Indol-3-yl-carbonyl-piperadine-benzimidazole derivatives as v1a receptor antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where the dotted line is either absent or denotes a double bond; R1 denotes H or C1-6-alkyl, possibly substituted with a CN group, or denotes a phenyl or sulphonyl phenyl, substituted with one or more B groups, or denotes -(CH2)m-Ra, where Ra denotes: NRiRii, C3-6-cycloalkyl, 6-member heterocycloalkyl, which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, aryl, which can be substituted with one or more B groups, or denotes -(CH2)n-(CO)-Rb or -(CH2)n-(SO2)-Rb, where Rb denotes: NRiRii, 5-6-member heterocycloalkyl, which denotes a univalent saturated group containing one or more heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms, aryl or 5- or 6-member heteroaryl, which denotes an aromatic ring containing two heteroatoms as ring members, the said heteroatoms selected from N or O, the rest are carbon atoms; which can possibly be substituted with one or more B groups, R2 denotes one or more H, halo, C1-6-alkyl, C1-6-alkoxy, R3 denotes H or-(CO)-Rc, where Rc denotes: C1-6-alkyl, 5-member heterocycloalkyl, which denotes a univalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms possibly substituted with C1-6-alkyl, or denotes C1-6-alkyl; R4 denotes H; R5 denotes H, C1-6-alkyl, -(CH2)m-NRiRii, -(CH2)n-(CO)-Rb, where Rb denotes NRiRii or a 6-member heterocycloalkyl which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, when the dotted line is absent or is absent when the dotted line denotes a double bond; R6 is absent, when the dotted line denotes a double bond; R7 denotes Cl or NReRf, where Re and Rf denotes H or C1-6-alkyl, or Re and Rf together with the nitrogen atom to which they are bonded form a 6-member heterocycloalkyl which denotes a univalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms; which can be substituted with C1-6-alkyl, or R6 and R7 together form a C=O group, when the dotted line is absent; B denotes halogen, C1-6-alkoxy, (CRiiiRiv)n-phenyl; Ri and Rii denote H, C1-6-alkyl -C(O)-C1-6-alkyl; Riii and Riv denote C1-6-alkyl; m equals to 1 or 2, n equals 0 or 1; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, as well as to use of compounds of formula (I), (I-a) or (1-b).

EFFECT: obtaining novel biologically active compounds having activity on V1a receptor.

12 cl, 48 ex

 

The present invention relates to compounds of formula (I):

where the dotted line is absent or represents a double bond;

R1represents H,

or represents a C1-6-alkyl, possibly substituted by a group CN

or represents aryl, 5 - or 6-membered heteroaryl or sulfonylureas, possibly substituted by one or more groups,

or represents -(CH2)m-Rawhere Rarepresents:

CN,

ORi,

NRiRii,

With3-6-cycloalkyl, 4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more groups,

or represents -(CH2)n-(CO)-Rbor -(CH2)n-(SO2)-Rbwhere Rbrepresents:

With1-6-alkyl,

With1-6-alkoxy,

With3-6-cycloalkyl,

-(CH2)m-NiiiRiv,

NRiRii,

With3-6-cycloalkyl, 4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more groups,

or R1and R3together with the indole ring to which they are attached, form a 5-or 6-membered heteroseksualci, which may be substituted by =O;

R2represents one Il is more than one N, HE, halo, CN, nitro, C1-6-alkyl, possibly substituted by a group NRiiiRivC1-6-alkoxy, -O-CH2-C2-6alkenyl, benzyloxy,

or two R2may form oxo or dioxo bridge together with the indole ring to which they are attached;

R3represents H,

or represents halo, or

represents -(CO)-Rcwhere Rcrepresents:

C1-6-alkyl,

-(CH2)n-NRiRii,

-(CH2)n-NRiiiRiv,

5 - or 6-membered heteroseksualci, possibly substituted C1-6-alkyl, or represents a C1-6is alkyl or aryl, which may be substituted

halo,

-O(CO)1-6-alkyl,

or-NH(CO)Rdwhere Rdrepresents a C1-6-alkyl, possibly substituted by a group of halo, or nitro, or Rdrepresents aryl or 5 - or 6-membered heteroaryl, possibly substituted by a group of halo, nitro, C1-6-alkyl or C1-6-haloalkyl;

R4represents one or more than one H, halo, C1-6-alkyl or C1-6-alkoxy, or two of R4may form oxo or dioxo bridge together with the phenyl ring to which they are attached;

R5represents H, C1-6-alkyl, -(CH2)m-NRiRii, aryl or -(CH2)n-(CO)-R bwhere Rbrepresents NRiRiior 4-7-membered heteroseksualci, when the dotted line is absent, or is absent when the dotted line represents a double bond;

R6absent when the dotted line represents a double bond;

R7represents H,

Cl or

NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rftogether with the nitrogen atom to which they are attached, form a 5 - or 6-membered heteroseksualci, which may be substituted C1-6-alkyl,

or R6and R7together form a C=O group, when the dotted line is absent;

Represents a halo, CN, NRiRiiWith1-6-alkyl, possibly substituted by a group of CN, halo, or C1-6-alkoxy, C1-6-alkoxy, C1-6-haloalkoxy,3-6-cycloalkyl, -C(O)O-C1-6-alkyl, -C(O)-NRiRii-C(O)-C1-6-alkyl, -S(O)2-C1-6-alkyl, -S(O)2-NRiRii, (CRiiiRiv)n-phenyl or - (CRiiiRiv)n5 - or 6-membered heteroaryl, where phenyl or a 5 or 6-membered heteroaryl fragment possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, NRiRiiC1-6-alkyl, possibly substituted by a group CN or C1-6-alkoxy, C1-6-alkoxy, C1-6-haloalkoxy,3-6-cycloalkyl, -C(O)O-C1-6of alkyl, -C(O)-NRiRii-C(O)-C1-6-alkyl, -S(O)2-C1-6-alkyl, -S(O)2-NRiRii;

Riand Riirepresent H, C1-6-alkyl, C1-6-alkyl-NRiiiRiv, -(CO)O-C1-6-alkyl, -C(O)-RiiiRiv-C(O)-C1-6-alkyl, -S(O)2-C1-6-alkyl or-S(O)2-NRiiiRiv;

Riiiand Rivrepresent N or C1-6-alkyl;

m is 1-6;

n is 0-4;

and their pharmaceutically acceptable salts.

The compounds of formula (I) can contain one or more asymmetric carbon atoms. Thus, the present invention includes all stereoisomeric forms of the compounds of formula I, including each of the individual enantiomers and mixtures thereof.

It is established that the compounds of formula (I) exhibit significant activity relative to the V1a receptor. Therefore, according to the invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of medicaments for the treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxiety and depressive disorders.

Vasopressin p is ecstasy a peptide of 9 amino acids, produced mainly paraventrikulyarnoe nucleus of the hypothalamus. There are three vasopressin receptor, which all belong to the class I receptors associated with G-proteins. The V1a receptor is expressed in brain, liver, vascular smooth muscle, lung, uterus, and testis, V1b or V3 receptor is expressed in the brain and the pituitary gland, the V2 receptor is expressed in the kidney, where it regulates the excretion of water and mediates the antidiuretic effects of vasopressin.

On the periphery of vasopressin acts as neurohormone and promotes vasoconstriction, glycogenolysis and antidiuresis. In brain vasopressin acts as a neuromodulator and is increased in the amygdala gland during stress (Ebner, K., ST Wotjak, et al. (2002). "Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats." Eur J Neurosci 15 (2): 384-8). V1a receptor is widely expressed in the brain and especially in the limbic areas like the amygdala gland, lateral septum and the hippocampus, which perform an important function in controlling anxiety. In fact V1a knock-out mice show reduced anxiety behavior in the cross-maze, open field and showed dark box (Bielsky, I.F., S..Hu, et al. (2003). "Profound in his or her Social Recognition and Reduction in Anxiety-Like Behavior in Vasopressin V1a Receptor Knockout Mice." Neuropsychopharmacology.). Negative reverse what I regulation V1a receptor using injections of antisense oligonucleotides in the wall also causes a reduction in anxious behavior (Landgraf, R., R. Gerstberger, et al. (1995). "V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats." Regul Pept 59 (2): 229-39).

Also V1a receptor mediates the cardiovascular effects of vasopressin in the brain through the Central regulation of blood pressure and heart rate in the nuclei of a single path (Michelini, L.. and M. Morris (1999). ”Endogenous vasopressin modulates the cardiovascular responses to exercise.” Ann N Y Acad Sci 897: 198-211). At the periphery it causes contraction of vascular smooth muscle and prolonged inhibition of V1a receptor improves hemodynamic parameters in rats with myocardial infarction (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). ”Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats.” Eur J Pharmacol 449(1-2):135-41).

Thus, antagonists vasopressin receptors are useful as medicines for conditions of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxiety and depressive disorders.

Preferred indications concerning the present invention are the treatment of anxiety and depressive disorders.

Used herein, the term "aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of mono-, bi - or tricyclic what about the aromatic ring. Examples of aryl groups include, but are not limited to, possibly substituted phenyl, naphthyl, tenantry, fluorenyl, indenyl, pentalene, azulene, acidifier, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfone, diphenylethylene, benzodioxane, benzofuranyl, benzodioxolyl, benzopyranyl, benzoxazines, benzoxazinones, benzoperylene, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity, as well as those specifically illustrated by the following examples. The substituents of aryl include, but are not limited to, halogen, C1-6-alkyl, C1-6-alkoxy. The preferred Allami are phenyl and naphthyl and the preferred phenyl.

The term "C1-6-alkyl" denotes a saturated group with a straight or branched chain, containing from 1 to 6 carbon atoms, for example: methyl, ethyl, propyl, isopropyl, n-butyl, ISO-butyl, 2-butyl, tert-butyl, as well as those specifically illustrated by the following examples. Preferred C1-6-alkyl groups are C1-4group, i.e. with 1-4 carbon atoms.

The term "C1-6-alkoxy" denotes a group, where the alkyl residues are as defined above, and which is attached via an oxygen atom. Preferred groups C 1-6-alkoxy are methoxy, ethoxy, as well as those specifically illustrated by the following examples.

The term "C2-6alkenyl" denotes a carbon chain of 2 to 6 carbon atoms containing a double bond in its chain. C2-6-alkeline groups include ethynyl, propen-1-yl, propen-2-yl, butene-1-yl, butene-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl, HEXEN-1-yl, HEXEN-2-yl, HEXEN-3-yl, HEXEN-4-yl and hexene-5-yl, as well as those specifically illustrated by the following examples.

The term "benzyloxy" refers to a benzyl group attached through an oxygen atom.

