to p is blithedale 1000 mg, in particular, from 1 mg to approximately 100 mg depending on the dosing is convenient to introduce the daily dose in the form of several single doses.

The pharmaceutical preparations contain from 0.1 to 500 mg, preferably from 0.5 to 100 mg of the compounds of General formula (I).

The following examples illustrate the present invention in more detail. They are, however, in no way limit its scope.

Examples

The intermediate compound (I): ethyl ester of 5-(1-isopropylpiperazine-4-yloxy)-1H-indole-2-carboxylic acid

a) stage 1: 1-Isopropylpiperazine-4-ol

To a cold (0°C.) solution of 1-isopropylpiperazine (from the firm Chemie Brunschwig AG, 100 g, 1.0 EQ.) in ethanol (500 ml) is added sodium borohydride (19.3 g, 0.7 EQ.) small portions. The reaction mixture is left to spontaneously warm to room temperature and stirred over night. After concentration in vacuum, add ice water (1 kg), aqueous sodium hydroxide solution (28 wt.%, 0.5 l) and dichloromethane (1 l). The mixture is vigorously stirred for 4 h, after which the aqueous layer was extracted with dichloromethane. The combined organic layers washed with brine, dried over sodium sulfate, filtered and purified using a fractionated vacuum distillation (20 mbar). One fraction (95°C at 20 mbar) allocate getting to 61.3 g (yield 60%) named in segaloviciene in the form of a colorless oil. MS (m/e): 144,5 (MN+, 100%).

b) stage 2: ethyl ester of 5-(1-isopropylpyrimidine-3-yloxy)-1H-indole-2-carboxylic acid

To a cold (0°C.) mixture of ethyl ester 5-hydroxy-1H-indole-2-carboxylic acid (10 g, 1.0 EQ.), 1-isopropylpiperazine-4-ol (intermediate compound (1), stage 1, to 7.32 g of 1.05 equiv.) and triphenylphosphine (15.3 g, 1.2 EQ.) in tetrahydrofuran (280 ml) is added slowly a solution of diisopropylcarbodiimide (11.8 g, 1.2 EQ.) in tetrahydrofuran (20 ml). The mixture is stirred for 30 min at 0°C and overnight at room temperature, concentrated in vacuo, dissolved in motivational ether (310 ml), washed with aqueous solution of sodium hydroxide (0.5 to normal), brine, dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel, elwira a mixture of dichloromethane/methanol/ammonia. The selected fraction is dried in vacuum, obtaining 7.0 g (yield 43%) of the desired product as a white solid. MS (m/e): 331,5 (MN+, 100%)

Example 1: (1,1-Diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]metano

a) stage 1: ethyl ester of 5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indole-2-carboxylic acid

To a mixture of ethyl ester 5-(1-isopropylpyrimidine-3-yloxy)-1H-indole-2-carboxylic acid (intermediate compound, 4 g, 1.0 EQ.) in digitiform the Ministry of foreign Affairs (40 ml) is added sodium hydride (dispersion in oil, 60 wt.%, 533 mg, 1.1 EQ.) several portions. The solution is stirred for 30 min at 70°C. Then add 2,2,2-triftoratsetilatsetonom (3,37 g, 1.2 EQ.) and the reaction mixture was stirred at 70°C for the night. Then the reaction mixture proportionibus between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with water and brine, evaporated in vacuo and then purified on silica gel, elwira a mixture of dichloromethane/methanol/ammonia. The selected fraction is dried in vacuum, obtaining of 3.9 g (yield 78%) of the desired product in the form of a whitish solid. MS (m/e): 413,5 (MN+, 100%).

b) stage 2: 5-(1-Isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indole-2-carboxylic acid (hydrochloric salt with 1 EQ. lithium chloride)

To a solution of ethyl ester 5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indole-2-carboxylic acid (3.9 g, 1.0 EQ.) in tetrahydrofuran (30 ml), water (15 ml) and methanol (7 ml) is added monohydrate of lithium hydroxide (460 mg, 1.16 EQ.). The reaction mixture is heated under reflux during the night. After concentration in vacuo the residue is acidified (pH 2) hydrochloric acid (2-normal). The resulting mixture is dried in vacuum, obtaining 4.4 g (yield 99%) of the desired product in the form of a whitish solid. MS (m/e): 462,5 (M-N- , 100%).

C) stage 3: (1,1-Diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]metano

A mixture of 5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indole-2-carboxylic acid (hydrochloric salt with one equivalent. lithium chloride, 650 mg, 1.0 EQ.), tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (563 mg, 1.2 EQ.), thiomorpholine-1,1-dioxide (provided by the company Syntec, ref. M1201) and diisopropylethylamine (1,22 ml, 5 EQ.) in dimethylformamide was stirred at room temperature for 24 h, and then proportionibus between aqueous sodium hydrogen carbonate solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water and brine, dried over sodium sulfate, filtered, evaporated in vacuum and purified on silica gel, elwira a mixture of dichloromethane/methanol/ammonia. The selected fraction is dried in vacuum, obtaining 468 mg (yield 66%) of the desired product in the form of a whitish solid. MS (m/e): 502,5 (MN+, 100%).

