Quinoline derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

 

The present invention relates to new quinoline derivative, receiving them, containing their pharmaceutical compositions and their use as medicines. Active compounds 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 alkenyl,

cycloalkyl or lower cycloalkyl where cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group comprising lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,

lowest hydroxyalkyl,

lowest alkoxyalkyl and

lowest geterotsiklicheskikh, where the heterocyclic ring may be unsubstituted or substituted by one or two groups selected from lower alkyl and halogen;

R2selected from the group including hydrogen,

lower alkyl, lower alkenyl,

cycloalkyl or lower cycloalkyl where cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group comprising lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,

lowest hydroxyalkyl,

lowest alkoxyalkyl and

lowest geterotsiklicheskikh, where g is teracycline ring may be unsubstituted or substituted by one or two groups selected from lower alkyl and halogen; or

R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5-, 6 - or 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing, in addition, the heteroatom selected from nitrogen, oxygen or sulfur, with the specified saturated or partially unsaturated heterocyclic ring is unsubstituted or substituted one, two or three groups independently selected from the group comprising lower alkyl, halogen, halogenated, cyano, hydroxy-group, hydroxyalkyl, lower alkoxygroup, oxoprop, phenyl, benzyl, pyridyl and carbarnoyl;

And choose from

or

where

m denotes 0, 1 or 2;

R3denotes lower alkyl;

N denotes 0, 1 or 2;

R7denotes lower alkyl;

p denotes 0, 1 or 2;

q denotes 0, 1 or 2;

R5denotes hydrogen or lower alkyl; and

their pharmaceutically acceptable salts.

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

Histamine (2-(4-imidazolyl)ethylamine) is one of energicheskoj neurotransmitters, which are widely distributed in the body, such as in the gastro-Kish is cnom tract (Burks 1994 in Johnson L.R. ed. Discrimination of the Gastrointestinal Tract, Raven Press, NY, pp.211-242). Histamine regulates various pathophysiological manifestations type of gastric acid, intestinal motility (Leurs et al., Br J. Pharmacol. 1991, 102, pp 179-185), and vasomotor responses, intestinal inflammatory responses and allergic reactions (Raithel et al., Int. Arch. Allergy Immunol. 1995, 108, 127-133). In the human brain histamine is synthesized in histaminergic the body's cells, which are concentrated in lumpy-sokovich nuclei posterior basal hypothalamus. It follows that the cell body reflect the different areas of the brain (Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagaki et al., J. Al. Neurol 1988, 273, 283-300).

According to modern concepts, histamine mediates these effects in the Central nervous system (CNS)and the peripheral using the four different histamine receptors, histamine H1, H2, H3 and H4 receptors.

H3 receptors are preferentially localized in the Central nervous system. 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). As heteroreceptors H3 receptors modulate the secretion of other neurotransmitters such as acetylcholine, dopamine, serotonin and norepinephrine, along with others, as in the Central nervous system and in peripheral organisatie, as the lungs, cardiovascular system and gastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982, 107, 919-923; Blandina et al. in The Histamine H3 Receptor (Lews RL and Timmermann H eds, 1998, pp 27-40, Elsevier, Amcterdam, The Netherlands). H3 receptors show significant activity, this implies that 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 excretion of neurotransmitters. Consequently, it is essential that H3R antagonist may have activity inversion agonist as to both blocks of exogenous histamine effects, and the transition of the receptor from its constitutive active (inhibitory) forms in a neutral state.

The wide distribution of H3 receptors in the Central nervous system of mammals indicates the physiological role of this receptor. Consequently, various messages H3 receptor is regarded as a new drug target with therapeutic potential.

The introduction of H3R ligands as antagonists, inversion agonists, agonists or partial agonists can influence histamine levels or release of neurotransmitters in the brain or peripheral organs and therefore can be used in the treatment of various diseases. Such diseases which 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 disorders such as overactive disorder associated with attention deficit (ADHD), Alzheimer's disease, neurological disorders such as schizophrenia, depression, epilepsy, Parkinson's disease, seizures or convulsions, sleep disorders, narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction such as disease Morbus ménière's disease, drug abuse, and motion sickness (travel sickness) (Timmermann, J. Med. Chem. 1990, 33, 4-11).

Consequently, the object of the present invention offers a selective, directly acting antagonists, H3 receptor, respectively inversion agonists. Such antagonists / inversion agonists are used as therapeutically active substances, in particular for the treatment and/or prophylaxis of diseases that are associated with the modulation of H3 receptors.

In the present invention the term "alkyl", alone or in combination with other groups, refers to a branched or linear, monovalent, saturated aliphatic hydrocarbon radical containing from one to twelve carbon atoms, preferably from one to sixteen carbon atoms, more preferred is sustained fashion from one to ten carbon atoms.

The term "lower alkyl" or "C1-C8-alkyl", alone or in combination, means a straight or branched alkyl group containing from 1 to 8 carbon atoms, preferably a straight or branched alkyl group containing from 1 to 6 carbon atoms, and particularly preferably a straight or branched alkyl group containing from 1 to 4 carbon atoms. Examples of straight and branched alkyl groups containing from 1 to 8 carbon atoms, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily, isomeric Gately and the isomeric octile, preferably methyl and ethyl and most preferably methyl.

The term "lower alkenyl" or "C2-C8alkenyl", alone or in combination, means a straight or branched alkyl group containing alkyl group containing olefinic bond and up to 8, preferably up to 6, especially preferably up to 4, carbon atoms. Examples alkenyl groups are ethinyl, 1-propinyl, 2-propinyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and Isobutanol. Preferred is 2-propenyl.

The term "alkoxygroup" refers to the group R/-O-, where R/denotes alkyl. The term "lower alkoxygroup" refers to the group R/-O-, where R/means NISS the th alkyl, and the term "lower alkyl" has the previously described meaning. Examples of lower alkoxygroup are, for example, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan and tert-butoxide, preferably the methoxy group and ethoxypropan and most preferably a methoxy group.

The term "lower alkoxyalkyl" or "alkoxy-C1-C8-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted by alkoxygroup defined above. It is preferable Nissi alkoxyalkyl include methoxymethyl, methoxyethyl and ethoxymethyl, with methoxymethyl is the most preferred.

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

The term "lower halogenated" or "halogen-C1-C8-alkyl" refers to lower alkyl groups as 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. To the preferred halogenated lower alkyl groups include trifluoromethyl, deformity, vermeil and chloromethyl, this is trifluoromethyl cloth is preferred.

The term "lower halogenlampe" or "halogen-C1-C8-alkoxygroup" refers to the lower alkoxygroup defined 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. To the preferred halogenated lower alkoxygroup include tripterocarpa, dipterocarp, formicoxenus and chlorethoxyfos, tripterocarpa is especially preferred.

The term "lower hydroxyalkyl" or "hydroxy-C1-C8-alkyl" refers to lower alkyl groups as 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 "cycloalkyl" or "C3-C7-pilooski" refers to cycloalkyl ring containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl ring may be optionally substituted as defined in the description. Especially preferred is cyclopyrrolones.

The term "lower cycloalkenyl" or "C3-C7-cycloalkyl-C1-C8-alkyl" refers to lower alkyl which the group defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted cycloalkyl group defined above. Examples of preferred lower cycloalkenyl groups are cyclopropylmethyl or cyclopropylethyl where cyclopropyl group substituted by lower alkyl, lower hydroxyalkyl or lower alkoxyalkyl, preferably by methoxymethyl.

The term "heterocyclyl" means a monovalent saturated or partially unsaturated ring containing one, two or three heteroatoms selected from nitrogen, oxygen or sulfur. Heterocyclic ring may be optionally substituted as defined in the description. Examples of heterocyclic fragments include azetidine, oxetane, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isooxazolyl, diazolidinyl, isothiazolinones, dihydropyridin, piperidyl, piperazinil, morpholinyl or thiomorpholine, azepine, dihydropyrrole, pyrrolidine, pyrazolidine, imidazoline, dihydrofuran, tetrahydrofuran, dihydropyran or tetrahydropyranyl. Especially preferred are oxetanyl, piperidinyl and morpholinyl.

The term "lower geterotsiklicheskikh" or "heterocyclyl-C1-C8-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms nor the necks alkyl group substituted heterocyclic group, defined above. An example of a preferred lower heterocyclic group is a 3-Torosyan-3-yl.

The term "4-, 5-, 6 - or 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing, in addition, the heteroatom selected from nitrogen, oxygen or sulfur"refers to saturated or partially unsaturated N-heterocyclic ring, which may optionally contain an additional nitrogen atom, oxygen or sulfur, such as 2.5-dihydropyrimidines, pyrrolidinyl, imidazolidinyl, pyrazolidine, oxazolidine, isooxazolyl, diazolidinyl, isothiazolinones, piperidyl, piperazinil, morpholinyl, thiomorpholine or 3,6-dihydro-2H-pyridinyl. The heterocyclic ring can be unsubstituted or substituted one, two or three groups independently selected from lower alkyl, lower alkoxygroup and halogen.