The term "halogen" or "halo" refers to chlorine (Cl), iodine (I), fluorine (F) and bromine (Br).

The term "C1-6-haloalkyl" represents C1-6is an alkyl group as defined above that is substituted by one or more Halogens. Examples of C1-6-haloalkyl include, but are not limited to: methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more atoms of Cl, F, Br or I, and groups, particularly illustrated by the following examples. Preferred C1-6-haloalkyl are debtor or trifter-methyl or ethyl.

"C1-6-haloalkoxy" refers to a group C1-6-alkoxy, as defined above, which is substituted by one or more Halogens. Examples of C1-6-ha is alkoxy include, but not limited to, methoxy or ethoxy substituted by one or more atoms of Cl, F, Br or I, and groups, particularly illustrated by the following examples. Preferred C1-6-haloalkoxy are debtor or trifter-methoxy or ethoxy.

The term "C3-6-cycloalkyl" denotes a monovalent or divalent saturated carbocyclic group consisting of a monocyclic ring. Cycloalkyl may be substituted by one, two, three or four substituents, where each Deputy independently from each other represents a hydroxy, C1-6-alkyl, C1-6-alkoxy, halogen, amino, unless otherwise specified. Examples cycloalkyl groups may include substituted cyclopropyl, possibly substituted cyclobutyl, possibly substituted cyclopentyl and possibly substituted cyclohexyl, as well as those specifically illustrated by the following examples.

The term "4-7-membered heteroseksualci" means a monovalent saturated group containing one cycle of 4-7 atoms as members of the cycle, including one, two or three heteroatoms selected from nitrogen, oxygen or sulfur, and the rest are carbon atoms. 4-7-membered heteroseksualci may be substituted by one, two, three or four substituents, where each Deputy independently from each other represents the Wallpaper hydroxy, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, halo, C1-6-haloalkyl, C1-6-hydroxyalkyl, alkoxycarbonyl, amino, C1-6-alkylamino, di(C1-6)alkylamino, aminocarbonyl or carbylamine, unless otherwise specified. Examples of heterocyclic groups include, but are not limited to, possibly substituted oxetane, possibly substituted tetrahydrofuranyl, possibly substituted piperidinyl, possibly substituted pyrrolidinyl, possibly substituted morpholinyl, possibly substituted piperazinil and the like or those, examples of which in particular here. The substituents can be selected from C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkyl, halo, CN, HE, NH2and those deputies that are specifically illustrated by the examples below.

Preferred 4-7-membered heteroseksualnymi are 5-6-membered heterocicluri.

The term "5-or 6-membered heteroaryl" means an aromatic ring of 5 or 6 ring atoms, containing as ring members one, two or three heteroatoms selected from N, O or S, the remainder are carbon atoms. 5 or 6-membered heteroaryl may be substituted by one, two, three or four substituents, where each Deputy independently from each other represents a hydroxy, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl halo, C1-6-haloalkyl, C1-6-hydroxyalkyl, alkoxycarbonyl, amino, C1-6-alkylamino, di(C1-6)alkylamino, aminocarbonyl or carbylamine, unless otherwise specified. Examples of heteroaryl groups include, but are not limited to, possibly substituted imidazolyl, possibly substituted oxazolyl, possibly substituted thiazolyl, possibly substituted pyrazinyl, possibly substituted pyrrolyl, possibly substituted pyrazinyl, possibly substituted pyridinyl, possibly substituted pyrimidinyl, possibly substituted furanyl and those examples are in particular here.

The term "sulfonylureas" denotes an aryl group as defined above which is attached via sulfonyloxy group.

The expression "two R2may form oxo or dioxo bridge together with the indole ring to which they are attached or two R4may form oxo or dioxo bridge together with the phenyl ring to which they are attached" means oxo or dioxo bridge the following formulas:

or

which connects two adjacent carbon atoms of the phenyl or indole ring of the compounds of formula (I)which either R2or R4connected.

Examples illustrating the expression "R1and R3together with in the Aulnay ring, to which they are attached, form a 5 - or 6-membered heteroseksualci, which may be substituted by =O", represent:

and

The expression "Reand Rftogether with the nitrogen atom to which they are attached, form a 5 - or 6-membered heterocyclyl, which may be substituted With1-6-alkyl" denotes a 5 - or 6-membered geterotsyklicescoe group, as defined above, which may be substituted by one or more1-6-alkyl, as defined above.

The term "pharmaceutically acceptable acid additive salts" includes salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid, as well as those specifically illustrated by the following examples.

In a particular embodiment of the compounds according to the invention are compounds of formula (I), where:

the dotted line is absent or represents a double bond;

R5represents H, C1-6-alkyl, -(CH2)m-NRiRiior aryl, when the dotted line is absent, or without the duty to regulate, when the dotted line represents a double bond;

and R1, R2, R3, R4, R6and R7are as defined above, and their pharmaceutically acceptable salts.

In an additional embodiment of the compounds according to the invention are compounds of formula (I), where:

R1represents N, or

C1-6-alkyl, possibly substituted by a group CN or C1-6-alkoxy, or

aryl, or

5 - or 6-membered heteroaryl, or

sulfonylureas, or

-(CH2)m-Rawhere Rarepresents a C3-6-cycloalkyl, 5 - or 6-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by halo, C1-6-alkyl, C1-6-haloalkyl or C1-6-alkoxy,

-(CH2)m-NRiRiior

-(CH2)n-(CO)-Rbwhere Rbrepresents aryl or 5 - or 6-membered heteroseksualci;

R2represents one or more than one H, halo, CN, nitro, C1-6-alkyl, C1-6-alkoxy, -O-CH2-C2-6alkenyl, benzyloxy, or two of R2may form oxo or dioxo bridge together with the Indus is the d ring, to which they are attached;

R3represents N, or

halo, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5 - or 6-membered heteroseksualci, possibly substituted C1-6-alkyl, or Rcrepresents -(CH2)n-NRiRiior

C1-6is alkyl or aryl, which may be substituted

-O(CO)1-6-alkyl,

or-NH(CO)Rdwhere Rdrepresents a C1-6-alkyl, possibly substituted by a group of halo, or nitro, or Rdrepresents aryl or 5 - or 6-membered heteroaryl, possibly substituted by a group of halo, nitro, C1-6-alkyl or C1-6-haloalkyl;

R4represents one or more than one H, halo, C1-6-alkyl or C1-6-alkoxy, or two of R4may form oxo or dioxo bridge together with the phenyl ring to which they are attached;

R5represents H, C1-6-alkyl, -(CH2)m-NRiRiior aryl, when the dotted line is absent,

or is absent when the dotted line represents a double bond;

R6absent when the dotted line represents a double bond;

R7represents H,

Cl or

NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rfin the natural with the nitrogen atom, to which they are attached, form a 5 - or 6-membered heteroseksualci,

or R6and R7together form a C=O group, when the dotted line is absent;

Riand Riiindependently from each other selected from H, C1-6-alkyl or -(CO)O-C1-6-alkyl;

m is 1-6;

n is 0-4;

and their pharmaceutically acceptable salts.

Also included are the compounds of formula (I), which represent the following compounds of formula (I-a) according to the invention:

where R1-R4and R7are as defined above for formula (I).

In addition, according to the invention includes compounds of formula (I-a), where:

R1represents N, or

With1-6-alkyl, possibly substituted by a group CN or C1-6-alkoxy, or

aryl, or

5 - or 6-membered heteroaryl, or

sulfonylureas, or

-(CH2)m-Rawhere Rarepresents a C3-6-cycloalkyl, 5 - or 6-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by a group of halo, C1-6-alkyl, C1-6-haloalkyl is whether C 1-6-alkoxy,

-(CH2)m-NRiRiior

-(CH2)n-(CO)-Rbwhere Rbrepresents aryl or 5 - or 6-membered heteroseksualci;

R2represents one or more than one H, halo, CN, nitro, C1-6-alkyl, C1-6-alkoxy, -O-CH2-C2-6alkenyl, benzyloxy, or two of R2may form oxo or dioxo bridge together with the indole ring to which they are attached;

R3represents N, or

halo, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5 - or 6-membered heteroseksualci, possibly substituted C1-6-alkyl, or Rcrepresents -(CH2)n-NRiRiior

C1-6is alkyl or aryl, which may be substituted

-O(CO)1-6-alkyl,

or-NH(CO)Rdwhere Rdrepresents a C1-6-alkyl, possibly substituted by a group of halo, or nitro, or Rdrepresents aryl or 5 - or 6-membered heteroaryl, possibly substituted by a group of halo, nitro, C1-6-alkyl or C1-6-haloalkyl;

R4represents one or more than one H, halo, C1-6-alkyl or C1-6-alkoxy, or two of R4may form oxo or dioxo bridge together with the phenyl ring to which they are attached;

R7represents H,

Cl or

NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rftogether with the nitrogen atom to which they are attached, form a 5 - or 6-membered heteroseksualci, which may be substituted C1-6-alkyl;

Riand Riiindependently from each other selected from H, C1-6-alkyl or -(CO)O-C1-6-alkyl;

m is 1-6;

n is 0-4;

and their pharmaceutically acceptable salts.

Preferred compounds of the formula (I-a) are those compounds of formula (I-a), where:

R1represents N, or

C1-6-alkyl, possibly substituted by a group CN or

-(CH2)m-Rawhere Rarepresents aryl, which is possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by a group of halo, C1-6-alkyl, C1-6-haloalkyl or C1-6-alkoxy,

R2represents one or more than one H, halo, or C1-6-alkoxy;

R3represents N, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl or 5 - or 6-membered heteroseksualci, possibly substituted C1-6-alkyl, or

C1-6-alkyl;

R represents N;

R7represents Cl or

NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rftogether with the nitrogen atom to which they are attached, form a 5 - or 6-membered heteroseksualci, which may be substituted C1-6-alkyl;

m is 1-6;

and their pharmaceutically acceptable salts, for example the following compounds:

(1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanon;

(1-benzyl-2-methyl-1H-indol-3-yl)-{4-[2-(4-methyl-piperazine-1-yl)-benzimidazole-1-yl]-piperidine-1-yl}-methanon;

(1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-morpholine-4-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanon;

(1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-piperidine-1-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanon;

[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanon;

[4-(2-dimethylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanon and

[4-(2-methylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanon.

Also included are the compounds of formula (I), which represent the following compounds of formula (I-b) according to the invention:

where R1-R5are as defined above for formula (I).