Example 2: (1,1-Diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano

a) stage 1: 5-(1-Isopropylpiperazine-4-yloxy)-1H-indole-2-carboxylic acid (hydrochloric salt with one equivalent. lithium chloride)

A mixture of ethyl ester 5-(1-isopropylpyrimidine-3-yloxy)-1H-indole-2-carboxylic acid (intermediate connect the tion (1), 1.98 g, 1.0 EQ.) and monohydrate of lithium hydroxide (300 mg, 1.15 mmol) in tetrahydrofuran (30 ml), methanol (30 ml) and water (15 ml) is heated at a temperature of 100°C for 2 hours the Organic solvents were removed and add 1-normal water ReSTOR Hcl to obtain a pH in the range from 2 to 3. Then the mixture is evaporated without dried and used without further purification in the next stage. MS (m/e): 301,5 (M-N-, 100%).

b) stage 2: (1,1-Diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano

Similarly to the procedure described in the synthesis example 1, stage 3, named in the title compound synthesized from 5-(1-isopropylpiperazine-4-yloxy)-1H-indole-2-carboxylic acid (hydrochloric salt with one equivalent. lithium chloride) (example 2, step 1) and thiomorpholine-1,1-dioxide (provided by the company Syntec, ref. M1201). Named the title compound is obtained with a 75%yield as a white solid. MS (m/e): 420,5 (MN+, 100%).

Example 3: (1,1-Diocletianopolis-4-yl)-[1-isopropyl-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano

To a mixture of (1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]methanone (example 2, 100 mg, 1.0 EQ.) and isopropylcarbonate (67 mg, 2.0 EQ.) in dimethylformamide (4 ml) is added cesium carbonate (156 mg, 2.0 EQ.). The solution is stirred for 22 hours at a temperature of 95°C. the Reaction is MES concentrated in vacuo and the residue partitioned between water and methyl tert-butyl ether. The aqueous layer was extracted with methyl tert-butyl ether. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and then purified on silica gel, elwira with a mixture of cyclohexane/ethyl acetate. The selected fraction is dried in vacuum, obtaining 52 mg (yield 47%) of the desired product in the form of a whitish solid. MS (m/e): 462,5 (MN+, 100%)

Example 4: (1,1-Diocletianopolis-4-yl)-[5-(1-isopropylpyrimidine-3S-yloxy)-1H-indol-2-yl]metano

a) stage 1: ethyl ester of 5-((S)-1-benzylpyrrolidine-3-yloxy)-1H-indole-2-carboxylic acid

To a cold (0°C.) mixture of ethyl-5-hydroxyindole-2-carboxylate (provided by the company Biosynth, N-6350, 20,5 g, 1.0 EQ.), (R)-1-benzyl-3-pyrrolidinone (23 g, 1.3 EQ.) and tri-n-butylphosphine (58 ml, 2.0 EQ.) slowly add 1,1'-(azodicarbon)dipiperidino (of 50.4 g, 2.0 EQ.) several portions. The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated in vacuo and add diethyl ether. The precipitate is filtered off, the filtrate was concentrated in vacuo and purified on silica gel, elwira a mixture of dichloromethane/methanol/ammonia. The selected fraction is dried in vacuum, obtaining 18 mg (yield 49%) of the desired product as a slightly yellow foam. MS (m/e): 365,5 (MN+, 100%).

b) stage 2: ethyl ester of 5-((S)-1-isopropylphenol is lidin-3-yloxy)-1H-indole-2-carboxylic acid

To a mixture of ethyl ester of 5-((S)-1-benzylpyrrolidine-3-yloxy)-1H-indole-2-carboxylic acid (18.0 g, 1.0 EQ.) and acetic acid (28 ml, 10 EQ.) in ethanol (500 ml) is added palladium on charcoal (10 wt.%, 2,0 g of 0.04 EQ.) and the reaction vessel is rinsed with hydrogen (1 ATM). The reaction mixture was stirred for 18 h at room temperature, then filtered and concentrated in vacuo. The residue (28.4 g) was dissolved in dimethylformamide (500 ml) and add potassium carbonate. The mixture is stirred for 15 min at room temperature. Then add 2-jumprope (42 g, 5.0 EQ.) and the mixture is stirred for 4 h at 50°C. the Reaction mixture is filtered and the filtrate is evaporated in vacuum. The residue is dissolved in acetone, filtered and the filtrate is evaporated in vacuo, and purified on silica gel, elwira a mixture of dichloromethane/methanol/ammonia. The selected fraction is dried in vacuum, obtaining 9.3 g (yield 59%) of the desired product as a slightly brown solid. MS (m/e): 317,4 (MN+, 100%).