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

The term "pharmaceutically acceptable salt" refers to standard acid-additive or basic additive salts that are acceptable from a biological or other points of view. Salt is produced by interaction with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid and the like, prepost is positive 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, mandelic acid, cinnamic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, N-acetylcysteine, and the like. In addition, these salts can be obtained by attaching an inorganic or organic base to the free acid. Salts derived from inorganic bases include but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including substituted amines of natural origin, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polianinova resin and the like. The compounds of formula I may be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are hydrochloride.

The compounds of formula (I) can also be the solvated, for example gidratirovana. Solvation can be performed in the process of obtaining or may take place, for example, due to the hygroscopic properties of the initially anhydrous compound of formula (I) (hydration). The term "pharmaceutically acceptable salt" also includes pharmaceutically acceptable solvate.

"Isomers are compounds with the same molecular formula, but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in arrangement of atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other, are called "diastereoisomers, and stereoisomers, mirroring which are not the same, are called "enantiomers" or, sometimes, "optical isomers". The carbon atom associated with four different substituents, is called a "chiral center".

Specifically, the present invention relates to compounds of General formula

where

R1choose the group including hydrogen,

lower alkyl, lower alkenyl,

cycloalkyl or lower cycloalkyl where cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group comprising lower and the keel, lowest hydroxyalkyl and lower alkoxyalkyl,

lowest hydroxyalkyl,

lowest alkoxyalkyl and

lowest geterotsiklicheskikh, where the heterocyclic ring may be unsubstituted or substituted by one or two groups selected from lower alkyl and halogen;

R2choose the group including hydrogen,

lower alkyl, lower alkenyl,

cycloalkyl or lower cycloalkyl where cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group comprising lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,

lowest hydroxyalkyl,

lowest alkoxyalkyl and

lowest geterotsiklicheskikh, where the heterocyclic ring may be unsubstituted or substituted by one or two groups selected from lower alkyl and halogen; or

R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring, optionally containing, in addition, the heteroatom selected from nitrogen, oxygen or sulfur, with the specified saturated or partially unsaturated heterocyclic ring is unsubstituted or substituted one, two or three groups independently selected from the group comprising lower alkyl, halogen, halogenated, cyano, Hydra is xygraph, hydroxyalkyl, lower alkoxygroup, oxoprop, phenyl, benzyl, pyridyl and carbarnoyl;

And choose from

or

where

m denotes 0, 1 or 2;

R3denotes lower alkyl;

n denotes 0, 1 or 2;

R7denotes lower alkyl;

p denotes 0, 1 or 2;

q denotes 0, 1 or 2;

R5denotes hydrogen or lower alkyl;

and their pharmaceutically acceptable salts.

Preferred compounds of formula I of the present invention are such compounds where R1choose the group including hydrogen, lower alkyl, lower alkenyl, cycloalkyl, lower cycloalkyl where cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from lower alkyl, lower hydroxyalkyl or lower alkoxyalkyl, and lower geterotsiklicheskikh, where the heterocyclic ring may be unsubstituted or substituted by one or two groups selected from lower alkyl or halogen, and R2denotes hydrogen go lower alkyl.

More preferred are the compounds of formula I of the present invention, where R1choose the group comprising lower alkyl, cycloalkyl, lower cycloalkenyl where cycloalkyl ring may be unsubstituted and the and substituted lower alkoxyalkyl, lowest alkoxyalkyl and lower geterotsiklicheskikh, where the heterocyclic ring may be unsubstituted or substituted by one or two groups selected from lower alkyl or halogen, and R2denotes hydrogen or lower alkyl.

Especially preferred are the compounds of formula I, where R1and R2represent lower alkyl.

Another group of preferred compounds of formula I of the present invention is the compound where R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring, optionally containing, in addition, the heteroatom selected from nitrogen, oxygen or sulfur, with the specified heterocyclic ring is unsubstituted or substituted one, two or three groups independently selected from the group comprising lower alkyl, halogen, halogenated, cyano, hydroxy-group, hydroxyalkyl, lower alkoxygroup, oxoprop, phenyl, benzyl, pyridyl and carbarnoyl.

Preferred compounds of formula I are compounds where R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-or 7-membered saturated or partially saturated heterocyclic ring, optionally containing, in addition, gateroad is m, selected from nitrogen, oxygen or sulfur, with the specified heterocyclic ring is unsubstituted or substituted one, two or three groups independently selected from the group comprising lower alkyl, halogen, halogenated, cyano, hydroxy-group, the lower alkoxygroup, oxoprop, phenyl, benzyl, pyridyl and carbarnoyl.

More preferred compounds of formula I are compounds where R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring, optionally containing, in addition, the heteroatom selected from nitrogen, oxygen or sulfur, with the specified heterocyclic ring is unsubstituted or substituted one, two or three groups independently selected from the group comprising lower alkyl, halogen, halogenated, cyano, hydroxy-group, the lower alkoxygroup and oxoprop.

Even more preferred compounds of formula I are compounds where R1and R2together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group comprising morpholine, piperidine, 2,5-dihydropyrrol, pyrrolidin, ASEAN, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, but such a heterocyclic ring is the tsya unsubstituted or substituted by one, two or three groups independently selected from the group comprising lower alkyl, halogen, halogenated, cyano, hydroxy-group, the lower alkoxygroup and oxoprop.

Especially preferred compounds of formula I are compounds where R1and R2together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, 3,6-dihydro-2H-pyridinyl, piperidinyl, 2-methylpiperidine, 3-methylpiperidine, 4-hydroxypiperidine, 4,4-ceftobiprole, 2,5-dihydropyrrole, 4-methylpiperidine, pyrrolidine, 2-methylpyrrolidine, 2-cryptomaterial, 2-cyanopyrrolidine, 3-hydroxypyrrolidine and azetidine.

In addition, the compounds of formula I of the present invention, where a denotes

and where m denotes 0, 1 or 2 and R3denotes lower alkyl, are preferred.

Within this group, such compounds of formula I are preferred, where m=0, and consequently, pyrolidine group are preferred.

Another preferred group includes the compounds of formula I, where m=1, and consequently piperidino group are also preferred.

Also preferred are the compounds of formula I according to the present invention, where And denotes

and where n denotes 0, 1 or 2 and R4denotes lower alkyl, along with such compounds, where n=0, denoting pyrolidine derivatives are more preferred.

Further, preferred compounds of formula I of the present invention are such compounds where a denotes

where p denotes 0, 1 or 2, q represents 0, 1 or 2 and R5denotes hydrogen or lower alkyl.

Within this group, such compounds of formula I are preferred, where R=1, and consequently piperidino group are preferred. Especially preferred are such compounds of formula I, where p=1 and q=1.

In addition, compounds where R5denotes hydrogen, are preferred.

Examples of preferred compounds of formula I are the following:

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon,

(2.5-dihydropyrrol-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

ethylmethylamino 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-methylpyrrolidine-1-yl)methanon,

tert-butylamide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

cyclopropylmethyl the d 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-methylpiperidin-1-yl)methanon,

(4-hydroxypiperidine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(3-methylpiperidin-1-yl)methanon,

hydrochloride(3,4-dihydro-1H-isoquinoline-2-yl)-[6-(3-piperidine-1-ylpropionic)naphthalene-2-yl]methanone (1:1),

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]thiomorpholine-4-ylmethanone,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,

ethyl(2-methoxyethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

azetidin-1-yl-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

(3,6-dihydro-2H-pyridine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

(1-ethoxymethylenemalonic)amide 6-(1-isopropylpyrimidine-4-yloxy)quinoline-2-carboxylic acid,

[2-(tetrahydropyran-4-yl)ethyl]amide{6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]morpholine-4-ylmethanone,

cyclohexylethylamine 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

(4,4-deformability-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

(3-hydroxypyrrolidine-1-yl)-[6-(1-isopropy the piperidine-4-yloxy)quinoline-2-yl]metano,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]pyrrolidin-1-ylmethanone,

(R)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,

(1,1-diocletianopolis-4-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

dimethylamide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

(2.5-dihydropyrrol-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,

([6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon,

ethylmethylamino 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

([6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)-methanon,

[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(2-methylpyrrolidine-1-yl)-methanon,

tert-butylamide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

cyclopropanemethylamine 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

{[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(2-methylpiperidin-1-yl)methanon,

[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(3-methylpiperidin-1-yl)methanon,

isopropylacrylamide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]thiomorpholine-4-ylmethanone,

[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,

this is l(2-methoxyethyl)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

azetidin-1-yl-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,

(3,6-dihydro-2H-pyridine-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,

(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

(1-ethoxymethylenemalonic)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

[2-(tetrahydropyran-4-yl)ethyl]amide of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,

(4,4-deformability-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]morpholine-4-ylmethanone,

(4-methoxypiperidine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

(4 methylpiperidin-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

morpholine-4-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

(2 methylpyrrolidine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

cyclopropanemethylamine 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,

(2.5-dihydropyrrol-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

ethyl(2-methoxyethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

azetidin-1-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

(3,6-dihydro-2H-pyridine-1-yl)-[6(3-piperidine-1-ylpropionic)quinoline-2-yl]-methanon,

(4,4-deformability-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

cyclohexylethylamine 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

(1-ethoxymethylenemalonic)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

(3-Torosyan-3-ylmethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

[2-(tetrahydropyran-4-yl)ethyl]amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

(tetrahydropyran-4-yl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,

(2 methylpiperidin-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]pyrrolidin-1-ylmethanone,

(R)-1-[6-(3-piperidine-1-ylpropionic)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,

(1,1-diocletianopolis-4-yl)-[6-(3-piperidine-1-yl-propoxy)quinoline-2-yl]metano,

(4 methylpiperidin-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,

{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}pyrrolidin-1-ylmethanone,

(R)-1-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carbonyl}pyrrolidin-2-carbonitrile,

(1,1-diocletianopolis-4-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,

(4-methoxypiperidine-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,

{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}morpholine-4-ylmethanone,

azetidin-1-yl-{6-[2-(1-who ethylpyrrolidin-2-yl)ethoxy]quinoline-2-yl}mechanon,

[2-(tetrahydropyran-4-yl)ethyl]amide 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid,

(3-Torosyan-3-ylmethyl)amide 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid,

(2 methylpyrrolidine-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,

(S)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)methanon,

(4-hydroxyethylpiperazine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

isobutyramide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

cyclohexylethylamine 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid

and their pharmaceutically acceptable salts.