In addition, according to the invention are included the compounds is of the formula (1-b)

where:

R1represents N, or

C1-6-alkyl, possibly substituted by a group CN or C1-6-alkoxy, or

aryl, or

5 - or 6-membered heteroaryl, or

sulfonylureas, or

-(CH2)m-Rawhere Rarepresents a C3-6-cycloalkyl, 5 - or 6-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by a group of halo, C1-6-alkyl, C1-6-haloalkyl or C1-6-alkoxy,

-(CH2)m-NRiRiior

-(CH2)n-(CO)-Rbor -(CH2)n-(SO)-Rbwhere Rbrepresents:

NRiRii,

4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more halo, C1-6-alkyl, possibly substituted by a group of CN, halo, or C1-6-alkoxy, C1-6-alkoxy, C1-6-haloalkoxy or (CRiiiRiv)n-phenyl;

R2represents one or more than one H, halo, CN, nitro, C1-6-alkyl, C1-6-alkoxy, -O-CH2-C2-6alkenyl, benzyloxy, or two of R2may form oxo or dioxo bridge in the natural with the indole ring, to which they are attached;

R3represents N, or

halo, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5 - or 6-membered heteroseksualci, possibly substituted C1-6-alkyl, or Rcrepresents -(CH2)n-NRiRiior

C1-6is alkyl or aryl, which may be substituted

-O(CO)1-6-alkyl,

or-NH(CO)Rbwhere Rbrepresents a C1-6-alkyl, possibly substituted by a group of halo, or nitro, or Rdrepresents aryl or 5 - or 6-membered heteroaryl, possibly substituted by a group of halo, nitro, C1-6-alkyl or C1-6-haloalkyl;

R4represents one or more than one H, halo, C1-6-alkyl or C1-6-alkoxy, or two of R4may form oxo or dioxo bridge together with the phenyl ring to which they are attached;

R5represents H, C1-6-alkyl, -(CH2)m-NRiRii, aryl or -(CH2)n-(CO)-Rbwhere Rbrepresents NRiRiior 4-7-membered heteroseksualci;

Riand Riiindependently from each other selected from H, C1-6-alkyl or -(CO)O-C1-6-alkyl;

Riiiand Rivrepresent N or C1-6-alkyl;

m is 1-6;

n is 0-4;/p>

and their pharmaceutically acceptable salts.

Preferred compounds of the formula (I-b) are those compounds of formula (I-b), where:

R1represents N, or

C1-6-alkyl, possibly substituted by a group CN or

-(CH2)m-Rawhere Rarepresents aryl, which is possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by a group of halo, C1-6-alkyl, C1-6-haloalkyl or C1-6-alkoxy, or

-(CH2)m-NRiRiior

-(CH2)n-(CO)-Rbor -(CH2)n-(SO2)-Rbwhere Rbrepresents:

NRiRii,

4-7-membered heteroseksualci, aryl or 5-or 6-membered heteroaryl, possibly substituted by one or more halo, C1-6-alkyl, possibly substituted by a group of CN, halo, or C1-6-alkoxy, C1-6-alkoxy, C1-6-haloalkoxy or (CRiiiRiv)n-phenyl;

R2represents one or more than one H, halo, or C1-6-alkoxy;

R3represents N, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl or 5-or 6-membered heteroseksualci, possibly substituted With a 1-6-alkyl or C1-6-alkyl;

R4represents N;

R5represents H, C1-6-alkyl, -(CH2)m-NRiRii, aryl or -(CH2)n-(CO)Rb,

where Rbrepresents NRiRiior 4-7-membered heteroseksualci;

Riand Riiindependently from each other selected from H, C1-6-alkyl or -(CO)O-C1-6-alkyl;

Riiiand Rivrepresent N or C1-6-alkyl;

m is 1-6;

n is 0-4;

and their pharmaceutically acceptable salts.

In additional embodiments of the invention the compounds of formula (1-b)where:

R1represents N, or

C1-6-alkyl, possibly substituted by a group CN or C1-6-alkoxy, or

aryl, or

5 - or 6-membered heteroaryl, or

sulfonylureas, or

-(CH2)m-Rawhere Rarepresents a C3-6-cycloalkyl, 5 - or 6-membered heteroseksualci, aryl or 5-or 6-membered heteroaryl, possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by a group of halo, C1-6-alkyl, C1-6haloalkyl or C1-6-alkoxy,

-(CH2)m-NRiR iior

-(CH2)n-(CO)-Rbwhere Rbrepresents aryl or 5-or 6-membered heteroseksualci;

R2represents one or more than one H, halo, CN, nitro, C1-6-alkyl, C1-6-alkoxy, -O-CH2-C2-6alkenyl, benzyloxy, or two of R2may form oxo or dioxo bridge together with the indole ring to which they are attached;

R3represents N, or

halo, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5 - or 6-membered heteroseksualci, possibly substituted C1-6-alkyl, or Rcrepresents -(CH2)n-NRiRiior

C1-6is alkyl or aryl, which may be substituted

-O(CO)-C1-6-alkyl,

or-NH(CO)Rdwhere Rdrepresents a C1-6-alkyl, possibly substituted by a group of halo, or nitro, or Rdrepresents aryl or 5-or 6-membered heteroaryl, possibly substituted by a group of halo, nitro, C1-6-alkyl or C1-6-haloalkyl;

R4represents one or more than one H, halo, C1-6-alkyl or C1-6-alkoxy, or two of R4may form oxo or dioxo bridge together with the phenyl ring to which they are attached;

R5represents H, C1-6-alkyl, -(CH2)m-NRiRii/sup> or aryl;

Riand Riiindependently from each other selected from H, C1-6-alkyl or -(CO)O-C1-6-alkyl;

m is 1-6;

n is 0-4;

and their pharmaceutically acceptable salts.

An additional embodiment of the invention encompasses the compounds of formula (I-b), where:

R1represents N, or

C1-6-alkyl, possibly substituted by a group CN or

-(CH2)m-Rawhere Rarepresents aryl, which is possibly substituted by one or more substituents selected from the group consisting of:

halo, CN, C1-6-alkyl, C1-6-alkoxy, C1-6-haloalkoxy, -C(O)O-C1-6-alkyl and phenyl, possibly substituted by a group of halo, C1-6-alkyl, C1-6-haloalkyl or C1-6-alkoxy,

R2represents one or more than one H, halo, or C1-6-alkoxy;

R3represents N, or

-(CO)-Rcwhere Rcrepresents a C1-6-alkyl or 5-or 6-membered heterocyclyl, possibly substituted C1-6-alkyl or C1-6-alkyl;

R4represents N;

R5represents N or C1-6-alkyl;

m is 1-6;

and their pharmaceutically acceptable salts.

The following examples according to the invention are:

1-[1-(1-methyl-1H-indole-3-carbonyl)-Pieper is DIN-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(1H-indol-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-{1-[2-(pyrrolidin-1-carbonyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

1-{1-[6-chloro-1-(3,5-debtor-benzazolyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it.

Preferred are the following examples according to the invention:

1-[1-(1-benzyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-3-methyl-1,3-dihydro-benzimidazole-2-he;

1-[1-(2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(1-isopropyl-6-methoxy-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(6-fluoro-1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(1-cyclohexylmethyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(3-fluoro-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he;

1-(1-{6-chloro-1-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(2-fluoro-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-di hydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(2,3-debtor-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzoni the azole-2-he;

1-{1-[6-chloro-1-(3,5-debtor-benzyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(3,5-debtor-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he;

1-(1-{6-chloro-1-[2-(3,4-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(3,5-debtor-phenyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(piperidine-1-carbonyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(2-oxo-2-piperidine-1-yl-ethyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-3-(2-oxo-2-piperidine-1-yl-ethyl)-1,3-dihydro-benzimidazole-2-he;

2-{3-[1-(6-chloro-1-diethylcarbamoyl-1H-indole-3-carbonyl)-piperidine-4-yl]-2-oxo-2,3-dihydro-benzimidazole-1-yl)-N,N-diethyl-ndimethylacetamide;

1-(1-{6-chloro-1-[2-(3,5-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

1-(1-{6-chloro-1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it.

Most preferred are the following compounds according to the invention is:

1-{1-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he;

1-(1-{6-chloro-1-[2-(2-fluoro-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he;

2-{6-chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidin-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide;

1-[1-(6-chloro-1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-[1-(1-benzyl-6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

2-{5,6-dichloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide;

1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-he;

1-[1-(6-chloro-5-fluoro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

2-{6-chloro-5-methyl-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide;

1-(1-{6-chloro-1-[2-(2,5-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he;

1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-he;

{6-chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile;

1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-(1-{6-chloro-1-[2-(2,4-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he;

1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he;

1-{1-[6-chloro-1-(3-fluoro-benzyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

1-{1-[2-(2-methyl-butyryl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazo the l-2-it.

The invention encompasses the compounds of formula (I), (I-a) or (I-b) for use in the prevention or treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxiety and depressive disorders.

The invention also encompasses a pharmaceutical composition comprising a compound of formula (I), (I-a) or (I-b), which is useful from dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxiety and depressive disorders.

In addition, the invention encompasses the use of compounds of formula (I), (I-a) or (I-b) to obtain a drug which is useful from dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxiety and depressive disorders.

In a particular embodiment of the compounds of formula (I) according to the invention can be manufactured according to a process comprising a stage on which is subjected to the interaction of the compound of formula (II):

with the compound of the formula (III):

to obtain the compound of formula (I), where R1-R7are as defined above. This method is described in more detail on the General scheme and procedure A.

In a particular embodiment of the compounds of formula (I) can be produced according to a process comprising a stage on which is subjected to the interaction of the compound of formula (IV):

with the compound of the formula R1-X, to obtain the compound of formula (I), where R1-R7are as defined above. This method is described in detail on the General scheme and procedure,

In a particular embodiment of the compounds of formula (I-a) can be produced according to a process comprising a stage on which is subjected to the interaction of the compound of formula (I-A1):

with an amine of the formula HNReRfto obtain the compound of formula (I-a), where R7represents NReRfand R1- R4are as defined above. This method is described in more detail on the General scheme and procedure B.

In a particular embodiment of the compounds of formula (1-a) can be produced according to a process comprising a stage on which is subjected to the interaction of the compound of formula (I-B1):

with POCl3to obtain the compound of formula (I-a), where R7represents Cl, and 1-R4are as defined above. This method is described in more detail on the General scheme and procedure B.

In a particular embodiment of the compounds of formula (I-b) can be produced according to a process comprising a stage on which is subjected to the interaction of the compound of formula (I-B1):

with the compound of the formula R5-X, to obtain the compound of formula (I-b), where R1and R5other than N, and where R2-R4are as defined above. This method is described in more detail on the General scheme and the procedure Century

Obtaining the compounds according to the invention is hereinafter described in more detail at the General schemes a - D and corresponding common procedures.

