UA65552C2 - Novel compounds with analgesic action - Google Patents

Abstract

Compounds of general formula (I) are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain. (I)

Description

This invention relates to new compounds, the method of their preparation, their use and pharmaceutical compositions containing new compounds. The new compounds can be used in therapy, especially in the treatment of pain.

Background of the Invention and Prior Art The 5-receptor has been identified as playing a role in many bodily functions, such as the cardiovascular and pain systems. Ligands for the 5-receptor may therefore find potential use as analgesic and/or antihypertensive agents. It was also found that ligands for the b-receptor have immunomodulatory activity.

At least three different populations of opioid receptors (n, b, and ge) have now been identified, and all three are found in both the central and peripheral nervous systems of many animal species, including humans. Analgesia has been observed in various animal models when one or more of these receptors have been activated.

With rare exceptions, currently available selective opioid β-ligands are peptide compounds in nature and are not suitable for systemic administration. Some non-peptide β-antagonists have become available in recent times (see TaKetogi apa Ropodnese, 1992, App. Nem. RNpaptosai. Toh., 32: 239-269.). These compounds, for example, naltrindole, are characterized by rather weak (i.e., 10 times weaker) binding selectivity of the b-receptor compared to the n-receptor and do not show analgesic activity, a fact that suggests the need for the development of highly selective non-peptide 5-ligands.

Thus, the problem underlying this invention was to obtain new analgesics with increased analgesic effect, as well as an improved side effect profile compared to modern r-agonists and significant oral efficacy.

Analgesics that have been identified and described in the prior art have many disadvantages, which are manifested in the fact that they have poor pharmacokinetics and do not have an analgesic effect when administered in systemic ways. In addition, more acceptable compounds described in the prior art have also been documented to exert significant anticonvulsant effects when administered systemically.

The above problem has been solved by developing new compounds that have a piperidine ring with an exocyclic double bond, as will be described below.

Description of the invention

The new compounds according to the present invention have the general formula (I)

A. V

From 2

M and where B' is selected from hydrogen, branched or unbranched C1-C8-alkyl, C1-C8-alkenyl, C3-C8-cycloalkyl, Ca-C8-(alkylcycloalkyl), where alkyl is C1-C8-alkyl, and cycloalkyl is C3-C8 cycloalkyl;

S-Cio-aryl or heteroaryl having from 5 to 10 atoms selected from C, 5, M and O; where aryl or heteroaryl may be optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CHbz, -(CHe)oCE", halogen, -SOMA?B", -СООВ», -СОВ», -«( СНа)рМА?ВУ,. -"(СНазрСНа(СНг)р5ОВВУ,. -(СНг)р5О»Б and - (СНнг)о5О2МВХ, where В" and В» are each independently as defined above for В", and p is 0, 1 or 2; (C1-C0-alkyl) - (Ce-C0-aryl) or (C1-C8-alkyl) heteroaryl, and the heteroaryl parts have from 5 to 10 atoms selected from C, 5, Mi 0; and wherein aryl or heteroaryl may be optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CHbz, -(CHg)aSEz, halogen, -SOMA»VU, -SOOV», -SONU, - (CHg )zamA?VU,. -«(СНазаСНа(СНг)зявОВВУ,. -(СНг)я5О»2в ии -(СНг)рОВ?, where В" and В, each independently, is as defined above for В", and 4 is equal to 0, 1 or 2; and

M i o M 5 and code onena d'? in" in. where B!8. B! d2o. DV?! dgg, d23. some | Where. each independently, represent hydrogen, Ci1i-Cv-alkyl or Ci-Cv-alkenyl;

B2 and BZ, each independently, represent hydrogen or Ci-Cv-alkyl;

And choose from

Вк Х х sword х в i, х b pd " | ha | ih o 14 d' iv ІІ і і 9 I і в- -585В--14 in Kt ha, her, ih у4 (v) і ой . і de В, ВУ, ВС, В", В", ВЗ, дя, д/5, ВИ | Д!", each independently, such as defined above for В", and where the phenyl ring of each substituent A may be optional and independently substituted at any position of the phenyl ring by 1 or 2 substituents 7! and 27, each independently selected from hydrogen, CHbz, (CHg)aSEz, halogen, -"SOMAV", -СООНе, -СОНУ, - ( SNg) "MAeV, "-ESNHaSNa(SNng zov, -"SNg) ZO" and -SNg)5O2MAV, where

