Benzocycloheptane and benzoxepine derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I), including any stereochemical isomer forms thereof, or a pharmaceutically acceptable salt thereof, , wherein A is phenyl or 6-member aromatic heterocycle containing 1 or 2 nitrogen atom; wherein said phenyl or 6-member aromatic heterocycle may be optionally condensed with phenyl; Z is CH2 or O; R1 is halogen, hydroxyl, C1-4alkyl, C1-4alkyloxy, or provided A is phenyl, then two neighbour substitutes R1 may be taken together to produce a radical of formula: -O-CH2-O- (a-1) or -O-CH2-CH2-O- (a-2); R2 is hydrogen or C1-4alkyl; each R3 and R4 independently is hydrogen, C1-6alkyl, C1-4alklyloxyC1-6alkyl or phenylC1-4alkyl; or R3 and R4 taken together with a nitrogen atom whereto attached form a radical of formula or , wherein X1 is CH2 or CHOH; and X2 is CH2, O or NR6; R5 is hydrogen, halogen, C1-4alkyl or C1-4alkyloxy; R6 is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; n is equal to an integer 0, 1 or 2; provided the compound is other than , or a pharmaceutically acceptable salt thereof.

EFFECT: compounds are used to treat the diseases the treatment of which is affected, mediated or promoted by GHSlA-r receptor activation The present invention also refers to pharmaceutical compositions and an intermediate compound of formula II: .

22 cl, 10 tbl, 11 ex

 

The technical field to which the invention relates.

The present invention relates to the derivatives of benzocycloheptene and benzocaine, with activity on the modulation of the ghrelin receptor, in particular, agonistic properties to the ghrelin receptor (agonist properties to GHS1A-r). The present invention also relates to methods for their preparation and pharmaceutical compositions containing them. The present invention also relates to the use of such compounds for obtaining drugs for prevention or treatment of diseases through the activation of the ghrelin receptor.

A description of the shape

The figure 1 shows the contents of the stomach (measured as units of attenuation phenol red), the remaining 15 minutes after the introduction of phenol red, containing the tested food through the gastric tube in mice GHS1A-r+/+(WT) and GHS1A-r-/-(KO), pre-treated with saline (media) or compound 3 (10 mg/kg SC) for 30 minutes to obtain food (individual data and the mean, n=3).

Description of the prior art

Publication Protiva et al., Collection of Czechoslovak Chemical Communications, 37(6), 1972, 2081-2090, refers to benzocycloheptene and heterocyclic analogues as potential drugs. Described that the pharmacodynamic effects of the compounds are weak. Publication Prtiva et al., Collection of Czechoslovak Chemical Communications, 37(3), 1972, 868-886, refers to benzocycloheptene and heterocyclic analogues as potential drugs. Described that even if some compounds are described as having signs of interest, activity, experimental findings have not been confirmed in any case, further pharmacological or Toxicological studies.

In the US 6013809 described substituted heterocyclic benzocyclobutene and their use as substances with analgesic effect.

Description of the invention

Compounds in accordance with the present invention differ from the compounds of the prior art structure, the pharmaceutical activity and/or pharmacological effectiveness.

In one aspect the present invention relates to a compound of the formula:

including any of its stereochemical isomeric forms, where

A is a phenyl, teinila, TuranAlem or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atom; where the specified phenyl, thienyl, furanyl or 6-membered aromatic heterocycle optionally may be condensed with a phenyl or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atom;

Z is CH2or O;

R1is halogen, hydroxy who Ohm, C1-4the alkyl, C1-4alkyloxy, polyhalogen1-4the alkyl, cyano, nitro, amino, mono - or di(C1-4alkyl)amino; or

if a is a phenyl, two adjacent substituent R1can be taken together with the receipt of the radical of the formula

-O-CH2-O- (a-1); or

-O-CH2-CH2-O- (a-2);

R2is hydrogen or C1-4by alkyl;

R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; or

R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1) or (b-2):

where X1is CH2or CHOH; and X2is CH2, O, or NR6;

R5is hydrogen, halogen, C1-4the alkyl, C1-4alkyloxy or trifluoromethyl;

R6is hydrogen, C1-4the alkyl, C1-4alkylcarboxylic, C1-4allyloxycarbonyl, vinyloxycarbonyl;

n is an integer 0, 1, 2, 3, 4 or 5;

its N-oxide, its pharmaceutically acceptable salt or MES; provided that the compound is not

or its pharmaceutically acceptable salt.

The present invention also relates to the use of compounds of formula (I) to obtain a medicinal medium spans the VA for the prevention or treatment of disease activation of the ghrelin receptor, in particular, for the treatment of disease by activation of the ghrelin receptor.

In the present description C1-4the alkyl group or part of a group that defines straight or branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl; C1-6the alkyl group or part of a group that defines straight or branched saturated hydrocarbon radicals containing from 1 to 6 carbon atoms such as the groups described for C1-4of alkyl, and pentyl, hexyl, 2-methylbutyl and the like.

The term halogen is shared by fluorine, chlorine, bromine and iodine. In the present description polyhalogen1-4the alkyl group or part of a group is defined as mono - or polyhalogen C1-4alkyl, for example methyl, substituted by one or more fluorine atoms, for example, deformity or trifluoromethyl, 1,1-dottorati or 1,1-debtor-2,2,2-triptorelin and the like. In the case of joining more than one halogen atom to C1-4the alkyl group in the definition of polyhalogen1-4of alkyl, they may be the same or different.

If any variable is used more than one time in any constituent, each definition is independent.

Line drawn from the substituents for ring systems, mean that swapimage to be attached to any suitable atom of the ring.

For therapeutic use, salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are not pharmaceutically acceptable may also be used, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts, such as pharmaceutically acceptable and not included in volume C of the invention.

Pharmaceutically acceptable salt in the present description means a therapeutic active non-toxic acid additive salts, which can form compounds of formula (I). The latter can be obtained by treating the base with such appropriate acids as inorganic acids, for example, halogen acids, e.g. hydrochloric, Hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. On the contrary, the salt may be converted by treatment SEL is in whose free base.

The compounds of formula (I)containing acidic protons may be converted into a therapeutically active non-toxic metal or amine salt additive treatment with a suitable organic or inorganic base. Pharmaceutically acceptable salt in the present description also includes therapeutically active non-toxic metal or amine salt additive (basically additive salts), which can form compounds of formula (I). Suitable primary additive salts include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, primary, secondary and tertiary aliphatic or aromatic amines, such as methylamine, ethylamine, Propylamine, Isopropylamine, the four isomeric state of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, Diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, Tripropylamine, heyligen, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propandiol, salt geranamine and salts with amino acids such as, for example, arginine, lysine and the like.

On the contrary, the salt can be converted by treatment with acid into the free acid.

The term salt is also what engages Quaternary ammonium salt (Quaternary amines), which compounds of formula (I) can form in the interaction of the basic nitrogen compounds of formula (I) and a suitable quarternizing agent, such as, for example, optionally substituted C1-6alkylhalogenide, aryl halides, C1-6alkylhalogenide, arylcarbamoyl or arils1-6alkylhalogenide, for example, methyliodide or benzylated, where the aryl is substituted or unsubstituted phenyl. Other reagents with good leaving groups can also be used, such as, for example, C1-6alkylarylsulfonate, C1-6alkylarylsulfonate and C1-6alkyl-p-toluensulfonate. The Quaternary amine is positively charged nitrogen. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triptorelin, acetate, triflate, sulfate, sulfonate. Selected counterion can be introduced using ion-exchange resins.

Preferably, the term salt refers pharmaceutically acceptable acid additive salt and a pharmaceutically acceptable metal or amine additive salt.

N-oxides of the compounds in accordance with the present invention include compounds of formula (I)wherein one or several tertiary nitrogen atoms oxidized to the so-called N-oxide.

The term MES includes hydrates and additive soluble form, which is capable of brazability the compounds of formula (I), and also their salts. Examples of such forms include, for example, hydrates, alcoholate and the like.

It should be clear that some of the compounds of formula (I) and their N-oxides, salts and solvate may contain one or more centers of chirality and exist in the form of stereochemical isomeric forms.

The term "stereochemical isomeric form" in the present description defines all the possible stereoisomeric forms which can have the compounds of formula (I)and their N-oxides, salts or solvate. Unless otherwise indicated, the chemical designation of compounds denotes all possible stereochemical isomeric forms, as well as every single isomeric form of formula (I) and its N-oxides, salts or solvate practically free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2%, and most preferably less than 1% of other isomers. Thus, if the compound of formula (I), for example, is defined as CIS, this means that the compound contains almost no TRANS isomer. Or if the compound of formula (I), for example, is designated as CIS(+), this means that the compound contains almost no Cys(-) isomer.

From the formula (I), it is evident that the compounds in accordance with the present invention have at least two asymmetric carbon atoms in the structures, namely the carbon atom bearing-OR2and-CH2CH2 CH2-NR3R4the Deputy, and the carbon atom carrying-A-(R1)nthe Deputy. In the structure below, these asymmetric carbon atoms marked as *1 and *2.

Depending on the nature of the substituents R1-R5the compounds of formula (I) may contain a third or more asymmetric atoms. Therefore, the compounds of formula (I) may exist in various stereochemical isomeric forms. Unless otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, where these mixes contain all diastereoisomers and enantiomers basic molecular structure.

The absolute configuration of each asymmetric center may be indicated by the stereochemical identity of R and S where R and S legend correspond to the rules described in Pure Appl. Chem. 1976, 45, 11-30, and well known to specialists in this field of technology. Following the conventions of nomenclature CAS, if two stereogenic center is known absolute configuration are present in the molecule, R or S designation is assigned based on the rules of the sequence of Kan-Ingold-Prelog) chiral center with the lowest number, the reference center. The configuration of the second stereogenic center marked with the use of the family who built a legend [R*,R*] or [R*,S*], where the first R* always defined as a reference centre and [R*,R*] denotes the centers with the same chirality, and [R*,S*] denotes the centers with different chirality. For example, if a chiral center with the lowest number in the molecule is S-configuration, and the second center is R, the conditional stereobitrate will be designated as S-[R*, S*]. If you use "α" and "β": the position of the substituent higher priority on the asymmetric carbon atom in the ring system, with the lowest number of atoms in the ring optionally is always in the position "α" average plane defined by a system of rings. The position of the substituent with the highest priority on the other asymmetric carbon atom in the ring system relative to the position of the highest priority reference atom denoted by "α", if it is on the same side of the mean plane defined by a system of rings, or "β", if it is on the other hand, the average plane defined by a system of rings.

The terms CIS and TRANS are used here in accordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2849-2867), and they relate to the position of the substituents on the group ring, more specifically, cycloheptanone or doxepinum ring of compounds of formula (I). For example, when establishing the CIS and TRANS configuration cycloheptanone or oxepanone rings counted Deputy with the highest prio what iteam on the carbon atom *1 cycloheptanone or oxepanone rings and Deputy with the highest priority on the carbon atom *2 cycloheptanone or oxepanone ring (priority substituent is defined under rule sequence Cana-Ingold-Prelog). When two deputies with the highest priority are on the same side of the ring, then the configuration is denoted CIS, if not, the configuration is denoted TRANS.

It is obvious that CIS and TRANS racemates can be further divided into optical isomers, CIS(+) and CIS(-), respectively, TRANS(+) and TRANS(-) using known in the art techniques. In the presence of an additional asymmetric center in the above compounds, the mixture of stereoisomers can be further divided known in the art methods described below. Preferably, if desired specific stereochemical form, this connection can be synthesized by stereoselective methods of obtaining, in which mainly apply enantiomerically pure starting materials.

Since the stereochemical configuration (CIS or TRANS) may already be fixed in the intermediate compounds of formula (II) via the Protocol synthesis, it is already possible to separate CIS and TRANS forms at this stage of receipt. Intermediate compounds of formula (II) preferably have a CIS configuration. The compounds of formula (I) is obtained from CIS intermediates of formula (II), also having the CIS configuration. The compounds of formula (I) preferably have the CIS con is Horatio.

Stereochemical isomeric forms of the compounds of formula (I) is obviously included in the scope of the present invention.

The compounds of formula (I) can be synthesized in the form of racemic mixtures of enantiomers which can be separated from each other below known in the art methods of separation. Racemic compounds of the formula (I) can be converted into the corresponding diastereomeric salt interaction with a suitable chiral acid. These diastereomeric salt further divided, for example, selective or fractional crystallization, and the enantiomers are released from them with the use of alkali. An alternative method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction takes place stereospecific. Preferably, if desired specific stereoisomer, the specified connection synthesize stereospecific methods of getting them. In these methods mainly used enantiomerically pure starting materials.

Some compounds of formula (I) can also exist in tautomers the sixth form. Such forms, although it is not stated clearly in the above formula (I), included in the scope of the present invention.