The General scheme of the procedure And describe the most common method of obtaining compounds of formula (I) and (IV), from which additional compounds of formula (I), (I-a) and (I-b) can be obtained according to the General schemes and procedures B, C, and,

The General scheme And

The General procedure And

To obtain the compounds of formula (I-b) in a specific embodiment of the invention, the source compound of formula III-b can be used for analogues with the General scheme, namely exposing the interaction of the compound of formula II with the compound of the formula (III-b):

where R1-R5such as defined above.

Connection is by means of formula (I-b) can be obtained by amide combination between indole-3-carboxylic acid of formula (II) and piperidinium derivative of the formula (III). Indole-3-carboxylic acid of formula (II) or are commercially available or easily obtained using the procedure described in J.Med. Chem. 1991, 34, 140, or get them using the procedure described in the examples below. Alternatively, the compounds of formula (II) can be obtained following the General scheme, Piperidine derivatives of the formula (III) are either commercially available, or get them using conventional methods with commercially available source material. Also an example of a common procedure And the General procedure I in the examples below.

The General scheme B

General procedure B

The compounds of formula (I-a2) (compounds of formula (I-a), where R7represents NReRf) can be obtained during the reaction chlorobenzimidazole derivative of the formula (I-A1) (compounds of formula (I-a), where R7represents Cl) with a substituted primary or secondary a commercially available amine. Derivatives of the formula (I-A1) is obtained by treatment of compounds of formula (I-B1) (compounds of formula (I-b), where R5=N) with POCl3at high temperature (e.g. reflux). In addition, the General procedure B is illustrated by the examples below.

The General scheme In

The General procedure In

The General procedure is suitable for producing compounds of the formula (1-b), where R1and R5other than N. Such compounds can be obtained during alkylation or arilirovaniya the compounds of formula (I-B1), where R1is not H, obtained according to General procedure A, with a commercially available electrophilic reagent R5-X, where R5represents a C1-6is alkyl or aryl, and X represents halo. In addition, the General procedure illustrated In the examples below.

The General scheme G

General procedure G

The compounds of formula (I) with R1different from H can be obtained during the N-deprotonation indole derivative (IV) (compounds of formula (I), where R1represents H) followed by treatment with an electrophilic reagent R1-X (where X is a leaving group such as halo), which is either commercially available or easily obtained according to well known in this field means and from commercially available starting materials. Derivatives (IV) are obtained using the method described in the General schemes and procedures a, B and C. the General scheme of G then further illustrates General procedures II, III and IV.

The General scheme D

General procedure D

Treatment of indole derivative (V-a) triperoxonane anhydride in DMF gives the intermediate compound (VI), which can then hydrolyze with the aqueous hydroxide solution n is sodium, receiving a derivative of indole-3-carboxylic acid (II-a). Alternatively, (VI) can interact with an electrophilic reagent R1-X education (VII), which is then converted into the corresponding carboxylic acid derivative (II-b) with NaH/N2Oh in DMF (see J. Org Chem., 1993, 10, 2862). Alternatively, the intermediate compound (VII) can be obtained by processing the indole derivative (V-b) with triperoxonane anhydride in a suitable solvent, such as DMF, dichloromethane or 1,2-dichloroethane. It may be effective to add a suitable base.

General procedure I: amide combination

General procedure 1 represents an embodiment of a General procedure A. To a stirred solution derived indole-3-carboxylic acid (1 mmol) in 10 ml of CH3Cl2added (1.3 mmol) EDC (1,2-dichloroethane), (1.3 mmol), HOBt, (1.3 mmol) Et3N and (1 mmol) of the amine derivative. The mixture was stirred over night at room temperature, then poured into water and was extracted with CH2Cl2. The combined organic phase was dried over Na2SO4and concentrated in vacuum. Flash chromatography or preparative HPLC gave specified in the header of the connection.

General procedure II, the alkylation

To a stirred solution of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it in D the f was added 2.1 equiv. NaH (60% in oil). The mixture was stirred at room temperature for 30 minutes before addition of the electrophilic reagent R1-X (1.1 equiv.). The mixture was stirred for another 14 hours at 60°C and then poured into water and was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4and concentrated in vacuum. Purification using preparative HPLC gave the corresponding derivatives.

General procedure III: acylation

A solution of indole in anhydrous DMF was treated with sodium hydride (1.05 equiv.) and was stirred for 15 minutes at room temperature, then treated with acid chloride (1.1 equiv.) and stirred at room temperature for 2 hours. Purification using preparative HPLC gave the desired product.

General procedure IV: sulfonylamine

A solution of indole in anhydrous DMF was treated with sodium hydride (1.05 equiv.) and was stirred for 15 minutes at room temperature, then treated with sulphonylchloride (1.1 equiv.) and stirred at room temperature for 2 hours. Purification using preparative HPLC gave the desired product.

Results - V1a activity

Materials and method:

V1a receptor human cloned using RT-PCR (polymerase chain reaction with reverse transcriptase) from total RNA human liver. Coding on sledovatelnot was subcloned into the expression vector after sequencing, to confirm the identity of the amplified sequence. For detection of the affinity of the compounds of the present invention to V1a receptor person carried out the analyses of the binding. Cell membranes were obtained from cells NECK, temporarily transfected with the expression vector and cultured in 20 liter fermentors according to the following Protocol.

50 g of cells resuspended in 30 ml of freshly prepared ice-lyse buffer (50 mm HEPES, 1 mm EDTA, 10 mm MgCl2brought to pH 7.4 + complete set of protease inhibitors (Roche Diagnostics)). Homogenize with Poltrona for 1 minute and exposed to ultrasound on ice for 2×2 minutes at 80% intensity (Vibracell ultrasonic device). The preparation is centrifuged for 20 minutes at 500 g at 4°C, the precipitate discarded and the supernatant centrifuged for 1 hour at 43000 g at 4°C (19000 rpm). Sediment resuspended 12.5 ml lyse buffer + 12.5 ml 20% sucrose and homogenized using Polytron within 1-2 minutes. The protein concentration was determined by Bradford method and aliquots stored at -80°C until use. For analyses of linkage 60 mg of beads of yttrium silicate SPA-analysis (Amersham) is mixed with an aliquot of the membrane in binding buffer (50 mm Tris, 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 10 mm MgCl2within 15 minutes with stirring. Then 50 μl of the mixture of beads / MEM is wound added to each well of 96-hole tablet, then 50 μl of 4 nm 3H-vasopressin (American Radiolabeled Chemicals). To measure total binding 100 ál of binding buffer added to the appropriate wells, for nonspecific binding of 100 μl of 8.4 mm cold vasopressin and for the studied compounds 100 μl of a serial solution of each compound in 2% DMSO. The tablet is incubated for 1 hour at room temperature, centrifuged for 1 minute at 1000 g and read on a Packard Top-Count. Units subtract nonspecific binding to each well and the data is normalized relative to the maximum specific binding, normalized to 100%. To calculate IR50build curve using nonlinear regression model (XLfit), and Kicalculated using the equation of Cheng-Prusova.

13
Connection exampleKi (nm)Connection exampleKi (nm)
1452812
3182922
463035
83125
9133315
1039349
1120355
1213366
1323715
1432382
1873918
1954013
2054114
2164218
221 4362
2364417
2424543
2520462
260,7475
275483

The compounds of formula (I)and their pharmaceutically acceptable acid salt additive can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, can be effective rectal administration, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

The compounds of formula (I) and their pharmaceutically acceptable acid additive salts can be processed with pharmaceutically inert inorganic or organic excipients for the manufacture of tablets, tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, coated tablets and hard gelatin capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like

Suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

The dosage may vary within wide limits and, of course, must be chosen according to individual potrebnostyam each case. In General, in the case of oral administration a daily dosage of approximately 10-1000 mg per person of compounds of General formula I should be appropriate, although the upper limit can also be exceeded when this is necessary.

The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

Example

Tablets of the following composition are produced in the usual way:

mg tablet
The active ingredient5
Lactose45
Corn starch15
Microcrystalline cellulose34
Magnesium stearate1
Weight pills100

Example B

Make capsules of the following composition:

mg/capsule
The active ingredient10
Lactose 155
Corn starch30
Talc5
The weight of the contents of the capsules200

The active ingredient, lactose and corn starch are first mixed in a mixer and then into the shredder. The mixture is transferred into a blender, add the powder and mix thoroughly. The mixture is filled through the machine hard gelatin capsules.

The example In

Make suppositories of the following composition:

mg/supp.
The active ingredient15
The weight of the suppository1285
Only1300

The weight of the suppository is melted in a glass or steel vessel, mix thoroughly and cooled to 45°C. Then add it to the finely ground active ingredient and mix up until it is fully distributed. The mixture is poured into molds for suppositories suitable size, leave to cool, then suppositories are removed from the forms and individually wrapped in waxed paper or metal is ical foil.

Examples

General procedure I: amide combination

General procedure 1 represents an embodiment of a General procedure A. To a stirred solution derived indole-3-carboxylic acid (1 mmol) in 10 ml of CH2Cl2added (1.3 mmol) EDC (1,2-dichloroethane), (1.3 mmol), HOBt, (1.3 mmol) Et3N and (1 mmol) of the amine derivative. The mixture was stirred over night at room temperature, then poured into water and was extracted with CH2Cl2. The combined organic phase was dried over Na2SO4and concentrated in vacuum. Flash chromatography or preparative HPLC gave specified in the header of the connection.

Examples of compounds of formula I-and

Example 1

(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanon

A mixture of 0.45 g (0.97 mmol) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-she (the receipt of which is described below) and phosphorus oxychloride (6 ml) was stirred at 100°C for 2 hours and then cooled. The reaction mixture was poured into ice water, 10 N. NaOH was added to pH 14, and the mixture was extracted with AcOEt. The combined organic phase was dried over Na2SO4and concentrated in vacuum. Recrystallization in Et3O gave 0.32 g (68%) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanone in videbaek crystals. ES-MS m/e (%): 483,6 (M+H+).

1-[1-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available)

- Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (receipt of which is described below).

ES-MS m/e (%): 463,2 (M+H+).

1-Benzyl-2-methyl-1H-indole-3-carboxylic acid

Using the procedure described below in example 8, from 2-methyl-1H-indole-3-carboxylic acid (described in J.Heterocyclic Chem. 1977, 14, 1123) was obtained 1-benzyl-2-methyl-1 H-indole-3-carboxylic acid.