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

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-methylpyrrolidine-1-yl)methanon,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-trifluoromethyl-pyrrolidin-1-yl)methanon,

azetidin-1-yl-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,

(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,

(1-ethoxymethylenemalonic)amide 6-(1-isopropylpiperazine-4-is lexi)quinoline-2-carboxylic acid,

[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]pyrrolidin-1-ylmethanone,

(R)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,

azetidin-1-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,

(R)-1-[6-(3-piperidine-1-ylpropionic)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,

(S)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile

and their pharmaceutically acceptable salts.

In addition, pharmaceutically acceptable salts of compounds of formula I and pharmaceutically acceptable esters of compounds of formula I independently presented as the preferred objects of the present invention.

The compounds of formula I can form acid additive salts with standard pharmaceutically acceptable acids, such as, for example, hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulfate, pyruvate, citrate, lactate, mandelate, tartrate and methanesulfonate. The preferred salts are hydrochloride. The solvate and hydrates of the compounds of formula I and their salts form part of 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, such as, for example, racemates, optically pure diastereoisomers, the mixture diastereoisomer is s, diastereoisomers the racemates or mixtures diastereoisomeric racemate. Optically active forms may be obtained, for example, racemate separation by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or additionally separated by). The invention also includes these forms.

It should be noted that compounds of General formula I according to this invention can be derivationally functional groups with obtaining derivatives, which are capable of being converted into the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which can become a source of compounds of General formula I in vivo, are also included in the scope of the present invention.

The next aspect of the present invention is a method of obtaining compounds of formula I, defined above, which includes

the interaction of the compounds of formula II

where R denotes lower alkyl, with an alcohol of the formula III

where is As defined above, in the presence of trialkylphosphine or triphenylphosphine and diazocompounds with obtaining the compounds of formula IV

and the transformation of ester of formula IV with an acid of formula V

in acidic Elimelech conditions

and condensation of the compounds of formula V with an amine of the formula VI

where R1and R2defined above, using a condensing agent in alkaline conditions to obtain compounds of formula I

where A, R1and R2defined above, and, if necessary, transformation

the compounds obtained into pharmaceutically acceptable salt.

Condensing agents for the reaction of compounds of formula V with amines of the formula VI are, for example, N,N'-carbonyldiimidazole (CBI), N,N'-dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), hexaflurophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide (HATU), tetrafluoroborate 1-hydroxy-1,2,3-benzotriazole (NOVT) or tetrafluoroborate O-benzotriazol-1-Il-N,N,N',N'-tetramethylurea (TBTU).

In more detail, the compounds of formula I can be obtained by the methods given below, by the methods given in the examples, or similar methods. Appropriate reaction conditions for the individual reaction stages known to specialists in this field of technology. The parent compound either commercially available or can be obtained by methods similar to the methods below, the methods described in the cited text publications, or by methods known level of the technology.

Scheme 1

The compounds of formula II can be produced from commercially available 6-methoxyquinoline (1), which can be converted into N-oxide (2) reaction with hydrogen peroxide in the solvent-type acetic acid under the conditions of heating under reflux. 6-Methoxyquinoline-1-oxide is introduced into the reaction with the cyanide of silver and benzoyl chloride, getting 6-methoxyquinoline-2-carbonitrile (3) by reaction of Reissert (Ber., 38, 1610 (1905). Hydrolysis of ceanography performed using an acidic or alkaline environment. We have found suitable for use is based on sodium hydroxide, after acid treatment mixture which was obtained the corresponding 6-methoxyquinoline-2-carboxylic acid (4). Removal of the methyl group with 48%aqueous Hydrobromic acid gives 6-hydroxyquinolin-2-carboxylic acid (5). The acid may be converted into an ester of 6-hydroxyquinolin-2-carboxylic acid II, for example, ethyl ester 6-hydroxyquinolin-2-carboxylic acid (IIa), processing it with alcohol, for example ethanol, mixed with acid, such as sulphuric acid.

Obtaining compounds of the formula I according to the present invention can be carried out using a sequential or convergent ways. The synthesis according to the invention is represented in the following the existing scheme. Carrying out the reaction and purification of the resulting products are known to specialists in this field of technology. The substituents and indices used in the following description, have the above meanings, unless otherwise indicated.

Scheme 2

Compounds of General formula I can be obtained according to scheme 2 as follows:

a) synthesis of esters are widely described in the literature, and methodology known from the prior art. (Used for such reactions, the reaction conditions described in literature, see: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, 1999.) The transformation can be carried out using reaction conditions that are used in the so-called "reaction Mitsunobu", which is known to experts in the art and described in detail (Hughes, David L. The Mitsunobu reaction. Organic Reactions (John Wiley & Sons, New York, 1992, 42, 335-656). We have found suitable conditions for the condensation of ester of the formula II with alcohols of formula III are either commercially available or accessible by methods described in references or by methods known from the prior art), using a phosphine, such tributylphosphine ((n-Bu)3,R), triphenylphosphine (Ph3P), and the like, and diazocompounds, such as diethylazodicarboxylate (DEAD), India is propylenecarbonate (DYADS) (optional polymer bound), tetramethyldisiloxane and the like, in solvents commonly used in such reactions, type of tetrahydrofuran (THF), toluene, dichloromethane and the like. No special restrictions on the type of solvent no, provided that it does not exert undesirable influence on the reaction or the reagents and that he dissolve the reagents, at least to some extent. The reaction may proceed in a wide range of temperatures, and the temperature is not critical in this invention. We found a suitable temperature conditions for the reaction are in the range from room temperature to the boiling temperature of the solvent. The time of reaction can vary widely depending on many factors, namely, the reaction temperature and the nature of the reagents. However, the period of from 0.5 h to several days is usually sufficient to obtain the compounds of formula IV;

b) hydrolysis of esters are widely described in the literature, and methodology known from the prior art. The reaction conditions described in literature for such reactions, for example, are as follows: the reaction can be carried out using acid or alkaline environment. We found that the appropriate condition is acidic with use the reattaching acid, like HCl, and the solvent type dioxane, THF and the like. No particular limitations on the type of solvent no, provided that it does not exert undesirable influence on the reaction or the reagents and that he dissolve the reagents, at least to some extent. The reaction may proceed in a wide range of temperatures, and the temperature is not critical in this invention. We found a suitable temperature conditions for the reaction are in the range from room temperature to the boiling temperature of the solvent. The time of reaction can vary widely depending on many factors, namely, the reaction temperature and the nature of the reagents. However, the period of from 0.5 h to several days is usually sufficient to obtain the compounds of formula VI;

C) condensation of carboxylic acids with amines is widely described in the literature, and methods of its implementation are known from the prior art. The reaction conditions described in literature for such reactions, see, for example, in: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard .Larock. John Wiley & Sons, New York, 1999). 6-Alkoxyimino-2-carboxylic acid of formula IV standard can be converted into the corresponding amides by condensation with amines V (either commercially available, or is available through methods, described in references or by methods known from the prior art) using suitable condensing agents. For example, condensing agents of type N,N'-carbonyldiimidazole (CBI), N,N'-dicyclohexylcarbodiimide (DCC), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), hexaflurophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide (HATU), tetrafluoroborate 1-hydroxy-1,2,3-benzotriazole (NOVT) or tetrafluoroborate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea (TBTU) and the like can equally be used for such reactions. We found that suitable conditions for the reaction is a solvent type of dimethylformamide (DMF) in the presence of alkali. No special restrictions on the type of solvent no, provided that it does not exert undesirable influence on the reaction or the reagents and that he dissolve the reagents, at least to some extent. Examples of suitable solvents include DMF), dichloromethane (DHM), dioxane, THF and the like. No special restrictions on the type of Foundation at this stage there, and so with equal success can be used any base commonly used in this type of reactions. Examples of such bases include triethylamine, diiso relationin and the like. The reaction may proceed in a wide range of temperatures, and the temperature is not critical in this invention. We found a suitable temperature conditions for the reaction are in the range from room temperature to the boiling temperature of the solvent. The time of reaction can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents. The interval from 0.5 h to several days is usually sufficient to obtain the amide derivatives of formula I.