In the present description, the term "compounds of formula (I)or any subgroup also include their N-oxides, and their salts, their stereochemical isomeric forms and their solvate. Of particular interest are those compounds of formula (I), which are stereochemical clean.

In the present description, if the substituents may be selected independently from a list of multiple definitions, there are included all possible combinations, which are chemically possible.

An interesting variant of the present invention are those compounds of formula (I), where A is phenyl or phenyl substituted from 1 to 5 substituents R1in particular, from 1 to 3 substituents R1more specifically, 1 or 2 substituents R1.

An interesting variant of the present invention are the compounds of formula (I), where A is

An interesting variant of the present invention are the compounds of formula (I), where A is A 6-membered aromatic heterocycle containing 1 or 2 atoms of hydrogen, or A is A 6-membered aromatic heterocycle containing 1 or 2 nitrogen atom, substituted by 1 to 5 substituents R1in particular, from 1 to 3 substituents R1more specifically, 1 or 2 substituents which R 1; in particular, a is pyridium or pyrimidinyl, each of these pyridyl or pyrimidinyl optionally substituted from 1 to 5 substituents R1in particular, from 1 to 3 substituents R1more specifically, 1 or 2 substituents R1.

An interesting variant of the present invention are the compounds of formula (I), where A is A 6-membered aromatic heterocycle containing 1 or 2 nitrogen atom; where the heterocycle condensed with phenyl; specified bicikl optionally substituted from 1 to 5 substituents R1in particular, from 1 to 3 substituents R1more specifically, 1 or 2 substituent R1; in particular, a is hyalinella or hyalinella substituted from 1 to 5 substituents R1in particular, from 1 to 3 substituents R1more specifically, 1 or 2 substituents R1.

An interesting variant of the present invention are the compounds of formula (I), where a is tanila or TuranAlem.

An interesting variant of the present invention are the compounds of formula (I), where a is tanila or TuranAlem, each of which is substituted by 1 or 2 substituents R1.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where Z is CH2.

an Interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where Z is O.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R1is halogen, hydroxyl, C1-4the alkyl or C1-4alkyloxy.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R2is hydrogen.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R2is C1-4the alkyl, in particular, stands.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; or

R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1) or (b-2):

where X1is the tsya CH 2or CHOH; and X2is CH2, O, or NH; in particular, R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; or

R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1) or (b-2):

where X1is CH2or CHOH; and X2is CH2; more specifically, R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; or

R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1):

where X1is CH2or CHOH; even more specifically, R3and R4each independently is hydrogen, C1-6the alkyl, in particular, stands or ethyl; C1-4alkalosis1-6the alkyl, in particular, methoxyethyl; or R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1):

where X1is CH2or CHOH.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup specified in the present description the AK interesting option, where R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; in particular, R3and R4each independently is hydrogen, C1-6the alkyl or C1-4alkalosis1-6by alkyl; more specifically, R3and R4each independently is hydrogen, stands, ethyl or methoxyethyl.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R3and R4taken together with the nitrogen atom to which they are attached, getting a radical of formula (b-1) or (b-2):

where X1is CH2or CHOH; and X2is CH2, O, or NR6; in particular, where R3and R4taken together with the nitrogen atom to which they are attached, getting a radical of formula (b-1) or (b-2):

where X1is CH2or CHOH; and X2is CH2, O, or NH; more specifically, where R3and R4taken together with the nitrogen atom to which they are attached, getting a radical of formula (b-1) or (b-2):

where X1is CH2or CHOH; and X2is CH2even more specifically, R3 and R4taken together with the nitrogen atom to which they are attached, getting a radical of formula (b-1):

where X1is CH2or CHOH.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R5is hydrogen, C1-4the alkyl, C1-4alkyloxy or trifluoromethyl.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R5is hydrogen.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where R5is halogen, C1-4the alkyl, C1-4alkyloxy or trifluoromethyl; in particular, halogen, C1-4the alkyl or C1-4alkyloxy; more specifically, halogen, stands or methoxy; even more specifically, stands or methoxy.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where n is an integer with a value of 0. This means that Zam is stately And not replaced.

An interesting variant of the present invention are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where n is an integer with value 1 or 2. This means that A Deputy has 1 or 2 substituent R1.

An interesting variant of the present invention are the compounds of formula (I), where a is a phenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, pyridium, pyrimidinium, hyalinella; each of these rings is optionally substituted by 1 or 2 substituents, each of which is independently selected from halogen, hydroxyl, C1-4the alkyl or C1-4alkyloxy; R3and R4each independently is hydrogen, C1-4the alkyl, C1-4alkalosis1-4the alkyl, panels1-4by alkyl; or R3and R4taken together with the nitrogen atom to which they are attached, obtaining pyrrolidinyl, optionally substituted in position 3 by hydroxyl; piperidinyl; morpholinyl; piperazinil, optionally substituted C1-4the alkyl or C1-4alkylcarboxylic; R2is hydrogen or stands; R5is hydrogen, halogen or C1-4alkyloxy, in particular, hydrogen, halogen or methoxy, even more specifically, hydrogen or methoxy.

An interesting variant of the present invented the I are the compounds of formula (I) or, if possible, any subgroup, referred to in this description as an interesting option, where the substituents on cycloheptanone or doxepinum ring have the CIS configuration.

An interesting variant of the present invention are the compounds of formula (I)where the compound is chosen from the following:

oxalate (±) CIS-6-(4-chloro-3-methoxyphenyl)-5-(3-diethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-6-(3-chlorophenyl)-5-(3-diethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-4-(4-chloro-3-methoxyphenyl)-5-(3-diethylamino-propyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-ol;

oxalate (±) CIS-6-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

(±) CIS-6-(4-chloro-3-methoxyphenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-6-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-(4-forfinal)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-phenyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-6-(4-chloro-3-methoxyphenyl)-5-{3-[(2-methoxyethyl)methylamino]propyl}-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (is) CIS-5-(3-dimethylaminopropyl)-6-p-tolyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-5-(3-diethylaminopropyl)-6-(4-forfinal)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-6-(2,4-differenl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-4-(4-chloro-3-methoxyphenyl)-5-(3-dimethylaminopropyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-ol;

oxalate (±) CIS-5-(3-diethylaminopropyl)-6-p-tolyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

hydrochloride is (±) CIS-5-(3-diethylaminopropyl)-6-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

oxalate (±) CIS-6-(4-bromophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

hydrochloride is (±) CIS-6-(5-chloropyridin-3-yl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

(±) CIS-5-(3-dimethylaminopropyl)-6-quinoline-3-yl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;

hydrochloride is (±) CIS-5-(3-dimethylaminopropyl)-6-(6-methylpyridin-3-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol.

An interesting variant of the present invention is the oxalate (±) CIS-6-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol.

The present invention also relates to the compound of formula (II):

including any of its stereochemical isomeric forms, where A, Z, R1, R2, R5and n are such as defined for compounds of formula (I); its N-oxide, its formats whitesky acceptable salt or MES.

In particular, the present invention also relates to the compound of formula (II)where the substituents on cycloheptanone or doxepinum ring have the CIS configuration.

If possible, any interesting variant of the compounds of formula (I), from those listed above, are also suitable for compounds of formula (II).

In General, the compounds of formula (I) can be obtained by the interaction of the intermediate compounds of formula (II) with an intermediate compound of formula (III) in the presence of a suitable catalyst, such as, for example, Rh(cod)2BF4not necessarily in the presence of the second catalyst (for recovery), such as, for example, Ir(cod)2BF4in the presence of a suitable ligand such as Xantphos or X-Phos, in a suitable solvent, such as, for example, tetrahydrofuran and an alcohol, e.g. methanol, in the presence of CO and H2(under pressure) at elevated temperature.

The above reaction can also be carried out to obtain the compounds of formula (I-a) from the intermediate compounds of formula (II-a), where P is a suitable protecting group, such as, for example, -Si(CH3)2C(CH3)3, trimethylsilyl, triethylsilyl, benzyl, tetrahydropyranyl. After the reaction, the protective group may be removed, for example, by treatment with a fluoride of tetrabutyl the Oia in the case of Si-containing protective groups, obtaining the compounds of formula (I-a).

The compounds of formula (I), where R2is hydrogen, which is represented by formula (I-b)can also be obtained by the interaction of the intermediate compounds of formula (IV) with an intermediate compound of formula (V), where W1is a suitable leaving group, such as, for example, halogen, e.g. chlorine, bromine and the like, in the presence of Mg, a suitable initiator is the Grignard reaction, such as, for example, 1,2-dibromethane or crystals I2and a suitable solvent, such as tetrahydrofuran or diethyl ether.

The compounds of formula (I), where R3is benzyl, represented by formula (I-c)can be converted into a compound of formula (I), where R3is hydrogen, represented by formula (I-d), by hydrogenation in the presence of a suitable catalyst, such as palladium on charcoal, in the presence of a suitable solvent, such as, for example, an alcohol, e.g. methanol.

The compounds of formula (I) can also be obtained by conversion of compounds of formula (I) into each other is known in the art reactions of the transformation.

The compounds of formula (I) can be converted into the corresponding N-oxides using known data is th technical field of methods of transformation of trivalent nitrogen into its N-oxide. This reaction N-oxidation can usually be carried out by the interaction of the educt of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metal or alkaline earth metal, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene, or substituted by a halogen benzonorbornadiene, for example, 3-chlorobenzalmalononitrile, paracalanidae acid, for example, purakayastha acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The compounds of formula (I) and some intermediate compounds in accordance with the present invention contain at least two asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds can be obtained by applying known in the art techniques. For example, diastereoisomers can be separated by physical methods, such as villages is active crystallization, or chromatographic techniques, e.g. counter current distribution, chiral liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures first transformation of these racemic mixtures with suitable separating agents such as, for example, chiral acids, mixtures of diastereomeric salts or compounds; then physical separation of these mixtures of diastereomeric salts or compounds, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting these separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemical isomeric form can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, provided that the intermediate reaction undergoes stereospecific.

An alternative way of separating the enantiomeric forms of the compounds of formula (I) and intermediates is liquid chromatography or chromatography with SCI (supercritical fluid), in particular, the use of chiral stationary phase.

The compounds of formula (I) can also be converted into pharmaceutically acceptable acid-additive solutiondate with a suitable acid, such as, for example, hydrochloric acid or oxalic acid, in a suitable solvent, such as, for example, an alcohol, for example, 2-propanol, diethyl ether, diisopropyl ether.

Some of the intermediate and source materials are known compounds and can be commercially available or can be obtained well-known in the art methods.

In General, the intermediate compounds of formula (II), where R2is hydrogen, which is represented by formula (II-b)can be obtained by the interaction of the intermediate compounds of formula (IV) bromide vinylmania, in the presence of suitable additives to prevent enolizatsii, such as, for example, CeCl3or other halides of the lanthanides, and a suitable solvent, such as tetrahydrofuran. This reaction is preferably carried out at reduced temperature, for example, -78°C followed by heating to, for example, room temperature.

The intermediate of formula (II-b) can be converted into an intermediate compound of formula (II), where R2is C1-4the alkyl, the above intermediate compound represented by formula (II-c), interaction with C1-4alkylation, in the presence of a suitable base, such as sodium hydride and in a suitable of rest retele, such as, for example, tetrahydrofuran.

Intermediate compounds of formula (II-a) can be obtained by the interaction of the intermediate compounds of formula (IV-a) with bromide vinylmania, in the presence of suitable additives to prevent enolizatsii, such as, for example CeCl3or other halides lanthanide, such as other chlorides of lanthanide, and a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (IV) can be obtained by the interaction of the intermediate compounds of formula (VI) with an intermediate compound of formula (VII), where W2is a suitable leaving group, such as, for example halogen, e.g. bromo and the like, in the presence of a suitable catalyst, such as, for example Pd(OAc)2suitable ligand, such as, for example, Xanthos or Tris(1,1-dimethylethyl)phosphine, a suitable base, such as, for example Cs2CO3or tertiary piperonyl sodium, and a suitable solvent, such as, for example, xylene or tetrahydrofuran. The reaction is preferably carried out in nitrogen atmosphere and at an elevated temperature.

Intermediate compounds of formula (IV-a) can be obtained by the method described above reaction interaction elapsed is knogo the compounds of formula (VI) with an intermediate compound of formula (VII-a).

Intermediate compounds of formula (IV) can also be obtained by the interaction of the intermediate compounds of formula (VIII) with an intermediate compound of formula (VII) in the presence of a suitable catalyst, such as Pd(OAc)2in the presence of tri-o-tolylphosphino or dichlorobis(tri-o-tolylphosphino)palladium, tributylstannyl, and a suitable solvent, such as toluene, optionally in the presence of KF.