Example 2

(1-Benzyl-2-methyl-1H-indol-3-yl)-{4-[2-(4-methyl-piperazine-1-yl)-benzimidazole-1-yl]-piperidine-1-yl}-metano

A mixture of 20 mg level (0.041 mmol) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanone (the receipt of which is described in example 1) and N-methyl-piperazine was heated in a sealed tube at 90°C for 8 hours, cooled to room temperature and then concentrated in vacuum. Flash chromatography (CH2Cl2/Meon 9/1) gave 5 mg (22%) (1-benzyl-2-methyl-1H-indol-3-yl)-{4-[2-(4-methyl-piperazine-1-yl)-benzimidazole-1-yl]-piperidine-1-yl}-methanone in the form of a white solid.

ES-MS m/e (%): 547,5 (M+H+).

Example 3

(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-morpholine-4-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanon

Using akuu same procedure that described in example 2, 30 mg (0,062 mmol) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanone (the receipt of which is described in example 1) and research (0.5 ml) received 20 mg (60%) (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-morpholine-4-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanone in the form of a light yellow solid.

ES-MS m/e (%): 534,2 (M+H+).

Example 4

(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-piperidine-1-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanon

Using the same procedure as described in example 2, 30 mg (0,062 mmol) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanone (the receipt of which is described in example 1) and piperidine (0.5 ml) received 18 mg (54%) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-piperidine-1-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanone in the form of a light yellow solid.

ES-MS m/e (%): 532,5 (M+H+).

Example 5

[4-(2-Chloro-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanon

Using the same procedure as described in example 1, from 1,700 g (of 4.54 mmol) 1-[1-(2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-she (the receipt of which is described in example 10) and phosphorus oxychloride (40 ml) was obtained 0.50 g (35%) [4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone in the form of a light brown solid.

ES-MS m/e (%): 393,2 (M+H+).

Note the p 6

[4-(2-Dimethylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanon

Using the same procedure as described in example 2. from 50 mg (to 0.127 mmol) [4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone (the receipt of which is described in example 5) and dimethylamine (1.5 ml, 5.6 M in tO) received 42 mg (43%) [4-(2-dimethylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indole-3-yl)-methanone in the form of a light yellow solid.

ES-MS m/e (%): 402,2 (M+H+).

Example 7

[4-(2-Methylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanon

Using the same procedure as described in example 2, 50 mg (to 0.127 mmol) [4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone (the receipt of which is described in example 5) and methylamine (1.5 ml, 8 M in EtOH) was obtained 76 mg (78%) of [4-(2-methylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone in the form of a light yellow solid.

ES-MS m/e (%): 388,1 (M+H+).

Examples of compounds of Formula 1-b

Example 8

1-[1-(1-Benzyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available)

- Acid: 1-benzyl-1H-indole-3-carboxylic acid (receipt of which is described below).

ES-MS m/e (%): 451,3 (M+H+).

1-Benzyl-1H-indol-3-to robonova acid

To a stirred solution of 0.50 g (3.10 mmol) 1 H-indole-3-carboxylic acid in 5 ml of DMF was added 0.27 g (of 6.75 mmol) NaH (60% in oil). The mixture was stirred at room temperature for 30 minutes and then added to 0.39 ml (or 3.28 mmol) benzylbromide. The mixture was stirred for another hour, then poured into water and was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4and concentrated in vacuum. Crystallization in Et2O gave 0,61 g (78%) of 1-benzyl-1H-indole-3-carboxylic acid as a white solid.

ES-MS m/e (%): 250 (M-H+).

Example 9

1-{1-[(1-Benzyl-2-methyl-1H-indol-3-yl)carbonyl]piperidine-4-yl}-3-methyl-1,3-dihydro-2H-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-methyl-3-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (described in WO 0214315),

- Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (described in example 1).

ES-MS m/e (%): 479,4 (M+H+).

Example 10

1-[1-(2-Methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 2-Methyl-1H-indole-3-carboxylic acid (described in Chem J.Heterocyclic. 1977, 14, 1123).

ES-MS m/e (%): 375,2 (M+H+).

Example 11

1-[1-(1-Isopropyl-6-methoxy-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-the n

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (described in US 20040067939).

ES-MS m/e (%): 433,6 (M+H+).

Example 12

1-[1-(6-Fluoro-1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (described in US 20040067939).

ES-MS m/e (%): 421,5 (M+H+).

Example 13

1-[1-(6-Chloro-1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (described in US 20040067939).

ES-MS m/e (%): 437,5 (M+H+).

Example 14

1-[1-(1-Isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 1-isopropyl-1H-indole-3-carboxylic acid (described in J. Med. Chem. 1994, 37, 2090).

ES-MS m/e (%): 403,5 (M+H+).

Example 15

1-[1-(1-Methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Mednoe combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 1-methyl-1H-indole-3-carboxylic acid (commercially available).

ES-MS m/e (%): 375,5 (M+H+).

Example 16

1-[1-(1H-Indol-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 1H-indole-3-carboxylic acid (commercially available).

ES-MS m/e (%): 361,2 (M+H+).

Example 17

1-{1-[2-(Pyrrolidin-1-carbonyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 2-(pyrrolidin-1-carbonyl)-1H-indole-3-carboxylic acid (getting described below).

ES-MS m/e (%): 456,4 (M+H+).

a) (1H-Indol-2-yl)-pyrrolidin-1-yl-metano

To mix the solution 0,300 g (of 1.86 mmol) of 1H-indole-2-carboxylic acid in CH2Cl2(10 ml) was added 0,428 g (of 2.23 mmol) EDC, 0,302 g (of 2.23 mmol) HOBt, and 0.28 ml (2.04 mmol) Et3N and 0.17 ml (2.04 mmol) of pyrrolidine. The reaction mixture was stirred at room temperature overnight, then poured into water and was extracted with CH2Cl2. The combined organic phase was dried over Na2SO2and concentrated in vacuum. recristallization in Et 2O gave 0.31 g (78%) (1H-indol-2-yl)-pyrrolidin-1-yl-methanone in the form of white crystals.

b) 2-(Pyrrolidin-1-carbonyl)-1H-indole-3-carboxylic acid

Using the procedure described in J. Med. Chem. 1991, 34, 140, 100 mg (0.46 mmol) of (1H-indol-2-yl)-pyrrolidin-1-yl-methanone received 28 mg (23%) of 2-(pyrrolidin-1-carbonyl)-1H-indole-3-carboxylic acid as a light brown solid.

ES-MS m/e (%): 257 (M+H+).

Example 18

1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 6-chloro-1H-indole-3-carboxylic acid (described below).

ES-MS m/e (%): 395,4 (M+H+).

6-Chloro-1H-indole-3-carboxylic acid

Using the procedure described in J. Med. Chem. 1991, 34, 140, 7.0 g (0.046 mmol) 6-chloro-1H-indole was obtained 5,80 g (64%) of 6-chloro-1H-indole-3-carboxylic acid as a light brown solid.

ES-MS m/e (%): 194 (M+H+).

Example 19

1-[1-(6-Chloro-5-fluoro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 6-Chloro-5-fluoro-1H-indole-3-carboxylic acid (receipt of which is described below).

ES-MS m/e (%): 413,2 (M+H+).

a) 6-Chloro-5-fluoro-1H-indole:

The trail of the procedure, described in WO 9747598, from 6-Chloro-5-fluoro-1H-indole-2,3-dione was obtained 6-Chloro-5-fluoro-1H-indole.

b) 6-Chloro-5-fluoro-1H-indole-3-carboxylic acid:

Following the procedure described in J. Med. Chem. 1991, 34, 140, 0.25 g (1,47 mmol) 6-chloro-5-fluoro-1H-indole was obtained 0.35 g (90%) of 6-chloro-5-fluoro-1H-indole-3-carboxylic acid as a light brown solid.

ES-MS m/e (%): 213 (M+H+).

Example 20

1-[1-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-he

To a mixed solution of 20 mg (0,043 mmol) 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-she (the receipt of which is described below) in DMF (3 ml) at room temperature was added 2.0 mg (0,051 mmol) NaH (60% in oil). The mixture was stirred for 20 minutes and then was added 5.6 mg (0,051 mmol) (2-chloro-ethyl)-dimethyl-amine in 1 ml DMF. The mixture was stirred for additional 5 hours at 50°C, then poured into water and was extracted with ethyl acetate. The combined organic phase was dried over Na2SO2and concentrated in vacuum. Flash chromatography (CH2Cl2/Meon 8/2) gave 12 mg (50%) 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-it is in the form of a viscous oil.

ES-MS m/e (%): 536,2 (M+H+).

1-[1-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he

And ignoe combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (described in example 1).

ES-MS m/e (%): 463,2 (M+H+).

Example 21

{6-Chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile

To a mixed solution of 40 mg (0,101 mmol) 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-she (the receipt of which is described in example 18) in 5 ml DMF was added 4.2 mg (0,105 mmol) NaH (60% in oil). The mixture was stirred at room temperature for 30 minutes and then added to 8.3 mg (0.11 mmol) of chloroacetonitrile. The mixture was stirred for another hour, then poured into water and was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4and concentrated in vacuum. Preparative HPLC gave 6 mg (14%) of {6-chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile as a white solid.

ES-MS m/e (%): 434 (M+H+).

Example 22

1-{1-[2-(2-Methyl-butyryl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available).

- Acid: 2-(2-methyl-butyryl)-1H-indole-3-carboxylic acid (commercially available),

ES-MS m/e (%): 445 (MH +).

Example 23

1-[1-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (described herein above).

ES-MS m/e (%): 463,0 (M+H+).

Example 24

1-[1-(1-Benzyl-6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

a) 6-Chloro-1H-indole-3-carboxylic acid

Using the procedure described in J. Med. Chem. 1991, 34, 140, 7.0 g (0.046 mmol) 6-chloro-1H-indole was obtained 5,80 g (64%) of 6-chloro-1H-indole-3-carboxylic acid as a light brown solid.

ES-MS m/e (%): 194 (M+H+).

b) Methyl ester of 6-chloro-1H-indole-3-carboxylic acid

1 g of 6-chloro-1H-indole-3-carboxylic acid was heated under reflux in the Meon with 3 drops of concentrated H2SO4throughout the night. Concentration in vacuo gave specified in the title compound in quantitative yield.

C) 6-Chloro-1-(2-dimethylamino-ethyl-1H-indole-3-carboxylic acid

To a mixed solution of 80 mg (0.38 mol) of methyl ester of 6-chloro-1H-indole-3-carboxylic acid in 5 ml of DMF was added 50 mg of NaH (3 equiv., 55% in oil) at room temperature. After 20 minutes, 66 mg (0.45 mmol, 1.2 equiv.) hydrochloride (2-chloro-ethyl)-dimethyl-amine was added and continued peremeshivaete over night at 60°C. Extraction with EtOAc / aq. NH4Cl and subsequent flash chromatography gave 45 mg of the crude methyl ester of 6-chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carboxylic acid.