As described above, the compounds of formula I of the present invention can be used as medicines for the treatment and/or prevention of diseases associated with the modulation of H3 receptors. Examples of such diseases are: obesity, metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, age-related memory dysfunction, the average cognitive impairment, cognitive deficit, hyperactive disorder associated with attention deficit, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, sickness and sleep disorders, including narcolepsy, and other diseases, including asthma, allergies, call the by the allergic responses of the respiratory tract, hyperemia, chronic destructive lung disease and gastrointestinal disease. The use of compounds of formula I, defined above, for the treatment and/or prevention of obesity is preferred.

In addition, the invention relates to pharmaceutical compositions comprising the compound defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Further, 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. Examples of such diseases are: obesity, metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, age-related memory dysfunction, the average cognitive impairment, cognitive deficit, hyperactive disorder associated with attention deficit, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, sickness and sleep disorders, including narcolepsy, and other diseases, including asthma, allergies caused by allergic responses in the respiratory tract, hyperemia, chronic destructive disease of the lungs and also the docno-intestinal diseases. The use of compounds of formula I, defined above, for the preparation of drugs intended for the treatment and/or prevention of obesity, is preferred.

Another aspect of the invention relates to a method of treatment and/or prevention of diseases associated with the modulation of H3 receptors. Examples of such diseases are: obesity, metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, age-related memory dysfunction, the average cognitive impairment, cognitive deficit, hyperactive disorder associated with attention deficit, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, sickness and sleep disorders, including narcolepsy, and other diseases, including asthma, allergies caused by allergic responses in the respiratory tract, hyperemia, chronic destructive disease of the lungs and gastro-intestinal diseases. Method for treatment and/or prevention of obesity is preferred.

The invention relates further to the use of compounds of formula I, defined above, for the treatment and/or prevention of diseases associated with the modulation of H3 receptors. Examples of such diseases are: obesity, metabolic Sindh is ω (syndrome X), neurological diseases, including Alzheimer's disease, dementia, age-related memory dysfunction, the average cognitive impairment, cognitive deficit, hyperactive disorder associated with attention deficit, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, sickness and sleep disorders, including narcolepsy, and other diseases, including asthma, allergies caused by allergic responses in the respiratory tract, hyperemia, chronic destructive lung disease and gastrointestinal disease. The use of compounds of formula I, defined above, for the treatment and/or prevention of obesity is preferred.

In addition, the invention relates to the use of compounds of formula I, defined above, for the preparation of drugs intended for the treatment and/or prevention of diseases associated with the modulation of H3 receptors. Examples of such diseases are: obesity, metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, age-related memory dysfunction, the average cognitive impairment, cognitive deficit, hyperactive disorder associated with attention deficit, epilepsy, neuropathic pain, Pospolita the Naya pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, sickness and sleep disorders, including narcolepsy, and other diseases, including asthma, allergies caused by allergic responses in the respiratory tract, hyperemia, chronic destructive lung disease and gastrointestinal disease. The use of compounds of formula I, defined above, for the preparation of drugs intended for the treatment and/or prevention of obesity, is preferred.

The compounds of formula I and their pharmaceutically acceptable salts possess various pharmacological properties. In particular, it has been found that compounds of the present invention are good antagonists and/or inversion agonists histamine 3 receptor (H3R).

To determine the activity of compounds of formula (I) conducted the following analysis.

Analysis of the binding3N-(R)α-methylhistamine

Experiments saturation binding is performed using HR3-Cho membranes obtained as described in: Takahashi, K, Tokita, S., Kotani, H. (2003) J. Pharmacol. Exp.Therapeutics 307, 213-218.

The appropriate amount of membrane (60 to 80 mg protein/cell) and incubated with the dihydrochloride3N(R)α-methylhistamine in increasing concentrations (from 0.10 to 10 nm). Non-specific binding determine ISOE is isua 200-fold excess of dihydrobromide (R)α-methylhistamine (final concentration 500 nm). Incubation was performed at room temperature (globalclimate tablet with shaking for 3 h). The final volume in each cell was 250 μl. After incubation should rapid filtration on GF/B filters (pre-soaked in 100 μl of 0.5% PEI in Tris 50 mm, shaking at 200 rpm for 2 h). Filtering is carried out with use of a cellular reservoir, after which the tablets to filter five times washed with ice buffer to filter containing 0.5 M NaCl. After harvestore tablets are dried at 55°C for 60 min, then add acquired scintillation fluid (Microscint 40, 40 microl in each cell) and the amount of radioactivity on the filter is determined on a Packard top-count 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× 6N2About pH 7.4.

Buffer to wash: 50 mm Tris-HCl pH 7.4 and 5 mm MgCl2× 6H2O and 0.5 M NaCl pH 7.4.

Indirect measurement of affinity H3R inversion agonists

Selected compounds with a 12-fold increased concentrations (range from 10 μm to 0.3 nm) was tested in experiments on competitive binding using membranes of human HR3-CHO cell line. The appropriate amount of protein, for example, 500 pulses/min at RAMAH Kd, incubated for h at room temperature with a final volume of 250 μl in 96-honeycomb tablet in the presence of 3N(R)α-methylhistamine (1 nm final concentration = Kd). Non-specific binding determine using 200-fold excess of dihydrobromide (R)α-methylhistamine.

All compounds tested at each concentration in a double loop. Compounds showing inhibition of [3H]-RAMH more than 50%were tested again to determine the IC50in the experiment in serial dilution. Values of Kiwere 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 have values Foriin the range from 1 nm to approximately 1000 nm, preferably from approximately 1 nm to 100 nm and more preferably from approximately 1 nm to 30 nm.

The following table presents the measured values for some selected compounds of the present invention.

Ki(nm)
Example 2200
Example 1478
Example 64450

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as a medicinal cf the of funds, for example in the form of pharmaceutical preparations for enteral, parenteral or local administration. They can be introduced, for 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 topically, e.g. in the form of ointments, creams or oils.

Manufacture of pharmaceutical preparations carried out by methods known to anyone skilled in the art, making the described compounds of formula (I) and their pharmaceutically acceptable salts in a pharmaceutically input form together with suitable, non-toxic, inert, therapeutically similar solid or liquid carrier and, if desired, usual pharmaceutical adjuvants.

Suitable carriers can serve not only inorganic but also organic materials. So, for example, lactose, corn starch or its derivatives, 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 gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, outside hung is on the nature of the active ingredient, in the case of hard gelatin capsules no media required). Suitable carriers for the manufacture 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 or hydrogenated oils, waxes, fats and semi-solid or liquid polyols. Suitable carriers for topical preparations are, for example, 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 and emulsion agents, agents for improving the consistency, flavor agents, salts for modifying the osmotic pressure, buffer substances, solvents, dyes and masking agents and antioxidants are considered as pharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration and must comply with, of course, the individual requirements of each individual is the best. For adult patients, the daily dose is from about 1 mg to 1000 mg, in particular from about 1 mg to 100 mg depending on the dose that corresponds to the introduction of a daily dose of several single doses.

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

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

Examples

Intermediate compound 1: Ethyl ester of 6-hydroxyquinolin-2-carboxylic acid

a) 6-Methoxyquinoline-1-oxide

6-Methoxyquinoline (15 g, 0,094 mole) is dissolved in acetic acid (97 ml) and treated with hydrogen peroxide (37 ml). The mixture is stirred at 100°C for 2 h After evaporation until dry to the residue add 100 ml of water until the precipitate. Filtration and washing with water gives a yellow precipitate, which is dried in vacuum, obtaining 13.5 g named the title compound as a slightly yellow solid (yield 82%). MC(m/e): 176,3 (M+N)+.

b) 6-Methoxyquinoline-2-carbonitril

6-Methoxyquinoline-1-oxide (13,48 g, 0,076 mole) in 30 ml of chloroform is treated with a 3.87 g (0,028 mole) of benzoyl chloride and the 3.65 g (or 0.027 mole) of cyanide of silver. The mixture is stirred for 4 h at room temperature the re, and then heated under reflux with stirring for 14 hours After the solvent is evaporated to half volume, the mixture is cooled to 0°C and remove the precipitate of the silver salt. The mixture is filtered, the solution concentrated, and the residue solid was washed with diethyl ether and dried in vacuum, obtaining with the release of 11 g (82%) indicated in the title compound as a slightly brown solid. MS (m/e): 185,3 (M+N)+.