Intermediate compounds of formula (VIII) can be obtained by the interaction of the intermediate compounds of formula (VI) with CH3-C(=O)-O-C(CH3)=CH2in the presence of a suitable acid, such as, for example, p-toluensulfonate acid.

Pharmacological

The compounds of formula (I) or any subgroup shows agonistic properties to the ghrelin receptor.

Ghrelin is an endogenous hormone peptide, discovered in the late 1990 X. It is mainly produced in the stomach and is a natural ligand for the receptor of secretagogue growth hormone type 1 (GHS1A-r) (Kojima et al., Nature 1999, 402:656-660). This coupled with G-protein receptor was first cloned only a few years ago (Howard et al., Science 1996, 273:974-977) and is expressed predominantly in the brain (arc and intramed the social nucleus in the hypothalamus, the hippocampus and the black substance) and in the pituitary gland. Apart from these tissues, the receptor has also been identified in other areas of the Central nervous system and in various peripheral tissues, for example, the adrenal and thyroid glands, heart, lungs, kidneys, skeletal muscle and gastrointestinal tract.

In the pituitary gland activation GHS1A-r causes the secretion of growth hormone that is considered to be one of the primary functions of ghrelin-GHS1A-r system. (GHS1A-r functionally and structurally different from the receptor hormone that stimulates growth hormone (GHRH receptor). Another important role is mediated by ghrelin signals is stimulating appetite and eating behavior in positive regulation of energy homeostasis, thereby contributing to obesity, and therefore, it contributes to obesity. As was recently proposed, ghrelin, for this reason, may be called "salinarum" (fattening) peptide.

Apart from stimulating the secretion of growth hormone and positive regulation of energy homeostasis, it has been shown that ghrelin and many synthetic secretion products of growth hormone also: 1) demonstrate hypothalamic activity, which causes the secretion of prolactin (PRL) and ACTH; 2) adversely affect the sex glands-the pituitary gland at Central and peripheral level; 3) affect sleep and led the e; 4) control of intestinal motility and secretion of acid; 5) modulate the exocrine and endocrine functions of the pancreas and affects glucose levels; 6) modulate homeostasis of cartilage and bone; 7) modulate the immune system; and 8) have an effect on cell proliferation (Van der Lely et al., Endocrine Reviews 2004, 25:426-457; Lago et al., Vitamins and Hormones. 2005, 71:405-432).

Elucidation of these different effects of ghrelin paves the way for therapeutic approaches to the treatment of various diseases, in which ghrelin and its receptor play a role. Before the discovery of ghrelin attempts to develop compounds-secretion products of growth hormone for the treatment of conditions associated with growth hormone deficiency, have been held since the late 1970s (Bowers, Curr. Opin. Endocrinol. Diabetes 2000, 7:168-174). Designed compounds were orally active stimulants allocation of growth hormone, which has been tested on humans, including small peptides, such as hexarelin (Zentaris) and ipamorelin (Novo Nordisk), and analogues of adenosine, as well as small molecules such as capromorelin (Pfizer), L-252564 (Merck), MK-0677 (Merck), NN7203 (Novo Nordisk), G-7203 (Genentech), S-37435 (Kaken), SM-130868 (Sumitomo), and others. After identification of ghrelin as the endogenous ligand for GHS1A-r, it was confirmed that these compounds interact with GHS1A-r and behave as agonists. In experimental models it has been shown that many of these compounds demonstrate the effects are very similar to the effects described for ghrelin.

After the discovery of ghrelin and subsequent descriptions of many of its physiological role and effects, attempts according to the invention medicines were extended to a wider range of potential therapeutic applications, such as digestive disorders, requiring prokinetics therapy. Examples of such conditions include idiopathic or diabetic gastroparesis, postoperative ileus caused by opioids dysfunction of the large intestine, short bowel syndrome, chronic intestinal pseudoprobability, vomiting, constipation such as associated with phase hypokinesia with irritable bowel syndrome (IBS), delayed gastric emptying associated with wasting, disease gastro-esophageal reflux (SIPR), stomach ulcers and others (Murray et al., Gastroenterology 2003, 125:1492-1502). In addition, such conditions are often encountered in veterinary medicine that involves the use of such therapeutic agents in this area. As an example, colic are dysfunction motility of the gastrointestinal tract, and they are one of the most frequent causes of death in horses.

According to the literature the present study in laboratory conditions showed that intravenous administration of ghrelin to mice stimulates Oborona is their stomach from the test food (ED 50=0.100 mg/kg, 95% confidence interval 0,058-0,174). But interestingly, ghrelin, administered at a dose of up to 2.5 mg/kg, had no effect on transgenic mice with a deletion of the GHS1A-r. These observations confirm that the gastrointestinal prokinetics properties of the ligand ghrelin mediated by direct interaction with GHS1A-r. Small molecules have shown affinity for GHS1A-r, and therefore their activation involves the stimulation of gastrointestinal motility in General, and bowel movements in particular.

Prokinetics action of ghrelin is independent from the action on the secretion of growth hormone and seems to be mediated vegasno-cholinergic muscarinic way. The required dosing levels equivalent to those required for the secretion of growth hormone and stimulate appetite (Peeters, Physiol. Pharmacol. 2003, 54 (Suppl. 4):95-103). Apart from actions to stimulate GHS1A-r in the gastro-intestinal system, agonists GHS1A-r also play an important role in their functioning. It includes, for example, aspects of reproduction, such as the control of fertility in men and women (antykoncepcja) (ghrelin inhibits the secretion of luteinizing hormone and testosterone) (Arvat et al., Endocrine 2001, 14:35-43; Barreiro and Tena-Sempre, MoI Cell Endocrinol 2004, 226:1-9); neonatal development, where ghrelin affects lactation (Nakahara et al., Biochem Biophys Res Comm 2003, 303:751-755) and the control of growth hormone is ri postnatal growth in children, born with a low weight for this gestational age (Cianfarani et al., Hormone Research 2006, 65(Suppl 3):70-74); cardiovascular system (ghrelin is a potent vasodilator, thus, ghrelin agonists are potential for the treatment of chronic heart failure and cardioprotection: Nagaya and Kangawa, Regul. Pept. 2003, 114:71-77, and Curr. Opin. Pharmacol. 2003, 3:146-151; Intl. Pat. Appl. Publ. WO 2004/014412), and nervous system disorders, such as anxiety, deterioration of cognitive abilities (Carlini et al., Biochem. Biophys. Res. Commun. 2002, 299:739-743), depression, including symptoms of depression in chronic stress (Lutter et al., Nature Neuroscience (2008), vol. 11, No. 7:752-753), neurodegenerative disorders, such as disorders with neurodegeneration compact part of the black substance, such as, for example, Parkinson's disease (it was found that ghrelin exerts a neuroprotective effect) (Jiang et al., Experimental neurology (2008) 212:532-537; Dong et al., J. Mol. Neurosci. (2009), 37:182-189; WO2008/143835). Properties of ghrelin to stimulate appetite mean that agonists GHS1A-r can also be useful agents in the treatment of conditions such as malnutrition and anorexia nervosa. In addition, based on various other reactions to the introduction ghrelin, which have been described, therapeutic application of agonists of the ghrelin also evident in disorders such as: patients with low cortisol levels or symptoms and renegotiating failure (stimulus selection ACTH), rhythm sleep-Wake (ghrelin promotes wakefulness (Szentirmai et al., Am. J. Physiol 2007, 292:R575-R585)), exocrine pancreatic insufficiency, such as people with cystic fibrosis or chronic pancreatitis (ghrelin stimulates the secretion of the pancreas (Am. J. of Physiol 2006:290:G1350-G1358)), protection of organs during pancreatitis (Dembinski et al., J. Physiol Pharmacol 2003, 54:561-573,), osteoporosis (ghrelin directly regulates bone formation) (Fukushima et al., J. Bone Min Res 2005:20:790-798)), memory and learning (Diano et al., Nature Neuroscience 2006, 9:381-388).

Based on the above observations, the use of agonists of the ghrelin presumably causes of therapeutic interest, especially for the treatment of digestive disorders requiring prokinetics therapy, such as, for example, idiopathic or diabetic gastroparesis, postoperative ileus caused by opioid dysfunction of the colon, short bowel syndrome, chronic intestinal pseudoprobability, vomiting, constipation such as associated with phase hypokinesia with irritable bowel syndrome (IBS), delayed gastric emptying associated with wasting, disease gastro-esophageal reflux (SIPR), stomach ulcers, colic; for the treatment of cardiovascular diseases, such as, for example, chronic heart failure or provision is adisasta, as well as to treat disorders of the Central nervous system, such as, for example, anxiety, worsening of cognitive ability, depression, including similar to depression symptoms of chronic stress, neurodegenerative diseases, for example, disease and neurodegeneration compact part of the black substance, such as, for example, Parkinson's disease; to stimulate the appetite, for example, in the treatment of cachexia and anorexia nervosa; for the treatment of patients with low levels of cortisol or symptoms of adrenocortical insufficiency; for treatment of rhythm disorders sleep-Wake; for the treatment of exocrine pancreatic insufficiency, for example, people affected by cystic fibrosis or chronic pancreatitis; to protect organs during pancreatitis; for the treatment of osteoporosis; for improving memory and ability to learn. Agonists of the ghrelin can also be used as a contraceptive.

Due to agonistic action to GHS1A-r of the compounds of formula (I), their N-oxides, their pharmaceutically acceptable salt or solvate used as a medicine, in particular for the treatment or prevention, in particular, for the treatment of diseases, for the treatment or prevention of which is affected, mediates or contributes to activation of the receptor GHS1A-r.

Considering you described what s the pharmacological properties of the compounds of formula (I), their N-oxides, their pharmaceutically acceptable salt or solvate can be used as a medicine, in particular for the treatment or prevention, in particular, for the treatment of diseases, for the treatment or prevention of which is affected, mediates or contributes to activation of the receptor GHS1A-r; more specifically, the compounds of formula (I), their N-oxides, their pharmaceutically acceptable salt or solvate can be used for treatment or prevention, in particular, for the treatment of diseases, for the treatment or prevention of which is affected, mediates or contributes to activation of the receptor GHS1A-r. In particular, these compounds can be used for getting medicines for the treatment or prevention of disease, in the treatment or prevention of which is affected, mediates or contributes to activation of the receptor GHS1A-r, in particular, for the treatment of disease, the treatment of which affect, mediates or contributes to activation of the receptor GHS1A-r. More specifically, the compounds in accordance with the present invention can be applied to obtain drugs for treatment or prevention, in particular treatment of digestive disorders requiring prokinetics therapy, such as, for example, idiopathic or diabetic gastroparesis, postoperative ileus caused by opioid DISP nccia colon, short bowel syndrome, chronic intestinal pseudoprobability, vomiting, constipation such as associated with phase hypokinesia with irritable bowel syndrome (IBS), delayed gastric emptying associated with wasting, disease gastro-esophageal reflux (SIPR), stomach ulcers, colic; for the treatment of cardiovascular diseases, such as chronic heart failure or to provide cardiotoxic, as well as to treat disorders of the Central nervous system, such as, for example, anxiety, worsening of cognitive ability, depression, including similar to depression symptoms of chronic stress, neurodegenerative diseases, for example, the disease neurodegeneration compact part of the black substance, such as, for example, Parkinson's disease; osteoporosis; rhythm sleep-Wake; exocrine pancreatic insufficiency, for example, people affected by cystic fibrosis or chronic pancreatitis; to stimulate the appetite, for example, in the treatment of cachexia and anorexia nervosa; for the treatment of patients with low levels of cortisol or symptoms of adrenocortical insufficiency; to protect organs during pancreatitis; to improve memory and ability to learn.

From the point of view of applicability of the compounds of formula (I)are presented in the Yong way of treating warm-blooded mammals, including humans, suffering from disease, the treatment or prevention of which is affected, mediates or contributes to activation of the receptor GHS1A-r; in particular, a method of treating warm-blooded mammals, including humans, suffering from disease, the treatment of which affect, mediates or contributes to activation of the receptor GHS1A-r. These methods include the introduction of an effective amount of the compounds of formula (I), its N-oxide, its pharmaceutically acceptable salt or MES warm-blooded mammal, including humans.

The present invention also provides a composition for prevention or treatment of disease, the treatment or prevention of which is affected, mediates or contributes to activation of the receptor GHS1A-r; in particular, for the treatment of disease, the treatment of which affect, mediates or contributes to activation of the receptor GHS1A-r. These compositions contain a therapeutically effective amount of a compound of formula I, its N-oxide, its pharmaceutically acceptable salt or MES, and a pharmaceutically acceptable carrier or diluent.

