RU2603962C2 - Novel class of selective agonists of somatostatin receptors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or its pharmaceutically acceptable salt, wherein R1, R5 are independently selected from H; R2, R3 and R4 are selected from H and ring A, wherein one of R2, R3 or R4 independently represents ring A; ring A is a 6-member monocyclic or 10-member bicyclic aromatic ring which optionally contains 1 heteroatom, which is N, wherein ring A can be optionally substituted with 1-3 substitutes independently selected from halogen, OH, COOH, C₁-C₆-alkyl, C₁-C₆-alkoxy, -C(O)C₁-C₆-alkyl, -NO₂; ring B is a 5-6-member non-aromatic ring, optionally containing 1 heteroatom, which is O, wherein ring B can be optionally substituted with 1-3 substitutes independently selected from -C₁-C₆-alkyl, -C(O)C₁-C₆-alkyl, -C₁-C₆-alkoxy; R6 is selected from H or C₁-C₆-alkyl, R7 denotes H or-(Z)_m-(D)_p, where independently m=0-1, p=0-1, wherein m=p=0 does not hold; Z is selected from C₁-C₆-alkyl; D is a 5-6-member non-aromatic ring, optionally containing one N heteroatom, wherein ring D can be optionally substituted with one substitute selected from C₁-C₆-alkyl, C₁-C₆-alkoxy. Compound of formula I or pharmaceutically acceptable salt thereof are intended for use as sst4 receptor agonist for preparing a pharmaceutical composition for treating and/or preventing a pathological condition or disease involving somatostatin receptors subtype 4 (sst4). Invention also relates to a pharmaceutical composition for treating and/or preventing a pathological condition or disease, treatment and/or prevention of which requires use of somatostatin receptor agonist subtype 4 (sst4), containing a therapeutically effective amount of compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, solvent and/or filler.

EFFECT: chemical compounds, which are selective agonists of human sst4 receptors.

15 cl, 4 dwg, 3 tbl, 6 ex

Description

The invention relates to a new class of selective somatostatin receptor agonists of subtype 4 and can be used for the treatment of diseases associated with neurogenic inflammation, in particular rheumatoid arthritis and bronchial asthma, as well as for the treatment of pathological conditions or diseases of the brain, such as Alzheimer's disease, disease Parkinson's, alcohol intoxication and alcohol dependence.

State of the art

Experiments with mice in which the gene for somatostatin receptors of the 4th subtype was removed in models of diseases such as chronic rheumatoid arthritis, inflammation of the airways followed by bronchial edema, (Helyes Z., Pinter E. et. Al., PNAS, 2009, 13088-13093), demonstrated the role of these receptors in the development of physiological and pathophysiological processes, as well as the potential significance of the target of somatostatin receptors of the 4th subtype (sst4) for the creation of new anti-inflammatory, analgesic and anti-asthma drugs. A study of the expression, localization, and inflammation-induced changes in sst4 receptors in rodent and human lungs also confirms the possibility of using this target in the treatment of acute and chronic airway inflammation (Zoltán Varecza et. Al., J Histochem Cytochem, 2009, 57, 1127-1137).

The mechanism by which somatostatin exhibits its anti-inflammatory properties can be described as follows. When exposed to capsaicin-sensitive nerve endings, proinflammatory neuropeptides are released, including substance P, neurokinin A and neurokinin B, a peptide associated with the calcitonin gene, as well as anti-inflammatory and antinociceptive neuropeptides, such as somatostatin, opiate peptides and pituitary peptides RASAR). Somatostatin inhibits the release of pro-inflammatory neuropeptides from nerve endings, and also acts on the receptors of vascular endothelial cells, inflammatory and immune cells. It is important that somatostatin released in activated capsaicin-sensitive nerve endings not only exerts a local effect, but can reach distant parts of the body through the circulatory system and have a systemic anti-inflammatory and analgesic effect (Szolcsanyi, J., Helyes, Z. et al ., Br. J. Pharmacol, 1998, 123 (5), 936-942; Szolcsanyi J. et. Al. Br. J. Pharmacol., 1998, 125 (4), 916-922).

Exogenously administered somatostatin has been shown to reduce neurogenic inflammation and nociception (Karalis K. et. Al., J Clin Invest., 1994, 93, 2000-2006; Fioravanti A. et. Al., Drugs Exp Clin Res, 1995, 21 , 97-103), relieves chronic arthritis and mechanical allodynia (Helyes Zs. Et. Al. Arthritis Rheum, 2004, 50, 1677-1685), acute and chronic inflammation of the airways (Helyes Zs. Et al. Am J Physiol Lung Cell Mol Physiol, 2007,292 (5), L1173-L1181). At the same time, the clinical value of somatostatin is greatly limited by its properties such as rapid degradation in the body (half-life less than 3 minutes) and low selectivity. As a result of its effect not only on sst4, but also on other subtypes of somatostatin receptors, somatostatin induces a number of endocrine effects, for example, inhibition of the release of growth hormone, glucagon and insulin, which can be evaluated as undesirable side effects when used clinically.

Of the five known somatostatin receptors, it is believed that the sst4 receptor is primarily responsible for the anti-inflammatory and antinociceptive effects of somatostatin.

A number of peptide and non-peptide analogues of somatostatin, selective for sst4, have been proposed. Among them, the cyclic heptapeptide analogue of TT-232 and the non-peptide compounds J-2156 and NNC-26-9100 are distinguished. Studies have been conducted showing the effectiveness of these compounds in models of inflammation (Helyes, Z. et al. British J. Pharmacology, 2006, 405-415), chronic and acute pain (analgesic effect) (Katalin Sándor et al., European Journal of Pharmacology , 2006, 539 71-75), acute and chronic inflammation of the airways (Krisztián Elekes et al., European Journal of Pharmacology, 2008, 578, 313-322), bladder dysfunction (Masashi Honda et al. Urology, 2012, 80 (6), 1391. e9-13; http://dx.doi.org/10.1016/j.urology.2012.07.007). It was found that, unlike somatostatin itself, its non-peptide synthetic analogue J-2156 causes significantly less desensitization (Engstrom M., J Pharmacol Exp Ther., 2006, 316, 1262-1268). In addition, it was found that, due to its ability to cross the blood-brain barrier, NNC-26-9100 improves learning and memory and can be effectively used in the treatment of Alzheimer's disease and other cognitive impairments (WO 2011/047165; Karin E. Sandova et al ., European Journal of Pharmacology, 2011, 654, 53-59; Jacques Epelbaum et al., Progress in Neurobiology, 2009, 89, 153-161), as well as alcohol dependence (Zhao, R. et. Al., Asia- Pacific Psychiatry: Official Journal of the Pacific Rim College of Psychiatrists, 2013, 5 (1), 39-50, doi: 10.1111 / appy. 12010).

Disclosure of invention

The objective (technical result) of the present invention is to obtain new chemical compounds that are selective agonists of human sst4 receptors, as well as increased selectivity and bioavailability, and promising for use in the treatment of pathological conditions and diseases such as acute and chronic inflammation of the respiratory tract, chronic arthritis, mechanical allodynia, neurogenic inflammation, Alzheimer's disease, alcohol dependence.