C) stage 3: 5-((S)-1-Isopropylpyrimidine-3-yloxy)-1H-indole-2-carboxylic acid (hydrochloric salt with 1 EQ. lithium chloride)

To a solution of ethyl ester 5-((S)-1-isopropylpyrimidine-3-yloxy)-1H-indole-2-carboxylic acid (8,9 g, 1.0 EQ.) in tetrahydrofuran (100 ml), water (50 ml) and methanol (10 ml) add monohydrate of lithium hydroxide (13 g, of 1.10 EQ.). The reaction mixture is heated under reflux overnight and then concentrated in vacuo. The residue is acidified (pH 2) hydrochloric acid (2-normal). The resulting mixture is dried in vacuum, obtaining 10.5 g (yield 100%) of the desired product as a brown foam. MS (m/e): 287,0 (M-N-, 100%).

d) stage 4: (1,1-Diocletianopolis-4-yl)-[5-(1-isopropylpyrimidine-3S-yloxy)-1H-indol-2-yl]metano

Similarly to the procedure described for the synthesis of example 1, stage 3, named the title compound is obtained from 5-((S)-1-isopropylpyrimidine-3-yloxy)-1H-indole-2-carboxylic acid (hydrochloric salt with 1 EQ. lithium chloride (example 4, step 3) and thiomorpholine-1,1-dioxide (provided by the company Syntec, ref. M1201). The desired product is obtained with a yield of 67% in the form of a white solid. MS (m/e): is 406.5 (MN+, 100%).

Example 5: 5-[2-(1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]pyridine-2-carbonitrile

To a mixture of (1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]methanone (example 2, 150 mg, 1.0 EQ.), anhydrous copper acetate(II) (131 mg, 2 equiv.) pyridine (120 microl, 4 EQ.) in dichloromethane (3.5 ml), add pinacolyl ester 2-cyano-5-Bronevoy acid (247 mg, 3 EQ.). The reaction mixture is stirred for 4 days and then concentrated in vacuo. The residue is purified on forces is the Kagel, elwira a mixture of dichloromethane/ methanol in the ratio of 98:2. The selected fraction is dried in vacuum, obtaining 57 mg (yield 23%) of the desired product as a slightly yellow oil. MS (m/e): 522,5 (MN+, 100%).

Example 6: [6-Bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

a) stage 1: ethyl ester of 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid

A solution of ethyl ester of 6-bromo-5-methoxy-1H-indole-2-carboxylic acid (8,30 g, 27.8 mmol) (obtained according to J. Org. Chem. 1974, 39, 3580) in 160 ml of dichloromethane cooled to a temperature of -78°C. At this temperature, to the solution was added 55,7 ml tribromide boron (55.7 mmol; 1-molar solution in dichloromethane). The solution is kept spontaneously warm to room temperature, then leave for another 30 minutes Then the solution is transferred into a 10%aqueous sodium bicarbonate solution, the phases are separated and the aqueous phase is shaken out three times with ethyl acetate. The combined organic layers washed with water, brine, dried over magnesium sulfate, filtered and evaporated. The residue is purified using rapid chromatography on silica gel, elwira a mixture of n-hexane: ethyl acetate (2:1 ratio)to give 5.7 g (yield 72%) of product as a pale yellow solid. MS (m/e): 282,2 (M-N+, 100%).

b) stage 2: ethyl ester of 6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-ind the l-2-carboxylic acid

To a suspension of 0.25 g of ethyl ester (0.88 mmol) of 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid in 5 ml of tetrahydrofuran added 0.15 g (1.05 mmol) of 1-isopropylpiperazine-4-ol (commercially available) and 0.28 g (1.07 mmol) of tributylphosphine. The suspension is cooled to a temperature of 0°C, add 0,244 g (1.06 mmol) di-tert-utilization.bacteria and the reaction left to spontaneously warm to room temperature. After 48 h, the suspension is filtered and the filtrate is evaporated. The residue is purified using rapid chromatography on silica gel, elwira a mixture of dichloromethane: methanol (in a ratio of from 100:0 to 60:40)to give 0.20 g (yield 55%) of product as a pale yellow foam. MS (m/e): 409,0 (M-N+, 100%).

C) stage 3: 6-Bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indole-2-carboxylic acid (hydrochloric salt mixed with lithium chloride)

A mixture of ethyl ester of 6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indole-2-carboxylic acid (3.4 g, 1.0 EQ.) and lithium hydroxide (249 mg, 1.25 EQ.) in a mixture of tetrahydrofuran (170 ml) with water (85 ml) is heated under reflux for 2 h and then the solvents removed in vacuum and bring the pH to approximately 2. The suspension is dried by azeotropic distillation of water (with toluene), receiving of 3.95 g of the desired product as a pale yellow solid which is used without further purification. MS (m/e): 416,5 (M-N+, 100%).

d) stage 4: [6-Bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 1, stage 3, named the title compound is obtained from 6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indole-2-carboxylic acid (hydrochloric salt mixed with lithium chloride) (example 6, step 3) and thiomorpholine-1,1-dioxide (provided by the company Syntec, ref. M1201). The desired product is obtained with a yield of 60% as a pale yellow solid. MS (m/e): 499,5 (MN+100%).

Example 7: [6-Bromo-1-isopropyl-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 3, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (example 6, step 4) and isopropylmyristate. The desired product is obtained with a yield of 69% as a pale yellow solid. MS (m/e): 540,3 (M+H, 100%).

Example 8: [6-Bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 1, stage 1, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4 and is)methanone (example 6, stage 4) and 2,2,2-triftoratsetilatsetonom. The desired product is obtained with a yield of 15% in the form of a white solid. MS (m/e): 580,1 (M+H, 100%).