Compounds in accordance with the present invention can be formulated into various pharmaceutical forms for different administration. Suitable compositions may be listed all the songs that are normally used for system introduction the of medicines. To obtain pharmaceutical compositions in accordance with the present invention an effective amount of a particular compound, optionally in salt form, as active ingredient combine thorough mixing with a pharmaceutically acceptable carrier, where the carrier may take many forms depending on the preparation desired for administration. These pharmaceutical compositions are desirable in a standard dosage forms, suitable, especially, for administration orally, rectally, transdermally, or parenterally by injection. For example, to obtain compositions in oral dosage form may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like for liquid oral compositions, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricating agents, binding agents, loosening agents and the like in the case of powders, pills, capsules and tablets. Because of the ease of use of tablets and capsules represent the most preferred oral dosage form, in which use solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least mostly, though, may be the ü included other ingredients for example, the solubility improvers. Injectable solutions, for example, can be obtained with a carrier, which is a saline solution, glucose solution or a mixture of saline and glucose solution. Suspension for injection can also be obtained with the use of suitable liquid carriers, suspendida agents and the like. Also looks solid compositions which are intended for turning, immediately before use, in a liquid composition. In the compositions suitable for percutaneous administration, the carrier optionally contains an agent that improves the penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor quantities, where the additive does not have a significant adverse effect on the skin. These additives can facilitate introduction into the skin and/or assist in obtaining the desired compositions. These compositions can be administered in various ways, for example, in the form of a transcutaneous patch, spot, in the form of ointment.

Compounds in accordance with the present invention can also be administered by inhalation or insufflation using the methods and compositions used in the introduction this way. Thus, in General, the compounds in accordance with the present invention can be introduced into the light is in the form of a solution, suspension or dry powder. Any system designed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation, suitable for the introduction of compounds in accordance with the present invention.

Compounds in accordance with the present invention can also be administered topically in the form of drops, in particular, eye drops. These eye drops can be in the form of a solution or suspension. Any system designed for the delivery of solutions or suspensions in the form of eye drops, suitable for the introduction of compounds in accordance with the present invention.

Especially, it is preferable to make the above pharmaceutical composition in a standard dosage form for ease of administration and uniformity of dosage. Standard dosage forms include physically discrete units suitable for single dosing, where each unit contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms include tablets (including tablets with notches or in the shell), capsules, pills, sachets of powder, wafers, suppositories, solutions or suspensions for injection and the like, and is segregated set.

The exact dose and frequency of administration depends on the particular applicable compounds of formula (I), specific treat the condition, the severity treat the condition, age, weight, sex, duration of the disease and the General physical condition of the particular patient, and other medications that can be taken by a patient, as is well known to specialists in this field of technology. Further, it is obvious that the effective daily amount may be reduced or increased depending on the reaction treat the patient and/or depending on the evaluation of the physician prescribing the compounds in accordance with the present invention.

Depending on the method of administration of the pharmaceutical composition preferably contains from 0.05 to 99 wt. -%, more preferably from 0.1 to 70 wt. -%, even more preferably from 0.1 to 50 wt%. the active ingredient and from 1 to 99.95 wt. -%, more preferably from 30 to 99.9 wt. -%, even more preferably from 50 to 99.9% of the mass. pharmaceutically acceptable carrier, where all percentages are relative to the total weight of the composition.

The following examples illustrate the present invention.

Experimental part

In the present description, the term "CHM" means dichloromethane, "MeOH" means methanol, "EtOAc" means ethyl acetate, "DIPE" means diisopropyl ether, T is f" means tetrahydrofuran, "EHMS" means liquid chromatography/mass spectrometry, "EQ." Means the equivalent of, "HPLC" means high performance liquid chromatography, "K.T." means room temperature, "Rh(COD)2BF4means tetrafluoroborate(1-) bis[(1,2,5,6-η)-1,5-cyclooctadiene]rhodium(1+), "Ir(COD)2BF4means tetrafluoroborate(1-) bis[(1,2,5,6-η)-1,5-cyclooctadiene]iridium(1+), Pd(Oac)2" means palladium acetate, X-Phos" means DICYCLOHEXYL[2',4',6'-Tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine, "Xantphos" means (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine], "SIH means of supercritical fluid chromatography, "MeI" means methyliodide, "NH4Oac" means ammonium acetate, "S.N." means "how much" and "K.T." means room temperature.

A. Obtaining intermediates

Example A1

a-1) preparation of intermediate compound 1

The mixture 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-it is 37.2 ml, 0,2480 mol), 1-bromo-4-chlorobenzene (47,4 g, 0,2480 mol) and Cs2CO3(179,2 g) in xylene (600 ml) are mixed and washed with N2. Add Pd(OAc)2(2.8 g) and X-Phos (11.6 g) and the reaction mixture is heated to 150°C. the mixture is Then cooled to K.T. and filtered. The filtrate is diluted with DHM. This organic mixture was washed with aqueous solution of NH4Cl, dried (MgSO4), filtered and the solvent is evaporated. About who headed the remainder of the purified by distillation (distillation Cuellar) to obtain 44 g of intermediate compound 1 (66%).

a-2) Obtaining intermediate compounds 1

A mixture of THF (100 ml), Pd(OAc)2(1.4 g, 0,0062 mol) and tert-butoxide sodium (8,3 g, 0,0870 mol) is stirred for 15 minutes at K.T. in an atmosphere of N2. Then first add Tris(1,1-dimethylethyl)phosphine (1.3 g, 0,0062 mol), then add 1-bromo-4-chlorobenzene (10.8 g, 0,0560 mol) and, finally, 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-Oh (10 g, 0,0624 mol). The reaction mixture is slowly heated to 50°C and the mixture is kept at this temperature for 3 hours, after which it is stirred over night at K.T. Mixture again heated for 4 hours at 75°C and then cooled to K.T. Mixture is quenched with saturated solution of NH4Cl and extracted with 3x DHM. The combined organic extracts are washed (H2O), dried (MgSO4), filtered and the solvent is evaporated. The residue is purified on silica gel (eluent: DHM). Pure fractions concentrated in vacuo. The residue is triturated in n-hexane. The precipitate is filtered and dried (40°C, 2 hours) to obtain 2.9 g of intermediate compound 1.

b) Receiving the intermediate 2

CIS relative stereochemistry

CeCl3(112 g, 0,450 mol) is dried overnight at 140°C and then cooled to K.T. and stirred in THF (S.N.) for 90 minutes. The white suspension is cooled to -78°C and added dropwise bromide vinylmania (,7 M in THF) (450 ml, 0,315 mol) over 30 minutes. Light orange suspension is stirred for 30 minutes and the mixture of intermediate compound 1 (40 g, 0,150 mol) in THF (500 ml) is added dropwise within 30 minutes. The reaction mixture is slowly heated over night to K.T. Then the mixture is quenched with aqueous solution of NH4Cl. Resinous precipitate is filtered and washed with simple ether. The layers are separated and the aqueous phase is extracted with simple ether. The combined organic layers are washed (H2O), dried (MgSO4), filtered and the filtrate is evaporated to obtain a thick brown oil. Output: intermediate compound 2.

c) Obtaining an intermediate compound 14

CIS relative stereochemistry

Intermediate compound 2 (1 g, 0,0033 mol) is stirred in THF (50 ml). Add NaH (0.3 g, 0,006 mol) and the reaction mixture is stirred for 30 minutes. Add MeI and the reaction mixture was stirred over night. The mixture is then concentrated, washed (H2O), dried, filtered and the solvent is evaporated (in vacuo). The residue is purified by chromatography on a column of silica gel (eluent: DHM/heptane 50/50). Fractions of product are collected and the solvent is evaporated. Yield: 0.7 g of intermediate compound 14.

Example A2

a) Obtaining an intermediate compound 3

The mixture 6,7,8,9-tetrahydro-5H-benzac kogepan-5-it (18.6 ml, 0,124 mol), (4 bromophenoxy)-tert-butyldimethylsilyl (30,34 ml, 0,124 mol) and CsCO3(89,6 g) in xylene (400 ml) is stirred and washed with N2. Then add Pd(OAc)2(1.4 g) and X-Phos (5,80 g) and the reaction mixture is heated to 150°C and stirred over night at 80°C. the Mixture is cooled to K.T., filtered, diluted with DHM, washed with a solution of NH4Cl), dried (MgSO4), filtered and the solvent is evaporated. After processing, the residue is purified HPLC with reversed phase (Shandon Hyperprep® C18 BDS (base deactivated silica) 8 μm, 250 g, E, 5 cm). Apply the gradient from 3 mobile phases. Phase A: a 0.25% solution of NH4HCO3in water; phase B: MeOH; phase C: CH3CN). The desired fractions are collected. After processing gain of 6.61 g of intermediate compound 3.

b) Obtaining an intermediate compound 4

CIS relative stereochemistry

CeCl3(14,7 g) is stirred in THF (150 ml, dry) to obtain the suspension. This mixture is stirred for 2 hours. Then add the bromide vinylmania (0,7 M in THF) (57 ml, 0.040 mol) dropwise within 15 minutes at -78°C. and Then added dropwise intermediate compound 3 (of 6.61 g, 0.018 mol) in 90 minutes and the mixture was stirred at -78°C for 2 hours. Then the reaction mixture is heated slowly to K.T. (during the night). Then the mixture is again cooled to 0°C and quenched with a solution of NH4 Cl. The mixture is filtered over Dicalite. The solvent is evaporated and to the residue add DHM. This organic mixture was washed with a solution of NH4Cl), dried (MgSO4), filtered and the solvent is evaporated. The crude compound purified flash chromatography on a column (eluent: heptane to DHM). The desired fractions are collected and the solvent is evaporated. Output: 6,05 g of intermediate compound 4 (85%).

Example A3

a) Obtaining an intermediate compound 5

A mixture of 2,3,4,5-tetrahydro-1-benzoxazin-5-it (2 g, 0,0120 mol), 2-acetoxy-1-propene (2,9 ml, 0,0260 mol) and p-toluensulfonate acid (0.24 g, 0,0010 mol) is stirred and refluxed overnight. Add EtOAc. The organic layer was washed with K2CO3(10% solution), dried (MgSO4), filtered and the solvent is evaporated. The residue (3.2 g) purified by chromatography on a column of silica gel (eluent: cyclohexane/EtOAc 95/5; 15-40 μm). Pure fractions are collected and the solvent is evaporated. Yield: 2.6 g of intermediate compound 5 (100%).

b) Obtaining an intermediate compound 6

A solution of Pd(OAc)2(0.03 g, 0.0001 mol) and tri-O-tolylphosphino (0.08 g, is 0.0002 mol) is added to a solution of intermediate compound 5 (2.6 g, 0,0130 mol) in toluene (25 ml). Then add brobinson (1.5 ml, 0,0140 mol) and tributylamine (3,7 ml, 0,0130 mol) and re is clonney the mixture is refluxed over night. Add K2CO3and the mixture filtered through Celite. Celite was washed with EtOAc. The filtrate is washed with water saturated NaCl), dried (MgSO4), filtered and the solvent is evaporated. The residue (2.7 g) purified by chromatography on a column of silica gel (eluent: cyclohexane/EtOAc 97/3; 15-40 μm). Pure fractions are collected and the solvent is evaporated. Yield: 1.1 g of intermediate compound 6 (36%).

Example A4

a) Obtaining an intermediate compound 7

A mixture of 2,3,4,5-tetrahydro-1-benzoxazin-5-she (3.8 g, is 0.023 mol), 5-bromo-2-methylpyridine (4 g, is 0.023 mol), Cs2CO3(18 g) and xylene (100 ml) is stirred and washed with N2within 20 minutes. Add Pd(OAc)2(0.27 g) and X-Phos (1.18 g) and the reaction mixture was stirred and refluxed in an atmosphere of N2within 5 hours. The mixture is then cooled and filtered. The filtrate was washed with aqueous solution of NH4Cl. The organic layer is dried and concentrated. The residue is purified over silica gel (eluent: DHM/MeOH 95/5). Fractions of product are collected and the solvent is evaporated. Yield: 4.5 g of intermediate compound 7.

b) Obtaining an intermediate compound 8

CIS relative stereochemistry

CeCl3(5.9 g) is dried overnight in vacuum at 140°C. the Dried CeCl3stirred in THF (60 ml) for 2 hours in almost the re N 2. This mixture is cooled to -78°C and add the bromide vinylmania (32 ml, to 0.032 mol; 1M solution in THF) over 10 minutes. Then add the intermediate compound 7 (2.2 g, 0,008 mol) in THF (50 ml) for 30 minutes. The reaction mixture is heated to K.T. and stirred for 1 hour. Then the reaction mixture is cooled on ice and added an aqueous solution of NH4Cl (6 ml). The reaction mixture is stirred for 1 hour and then filtered. The filtrate is dried, filtered and the solvent of the filtrate is evaporated. The residue is purified over silica gel (eluent: DHM/MeOH 98/2). Fractions of product are collected and the solvent is evaporated. Yield: 1.2 g of intermediate compound 8.