The specified technical result is achieved by obtaining compounds of General formula (I):

or a pharmaceutically acceptable salt or hydrate or solvate thereof, in which R1, R5 are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, R2, R3 and R4 are selected from H, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen and ring A, wherein one of R2, R3 or R4 is necessarily ring A; cycle A is a 5-6 membered monocyclic or 9-10 membered bicyclic aromatic ring, optionally containing from 1 to 4 heteroatoms independently selected from N, O and S, while cycle A may optionally be substituted by 1-3 substituents independently selected from halogen,

IT,

COOH,

C ₁ -C ₆ alkyl optionally substituted with 1-3 halogen atoms,

C ₂ -C ₆ alkenyl,

C ₂ -C ₆ alkynyl,

C ₁ -C ₆ alkoxy optionally substituted with 1-3 halogen atoms,

-C (O) C ₁ -C ₆ alkyl,

-NO ₂ ,

-O- (CH ₂ ) _n- phenyl, -C (O) - (CH ₂ ) _n- phenyl,

where n = 0-3, and phenyl may optionally be substituted with 1-3 substituents independently selected from halogen, C ₁ -C ₆ alkyl optionally substituted with 1-3 halogen atoms, and C ₁ -C ₆ alkoxy optionally substituted by 1-3 halogen atoms,

-O- (CH ₂ ) _n- heteroaryl, -C (O) - (CH ₂ ) _n- heteroaryl,

where n = 0-3, and heteroaryl is a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from O and N, and optionally substituted with 1-3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, possibly substituted by 1-3 halogen atoms, and C ₁ -C ₆ -alkoxy, optionally substituted by 1-3 halogen atoms;

cycle B is a 5-7 membered non-aromatic ring, optionally containing 1-2 double bonds and optionally containing 1-2 heteroatoms independently selected from O and N, wherein cycle B may be optionally substituted with 1-3 substituents independently selected of

-C ₁ -C ₆ -alkyl,

-C (O) C ₁ -C ₆ alkyl,

-C ₁ -C ₆ alkoxy, and

-O- (CH ₂ ) _n- phenyl, -C (O) - (CH ₂ ) _n- phenyl,

where n = 0-3, and phenyl may optionally be substituted with 1-3 substituents independently selected from halogen, C ₁ -C ₆ alkyl optionally substituted with 1-3 halogen atoms, and C ₁ -C ₆ alkoxy optionally substituted by 1-3 halogen atoms,

-O- (CH ₂ ) _n- heteroaryl, -C (O) - (CH ₂ ) _n- heteroaryl,

where n = 0-3, and heteroaryl is a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from O and N, and optionally substituted with 1-3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, possibly substituted by 1-3 halogen atoms, and C ₁ -C ₆ -alkoxy, optionally substituted by 1-3 halogen atoms;

R6 is selected from H or C ₁ -C ₆ alkyl,

R7 represents H or

- (Z) _m - (D) _P , where independently from each other

m = 0-1, p = 0-1, while it cannot be m = p = 0,

Z is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ - (mono) alkylamino,

D is a 5-7 membered non-aromatic ring, optionally containing 1-2 double bonds, optionally containing one N heteroatom, wherein cycle D may optionally be substituted with one substituent selected from = O, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C (O) C ₁ -C ₆ alkyl; or R7 and R6 together with the nitrogen atom to which they are bonded form a non-aromatic 5-7 membered heterocycle, optionally containing 1-2 double bonds and optionally containing one additional heteroatom selected from N or O, wherein said heterocycle may be optionally substituted with 1-2 substituents selected from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -C (O) C ₁ -C ₆ -alkyl.

A separate subclass of compounds of interest includes compounds of formula I in which:

R1, R5 are independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen,

R2, R3 and R4 are selected from H, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halogen and cycle A, moreover, one of R2, R3 or R4 is necessarily ring A and ring A is phenyl , pyridinyl, pyrazolyl, thiophenyl or quinolinyl optionally substituted with 1-3 substituents independently selected from halogen,

IT,

COOH,

C ₁ -C ₃ alkyl optionally substituted with 1 to 3 halogen atoms,

C ₁ -C ₆ alkoxy optionally substituted with 1-3 halogen atoms,

-C (O) C ₁ -C ₆ alkyl,

-NO ₂ .

Another separate subclass of compounds of interest includes compounds of formula I in which:

cycle B is a 5-6 membered non-aromatic ring selected from cyclohexane, piperidine, piperazine, tetrahydropyran, tetrahydrofuran, and cycle B may optionally be substituted with 1-2 substituents independently selected from

C ₁ -C ₃ alkyl

-C (O) C ₁ -C ₆ alkyl,

C ₁ -C ₃ alkoxy,

-O- (CH ₂ ) _n- phenyl, where n = 0-3; and phenyl may be optionally substituted with 1-3 substituents independently selected from halogen, C ₁ -C ₆ alkyl optionally substituted with 1-3 halogen atoms, and C ₁ -C ₆ alkoxy optionally substituted with 1-3 halogen atoms.

Another separate subclass of compounds of interest includes compounds of formula I in which:

R6 is selected from H or CH ₃ ,

R7 represents H or

- (Z) _m - (D) _p , where

independently from each other m = 0-1, p = 0-1, while there cannot be m = p = 0,

Z is selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ - (mono) alkylamino,

D is a 5-7 membered non-aromatic ring containing one N heteroatom so that it is 2-5 carbon atoms from the amide nitrogen atom, and the D ring may optionally be substituted on the N atom with one substituent selected from C ₁ -C ₃ -alkyl.

Another separate subclass of compounds of interest includes compounds of formula I in which:

R7 is 4-piperidine optionally substituted at the nitrogen atom with C ₁ -C ₆ alkyl.

Another other separate subclass of compounds of interest includes compounds of formula I in which:

R7 and R6, together with the nitrogen atom to which they are bonded, form a non-aromatic 5-7 membered heterocycle, possibly containing 1-2 double bonds and optionally containing one additional heteroatom selected from N or O, so that it is at a distance 2-5 carbon atoms from the amide nitrogen atom, wherein said additional nitrogen atom may optionally be substituted with a substituent selected from C ₁ -C ₆ alkyl or C (O) C ₁ -C ₆ alkyl.

Illustrative, but not limiting, examples of cycle A are presented below: phenyl, naphthyl, biphenyl; non-limiting examples of heteroaryl include furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indoltzinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolinol cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, naphthalenyl.

The present invention also relates to the use of the subject compounds for the preparation of a pharmaceutical composition for the treatment and / or prevention of pathological conditions or diseases in which somatostatin 4 subtype receptors (sst4) are involved.

More specifically, the present invention also relates to the use of the subject compounds for the preparation of a pharmaceutical composition for such pathological conditions or diseases for the treatment and / or prevention (prophylaxis) of which the use of sst4 receptor agonists is necessary. In particular, such pathological conditions or diseases for the treatment and / or prevention of which the use of full sst4 receptor agonists is necessary.

In particular, the compounds of the present invention and exhibiting the properties of sst4 receptor agonists can be used as an anesthetic in febrile conditions.

In addition, such diseases or pathological conditions in which sst4 receptors are involved and for the treatment and / or prevention of which the compounds of the present invention can be used are, in particular, pathological conditions or diseases of the brain, in particular Alzheimer's disease, Parkinson's disease, alcohol intoxication or alcohol dependence; acute or chronic inflammation of the airways, in particular bronchial asthma, chronic arthritis, in particular rheumatoid arthritis, mechanical allodynia, neurogenic inflammation, bladder dysfunction, neurodegenerative disease of the retina.

In addition, the present invention also relates to pharmaceutical compositions comprising at least one compound of the invention, or a salt, hydrate or other solvate thereof, in a therapeutically effective amount and at least one pharmaceutically acceptable carrier, adjuvant, solvent and / or excipient. Such compositions are intended for the treatment and / or prevention of a disease, pathological condition or disease in which somatostatin 4 subtype (sst4) receptors are involved, and can be administered to a subject in need of such treatment or prophylaxis in a therapeutically effective amount.