Example 9: [6-Bromo-1-(2-chloropyridin-4-yl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 5, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (example 6, step 4) and 2-chloropyridin-4-Bronevoy acid with a yield of 7% in the form of a white solid. MS (m/e): 609,0 (M+H, 100%).

Example 10: (1,1-Dioxo-1λ6-thiomorpholine-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(3-triptoreline)-1H-indol-2-yl]metano

Similarly to the procedure described for the synthesis of example 5, named the title compound is obtained from (1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]methanone (example 2) and (3-trifluoromethyl)phenylboronic acid with a yield of 77% as a pale yellow solid. MS (m/e): 564,5 (MN+, 100%).

Example 11: [1-(2-Chloropyridin-4-yl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 5, named the title compound is obtained from (1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-in the ol-2-yl]methanone (example 2) and 2-chloropyridin-4-Bronevoy acid with a yield of 8% in the form of a whitish solid. MS (m/e): 531,5 (M+, 100%).

Example 12: the rat-2-[2-(1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile

Similarly to the procedure described for the synthesis of example 1, stage 1, named the title compound is obtained from (1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]methanone (example 2) and 2-bromopropionitrile with a yield of 20% in the form of a light yellow foam. MS (m/e): to 473.6 (MN+, 100%).

Example 13: (1,1-Dioxo-1λ6-thiomorpholine-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-pyrimidine-5-yl-1H-indol-2-yl]metano

To a mixture of (1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]methanone (example 2, 1 g, 1.0 EQ.), TRANS-1,2-diaminocyclohexane (186 microl, of 0.65 equiv.) iodide copper (I) - (54 mg, 0,12 equiv.) potassium phosphate (1.06 g, 2.1 EQ.) and potassium carbonate (692 mg, 2.1 EQ.) in dioxane (20 ml) add 5-bromopyrimidine (417 mg, 1.1 EQ.). The reaction mixture is stirred for 5 days and then concentrated in vacuo, then the residue purified on silica gel, elwira a mixture of dichloromethane/methanol in the ratio of 98:2. The selected fraction is dried in vacuum, obtaining 158 mg (yield 13%) of the desired product as a pale yellow oil. MS (m/e): 498,6 (MH+, 100%).

Example 14: [6-Bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(2-methoxyethyl)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similar techniques is, described for the synthesis of example 1, stage 1, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (example 6, stage 4) and (2-bromacil)methyl ether with a yield of 70% in the form of a white foam. MS (m/e): 556,3 (M+H, 100%).

Example 15: [6-Bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(3-methoxypropyl)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 1, stage 1, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (example 6, step 4) and 1-bromo-3-methoxypropane with the release of 65% in the form of a light yellow foam. MS (m/e): 570,4 (M+H, 70%).

Example 16: [6-Bromo-1-(2-hydroxyethyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

a) stage 1: [6-Bromo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 1, stage 1, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6,-thiomorpholine-4-yl)methanone (example 6, stage 4) and (2 bromoethoxy)-tert-butyldimethylsiloxy with the release of 50% in the form of a colorless oil. MS (m/e): 656,4 (M+H, 50%)./p>

b) stage 2: [6-Bromo-1-(2-hydroxyethyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

A mixture of [6-bromo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (130 mg, 1.0 EQ.) and triperoxonane acid in dichloromethane is stirred for 1 h at room temperature and concentrated in vacuo. The crude mixture was partitioned between aqueous sodium hydroxide solution and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers washed with brine, dried over sodium sulfate, filtered and evaporated in a vacuum, getting 106 mg (yield 99%) of the desired product as a white foam. MS (m/e): 542,1 (M+H, 100%).

Example 17: [6-Bromo-1-(3-hydroxypropyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

a) stage 1: [6-Bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 1, stage 1, named the title compound is obtained from [6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (example 6, stage 4) and (3 bromopropane)-tert-butyldimethylsiloxy with the release of 65% in the form of colorless is the asle. MS (m/e): 670,5 (M+H, 100%).

b) stage 2: [6-Bromo-1-(3-hydroxypropyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

Similarly to the procedure described for the synthesis of example 16, step 1, named the title compound is obtained from [6-bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanone (example 17, step 1) with a yield of 99% in the form of a white foam. MS (m/e): 556,5 (M+H, 70%).

Examples 18 and 19: (S)-2-[2-(1,1-Dioxo-λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile and (R)-2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile

The racemic mixture of rat-2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile (example 12, 190 mg) in ethanol (8 ml) is decomposed with chiral chromatography using a DAICEL Chiralcel OD with a mixture of ethanol/heptane in a ratio of 25:75. Two factions of the opposite optical rotation of the isolated and dried in vacuum.

Fraction 1, negative rotation at 220 nm, 60 mg yellow solid, (32%) MS (m/e): 473,5 (MN+, 100%).

Fraction 2, a positive rotation at 220 nm, 84 mg of a yellow solid substance (44%) MS (m/e): 473,5 (MN+, 100%).

