Indole-3-yl-carbonyl-spiro-piperidine derivatives

FIELD: medicine.

SUBSTANCE: invention refers to indole-3-yl-carbonyl-spiro-piperidine derivatives which have an effect of Vla-receptor antagonists and are presented by Formula I: where a tail spiropiperidine group A and residual R1, R2 and R3 are such as specified in the patent claim.

EFFECT: higher efficiency of applying the compounds in drugs effective in dysmenorrhea, hypertension, chronic heart failure, inadequate vasopressin secretion, hepatic cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxious and depressive disorders.

22 cl, 42 ex

 

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

,

where

And selected from the following groups (a), (b), (C), (d), (e) and (f):

X may be the same or different and represent CRiiiRiv, NRiiior, where in (a) only one X can represent Oh, and the other represents CRiiiRivor NRiii;

R1represents H,

C1-6-alkyl, possibly substituted by CN,

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

or represents -(CH2)m-Rawhere Rarepresents:

ORi,

NRiRii,

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

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

C1-6-alkyl,

With1-6-alkoxy,

With3-6-cycloalkyl,

-(CH2)m-NRiiiRiv,

NRiRii,

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

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

R2represents one or more than one residue selected from H, HE, halogen, CN, nitro, C1-6-alkyl, possibly substituted by-NRiiiRivC1-6-alkoxy, -O-CH2-C2-6-alkenyl, benzyloxy or C1-6-halogenoalkane,

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

R3represents H,

or is halogeno,

or is a -(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

halogeno,

-O(CO)1-6-alkyl

or-NH(CO)Rdwhere Rdrepresents a C1-6-alkyl, possibly substituted, halogen or nitro, or Rdrepresents aryl or 5 - or 6-membered heteroaryl, that may be substituted Galaga is about, nitro, C1-6-alkyl or C1-6-halogenoalkanes;

R4represents one or more than one residue selected from N, halogeno, C1-6the alkyl or C1-6-alkoxy, CN, or two R4may form oxo or dioxaoctyl together with the phenyl ring to which they are attached;

In is halogen, CN, NRiRiiC1-6-alkyl, possibly substituted by CN, halogen or C1-6-alkoxy, C1-6-alkoxy, C3-6-halogenoalkane,3-6-cycloalkyl, -C(O)O-C1-6-alkyl, -C(O)ii-C(O)-C1-6-alkyl, -S(O)2-C1-6-alkyl, -S(O)2-NRiRii, (CRiiiRiv)n-phenyl or - (CRiiiRiv)n-5 - or 6-membered heteroaryl, where phenyl or 5 - or 6-membered heteroaryl group possibly substituted by one or more than one Deputy, selected from the group consisting of:

halogen, CN, NRiRiiC1-6-alkyl, possibly substituted by CN or C1-6-alkoxy, C1-6-alkoxy, C1-6-halogenoalkane,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;

Riand Riirepresent H, C1-6-alkyl, C1-6-alkylene-NRiiiRiv, -(CO)O-C1-6-alkyl, -C(O)-NRiRii-C(O)-C1-6-Alki is, S(O)2-NRiiiRiv-alkyl or-S(O)2-NRiiiRiv;

Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv)2;

Rivrepresents N or C1-6-alkyl;

m has a value of 1 to 6;

n is 0 to 4;

and their pharmaceutically acceptable salts.

The compounds of formula (I) may contain asymmetric carbon atoms. Accordingly, the present invention includes all stereoisomeric forms of the compounds of formula (I), including each individual enantiomer and mixtures thereof.

It is established that the compounds of formula (I) show significant activity in relation to the V1a-receptor. Therefore, in the invention it is proposed to use 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 is a peptide consisting of 9 amino acids, which is synthesized mainly paraventrikulyarnoe nuclei of the hypothalamus. There are three known receptor vasopressin, all of which belong to the class I G protein-conjugated receptor. V1a-receptor is expressed in the RAM of the brain, liver, vascular smooth muscle, lung, uterus, and testes. 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 action of vasopressin.

On the periphery of vasopressin acts as neurohormone and stimulates vasoconstriction, glycogenolysis and antidunes. In brain vasopressin acts as a neuromodulator, and its level increases in cerebellar amygdala during stress (Ebner, K., ..Wotjak, et at. (2002). "Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats"Eur J Neurosci15(2): 384-8). V1a-receptor is expressed in many areas of the brain, especially in limbic areas such as the amygdala, lateral septum and the hippocampus, which plays an important role in the regulation of anxiety. Indeed, V1a-knockout mice, a decrease of anxiety level in tests "maze", "open field" and "dark-light camera (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.). Suppression of the expression of the V1a-receptor using injections of antisense oligonucleotide in the wall also causes reduction of anxiety (Landgraf, R., R.Gerstberger, et at. (1995). “V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin inding, social discrimination abilities, and anxiety-related behavior in rats"Reaul Pept59(2): 229-39).

V1a-receptor also mediates the cardiovascular effects of vasopressin in the brain through the Central regulation of blood pressure and heart rate in the nucleus of the solitary path (Michelini, L.. and M. Morris (1999). "Endogenous vasopressin modulates the cardiovascular responses to exercise"Ann N Y Acad Sci897: 198-211). At the periphery it induces contraction of smooth muscles of vessels, and long-lasting inhibition of V1a-receptor improves hemodynamic characteristics in rats with experimental myocardial infarction (Van Kerckhoven, R., I. Lankhuizen, et at. (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).

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

Preferred indications in accordance with the present invention are anxious and depressive disorders.

In the context of this description, the term "aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of mono-, bi - or tricyclic aromatic ring. Examples of the aryl the data groups include a possibly substituted phenyl, naphthyl, tenantry, fluorenyl, indenyl, pentalene, azulene, acidifier, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfone and diphenylethylene, and aryl groups, illustrated with specific examples in the description below, but are not limited to them. The aryl substituents include halogen, C1-6-alkyl and C1-6-alkoxy, but are not limited to them. Preferably the aryl is a phenyl and naphthyl, more preferably phenyl. Aryl groups according to the invention can additionally be orthotamine two substituents which, together with the carbon atoms of the aryl group to form a condensed, saturated or partially saturated 5-6-membered ring containing one or two heteroatoms selected from O and N. Preferably, this additional ring is a 5-6-membered ring containing two atoms of oxygen. Examples of such substituted aryl groups include benzodioxane, dihydrobenzofuranyl, benzodioxolyl, benzopyranyl, benzoxazines, benzoxazinones, benzoperylene, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity, and substituted aryl groups, illustrated with specific examples in the description below, but not limited to.

The term "C16 -alkyl" means a group representing a saturated normal or branched hydrocarbon chain containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, ISO-butyl, 2-butyl, ISO-butyl, and the like. Preferred1-6-alkyl groups are C1-4groups, i.e. groups containing 1-4 carbon atoms.

The term "C1-6-alkoxy" means a group where the alkyl residues are as defined above, and which is attached via an oxygen atom. Preferred1-6-alkoxy groups are methoxy, ethoxy, and C1-6-alkoxy group, illustrated with specific examples in the description below.

The term "C2-6alkenyl" means a carbon chain of 2 to 6 carbon atoms containing a double bond in the chain. With2-6-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, and With2-6-alkeline group, illustrated with specific examples in the description below.