Description of drawings

Fig. 1. Curves of the anti-inflammatory activity of a compound of the invention (AST-1) versus time in comparison with ketoprofen and dexamethasone.

Fig. 2. Analgesic activity of the compounds of the invention (AST-3) in a rat formalin test.

Fig. 3. The effect of the compounds according to the invention (AST-1) on the consumption of 10% alcohol solution (with free access).

Fig. 4. Index of alcohol-deprivation effect of consumption of 10% alcohol solution (after its 3-day deprivation).

DETAILED DESCRIPTION OF THE INVENTION Terms and Definitions

The following terms and definitions apply throughout this document unless otherwise indicated. In addition, unless otherwise indicated, all occurrences of functional groups are independently selected.

The term “alkyl”, alone or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the indicated number of carbon atoms (i.e., C _1-6 means from one to six carbon atoms). Examples of alkyls include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, and n-hexyl.

The term "alkenyl" refers to an unsaturated alkyl radical having one or more double bonds. The term "alkynyl" refers to an unsaturated alkyl radical having one or more triple bonds. Examples of such unsaturated groups include vinyl, 2-propenyl, crotyl, 2-isopentyl, ethynyl, and others.

The term "heterocycle" ("heterocyclyl", "heterocyclic") means a cyclic system having from five to fourteen, usually from five to ten ring carbon atoms, in which there are one or more carbon cycles, usually from one to two , which along with carbon also includes atoms of other elements. Such heteroatoms according to the invention may be N, O or S, which are independently selected. The term “heterocycle” refers to saturated, partially unsaturated or aromatic rings (heteroaryl). The degree of saturation of the heterocycle is indicated separately. In some cases, the heterocycle is preferably a 5-7 membered non-aromatic ring, optionally containing 1-2 double bonds and optionally containing 1-2 heteroatoms independently selected from O and N. Examples of non-aromatic heterocyclic rings according to the invention include but are not limited to, the following: piperidine, piperazine, tetrahydropyran, tetrahydrofuran, 1, 4-dioxanyl, morpholinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, from.

The term “aryl”, unless otherwise specified, means an aromatic hydrocarbon group, which may be a single cyclic structure or several rings that are fused together. The term “heteroaryl” refers to aryl groups which contain from one to five heteroatoms independently selected from N, O, and S. In some cases, heteroaryl is preferably a 5-6 membered monocyclic or 9-10 membered bicyclic aromatic ring optionally containing from 1 to 4 heteroatoms independently selected from N, O and S. In some other cases, heteroaryl is preferably a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from O and N Non-limiting exemplary aryls of the invention include phenyl, naphthyl, biphenyl; non-limiting examples of heteroaryl include furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indoltzinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolinol cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, naphthalenyl.

The term "halogen" by itself or in part of another term refers to an atom of fluorine, chlorine, bromine or iodine. Examples of alkyls substituted with one, two or three halogen atoms include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, fluoromethyl.

The term “alkoxy” refers to alkyl groups corresponding to the definition given above, and which are attached to the rest of the molecule via a bridging oxygen atom. For example, the term “C ₁ -C-alkoxy” means —O-alkyl, where the alkyl group contains from 1 to 6 carbon atoms in the form of a linear (unbranched) or branched chain. By way of illustration, alkoxy groups include, but are not limited to, the following groups: methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and others.

The term “amino” means a group —NH ₂ .

The term “mono- and di (alkyl) amino” embraces secondary and tertiary alkylamino groups, where the alkyl groups are as defined above and contain the indicated number of carbon atoms. The point of attachment of the alkylamino group is a nitrogen atom. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino and methylpropylamino.

The term “amino (alkyl)” means an amino group bonded to an alkyl group with a specified number of carbon atoms. Similarly, “hydroxyalkyl” is a hydroxy group bound to an alkyl group. The point of attachment of the amino (alkyl) group is a carbon atom.

The term “acyl” means a group C (O) R (in which R is H, alkyl, aryl, as defined above). Examples of acyl groups include formyl, acetyl, benzoyl, phenylacetyl and similar groups.

The above groups, according to the invention, may also contain one or more substituents. Illustrative, but not limiting examples of substituents are halogen, alkyl, carboxy, alkoxy, alkylcarbonyl, hydroxy groups. This invention contains only those combinations of substituents and derivatives that form a stable or chemically possible compound. A stable or chemically feasible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are quite stable and do not decompose at temperatures up to 40 ° C in the absence of chemically active conditions for at least one week.

Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds, unless otherwise indicated.

Unless otherwise indicated, the compound structures given in the application materials also imply all stereoisomers, i.e., R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (> 90%, and preferably> 95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by resolving the racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base, followed by crystallization of the diastereomer mixture, followed by isolation of the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluolvic and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The resulting diastereomers can be separated by conventional methods, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

The optically active compounds of this invention can be prepared using optically active starting materials. Such isomers may be in the form of a free acid, free base, ester or salt.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to a complex wherein the solvent molecules are water.

Compounds according to this invention relate to biaryl.

Biaryl, alone or as part of another compound, refers to an arylaryl group having two aromatic ring systems that are connected directly to each other via a single bond. Typical biaryl groups include, but are not limited to, biphenyl, binaphthyl, phenyl pyrazole, phenyl pyridine and the like. According to the present invention, one of the aryls of the biaryl system is substituted phenyl. Another aryl included in the biaryl system (cycle A, as described above), is a 5-6-membered monocyclic or 9-10-membered bicyclic aromatic ring, optionally containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein aryl may optionally be substituted with 1-3 substituents. According to the invention, cycle A can be attached to the phenyl ring at the positions of meta or para with respect to the main phenyl substituent chain, as described in more detail above and reflected in the claims.

Non-limiting examples of cycle A entering the biaryl system are given below:

By “asterisk - *” here is meant a junction with a phenolic ring entering the biaryl system.

The compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or the resulting other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, heptofluorosulfonate, glucose gluconate, formate glucose phosphate heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, perspec ulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecane, valerate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic cations of ammonium, quaternary ammonium and amine obtained using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The term "pharmaceutically acceptable ester" as it is

used here, refers to an in vivo hydrolyzable ester that readily decomposes in the human body to the parent compounds or their salts. A suitable ester group includes, for example, derivatives of pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic, alkenic, cycloalkanoic and alkanedienic acids, in which each alkyl or alkenyl component usually has no more than 6 carbon atoms. Examples of specific esters include derivatives of formates, acetates, propionates, butyrates, acrylates and ethyl succinates. Obviously, esters can also be formed by a hydroxyl group or a carboxylic acid group of a compound of the invention.

The use of chemical compounds according to the invention

The compounds of the invention are selective sst4 receptor agonists. More preferably, said compounds are selective full sst4 receptor agonists.

The term “agonist” refers to chemical compounds (ligands) that, when interacting with a receptor, increase the biological response of the receptor. Agonists differ in the strength of the physiological response caused by them. The term “superagonist” refers to compounds that are capable of eliciting a stronger physiological response than an endogenous agonist. The term “complete agonist” refers to compounds that elicit the same response as an endogenous agonist. The term "partial agonist" refers to compounds that cause a lower response than an endogenous agonist, such compounds are unable to induce maximum activation of the receptor, regardless of the amount of drug used.

The term "sstr4 agonist" should be understood as a substance or preparation that has an affinity for somatostatin receptors of the 4th subtype and which activates these receptors when interacting with them.