Example A5

a) Obtaining an intermediate compound (9)

A mixture of 1-bromo-4-methylbenzene (3.2 g, 0,018709 mol)of 2,3,4,5-tetrahydro-1-benzoxazin-5-it (3 g, 0,018497 mol), Cs2CO3(18 g, 0,055245 mol) and xylene (100 ml) is stirred and washed with N2within 20 minutes. Add Pd(OAc)2(0.27 g, 0,000456 mol) and X-Phos (1.18 g) and the reaction mixture is refluxed under N2within 5 hours. The mixture is then cooled and filtered. The filtrate is washed with a solution of NH4Cl. The organic layer is dried and concentrated. The residue is purified by chromatography over silica gel (eluent: DHM). The desired fractions are collected and the solvent is evaporated. Yield: 4 g of the intermediate is placed 9 (85,7%).

b) Obtaining an intermediate compound 10

CIS relative stereochemistry

CeCl3(10.8 g, 0,043818 mol) is dried overnight in vacuum at 140°C. the Dried CeCl3stirred in THF (150 ml) for 2 hours in an atmosphere of N2). The mixture is then cooled to -78°C and add the bromide vinylmania (4 equivalent; 1 M solution in THF) over 10 minutes. Then add the intermediate compound 9 (4 g, 0,015853 mol) and THF (50 ml) for 30 minutes. The reaction mixture is heated to K.T. and stirred over night. Then the mixture is cooled on ice and add 10 ml of NH4Cl solution. The mixture is stirred for 1 hour and then filtered. The filtrate is dried, filtered and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (eluent: DHM). The desired fractions are collected and the solvent is evaporated. Yield: 3.4 g of intermediate compound 10 (76,5%).

Example A6

a) Obtaining an intermediate compound (11)

The mixture 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-she (1.6 g, 0,010 mol), 5-bromo-2-methylpyridine (1.7 g, 0,010 mol), Pd(OAc)2(0.11 g, of 0.0005 mol), X-Phos (0,477 g, 0.001 mol) and Cs2CO3(6.5 g, of 0.022 mol) in xylene (S.N.) is heated overnight at 140°C. Then the reaction mixture is cooled, the solvent is evaporated and the residue purified by chromatography on Biotage column, elwira what radianta 0-5% MeOH/DHM. Fractions of product are collected, and the solvent is evaporated to obtain intermediate compound (11).

b) Obtaining an intermediate compound 12

CIS relative stereochemistry

CeCl3(7,46 g, at 0.020 mol) is dried at 80°C under a pressure of 0.02 mbar for 2 hours, then at 110°C for 1 hour and finally at 140°C for 2 hours. After cooling, a white powder was stirred in dry THF (75 ml) in an atmosphere of N2when K.T. within 90 minutes. The white suspension is cooled to -78°C and add the bromide vinylmania (0,7M in THF) (20 ml) dropwise with obtaining a light yellow suspension. After 1 hour, add the intermediate compound 11 (1.65 g, 0,00657 mol) in THF (S.N.) dropwise at -78°C and the mixture is stirred for 1 hour. The mixture is then heated to -20°C and quenched with aqueous solution of NH4Cl. The mixture is then diluted with additional H2O and filtered through Celite. The filtrate is extracted with simple ether, dried (MgSO4), filtered and the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel, elwira 5% MeOH/DHM. Fractions of product are collected and the solvent is evaporated. The oil obtained is placed in DIPE and add n-heptane. The crystallized solid is filtered off and dried. Yield: 1.12 g of intermediate compound 12 (solid white).

Example A7

Getting Prohm is filling connection 13

A mixture of acetate 6,7-dihydro-5H-benzocycloheptene-9-ol (3 g, 0,0150 mol), 1-bromo-3-methoxybenzene (2.2 ml, 0,0180 mol), dichlorobis(three-o-tolylphosphino)palladium (0,23 g, 0,0082 mol) and tributyltinchloride (0,23 g, 0,0082 mol) in toluene (30 ml) is stirred and refluxed overnight. Add KF (10%) and the mixture is stirred over night at K.T. Precipitate is filtered through Celite. Celite was washed with EtOAc. The filtrate is extracted with EtOAc and the combined organic layers washed with water saturated with NaCl). The separated organic layer is dried (MgSO4), filtered and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (eluent: cyclohexane/EtOAc 95/5 to 90/10; 20-45 μm). Pure fractions are collected and the solvent is evaporated, to obtain 1.8 g of intermediate compound 13 (45%).

Example A8

a) Obtaining an intermediate compound 15

A mixture of 7-chloro-3,4-dihydro-1-benzoxazepin-5(2H)-she (9,8 g, 0,050 mol), 4-bromo-N,N-dimethylbenzenamine (9.5 g, 0,050 mol), X-Phos (2.4 g), Cs2CO3(4.11 g) and Pd(OAc)2(0.65 g) in xylene (150 ml) is heated to 110-120°C for 6 hours in an atmosphere of N2. After the reaction the mixture is filtered and the solvent is evaporated. The residue is purified by chromatography on a column (eluent: petroleum ether/EtOAc 1/1). The desired fractions are collected and the solvent vapour is granted. The residue is crystallized from ethanol to obtain 8.2 g of the intermediate compound 15 in the form of a solid Magenta (51,9% yield).

b) Obtaining an intermediate compound 16

CIS relative stereochemistry

CeCl3(0,0239 mol) is dried overnight in vacuum at 140°C. the Dried CeCl3stirred in THF (60 ml) for 2 hours in an atmosphere of N2. This mixture is cooled to -78°C and add the bromide vinylmania (to 0.032 mol; 1M solution in THF) for 19 minutes. Then add the intermediate compound 15 (0,008 mol) in THF (50 ml) for 30 minutes. The reaction mixture is heated to K.T. and stirred for 1 hour. Then the reaction mixture is cooled on ice and added an aqueous solution of NH4Cl (6 ml). The reaction mixture is stirred for 1 hour and then filtered. The filtrate is dried, filtered and the solvent of the filtrate is evaporated. The residue is purified by chromatography on a column. Output: intermediate connection 16.

Example A9

a) Obtaining an intermediate compound 17

A mixture of 3,4-dihydro-9-methoxy-1-benzoxazepin-5(2H)-she (1.92 g, 0,010 mol), 4-bromo-N,N-dimethylbenzenamine (2.0 g, 0,010 mol), X-Phos (0,48 g), Cs2CO3(6,54 g) and Pd(OAc)2(0.12 g) in xylene (40 ml) was heated to 110-120°C for 12 hours in an atmosphere of N2. After the reaction the mixture is filtered and rastvoritelyami. The residue is purified by chromatography on a column (eluent: petroleum ether/EtOAc 10/1). The desired fractions are collected and the solvent is evaporated. The residue is crystallized from ethanol to obtain 1.2 g of the intermediate compound 17 in a solid white color (38,7% yield).

b) Obtaining an intermediate compound 18

CIS relative stereochemistry

CeCl3(0,0239 mol) is dried overnight in vacuum at 140°C. the Dried CeCl3stirred in THF (60 ml) for 2 hours in an atmosphere of N2. This mixture is cooled to -78°C and add the bromide vinylmania (to 0.032 mol; 1M solution in THF) over 10 minutes. Then add the intermediate compound 17 (0,008 mol) in THF (50 ml) for 30 minutes. The reaction mixture is heated to K.T. and stirred for 1 hour. Then the reaction mixture is cooled on ice and added an aqueous solution of NH4Cl (6 ml). The reaction mixture is stirred for 1 hour and then filtered. The filtrate is dried, filtered and the solvent of the filtrate is evaporated. The residue is purified by chromatography on a column. Output: intermediate connection 18.

In tables 1-3 lists the compounds of formula (II), which are similar to the methods of the above examples (Ex. No.) and used for the synthesis of compounds of formula (I).

Table 1

Table 2

Table 3

B. Obtaining compounds

Example B1

a-1) preparation of compounds 1, 3 and 4

Connection 1 (CIS-relative stereochemistry; free base)

Connection 3 ([α]D20=+8,02° (0,6112 mass./vol.%, DMF); oxalate)

Compound 4 ([α]D20=-7,69° (0,5335 mass./vol.%, DMF); oxalate)

A mixture of intermediate compound 2 (15 g, 0,050 mol), Rh(COD)2BF4(0.02 g), Ir(COD)2BF4(0.05 g) and Xantphos (0.12 g) in Dima is ylamine (30% in MeOH) (8 ml), THF (50 ml) and MeOH (50 ml) in an atmosphere of CO/H2(7/33 ATM) and stirred for 32 hours at 100°C. Then the reaction mixture was concentrated and the residue purified by chromatography on a column (eluent: first DHM; then 5% MeOH/DHM; finally 10% (MeOH/NH3)/DHM). Pure fractions are collected to obtain 4 g of a yellow oil, which crystallizes upon maturation. The solid is triturated in heptane and collected by filtration. The product is dried overnight (50°C, vacuum), with 2.24 g of compound 1 in the form of a cream solid color (CIS mixture). The second fraction is crystallized from the filtrate to obtain a second party (0,390 g) of compound 1 as white crystals (CIS mixture). Part of the first batch (2 g) connection 1 further separated into its enantiomers preparative SIH (download: 55 mg/1.5 ml; column Chiralpak AD-H (30×250 mm); mobile phase (stored within 9 minutes): 25% MeOH (+0,2% 2-Propylamine)/75% CO2); flow: 50 ml/min; the temperature of the heater column: 40°C; the pressure in the injector: 100 bar). Two different fractions of product are collected and the solvent is evaporated. The compound, which eluted first from the column (as free base), crystallized in the form of oxalate with the release of 1.00 g of compound 3. The compound, which eluted second column (as free base), crystallized in the form of oxalate with the receipt of 1.00 g of compound 4.

a-2) Receiving connect the deposits 2, 3 and 4

Compound 2 (CIS-relative stereochemistry; oxalate)

Connection 3 ([α]D20=+8,02° (0,6112 mass./vol.%, DMF); oxalate)

Compound 4 ([α]D20=-7,69° (0,5335 mass./vol.%, DMF); oxalate)

A mixture of intermediate compound 2 (5 g, to 0.016 mol), dimethylamine (30% in MeOH) (3 ml), Rh(COD)2BF4(0.008 g), Ir(COD)2BF4(0.02 g) and Xantphos (0,048 g) in MeOH/toluene (40 ml; 1/1) in an atmosphere of CO/H2(7/33 ATM) is subjected to interaction within 32 hours at 100°C. This reaction is carried out 4 times. United party purified by chromatography on a column of silica gel (eluent: first DHM; then 5% MeOH/DHM; and finally 5% (MeOH/NH3)/DHM). The desired fractions are collected and the solvent is evaporated to obtain 15 g of crude oil. This oil is placed in 2-propanol and treated with oxalic acid. The solid is collected and dried in vacuum to obtain 10 g of compound 2 as a solid white color (CIS mixture). Compound 2 is separated into the enantiomers preparative SIH (column Chiralpak AD-H (30×250 mm); mobile phase: 28% MeOH (+0,2% 2-Propylamine)/72% CO2); flow: 50 ml/min; the temperature of the heater column: 40°C; the pressure in the injector: 100 bar). Two different fractions of product are collected and the solvent is evaporated. The compound, which eluted first from the column, converted into oxalate. Yield: 4.1 g of compound 3. Connected to the e, which eluted second column is converted into oxalate. Output: of 4.05 g of compound 4.

b) Obtaining compounds 1, 3, 4, 5 and 6

Connection 1 (CIS-relative stereochemistry; free base)

Compound 5 (free base)

Compound 5a (HCl salt)

Compound 6 (free base)

Compound 6a (HCl salt)

Connection 3 ([α]D20=+8,02° (0,6112 mass./vol.%, DMF); oxalate)

Compound 4 ([α]D20=-7,69° (0,5335 mass./vol.%, DMF); oxalate)

A mixture of 3-chloro-N,N-dimethyl-1-propanamine* (a small amount), Mg (1.45 g, 0,0610 mol) and 1,2-dibromethane (small amount) in THF (2 ml) was stirred at 60°C. Then add a solution of the hydrochloride of 3-chloro-N,N-dimethyl-1-propanamine (7,4 g, 0,0610 mol) in THF (50 ml). The reaction mixture is stirred for 1 hour and then cooled to 5°C. Slowly add a solution of intermediate compound 1 (5.5 g, 0.02 mol) in THF (50 ml). The mixture was stirred at K.T. within 18 hours. Add aqueous saturated solution of NH4Cl and the resulting mixture extracted with EtOAc. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated. The residue (6.3 g) purified by chromatography on a column of silica gel (eluent: DHM/MeOH/NH4OH from 96/4/0,3 to 95/5/0,5; 15-40 μm). The desired fraction is collected from the receipt of 2.35 g of compound 1 (CIS mixture). Connection 1 is cleaned chromium is ografia on a column of silica gel (Chiralpak AD; eluent: heptane/2-propanol/Et3N 97/3/0,1). Two different fractions are collected, and the solvent is evaporated. The compound, which eluted first from the column, gives 1.1 g of compound 5 (free base). The compound, which eluted second column gives 1.1 g of compound 6 (free base). The connection part 5 (1 g) dissolved in 2-propanol and converted into the HCl salt by addition of HCl/2-propanol (1.1 EQ.; 5 BC). The precipitate is filtered and dried. The residue is placed in MeOH and concentrated. To the residue is added diethyl ether and the mixture is concentrated to obtain 0.9 g of compound 5a (HCl salt). Also part of compound 6 (1 g) is converted into the HCl salt by the same method of obtaining 1.0 g of compound 6a (HCl salt). Compound 5a (0.9 g) is again converted into the free base by addition of H2O/K2CO3/DHM to obtain 0.9 g of the free base. The free base was dissolved in 2-propanone and converted into the salt of ethicality. The precipitate is filtered and dried. The residue is crystallized from 2-propanone/diethyl ether. The product is filtered and dried to obtain 0.8 g of compound 4. Also compound 6a (1.0 g) is transformed into its base. The residue (0.8 g) dissolved in 2-propanone and converted into the salt of ethicality. The precipitate is filtered and dried. The residue is crystallized from 2-propanone/diethyl ether. The product is filtered and dried to obtain 0,82 g of compound 3.