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

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

The term "C1-6-halogenoalkane" oznacza the t C 1-6is an alkyl group such as defined above, which is substituted by one or more than one halogen atom. Examples of C1-6-halogenoalkane include methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more than one atom of Cl, F, Br or I, and C1-6-halogenoalkane group, illustrated with specific examples in the description below, but are not limited to them. Preferred C1-6-halogenoalkane is debtor or trifter-methyl or ethyl.

"C1-6-halogenoalkane" means C1-6-alkoxy group, such as defined above, which is substituted by one or more than one halogen atom. Examples of C1-6-halogenoalkane include methoxy or ethoxy, substituted one or more than one atom of Cl, F, Br or I, and C1-6-halogenoalkane group, illustrated with specific examples in the description below, but are not limited to them. Preferred C1-6-halogenoalkane is debtor or trifter-methoxy or ethoxy.

The term "C3-6-cycloalkyl" means a monovalent or divalent saturated carbocyclic group consisting of a monocyclic ring. Cycloalkyl can be possibly substituted by one, two, three or four substituents, where each independent Deputy who represents hydroxy, C1-6-alkyl, C1-6-alkoxy, halogen atom, amino, unless specifically provided otherwise. Examples cycloalkyl groups may include substituted cyclopropyl, possibly substituted cyclobutyl, possibly substituted cyclopentyl and possibly substituted cyclohexyl and cycloalkyl groups, illustrated with specific examples in the description below.

The term "4-7-membered heteroseksualci" means a monovalent saturated group consisting of one ring containing 4-7 ring atoms, one, two or three of which are heteroatoms selected from nitrogen, oxygen or sulfur, and the remainder are carbon atoms. 4-7-membered heteroseksualci can be possibly substituted by one, two, three or four substituents, where each Deputy independently represents hydroxy, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, halogen, C1-6-halogenoalkane, C1-6-hydroxyalkyl, alkoxycarbonyl, amino, C1-6-alkylamino, di(C1-6)alkylamino, aminocarbonyl or carbylamine, unless specifically provided otherwise. Examples of heterocyclic groups include possibly substituted oxetane, possibly substituted tetrahydrofuranyl, possibly substituted piperidinyl, possibly substituted pyrrolidinyl, possibly substituted morpholinyl, the possibility is substituted on piperazinil and the like, or heterocyclic group, illustrated with specific examples given in this description, but is not limited to them. The substituents can be selected from C1-6-alkyl, C1-6-alkoxy, C1-6-halogenoalkane, halogen, CN, HE, NH2and of deputies, which is illustrated in the specific examples herein below.

The term "5 - or 6-membered heteroaryl" means an aromatic ring comprising 5 or 6 ring atoms as ring members containing one, two or three ring heteroatoms selected from N, O or S, and the carbon atoms (the remaining ring atoms). 5 - or 6-membered heteroaryl can be possibly substituted by one, two, three or four substituents, where each Deputy independently represents hydroxy, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, halogen, C1-6-halogenoalkane, C1-6-hydroxyalkyl, alkoxycarbonyl, amino, C1-6-alkylamino, di(C1-6)alkylamino, aminocarbonyl or carbylamine, unless specifically provided otherwise. Examples of heteroaryl groups include possibly substituted imidazolyl, possibly substituted oxazolyl, possibly substituted thiazolyl, possibly substituted pyrrolyl, possibly substituted pyrazinyl, possibly substituted pyridinyl, possibly substituted pyrimidinyl, possibly substituted furanyl and heteroaryl groups, to the verge illustrated with specific examples, given this description, but is not limited to them.

The term "sulfonylureas" means aryl group, such as defined herein above, which is attached via sulfonyloxy group.

The term "one or more than one"when he refers to R2and R4means from one to four residues, which can be independently selected from the following groups. Preferably one or more than one" in this context means one or two of the remainder R2and R4accordingly, the others are hydrogen.

The expression "two R2together with the indole ring to which they are attached, may form oxo or dioxaoctyl " means oxo - or dioxaoctyl the following formulas:

or,

which connects two adjacent carbon atoms of the phenyl or indole ring of the compounds of formula (I)is associated with each R2.

Examples of groups that illustrate the expression "R1and R3together with the indole ring to which they are attached, form a 5 - or 6-membered heteroseksualci, which may substituted by =O"are:

and.

The term "pharmaceutically acceptable salt (accession) acids" includes salts with inorganic and organic the ski 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, methane-sulfonic acid, paratoluenesulfonyl acid, and salts (accession) acids, illustrated with specific examples in the description below.

Specifically, one of the embodiments of the present invention relates to compounds of General formula (I):

where

And selected from the following groups (a), (b), (C), (d), (e) and (f):

,

X may be the same or different and represent CRiiiRiv, NRiiior, where in (a) only one X can represent Oh, and the other represents CRiiiRivor NRiii;

R1represents H,

C1-6-alkyl, possibly substituted by CN,

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

or represents -(CH2)m-Rawhere Rarepresents:

ORi,

NRiRii,

With3-6the cycle is alkyl, 4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more than one,

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

C1-6-alkyl,

C1-6-alkoxy,

With3-6-cycloalkyl,

-(CH2)m-NRiiiRiv,

NRiRii,

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

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

R2represents one or more than one residue selected from H, HE, halogen, CN, nitro, C1-6-alkyl, possibly substituted by-NRiiiRivC1-6-alkoxy, -O-CH2-C2-6-alkenyl, benzyloxy,

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

R3represents H,

or is halogeno,

or represents -(CO)-Rcwhere Rcrepresents:

C1-6-alkyl,

-(CH2)n-NRiRii,

-(CH2)n-NRiiiRiv,

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

halogeno,

-O(CO)1-6-alkyl

or-NH(CO)Rdwhere Rdrepresents a C1-6-alkyl, possibly substituted, halogen or nitro, or Rdrepresents aryl or 5-or 6-membered heteroaryl, that may be substituted, halogen, nitro, C1-6-alkyl or C1-6-halogenoalkanes;

R4represents one or more than one residue selected from N, halogeno, C1-6the alkyl or C1-6alkoxy, CN, or two R4may form oxo or dioxaoctyl together with the phenyl ring to which they are attached;

In is halogen, CN, NRiRiiC1-6-alkyl, possibly substituted by CN, halogen or1-6-alkoxy, C1-6-alkoxy, C1-6-halogenoalkane,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)n-5 - or 6-membered heteroaryl, where phenyl or 5 - or 6-membered heteroaryl group possibly substituted by one or more than one Deputy, selected from the group consisting of:

halogen, CN, NRiRiiWith1-6the alkyl may samemanner is CN or C 1-6-alkoxy, C1-6-alkoxy, C1-6-halogenoalkane,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;

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

Riiiand Rivrepresent N or C1-6-alkyl;

m has a value of 1 to 6;

n is 0 to 4;

and their pharmaceutically acceptable salts.

In one of the embodiments of the invention And, X, R1-R4, Ra, Rb, Rc, Rd,, Ri, Rii, m, and n are as described above, and

Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv)2and

Rivrepresents N or C1-6-alkyl.

In some embodiments of the invention R1selected from the group consisting of N,

C1-6-alkyl, possibly substituted by CN,

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

or represents -(CH2)m-Rawhere Rarepresents:

4-7-membered heteroseksualci or aryl, which may for whom emeny one or more than one,

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

C1-6-alkoxy,

NRiRii,

4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more than one;

In is halogeno, C1-6-alkyl or phenyl;

Riand Riiindependently represent N or C1-6-alkyl.