The compounds described in this invention exhibit activity of somatostatin receptor receptor agonists of the 4th subtype. Thus, the compounds described in this invention can be used to treat diseases and pathological conditions in the pathogenesis of which sst4 receptors are involved. The compounds according to the invention have anti-inflammatory and antinociceptive activity and can be used as an anesthetic and in febrile conditions, as well as for the treatment of diseases associated with neurogenic inflammation, providing a systemic anti-inflammatory and analgesic effect. Such diseases and conditions for the treatment of which the compounds described in this invention will be effective include acute and chronic inflammation of the respiratory tract, chronic arthritis, including rheumatoid arthritis, mechanical allodynia. In addition, as sst4 agonists, the compounds of this invention can be effective in the treatment of bladder dysfunction, neurodegenerative diseases of the retina.

In addition, since the compounds of the present invention are able to cross the blood-brain barrier, they can be used to treat and / or prevent pathological conditions or diseases of the brain. Such diseases and conditions for the treatment of which the compounds described in this invention will be effective include, in particular, cognitive diseases such as Alzheimer's disease and Parkinson's disease; alcohol intoxication and alcohol dependence.

The method of therapeutic use of the compounds.

The subject of this invention also includes the administration to a subject in need of appropriate treatment, a therapeutically effective amount of a compound of general formula I. By a therapeutically effective amount is meant the amount of one or more of the described compounds administered or delivered to a patient, in which the patient is most likely to exhibit the desired response to treatment (prevention). The exact amount required can vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.

The substance or pharmaceutical composition containing the substance can be introduced into the patient's body in any quantity and by any route of administration effective for treating or preventing a disease.

After mixing the drug with a specific suitable pharmaceutically acceptable carrier in the desired dosage, the compositions comprising the essence of the invention can be administered orally, parenterally, topically, and the like to the human or other animals.

An effective systemic dosage of a compound, administered in a single dose or in the form of several separate doses, usually lies in the range from 0.01 to 500 mg / kg, preferably from 0.1 to 125 mg / kg, even more preferably from 1 to 100 mg / kg Typically, the compound is administered to a patient in need of such treatment in a daily dosage of from about 50 to 2000 mg per patient. The introduction can be carried out both once and several times a day, week (or any other time interval), or from time to time. In addition, the compound can be introduced into the patient’s body every day for a certain period of days (for example, 2-10 days), and then a period without taking the substance (for example, 1-30 days) follows.

In the case where the compound of the present invention is used as part of a combination therapy regimen, a dose of each of the components of the combination therapy is administered during the required treatment period. The compounds that make up the combination therapy can be administered into the patient's body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

Pharmaceutical Compositions

The invention also relates to pharmaceutical compositions that contain at least one of the compounds described herein (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such that can be introduced into the patient’s body together with the compound that is the essence of this invention, and which do not destroy the pharmacological activity of this compound, and I are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form. Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers. Also in the composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

The subject of the present invention is also dosage forms — a class of pharmaceutical compositions, the composition of which is optimized for a specific route of administration into the body in a therapeutically effective dose, for example, for administration to the body orally, topically, by the intraocular route, pulmonary, for example, as an inhalation spray, or intravascular method, intranasally, subcutaneously, intramuscularly, as well as the infusion method, in recommended dosages.

The dosage form of the present invention may contain a compound of the formula described herein or a pharmaceutically acceptable salt thereof, and an additional preparation, for example, selected from the following: antidepressant, antitumor drug, antiviral drug, anti-inflammatory drug, and any pharmaceutically acceptable carrier, adjuvant or solvent. Dosage forms of the present invention may contain formulations prepared using liposome or microencapsulation methods, methods for preparing nanoforms of the preparation, and other examples known in the pharmaceutical art.

In preparing the composition, for example, in tablet form, the active principle is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.

Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.

A pharmaceutical composition in the form of a gelatin capsule can be prepared by mixing the active principle with a solvent and filling the mixture with soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used that contain pharmacologically compatible agents, for example propylene glycol or butylene glycol.

For example, a unit dosage form containing a compound of the invention in tablet form may contain the following ingredients, mg / tablet:

Compound one Mannitol 224 Croscarmellose sodium 5 Corn starch fifteen Hydroxypropylmethyl cellulose 2 Magnesium stearate 3.0

General scheme for the synthesis of compounds

Compounds of the invention may be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes.

Synthesis conditions:

a) SOCl ₂ , CH ₃ OH; b) LDA, THF, -75 ° C; c) Na ₂ CO ₃ , Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, boiling; d) NaOH, CH ₃ OH-THF, boiling; e) TBTU, Et ₃ N, DMAP, CH ₃ CN, where

LDA - lithium diisopropylamine (LDA), THF - tetrahydrofuran (THF), TBTU - N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoborate (TBTU), DMAP - 4-dimethylaminopyridine (DMAP ), MeOH — methanol, Et ₃ N — triethylamine; R are substituents of cycle A according to the present invention.

Examples of the synthesis of specific compounds

Example 1

Synthesis of 1- (2 ', 6'-Dimethoxybiphenyl-4-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (1-methylpiperidin-4-yl) -amide (AST-1)

Conditions: a) SOCl ₂ , MeOH; b) LDA, THF, -75 ° C; c) Na ₂ CO ₃ „Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, RF; d) NaOH, MeOH-THF, RF; e) TBTU, Et ₃ N, DMAP, CH ₃ CN.

4-Methoxy-cyclohexanecarboxylic acid methyl ester (2):

thionyl chloride (1.42 g, 12 mmol) was added dropwise to 30 ml of anhydrous methanol at -20 ° C, then 4-methoxy-cyclohexanecarboxylic acid (1) (1.58 g, 10 mmol) was added. The resulting solution was stirred at -5 ° C for 1 hour, then at room temperature for 1 hour, then the temperature was raised to 40 ° C and stirred for another 2 hours. At the end of the reaction, the solvent was distilled off in vacuo, 100 ml of dichloromethane was added to the residue, washed with saturated sodium carbonate solution (2 × 100 ml), the organic layer was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. 1.63 g (95%) of ether (2) are obtained.

1- (4-Bromobenzyl) -4-methoxy-cyclohexanecarboxylic acid methyl ester (4):

To a solution of N, N-diisopropylamine (5.5 g, 5.5 mmol) in 25 ml of anhydrous tetrahydrofuran, cooled to -78 ° C, n-butyllithium (1.6 M solution in THF, 3.75 ml, is added dropwise in an argon atmosphere). 6 mmol), stirred at this temperature for 20 min and a solution of ether (2) (0.815 g, 4.75 mmol) in 12 ml of THF was added dropwise, stirred at -75 ° С for 20 min, then a solution of 1-bromo-4 was added β-bromomethyl-benzene (3) (1.19 g, 4.75 mmol) in 12 ml of THF, stirred at this temperature for another 1 hour and left overnight at room temperature. The mixture was poured into 100 ml of a saturated solution of ammonium chloride, extracted with ethyl acetate (3 × 50 ml), the organic layer was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate-hexane (1: 4). Yield 0.99 g (61%). ¹ H NMR δ _H (400 MHz, D ₆ -DMSO): 1.10 (m, 2H), 1.25 (m, 2H), 1.85 (m, 2H), 1.94 (m, 2H), 2.7 (s, 2H), 3.15 (m, 1H), 3.22 (s, 3H), 3.55 (s, 3H), 6.85 (d, 2H), 7.45 (d, 2H).

APCI-MS (m / z (intensity)): 342.4 ([M + H] ⁺ , 100%). Compound (4) according to PCA is the cis isomer.