B and B", are each independently as defined above for B", and r is 0, 1, or 2;

O is a C-Ce hydroaryl or heterohydroaromatic radical having 5 or 6 atoms selected from C, 5, M and O; C5-Cv-cycloalkyl or heterocycloalkyl having 5 or b atoms selected from C, 5, Mi O; and where each O can optionally be replaced by 7! and 77 as defined above;

B is a substituted or unsubstituted aromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atoms selected from C, 5, M and O, and optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CHz, -(CHg)SEz, halogen, -(CH?g)

SOMAVU, "(SNgim Ave, ""SNgiSOV", -""SNg) "SO, -OV5, -"SNgiBOV", -"SNgyO"V and - (SngiZO2MAZVU, where В: and VU, each independently, such as defined above for B, and i is 0, 1, 2, or 3; and B: and B", each independently, as defined above for B!.

The scope of this invention also includes pharmaceutically acceptable salts of compounds of formula (I), as well as their isomers, hydrates, isomeric forms and prodrugs.

More acceptable compounds of the invention are compounds of formula (I), where

And they choose from in o de Ge! in her ssh ore and about:

PECK

7 7 o'clock

Ге) в" о в : ve g shchy and г, (3, у , х ! (в; there are ve 7 where В8, VU, VO, В, В», ВЗ, ДЯ, В", В! | Д' ", each independently, such as defined above for B", and wherein the phenyl ring of each substituent A may be optionally and independently substituted at any position of the phenyl ring by 1 or 2 substituents 7! and 27, each independently selected from hydrogen, CH», -(СНа)заСЕ»з, halogen, -SOMAEV", -СООВe, -СОВе, -(СНг) "МАВ, -СНngхСНау(СНг) ов", -(СНгу ЗО» and - (Снг ) ZO2MVeV, where

B and VU, each independently, are as defined above for B", and r is equal to 0, 1 or 2;

O is selected from morpholine, piperidine, and pyrrolidine; B", B? and B", are each independently selected from hydrogen, branched or unbranched C1-C4-alkyl, C3-C6-cycloalkyl, C4-C6-(alkylcycloalkyl), where alkyl is C1-C6-alkyl, and cycloalkyl is C3-C6-cycloalkyl; C1-C10-aryl or heteroaryl having from 5 to 6 atoms selected from C, 5, M and O; and wherein the aryl or heteroaryl may be optionally and independently substituted 1 or 2 substituents independently selected from hydrogen, CH3, -(CHg)pSEz, halogen, -SOMA?VU, -SOOV», -SOVU, - (CHg)vM AB", - (СНа)рCHз (CHg)рZOvVU, -(СНа)р5О2В and - (СНг)р5О2МВ, where B" and B", each independently, are as defined above for B", and p is equal to 0, 1 or 2;

B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, each of which optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, CE3, halogen, -"CHg)aSOMA»Ve, -"(CHg)aMm AB, -""CHg)zaSOV", -C(CHg) )аСО»В and -ОВ», where 4 is equal

O or 1, and where B" and B? are as defined above;

B2 and B3 are each independently hydrogen or methyl.

Particularly acceptable compounds of the invention are compounds of formula (I), where

A is in o x

Co

M. come on! where VZ and VU are both ethyl, and where the phenyl ring may optionally and independently be substituted at any position of the phenyl ring by two substituents 7! and 77, which, each independently, are selected from hydrogen, CH3, -(CHg)aSE3, halogen, -"SOMAUV", -COOHBe, -SOBe, -(Cng) MAV, - (CHg) "CH3 (CnHg)

ОВ, -СНг)5О2Ве and -"СНг)5О2МАВ, where В and В", each independently, are as defined above for В", and r is equal to 0, 1 or 2;

AW! selected from hydrogen, methyl, ethyl, -"СНаСНиСН", -СНо-cyclopropyl, -СНг-aryl or СНео-heteroaryl, and the heteroaryl parts have from 5 to 6 atoms selected from C, 5, Mi 0;

B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and indazolinyl, each of which is optional independently substituted with 1 or 2 substituents independently selected from hydrogen, SNH3,

SEz, halogen, -"CHnzaSOMA"VU, -""CHn)zaMAV, ""ENazaSOV", -"CHn)aSO" VZ and -OVU, where 4 is equal to 0 or 1, and where B and

A: as defined above;

B2 and B3 are each independently hydrogen or methyl.