Example 20: [5-(1-Cyclobutylmethyl-4-yloxy)-1-isopropyl-1 is-indol-2-yl]-(1,1-dioxo-1λ 6-thiomorpholine-4-yl)methanon

a) stage 1: ethyl ester of 5-benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid

To a mixture of ethyl ester 5-benzyloxyindole-2-carboxylic acid (30 g, 1.0 EQ.) and cesium carbonate (58 g of 1.75 EQ.) in acetonitrile (200 ml) add isopropylbenzenesulfonyl (24.8 g, a 1.75 EQ.). The reaction mixture is heated under reflux for 18 h, and then concentrated in vacuo. The residue is partitioned between water and methyl tert-butyl ether. The aqueous layer was extracted with methyl tert-butyl ether and the combined organic layers washed with brine, dried over sodium sulfate, filtered and dried in vacuo, then purified on silica gel, elwira a mixture of dichloromethane/methanol in the ratio of 98:2. The crude substance is purified by crystallization in methanol and dried in vacuum, obtaining 31 g (yield 90%) of the desired product in the form of a whitish oil. MS (m/e): 338,4 (MN+, 100%).

b) stage 2: 5-Benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid

Ethyl ester of 5-benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid (47,5 g, 1.0 EQ.) and lithium hydroxide (6,56 g, 1.1 EQ.) in a mixture of tetrahydrofuran (360 ml), water (180 ml) and methanol (120 ml) is heated under reflux for 2 h and then the reaction mixture was concentrated in vacuo. The remainder of the vigorously stirred aqueous solution of hydrochloric acid 2-normal, the final pH value of 2). The precipitated white filtered, washed with water and then dried in vacuum, obtaining of 41.6 g (yield 96%) of the desired product as a white oil. MS (m/e): 308,5 (M-H, 100%).

C) stage 3: 5-Hydroxy-1-isopropyl-1H-indole-2-carboxylic acid

A mixture of 5-benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid (41,6 g, 1.0 EQ.) and palladium on charcoal (10%, 4.3 g, 0.03 EQ.) in ethyl acetate (330 ml) and ethanol (235 ml) rinsed with hydrogen, and then vigorously stirred for 2.5 h at room temperature. Formed again, the suspension is filtered through a layer dicalite. The residue on the filter is washed with a mixture of ethyl acetate and ethanol, and then the liquid is evaporated in a vacuum, getting to 26.3 g (quantitative yield) of the desired product in the form of a whitish oil. MS (m/e): 218,2 (M-H, 100%).

d) stage 4: (1,1-Dioxo-1λ6-thiomorpholine-4-yl)-(5-hydroxy-1-isopropyl-1H-indol-2-yl)methanon

Similarly to the procedure described for the synthesis of example 1, stage 3, named the title compound is obtained from 5-hydroxy-1-isopropyl-1H-indole-2-carboxylic acid (example 20, step 3) and thiomorpholine-1,1-dioxide (provided by the company Syntec, ref. M1201) with 75% yield as a white solid. MS (m/e): 335,5 (M-H, 100%).

e) stage 5: tert-butyl ether 4-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-1-isopropyl-1H-indol-5-yloxy]piperidine-1-carboxylic acid

To altnoy (0°C) mixture of (1,1-dioxo-1λ 6-thiomorpholine-4-yl)-(5-hydroxy-1-isopropyl-1H-indol-2-yl)methanone (890 mg, 1.0 EQ.), 1-tert-butyloxycarbonyl-4-hydroxypiperidine (659 mg, 1.2 EQ.) and triphenylphosphine (858 mg, 1.2 EQ.) in tetrahydrofuran (6 ml) is added dropwise a solution of di-tert-utilization.bacteria (746 mg, 1.0 EQ.) in tetrahydrofuran (4 ml). The reaction mixture was stirred for 15 h at room temperature, concentrated in vacuo, then purified on silica gel, elwira with a mixture of cyclohexane/ethyl acetate.

The fraction allocated, getting 434 mg (yield of 31.6%) of the desired product as a white oil. MS (m/e): 520,7 (MN+, 100%).

(e) stage 6: (1,1-Dioxo-1λ6-thiomorpholine-4-yl)-[1-isopropyl-5-(piperidine-4-yloxy)-1H-indol-2-yl]metano

To a cold (0°C.) mixture of tert-butyl ester 4-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-1-isopropyl-1H-indol-5-yloxy]piperidine-1-carboxylic acid (410 mg, 1.0 EQ.) in dichloromethane (8 ml) is added dropwise triperoxonane acid (920 mg, 10 EQ.). The mixture is stirred over night at room temperature, and then concentrated in vacuo. The residue is partitioned between aqueous potassium carbonate solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and dried in vacuum. The residue is then purified on silica gel, elwira a mixture of dichloromethane/methanol/MMA the AK in the ratio 95:5:0.25, getting 296 mg (yield 86%) of the desired product in the form of a whitish oil. MS (m/e): 420,4 (MN+, 100%).

g) stage 7: [5-(1-Cyclobutylmethyl-4-yloxy)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon

To a mixture of (1,1-dioxo-1λ6-thiomorpholine-4-yl)-[1-isopropyl-5-(piperidine-4-yloxy)-1H-indol-2-yl]methanone (268 mg, 1.0 EQ.) in acetic acid (115 mg, 3.0 EQ.) add a solution of cyclobutene (90 mg, 2.0 EQ.) in tetrahydrofuran (8 ml). The mixture is stirred for 2 hours at a temperature of 55°C. Then the mixture is cooled to room temperature and add triacetoxyborohydride sodium (279 mg, 2.0 EQ.). The reaction mixture was stirred overnight at 65°C. the Residue is distributed between water and ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and dried in vacuum. Then the residue is purified on silica gel, elwira a mixture of dichloromethane/methanol and getting 97 mg (yield 32%) of the desired product in the form of a whitish oil. MS (m/e): 474,5 (MN+, 100%).