1- (2 ', 6'-Dimethoxybiphenyl-4-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid methyl ester (6):

to a solution of bromide (4) (0.341 g, 1 mmol) in 15 ml of a mixture of dioxane-water (10: 1), 2,6-dimethoxyphenylboronic acid (5) (0.273 g, 1.5 mmol), Pd catalyst (dppf) Cl ₂ (0.036 g, 0.05 mmol) and Na ₂ CO ₃ (0.159 g, 1.5 mmol). The reaction mixture was boiled for 16 h (TLC control, ethyl acetate-hexane, 1: 3), cooled, poured into water (30 ml), extracted with dichloromethane (3 × 50 ml), the organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate-hexane (1: 4). Yield 0.275 g (69%). APCI-MS (m / z (intensity)): 399.5 ([M + H] ⁺ , 100%).

1- (2 ', 6'-Dimethoxybiphenyl-4-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (7):

to a suspension of methyl ether (6) (0.275 g, 0.69 mmol) in 10 ml of a mixture of THF-MeOH (1: 1), a solution of NaOH (0.2 g, 5 mmol) in 5 ml of water is added. Boil for 8 hours (control by TLC). At the end of the reaction, the solvent was distilled off, 10 ml of water was added to the residue, and acidified with 1M HCl to pH 2-3. The precipitate formed is filtered off, washed with water and dried. Yield 0.26 g (98%). ¹ HNMRδ _H (400 MHz, D ₆ -DMSO): 1.09-1.26 (m, 4H), 1.81 (m, 2H), 2.02 (m, 2H), 2.70 (s, 2H), 3.07 (m, 1H), 3.21 (s, 3H), 3.56 (s, 6H), 6.71 (d, 2H), 7.12 (m, 4H), 7.75 (t, 1H).

APCI-MS (m / z (intensity)): 385.5 ([M + H] ⁺ , 100%)

1- (2 ', 6'-Dimethoxybiphenyl-4-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (1-methylpiperidin-4-yl) -amide (9):

to a suspension of acid (7) (0.26 g, 0.67 mmol) in 10 ml of anhydrous acetonitrile, TBTU (0.237 g, 0.74 mmol), 1-methyl-piperidin-4-ylamine (8) (0.115 g, 1 mmol), triethylamine (0.7 ml, 1 mmol) and 4-dimethylaminopyridine (0.008 g, 0.067 mmol). The mixture was boiled for 16 hours, then cooled, poured into 25 ml of a saturated potash solution, extracted with dichloromethane (3 × 25 ml), the organic extracts were combined, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on basic alumina, eluting with ethyl acetate-hexane (1: 1). Yield 0.257 g (80%).

¹ HNMRδ _H (400 MHz, D ₆ -DMSO): 1.11-1.25 (m, 4H), 1.40-1.62 (m, 4H), 1.74-1.92 (m, 4H), 2.04-2.17 (m, 5H), 2.62 -2.69 (m, 4H), 3.05 (m, 1H), 3.16 (s, 3H), 3.55 (m, 1H), 3.62 (s, 6H), 6.66 (d, 2H), 7.00 (m, 5H), 7.25 (t, 1H). APCI-MS (m / z (intensity)): 481.6 ([M + H] ⁺ , 100%).

Example 2

Synthesis of 1- (2 ', 6'-Dimethoxy-bephenyl-3-ylmethyl) -4-methoxy-cyclohexane-carboxylic acid (1-methylpiperidin-4-yl) -amide (AST-2)

Conditions: a) LDA, THF, -75 ° C; b) Na ₂ CO ₃ „Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, RF; c) NaOH, MeOH-THF, RF; d) TBTU, Et ₃ N, DMAP, CH ₃ CN.

1- (3-Bromobenzyl) -4-methoxycyclohexanecarboxylic acid methyl ester (11) is prepared analogously to compound (4), starting from ether (2) (0.815 g, 4.75 mmol) and 1-bromo-3-bromomethyl-benzene ( 10) (1.19 g, 4.75 mmol). Yield 0.956 g (59%). ¹ N NMR δ _H (400 MHz, D ₆ -DMSO): 1.05 (m, 2H), 1.25 (m, 2H), 1.79-1.96 (m, 4H), 2.70 (s, 2H), 3.06 (m , 1H), 3.16 (s, 3H), 3.55 (s, 3H), 7.01 (d, 1H), 7.19 (m, 2H), 7.39 (d, 1H). APCI-MS (m / z (intensity)): 342.2 ([M + H] ⁺ , 100%).

1- (2 ', 6'-Dimethoxy-bephenyl-3-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid methyl ester (12) was prepared analogously to compound (6) from compound (11) (0.341 g, 1 mmol). Yield 0.24 g (60%). APCI-MS (m / z (intensity)): 399.4 ([M + H] ⁺ , 100%).

1- (2 ', 6'-Dimethoxy-bephenyl-3-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (13) is obtained analogously to compound (7) from methyl ester (12) (0.24 g, 0.6 mmol) . Yield 0.218 g (95%). APCI-MS (m / z (intensity)): 385.4 ([M + H] ⁺ , 100%).

1- (2 ', 6'-Dimethoxy-bephenyl-3-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (1-methylpiperidin-4-yl) -amide (14) is obtained analogously to compound (9) from acid (13) ( 0.218 g, 0.57 mmol). Yield 0.224 g (82%).

¹ HNMRδ _H (400 MHz, D ₆ -DMSO): 1.13 (m, 4H), 1.36-1.52 (m, 4H), 1.72-1.87 (m, 4H), 2.01-2.12 (m, 5H), 2.60-2.69 (m, 4H), 3.01 (m, 1H), 3.32 (s, 3H), 3.51 (m, 1H), 3.62 (s, 6H), 6.69 (d, 2H), 6.92 (m, 2H), 7.04 ( d, 2H), 7.16 (t, 1H), 7.27 (t, 1H). APCI-MS (m / z (intensity)): 481.4 ([M + H] ⁺ , 100%).

Example 3

Synthesis of 4- (5'-Fluoro-2'-methoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (1-methylpiperidin-4-yl) -amide (AST-3)

Conditions: a) SOCl ₂ , MeOH; b) LDA, THF, -75 ° C; c) Na ₂ CO ₃ „Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, RF; d) NaOH, MeOH-THF, RF; e) TBTU, Et ₃ N, DMAP, CH ₃ CN.

Tetrahydropyran-4-carboxylic acid methyl ester (16) is prepared analogously to compound (2) from tetrahydropyran-4-carboxylic acid (15) (1.3 g, 10 mmol). Yield 1.4 g (97%).

4- (3-Bromobenzyl) -tetrahydropyran-4-carboxylic acid methyl ester (17) is prepared analogously to compound (4) from ether (16) (0.7 g, 4.85 mmol). Yield 0.99 g (65%). ¹ N NMR δ _H (400 MHz, D ₆ -DMSO): 1.51 (m, 2H), 1.80 (m, 2H), 2.77 (s, 2H), 3.19-3.28 (m, 2H), 3.59 (s, 3H ), 3.77 (m, 2H), 7.03 (d, 1H), 7.23 (m, 2H), 7.41 (d, 1H). APCI-MS (m / z (intensity)): 314.2 ([M + H] ⁺ , 100%).

4- (5'-Fluoro-2'-methoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid methyl ester (19) was prepared analogously to compound (6), starting from bromide (17) (0.313 g, 1 mmol) and 5-fluoro-2-methoxyphenylboronic acid (18) (0.255 g, 1.5 mmol). Yield 0.25 g (70%). APCI-MS (m / z (intensity)): 359.4 ([M + H] ⁺ , 100%).

4- (5'-Fluoro-2'-methoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (20) is obtained analogously to compound (7) from methyl ether (19) (0.25 g, 0.7 mmol) . Yield 0.234 g (97%). APCI-MS (m / z (intensity)): 344.2 ([M + H] ⁺ , 100%).