Substituents A and B, respectively, can be optionally substituted in any position of the ring.

The term "halogen" means chlorine, fluorine, bromine and iodine.

The term "aryl" refers to an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphthyl.

The term "heteroaryl" means an aromatic ring in which one or more of the 5-10 ring atoms are non-carbon atoms such as M, 5, and 0.

The term "hydroaromatic" means a partially or fully saturated aromatic ring having 5-10 ring atoms.

The term "heterohydroaromatics" means a partially or fully saturated aromatic ring in which one or more of the 5-10 ring atoms are non-carbon atoms, such as M, 5, and 0.

The term "isomers" means compounds of formula (I), which differ in the position of their functional group and/or orientation.

The term "orientation" refers to stereoisomers, diastereoisomers, regioisomers, and enantiomers.

The term "isoforms" refers to compounds of formula (I) that differ in their crystal lattice, such as crystalline compounds and amorphous compounds.

The term "prodrugs" means pharmacologically acceptable derivatives, for example, esters and amides, such that the biotransformation product of such a derivative that is formed is an active drug. Publication

Soodtap apa Siitap5, Te Rnaptasoodisa!I Braviz oi TNegareshiisv5, 8" ey., MeStgam/-Nii, pi. Ea. 1992, "Vioiigapeiyuptaiiiiop oi Ogydv, pp. 13-15, which describes prodrugs in general, is incorporated herein by reference.

The novel compounds of the present invention are useful in therapy, particularly in the treatment of various painful conditions such as chronic pain, acute pain, cancer pain, rheumatoid arthritis pain, migraine, visceral pain, and the like. This list, however, should not be interpreted as exhaustive.

The compounds of the invention are useful as immunomodulators, especially in autoimmune diseases such as arthritis, in skin transplantation, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as antitumor agents and antiviral agents.

The compounds of the invention are useful in disease states where there is degeneration or dysfunction of opioid receptors, or opioid receptors are involved in this paradigm. This application may include the use of isotopically labeled variants of the compounds of the invention in diagnostic techniques and in imaging applications such as positron emission tomography (PET).

The compounds of the invention can be used to treat diarrhea, depression, urinary incontinence, various mental illnesses, cough, pulmonary edema, various gastrointestinal disorders, spinal cord injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other addictions, and disorders of the sympathetic nervous system, for example, hypertension.

The compounds of the invention are useful as an analgesic agent for use during general anesthesia and to aid in controlled anesthesia. Combinations of agents with different properties are often used to achieve a balance of actions necessary to maintain an anesthetized state (for example, amnesia, analgesia, muscle relaxation, and sedative effects). This combination includes inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blocking agents, and opioids.

The compounds of this invention in isotopically labeled form can be used as a diagnostic agent.

The scope of this invention also includes the use of any of the compounds of the above formula (I) for the manufacture of a medicinal product for the treatment of any of the above conditions.

A further aspect of the invention is a method of treating a subject suffering from any of the above conditions, comprising administering an effective amount of a compound of the above formula (I) to a patient in need of such treatment.

Methods of obtaining

The compounds of this invention can be prepared as described below.

SCHEME I o A v on 2 with A B path

Vozh s-Kyu OO,

In the

And x is

In (in CY

In village, o (ju r uz

And in

IN.

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AND)

SCHEME her would

A sht, with b and . 7 т сх м7 mozh ov nyu M f che U mya

IN

Well, not at all

M. o. And I

Sl te i shih and t o . And the way

Vb z mo st t eV

I have and - but WHAT) ZK e y

Kk me

F Even more

Depdratyaniya r

Yes, yes! t v-no-ya a che

1st in the village

SCHEME 11

A.?