Example

Coated tablets containing the following ingredients can be obtained with the standard method:

IngredientPills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Polydon K3012.5 mg15,0 mg
Sodium starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)120,0 mg350,0 mg
Film wrapper:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient is sifted and mixed with microcrystalline cellulose, after which the mixture granularit with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and pressed, getting kernel weight of 120 or 350 mg, respectively. Kernel varnished using an aqueous solution/suspension of the above-mentioned film shell.

Example B

Capsules containing the following ingredients can be obtained with the standard method:

IngredientsPer capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Maize starch20.0 mg
Talc5.0 mg

Ingredients sifted, mixed and this mixture is filled capsules of size 2.

The example In

Injection solutions have the following composition:

The compound of formula (I)3.0 mgGelatin150,0 mgPhenol4,7 mgSodium carbonateto obtain pH 7Water for injection solutionsto 1.0 ml

Example D

Soft gelatin capsules containing the following ingredients can be obtained with the standard method:

The contents of the capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg
Gelatin capsule
75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the other ingredients, the mixture is filled soft gelatin capsules of appropriate size. Filled soft gelatin capsules are processed according to conventional procedures.

Example D

The bags containing the following ingredients can be obtained with the standard method:

The compound of formula (I)50.0 mg
Lactose, finely ground powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K3010.0 mg
Magnesium stearate 10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, after which the mixture granularit with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavors and filled with a mixture of bags.

1. Compounds of General formula

where R1selected from the group comprising hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenated, lower cianelli;
phenyl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl;
lowest phenylalkyl, where the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl; and
heteroaryl selected from pyridyl and pyrimidinyl, unsubstituted or substituted by one or two groups independently selected from halogen and cyanopropyl;
R2denotes hydrogen or halogen;
G denotes the Rupp, selected from
,
where m denotes 0, 1;
R3selected from lower alkyl, cycloalkyl and lower cycloalkenyl;
n denotes 0, 1;
R4denotes lower alkyl;
and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, where R1selected from the group comprising hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenated, lower cianelli, and
phenyl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, ceanography, lower halogenoalkane, low alkoxygroup, low halogenlampe and lower hydroxyalkyl.

3. The compounds of formula I according to claim 1, where R1selected from the group comprising hydrogen, lower alkyl and lower halogenated.

4. The compounds of formula I according to claim 1, where R1denotes hydrogen.

5. The compounds of formula I according to claim 1, where R1indicates the lowest halogenated.

6. The compounds of formula I according to claim 1, where R1indicates the lowest cianelli.

7. The compounds of formula I according to claim 1, where R1denotes heteroaryl selected from pyridyl and pyrimidinyl, unsubstituted or substituted by one or two groups independently selected from halogen and ceanography.

8. The compounds of formula I according to claim 1, where R2denotes hydrogen.

9. Connected to the I of the formula I according to claim 1, where R2denotes halogen.

10. The compounds of formula I according to claim 1, where G denotes

where m denotes 0, 1, and R3selected from lower alkyl, cycloalkyl and lower cycloalkenyl.

11. The compounds of formula I according to claim 1, where m denotes 0 or 1, and R3denotes lower alkyl.

12. The compounds of formula I according to claim 11, where R3represents isopropyl.

13. The compounds of formula I according to claim 1, where G denotes

where n denotes 0, 1, and R4denotes lower alkyl.

14. The compounds of formula I according to claim 1, selected from the group including:
(1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]metano,
(1,1-diocletianopolis-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano,
(1,1-diocletianopolis-4-yl)-[1-isopropyl-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]metano,
(1,1-diocletianopolis-4-yl)-[5-(1-isopropylpyrimidine-3S-yloxy)-1H-indol-2-yl]metano,
and their pharmaceutically acceptable salts.

15. The compounds of formula I according to claim 1, selected from the group including:
5-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]pyridine-2-carbonitrile,
[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
[6-bromo-1-isopropyl-5-(1-isopropylpiperazine-4-yloxy)-1H-indole-2-the l]-(1,1-dioxo-1λ 6-thiomorpholine-4-yl)methanon,
[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(2,2,2-triptorelin)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
[6-bromo-1-(2-chloropyridin-4-yl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
(1,1-dioxo-1λ6-thiomorpholine-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-(3-triptoreline)-1H-indol-2-yl]metano,
[1-(2-chloropyridin-4-yl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile,
(1,1-dioxo-1λ6-thiomorpholine-4-yl)-[5-(1-isopropylpiperazine-4-yloxy)-1-pyrimidine-5-yl-1H-indol-2-yl]metano,
[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(2-methoxyethyl)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
[6-bromo-5-(1-isopropylpiperazine-4-yloxy)-1-(3-methoxypropyl)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
[6-bromo-1-(2-hydroxyethyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
[6-bromo-1-(3-hydroxypropyl)-5-(1-isopropylpiperazine-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
(S)-2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropylpiperazine-4-yloxy)indol-1-yl]propionitrile,
(R)-2-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-5-(1-isopropy the piperidine-4-yloxy)indol-1-yl]propionitrile,
[5-(1-cyclobutylmethyl-4-yloxy)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon,
and their pharmaceutically acceptable salts.