In some embodiments of the invention R2represents one or more than one residue selected from the group consisting of N, halogeno, C1-6-alkyl or C1-6-alkoxy. Preferably R2is the 5th and/or 6th position of the indole. More preferably, when R2represents-OMe 5-th position; or F in the 5th position and Cl in 6 th position; or Me in 5th position and Cl in 6 th position; or H in the 6-th position; or Cl in the 6th position of the indole. Even more preferably, when R2represents Cl 6-th position of the indole or N in the 6th position of the indole. Most preferably, when R2represents Cl 6-th position of the indole.

In some embodiments of the invention R3represents a hydrogen atom or a C1-6-alkyl.

Preferably R4represents a hydrogen atom.

Another embodiment of the invention includes the compounds of formula (I), such as described in this description, or farmacevtichesky acceptable salt provided while not all R1, R2and R3represent N.

Another embodiment of the invention includes the compounds of formula (I), such as described herein, or their pharmaceutically acceptable salts, provided that at the same time not all R1, R2, R3and R4represent N.

In some embodiments of the invention, the group (a) compounds of formula (I) selected from (a') and (a"):

where Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv)2and Rivrepresents N or C1-6-alkyl; preferably Riiirepresents N or C1-6-alkyl; most preferably Riiirepresents N.

As you can see from the definition in the compounds of formula (I), the compounds of formula (I) include the following compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f):

,

,

,

,

,

where R1-R4and X are as defined herein above in relation to formula (I).

In one embodiments of the compounds according to the invention are those compounds of formula (I-a):

,

where

X may be the same or different and represent CRiiiRiv, NRiiior, where only one X can represent Oh, and the other represents CRiiiRivor NRiii;

R1represents H,

C1-6-alkyl, possibly substituted by CN,

or represents aryl, possibly substituted by one or more than one,

or represents -(CH2)m-Rawhere Rarepresents:

NRiRii,

aryl, possibly substituted by one or more than one,

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

C1-6-alkoxy,

NRiRii,

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

R2represents one or more than one residue selected from H or halogen, for example Cl,

R3represents N

or is a1-6-alkyl,

R4represents one or more than one residue selected from N, halogeno, C1-6the alkyl or C1-6alkoxy or CN;

In is halogen, CN, NRiRiiC1-6-alkyl, possibly substituted by CN, halogen or C-6 -alkoxy, C1-6-alkoxy, C1-6-halogenoalkane,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)n-5 - or 6-membered heteroaryl, where phenyl or 5 - or 6-membered heteroaryl group possibly substituted by one or more than one Deputy, selected from the group consisting of:

halogen, CN, NRiRiiC1-6-alkyl, possibly substituted by CN or C1-6-alkoxy, C1-6-alkoxy, C1-6-halogenoalkane,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;

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

Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv)2;

Rivrepresents N or C1-6-alkyl;

m has a value of 1 to 6;

n is 0 to 4;

and their pharmaceutically acceptable salts.

In this embodiment (a) is preferably selected from (a') and (a").

In one embodiments of the compounds the Oia of the formula (I-a) represents the connection where R1represents H, for example the following compounds:

1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

6'-bromo-1-(1H-indol-3-ylcarbonyl)-1H-Spiro[piperidine-4,4'-quinoline]-2'(3 N)-he;

6-chloro-1'-[(6-chloro-1H-indol-3-yl)carbonyl]-1-[2-(dimethylamino)ethyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

6-chloro-1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he.

In one embodiments of the compounds of formula (I-a) represents those compounds where R1represents aryl, possibly substituted by one or more than one, and is such as defined here above in the description of formula (I-a), for example, the following connection: 1'-{[6-chloro-1-(3,5-differenl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he.

In one embodiments of the compounds of formula (I-a) are those compounds where R1represents -(CH2)m-Rawhere Randrepresents CN, NRiRiior aryl, possibly substituted by one or more than one, and m, Ri, Riiand b are as defined here above in the description of formula (I-a), for example, the following connections:

1'-{[6-chloro-1-(3,5-diferensial)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-{[6-chloro-1-(3-terbisil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-PIP is ridin]-2(1H)-he;

3-{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile and

2-{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile.

In one embodiments of the compounds of formula (I-a) are those compounds where R1represents -(CH2)n-(CO)-Rbor -(CH2)n-(SO2)-Rbwhere Rbrepresents a C1-6-alkoxy, NRiRii, 4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more than one, and n, Ri, Riiand b are as defined here above in the description of formula (I-a), for example, the following connections:

1'-{[6-chloro-1-(3-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-{[6-chloro-1-(2-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-{[6-chloro-1-(2,3-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-({6-chloro-1-[(3,5-differenl)sulfonyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-({6-chloro-1-[2-(3-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-({6-chloro-1-[2-(3,4-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

<> 1'-{[1-(biphenyl-3-ylcarbonyl)-6-chloro-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-{[6-chloro-1-(2-oxo-2-piperidine-1-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-{[6-chloro-1-(2-morpholine-4-yl-2-oxoethyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

2-{6-chloro-3-[(2-oxo-1,2-dihydro-1H-Spiro[3,1-benzoxazine-4,4'-piperidine]-1-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide;

2-{6-chloro-3-[(2-oxo-1,2-dihydro-1H-Spiro[3,1-benzoxazine-4,4'-piperidine]-1-yl)carbonyl]-1H-indol-1-yl}-N,N-diethylacetamide;

1'-{[6-chloro-1-(piperidine-1-ylcarbonyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

tert-butyl {6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}acetate;

1'-{[6-chloro-1-(3,5-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-({6-chloro-1-[2-(3,5-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-({6-chloro-1-[2-(2-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he;

1'-{[6-chloro-1-(2-oxo-2-pyridin-2-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1"-({6-chloro-1-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he.

In the compounds of formula (I-a), regardless of the op is edeleny R 1-R4one X can represent NH, and the other O.

In one of the embodiments of the invention of formula (I) includes the compounds of formula (I-b), where X and R1-R4are as defined above, preferably

X represents NH;

R1represents H,

C1-6-alkyl, possibly substituted by CN,

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

or represents -(CH2)m-Rawhere Rarepresents:

4-7-membered heteroseksualci or aryl, which may be substituted by one or more than one,

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

C1-6-alkoxy,

NRiRii,

4-7-membered heteroseksualci, aryl or 5 - or 6-membered heteroaryl, possibly substituted by one or more than one;

In is halogeno, C1-6-alkyl or phenyl;

Riand Riiindependently represent N or C1-6-alkyl;

more preferably R1represents -(CH2)n-(CO)-Rbwhere Rbrepresents NRiRiiand Riand Riiindependently represent N or C1-6-alkyl.

R2represents H or halogeno;

R3presented EET a N;

R4represents N.

Example of compounds of formula (I-b) is 2-{6-chloro-3-[(1-oxo-2,3-dihydro-1H,1 N-Spiro[isoquinoline-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N-methylacetamide.

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

The invention additionally includes the use of compounds of formula (I), (I-a), (I-b), (I-e), (I-d), (I-e) or (I-f) in the preparation of medicines, which is useful when dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.

In the nome of the embodiments of compounds of formula (I) according to the invention, where R1represents H, can be obtained in accordance with the method, including the stage of interaction of the compounds of formula (II-a):

with the compound of the formula A-N to obtain the compounds of formula (I), where R1represents N and A, R2and R3are as defined herein above.