AND

KE x Sh ne y Welcome t eh yak re y and write te de

M 7 - ЧУ - ! g t sh Sto od: (c) y '

AV pi a a SlyhRyssniya Suzuki still g : tu et Y SHI tlya shcha Y | what

Her ! : in the V

In and (5 (in (o

SCHEME OF IU kke a in kodi iIiOVy Kryk -

Op - fa tt, y Ge va hi U va wai ip) and re e cafe t still still in p t her KI po 7 y Zh v-m that a She ak Zh V

In Av 5 BA c

I am Tanya

VE hundred Var vve r - 8 x vk and you and 8 and not I

Ch No; iia Khii st

ON still more eh

As shown above in schemes I and II, compounds of the above formula (I) can be obtained by dehydration of hydroxy compounds (9) or (n), where B', B, VU, A and B are as defined above in formula (I ). Further dehydration of hydroxyl compounds (9) or (n), where B', B, VU, A and B are as defined above in formula (I), can be carried out without solvents or in a solvent such as water, alcohols, esters . such as AI2Oz, Sit2Oz, TO», MOz, Raz or the like, or in the presence of other dehydrating agents such as I», dimethylsulfoxide, KHbOO», SibOm, phthalic anhydride or the like.

Substituents B, B?, and BZ and the substituents on A and B of compound (I) as defined above can be modified in ways known in the art and illustrated in the literature, see, e.g.,

Modegt bZupipeziz Neasiiope Bu Noize, which are well known to a person skilled in the art, after or in the process of obtaining (I) from (9) and (n). what

As shown in the method according to scheme I, compounds of formula (9) as described above can be obtained by the reaction between a ketone of formula (c) where B", B: and B3 are as defined in formula (I) and a compound of formula ( is) where A and B are as defined in formula (I) and X represents a suitable group such as H, CI, V, I, OBO" or the like.

The reaction can be carried out without solvents or in an organic solvent such as THF, toluene, ether, dimethylsulfoxide, or a mixture of solvents by treatment with a suitable metal such as magnesium, lithium, copper, cerium or the like, or by treatment with a metal halide such as Oti." SiSi" or the like, or by treatment with organometallic agents such as alkylmagnesium halides, alkyllithium or the like.

AT, B2 and BZ and substituents on A and B of compounds of formula (9), as defined above, can be modified by methods known in the field, after or during the reaction of organometallic compounds (Magsy, y., Adymapsey Ogdapis

Spetivigu, 4th Ed, add. UL/iIeu apa Zopv, 1992).

Compounds of formulas (c) or (e) may be commercially available or may be prepared by methods known in the art (Magsy, y., Admapseid Ogdapis Spetivigu, 4th Ed, dop U/iIeu apa bopv, 1992).

As shown in method B in scheme (II), compounds of formula (n), as described above, can be obtained by the reaction between a ketone of formula (i), where B, B? and B3 and B are as defined in formula (I) , and an organometallic reagent of formula (|) where A is as defined in formula (I) and M is a group of a suitable metal such as magnesium, lithium, zinc, copper, cerium or the like. The reaction can be carried out without solvents or in an organic solvent such as THF, toluene, ethers, dimethylsulfoxide, or in solvent mixtures.

As shown in method c in Scheme I, compounds of formula (n) can also be prepared by reactions between a carbonyl compound of formula (I) where B, B?, and BZ are as defined in formula (I) and X is a suitable group , leaving, such as СИ, Ви, ОН, ОВ, 5ВА, МА», ШЧОР)В or similar, and organometallic reagents of formulas (i) and (K), where A and B are as defined in formula (I) , where M is a group of a suitable metal such as magnesium, lithium, zinc, copper, cerium, or the like.The reactions can be carried out without solvents or in solvents such as

THF, toluene, ethers, dimethylformamide, dioxane, dimethylsulfoxide, or in solvent mixtures.