* Intense races of the thief NaHCO 3(205 ml) is added slowly to a suspension of the hydrochloride of 3-chloro-N,N-dimethyl-1-propanamine (25 g, 0,158 mol, CAS [4584-46-7]) Et2O (200 ml). The mixture is stirred at RT for 1 hour, then saturated with K2CO3(solid). The mixture is extracted with Et2O. the Organic layer is dried over MgSO4and concentrate at RT under vacuum to obtain 15.5 g of 3-chloro-N,N-dimethyl-1-propanamine (yield 75%).

Example B2

Obtain compound 7

Compound 7 (CIS relative stereochemistry)

A mixture of intermediate compound 4 (0.4 g, 0,00101 mol), research (0.3 g), Rh(COD)2BF4(0.004 g), Ir(COD)2BF4(0.01 g) and Xantphos (0,024 g) in MeOH/THF (40 ml; 1/1) in an atmosphere of CO/H2(7/33 ATM) is subjected to interaction in a sealed tube for 32 hours at 100°C. Then the mixture is cooled to K.T., filtered and the filtrate is evaporated (in vacuo). The product was then purified HPLC with reversed phase (Shandon Hyperprep® C18 BDS (base deactivated silica) 8 μm, 250 g, E, 5 cm). Apply the gradient from 3 mobile phases. Phase A: 90% to 0.5% NH4OAc solution in water + 10% CH3CN; phase B: MeOH; phase C: CH3CN). The desired fractions are collected and the organic solvent is evaporated. The aqueous concentrate is extracted DHM and washed with aqueous solution of Na2CO3(10%; 2x). The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated. About who headed the remainder of crystallized from DIPE, filtered and dried. Compound 7 obtained as a white powder.

Example B3

Getting connection 8

Compound 8a (CIS-relative stereochemistry; free base)

Compound 8 (CIS-relative stereochemistry; oxalate)

A small amount of 3-chloro-N,N-dimethyl-1-propanamine (obtained as described in B1b), Mg (0.5 g, 0.02 mol) and 1,2-dibromethane (small amount) in THF (2 ml) was stirred at 60°C. Slowly add a solution of the hydrochloride of 3-chloro-N,N-dimethyl-1-propanamine (0.02 mol) in THF (15 ml). The mixture is stirred for 1 hour and then cooled to 50°C. Slowly add a solution of intermediate compound 6 (1.1 g, 0,0070 mol) in THF (10 ml). The mixture was stirred at K.T. during the night. Add saturated aqueous solution of NH4Cl. The mixture is extracted with EtOAc. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated. The residue (1.5 g) purified by chromatography on a column of over Kromasil (eluent: DHM/MeOH/NH4OH 93/7/0,5; 15-40 μm). Purified fractions collected and the solvent is evaporated. Yield: 1.1 g of compound 8a (free base; 80%). These fractions are dissolved in 2-propanone and converted into the salt of ethicality (= oxalate). The precipitate is filtered and dried. Yield: 0.6 g of compound 8.

Example B4

Obtaining the compound (9)

Compound 9 (CIS, relative stereo is IMIA)

A mixture of intermediate compound 8 (1.3 g, 0,0046 mol), dimethylamine (2 ml MeOH), Rh(COD)2BF4(0.004 g), Ir(COD)2BF4(0,010 g) and Xantphos (0,024 g) in MeOH/THF (40 ml; 1/1) in an atmosphere of CO/H2(7/32 stranded ATM) is subjected to interaction within 32 hours at 100°C. After cooling, the reaction mixture is filtered and the filtrate concentrated in vacuo. The residue (1.6 g) purified HPLC with reversed phase (Shandon Hyperprep® Cl8 BDS (base deactivated silica) 8 μm, 250 g, E, 5 cm). Apply the gradient with buffer solution and organic solvents. Then the product absoluut HPLC. Fraction of the product are collected and processed. Yield: 0.6 g of compound (9).

Example B5

a) Receiving connection 10

Compound 10 (CIS relative stereochemistry)

The reaction is carried out in an autoclave in an atmosphere of N2. A mixture of intermediate compound 10 (1 g, 0,003567 mol), Rh(COD)2BF4(0,001448 g), Ir(COD)2BF4(0,001766 g), Xantphos (0,020616 g) and N-methylbenzeneethanamine (2 equivalent, 0,864429 g, 0,007133 mol) in MeOH/THF (40 ml, 1/1) is loaded into the autoclave and the autoclave create pressure up to 50 bar CO/H2(1/3). The mixture is subjected to interaction within 32 hours at 100°C. the mixture is Then filtered and the solvent is evaporated. The residue is purified over silica gel (eluent: DHM). The desired fractions are collected and the solvent is evaporated to obtain 0.8 g with the organisations 10.

b) Obtaining the compound (11)

Compound 11a (CIS-relative stereochemistry; free base)

Compound 11 (CIS-relative stereochemistry; oxalate)

Pd/C 10% (0,100 g) is suspended in MeOH (50 ml) in a stream of N2. Add connection 10 (0.9 g, 0,002166 mol) and the reaction mixture was stirred at 25°C in an atmosphere of H2to the absorption of 1 equivalent. The catalyst is filtered off over Dicalite. The filtrate is concentrated and the residue (compound 11a; free base) crystallized in the form of oxalate from diethyl ether/2-propanol/oxalic acid in 2-propanol. Output: 0,420 g of compound 11.

Example B6

a) Obtaining compounds 12

Compound 12 (CIS-relative stereochemistry; oxalate)

The reaction is carried out in an autoclave in an atmosphere of N2. A mixture of intermediate compound 12 (0.935 g, 0,003347 mol), Rh(COD)2BF4(0,001359 g), Ir(COD)2BF4(0,001658 g), Xantphos (0,019364 g) and dimethylamine (2,0M solution in MeOH) (2 equivalent) in MeOH/THF (40 ml, 1/1) is loaded into the autoclave, and the autoclave create pressure up to 50 bar CO/H2(1/3). The mixture is subjected to interaction within 32 hours at 100°C. the Reaction mixture is filtered, the solvent is evaporated and the residue purified by chromatography on a column over silica gel (eluent: first DHM; then 5% MeOH/DHM; and finally 5% (MeOH/NH3)/DHM). The desired fraction is increasing and the solvent is evaporated to obtain oil, which is crystallized in the form of oxalate. Output: 0,120 g of compound 12 (8.37 per cent; hygroscopic solid white, oxalate).

b) Receiving connection 16

Compound 16 (CIS-relative stereochemistry;.2 HCl)

A mixture of intermediate compound 12 (0.1 g, of 0.0004 mol), 1 ml of a solution of dimethylamine (MeOH), Rh(COD)2BF4(0.002 g), Ir(COD)2BF4(0.005 g) and Xantphos (0,012 g) in THF/MeOH (20 ml) under 7 ATM CO and 33 ATM H2stirred for 32 hours at 100°C. Then the mixture is cooled, filtered, and the solvent is evaporated. The residue is purified HPLC with reversed phase (Shandon Hyperprep® Cl8 BDS (base deactivated silica) 8 μm, 250 g, E, 5 cm). Apply the gradient from 3 mobile phases. Phase A: 90% 0,5% solution of NH4OAc in water + 10% CH3CN; phase B: CH3OH; phase C: CH3CN). The desired fractions are collected. After processing, the residue is placed in DIPE and treated with 2-propanol/HCl. The solid is collected and dried in an oven (hygroscopic substance), with the connection 16 in the form of HCl salt (.2 HCl)

Example B7

The connection 13

Compound 13 (CIS-relative stereochemistry;.HCl)

A mixture of intermediate compound 2 (0.4 g, 0,0013 mol), 2-methoxy-N-methylethanamine (0.3 g, 0,00337 mol), Rh(COD)2BF4(0.004 g), Ir(COD)2BF4(0,010 g) and Xantphos (0,024 g) in MeOH/THF (40 ml, 1/1) at which osphere CO/H 2(7/33 ATM) is subjected to interaction in a sealed tube for 32 hours at 100°C. After cooling to K.T. solution is filtered and the filtrate is evaporated. The residue is purified HPLC with reversed phase (Shandon Hyperprep® Cl8 BDS (base deactivated silica) 8 μm, 250 g, E, 5 cm). Apply the gradient from 3 mobile phases. Phase A: a 0.25% solution of NH4HCO3in water; phase B: CH3OH; phase C: CH3CN). The desired fractions are collected and processed. The product is dissolved in DIPE and add HCl/2-propanol to obtain compound 13 in the form of HCl salt.

Example B8

The connection 14

Compound 14a (CIS-relative stereochemistry; free base)

Compound 14 (CIS-relative stereochemistry; oxalate)

A small amount of 3-chloro-N,N-dimethyl-1-propanamine (obtained as described in B1b), Mg (0.5 g, 0.02 mol) and 1,2-dibromethane (small amount) in THF (2 ml) is heated at 60°C. After reaction start slowly add a solution of the hydrochloride of 3-chloro-N,N-dimethyl-1-propanamine (2.5 g, 0.02 mol) in THF (25 ml). The reaction mixture is stirred for 1 hour at 60°C and then cooled to 5°C. Slowly add a solution of intermediate compound 13 (1.8 g, 0,0070 mol) in THF (25 ml). The mixture is stirred over night at K.T. Add NH4Cl (10%) and the mixture is filtered over Telicom. The filtrate is extracted with EtOAc. The organic is the third layer is separated, dried (MgSO4), filtered and the solvent is evaporated. The residue (2.2 g) purified by chromatography on a column of silica gel (eluent: DHM/MeOH/NH4OH 95/5/0,2; 15-40 μm). Pure fractions are collected and the solvent is evaporated to obtain compound 14a (free base). Compound 14a (1 g) is converted into the oxalate with the receipt of 0.615 g of compound 14.

Example B9

The connection 15

Compound 15 (CIS relative stereochemistry)

A mixture of intermediate 14 (0.5 g, 0,0016 mol), a solution of dimethylamine (1 ml; MeOH), Rh(COD)2BF4(0.004 g), Ir(COD)2BF4(0,010 g) and Xantphos (0,024 g) in THF/MeOH (40 ml, 1/1) and stirred for 32 hours at 100°C in an atmosphere of CO/H2(7 ATM/32 ATM). After cooling, the reaction mixture is filtered and concentrated in vacuo. The residue is twice purified by chromatography on a column of silica gel (eluent: DHM/MeOH 95/5). Fractions of product are collected and the solvent is evaporated. Output: 0,0685 g of compound 15.

Example B10

The connection 17

Compound 17 (CIS relative stereochemistry)

The reaction is carried out in an autoclave in an atmosphere of N2. A mixture of intermediate 16 (0,003347 mol), Rh(COD)2BF4(0,001359 g), Ir(COD)2BF4(0,001658 g), Xantphos (0,0000334 mol) and dimethylamine (2,0M solution in MeOH) (2 equivalent) in MeOH/THF (40 ml, 1/1) is loaded into autocl is in and the autoclave create pressure up to 50 bar CO/H 2(1/3). The mixture is subjected to interaction within 32 hours at 100°C. the Reaction mixture is filtered, the solvent is evaporated and the residue purified by chromatography on a column of silica gel. Output: Connection 17.