4- (5'-Fluoro-2'-methoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (1-methylpiperidin-4-yl) -amide (21) is obtained analogously to compound (9) from acid (20) ( 0.234 g, 0.68 mmol). Yield 0.233 g (78%).

¹ N NMR δ _H (400 MHz, D ₆ -DMSO): 1.40-1.57 (m, 6H), 1.84 (t, 2H), 1.95 (d, 2H), 2.11 (s, 3H), 2.65 (m, 2H ), 2.81 (s, 2H), 3.30 (m, 2H), 3.52 (m, 1H), 3.61-3.75 (m, 5H), 7.03-7.15 (m, 4H), 7.19 (s, 1H), 7.23- 7.34 (m, 3H). APCI-MS (m / z (intensity)): 441.4 ([M + H] ⁺ 100%).

Example 4

Synthesis of 4- (2 ', 6'-Dimethoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (1-methyl-piperidin-4-yl) -amide (AST-4)

Conditions: a) Na ₂ CO ₃ „Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, RF; b) NaOH, MeOH-THF, RF; c) TBTU, Et ₃ N, DMAP, CH ₃ CN.

4- (2 ', 6'-Dimethoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid methyl ester (22) was prepared analogously to compound (6) from bromide (17) (0.313 g, 1 mmol). Yield 0.203 g (55%). APCI-MS (m / z (intensity)): 371.4 ([M + H] ⁺ , 100%).

4- (2 ', 6'-dimethoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (23) is prepared analogously to compound (7) from methyl ester (22) (0.203 g, 0.55 mmol). Yield 0.18 g (92%). APCI-MS (m / z (intensity)): 357.4 ([M + H] ⁺ , 100%).

4- (2 ', 6'-Dimethoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (1-methyl-piperidin-4-yl) -amide (24) is obtained analogously to compound (9) from acid (23) ( 0.18 g, 0.50 mmol). Yield 0.17 g (75%).

¹ HNMRδ _H (400 MHz, D ₆ -DMSO): 1.25-1.68 (m, 8H), 1.95 (d, 2H), 2.35 (m, 3H), 2.81 (s, 2H), 2.95 (m, 2H), 3.30 (m, 3H), 3.70 (m, 8H), 6.72 (d, 2H), 6.96 (m, 2H), 7.04 (d, 1H), 7.18-7.29 (m, 2H), 7.39 (br, 1H) . APCI-MS (m / z (intensity)): 453.6 ([M + H] ⁺ , 100%)

Example 5

Synthesis of 1- (2 ', 6'-Dimethoxy-biphenyl-4-ylmethyl) -3-methoxy-cyclohexanecarboxylic acid (1-methyl-piperidin-4-yl) -amide (AST-5)

Conditions: a) SOCl ₂ , MeOH; b) LDA, TFH, -75 ° C; c) Na ₂ CO ₃ „Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, RF; d) NaOH, MeOH-THF, RF; e) TBTU, Et ₃ N, DMAP, CH ₃ CN.

3-Methoxycyclohexanecarboxylic acid methyl ester (26)

Prepared analogously to compound (2) from 3-methoxy-cyclohexanecarboxylic acid (25) (1.58 g, 10 mmol). Yield 1.65 g (96%).

1- (4-Bromobenzyl) -3-methoxycyclohexanecarboxylic acid methyl ester (27)

Obtained analogously to compound (4) from ether (26) (0.83 g, 4.8 mmol). Yield 0.98 g (60%). APCI-MS (m / z (intensity)): 342.2 ([M + H] ⁺ , 100%)

1- (2 ', 6'-Dimethoxy-biphenyl-4-ylmethyl) -3-methoxycyclohexanecarboxylic acid methyl ester (28)

Obtained similarly to compound (6), starting from bromide (27) (0.341 g, 1 mmol). Yield 0.230 g (58%). ¹ HNMRδ _H (400 MHz, D ₆ -DMSO): 0.92 (m, 1H), 1.12-1.20 (m, 2H), 1.60-1.63 (m, 1H), 1.88-2.04 (m, 2H), 2.31 (m , 1H), 2.47 (m, 2H), 2.67-2.86 (m, 2H), 3.06 (m, 1H), 3.21 (s, 3H), 3.58 (s, 2H), 3.64 (s, 6H), 6.68 ( d, 2H), 6.94 (d, 2H), 7.08 (d, 2H), 7.22 (m, 1H). APCI-MS (m / z (intensity)): 399.5 ([M + H] ⁺ , 100%)

1- (2 ', 6'-Dimethoxybiphenyl-4-ylmethyl) -3-methoxycyclohexanecarboxylic acid (29) was prepared analogously to compound (7) from methyl ester (28) (0.23 g, 0.58 mmol). Yield 0.209 g (94%). APCI-MS (m / z (intensity)): 385.4 ([M + H] ⁺ , 100%).

1- (2 ', 6'-Dimethoxy-biphenyl-4-ylmethyl) -3-methoxy-cyclohexanecarboxylic acid (1-methyl-piperidin-4-yl) -amide (30) is obtained analogously to compound (9) from acid (29 ) (0.209 g, 0.54 mmol). Yield 0.220 g (85%).

¹ HNMRδ _H (400 MHz, D ₆ -DMSO): 0.81-0.90 (m, 2H), 1.01-1.24 (m, 2H), 1.41-1.66 (m, 4H), 1.87 (m, 3H), 2.01-2.15 (m, 3H), 2.40 (m, 1H), 2.45 (m, 3H), 2.80 (m, 3H), 3.1 (m, 1H), 3.21 (m, 3H), 3.55 (m, 1H), 3.64 ( s, 6H), 6.71 (d, 2H), 6.95-7.06 (m, 4H), 7.16-7.26 (m, 2H). APCI-MS (m / z (intensity)): 481.4 ([M + H] ⁺ , 100%).

Example 6

Synthesis of 2- (5'-Fluoro-2'-methoxy-biphenyl-4-ylmethyl) -tetrahydrofuran-2-carboxylic acid (2-methyl-3-pyrrolidin-1-ylpropyl) -amide (AST-6)

Conditions: a) SOCl ₂ , MeOH; b) LDA, TFH, -75 ° C; c) Na ₂ CO ₃ „Pd (Ph ₃ P) ₄ , dioxane / H ₂ O, RF; d) NaOH, MeOH-THF, RF; e) TBTU, Et ₃ N, DMAP, CH ₃ CN.

Tetrahydrofuran-2-carboxylic acid methyl ester (32) is prepared analogously to compound (2) from tetrahydrofuran-2-carboxylic acid (31) (1.16 g, 10 mmol). Yield 1.21 g (93%).

2- (4-Bromobenzyl) -tetrahydrofuran-2-carboxylic acid methyl ester (33) was prepared analogously to compound (4) from ether (32) (0.61 g, 4.65 mmol). Yield 0.74 g (53%). APCI-MS (m / z (intensity)): 300.1 ([M + H] ⁺ , 100%).

2- (5'-Fluoro-2'-methoxy-biphenyl-4-ylmethyl) -tetrahydrofuran-2-carboxylic acid methyl ester (34) was prepared analogously to compound (19), starting from bromide (33) (0.299 g, 1 mmol ) Yield 0.220 g (64%). APCI-MS (m / z (intensity)): 345.4 ([M + H] ⁺ , 100%).

2- (5'-Fluoro-2'-methoxy-biphenyl-4-ylmethyl) -tetrahydrofuran-2-carboxylic acid (35) was prepared analogously to compound (7) from methyl ester (34) (0.22 g, 0.64 mmol). Yield 0.207 g (98%). APCI-MS (m / z (intensity)): 331.4 ([M + H] ⁺ , 100%).