B", B? and BZ and substituents on A and B of compounds (I) as defined above can be modified in ways known in the art and illustrated in the literature, see, for example, Rgoiesiipd dgoire Bu Stgeep, og Modegp Zupipeviv

Aeasipe ru Noizhee, which are well known to a person skilled in the art, after or during reactions of organometallic compounds.

Compounds of formulas (Yi), (|), (U and (I) may be commercially available or may be prepared by methods known in the art (Magsny, y). apa bopv, 1992).

As shown above in scheme II, compounds of the above formula (I) can be obtained by coupling according to

Suzuki of vinyl halide (o) (ХУ:Вг, І) with boronic acid, boronate ether (р) in the presence of a base such as

Ma?2bOz, K»SbOz, KzROch4, triethylamine, C5E, MaOH, or alkoxides and a palladium catalyst such as (PPIz)4Ra, bis(dibenzylideneacetone)Ryaa(O), Ra on coal with PPIz; as a catalyst, you can also use compounds PaI), including (PPH3)2Rasi", 1,4-bis(diphenylphosphinobutane)palladium(II) chloride, palladium acetate, bis(acetonitrile) palladium (II) chloride, dichloro(1, 1-bisidiphenylphosphino)ferrocenipalladium (II) and palladium-tri(o-tolyl)phosphine acetate, where B', B, VU, A and B are as defined above in formula (I). The Suzuki coupling can be carried out in toluene, xylene, anisole, DMF, THF, alcohols, ethers, water or in a mixture of solvents.

Compounds of formula (p), where B is as defined in formula (I) and 7 is B(OH)g, may be commercially available or may be obtained by hydrolysis of boronate ether. Compounds of formula (p), where B is as defined in formula (I), and 7 is B(OH)2 (A-Me, E), can be obtained by the reaction of compounds of formula B-M and B(OR)". where AB is Me or Ei, and M is a group of a suitable metal such as lithium or magnesium or the like. Compounds of formula (p), where B is as defined in formula (I), and 7 is 9-borabicyclo!|3.3.1|nonane (9-BBN), can be obtained by the reaction of alk-1-ine with borabicyclo|3.3. 1|nonane.

Substituents B", B: and B3 and substituents on A and B of the compounds of formula (I) as defined above can be modified in ways known in the art and illustrated in the literature, see, e.g.,

Modet 5bupipeziz Neasiiope Bou Noize, well known to a person skilled in the art, after or in the process of obtaining (I) from (o) and (p).

As shown in the IP scheme, compounds of formula (0), where X is B or I, can be obtained by halogenation and cleavage of an alkene of formula (n), B", B, B3 and A as defined in formula (I). Halogenation can be carried out in a solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or acetic acid using molecular bromine or iodine as the halogenating agent.The next cleavage step is carried out in a solvent such as water, alcohols, DMF or ethers using bases such as sodium hydroxide, potassium hydroxide, metal alkoxides or triethylamine.

As shown in scheme II, the compounds of formula (n), as described above, can be prepared by the Wittig reaction of the ketone of formula (c), where B", B? and BZ are as defined in formula (I) and the reagent of formula (t) , where A is as defined in formula (I) and M is a suitable phosphonate or phosphonium salt. The Wittig reaction can be carried out under various conditions known in the art and illustrated in the literature (Magsy, y., Admapsei Ogdapis Snpetivighu, 4

EYA, hopp UmiiIieu apa bopv, 1992).

Reagents of formula (c) and (t) may be commercially available or may be prepared by methods known in the art (Magsn, 9., Aamapsea Ogdapis Spetivigu, 4" Ed, donp ULiIIeu apa bopv, 1992).

As shown in the IM scheme above, compounds of formula (y) can be obtained by dehydration of a hydroxy compound (O), where B", B2, VU, B", B!Z and B are as defined above. Dehydration can be carried out without a solvent or in a solvent such as water, alcohols, esters, NMPA, dichloromethane, toluene, ethers, ketones, carboxylic acids, or in a solvent mixture in the presence of Bronstedt or Lewis acids such as sulfuric acid, hydrochloric acid , trifluoroacetic acid, aluminum trichloride, 7psSi2 or the like, or in the presence of metal oxides, such as AI2Oz, Si2Oz, TiO», MOz, P2bOz or the like, or in the presence of other dehydrating agents, such as IF, dimethyl sulfoxide, KNOO». SibOm, phthalic anhydride or the like.