Example B11

The connection 18

Compound 18 (CIS relative stereochemistry)

The reaction is carried out in an autoclave in an atmosphere of N2. A mixture of intermediate 18 (0,003347 mol), Rh(COD)2BF4(0,001359 g), Ir(COD)2BF4(0,001658 g), Xantphos (0,0000334 mol) and dimethylamine (2,0M solution in MeOH) (2 equivalent) in MeOH/THF (40 ml, 1/1) is loaded into the autoclave, and the autoclave create pressure up to 50 bar CO/H2(1/3). The mixture is subjected to interaction within 32 hours at 100°C. the Reaction mixture is filtered, the solvent is evaporated and the residue purified by chromatography on a column of silica gel. Output: Connection 18.

The following compounds of formula (I)listed in tables 4-7, get similarly to the above examples (Ex. No.) with the use of alternative raw materials accordingly.

Table 4

Table 5

Table 6

Table 7

C. the Analytical part

Melting point

Method (a): melting point (TPL) is determined using DSC823e (Mettler-Toledo). The melting temperature is measured with a temperature gradient of 30°C/minute. The values shown are peak values.

SPO is about (b): melting point are obtained from the use of thermotoga of Kofler, which consists of a heated plate with a linear temperature gradient, moving arrows and temperature scale in degrees Celsius. The stand is calibrated using standard substances.

Table 8
Melting point

IHMS

GHMC General method A

Measurement of HPLC is carried out with application systems Alliance HT 2790 (Waters), including a pump for four-component mixtures with degasser, auto probsably, column thermostat (set at 40°C, unless otherwise noted), the detector diode matrix (DDM) and the column specified in the respective methods below. Flow from the column share for MS spectrometer. MS detector configure the source ionization elektrorazpredelenie. The mass spectrum is obtained by scanning from 100 to 1000 for 1 second using exposure time of 0.1 seconds. The voltage on the capillary needle is 3 kV and the source temperature is maintained at 140°C. Nitrogen is used as a gas atomizer. Data collection is done with the use of data systems Waters-Micromass MassLynx-Openlynx.

GHMC General method B

The dimension LC is carried out with the use of the system is we Acquity UPLC (Waters), includes pump for two-component mixtures, the organizer of the samples, the column heater (set at 55°C), the detector diode matrix (DDM) and the column specified in the respective methods below. Flow from the column share for MS spectrometer. MS detector configure the source ionization elektrorazpredelenie. The mass spectrum is obtained by scanning from 100 to 1000 for 0.18 seconds using exposure time of 0.02 seconds. The voltage on the capillary needle is 3.3 kV and the source temperature is maintained at 140°C. Nitrogen is used as a gas atomizer. Data collection is done with the use of data systems Waters-Micromass MassLynx-Openlynx.

GHMC General methods With

Measurement of HPLC is carried out with application systems Alliance HT 2795 (Waters), including a pump for four-component mixtures with degasser, auto probsably, the detector diode matrix (DDM) and the column specified in the respective methods below, the column is maintained at a temperature of 30°C. Flow from the column share for MS spectrometer. MS detector configure the source ionization elektrorazpredelenie. The voltage on the capillary needle is 3 kV and the source temperature is maintained at 100°C for LCT Time of Flight Zspray™ mass spectrometer from Waters - methods IHMS 7 and 8), and 3.15 kV at 110°C in ZQ™ (simple four-mass-Spectro is the EPR Zspray™ from Waters - for methods IHMS 9 and 10). N2applied as a gas atomizer. Data collection is done with the use of data systems Waters-Micromass MassLynx-Openlynx.

IHMS - Method 1

In addition to General method A: HPLC with reversed phase is performed on the column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Three mobile phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) used for obtaining conditions of the gradient from 100% A to 1% A, 49% B and 50% C in 6.5 minutes, to 1% and A 99% B for 1 minute and maintain these conditions for 1 minute and re-balance 100% A for 1.5 minutes. Apply volume injection of 10 µl. The cone voltage is 10 V for positive ionization and 20 V for negative ionization.

IHMS - Method 2

In addition to General method A: HPLC with reversed-phase column (Atlantis C18 (3.5 µm, a 4.6×100 mm) (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Two mobile phases (mobile phase A: 70% methanol + 30% H2O; mobile phase B: 0.1% of formic acid in H2O/methanol 95/5) used for obtaining conditions of the gradient from 100% B to 5% B + 95% A for 12 minutes. Apply volume injection of 10 µl. A cone voltage of 10 V for positive ionization and 20 V for negative ionization.

IHMS - Method 3

In addition to General method a: column heater set at 60°C. WAS the reversed-phase performed on column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Three mobile phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) used for obtaining conditions of the gradient from 100% A to 50% B and 50% C in 6.5 minutes, to 100% B for 0.5 minutes, and maintain these conditions for 1 minute and re-balance 100% A for 1.5 minutes. Apply volume injection of 10 µl. The cone voltage is 10 V for positive ionization and 20 V for negative ionization.

IHMS - Method 4

In addition to General method a: column heater set at 45°C. HPLC with reversed phase is performed on the column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Three mobile phases (mobile phase A: 0.1% of formic acid in H2O/methanol 95/5; mobile phase B: acetonitrile; mobile phase C: methanol) used for obtaining conditions of the gradient from 100% A to 1% A, 49% B and 50% C in 7 minutes, and maintain these conditions for 1 minute. Apply volume injection of 10 µl. A cone voltage of 10 V for positive ionization.

IHMS - Method 5

In addition to General method B: HPLC with reversed phase high performance liquid chromatography) is conducted on the bridge etisalats/silica hybrid (BEH) C18 column (1.7 mm, and 2.1×50 mm; Waters Acquity) with a flow rate of 0.8 ml/min Two mobile phases (mobile phase A: 0.1% of Moore is Gina acid in N 2O/methanol 95/5; mobile phase B: methanol) used for obtaining conditions of the gradient from 95% A and 5% B to 5% A and 95% B in 1.3 minutes and incubated for 0.2 minutes. Apply the amount of injection of 0.5 µl. A cone voltage of 10 V for positive ionization and 20 V for negative ionization.

IHMS - Method 6

In addition to General method a: column heater set at 45°C. HPLC with reversed phase carried out on a column of Atlantis C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Two mobile phases (mobile phase A: 70% methanol + 30% H2O; mobile phase B: 0.1% of formic acid in H2O/methanol 95/5) used for obtaining conditions of the gradient from 100% B to 5% B + 95% A in 9 minutes, and maintain these conditions for 3 minutes. Apply a volume of 10 ál injection.

IHMS - Method 7

In addition to General method C: HPLC with reversed phase is performed on the column Kromasil C18 (5 μm, a 4.6×150 mm) with a flow rate of 1.0 ml/min. Three mobile phases (mobile phase A: 100% 7 mm ammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C: 0,2% formic acid + 99,8% ultrapure water) is used to obtain conditions gradient from 30% A, 40% B and 30% C (hold for 1 minute) to 100% B in 4 minutes, 100% B for 5 minutes and re-balance the initial conditions for 3 minutes. Apply the amount of injection of 5 µl. The cone voltage 20 V for positive ions the promotion. The mass spectrum is obtained by scanning from 100 to 900 per 0.8 seconds using the delay between scans of 0.08 seconds.

IHMS - Method 8

In addition to General method C: HPLC with reversed phase is performed on the column Xterra MS C18 (5 μm, a 4.6×150 mm) with a flow rate of 1.0 ml/min Two mobile phases (mobile phase A: 100% 7 mm ammonium acetate; mobile phase B: 100% acetonitrile) is used to obtain conditions gradient from 85% A, 15% B (hold for 3 minutes) to 20% A, 80% B for 5 minutes, incubated at 20% A and 80% B for 6 minutes and re-balance the initial conditions for 3 minutes. Apply the amount of injection of 20 µl. The cone voltage 20 V for positive ionization. The mass spectrum is obtained by scanning from 100 to 900 per 0.8 seconds using the delay between scans of 0.08 seconds.

GHMC Method 9

In addition to General method C: HPLC with reversed phase is performed on the column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 0.8 ml/min Two mobile phases (mobile phase A: 100% 7 mm ammonium acetate; mobile phase B: 100% acetonitrile) is used to obtain conditions gradient from 80% A, 20% B (hold for 0.5 min) to 10% A, 90% B in 4.5 minutes, maintained at 10% A and 90% B within 4 minutes, and re-balance the initial conditions for 3 minutes. Apply volume injection of 10 µl. The cone voltage 20 V for positive and negative the second ionization. The mass spectrum is obtained by scanning from 100 to 1000 for 0.4 seconds with the use of delay between scans of 0.3 seconds.

IHMS - Method 10

In addition to General method C: HPLC with reversed phase is performed on the column Sunfire C18 (3.5 µm, a 4.6×100 mm) with an initial flow rate of 0.8 ml/min Two mobile phases (mobile phase A: 35% 6.5 mm ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml/l); mobile phase B: 100% acetonitrile) is used to obtain conditions gradient from 100% A (hold for 1 minute) to 100% B in 4 minutes, hold at 100% B a flow rate of 1.2 ml/min for 4 minutes and re-balance the initial conditions for 3 minutes. Apply volume injection of 10 µl. The cone voltage 20 V for positive and negative ionization. The mass spectrum is obtained by scanning from 100 to 1000 for 0.4 seconds with the use of delay between scans of 0.3 seconds.

Table 9
Analytical data JHMS: Rtthe retention time in minutes; [MH]+protonirovaniya weight compounds; GHMC method

Optical rotation

Optical rotation was measured using polarimetric Elmer 341. [α]D20mean optical rotation measured with light at a wavelength of D-line of sodium (589 nm) at 20°C. the path length of the cell is 1 inch in Addition to obtained values are the concentration and solvent of the solution, which is used for the measurement of optical rotation.

Table 10
Data optical rotation

D. Pharmacological example

Agonism to ghrelin in HEK293 cells

The day before the experiment the cells HEK293, permanent transfetsirovannyh sequence of genes for expression of the receptor GHS1A, seeded covered in poly-D-lysine 96-well tablets with a transparent bottom and grow up to ≈5% of confluently the next day.

The cells are then incubated sensitive to intracellular calcium fluorescence breakdown fluo-4 or Kit-3 for 1 h at 37°C. Fluorescence, representing the free intracellular calcium in cells, measured in the FLIPR system (excitation at 488 nm, emission > 520 nm). Test compounds added to each well in the desired concentration, and the fluorescence signal is simultaneously recorded for all wells. The selection of intracellular calcium, initsiirovannoi the activation of receptors adding the test compound, measure both the emitted fluorescence of the calcium complex and fluorescent samples. The action of the medicinal product on the fluorescence intensity is expressed relative to the maximum intensity of the fluorescence measured in cells treated with calcium-ionophores ionomycin. The graphing data concentration-response is used to determine the values of pEC50for the tested compounds (pEC50= -log EC50; EC50the effective dose M, determined at a concentration of test compound giving effect equal to 50% of maximum effect (=100%), which can be achieved). In table 11, below, shows the values of pEC50. As a positive control, use increased fluorescence depending on the dose of the reference compounds GHRP-6 with a mean pEC509,0±0,1 (mean±, n=19).

Table 11
The pEC values50

Increased gastric emptying and propulsive small intestine in mice NMRI

Male NMRI mice weighing about 25 grams, not fed for 20 h to give free access to drinking water. The test compound is administered to the animals by subcutaneous for 30 min is t to the feeding test food through the gastric tube. Test food consists of 0.3 ml of a solution nutritious chocolate cocktail (1.0 kcal/ml)containing phenol red marker (5 mg/ml). Fifteen minutes after the introduction of food mice killed by inhalation of CO2gas. The content of phenol red remaining in the stomach (extracted from the stomach with NaOH), is determined at 557 nm in the spectrophotometer and expressed as units of extinction. Propulsion small intestine is defined as the distance that passes phenol red marker in the intestine, and expressed as a percentage of the total length of the small intestine (from pylorus ileocecal connection).

Criteria "all or nothing" for a significant (p<0.05) of the effects is determined by analysis of the distribution of the frequency control data: threshold criteria for content in the stomach phenol red, below which gastric emptying is significantly enhanced, installed by 0.9 units extinction. Propulsion small intestine believe is greatly enhanced if the front part of the phenol red is more than 85% of the length of the small intestine. The effect of the drug in the dose is considered active if >60% of the tested animals showed a significant effect on any parameter. The lowest dose that is active, it is marked as the lowest active dose (PAD). Table 12 shows how knowledge is to be placed ABOVE. ABOVE for the reference compounds GHRP-6 0.63 mg/kg to enhance gastric emptying and 2.5 mg/kg to stimulate propulsive small intestine (n=3/dose).