The ether was subjected to hydrolysis in a mixture of N2O/THF/Meon (ratio 1:1:1) with LiOH·H2O (3 equiv.). The reaction mixture was stirred at 40°C during the night. The acid was extracted with EtOAc several times and the combined organic phase was dried over Na2SO4. Recrystallization in Et2O gave 35 mg (total yield 34%) indicated in the title compound as a white solid.

ES-MS m/e (%): 265,8 (M+H+).

g) 1-[1-(1-Benzyl-6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Following General procedure I, the combination of 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-she (commercially available) with 1-benzyl-6-chloro-1H-indole-3-carboxylic acid gave specified in the header of the connection.

ES-MS m/e (%): 485,5 (M+H+).

Example 25

1-[1-(1-Cyclohexylmethyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-he

Following General procedure I, the combination of 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-she (commercially available) 1-cyclohexylmethyl-1H-indole-3-carboxylic acid (described in Bioorganic & Medicinal Chemistry Letters (2005), 15(11), 2734-2737) gave specified in the header of the connection.

ES-MS m/e (%): 457,6 (M+H+).

Example 26

1-{1-[6-Chloro-1-(2-dimethylaminoethyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 6-chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carboxylic acid (described below).

ES-MS m/e (%): 466,0 (M+H+).

Example 27

1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-he

a) tert-Butyl ester 4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylic acid

To a stirred solution of 300 mg (1.4 mmol) of 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-she (commercially available) in 15 ml of CH2Cl2added 34 mg (0.28 mmol, 0.2 equiv.) DMAP (dimethylaminopyridine), 190 μl (1.4 mmol, 1 equiv.) Et3N and 301 mg (1.4 mmol, 1 equiv.) (VOS)2O. After stirring at room temperature overnight, the reaction mixture was poured into water and was extracted with CH2Cl2. Column chromatography (SiO2, EtOAc / heptane 1:1) gave 360 mg (82%) indicated in the title compound as a white solid.

b) 1-(2-Dimethylamino-ethyl)-3-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he

To a solution of 320 mg (1 mmol) of tert-butyl ester 4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylic acid in 5 ml of DMF was added 218 mg (1.5 mmol, 1.5 equiv.) hydrochloride (2-chloro-ethyl)-dimethyl-amine and 418 mg (3 mmol, 3 equiv.) K2CO3. Continued to mix n and 60°C during the night. The mixture was poured into water and the product was extracted with EtOAc. The organic phase was dried over Na2SO4and concentration in vacuo gave the crude tert-butyl ester 4-[3-(2-dimethylamino-ethyl)-2-oxo-2,3-dihydro-benzimidazole-1-yl]-piperidine-1-carboxylic acid as off-white solid. This crude material was then dissolved in 5 ml of CH2Cl2and 1 ml of TFU was added. After 2 hours at room temperature the reaction was suppressed by adding aq. NaHCO3(pH 9), and the product was extracted with CH2Cl2. Concentration in vacuo gave 200 mg (61%) indicated in the title compound as a white solid.

ES-MS m/e (%): 289,3 (M+H+).

C) 1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-he

Amide combination, following the General procedure I:

- Amine: 1-(2-dimethylamino-ethyl)-3-piperidine-4-yl-1,3-dihydro-benzimidazole-2-it,

- Acid: 6-chloro-1H-indole-3-carboxylic acid.

ES-MS m/e (%): 466,0 (M+H+).

Example 28

1-{1-[6-Chloro-1-(3-fluoro-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following the General procedure III, the acylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 3-fluoro-benzoyl chloride gave specified in the header of the connection.

ES-MS m/e (%): 517,4 (M+H+).

Example 29

1-(1-{6-Chloro-1-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2-bromo-1-(3-fluoro-phenyl)-atenonol gave specified in the header of the connection.

ES-MS m/e (%): 531,3 (M+H+).

Example 30

1-{1-[6-Chloro-1-(2-fluoro-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following the General procedure III, the acylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2-fluoro-benzoyl chloride gave specified in the header of the connection.

ES-MS m/e (%): 517,4 (M+H+).

Example 31

1-{1-[6-Chloro-1-(2,3-debtor-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following the General procedure III, the acylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2,3-debtor-benzoyl chloride gave specified in the header of the connection.

ES-MS m/e (%): 535,4 (M+H+).

Example 32

1-{1-[6-Chloro-1-(3,5-debtor-benzazolyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following General procedure IV, sulfonylamine 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 3,5-debtor-benzosulphochloride Yes the Alo specified in the header of the connection.

ES-MS m/e (%): 571,4 (M+H+).

Example 33

1-{1-[6-Chloro-1-(3,5-debtor-benzyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 1-chloromethyl-3,5-differentlal gave specified in the header of the connection.

ES-MS m/e (%): 521,4 (M+H+).

Example 34

1-{1-[6-Chloro-1-(3-fluoro-benzyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 1-chloromethyl-3-fluoro-benzene gave specified in the header of the connection.

ES-MS m/e (%): 503,4 (M+H+).

Example 35

1-(1-{6-Chloro-1-[2-(2,5-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2-chloro-1-(2,5-debtor-phenyl)-atenonol gave specified in the header of the connection.

ES-MS m/e (%): 549,4 (M+H+).

Example 36

1-(1-{6-Chloro-1-[2-(2,4-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it has what I sell 2-chloro-1-(2,4-debtor-phenyl)-atenonol gave specified in the header of the connection.

ES-MS m/e (%): 549,4 (M+H+).

Example 37

1-{1-[6-Chloro-1-(3,5-debtor-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

Following the General procedure III, the acylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 3,5-debtor-benzoyl chloride gave specified in the header of the connection.

ES-MS m/e (%): 535,4 (M+H+).

Example 38

1-(1-{6-Chloro-1-[2-(2-fluoro-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2-chloro-1-(2-fluoro-phenyl)-atenonol gave specified in the header of the connection.

ES-MS m/e (%): 531,4 (M+H+).

Example 39

1-(1-{6-Chloro-1-[2-(3,4-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2-chloro-1-(3,4-debtor-phenyl)-atenonol gave specified in the header of the connection.

ES-MS m/e (%): 549,4 (M+H+).

Example 40

1-{1-[6-Chloro-1-(3,5-debtor-phenyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

a) 1-{1-[6-Chloro-1-(3,5-debtor-phenyl)-1H-indol-3-yl]-2,2,2-Cryptor-alanon

To a solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-Cryptor-ethanone (description is in US 2004067939) in CH 2Cl2(in the presence of 0.4 nm molecular sieves) was added anhydrous Cu(SLA)2(2 equiv.), 3,5-diftorhinolonom acid (3 equiv.) and pyridine (4 equiv.). The reaction mixture was stirred at room temperature for 16 hours in air, filtered through dekalim, washed with CH2Cl2and concentrated in vacuum. Chromatography (hexane / EtOAc 9:1) gave specified in the title compound with yield of 71%.

ES-MS m/e (%): 360,0 (M+H+).

b) 6-Chloro-1-(3,5-debtor-phenyl)-1H-indole-3-carboxylic acid

A suspension of 1-[6-chloro-1-(3,5-debtor-phenyl)-1H-indol-3-yl]-2,2,2-Cryptor-ethanone 3 N. aqueous NaOH was stirred at 70°C for 48 hours. After washing with CH2Cl2the aqueous phase was acidified to pH 1 and extracted with CH2Cl2. Concentration in vacuo gave specified in the title compound with yield of 70%.

ES-MS m/e (%): 306,0 (M+H+).

C) 1-{1-[6-Chloro-1-(3,5-debtor-phenyl)-1H-indol-3-carbonyl-piperidine-4-yl}1,3-dihydro-benzimidazole-2-he

Following General procedure I, the combination of 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-she (commercially available) with 6-chloro-1-(3,5-debtor-phenyl)-1H-indole-3-carboxylic acid gave specified in the header of the connection.

ES-MS m/e (%): 507,0 (M+H+).

Example 41

1-{1-[6-Chloro-1-(piperidine-1-carbonyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-he

To a stirred solution of 30 mg of 1-[1-6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it 1 ml of DMF was added 1.1 equiv. NaH (55% in oil). The reaction mixture was stirred for 30 minutes before addition of 1.2 equiv. piperidine-1-carbonylchloride. The crude reaction mixture was purified using preparative HPLC, receiving 21 mg specified in the title compound as a yellow powder.

ES-MS m/e (%): 506,4 (M+H+).

Example 42

1-{1-[6-Chloro-1-(2-oxo-2-piperidine-1-yl-ethyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-3-(2-oxo-2-piperidine-1-yl-ethyl)-1,3-dihydro-benzimidazole-2-he

To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it 1 ml of DMF was added 1.1 equiv. NaH (55% in oil). The reaction mixture was stirred for 30 minutes before addition of 1.2 equiv. 2-chloro-1-piperidine-1-yl-ethanone. The crude reaction mixture was directly purified using preparative HPLC, receiving 4 mg specified in the title compound as a white powder.

ES-MS m/e (%): 645,0 (M+H+).

Example 43

2-{6-Chloro-3-[4-(3-diethylcarbamoyl-2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-diethyl-ndimethylacetamide

To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it 1 ml of DMF was added 1.1 equiv. NaH (55% in oil). The reaction mixture was stirred for 30 minutes before addition of 1.2 equiv. 2-chloro-N,N-diethyl-ndimethylacetamide. The crude reaction mixture was purified through the Yu preparative HPLC, receiving 6 mg specified in the title compound as a white powder.

ES-MS m/e (%): 621,0(M+H+).

Example 44

1-(1-{6-Chloro-1-[2-(3,5-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with commercially available 2-chloro-1-(3,5-debtor-phenyl)-atenonol gave specified in the header of the connection.

ES-MS m/e (%): 549,4 (M+H+).

Example 45

1-(1-{6-Chloro-1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-he

Following General procedure II, the alkylation of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-one with 2-bromo-1-(5-methyl-2-phenyl-oxazol-4-yl)-atenonol (described in Journal of Medicinal Chemistry (1992), 35(14), 2617-26) gave specified in the header of the connection.

ES-MS m/e (%): 594,4 (M+H+).

Example 46

2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide

To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it 1 ml of DMF was added 1.1 equiv. NaH (55% in oil). The reaction mixture was stirred for 30 minutes before addition of 1.2 equiv. 2-chloro-N,N-dimethyl-ndimethylacetamide. The crude reaction mixture was purified using preparative HPLC to give 10 mg of the criminal code the data in the title compound as a white powder.

ES-MS m/e (%): 480,5 (M+H+).