In another embodiment of the compounds of formula (I) according to the invention can be obtained in accordance with the method, including the stage of interaction of the compounds of formula (I-1):

with an electrophilic compound of formula R1-Z with obtaining the compounds of formula (I), where A, R1, R2and R3are as defined herein above, and Z represents halogen, preferably Br or Cl.

In yet another embodiment of the compounds of formula (I) according to the invention can be obtained in accordance with the method, including the stage of interaction of the compounds of formula (II-b):

with the compound of the formula A-N to obtain the compounds of formula (I), where R1, R2, R3and a are as defined herein above.

Obtaining the compounds according to the invention of formula (I), (I-a), (I-b), (I-e), (I-d), (I-e) and (I-f) are described in more detail in the following General schemes a, B and C, where R1, R2, R3 and a are as defined herein above.

The General scheme And

General procedure a

The compounds of formula (I-1) (compounds of formula (I), where R1represents N) can be obtained by amide synthesis from indole-3-carboxylic acid (II-a) and spirobiindane (A-N), see, for example, a General method for the synthesis of amide described in this description below. Indole-3-carboxylic acid (II-a) or are commercially available or can easily be obtained using the techniques described in J. Med. Chem. 1991, 34, 140. Alternative soedineniya (II-a) can be obtained according to scheme C. Derivatives spirobiindane A-N either available commercially or can be obtained using published methods, or can be obtained using methods described herein below in the examples.

The General scheme B

General method B

The compounds of formula (I), where R1different from H can be obtained by alkylation of indole derivative (I-1) electrophile R1-Z, where Z is halogen, (commercially available) using standard techniques. Derivatives (I-1) is obtained using the methodology described in the General scheme A.

The General scheme In

General method In

In which the result of processing indole (III) triperoxonane anhydride obtain the compound (IV), which can be hydrolyzed to obtain the corresponding indole-3-carboxylic acid (II-a). Alternative compound (IV) can optionally be converted into the compound (V) by reacting with a reagent R1-Z, where Z is halogen, using well-known techniques. As a result of hydrolysis of compound (V) obtain the compound (II-b), from which by standard amide synthesis using A-N receive derivative (I).

General schemes and methods presented in this description above, additionally illustrated by the following examples of the preparation of compounds according to the invention.

Results: V1a-activity

Materials and Methods

V1a-receptor human cloned by RT-PCR (polymerase chain reaction involving reverse transcriptase) from total RNA human liver. After sequencing, confirming the identity of the amplified sequence, the coding sequence was subcloned into the expressing vector. To prove the affinity of the compounds of the present invention to V1a-receptor person performed the analysis of binding. Cell membranes were obtained from HEK293 cells, temporarily transfected received expressing vector and grown in 20-liter fermenter in accordance with the following Protocol is.

50 g of cells resuspended in 30 ml freshly prepared and cooled to 0°C buffer for lysis (50 mm HEPES (hydroxyethylpiperazine-N'-2-econsultancy acid), 1 mm EDTA (ethylenediaminetetraacetate), 10 mm MgCl2(the pH is brought to pH 7.4)+ full mix of ingibiruet proteases (Roche Diagnostics)). Homogenize using a transmitter station for 1 min and destroy ultrasound on ice 2×2 min with intensity of 80% (Vibracell ultrasonic device). This preparation is centrifuged 20 min at 500 g at 4°C, the precipitate is removed and the supernatant centrifuged for 1 hour at 43000 g at 4°C (19000 rpm). Sediment resuspended in a mixture of 12.5 ml of buffer for lysis +12.5 ml 20% sucrose and homogenized using a transmitter station within 1-2 minutes the protein Concentration determined by the method of Bradford and aliquots stored at -80°C. For analysis of binding 60 mg SPA beads with a core of yttrium silicate (Amersham) is mixed with an aliquot of membranes in buffer for binding (50 mm Tris, 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 10 mm MgCl2within 15 minutes with stirring. Then to each well of 96-hole tablet add 50 ál of the mixture balls/diaphragms and then 50 μl of 4 nm 3H-vasopressin (American Radiolabeled Chemicals). To measure total binding in the appropriate wells add 100 ál of buffer to bind to measure nonspecific binding of 100 μl of 8.4 mm cold vasopressin and for measuring when Azania of the investigated compounds 100 μl of serial dilutions of each compound in 2% DMSO (dimethyl sulfoxide). The tablet is incubated for 1 h at room temperature, centrifuged 1 min at 1000 g and the count on the counter Packard Top-Count. From the values obtained for each hole, subtract the value for nonspecific binding and the resulting values are normalized to the value of the maximum specific binding, taken as 100%. The IC50 value (concentration required for 50% inhibition of binding) is calculated by fitting the curve using nonlinear regression (XLfit), and the value of Ki is calculated using the equation of Cheng-Prussoff.

/tr>
ExampleKi (nm) [V1a man]ExampleKi (nm) [V1a man]
1321620
2205317the 5.7
3402186
43101946
51302010
61182188
711722200
8136232
1032410
1152528
127268
1382729
15728166

The compounds of formula (I)and their pharmaceutically acceptable salts accession acids can be used as medicaments, e.g. in the form of pharmaceutical preparations. Data pharmaceutical preparation be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be performed rectally, for example in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The manufacture of tablets, coated tablets, dragées and hard gelatin capsules may include the treatment of compounds of formula (I) and their pharmaceutically acceptable salts accession acids together with pharmaceutically inert, inorganic or organic excipients. As such excipients, for example, tablets, coated tablets and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts, and so forth.

The excipients suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and so on.

The excipients suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and so on.

The excipients suitable for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, and so forth.

The excipients suitable for suppositories are, for example, natural the material or solidified oil, waxes, fats, semi-liquid or liquid polyols and so on.

Furthermore, these pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffer agents, masking agents or antioxidants. They can also contain other therapeutically useful substances.

The dose can vary within wide limits and in each case, of course, corresponds to the individual requirements. Usually in the case of oral administration a suitable daily dose for a person should be from about 10 to 1000 mg of the compounds of General formula (I), although if necessary, the above-mentioned upper limit can also be exceeded.

The present invention is illustrated in the following not limiting examples. All temperatures are given in degrees Celsius.

Example

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

mg tablet
The active ingredient5
actose 45
Corn starch15
Microcrystalline cellulose34
Magnesium stearate1
Weight pills100

Example B

Manufacture of capsules having the following composition:

mg/capsule
The active ingredient10
Lactose155
Corn starch30
Talc5
Mass content capsules200

The active ingredient, lactose and corn starch are first mixed in a mixer and then into the shredder. The mixture is again transferred into the mixer, add the powder and mix thoroughly. This mixture using SP is a special device fill hard gelatin capsules.

The example In

The manufacture of suppositories having the following composition:

mg/suppository
The active ingredient15
The weight of the suppository1285
ONLY1300

Mass for suppositories is melted in a glass or steel vessel, mix thoroughly and cooled to 45°C. Then, to this mixture, add the finely ground active ingredient and mix until until it is completely dispersed. This mixture is poured into molds for suppositories suitable size, leave to cool, then suppositories removed from the forms and individually wrapped in waxed paper or metal foil.