Substituents B, B: and B and substituent B of the compound(s) as defined above can be modified in ways known in the art and illustrated in the literature, see, for example, Rgoiesiipd dgoire ru Steep, og Modegp Zupineev

Aeasiopev ru Noshize, well known to a person skilled in the art, after or in the process of obtaining (s) from (|).

As shown in the IM scheme above, compounds of formula ()) can be obtained from compound (5), where B", B, VU,

B!C and B are as defined above using an alkylation reaction with an alkyl halide such as Mey in the presence of a base such as sodium hydroxide and a phase transfer agent such as ViaMNOO»x. Compounds of formula (5) can be obtained by the reaction between a ketone of formula (0), where B", B2, VU, B'"Z are as defined above, and an organometallic reagent of formula (K), where B is as defined in formula (I), and M is a group of a suitable metal such as magnesium, lithium, zinc, copper, cerium or the like. The reaction can be carried out without a solvent or in solvents such as THF, ethers, dimethylformamide, dioxane, dimethylsulfoxide, or in a mixture of solvents.

Substituents B", B, BZ, B"Z of compound (5), as defined above, can be modified in ways known in the art and which are illustrated in the literature, see, for example, Rgoiesiipd dgoire Bu Steep, og Modegt 5Bupipeviv

Aeasiopev ru Noise, well known to a person skilled in the art, after or in the process of obtaining (5) from (d) and (JK).

As shown in Scheme IM, a compound of formula (i) can be prepared by reactions between a carbonyl compound of formula (I) where B, B: and BZ are as defined in formula (I) and X represents a suitable leaving group, such as SI, Bi, OH, OB, 58, MA», MOV')B or the like, and an organometallic reagent obtained first by treatment with a base, such as Man, of compounds (4), where B"Z is as defined above, followed by remetallation using an alkyllithium like you! eat The reaction can be carried out in solvents such as THF, toluene, ethers, dimethylformamide, dioxane, or in a mixture of solvents. Substituents B, B2, VU, BZ of compound (d), as defined above, can be modified in ways known in the art and illustrated in the literature, see, for example, Rgoiesiipd dgoire Bu Stgeep, og Modegp Zupinevziz Neasiiope5 Bu Noise, which well known to a person skilled in the art, after or in the process of obtaining (i) from (e) and (1).

As shown in Scheme IM, compounds of formula (e) can be prepared by acylation of 4-iodaniline using either an acyl anhydride or an acyl chloride in an organic solvent such as dichloromethane. Substituent B"Z of compound (d) is as defined earlier.

The invention is further described in more detail by means of the following examples, which should not be construed as limiting the invention in any way.

A) Synthesis scheme of compounds of examples 1-7

The compounds of Examples 1-7 were prepared according to the following procedure shown in Scheme 1 below.

SCHEME 1 oMe at 9 o'clock, winter! ud 7 o What

S Vo y 5 -- 85 zhyufrzRr m" 2. Me(meomn "m y i-RYMaSI os M y a GI o o

ME MEEE

Ag Ag sa on

M M

Vos n

AgH-1-naphthyl, (4);

Ag-2, b-dimethylphenyl, (5)

Ag-phenyl, (6) Example 1

AgH-1-naphthyl, (7) Example 2

AgH-2,6-dimethylphenyl, (8) Example C

Ha)

ME

Ag

M in

AG-RII, V-RYSN»5, (10) Example 5

AG-RyI, A-cyclopropylmethyl, (12) Example 7

AG-RI, B-2, Z-epoxypropyl, (11) Example 6

AgH-1-naphthyl, A-allyl, (9) Example 4 () Stripping of M-tert-butaxylcarbonyl-M-methyl-M-methoxylisonepecotamide (compound 2)

A mixture of ethylisonipecotate (compound I) (4.71g 30, 00mmol), di-tert-butyl dicarbonate (6.55g, 30, 0mmol) and

Majo»z (4.77g, 45mmol) in NgOo-THF (90/100ml) was refluxed for 2 hours.