2- (5'-Fluoro-2'-methoxy-biphenyl-4-ylmethyl) -tetrahydrofuran-2-carboxylic acid (2-methyl-3-pyrrolidin-1-ylpropyl) -amide (37) is obtained analogously to compound (9) from acid (35) (0.207 g, 0.63 mmol) and amine (36) (0.134 g, 0.94 mmol). Yield 0.146 g (51%). APCI-MS (m / z (intensity)): 455.6 ([M + H] ⁺ , 100%).

Other non-limiting examples of compounds of the invention are shown in Table 1:

In vitro study

Method for the determination of inhibitors, modulators and activators of somatostatin G-protein-conjugated receptors with 7 transmembrane domains (GPCR) of human sst4 (hSST4) and rat sst4 (rSST4).

The activity of compounds was determined by measuring intracellular calcium Ca ²⁺ on a FLIPR TETRA device (Fluorometric Imagining Plate Reader System from Molecular Devices). This method allows the detection of a fluorescent signal upon excitation of stomatostatin receptors for transfected cells and the production of calcium Ca ²⁺ , which forms a fluorescent complex with dye molecules Fluo-4AM (Molecular Probes, F-14201). Millipore HTS125C (hSST4) cell line transfected with human sst4 DNA and CHO cell line transfected with rat sst4 DNA in our company (rSST4) are used in the work. As an activator, an endogenous ligand, somatostatin-14 peptide (SRIF-14), is used. To determine the modulatory activity of the compounds, the concentration of SRIF-14 is EC5, for the antagonistic, EC80.

Primary screening (determination of the activity of compounds in one repetition at a concentration of 10 μM, DMSO - 1%)

Cells were planted 24 hours before the experiment in black polystyrene 96-well plates with a transparent bottom (Corning. 3904) at 100 μl per well with a density of 175 ± 25 thousand / ml.

Upon reaching the formation of 80-90% monolayer, the cells are washed gently with Hanks buffer (Paneko, P022) containing 20 mM HEPES and 2.5 mM probenicide by aspirating the liquid from the wells of the plate and adding 100 μl to the buffer well.

After washing, 50 μl of the dye solution in Hanks' buffer (2 μg / ml Fluo-4AM, 480 μg / ml Pluronic-127) is added to the wells with cells and left for 1.5 hours in an incubator at a temperature of 37 ° C, 95% humidity and 5% CO ₂ . After the incubation time has elapsed, the cells are washed with Hanks buffer (see above) and 65 μl are added to the well buffer. Further, all operations for adding solutions to the tablet and reading the fluorescent signal are carried out on the FLIPRTETRA device according to previously created protocols.

As a positive control, a 25 nM concentration of SRIF-14 is used.

To determine the activity of agonists using the device, 25 μl of 50 μM solutions of the compounds in Hanks buffer (5% DMSO) are transferred to a cell plate.

To determine the modulatory activity of the compounds using the device, 12.5 μl of 0.25 nM SRIF-14 solution are transferred to all wells in a plate with cells and substances (negative control - wells with 0.025 nM SRIF-14 solution).

To determine the antagonistic activity using the device, 12.5 μl of 100 nM SRIF-14 solution are transferred to all wells in a plate with cells and substances.

Further, for compounds showing more than 50% activity, IC50 values (for antagonists) or EC50 (for agonists and modulators) are determined.

Concentrations of compounds: 50, 16.6, 5.5, 1.85, 0.6, 0.2, 0.07, 0.02 μM, DMSO - 1%. The concentrations of ligand SRIF-14 are the same as in the primary screening.

The experimental results are presented in Table 2:

The study of the activity of compounds in cell models of Alzheimer's disease

The results of studies on cell models of Alzheimer's disease show the inhibitory effect of the compounds of the invention on the formation of neurotoxic amyloid beta. It was also shown that these compounds are able to penetrate the blood-brain barrier.

In vivo studies

Study of the anti-inflammatory effect of AST-1 in a model of carrageenan inflammation

Study Description:

For the study, white SHK male mice were used, 5-7 weeks old with a body weight of 23-25 g. Mice were marked and assigned to the groups before the start of the experiment: 8 males per test substance.

All test substances were administered orally for 30 minutes. before the introduction of a 1% solution of lambda carrageenan (Lambda Carrageenan). Lambda carrageenan was injected subcutaneously into the pad of the left hind paw at 0.025 ml / paw.

An oncometric method was used as criteria for evaluating the effectiveness of the studied substances — determining the volume of paws by the amount of liquid displaced from the vessel. Paws were measured using a plethysmometer instrument (Plethysmometer Cat. No. 7140, www.ugobasile.com).

The first measurement was made an hour after the administration of lambda carrageenan, then once an hour, for 6 hours, the last measurement was carried out after 24 hours.

The data were entered into the protocol and further processed in the Libreofice 3.3 program.

We took the difference in the readings for the left and right paws, calculated the average values and standard deviations for the groups, and built graphs (Fig. 1).

Comparisons were also made between the groups administered the test substances (ketoprofen 6 mg / kg, dexamethasone 10 mg / kg or AST-1 at a dose of 5, 10 or 25 mg / kg) and the control (lambda carrageenan 1% solution), s using t - test for independent groups (significance of differences at p <0.05).

Conclusion:

Based on the data obtained, it can be concluded that all tested substances, except for AST-1 at a dose of 5 mg / kg, had a pronounced anti-inflammatory effect and significant suppression of paw edema in mice induced by 1% carrageenan (Table 3). The anti-inflammatory effect of AST-1 is dose-dependent.

The study of the analgesic activity of AST-3 in the formalin test on rats

For the study, male Sprague-Dawley rats (125-175 g, Charles River, France) were used, which were kept at a temperature of 19.5 ° C-24.5 ° C, relative humidity 45% -65%, and light mode 12 hours - light / 12 hours darkness. Morphine hydrochloride (4 mg / kg subcutaneously) was used as a reference compound.

The compound AST-3 was studied at doses of 0.1, 1, 3, and 10 mg / kg and was administered intraperitoneally (ip) (10 ml / kg) (the reference compound morphine was administered subcutaneously 5 ml / kg) for 30 minutes. before subplanar injection into the right hind paw of 50 μl of a 2.5% formalin solution.

Paw licking times were recorded in 5-minute periods from 0 to 10 minutes. (early phase) and from 15 to 30 minutes. (late phase) after administration of formalin.

The results of the study are shown in Fig. 2. It was found that the compound AST-3 does not cause a statistically significant antinociceptive effect, there is a tendency to reduce the time of licking the paws in the second phase of the study (15-35 min.).

Alcoholic motivation.

Studies were conducted on male mice of the C57B L6 line.

After a period of acclimatization, the animals were given free access to water, food and a 10% alcohol solution for 2 months.

The preparation of a new alcohol solution was carried out every 2-3 days. At the same time, a bottle of alcohol was put in the place where the water was, and instead of alcohol, water was put.

To assess alcohol motivation, we calculated the degree of increase in voluntary consumption of a 10% alcohol solution during a 90-minute test after 3 days of alcohol deprivation compared with the same test performed before 3 days of alcohol deprivation (alcohol deprivation effect, ADE). The ADE index was calculated as the ratio of alcohol consumption after its cancellation (calculated per gram of pure alcohol per kilogram of body weight) to its total consumption before and after withdrawal of access to alcohol. If the ADE index has a value greater than or less than 0.5, then this means, respectively, the presence or absence of alcohol dependence.

At the end of the 2-month period of free access of mice to water, food, and alcohol, the ADE assessment described above was performed and mice were selected for further experiments with an ADE index greater than 0.5 (approximately 80% of the sample). These mice were divided into groups of 10-13 individuals that did not differ from each other in ADE.