EXAMPLES

Examples of compounds of the formula (I-1)

General methods of synthesis of amide

To mix the solution derived indole-3-carboxylic acid (1 mmol) in 10 ml of CH2Cl2added (1.3 mmol) EDC (ethyldimethylammonium), (1.3 mmol), HOBt, (1.3 mmol) Et3N and (1 mmol) of the amine derivative. This mixture p is remedial over night at room temperature and then poured into water and was extracted with CH 2Cl2. The combined organic phases were dried over Na2SO4and concentrated under vacuum. After flash chromatography or preparative jhud has been specified in the header of the connection.

Where examples are links example was performed using the conditions and the source of the substances specified in the list of reagents, which are listed in the link. All techniques contained in such links, well-known medium-sized specialists in this field of technology. All journal references cited herein, incorporated by reference.

Example 1

1'-[(6-Chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

Synthesis of amide: Amin: Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he (J. Med. Chem., 1983, 26(5), 657)

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

ES-MS (mass spectrometry with elektrorazpredelenie) mass/charge (%): 396,1 (M+H+).

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

Using the techniques 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 mass/charge (%): 194 (M-H+).

Example 2

6'-Bromo-1-(1H-indol-3-ylcarbonyl)-1 N-Spiro[piperidine-4,4'-quinoline]-2'(3 N)-he

Synthesis of amide: Amin: 6'-bromo-1 N-Spiro[Pieper is DIN-4,4'-quinoline]-2'(3 N)-he

- Acid: 1H-indole-3-carboxylic acid (commercial reagent) ES-MS mass/charge (%): 439,1 (M+H+).

6'-Bromo-1 N-Spiro[piperidine-4,4'-quinoline']-2'(3 N)-he

Mix a solution of 1 N-Spiro[piperidine-4,4'-quinoline]-2'(3 M)-she (described in US 6013652) was treated with solid sodium bicarbonate (7 g), di-tert-butyl-pyrocarbonate (7.2 g) in 250 ml of methylene chloride and was stirred for 2 hours at ambient temperature. The organic layer was separated and the aqueous portion was washed with methylene chloride (2×50 ml). The combined organic extract and the organic fraction obtained when washing, washed with brine, dried (anhydrous Na2SO4), concentrated under vacuum to obtain foamy substance, which was chromatographically on silica gel (1:3 ethyl acetate-hexane, then 1:1 ethyl acetate-hexane) to obtain 1'-(tert-butyloxycarbonyl)Spiro(tetrahydroindole-2-he)-4'-piperidine in the form of a creamy white solid, TPL (melting point) 198°C; GC-MS (EI) (gas chromatography/mass spectrometry with electron ionization) mass/charge: 316.

A solution of this compound (10 g, of 31.6 mmol) in dry acetonitrile (250 ml) was cooled to -10°C and portions under stirring was added N-bromosuccinimide (5,62 g of 31.6 mmol). This reaction mixture was stirred for 1 h at -10°C, 2 h at 0°C and then for 24 hours at a temperature surrounding the it environment. The solvent was removed and the residue was dissolved in methylene chloride (500 ml), the organic extract was washed with a mixture of brine-water (1:1) (3×50 ml), dried (anhydrous Na2SO4), concentrated under vacuum to obtain a creamy white solid, which was chromatographically on silica gel (1:3 ethyl acetate-hexane, then 1:1 ethyl acetate-hexane) to give 6-bromo-1'-(tert-butyloxycarbonyl)Spiro(tetrahydroindole-2-he)-4'-piperidine (11.8 g, 94%) as a white solid; TPL 226°C; GC-MS (EI) mass/charge (M-100): 294.

Through methanol (750 ml)containing this compound (10 g, to 25.3 mmol)was passed dry HCl for 10 hours and stirring continued over night. The reaction mixture was neutralized aqueous ammonia (75 ml) at 0°C. the Methanol and excess ammonia was removed under vacuum and the residue was dissolved in methylene chloride (500 ml)was then added 25 ml of aqueous ammonia to dissolve the remaining solid. The organic layer was separated and the aqueous portion washed/was extracted with methylene chloride (3×150 ml), dried (anhydrous Na2SO4), concentrated under vacuum to obtain specified in the title compound as a creamy white solid (7.0 g, 94%); TPL 218°C; GC-MS (EI) mass/charge: 294.

Example 3

6-Chloro-1-[(6-chloro-1 N-indol-3-yl)carbonyl]-1-[2-(dimethylamino)ethyl]Spiro[3,1-benzoxazine-4,4'-piperidine-2(1H)-he

Synthesis of amide: - amine: 6-chloro-1-[2-(dimethylamino)ethyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he (described below)

- Acid: 6-chloro-1H-indole-3-carboxylic acid (described in example 2)

ES-MS mass/charge (%): 501,2 (M+H+).

6-Chloro-1-[2-(dimethylamino)ethyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

To a solution 0,100 g (0,283 mmol) of tert-butyl 6-chloro-2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-carboxylate (described in WO 0122919 A2 and also obtained using the techniques described in J. Med. Chem., 1983, 26(5), 657, using as the starting material 4-Chloroaniline) in 7 ml THF was added 0.025 g (0,566 mmol) NaH. After keeping for 30 minutes at room temperature was added 0,063 g (0,566 mmol) (2-chloro-ethyl)-dimethyl-amine. This reaction mixture was stirred at 60°C. overnight, then poured into an aqueous solution of NH4Cl and was twice extracted with EtOAc. The combined organic phases were dried over Na2SO4and concentrated under vacuum to obtain 60 mg of a white solid. Then, this crude substance was dissolved in 5 ml of CH2Cl2and added 1 ml of TFU. After incubation for 2 hours at room temperature the solvent was removed under vacuum and the oil obtained was transferred into a CH2Cl2and washed in an aqueous solution of NaHCO3. The organic phase is dried the over Na 2SO4and concentrated under vacuum to obtain 6-chloro-1-[2-(dimethylamino)ethyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-it is in the form of a white solid.

Example 4

6-Chloro-1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

Synthesis of amide: - amine: 6-chlorpro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he (described in WO 0122919 A2 and also obtained using the techniques described in J. Med. Chem., 1983, 26(5), 657, using as the starting material 4-chloro-aniline)

- Acid: 6-chloro-1H-indole-3-carboxylic acid (described in example 2)

ES-MS mass/charge (%): 431,4 (M+H+).

Example 5

1'-{[6-Chloro-1-(3,5-differenl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

Synthesis of amide: Amin: Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he (J. Med. Chem., 1983, 26(5), 657)

- Acid: 6-chloro-1-(3,5-differenl)-1H-indole-3-carboxylic acid

ES-MS mass/charge (%): 508,0 (M+H+).

6-Chloro-1-(3,5-differenl)-1H-indole-3-carboxylic acid

To a solution of 200 mg (0,807 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-Cryptor-ethanone (obtained from 6-chloro-indole and triperoxonane anhydride in the manner described in US 2004067939 A1) in 8 ml of CH2Cl2added 293 mg (near 1.615 mmol) Cu(SLA)2, of 0.26 ml (3,23 mmol) of pyridine and 383 mg (2,42 mmol) of 3,5-diperpanjang acid. This Rea is operating and the mixture was stirred at room temperature overnight, filtered through dekalim and concentrated under vacuum. In the result column chromatography on silica gel (hexane, then 1:9 ethyl acetate-hexane) received 206 mg (71%) of 1-[6-chloro-1-(3,5-differenl)-1H-indol-3-yl]-2,2,2-Cryptor-ethanone in the form of a light brown solid. To a suspension of this compound in 10 ml of N2Oh was added 1.2 g of NaOH. This reaction mixture was stirred at 70°C for 2 days, cooled to room temperature and acidified aqueous HCl (1 BC) to pH 1. The product was extracted with CH2Cl2and the organic phase was dried over Na2SO4. In the evaporation of the solvent under vacuum was obtained 120 mg (70%) of 6-chloro-1-(3,5-debtor-phenyl)-1H-indole-3-carboxylic acid as a white solid.