C) 6-Methoxyquinoline-2-carboxylic acid

6-Methoxyquinoline-2-carbonitrile (9.3 g, 0,050 mol) in 96 ml of methanol is treated with 240 ml of 20%NaOH solution and the mixture is heated at 120°C in a sealed tube overnight. After cooling to 0°C precipitate appears. The mixture is filtered, obtaining the sodium salt, which is suspended in the water. Add 25%solution of HCl to pH 3-4, receiving acid as a precipitate, which is filtered off and dried in vacuum. The mother liquor of the first filter, acidified with 25%HCl to pH 3-4 to the appearance of the precipitate. The precipitate is filtered, the solid washed with water and dried in vacuum, obtaining 9.6 g (yield 86%) indicated in the title compound as a slightly brown solid. MS (m/e): 204 (M+N)+.

g) 6-Hydroxyquinolin-2-carboxylic acid

6-Methoxyquinoline-2-carboxylic Ki the lot (4 g, 0,019 mole) is suspended in 48%aqueous solution of Hydrobromic acid (80 ml) and the mixture is heated at 125°C during the night. After cooling to 0°C. add ammonium hydroxide until a pH of 6-7, and then add HCl to pH 3-4, and then the compound precipitates. The solid is filtered off, washed with water and dried in vacuum, obtaining 3.5 g (0,0185 mol, yield 97% of theoretical) named in the title compound in the form of solid MS (m/e): 190,1 (M+N)+.

d) Ethyl ester of 6-hydroxyquinolin-2-carboxylic acid

6-Hydroxyquinolin-2-carboxylic acid (2.3 g, a 0.012 mole) is dissolved in absolute ethanol (150 ml). Add sulfuric acid (0,550 ml, 0,0096 mol) and the mixture heated under reflux for 16 hours After cooling to room temperature, evaporated ethanol and add 60 ml of ethyl acetate and 50 ml of chilled water. The pH value was adjusted to 7 with solid NaHCO3. Extraction and concentration of the organic phase gives named the title product as a slightly yellow solid, which is used in the next stage without further purification (yield 2.1 g, 81% of theoretical). MS (m/e): 218,4 (M+N)+.

Intermediate compound 2: Hydrochloride (6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1)

a) Ethyl EF the R 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid

A mixture of 1 g (0,0046 mole) ethyl ester 6-hydroxyquinolin-2-carboxylic acid, 2.4 g (0,0092 mole) of triphenylphosphine (firm Fluka), 2.4 g (0,0092 mole) 1-isopropylpiperazine-4-ol and 1.6 ml (0,0092 mol) di-tert-butylacetoacetate (40%solution in toluene) in 100 ml THF is stirred for an extended period of time at 35°C. the Mixture is filtered through a layer of silica gel and washed with 30 ml THF. The mixture is evaporated until dry and purify on silica gel, elwira gradient DHM/Meon in the ratio of 98:2. The obtained fractions are evaporated and the residue tracuriroot with ethyl ether, receiving after drying in vacuum with the release of 1.3 mg (83%) indicated in the title compound as a white solid. MS (m/e): 343,3 (M+N)+.

b) Hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1)

Ethyl ester of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1.1 g, 0,0033 mol) dissolved in dioxane (25 ml). Then add 37%HCl solution (to 2.06 ml of 0.066 mol) and the mixture was stirred at 85°C for 16 hours, the Dioxane is evaporated and use toluene (three times 15 ml) to remove residual water by azeotropic distillation. After evaporation of the toluene and drying in vacuo get mentioned in the title compound as yellow solid (yield 1.3 g, 100% of theoretical). MS (m/e): 315,2 (M+N)+.

Intermediate compound 3: Hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1)

a) Ethyl ester of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid

The mixture 0,960 g (0,0044 mole) ethyl ester 6-hydroxyquinolin-2-carboxylic acid, 2,32 g (0,0088 mmole) of triphenylphosphine (firm Fluka), 0,739 g (0,0057 mmole) of 1-isopropyl-3-pyrrolidinone and 1.61 ml (0,0088 mmole) of di-tert-butylacetoacetate (40%solution in toluene) in 100 ml THF is stirred for an extended period of time at 35°C. the Mixture is filtered through a layer of silica gel and washed with 30 ml THF. The mixture is evaporated until dry and purify on silica gel, elwira gradient DHM/Meon in the ratio of 98:2. The obtained fractions are evaporated and the residue tracuriroot with ethyl ether, receiving after drying in vacuum with the release of 1.3 mg (83%) indicated in the title compound as a white solid. MS (m/e): 329,3 (M+H)+.

b) Hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1)

Ethyl ester of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (0.5 g, of 0.002 mol) dissolved in dioxane (20 ml). Then add 37%HCl solution (0,94 ml of 0.03 mol) and the mixture was stirred at 85°C for 16 hours, the Dioxane is evaporated and use tolua is (three times 15 ml) to remove residual water by azeotropic distillation. After evaporation of the toluene and drying in vacuo get mentioned in the title compound as yellow solid (yield 0,570 g, 100% of theoretical). MS (m/e): 301,2 (M+N)+.

Intermediate compound 4: Hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid 0:1)

a) Ethyl ester of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid

A mixture of 0.400 g (0,002 mol) ethyl ester 6-hydroxyquinolin-2-carboxylic acid, 0,966 g (of 0.004 mmole) of triphenylphosphine (firm Fluka), 0,396 g (0,003 mmole) 3-piperidine-1-improper-1-ol and 0.68 ml of 0.004 mmole) of di-tert-butylacetoacetate (40%solution in toluene) in 100 ml THF is stirred for an extended period of time at 35°C. the Mixture is filtered through a layer of silica gel and washed with 30 ml THF. The mixture is evaporated until dry and purify on silica gel, elwira gradient DHM/MeOH/NH4OH in a ratio of from 97:3:0.5 to 90:100:0.5 in. The obtained fractions are evaporated and the residue tracuriroot with ethyl ether, receiving after drying in vacuum exit 0,600 mg (93%) indicated in the title compound as a white solid. MS (m/e): 343,3 (M+N)+.

b) Hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1)

Ethyl ester of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (0.6 g, 0,002 mol) R is straut in dioxane (20 ml). Then add 37%HCl solution (1.08 ml, a 0.035 mole) and the mixture was stirred at 85°C for 16 hours, the Dioxane is evaporated and use toluene (three times 15 ml) to remove residual water by azeotropic distillation. After evaporation of the toluene and drying in vacuo get mentioned in the title compound as yellow solid (yield 0,592 g, 96% of theoretical). MS (m/e): 315,3 (M+N)+.

The intermediate compound 5: Hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]2-carboxylic acid (1:1)

a) Ethyl ester of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid

A mixture of 0.400 g (0,002 mol) ethyl ester 6-hydroxyquinolin-2-carboxylic acid, 0,966 g (of 0.004 mmole) of triphenylphosphine (firm Fluka), 0,396 g (0,003 mmole) of 1-methyl-2-pyrrolidineethanol and 0.68 ml of 0.004 mmole) of di-tert-butylacetoacetate (40%solution in toluene) in 40 ml THF is stirred for an extended period of time at 35°C. the Mixture is filtered through a layer of silica gel and washed with 30 ml THF. Then the mixture is evaporated until dry and purify on silica gel, elwira gradient DHM/MeOH/NH4OH in a ratio of from 97:3:0.5 to 90:100:0.5 in. The obtained fractions are evaporated and the residue tracuriroot with ethyl ether, receiving after drying in vacuum with the release of MX 0.317 g (53%) indicated in the title compound as a white solid matter what. MS (m/e): 329,2 (M+H).

b) Hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1)

Ethyl ester of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (0,310 g of 0.001 mol) dissolved in dioxane (10 ml). Then add 37%HCl solution (0,580 ml 0,019 mol) and the mixture was stirred at 85°C for 16 hours, the Dioxane is evaporated and use toluene (three times 10 ml) to remove residual water by azeotropic distillation. After evaporation of the toluene and drying in vacuo get mentioned in the title compound as yellow solid (yield 0,395 g, 96% of theoretical). MS (m/e): 301,3 (M+N)+.

Example 1: [6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon

The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) (30 mg, 0,086 mmole, see intermediate compound 2) was dissolved in DMF (0,300 ml). Then add 1,1'-carbonyldiimidazole (17 mg, 0.10 mmole) and the mixture is stirred for half an hour. Add 4-methoxypiperidine (6 mg, of 0.014 mmole) and the mixture is stirred over night. The mixture is diluted with 0.4 ml of methanol and purified using reverse-phase preparative HPLC, elwira with a gradient of acetonitrile/water/triethylamine. The fractions obtained is evaporated until dry, receiving with the release of 4.7 mg (14%) specified in the header with the Association in the form of a slightly brown solid. MS (m/e): 412,4 (MN+, 100%).

According to the procedure described for the synthesis of example 1, subsequent derivatives are synthesized from the hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and the corresponding amines. The results are shown in table 1 and include examples from 2 to 26.