Example 47

2-{6-Chloro-5-methyl-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide

a) 1-(6-Chloro-5-methyl-1H-indol-3-yl)-2,2,2-Cryptor-alanon

Using the procedure described in J. Med. Chem. 1991, 34, 140, 0,250 g (0.002 mol) of 6-Chloro-5-methyl-1H-indole was obtained 0,38 g (96%) indicated in the title compound as a white solid.

b) 2-[6-Chloro-5-methyl-3-(2,2,2-Cryptor-acetyl)-indol-1-yl]-N,N-dimethyl-ndimethylacetamide

To a stirred solution of 1-(6-chloro-5-methyl-1H-indol-3-yl)-2,2,2-Cryptor-ethanone (0,38 g) in 10 ml of DMF at 0°C was added 64 mg (1.1 equiv.) NaH (60% in oil). The mixture was stirred for 30 minutes before addition of 0.16 ml (1.1 equiv.) dimethylamino-acetylchloride. The mixture was stirred for another hour, then poured into water and was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4and concentrated in vacuum, receiving 300 mg (60%) indicated in the title compound as a white solid.

C) 6-Chloro-1-dimethylcarbamoyl-5-methyl-1H-indole-3-carboxylic acid

Using a procedure similar to that described in J. Med. Chem. 1991, 34, 140, 0,280 g of 2-[6-chloro-5-methyl-3-(2,2,2-Cryptor-acetyl)-indol-1-yl]-N,N-dimethyl-ndimethylacetamide was obtained 0.18 g (76%) indicated in the title compound as a white solid.

g), 2-{6-Chloro-5-methyl-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-PI is Eridan-1-carbonyl-indol-1-yl}-N,N-dimethyl-ndimethylacetamide

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 6-chloro-1-dimethylcarbamoyl-5-methyl-1H-indole-3-carboxylic acid.

ES-MS m/e (%): of 494.5 (M+H+).

Example 48

2-{5,6-Dichloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide

a) 1-(5,6-Dichloro-1H-indol-3-yl)-2,2,2-Cryptor-alanon

Using the procedure described in J. Med. Chem. 1991, 34, 140, 0,120 g (0.64 mmol) of 5,6-dichloro-1H-indole was obtained 0.11 g (59%) indicated in the title compound as a white solid.

b) 2-[5,6-Dichloro-3-(2,2,2-Cryptor-acetyl)-indol-1-yl]-N,N-dimethyl-ndimethylacetamide

To a stirred solution of 1-(5,6-dichloro-1H-indol-3-yl)-2,2,2-Cryptor-ethanone (0.11 g) in 3 ml of DMF at 0°C was added 18 mg (1.05 equiv.) NaH (60% in oil). The mixture was stirred for 30 minutes and then was added 0.04 ml (1.0 equiv.) dimethylamino-acetylchloride. The mixture was stirred for another hour, then poured into water and was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4and concentrated in vacuum, receiving 112 mg (78%) indicated in the title compound as a white solid.

C) 5,6-Dichloro-1-dimethylcarbamoyl-1H-indole-3-carboxylic acid

Using a similar procedure described in J. Meet. Chem. 1991, 34,140, 0,112 g of 2-[5,6-dichloro-3-(2,2,2-Cryptor-acetyl)-indol-1-the l]-N,N-dimethyl-ndimethylacetamide received 0,047 g (49%) indicated in the title compound as a white solid.

g) 2-{5,6-Dichloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl)-N,N-dimethyl-ndimethylacetamide

Amide combination, following the General procedure I:

Amin: 1-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he (commercially available),

- Acid: 5,6-dichloro-1-dimethylcarbamoyl-1H-indole-3-carboxylic acid.

ES-MS m/e (%): 515,3 (M+H+).

1. Compounds of General formula (I)

where the dotted line is absent or represents a double bond;
R1represents H,
or represents a C1-6-alkyl, possibly substituted by a group CN,
or represents phenyl or sulfanilyl, which is substituted by one or more groups,
or represents -(CH2)m-Rawhere Rais:
NRiRii,
With3-6-cycloalkyl, 6-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, aryl, possibly substituted by one or more groups,
or represents -(CH2)n-(CO)-Rbor -(CH2)n(SO2)-Rbwhere Rbis:
NRiRii,
5-6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms, chosen is different from nitrogen, oxygen, the rest are carbon atoms, aryl or 5-or 6-membered heteroaryl, which denotes an aromatic ring containing as ring members with one or two heteroatoms selected from N or O, and the rest are carbon atoms; which may be substituted by one or more groups,
R2represents one or more than one H, halo, C1-6-alkyl, C1-6-alkoxy,
R3represents H, or a -(CO)-Rcwhere Rcis:
C1-6-alkyl,
5-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, possibly substituted C1-6-alkyl,
or represents a C1-6-alkyl;
R4represents H;
R5represents H, C1-6-alkyl, -(CH2)mNRiRii, -(CH2)n-(CO)-Rbwhere Rbrepresents NRiRiior 6-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, when the dotted line is absent
or is absent when the dotted line represents a double bond;
R6absent when the dotted line represents a double bond;
R 7represents a
Cl or
NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rftogether with the nitrogen atom to which they are attached, form a 6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, and the rest are carbon atoms;
which may be substituted C1-6-alkyl,
or R6and R7together form a C=O group, when the dotted line is absent;
Represents a halo, With1-6-alkoxy, (CRiiiRiv)nis phenyl;
Riand Riirepresent H, C1-6-alkyl, -C(O)-C1-6-alkyl;
Riiiand Rivrepresents a C1-6-alkyl;
m is 1-2;
n is 0-1;
and their pharmaceutically acceptable salts.

2. Compounds according to claim 1 of General formula (I), where:
the dotted line is absent or represents a double bond;
R5represents H, C1-6-alkyl, -(CH2)m-NRiRiiwhen the dotted line is absent, or is absent when the dotted line represents a double bond;
and R1, R2, R3, R4, R6and R7are as defined in claim 1, and their pharmaceutically acceptable salts.

3. With the unity according to claim 1 of formula (I), where:
the dotted line is absent or represents a double bond;
R1represents N or
With1-6-alkyl, possibly substituted by a group CN or
phenyl, or
sulfanilyl, or
-(CH2)m-Rawhere Rarepresents a C3-6-cycloalkyl, 6-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, aryl, possibly substituted by one or more substituents selected from the group consisting of:
halo, C1-6-alkoxy, and phenyl,
-(CH2)m-NRiRiior
-(CH2)n-(CO)-Rbwhere Rbrepresents aryl or 5-or 6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, and the rest are carbon atoms;
R2represents one or more than one H, halo, C1-6-alkyl, C1-6-alkoxy;
R3represents N or
-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, possibly substituted With1-6-alkyl, or
C1-6-al is the sludge;
R4represents H;
R5represents H, C1-6-alkyl, -(CH2)m-NRiRiiwhen the dotted line is absent, or is absent when the dotted line represents a double bond;
R6absent when the dotted line represents a double bond;
R7represents a
Cl or
NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rftogether with the nitrogen atom to which they are attached, form a 6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms, selected from nitrogen and oxygen, the rest are carbon atoms,
or R6and R7together form a C=O group, when the dotted line is absent;
Riand Riiindependently from each other selected from H, C1-6-alkyl;
m is 1-2;
n is 0-1;
and their pharmaceutically acceptable salts.

4. Connection pop formula (I-a):

where R1-R4and R7are as defined in any one of claims 1 to 3.

5. Compounds according to claim 4 of the formula (I-a)where:
R1represents N or
C1-6-alkyl, possibly substituted by a group CN or
phenyl, or
sulfanilyl, or
-(CH2)m-Ra/sup> where Rarepresents a C3-6-cycloalkyl, 6-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, aryl, possibly substituted by one or more substituents selected from the group consisting of:
halo, C1-6-alkoxy, and phenyl,
-(CH2)m-NRiRiior
-(CH2)n-(CO)-Rbwhere Rbrepresents aryl, 5 or 6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, and the rest are carbon atoms;
R2represents one or more than one H, halo, C1-6-alkyl, C1-6-alkoxy;
R3represents N or
-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, possibly substituted C1-6-alkyl, or
With1-6-alkyl;
R4represents H;
R7represents Cl or
NReRfwhere Reand Rfrepresent N or C1-6-alkyl, or Reand Rftogether with the nitrogen atom to which they are attached, about atout 6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, and the rest are carbon atoms, which may be substituted With1-6-alkyl;
Riand Riiindependently from each other selected from H, C1-6-alkyl;
m is 1-2;
n is 0-1;
and their pharmaceutically acceptable salts.

6. Compounds according to claim 5 of the formula (I-a), which is selected from the group consisting of:
(1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-methanone;
(1-benzyl-2-methyl-1H-indol-3-yl)-{4-[2-(4-methyl-piperazine-1-yl)-benzimidazole-1-yl]-piperidine-1-yl}-methanone;
(1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-morpholine-4-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanone;
(1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-piperidine-1-yl-benzimidazole-1-yl)-piperidine-1-yl]-methanone;
[4-(2-chloro-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone;
[4-(2-dimethylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone and
[4-(2-methylamino-benzimidazole-1-yl)-piperidine-1-yl]-(2-methyl-1H-indol-3-yl)-methanone.

7. The compound according to claim 1 of formula (I-b):

where R1-R5are as defined in any one of claims 1 to 3.

8. The connection according to claim 7 of the formula (I-b), where:
R1represents N or
C1-6the alkyl may samisen the th group CN, or
phenyl, or
sulfanilyl, or
-(CH2)m-Rawhere Rarepresents a C3-6-pilooski, 6-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, aryl, possibly substituted by one or more substituents selected from the group consisting of:
halo, C1-6-alkoxy and phenyl,
-(CH2)m-NRiRiior
-(CH2)n-(CO)-Rbor -(CH2)n-(SO2)-Rbwhere Rbis:
NRiRii,
5-6-membered heteroseksualci, which means a monovalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, and the rest are carbon atoms, aryl, 5 or 6-membered heteroaryl, which denotes an aromatic ring containing as ring members with one or two heteroatoms selected from N or O, and the rest are carbon atoms, possibly substituted by one or more halo, C1-6-alkoxy or (CRiiiRiv)n-phenyl;
R2represents one or more than one H, halo, C1-6alkyl, C1-6-alkoxy;
R3represents N or
-(CO)-Rcwhere Rcrepresents a C1-6-alkyl, 5-membered hetaeras cycloalkyl, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms, possibly substituted With1-6-alkyl, or
C1-6-alkyl;
R4represents H;
R5represents H, C1-6-alkyl, -(CH2)m-NRiRiior -(CH2)n-(CO)-Rbwhere Rbrepresents NRiRiior 6-membered heteroseksualci, which means a monovalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms;
Riand Riiindependently from each other selected from H, C1-6-alkyl;
Riiiand Rivrepresent1-6-alkyl;
m is 1-2;
n is 0-1;
and their pharmaceutically acceptable salts.