16. Pharmaceutical composition having antagonist and/or inverse agonistic activity against histamine receptor 3 (H3R), comprising the compound according to claim 1 and pharmaceutically acceptable carrier and/or excipient.

17. The pharmaceutical compositions according to article 16, for the treatment and/or prevention of diseases associated with the modulation of H3 receptors.

18. Compounds according to claim 1, having antagonist and/or inverse agonistic activity against histamine receptor 3 (H3R), for use as therapeutically active substances.

19. Compounds according to claim 1, having antagonist and/or inverse agonistic activity against histamine receptor 3 (H3R), for use as therapeutically active substances for the treatment and/or prevention of diseases associated with the modulation of H3 receptors.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), where R1 denotes a 5- or 6-member ring of formulae

(II) or (III), respectively: R2 denotes H, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m,-Ra; R3 denotes aryl or heteroaryl, which can be substituted with CN, Cl, F, Br, CF3, CHF2, C3-C6-cycloalkyl or denotes heteroaryl which can be possibly substituted with C1-C7-alkyl; R4 denotes H, -OH, Cl, F, Br, CN, -CHF2, CF3, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m-Re; R5 denotes C1-C7-alkyl, -(CH2)n-O-Rf, or -(CH2)n-Re; Ra denotes -OH; Re denotes -OH; Rf denotes C1-C7-alkyl; m equals 1-4; n equals 2-6; and pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent containing said derivatives, use thereof in preparing medicinal agents suitable for treating diseases of the central nervous system.

EFFECT: novel compounds suitable for treating diseases of the central nervous system are obtained and described.

29 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel antibacterial compounds of formula (I). Compounds of formula (I) Q-NH-CO-R3, where Q stands for group of the following structure , R1 represents hydrogen, halogen, hydroxy, amino, mercapto, alkyl, heteroalkyl, alkeloxy, heteroalkyloxy, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, cycloalkyloxy, alkylcycloalkyloxy, heterocycloalkyloxy or heteroalkylcycloalkyloxy, X1, X2, X3, X4, X5 and X6 each independently on each other represent nitrogen atom or group of formula CR2, R2 represents hydrogen, halogen or hydroxy, amino, alkyl, alkenyl, alkinyl or heteroalkyl group, R3 is selected from the following groups R5 represents group of formula -B-Y, where B represents alkylene, alkenylene, alkinylene, -NH- or heteroalkylene, and Y represents aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or heteroalkylcycloalkyl, or their pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable composition, as well as to pharmaceutical composition, which possesses antibacterial activity, based on said compounds and to their application for preparation of medication, intended for treatment of bacterial infections.

EFFECT: obtained and described are compounds, which can be useful in medicine.