Table 1
Example No.The systematic nameMMEductMM was found. (M+H)+
2(2.5-Dihydropyrrol-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano365,4The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 5-dihydropyrrol (commercially available)366,4
3Ethylmethylamino 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid355,48The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and ethylmethylamine (commercially available)
Example No.The systematic nameMMEductMM was found. (M+H)+
5tert-Butylamide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid369,51The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and tert-butylamide (commercially available)370,3
6Cyclopropylmethyl-propelled 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid409,57The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and cyclopropylmethyl-propylamide (commercially available)410,5
76-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-methylpiperidin-1-yl)methanon395,55The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 2-methylpiperidine (commercially available)
8(4-Hydroxypiperidine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano397,52The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 4-hydroxypiperidine (commercially available)398,4
9[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]-(3-methylpiperidin-1-yl)methanon395,55The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 3-methylpiperidin (commercially available)396,3
10Hydrochloride (3,4-dihydro-lH-isoquinoline-2-yl)-[6-(3-piperidine-1-ylpropionic)naphthalene-2-yl]metano (1:1)369,51The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and isopropylparaben (commercially available)370,4
Example No.The systematic nameMMEductMM was found. (M+N) +
11[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]-thiomorpholine-4-ylmethanol399,56The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and thiomorpholine (commercially available)400,4
12[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon435,49The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 2-triftormetilfullerenov (commercially available)436,4
13Ethyl-(2-methoxyethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid399,53The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and ethyl-(2-methoxyethyl)amine (commercially available)400,5
14Azetidin-1-yl-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano353,47The hydrochloride of 6-(1-isoprop piperidin-4-yloxy)quinoline-2-carboxylic acid (1:1), azetidin (commercially available) 354,4
15(3,6-Dihydro-2H-pyridine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano379,5The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 1,2,3,6-tetrahydropyridine (commercially available)380,5
16(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid401,48The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid 1:1 and (3-Torosyan-3-yl)-methylamine (commercially available)401,48
Example No.The systematic nameMMEductMM was found. (M+H)+
17(1-Methoxymethyl-propylether)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid411,55The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and(1-methoxymethyl-propylether)amine (commercially available) 412,4
18[2-(Tetrahydropyran-4-yl)ethyl]amide{6-(1-isopropylpiperazine-4-yloxy)quinoline-2}-carboxylic acid425,57The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 2-(tetrahydropyran-4-yl)ethylamine (commercially available)426,4
19[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]morpholine-4-ylmethanol383,4The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and morpholine (commercially available)384,3
20Cyclohexylethylamine 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid409,57The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and cyclohexylamine (commercially available)410,6
21(4,4-Deformability-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano417,497 The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 4,4-ceftobiprole (commercially available)418,3
22(3-Hydroxypyrrolidine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano383,4The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 3-hydroxypyrrolidine (commercially available)384,3
Example No.The systematic nameMMEductMM was found. (M+N)+
23[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]-pyrrolidin-1-ylmethanone367,49The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and pyrrolidine (commercially available)368,2
24(R)-1-[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile392,5The hydrochloride of 6-(1-is isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and (R)-pyrrolidin-2-carbonitrile (commercially available) to 393.3
25(1,1-Diocletianopolis-4-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano431,5The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and 1,1-dioxide thiomorpholine432,4
26Dimethylamide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid341,5The hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1) and dimethenamid (commercially available)342,2

Example 27: (2.5-Dihydropyrrol-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano

According to the procedure described for the synthesis of compounds of example 1 (2.5-dihydropyrrol-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano hydrochloride synthesized from 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) (intermediate compound 3) and 2,5-dihydropyrrole (commercially available). Specified in the title compound is obtained in yield of 18% (5.7 mg) as an almost white solid. MS (m/e): AZN 352.5 (MH+, 100%).

Consequently, derivatives obtained from hydro is lorida 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and the corresponding amines. The results are shown in table 2 and include examples from 28 to 46.

Table 2
Example No.The systematic nameMMThe source connectionsMM was found. (M+N)+
28([6-(1-Isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon397,52The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 4-methoxypiperidine398,4
29Ethylmethylamino 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid341,45The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and ethylmethylamine (commercially available)342,2
30([6-(1-Isopropyl-pyrrolidin-3-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)methanon381,52The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (:1) and 4-methylpiperidine (commercially available) 382,3
31[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-yl]-(2-methylpyrrolidine-1-yl)methanon367,49The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 2-methylpyrrolidine (commercially available)368,3
32tert-Butylamide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid355,48The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and tert-butylamide (commercially available)356,4
33Cyclopropylmethyl-amide 6-(1-isopropyl-pyrrolidin-3-yloxy)quinoline-2-carboxylic acid395,55The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and cyclopropylmethyl-propylamide (commercially available)396,3
34{[6-(1-Isopropyl-pyrrolidin-3-yloxy)quinoline-2-yl]-(2-methylpiperidin-1-yl)}metano381,52The hydrochloride of 6-(1-isopropylphenol is lidin-3-yloxy)quinoline-2-carboxylic acid (1:1) and 2-methylpiperidine (commercially available) 382,3
Example No.The systematic nameMMThe source connectionsMM was found. (M+N)+
35[6-(1-Isopropyl-pyrrolidin-3-yloxy)quinoline-2-yl]-(3-methylpiperidin-1-yl)methanon381,52The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 3-methylpiperidin (commercially available)382,3
36Isopropylacrylamide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid355,48The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and isopropylparaben (commercially available)356,4
37[6-(1-Isopropylpyrimidine-3-yloxy)quinoline-2-yl]-thiomorpholine-4-ylmethanol385,53The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and thiomorpholine (commercially available)386,3
38 [6-(1-Isopropyl-pyrrolidin-3-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon421,46The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 2-triftormetilfullerenov (commercially available)422,3
39Ethyl-(2-methoxyethyl)amide 6-(1-isopropyl-pyrrolidin-3-yloxy)quinoline-2-carboxylic acid385,51The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and ethyl(2-methoxyethyl)amine (commercially available)386,4
40Azetidin-1-yl-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano339,44The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1), azetidin (commercially available)340,3
41(3,6-Dihydro-2H-pyridine-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano365,48The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 1,2,3,6-tetrahydropyridine (whom archacki available) 366,2
Example No.The systematic nameMMThe source connectionsMM found (M+H)+
42(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid387,45The hydrochloride of 6-(1-isopropyl-pyrrolidin-3-yloxy)quinoline-2-carboxylic acid (1:1) and (3-Torosyan-3-yl)methylamine388,3
43(1-Methoxymethyl-cyclopropylmethyl)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid397,52The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and (1-methoxymethyl-cyclopropyl)methylamine398,4
44[2-(Tetrahydropyran-4-yl)ethyl]amide of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid411,55The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 2-(tetrahydropyran-4-yl)-ethylamine4124
45(4,4-Deformability-1-yl)-[6-(1-isopropyl-pyrrolidin-3-yloxy)quinoline-2-yl]metano403,5The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and 4,4-ceftobiprole (commercially available)404,4
46[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]morpholine-4-ylmethanol369,4The hydrochloride of 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid (1:1) and morpholine (commercially available)370,3

Example 47: (4-Methoxypiperidine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano

According to the procedure described for the synthesis of compounds of example 1, (4-methoxypiperidine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano obtained from hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) (intermediate compound 4) and 4-methoxypiperidine (commercially available). Specified in the title compound is obtained with a yield of 22% (7.8 mg) in the form of an almost white solid. MS (m/e): 412,4 (MN+, 100%).

Consequently, derivatives obtained from hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1, and the corresponding amines. The results are shown in table 3 and include examples from 48 to 66.

Table 3
Example No.The systematic nameMMThe source connectionsMM was found. (M+N)+
48(4 Methylpiperidin-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano395,55The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and 4-methylpiperidine (commercially available)396,3
49Morpholine-4-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano383,49The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and morpholine (commercially available)384,3
50(2 Methylpyrrolidine-1-yl)[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano381,52The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and 2-methylpyrrolidine (commercially is available) 382,4
51Cyclopropylmethyl-propelled 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid409,57The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and cyclopropylmethyl-propylamide (commercially available)410,4
52[6-(3-piperidine-1-ylpropionic)quinoline-2-yl](2-trifluoromethyl-pyrrolidin-1-yl)methanon435,49The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and 2-trifluoromethyl-pyrrolidine (commercially available)436,3
Example No.The systematic nameMMThe source connectionsMM was found. (M+N)+
53(2.5-Dihydropyrrol-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano365,48The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and 2.5-dihydropyrrol (commercially available)366,3
54Ethyl(2-methoxyethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid399,53The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and ethyl(2-methoxy ethyl)amine (commercially available)400,3
55Azetidin-1-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano353,47The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1), azetidin (commercially available)354,3
56(3,6-Dihydro-2H-pyridine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano379,5The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and 1,2,3,6-tetrahydropyridine (commercially available)380,4
57(4,4-Deformability-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano417,5The hydrochloride of 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid (1:1) and 4,4-ceftobiprole (commercially available)418,4
58Cyclohexylethylamine 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid409,57The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and cyclohexylamine (commercially available)410,4
Example No.The systematic nameMMThe source connectionsMM was found. (M+N)+
59(1-Methoxymethyl-cyclopropylmethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid411,55The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and (1-methoxymethyl-cyclopropylmethyl)amine (commercially available)412,4
60(3-Torosyan-3-ylmethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid401,48The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and (3-Torosyan 3-yl)methylamine (commercially available)402,4
61 6-(3-piperidine-1-yl-propoxy)quinoline-2-carboxylic acid[2-(tetrahydropyran-4-yl)-ethyl]amide425,57The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and 2-(tetrahydropyran-4-yl)ethylamine (commercially available)426,3
62(Tetrahydropyran-4-yl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid397,52The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and 4-aminotetraline-Piran (commercially available)398,3
63(2 Methylpiperidin-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano395,55The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and 2-methylpiperidine (commercially available)396,3
64[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]pyrrolidin-1-ylmethanone367,49The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and pyrrolidine (commercially available)368,2
Example No.The systematic nameMMThe source connectionsMM was found. (M+N)+
65(R)-1-[6-(3-piperidine-1-ylpropionic)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile392,5The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1) and (R)-pyrrolidin-2-carbonitrile (commercially available)to 393.3
66(1,1-Diocletianopolis-4-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano431,55The hydrochloride of 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid (1:1)) and 1,1-dioxide thiomorpholine432,4

Example 67: (4 Methylpiperidin-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}metano

According to the procedure described for the synthesis of compounds of example 1, (4 methylpiperidin-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}meanon obtained from hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) (intermediate compound 5) and 4-methylpiperidine (commercially available). Specified in the title compound is obtained with a yield of 13% (4,2 mg) as a white solid. MS (m/e): 382,4 (MN+, 100%).