9. The compound of claim 8 of formula (I-b), which are selected from the group consisting of:
1-[1-(1-benzyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-{1-[(1-benzyl-2-methyl-1H-indol-3-yl)carbonyl]piperidine-4-yl}-3-methyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[1-(2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-isopropyl-6-methoxy-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(6-fluoro-1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(6-chloro-1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-isopropyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1H-indol-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-{1-[2-(pyrrolidin-1-carbonyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(6-chloro-5-fluoro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-it;
{6-chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile;
1-{1-[2-(2-methyl-butyryl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-benzyl-6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-[1-(1-cyclohexylmethyl-1H-indole-3-carbonyl)-piperidine-4-yl]-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidine-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(3-fluoro-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-(1-{6-chloro--[2-(3-fluoro-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(2-fluoro-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(2,3-debtor-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(3,5-debtor-benzazolyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(3,5-debtor-benzyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(3-fluoro-benzyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-(1-{6-chloro-1-[2-(2,5-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
1-(1-{6-chloro-1-[2-(2,4-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(3,5-debtor-benzoyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-(1-{6-chloro-1-[2-(2-fluoro-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
1-(1-{6-chloro-1-[2-(3,4-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(3,5-debtor-phenyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(piperidine-1-carbonyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-1,3-dihydro-benzimidazole-2-it;
1-{1-[6-chloro-1-(2-oxo-2-piperidine-1-yl-ethyl)-1H-indole-3-carbonyl]-piperidine-4-yl}-3-(2-oxo-2-piperidine-1-yl-ethyl)-1,3-dihydro-benzimidazole-2-it;
2{3-[1-(6-chloro-1-diethylcarbamoyl-1H-indole-3-carbonyl)-piperidine-4-yl]-2-oxo-2,3-dihydro-benzimidazole-1-yl}-N,N-diethyl-ndimethylacetamide;
1-(1-{6-chloro-1-[2-(3,5-debtor-phenyl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
1-(1-{6-chloro-1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-2-oxo-ethyl]-1H-indole-3-carbonyl}-piperidine-4-yl)-1,3-dihydro-benzimidazole-2-it;
2-{6-chloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide;
2-{6-chloro-5-methyl-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide;
2-{5,6-dichloro-3-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-ndimethylacetamide.

10. The compound according to any one of claims 1 to 9 of the formula (I), (I-a) or (I-b), with activity relative to the V1a receptor.

11. Pharmaceutical composition having activity relative to the V1a receptor containing the compound of formula (I), (I-a) or (I-b) according to any one of claims 1 to 9.

12. The use of the compounds of formula (I), (I-a) or (I-b) according to any one of claims 1 to 9 to obtain drugs having activity relative to the V1a receptor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula: or to its pharmaceutically acceptable salt, where: Ar2 represents phenyl or pyridyl, each of which is substituted by 0-4 substituents, independently selected from R2; X and Z represent N; Y represents CRX; D represents N; F represents N, CH or carbon, substituted by substituent, representing R1 or R10; Rx in each case is independently selected from hydrogen, halogen, C1-C4alkyl, amino, cyano and mono- or di-(C1-C4alkyl)amino; R1 represents 0-3 substituents, independently selected from: (a) halogen, cyano and nitro; (b) groups of formula -Q-M-Ry; R10 represents one substituent, selected from: (a) groups of formula -Q-M-Ry; so that R10 is not hydroxy, amino or unsubstituted group, selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, C1-C6aloxy, C2-C6alkyl, ether, C2-C6alkanoyl, C3-C6alcanone, C1-C6halogenalkyl, C1-C6halogenoalkoxy, mono- or di-(C1-C6alkyl)amino, C1-C6alkylsulfonyl, mono- or di-(C1-C6alkyl)aminosulfonyl or mono- or di-(C1-C6alkyl)aminocarbonyl; each Q is independently selected from C0-C4alkylene; each M is independently absent or is selected from O, C(=O), OC(=O), C(=O)O, S(O)m, N(RZ), C(=O)N(Rz), C(=NH)N(Rz), N(Rz)C(=O), N(Rz)C(=NH), N(Rz)S(O)m, S(O)mN(Rz) and N[S(O)mRz]S(O)m, where m equals 2; and Rz in each case is independently selected from hydrogen, C1-C8alkyl and groups, which taken together with Ry, form possibly substituted (4-7)-member heterocycle; and each Ry independently represents hydrogen, C1-C8halogenalkyl, C1-C8alkyl, C2-C8alkenyl, (C3-C8carbocycle)C0-C4alkyl, ((4-7)-member heterocycle)C0-C4alkyl or taken together with Rz forms (4-7) member heterocycle, where each alkyl, carbocycle and heterocycle is substituted by 0-4 substituents, independently selected from hydroxy, halogen, amino, cyano, nitro, -COOH, aminocarbonyl, aminosulfonyl, C1-C6alkyl, C3-C7cecloalkyl, C2-C6alkyl ether, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C8alkoxy, C1-C8hydroxyalkyl, mono- and di-(C1-C6alkyl)aminocarbonyl, mono- and di-(C1-C6alkyl)aminosulfonyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkanoylamino and phenyl; so that Ry is not hydrogen, if Q represents C0alkyl and M is absent; each R2: (a) is independently selected from (1) hydroxyl, amino, cyano, halogen, -COOH, nitro and (2) C1-C6alkyl, (C3-C8cycloalkyl)C0-C4alkyl, C1-C6halogenalkyl; R3 is selected from: (1) hydrogen; (2) C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl; and (3) groups of formula: where L represents C0-C6alkylene; R5 and R6: (a) are independently selected from C1-C12alkyl, (C3-C8cycloalkyl)C0-C4alkyl; or (b) are combined with formation of (4-6)-member heterocycle, containing one or two heteroatoms independently selected from O and N; and where each of (2) and (3) is substituted by 0-4 substituents, independently selected from: C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl, each of which is substituted by 0-4 secondary substituents, independently selected from hydroxy, C1-C4alkyl and C1-C4alkoxy; and R4 represents 0-2 substituents, independently selected from C1-C3alkyl.

EFFECT: claimed are pharmaceutical compositions for modulation of capsaicin receptor activity and methods of applying said compounds for treatment of such disorders as pain, itch, cough, hiccup, urinary incontinence or obesity.

65 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a sodium salt N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide in form of a polymorph, characterised by peaks on an x-ray powder diffraction (XRD) pattern at approximately 22.38 and 23.38 degrees 2-theta. The invention also relates to methods of producing said polymorph and to a pharmaceutical composition based on said polymorph, having endothelin antagonist activity.

EFFECT: polymorphous form is more stable and can be used in medicine to treat pulmonary hypertension.

17 cl, 9 tbl, 31 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

FIELD: medicine, pharmaceutics.

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

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

19 cl, 18 tbl

Organic compounds // 2411239

FIELD: chemistry.

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

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

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

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

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole and indole derivatives or pharmaceutically acceptable salts of general formula 1, where m assumes values from 0 to 2; n equals 1, X denotes: -NRa-; -CRbRc-; or -C(O)-; where: Ra is hydrogen or C1-6alkyl; Rb is hydrogen or C1-6alkyl; Rc is hydrogen, C1-6alkyl, hydroxy; or Ar denotes: phenyl, possibly substituted with 1-2 halogens; or isoxazole, possibly substituted with C1-6alkyl; R1 is a group of formula p assumes values from 1 to 3; Y denotes: -O-; -NRd-; or -CReRf-; where Rd, Re and Rf each independently denotes hydrogen or C1-6alkyl; each R2 independently denotes: halogen; C1-6alkyl; R3 and R4 each independently denotes hydrogen or C1-6alkyl; R5 and R6 each independently denotes; and R7 and R8 each independently denotes hydrogen or C1-6alkyl; or one of R7 and R8 and one of R5 and R6 together with atoms to which they are bonded can form a 4-6-member ring; or one of R7 and R8 together with Rd and atoms to which they are bonded can form a 6-7-member ring; or one of R7 and R8 and one of Re and Rf together with atoms to which they are bonded can form a 5-6-member ring. The invention also relates to a pharmaceutical composition based on compounds of formula I-VI and use of the compounds of formula I-VI.

EFFECT: obtaining novel benzimidazole and indole derivatives with selective 5-and/or 6-HT2A receptor antagonist properties.

27 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel substituted imidazole compounds of formula I where values of radicals are given in description, as well as to their based on them pharmaceutical compositions.

EFFECT: formula I compounds, as well as their salts, esters and compositions based on them possess ability to inhibit protein of kinesin spindle (KSP) and can be used for treatment of cancer diseases.

40 cl, 15 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where: R1 denotes C1-C10alkyl, C3-C10cycloalkyl; R3 denotes H, halide; R4 denotes a 6-member monocyclic heteroaryl containing 1-2 nitrogen atoms, one of which can be oxidised, optionally substituted with a halide; n ranges from 0 to 3; provided that R1 denotes C3-C10cycloalkyl and/or R4 denotes a 6-member monocyclic heteroaryl optionally substituted with a halide and containing 2 ring N heteroatoms, one of which can be oxidised or pharmaceutically acceptable salt thereof.

EFFECT: obtaining peptidyl deformylase (PDF) inhibiting compounds.

12 cl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidinium derivatives of formula I

in enantiomer form or pharmaceutically acceptable salt thereof, where R1 and R3 each independently denotes cyclopentyl, cyclohexyl, phenyl; R2 denotes OH; R4 denotes C1-C4alkyl; R5 denotes C1alkyl, substituted with a CO-NH-R6 group; R6 denotes a 5-member unsaturated heterocyclic group containing one N atom and one O atom in the ring, a 6-member heterocyclic group containing two N atoms in the ring.

EFFECT: compounds can inhibit binding of aceylcholine with M3 muscarinic receptors, which facilitates their use in a pharmaceutical composition.

6 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

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

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

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

19 cl, 1 tbl, 24 ex

FIELD: chemistry.

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

,

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

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

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

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

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

54 cl, 412 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns methods of treating diseases with using VEGF antagonists. Substance of the invention involves application of a VEGF antagonist containing VEGFR1R2-FcΔ C1 (a) SEQ ID NO:4 in preparing a drug for hypertension reduction, in treating the diseases associated with administering the VEGF antagonist where the treatment is conducted by subcutaneous introduction.

EFFECT: advantage of the invention consists in reducing side effects associated with treating the diseases by administering the VEGF antagonist.

8 cl, 3 ex, 1 tbl

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