Table 12
Values ABOVE (mg/kg) to enhance gastric emptying and stimulation of propulsive small intestine

Increased gastric emptying in wild and GHS1A-r-/-, KO mice

Connection 3 or the carrier injected (10 mg/kg subcutaneously) mice with a deletion of the GHS1A-r (GHS 1A-r-/-, KO) or their relatives wild-type (GHS1A-r+/+, WT) for 30 minutes prior to the introduction of the test food containing phenol red, via a stomach tube. After 15 minutes after administration of the test meal, the contents of the food remaining in the stomach, determined as described above, in the method for NMRI mice. The stomachs of WT mice treated with compound 3, was oporornis more than the stomachs of WT mice treated with media. The same re is processing them KO mice showed no differences in food remains in the stomachs of mice, treated with compound or vehicle (see figure 1).

E. Examples of compositions

"Active ingredient" (A.I.) in these examples relates to a compound of formula (I), including any chemical isomeric forms, N-oxide, its pharmaceutically acceptable salt or MES; in particular, any of the presented compounds.

Typical examples of recipes for compositions in accordance with the present invention:

1. Tablets

The active ingredient5-50 mg
The dicalcium phosphate20 mg
Lactose30 mg
Talc10 mg
Magnesium stearate5 mg
Potato starchup to 200 mg

2. Suspension

Aqueous suspension of gain for oral administration so that each ml contains 1-5 mg of the active ingredient, 50 mg of carboxymethylcellulose sodium, 1 mg sodium benzoate, 500 mg of sorbitol and water up to 1 ml

3. Injection

Parenteral composition is produced by mixing a 1.5% (weight/volume) of the active ingredient in 0.9% NaCl solution.

The active ingredient5-1000 mg
Stearyl alcohol3 g
Lanolin5 g
White petrolatum15 g
Waterto 100 g

1. The compound of the formula I

where a is a phenyl or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atom; where the specified phenyl or 6-membered aromatic heterocycle optionally may be condensed with phenyl;
Z is CH2or O;
R1is halogen, hydroxyl, C1-4the alkyl, C1-4alkyloxy, or
if a is a phenyl, two adjacent substituent R1can be taken together with obtaining a radical of the formula:
-O-CH2-O- (a-1)or
-O-CH2-CH2-O- (a-2);
R is hydrogen or C1-4by alkyl;
R3and R4each independently is hydrogen, C1-4the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; or
R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1) or (b-2)

where X1is CH2or CHOH; and X2is CH2, O, or NR6;
R5is hydrogen, halogen, C1-4the alkyl or C1-4alkyloxy;
R6is hydrogen, C1-4the alkyl, C1-4alkylcarboxylic;
n is an integer 0, 1 or 2;
or its pharmaceutically acceptable salt, or its stereochemical isomeric form;
provided that the connection is not

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where a is a phenyl or a phenyl substituted with 1 or 2 substituents R1.

3. The compound according to claim 1, where a is a radical of the formula

4. The compound according to claim 1, where a is pyridium, pyrimidinium or hyalinella, where each of these pyridyl, pyrimidinyl or chinoline optionally substituted by 1 or 2 substituents R1.

5. The compound according to any one of the preceding paragraphs, where Z is CH2.

6. The compound according to claim 1, where Z is O.

7. The compound according to claim 1, where R1is halogen, hydroxyl, C1-4the alkyl or C1-4alkyloxy.

8. The compound according to claim 1, where R2is hydrogen.

9. The compound according to claim 1, where R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4as the kilometres; or
R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1) or (b-2)

where X1is CH2or CHOH, and X2is CH2.

10. The connection according to claim 9, where R3and R4each independently is hydrogen, C1-6the alkyl, C1-4alkalosis1-6the alkyl or panels1-4by alkyl; or R3and R4taken together with the nitrogen atom to which they are attached, form a radical of formula (b-1)

where X1is CH2or CHOH.

11. The compound according to claim 1, where n is an integer with value 1 or 2.

12. The compound according to claim 1, where n is equal to 0.

13. The compound according to claim 1, where a is a phenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, pyridium, pyrimidinium, hyalinella; each of these rings is optionally substituted by 1 or 2 substituents, each of which is independently selected from halogen, hydroxyl, C1-4the alkyl or C1-4alkyloxy; R3and R4each independently is hydrogen, C1-4by alkyl, C1-4alkalosis1-4the alkyl, phenyl C1-4by alkyl; or R3and R4taken together with the nitrogen atom to which they are attached, obtaining pyrrolidinyl, optionally substituted in position 3 by hydroxyl; piperidinyl; Moholy the sludge; the piperazinil, optionally substituted C1-4the alkyl or C1-4alkylcarboxylic; R2is hydrogen or stands.

14. The compound according to claim 1, where the substituents on cycloheptanone or doxepinum ring have the CIS configuration.

15. The connection 14, where the compound is enantiomerically pure form.

16. The compound according to claim 1, where the compound is chosen from the following:
oxalate (±) CIS-6-(4-chloro-3-methoxyphenyl)-5-(3-diethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-6-(3-chlorophenyl)-5-(3-diethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-4-(4-chloro-3-methoxyphenyl)-5-(3-diethylaminopropyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-ol;
oxalate (±) CIS-6-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
(±) CIS-6-(4-chloro-3-methoxyphenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-6-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-(4-forfinal)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-phenyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-6-(4-chloro-3-methoxyphenyl)-5-{3-[(2-methoxyethyl)mate the amino]propyl}-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-5-(3-dimethylaminopropyl)-6-p-tolyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-5-(3-diethylaminopropyl)-6-(4-forfinal)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-6-(2,4-differenl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-4-(4-chloro-3-methoxyphenyl)-5-(3-dimethylaminopropyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-ol;
oxalate (±) CIS-5-(3-diethylaminopropyl)-6-p-tolyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
hydrochloride is (±) CIS-5-(3-diethylaminopropyl)-6-(3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
oxalate (±) CIS-6-(4-bromophenyl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
hydrochloride is (±) CIS-6-(5-chloropyridin-3-yl)-5-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
(±) CIS-5-(3-dimethylaminopropyl)-6-quinoline-3-yl-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol;
hydrochloride is (±) CIS-5-(3-dimethylaminopropyl)-6-(6-methylpyridin-3-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol.

17. The compound according to claim 1 for use as a drug for the treatment of disease, the treatment of which affect, mediates or contributes to activation of the receptor GHSlA-r.

18. The compound according to claim 1 for the treatment of disease, the treatment of which affect, mediates or contributes to activation of the receptor GHSlA-r.

19. The compound according to claim 1 for the treatment of digestive disorders requiring prokinetics therapy, such as, for example, idiopathic or diabetic gastroparesis, postoperative ileus caused by opioid dysfunction of the colon, short bowel syndrome, chronic intestinal pseudoprobability, vomiting, constipation such as associated with phase hypokinesia with irritable bowel syndrome (IBS), delayed gastric emptying associated with wasting, disease gastro-esophageal reflux (SIPR), stomach ulcers, colic; for the treatment of cardiovascular diseases, such as chronic cardiac insufficiency; for treatment of disorders of the Central nervous system, such as, for example anxiety, worsening cognitive ability, depression, including similar to depression symptoms of chronic stress, neurodegenerative diseases, for example diseases, neurodegeneration compact part of the black substance, such as, for example Parkinson's disease; osteoporosis; rhythm sleep-Wake; exocrine insufficiency of the pancreas, for example, people affected by cystic fibrosis or chronic pancreatitis; for the treatment of patients with low levels of cortisol or symptoms of adrenocortical insufficiency;
or to be sure cardiotoxic;
to stimulate appetite, for example, p and the treatment of cachexia and anorexia nervosa;
to protect organs during pancreatitis;
to improve memory and ability to learn.

20. Pharmaceutical composition for the treatment of disease, the treatment of which affect, mediates or contributes to activation of the receptor GHSlA-r containing a pharmaceutically acceptable carrier and, as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 16.

21. Use connections to obtain drugs for the treatment of digestive disorders requiring prokinetics therapy, such as, for example, idiopathic or diabetic gastroparesis, postoperative ileus caused by opioid dysfunction of the colon, short bowel syndrome, chronic intestinal pseudoprobability, vomiting, constipation such as associated with phase hypokinesia with irritable bowel syndrome (IBS), delayed gastric emptying associated with wasting, disease gastro-esophageal reflux (SIPR), stomach ulcers, colic; for the treatment of cardiovascular diseases, such as chronic cardiac insufficiency; for treatment of disorders the Central nervous system, such as, for example anxiety, worsening of cognitive ability, depression, including similar to depression symptoms of chronic stress, neurodegenerative, for example the disease and neurodegeneration compact part of the black substance, such as, for example Parkinson's disease; osteoporosis; rhythm sleep-Wake; exocrine insufficiency of the pancreas, for example, people affected by cystic fibrosis or chronic pancreatitis; for the treatment of patients with low levels of cortisol or symptoms of adrenocortical insufficiency;
or to be sure cardiotoxic;
to stimulate appetite, for example, in the treatment of cachexia and anorexia nervosa;
to protect organs during pancreatitis;
to improve memory and ability to learn; where the compound is a compound according to any one of claims 1 to 16.

22. The compound of the formula

where A, Z, R1, R2, R5and n are such as defined in claim 1;
or its pharmaceutically acceptable salt or its stereochemical isomeric form.

23. Connection p.22, where the substituents on cycloheptanone or doxepinum ring have the CIS configuration.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing novel 2-(2-acylvinyl)indole derivatives of formula:

characterised by that 2-azidobenzylfurans are boiled in high-boiling organic solvents, such as bromobenzene or chlorobenzene or para-xylene or ortho-dichlorobenzene or diphenyl oxide or butyl acetate or dimethyl sulphoxide.

EFFECT: obtaining novel 2-(2-acylvinyl)indole derivatives.

2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an improved method for preparing 2-arylamino-4-hetarylpyrimidines of formula (I) which possess inhibitory action on serine-threonine kinase Haspin on the enzymatic level, and may be used as drug substances for oncological diseases. In formula (I), wherein Het = , , , , , , , , , , ,

R=H; 2-Me; 3-Me; 4-Me; 2,3-di-Me; 2-MeO; 3-MeO; 4-MeO; 4-EtO; 4-PhO; 2-Cl; 3-Cl; 4-Cl; 4-F; 2-Me, 3-Cl. The method consists in a reaction of related hetarylmethylketone and N,N-dimethylformamide dimethylacetale on boiling of reagents in isopropyl alchohol for 6 hours to produce 3-dimethylamino-1-hetaryl-2-propen-1-ones with adding in situ related aryl guanidine and further boiling for 2 hours. The process is conducted at molar ratio (mole) of hetarylmethylketone: N,N-dimethylformamide dimethylacetale : aryl guanidine = 1:1.5:1.

EFFECT: method simplifies the process due to cutting a process time and reducing consumption of the initial ingredients.

6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cyclic indole-3-carboxamide of formula (I) or physiologically acceptable salts thereof of formula (I): wherein the values A, R, R10, R20, R30, R40, n, p and q are specified in clause 1 of the patent claim. A method for preparing them is described.

EFFECT: compounds have renin-inhibitory activity that allows using them for preparing a pharmaceutical composition and a drug preparation for treating the diseases associated with renin activity.

11 cl, 4 tbl, 127 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on

The invention relates to new derivatives of thiourea, and containing antimicrobial agent against Helicobacter pylori and anti-ulcer agent

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for making a new compound 4-benzoyl-1H-benzo[c] oxepin-3-one of formula: consisting in the fact that 2-benzoyl-3-(2-bromomethylphenyl)propenic ethyl ether prepared by bromination of 2-benzoyl-3-(2-methylphenyl)propenic ethyl ethyl ether with N-bromsuccinimide, heated at temperature 230-260°C with simultaneous ethyl bromide distillation for 15-45 minutes. 4-Benzoyl-1H-benzo[c]oxepin-3-one shows analgesic activity.

EFFECT: preparation of the new compound showing analgesic activity.

1 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel alkyl esters of 3-oxo-1,3-dihydrobenzo[c]oxepin-4-carboxylic acid of general formula , where R is methyl, ethyl, propyl, isopropyl, butyl, isopentyl, involving heating dialkyl esters of 2-(2-bromomethylbenzylidene)malonic acid, obtained through bromation of dialkyl esters of 2-(2-methylbenzylidene)malonic acid with N-bromosuccinimide to temperature of 190-220°C with simultaneous distillation of alkylbromide for 1-5 hours.

EFFECT: compounds can be used as intermediate products for synthesis of different organic compounds, particularly biologically active compounds.

1 cl, 6 ex

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