According to the procedure described for the synthesis of example 67, subsequent derivatives obtained from hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and the corresponding amines. The results are shown in table 4 and include examples from 68 to 76.

Table 4
Example No.The systematic nameMMThe source connectionsMM found (M+H)+
68{6-[2-(1-Methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}pyrrolidin-1-ylmethanone353,47The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and pyrrolidine (commercially available)354,3
69(R)-1-{6-[2-(1-Methylpyrrolidine-2-yl)ethoxy]quinoline-2-carbonyl}pyrrolidin-2-carbonitrile378,48The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and (R)-pyrrolidin-2-carbonitrile (commercially available)379,4
70(1,1-Diocletianopolis-4-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}metano417,53The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and 1,1-dioxide thiomorpholine418,4
71(4-Methoxypiperidine-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}metano397,52The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and 4-methoxypiperidine (commercially available)398,3
72{6-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]quinoline-2-yl} morpholine-4-ylmethanol369,46The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and morpholine (commercially available)370,3
Example No.The systematic nameMMThe source connectionsMM found (M+N)+
73Azetidin-1-yl-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-the l}metano 339,44The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1), azetidin (commercially available)340,3
74[2-(Tetrahydropyran-4-yl)ethyl]amide 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid411,55The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and 2-(tetrahydropyran-4-yl)ethylamine (commercially available)412,4
75(3-Torosyan-3-ylmethyl)amide 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid387,45The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and (3-Torosyan-3-yl)methylamine (commercially available)388,3
76(2 Methylpyrrolidine-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}metano367,49The hydrochloride of 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid (1:1) and 2-methylpyrrolidine (commercially available)368,2

Example 77: (S) - 1-[6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile

According to the procedure described for the synthesis of compounds of example 1, (S)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile obtained from hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1), (S)-cyanopyrrolidine (commercially available) and tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea instead of 1,1'-carbonyldiimidazole. Specified in the title compound is obtained in yield of 45% (50 mg) as colorless foam. MS (m/e): 392,9 (M).

Example 78: [6-(1-Isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)methanon

According to the procedure described for the synthesis of compounds of example 1, [6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)methanon obtained from hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1), 4-methylpiperidine (commercially available) and 1,1'-carbonyldiimidazole. MS (m/e): 396,6 (M+H).

Example 79: (4-Hydroxyethylpiperazine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano

According to the procedure described for the synthesis of compounds of example 1, (4-hydroxyethylpiperazine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano obtained from hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1), 4-hydroxyethylpiperazine (commercially available) and 1,1'-carbonyldiimidazole. MS (m/e): 412,5 (M+H).

Primer: Isobutyramide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid

According to the procedure described for the synthesis of compounds of example 1, isobutylene (6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid is obtained from the hydrochloride of 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid (1:1), isobutylamine (commercially available) and 1,1'-carbonyldiimidazole. MS (m/e): 370,6 (M+H).

Example 81: Cyclohexylethylamine 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid

According to the procedure described for the synthesis of the compound of example 27, cyclohexylethylamine 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid is obtained from the hydrochloride of 6-(1-isopropylpyrimidine-3-oxy)quinoline-2-carboxylic acid (1:1) (intermediate compound 3), N-methylcyclohexylamine (commercially available) and 1,1'-carbonyldiimidazole. MS (m/e): 396,4 (M+H).

Example

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

IngredientsPills
Core:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline whole is ulosa 23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Polydon C12.5 mg15,0 mg
Sodium starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Earth core)120,0 mg350,0 mg
Shell:
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

Active ingredients p is osuivat, mixed with microcrystalline cellulose and granularit mixture in a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and pressed, receiving the core tablets weighing 120 or 350 mg, respectively. The core 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:

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

Components sift, mix and make into capsules of size 2.

The example In

Injectable solutions may have the following composition:

The compound of formula (I)3.0 mg
Gelatin150,0 mg
Phenol4,7 mg
Sodium carbonateto obtain the final pH 7
Water 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
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide 0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the other ingredients and the mixture is filled soft gelatin capsules of appropriate size. Filled soft gelatin capsules are processed using conventional methods.

Example D

The sachet 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 K10.0 mg
Magnesium stearate10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, and then granularit with a mixture of polyvinylpyrrolidone in water. Granulate) is t with stearate and flavors and bring in Sasha.

1. Compounds of General formula

where R1choose from a group that includes
hydrogen,
lower alkyl,
cycloalkyl or lower cycloalkyl where cycloalkyl ring may be substituted by lower alkoxyalkyl,
lowest alkoxyalkyl, and
tetrahydropyranyl and lower geterotsiklicheskikh, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which may be substituted with halogen;
R2selected from the group including hydrogen, lower alkyl,
cycloalkyl or lower cycloalkyl where cycloalkyl ring may be substituted by lower alkoxyalkyl, lower alkoxyalkyl, and
tetrahydropyranyl and lower geterotsiklicheskikh, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which may be substituted with halogen; or
R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5 - or 6-membered saturated or partially unsaturated heterocyclic ring optionally containing, besides heteroatom selected from oxygen or sulfur, with the specified saturated or partially unsaturated heterocyclic ring is unsubstituted or substituted by one or two groups independently selected from the group consisting of lower alkyl, halogen, halogenoalkane, cyano what the group hydroxy-group, lower hydroxyalkyl, low alkoxygroup, the carbonyl group;
And choose from
or
where m denotes 0 or 1;
R3denotes lower alkyl;
n denotes 0;
R4denotes lower alkyl;
p denotes 1;
q denotes 0, 1 or 2;
R5denotes hydrogen; and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, where R1selected from the group including hydrogen, lower alkyl,
cycloalkyl or lower cycloalkyl where cycloalkyl ring may be substituted by lower alkoxyalkyl,
lowest alkoxyalkyl, and
lowest geterotsiklicheskikh, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which may be substituted with halogen; and
R2denotes hydrogen or lower alkyl.

3. The compounds of formula I according to claim 1, where R1choose a group that includes
lower alkyl,
cycloalkyl or lower cycloalkyl where cycloalkyl ring may be substituted by lower alkoxyalkyl,
lowest alkoxyalkyl, and
lowest geterotsiklicheskikh, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which may be substituted with halogen; and
R2denotes hydrogen or lower alkyl.

4. The compounds of formula I according to claim 3 where R 1and R2denote lower alkyl.

5. The compounds of formula I according to claim 1, where R1and R2together with the nitrogen atom to which they are attached, form a 4-, 5 - or 6-membered saturated or partially unsaturated heterocyclic ring optionally containing, besides heteroatom selected from oxygen or sulfur, with the specified heterocyclic ring is unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, halogenoalkane, ceanography, hydroxy-group, the lower alkoxygroup, carbonyl group.

6. The compounds of formula I according to claim 1, where R1and R2together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group comprising morpholine, piperidine, 2,5-dihydropyrrol, pyrrolidin, azetidin, thiomorpholine, but such heterocyclic ring is unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, halogenoalkane, ceanography, hydroxy-group, the lower alkoxygroup and the carbonyl group.

7. The compounds of formula I according to claim 1, where R1and R2together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, piperidinyl, 2-methylpiperidine, 3 methylpiperidin the La, 4-hydroxypiperidine, 4,4-ceftobiprole, 2,5-dihydropyrrole, 4-methylpiperidine, pyrrolidine, 2-methylpyrrolidine, 2-cryptomaterial, 2-cyanopyrrolidine, 3-hydroxypyrrolidine and azetidine.

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

9. The compounds of formula I of claim 8, where m denotes 0.

10. The compounds of formula I of claim 8, where m denotes 1.

11. The compounds of formula I according to claim 1, where a denotes
,
where n represents 0; and R4denotes lower alkyl.

12. The compounds of formula I according to claim 1, where a denotes

where p represents 1, q represents 0, 1 or 2, and R5denotes hydrogen.