Example 6

1'-{[6-Chloro-1-(3-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

To a solution of 100 mg (0,252 mmol) 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) in dry DMF (5 ml) was added 10 mg of NaH (0.25 mmol, 60% in oil). After incubation for 15 minutes at room temperature was added 43,9 mg (0,277 mmol) 3-fluoro-benzoyl chloride and stirring continued over night. The reaction mixture was poured into an aqueous solution of ammonium chloride and the product was extracted twice with ethyl acetate. Joint the United organic phase was dried over Na 2SO4and the solvent evaporated under reduced pressure. In the purification by preparative Ehud received 1'-{[6-chloro-1-(3-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he.

ES-MS mass/charge (%): 518,4 (M+H+).

Example 7

1'-{[6-Chloro-1-(2-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(2-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl) carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-fluoro-benzoyl chloride using the method described in example 6.

ES-MS mass/charge (%): 518,4 (M+H+).

Example 8

1'-{[6-Chloro-1-(2,3-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(2,3-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2,3-debtor-benzoyl chloride using the method described in example 6.

ES-MS mass/charge (%): 536,4 (M+H+).

Example 9

1'-({6-Chloro-1-[(3,5-differenl)sulfonyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1-({6-Chloro-1-[(3-differenl)sulfonyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 3,5-debtor-benzosulfimide using the techniques described in example 6.

ES-MS mass/charge (%): 572,3 (M+H+).

Example 10

1'-{[6-Chloro-1-(3,5-diferensial)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(3,5-diferensial)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 1-methyl bromide-3,5-diferente using techniques described in example 6.

ES-MS mass/charge (%): 522,4 (M+H+).

Example 11

1'-{[6-Chloro-1-(3-terbisil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazin-5-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(3-terbisil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 1-methyl bromide-3,5-debtor-benzene using the techniques described in example 6.

ES-MS mass/charge (%): 504,4 (M+N+).

Example 12

1'-({6-Chloro-1-[2-(3-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-({6-Chloro-1-[2-(3-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-PI is Eridan]-2(1H)-she (described in example 1) and 2-bromo-1-(3-fluoro-phenyl)-ethanone using techniques described in example 6.

ES-MS mass/charge (%): 532,4 (M+N+).

Example 13

1'-({6-Chloro-1-[2-(3,4-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-({6-Chloro-1-[2-(3,4-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-bromo-1-(3,4-differenl)-ethanone using the techniques described in example 6.

ES-MS mass/charge (%): 550,4 (M+H+).

Example 14

1'-{[1-(Biphenyl-3-ylcarbonyl)-6-chloro-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[1-(Biphenyl-3-ylcarbonyl)-6-chloro-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and biphenyl-3-carbonylchloride using techniques described in example 6.

ES-MS mass/charge (%): 576,4 (M+H+).

Example 15

1'-{[6-Chloro-1-(2-oxo-2-piperidine-1-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(2-oxo-2-piperidine-1-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-Ben is oxazin-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-chloro-1-piperidine-1-yl-ethanone using techniques described in example 6.

ES-MS mass/charge (%): 521,1 (M+N+).

Example 16

1'-{[6-Chloro-1-(2-morpholine-4-yl-2-oxoethyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(2-morpholine-4-yl-2-oxoethyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-chloro-1-morpholine-4-yl-ethanone using the techniques described in example 6.

ES-MS mass/charge (%): 523,2 (M+H+).

Example 17

2-{6-Chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide

2-{6-Chloro-3-[(2-oxo-1,2-dihydro-1H-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide was obtained from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-chloro-N,N-dimethyl-ndimethylacetamide using the techniques described in example 6.

ES-MS mass/charge (%): 481,0 (M+H+).

Example 18

2-{6-Chloro-3-[(2-oxo-1,2-dihydro-1H-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-diethylacetamide

2-{6-Chloro-3-[(2-oxo-1,2-dihydro-1H-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-diethylacetamide was obtained from 1'-(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-chloro-N,N-diethyl-ndimethylacetamide using techniques described in example 6.

ES-MS mass/charge (%): 509,1 (M+N+).

Example 19

1'-{[6-Chloro-1-(piperidine-1-ylcarbonyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(piperidine-1-ylcarbonyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and piperidine-1-carbonylchloride using techniques described in example 6.

ES-MS mass/charge (%): 507,1 (M+N+).

Example 20

tert-Butyl{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}acetate

tert-Butyl{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}acetate was obtained from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and bromo-acetic acid tert-butyl ester using the method described in example 6.

ES-MS mass/charge (%): to 510.5 (M+N+).

Example 21

1'-{[6-Chloro-1-(3,5-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(3,5-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)Carbo is Il]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 3,5-differentiald using techniques described in example 6.

ES-MS mass/charge (%): 536,3 (M+H+).

Example 22

1'-({6-Chloro-1-[2-(3,5-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-({6-Chloro-1-[2-(3,5-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-bromo-1-(3,5-differenl)-ethanone using the techniques described in example 6.

ES-MS mass/charge (%): 550,3 (M+N+).

Example 23

1'-({6-Chloro-1-[2-(2-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-({6-Chloro-1-[2-(2-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-bromo-1-(2-forfinal)-ethanone using the techniques described in example 6.

ES-MS mass/charge (%): 532,3 (M+N').

Example 24

3-{6-Chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile

3-{6-Chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile was obtained from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]the pyro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 3-chloro-propionitrile using techniques described in example 6.

ES-MS mass/charge (%): 449,0 (M+H+).

Example 25

2-{6-Chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile

2-{6-Chloro-3-[(2-oxo-1,2-dihydro-1H-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile was obtained from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-chloro-propionitrile with using the techniques described in example 6.

ES-MS mass/charge (%): 449,0 (M+H+).

Example 26

1'-{[6-Chloro-1-(2-oxo-2-pyridin-2-retil)-1H-indol-3-yl]carbonyl}Spiro[3,benzoxazine-4,4'-piperidine]-2(1H)-he

1'-{[6-Chloro-1-(2-oxo-2-pyridin-2-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she (described in example 1) and 2-bromo-1-pyridin-2-yl-ethanone using the techniques described in example 6.

ES-MS mass/charge (%): 515,4 (M+H+).

Example 27

1'-({6-Chloro-1-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he

1'-({6-Chloro-1-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he received from 1'-[(6-chloro-1H-shall ndol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-it (described in example 1) and 2-bromo-1-(5-methyl-2-phenyl-oxazol-4-yl)-ethanone (described in J. Med. Chem. 1992, 35(14), 2617) using the techniques described in example 6.

ES-MS mass/charge (%): 595,0 (M+H+).

Example 28

2-{6-Chloro-3-[(1-oxo-2,3-dihydro-1H,1 N-Spiro[isoquinoline-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N-methylacetamide

To a stirred solution of 6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (described below) (1 EQ.) in DMF was added HATU (2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) (1.1 EQ.), Et3N (2 EQ.) and (2 EQ.) 2,3-dihydro-1H-Spiro[isoquinoline-4,4'-piperidine]-1-it (previously described in WO 9909984). This mixture was stirred over night at room temperature and then poured into water and was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4and concentrated under vacuum. In the preparative jhud has been specified in the header connection. ES-MS mass/charge (%): 465,3 (M+H+).