Within 14 days, the animals received the test substances with free access to food, water and a 10% alcohol solution. At the same time, daily consumption indications of alcohol of each group in terms of g / kg of pure alcohol per day were taken (Fig. 3).

After treatment, the animals were deprived of alcohol for three days and the ADE index was calculated according to the method described above (Fig. 4).

The compound AST-1 at a dose of 50 and 100 mg / kg statistically significantly reduces alcohol consumption in animals with free access to alcohol. There is a tendency to decrease ADE after the deprivation.

Although the present invention has been described above with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments described in detail should be considered as illustrative and not restrictive. It should be understood that various modifications are possible without departing from the gist of the present invention. Accordingly, the present invention is limited only by the following claims.

Claims (15)

1. The compound of formula I

or its pharmaceutically acceptable salt, in which
R1, R5 are independently selected from H,
R2, R3 and R4 are selected from H and cycle A,
moreover, one of R2, R3 or R4 necessarily represents a cycle A;
cycle A is
A 6-membered monocyclic or 10-membered bicyclic aromatic ring, optionally containing 1 heteroatom, representing N,
wherein cycle A may optionally be substituted with 1-3 substituents independently selected from
halogen
IT,
COOH,
C ₁ -C ₆ alkyl
C ₁ -C ₆ alkoxy,
-C (O) C ₁ -C ₆ alkyl,
-NO ₂ ,
cycle B is
5-6 membered non-aromatic ring, optionally containing 1 heteroatom, representing O,
moreover, the cycle may be optionally substituted by 1-3 substituents independently selected from
-C ₁ -C ₆ -alkyl,
-C (O) C ₁ -C ₆ alkyl,
-C ₁ -C ₆ alkoxy;
R6 is selected from H or C ₁ -C ₆ alkyl,
R7 represents H or
- (Z) _m - (D) _p , where independently from each other
m = 0-1, p = 0-1, while there cannot be m = p = 0,
Z is selected from C ₁ -C ₆ alkyl,
D represents a 5-6 membered non-aromatic ring, optionally containing one N heteroatom, wherein ring D may optionally be substituted with one substituent selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy. 2. The compound according to claim 1, in which
R1, R5 are independently selected from H,
R2, R3 and R4 are selected from H and cycle A, wherein one of R2, R3 or R4 is necessarily cycle A,
and cycle A represents phenyl, pyridinyl or quinolinyl optionally substituted with 1-3 substituents independently selected from
halogen
IT,
COOH,
C ₁ -C ₃ alkyl. 3. The compound according to claim 2, in which
cycle B is a 5-6 membered non-aromatic ring selected from cyclohexane, tetrahydropyran, tetrahydrofuran,
moreover, the cycle can be optionally substituted with 1-2 substituents independently selected from
C ₁ -C ₃ alkyl
-C (O) C ₁ -C ₆ alkyl,
C ₁ -C ₃ alkoxy. 4. The compound according to claim 3, in which
R6 is selected from H or CH ₃ ,
R7 represents H or
- (Z) _m - (D) _p , where
independently from each other, m = 0-1, p = 0-1, while there cannot be m = p = 0,
Z is selected from C ₁ -C ₃ alkyl,
D is a 5-6 membered non-aromatic ring containing one N heteroatom so that it is at a distance of 2-5 carbon atoms from the amide nitrogen atom, and the D ring may optionally be substituted on the N atom with one substituent selected from C ₁ -C ₃ -alkyl. 5. The compound according to claim 4, in which
R7 is 4-piperidine optionally substituted at the nitrogen atom by C ₁ -C ₆ alkyl. 6. The compound according to claim 1, selected from
1- (2 ′, 6′-dimethoxybiphenyl-4-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (1-methylpiperidin-4-yl) -amide,
1- (2 ′, 6′-dimethoxybiphenyl-3-ylmethyl) -4-methoxy-cyclohexanecarboxylic acid (1-methylpiperidin-4-yl) -amide,
4- (5′-fluoro-2′-methoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (1-methylpiperidin-4-yl) -amide,
4- (2 ′, 6′-dimethoxybiphenyl-3-ylmethyl) -tetrahydropyran-4-carboxylic acid (1-methyl-piperidin-4-yl) -amide,
1- (2 ′, 6′-dimethoxybiphenyl-4-ylmethyl) -3-methoxy-cyclohexanecarboxylic acid (1-methyl-piperidin-4-yl) -amide,
2- (5′-fluoro-2′-methoxybiphenyl-4-ylmethyl) -tetrahydrofuran-2-carboxylic acid (2-methyl-3-pyrrolidin-1-ylpropyl) -amide,
4 - ((4′-methoxybiphenyl-3-yl) methyl) -N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((3 ′, 5′-dimethylbiphenyl-3-yl) methyl) -N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((2′-methoxybiphenyl-3-yl) methyl) -N- (piperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((2′-ethoxybiphenyl-4-yl) methyl) -N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((4′-fluorobiphenyl-4-yl) methyl) -N-methyl-N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((2′-methylbiphenyl-4-yl) methyl) -N-methyl-N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((3′-acetylbiphenyl-4-yl) methyl) -N-methyl-N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((2′-ethoxybiphenyl-3-yl) methyl) -N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((2′-methoxy-5′-chlorobiphenyl-3-yl) methyl) -N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
4 - ((2 ′, 5′-dimethoxybiphenyl-4-yl) methyl) -N-methyl-N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide,
1 - ((2 ′, 3′-dimethylbiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2′-hydroxybiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((3′-fluorobiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((3′-methoxy-2′-fluorobiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2′-methoxy-5′-chlorobiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2′-methylbiphenyl-3-yl) methyl) -4-methoxy-methylpiperidin-4-yl) cyclohexane-carboxamide,
4-methoxy-1- (3- (2-methoxypyridin-3-yl) benzyl) -N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2′-acetylbiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
4-methoxy-1- (3- (quinolin-8-yl) benzyl) -N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2 ′, 3′-dimethoxybiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2′-nitrobiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
1 - ((2′-chlorobiphenyl-3-yl) methyl) -4-methoxy-N- (1-methylpiperidin-4-yl) cyclohexane-carboxamide,
4 - ((3′-methoxybiphenyl-4-yl) methyl) -N-methyl-N- (1-methylpiperidin-4-yl) tetrahydro-2H-pyran-4-carboxamide. 7. The use of a compound according to any one of claims 1 to 6 as an sst4 receptor agonist for the preparation of a pharmaceutical composition for the treatment and / or prevention of a pathological condition or disease in which somatostatin 4 receptor subtype (sst4) is involved. 8. The use according to claim 7, in which the compound is used as a full sst4 receptor agonist. 9. The use according to claim 7 as an anti-inflammatory agent. 10. The use according to claim 7 as an anesthetic. 11. The use according to claim 7 for the treatment and / or prevention of pathological conditions or diseases of the brain. 12. The use according to claim 11, in which the pathological condition or disease of the brain is Alzheimer's disease, Parkinson's disease, alcohol intoxication or alcohol dependence. 13. The use according to claim 7, in which the pathological condition or disease is an acute or chronic inflammation of the respiratory tract, chronic arthritis, mechanical allodynia, or neurogenic inflammation. 14. The use of claim 7, wherein the disease is bronchial asthma or rheumatoid arthritis. 15. A pharmaceutical composition for the treatment and / or prevention of a pathological condition or disease, the treatment and / or prevention of which requires the use of a somatostatin receptor agonist 4 subtype (sst4), characterized in that it contains a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier, diluent and / or excipient.

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