13. The compounds of formula I according to claim 1, selected from the group including:
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon,
(2.5-dihydropyrrol-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
ethylmethylamino 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-methylpyrrolidine-1-yl)methanon,
tert-butylamide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
cyclopropanemethylamine 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
6-(1-isop oilpipeline-4-yloxy)quinoline-2-yl]-(2-methylpiperidin-1-yl)methanon,
(4-hydroxypiperidine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(3-methylpiperidin-1-yl)methanon,
hydrochloride (3,4-dihydro-1H-isoquinoline-2-yl)-[6-(3-piperidine-1-ylpropionic)naphthalene-2-yl]methanone (1:1),
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]thiomorpholine-4-ylmethanone,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,
ethyl(2-methoxyethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
azetidin-1-yl-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
(3,6-dihydro-2H-pyridine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
(1-ethoxymethylenemalonic)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
[2-(tetrahydropyran-4-yl)ethyl]amide{6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]morpholine-4-ylmethanone,
cyclohexylethylamine 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
(4,4-deformability-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
(3-hydroxypyrrolidine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]pyrrolidin-1-ilma is anon
(R)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,
(1,1-diocletianopolis-4-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
dimethylamide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
(2.5-dihydropyrrol-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,
([6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon,
ethylmethylamino 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
([6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)methanon,
[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(2-methylpyrrolidine-1-yl)methanon,
tert-butylamide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
cyclopropanemethylamine 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(2-methylpiperidin-1-yl)methanon,
[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(3-methylpiperidin-1-yl)methanon,
isopropylacrylamide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]thiomorpholine-4-ylmethanone,
[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,
ethyl-(2-methoxyethyl)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
azetidin-1-yl-[-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,
(3,6-dihydro-2H-pyridine-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,
(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
(1-ethoxymethylenemalonic)amide 6-(1-isopropylpyrimidine-3-oxy)quinoline-2-carboxylic acid,
[2-(tetrahydropyran-4-yl)ethyl]amide of 6-(1-isopropylpyrimidine-3-oxy)quinoline-2-carboxylic acid,
(4,4-deformability-1-yl)-[6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-yl]metano,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]morpholine-4-ylmethanone,
(4-methoxypiperidine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
(4 methylpiperidin-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
morpholine-4-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
(2 methylpyrrolidine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
cyclopropanemethylamine 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,
(2.5-dihydropyrrol-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
ethyl-(2-methoxyethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
azetidin-1-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
(3,6-dihydro-2H-pyridine-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
(4,4-deformability-1-yl)-[6-(3-piperidine-1-ylpropionic)hee the Olin-2-yl]metano,
cyclohexylethylamine 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
(1-ethoxymethylenemalonic)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
(3-Torosyan-3-ylmethyl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
[2-(tetrahydropyran-4-yl)ethyl]amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
(tetrahydropyran-4-yl)amide 6-(3-piperidine-1-ylpropionic)quinoline-2-carboxylic acid,
(2 methylpiperidin-1-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]pyrrolidin-1-ylmethanone,
(R)-1-[6-(3-piperidine-1-ylpropionic)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,
(1,1-diocletianopolis-4-yl)-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
(4 methylpiperidin-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,
{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}pyrrolidin-1-ylmethanone,
(R)-1-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carbonyl} pyrrolidin-2-carbonitrile,
(1,1-diocletianopolis-4-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl} mechanon,
(4-methoxypiperidine-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,
{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}morpholine-4-ylmethanone,
azetidin-1-yl-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,
[2-(tetrahydropyran-4-yl)ethyl]amide 6-[2-(1-methylpyrrole the Jn-2-yl)ethoxy]quinoline-2-carboxylic acid,
(3-Torosyan-3-ylmethyl)amide 6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-carboxylic acid,
(2 methylpyrrolidine-1-yl)-{6-[2-(1-methylpyrrolidine-2-yl)ethoxy]quinoline-2-yl}mechanon,
(S)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methylpiperidin-1-yl)methanon,
(4-hydroxyethylpiperazine-1-yl)-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
isobutyramide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
cyclohexylethylamine 6-(1-isopropylpyrimidine-3-yloxy)quinoline-2-carboxylic acid,
and their pharmaceutically acceptable salts.

14. The compounds of formula I according to claim 1, selected from the group including:
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(4-methoxypiperidine-1-yl)methanon,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-methylpyrrolidine-1-yl)methanon,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]-(2-triftormetilfullerenov-1-yl)methanon,
azetidin-1-yl-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]metano,
(3-Torosyan-3-ylmethyl)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
(1-ethoxymethylenemalonic)amide 6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carboxylic acid,
[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-yl]pyrrolidin-1-ylmethanone,
(R)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carb the Nile]pyrrolidin-2-carbonitrile,
azetidin-1-yl-[6-(3-piperidine-1-ylpropionic)quinoline-2-yl]metano,
(R)-1-[6-(3-piperidine-1-ylpropionic)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,
(S)-1-[6-(1-isopropylpiperazine-4-yloxy)quinoline-2-carbonyl]pyrrolidin-2-carbonitrile,
and their pharmaceutically acceptable salts.

15. Pharmaceutical composition having antagonistic activity against receptor histamine 3 (H3-receptors), containing as active ingredient a compound according to any one of claims 1 to 14, as well as pharmaceutically acceptable carrier and/or adjuvant.

16. The pharmaceutical compositions according to § 15 for the treatment and/or prevention of diseases associated with the modulation of H3 receptors.

17. Compounds according to claim 1, which has antagonistic activity against receptors of histamine 3 (H3-receptors).

18. Compounds according to claim 1 for use as therapeutically active substances for the treatment and/or prevention of diseases associated with the modulation of H3 receptors.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and their pharmaceutically acceptable salts and esters. The disclosed compounds have cdk4 inhibition properties. In formula (I) n equals 0 or 1; R1 and R2 are each independently selected from a group consisting of H, lower alkyl, CO2R5, SO2R6 and COR6; or alternatively, R1 and R2 can form a ring containing 5-6 atoms in the ring, where the said ring contains carbon atoms, where the said carbon atoms are optionally substituted with oxygen, and the said atoms in the ring are optionally substituted with OR6; R3 is selected from a group consisting of H, lower alkyl, O-lower alkyl, halogen, OH, CN, NO2 and COOH; R4 is selected from a group consisting of H, lower alkyl, C3-C6-cycloalkyl, O-lower alkyl, halogen, NO2, S-lower alkyl, NR5R6, CONR7R8, OH and CN; or alternatively R3 and R4, together with two carbon atoms and the bond between them from the benzene ring, to which R3 and R4 are bonded, can form a ring containing 5-7 atoms, where the said 5-7-member ring contains carbon atoms, where the said carbon atoms are optionally substituted with one or two heteroatoms selected from O and N, and the said atoms in the ring are optionally substituted with CO2R6; R4 represents H or halogen; R5 and R6 are each independently selected from a group consisting of H and lower alkyl; R7 and R8 each represents H. The invention also relates to a pharmaceutical composition for treating or controlling diseases progression of which can be enhanced by inhibiting cdk4, containing an effective amount of the disclosed compound as an active ingredient, to use of disclosed compounds for preparing medicinal agents and method of producing said compounds.

EFFECT: more effective treatment.

30 cl, 1 tbl, 142 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

FIELD: chemistry.

SUBSTANCE: crystalline monohydrate has X-ray powder pattern which includes four or more values 2θ, selected from a group consisting of: 18.0 ± 0.2, 18.4 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.2 ± 0.2, 24.5 ± 0.2, 25.9 ± 0.2 and 28.0 ± 0.2. The invention also relates to a method of producing crystalline monohydrate, to a pharmaceutical composition for treating disorders caused by protein tyrosine kinase containing crystalline monohydrate, to a crystalline butanol solvate of formula and to a crystalline ethanol solvate compound of formula (IV).

EFFECT: increased effectiveness of using said compounds.

8 cl, 1 tbl, 6 dwg, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives of general formula

and ,

where: X1-X4 denote C; Z denotes H; R1 denotes alkyl, H, -(CH2)3-N-(C2H5)2; R2 and R3 denote alkyl, or together with the nitrogen atom to which they are bonded form a C4-7-monocyclic ring containing 1 or 2 heteroatoms, selected from O and N, possibly substituted with an alkyl; R4 denotes H; Y denotes S, -N-(C2H5); where in formula I compounds R5 and R6 together with the nitrogen atom to which they are bonded form a C9-10 a condensed bicyclic ring containing an N heteroatom, possibly substituted with R, where R denotes -N-(R2)-R3; in formula II compounds R5 denotes phenyl, optionally substituted with OCH3.

EFFECT: obtaining new compounds which can be used as protein kinase inhibiting agents.

2 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

Chemical method // 2386636

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a group of novel chemical compounds pharmacologically acceptable salts thereof having formula , where A represents COOH; B represents H; n equals 0; V represents -CH2-, a single bond; W represents a 5-7-member heteroaromatic group with one heteroatom selected from N, O, S which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, when V represents a -CH2-group, where if V represents a single bond, W represents a bicyclic condensed a ring -member heterocyclic group with one heteroatom selected from O, S, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; X represents a 5-7-member heteroaromatic group with one O atom and one or two N atoms, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Y represents C6-C10 aryl which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, a 5-7-member heteroatomatic group with one S atom which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Z represents C1-C8 alkyl, C3-C7 cycloalkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryloxy which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A, or C1-C12 aralkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; group of substitutes A represents halogen, C1-C6 alkyl, halogen C1-C6 alkyl, C1-C6 alkoxy.

EFFECT: compounds exhibit inhibitory activity towards HvGR which enables their use to prepare a pharmaceutical composition used in therapy for autoimmune diseases.

33 cl, 6 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

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