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

a) 2-[6-Chloro-3-(2,2,2-TRIFLUOROACETYL)-indol-1-yl]-N-methyl-ndimethylacetamide

To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-Cryptor-ethanone (described previously in US 2004067939) in DMF was added 2.1 EQ. NaH (60%in oil). This mixture was stirred at room temperature for 30 min and then was added (commercially available) 2-chloro-N-methyl-ndimethylacetamide (1.1 EQ.). This mixture was stirred updat the Executive for 14 hours at 60°C and then poured into water and was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4and concentrated under vacuum. In the purification by preparative jhud has been specified in the header of the connection.

ES-MS mass/charge (%): 319,3 (M+H+).

b) 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid

2-[6-Chloro-3-(2,2,2-Cryptor-acetyl)-indol-1-yl]-N-methyl-ndimethylacetamide suspended in DCE and processed (2.2 EQ.) trimethylsilanol sodium. After stirring at room temperature for 20 min the mixture was concentrated under vacuum and purified by preparative Ehud obtaining specified in the connection header.

ES-MS mass/charge (%): 265,0 (M-H+).

ExampleStructurepKi[V1a man]And
295.96and
305.57and
316.61and
32 6.91and

347.41e
358.59e
367.06f
377.20f

387.77f
398.00f

1. Compounds of General formula (I)
,
where a is selected from the following groups (a), (b), (e) and (f):

,
X may be the same or different and represent CRiiiRiv, NRiiior, where in (a) only one X can represent Oh, and the other represents CRiiiRivor NRiii;
R1represents H,
With1-6-alkyl, possibly substituted by a group CN,
or represents phenyl, which is possibly substituted by one or more than one,
or represents -(CH2)m-Rawhere Rais:
NRiRii,
phenyl, which is possibly substituted by one or more than one,
or represents -(CH2)n-(CO)-Rbor -(CH2)n-(SO2)-Rbwhere Rbis:
With1-6-alkoxy,
NRiRii,
phenyl or piperidinyl, morpholinyl, pyridinyl, 1,3-oxazolyl, possibly substituted by one or more than one,
R2represents H or halogen,
R3represents H,
R4represents one or more than one residue selected from N, halogeno,1-6-alkoxy,
In is halogeno,1-6-alkyl, (CRiiiRiv)n-phenyl,
Riand Riirepresent H, C1-6-alkyl, -(CO)O-C1-6-alkyl,
Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv )2;
Rivrepresents N or C1-6-alkyl;
m has the value 1, 2;
n is 0, 1;
and their pharmaceutically acceptable salts.

2. The compound of formula (I) according to claim 1, where
R2represents H or halogeno, and
Riiiand Rivrepresent N or C1-6-alkyl.

3. The compound according to claim 1 of formula (I-a):
,
where X may be the same or different and represent CRiiiRiv, NRiiior, where only one X can represent Oh, and the other represents CRiiiRivor NRiii;
R1represents H,
C1-6-alkyl, possibly substituted by CN,
or phenyl, possibly substituted by one or more than one,
or represents -(CH2)m-Rawhere Rais:
NRiRii,
phenyl, possibly substituted by one or more than one,
or represents -(CH2)n-(CO)-Rbor -(CH2)n-(SO2)-Rbwhere Rbis:
With1-6-alkoxy,
NRiRii,
phenyl or piperidinyl, morpholinyl, pyridinyl, 1,3-oxazolyl, possibly substituted by one or more than one,
R2represents H or halogen,
R3represents H,
R4represents one or more than od of the n residue, selected from N, halogeno, C1-6alkoxy;
In is halogeno, C1-6-alkyl, (CRiiiRiv)n-phenyl,
Riand Riirepresent H, C1-6-alkyl, -(CO)O-C1-6-alkyl,
Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv)2;
Rivrepresents N or C1-6-alkyl;
m has the value 1, 2;
n has a value of 0.1;
as well as its pharmaceutically acceptable salt.

4. The compound according to claim 3 of the formula (I-a), where Riiiand Rivrepresents N or C1-6-alkyl.

5. The compound according to claim 3 of formula (I)where the group (a) compounds of the formula (I-a) selected from (a') and (a"):
or
where Riiirepresents H, C1-6-alkyl or C1-6-alkylene-N(Riv)2and Rivrepresents N or C1-6-alkyl.

6. The compound according to claim 3 of the formula (I-a), where R1represents N.

7. Compounds according to claim 6 of the formula (I-a), where the indicated compounds selected from the group consisting of:
1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
6'-bromo-1-(1H-indol-3-ylcarbonyl)-1 N-Spiro[piperidine-4,4'-quinoline]2'(3'H)-she;
6-chloro-1'-[(6-chloro-1H-indol-3-yl)carbonyl]-1-[2-(dimethylamino)ethyl]Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-it
6-chloro-1'-[(6-chloro-1H-indol-3-yl)carbonyl]Spiro,1-benzoxazine-4,4'-piperidine]-2(1H)-it.

8. Compounds according to claim 3 of the formula (I-a), where R1represents phenyl, possibly substituted by one or more than one, and is the same as defined in item 3.

9. The compound of claim 8 of formula (I-a), where the specified connection is a 1'-{[6-chloro-1-(3,5-differenl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-he.

10. Compounds according to claim 3 of the formula (I-a), where R1represents -(CH2)m-Rawhere Rarepresents NRiRiior phenyl, possibly substituted by one or more than one, and m, Ri, Riiand b are as defined in item 3.

11. The compound of claim 10 of formula (I-a), where the indicated compounds selected from the group consisting of:
1'-{[6-chloro-1-(3,5-diferensial)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[6-chloro-1-(3-terbisil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
3-{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile and
2-{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}propanenitrile.

12. Compounds according to claim 3 of the formula (I-a), where R1represents -(CH2)n-(CO)-Rbor -(CH2)n(SO2)-Rbwhere Rbrepresents a C1-6-alkoxy, NRiRii,phenyl or piperidinyl, morpholinyl, pyridinyl, 1,3-oxazolyl, possibly substituted by one or more than one, and n, Ri, Riiand b are as defined in item 3.

13. The connection section 12 of the formula (I-a), where the indicated compounds selected from the group consisting of:
1'-{[6-chloro-1-(3-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[6-chloro-1-(2-perbenzoic)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[6-chloro-1-(2,3-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-({6-chloro-1-[(3,5-differenl)sulfonyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-({6-chloro-1-[2-(3-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-({6-chloro-1-[2-(3,4-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[1-(biphenyl-3-ylcarbonyl)-6-chloro-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[6-chloro-1-(2-oxo-2-piperidine-1-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[6-chloro-1-(2-morpholine-4-yl-2-oxoethyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
2-{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide;
2-{6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-Pipa is one]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-diethylacetamide;
1'-{[6-chloro-1-(piperidine-1-ylcarbonyl)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
tert-butyl {6-chloro-3-[(2-oxo-1,2-dihydro-1 N-Spiro[3,1-benzoxazine-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}acetate;
1'-{[6-chloro-1-(3,5-differentail)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-({6-chloro-1-[2-(3,5-differenl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-({6-chloro-1-[2-(2-forfinal)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-she;
1'-{[6-chloro-1-(2-oxo-2-pyridin-2-retil)-1H-indol-3-yl]carbonyl}Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-it
1'-({6-chloro-1-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-2-oxoethyl]-1H-indol-3-yl}carbonyl)Spiro[3,1-benzoxazine-4,4'-piperidine]-2(1H)-it.