9 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives of formula I

or pharmaceutically acceptable salts thereof, where R1 denotes (1-6C)alkyl; R2, R3 independently denote halogen, (1-4C)alkoxy; R4 denotes phenyl or a 5-6-member heteroaryl, having one or two heteroatoms selected from nitrogen, oxygen or sulphur, phenyl or said heteroaryl, substituted with R7 and optionally substituted on the (hetero)aromatic ring with one or two substitutes selected from halogen, nitro, trifluoromethyl and (1-4C)alkyl; R7 denotes H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R8R9-amino, R10R11-aminocarbonyl, R12R13-amino(1-4C)alkylcarbonyl-amino, R14R15-amino(1-4C)alkyl, R16-oxy, R17R18-aminocarbonyl (1-4C)alkoxy, R19-oxy(1-4C)alkyl, R19-oxycarbonyl(1-4C)alkyl, R20R21-aminosulphonyl, R20-oxysulphonyl, aminoiminomethyl, (di)(1-4C)alkylaminoiminomethyl, morpholinyliminomethyl, trifluoromethylsulphonyl; R23-oxycarbonyl, or R23R24-aminocarbonyl; R8 denotes H or (1-4C)alkyl; R9 denotes (1-4C)alkylsulphonyl, (1-6C)alkylcarbonyl, (2-6C)alkenylcarbonyl, (3-6C)cycloalkylcarbonyl, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (di)(1-4C)alkylaminocarbonyl, piperazinylcarbonyl, (5-8C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl or phenylcarbonyl, furylcarbonyl, thiophenylsulphonyl, 5-member heteraryl(1-4C)alkyl, having one or two nitrogen atoms, optionally substituted on the heteroaromatic ring with one, two or three substitutes selected from hydroxy, amino, halogen, nitro, trifluoromethyl, (1-4C)alkoxy; R10 denotes H or (1-4C)alkyl; R11 denotes hydroxy(2-4C)alkyl, (1-4C)alkoxy(2-4C)alkyl; R12, R13 independently denote H, (1-6C)alkyl, (3-6C)-cycloalkyl, (1-4C)alkoxy(2-4C)alkyl, (3-6C)cycloalkyl-(1-4C)alkyl, pyrrolidinyl(1-4C)alkyl, amino(2-4C)alkyl, (di)(1-4C)-alkylamino(2-4C)alkyl or phenyl(1-4C)alkyl, pyridinyl (1-4C)alkyl; or R12R13 in R12R13-amino(1-4C)alkylcarbonylamino can be bonded together with the nitrogen atom to which they are bonded into a (5-6C)heterocycloalkyl ring, having one or two nitrogen atoms, optionally substituted with hydroxy(1-4C)alkyl; R14, R15 independently denote H, (1-6C)alkyl, (1-6C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyridinyl(1-4C)alkyl, optionally substituted on the aromatic ring with one substitute selected from halogen; or R16 denotes (di)(1-4C)alkylamino(2-4C)alkyl, hydroxycarbonyl(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, phenyl(1-4C)alkyl or pyridinyl(1-4C)alkyl; R17, R18 independently denote H, (1-6C)alkyl, thiophenyl(1-4C)alkyl; or R17R18 in R17R18-aminocarbonyl(1-4C)alkoxy can be bonded into a morpholine or piperazine ring, R19 denotes H or (1-6C)alkyl; R20R21 independently denote H, (1-6C)alkyl or (1-4C)alkoxy(1-4C)alkyl; or R20R21 in R20R21-aminosulphonyl can be bonded into a morpholine ring; X denotes O or N-R22; Y denotes CH2 or C(O); Z denotes CN or NO2; R22 denotes H; R23, R24 independently denotes H; (1-4C)alkyl; or R23R24 in R23R24-aminocarbonyl can be bonded into a dihydropyridine ring; provided that compounds of formula I, in which X denotes O, R4 denotes phenyl and R7 is selected from H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R23-oxycarbonyl, and R23R24-aminocarbonyl, and compounds of formula I, in which X denotes O, R4 denotes (2-5C)heteroaryl and R7 denotes H are excluded. The invention also relates to use of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives to prepare a medicinal agent for treating sterility.

EFFECT: improved useful biological properties.

12 cl, 73 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for selective production of N-[3-(1,3,5-dithiazinan-5-yl)propyl]-N-[4-(1,3,5-dithiazinan-5-yl)butyl]amine and N1,N4-bis-[3-(1,3,5-dithiazinan-5-yl)propyl]-1,4-butane diamine which involves reaction of an amine with a hydrogen sulphide saturated aqueous solution of formaldehyde, where the amine used is polymethylenepolyamine (spermidine or spermine) in molar ratio polyamine: formaldehyde: hydrogen sulphide equal to 1:6:4 and the reaction is carried out at 20°C for 3 hours.

EFFECT: compounds can be used as selective sorbents and extraction agents of precious metals, special reagents for inhibiting bacterial activity in various media.

1 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: described are heterobicyclic derivatives of formula (I)

, in which V denotes -C(R7)-; W denotes a single bond or -C(R8R9)-; X denotes O, S, SO, SO2 or N(R10); Y denotes -C(R11R12)-, -C(R11R12)C(R13R14)C(R11R12)C(R13R14)C(R15R16)-, -C(R11R12)C(R13R14)C(R15R16)C(R17R18)- or- C(R11)=C(R12)-; R1, R2, R3, R4 and R5 independently denote hydrogen, halogen, (lower)alkyl, fluoro(lower)alkyl, (lower)alkoxy group, fluoro(lower)alkoxy group, NH2-C(O); R6 denotes a phenyl, pyridyl, pyrazolyl or thiazolyl group, where the group is optionally substituted with 1-4 substitutes selected from a group consisting of halogen, cyano group, (lower)alkyl, (lower)alkoxy group, COOH, 1H-tetrazol-5-yl, 5-oxo-4H-[1,2,4]oxadiazol-3-yl, where (lower)alkyl is optionally substituted with COOH. A pharmaceutical composition is also described.

EFFECT: said compounds inhibit L-CPT1 and can be used as medicinal agents.

27 cl, 120 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to derivatives of 2-pyridylmethylenecarboxamide of formula (I), where: -A represents a substituted or unsubstituted 5-member heterocyclyl group bound with carbonyl through carbon atom; -Z1 and Z2 which can be equal or different, represent hydrogen atom; C1-C5-alkyl; C5-alkoxycarbonyl; -Z3 represents substituted or unsubstituted C3-C7cycloalkyl; -Y represents C1-C5-halogenalkyl, containing to 5 halogen atoms which can be equal or different; X which can be equal or different, represents halogen atom, - n=0, 1, 2 or 3; and to their salts. Besides the invention describes a method of plant pathogenic fungi control with the use of such compounds.

EFFECT: there are prepared and described new derivatives of 2-pyridylmethylenecarboxamide which can be effective as fungicidal active agents.

8 cl, 96 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

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