14. Compounds according to claim 1 of formula (I-b), where the compound is selected from compounds of the formula (I-b):
.

15. The connection 14 of the formula (I-b), where the specified connection is a 2-{6-chloro-3-[(1-oxo-2,3-dihydro-1H,1 N-Spiro[isoquinoline-4,4'-piperidine]-1'-yl)carbonyl]-1H-indol-1-yl}-N-methylacetamide.

16. Compounds according to claim 1 of formula (I-e), where the compound is selected from compounds of the formula (I-e):
.

17. Compounds according to claim 1 of formula (I-f), where the compound is selected from compounds of the formula (I-f):
.

18. The compound of formula (I), (I-a), (I-b), (I-e) is Li (I-f) according to any one of claims 1 to 17 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.

19. Pharmaceutical composition having antagonistic activity against receptor vasopressin V1a containing the compound of formula (I), (I-a), (I-b), (I-e) or (I-f) according to any one of claims 1 to 17, together with pharmaceutically inert inorganic or organic excipients.

20. The pharmaceutical composition according to claim 19, where the pharmaceutical composition is useful for dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.

21. The use of the compounds of formula (I), (I-a), (I-b), (I-e) or (I-f) according to any one of claims 1 to 17 in the preparation of medicines, which has antagonistic activity against receptor vasopressin Via.

22. Use item 21, where the medication is useful for dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

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

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

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

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel indol-3-yl-carbonyl-asaspiro-derivatives of formula I: where R1 represents H,-(CH2)m-Ra, where Ra represents NRiRii, phenyl, possibly substituted by one or more than one B, -(CH2)n-(CO)-Rb , where Rb represents NRiRii; there exists one or more than one R2 , where each R2 is the same or different and represents one or more than one H, in halogen way; R3 represents H, C1-6-alkyl; B represents in halogen way; Ri and Rii each independently represents H, C1-6-alkyl, C1-6alkyl-NRiiiRiv; Riii and Riv each independently represents C1-6alkyl; m equals 1-6; n equals 1-4; A represents group : where R4 represents H or C1-6alkyl; R5 represents phenyl, possibly substituted in halogen way; or its pharmaceutically acceptable salt; on condition that 1-(1H-indol-3-yl-carbonyl)-4-(1,3-dioxolan-2-yl)pyperidine is excluded.

EFFECT: compounds demonstrate antagonistic activity with respect to Via vasopressin receptor, which makes it possible to apply them for obtaining pharmaceutical composition.

22 cl, 4 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to indol-3-yl-carbonyl-spiro-piperadine derivatives used as V1a receptor antagonists and which have formula I: , where the spiro-piperadine A head group and residues R1, R2 and R3 are as defined in claim 1 of the invention. The invention also pertains to pharmaceutical compositions which contain such compounds and use thereof in preparing medicines with V1a receptor antagonist activity.

EFFECT: high activity of derivatives.

37 cl, 1 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: described are spirocyclic derivatives of cyclohexane of general formula . Values of radicals are given in the formula of invention. The compounds have affinity to the ORL1 receptor and can be used for treating abstinence syndrome (withdrawal syndrome) and pain. Also described is a medicinal agent and use of formula (I) compounds for preparing respective medicinal agents.

EFFECT: increased effectiveness of using the compounds.

13 cl, 17 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel derivatives of diazaspiropiperidine of the formula I: , where A-B is -CH2-CH2-, -CH2-O- or -O-CH2-; X is hydrogen or hydroxy; R1 is aryl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, cyano, CF3, -OCF3, (lower) alkoxy, -SO2-(lower)alkyl, or heteroaryl with two nitrogen atoms; R2 is phenyl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, CF3 or (lower) alkoxy; R3 is hydrogen or (lower)alkyl; n is 0, 1 or 2; and their pharmaceutically acceptable salts.

EFFECT: medicine based on compounds of the formula 1 and their application in obtaining medicine for neuropathological and neuropsychiatric disease treatment.

12 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (1) where: R1 represents hydrogen atom, halogen, CP3, (1-3C)alkoxy group, m is an integer within 1 to 4, provided when m is equal to 2, 3 or 4, R1 substitutes can be either identical or different, R2 represents hydrogen atom, alkyl (1-6C) group optionally substituted with alkoxy group, cycloalkyl (3-6C) group, -CH2OH, -CH2OCH3, acetyl group, benzyl group optionally substituted with amino group, or group Q of the following composition (2): were: [ ]n symbolically represents -(CH2)n-, where n is an integer within 0 to 7, R3 represents hydrogen atom or alkyl (1-3C) group, R4 represents hydrogen atom, alkyl (1-6C) group optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkoxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, amido group dialkyl, carboxyl group, saturated, unsaturated or partially saturated mono- or dicyclic 5-10-meroud ring optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or alkyl (1-3C) group substituted with saturated, unsaturated or partially saturated five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen from alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or (R3+R4) together with nitrogen atom, they are attached to, represent saturated, unsaturated or partially saturated mono- or dicyclic five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl groups, as well as to all stereoisomers, to pharmaceutically acceptable salts. Additionally, the invention concerns pharmaceutical compositions and application of compounds.

EFFECT: production of new biologically active compounds with agonist activity to ORL1 receptors.

9 cl, 488 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula where A-B stands for CH2-CH2, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -N(R4)-CH2- or -CH2-N(R4)-; R1 stands for (lower)alkyl, (lower)alkenyl, cycloalkyl or stands for aryl, optionally substituted with one or two substitutes chosen from the group consisting of haloid, cyano, (lower)alkyl, CF3, OCF3 or (lower)alkoxy, or stands for heteroaryl representing cyclic aromatic hydrocarbon radical containing one or two heteroatoms chosen of the group consisting of sulphur or nitrogen, e.g. thiazolyl or thienyl, optionally substituted with one or two substitutes chosen from (lower)alkyl; R2 stands for (lower)alkyl, cycloalkyl or stands for aryl, optionally substituted with one or two substitutes chosen from the group consisting of haloid, (lower)alkyl, CF3, (lower)alkoxy, or stands for heteroaryl representing cyclic aromatic hydrocarbon radical containing one sulphur heteroatom, e.g. thienyl; R3 stands for hydrogen; R4 stands for hydrogen or benzyl; n stands for 0, 1 or 2; and to their pharmaceutically acceptable salts. Besides, the invention concerns a medical product.

EFFECT: production of new biologically active compounds inhibiting glycine carrier 1 (GlyT-1).

19 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, hematology, and can be applied for reduction of spontaneous erythrocyte aggregation in case of arterial hypertension with metabolic syndrome. For this purpose administered are dosed static and dynamic physical activity, daily swimming for not less than 40 min. per day in the middle of the day, as well as lisinopril in dose 10 mg 1 time per day in the morning and methformin 500 mg 2 times per day. Physical activity includes morning hygienic gymnastics, therapeutic-preventive gymnastics and divided physical exercises during the day. Treatment course is 2 months.

EFFECT: combination of treatment methods makes it possible to reduce spontaneous erythrocyte aggregation, which assists prevention of thrombotic complications in said category of patients.

2 ex

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