The reaction mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with saline solution, dried over Mo5Ox. Extraction of solvents gave M-tert-butoxylcarbonylethyl lysonipecotate (7.67): bn (400MHz, SOCI3) 1.25 (t, U-7.2Hz, ЗН), 1.45 (s, 9Н), 1.62 (m, 2H), 1.87 (m, 2H), 2.43 (m, 1H), 2.84 (m, 2H), 4.02 (m, 2H), 4.13 (kv, 9U-7.2Hz , 2H); bs-iz (100MHz, SOS") 0: 14.0, 27.8, 28.2, 40.9, 42.9, 60.2, 79.2, 154.4, 174.2.

The above M-tert-butoxylcarbonylethyl lisone pecotate was dissolved in THF (bOml) and mixed with

MNMe(OMe)ns!I (4.39 g, 45.0 mmol). The mixture was treated with iso-RI'MoCl (2.0 M in THF, 45 ml, 900 mmol) at -20"C and the resulting solution was stirred for 71 hours at -57C and then quenched with an aqueous solution of MNAacI and extracted with ethyl acetate (2x100 ml). The combined organic the layers were washed with a saline solution, dried over

M95BoO". Removal of the solvents afforded M-tert-butoxylcarbonyl-M'-methyl-M'-methoxylisonepecotamide (compound 2) (8.0g, 9890).

bn (400 MHz, SOSIz) 1.30 (s, 9H), 1.54 (m, 4H), 2.65 (m, ЗН), 3.02 (s, ЗН), 3.56 (s, ЗН) , 3.99 (width, 2H); bs-iz (1ooMHz, SOS") 6: 27.7, 28.1, 32.0, 37.8, 43.1, 61.3, 79.1, 154.4, 176.0. (i) Preparation of 4-(4-M,M-diethylaminocarbonylbenzoyl)-M-tert-butoxylcarbonylpiperidine (compound 3)

To a solution of 4-iodo-M,M-diethylbenzamide (9.09g, 30.0mmol) and TMEDA (6.96g, 60.00mmol) in dry THF (bOml) was added tert-butyllithium (35.Oml, 1.7M, 60.0 mmol) at -78°C. After 30 minutes, M-tert-butoxylcarbonyl-M'-methyl-M'-methoxylisone pecotamide (compound 2) (8.0 g, 294 mmol) in THF (10 ml) was added dropwise. The reaction mixture was heated to room temperature and then quenched with an aqueous solution of MNaCl, neutralized with hydrochloric acid (concentrated, 20 ml) at 0"C and extracted with ethyl acetate (2x100 ml).

The combined organic layers were washed with saline solution, dried over Md5O»4. Removal of the solvents gave the crude product, which was purified on a silica gel column eluting with Meon-SnNesig (2:98) to give 4-(4-

M',M'-diethylaminocarbonylbenzoyl)-M-tert-butoxylcarbonylpiperidine (compound 3) (3.15g, 2895): bn (400MHz, SOCI3") 1.08 (width, ЗН), 1.23 (width s, ЗН), 1.43 (s, 9Н), 1.61 (m, 2Н), 1.80 (m, 2Н), 2.89 (m, 2Н), 3.20 (width с, 2Н ), 3.40 (m, 1H), 3.53 (width s, 2H), 4.11 (width s, 2H), 7.44 (d, 9-8.0 Hz, 2H), 7, 94 (d, 9-8.0Hz, 2H). (her) Preparation of 4-(α-hydroxyl-d(4-M-tert-butoxylcarbonylpiperidinyl)-α-(1-naphthyl)methyl)-M,M-diethylbenzamide (compound 4)

To a solution of 1-bromonaphthalene (0.52g, 2.5mmol) in dry THF (10ml) was added n-butyllithium (1.1ml, 2.5M, 2.75mmol) at -78°C. After 30 minutes, 4- (4-M'N'-diethylaminocarbonylbenzoyl)-N-tert-butoxylcarbonylpiperidine (compound 3) (776 mg, 2.0 mmol) in THF (2 mL). The reaction mixture was warmed to room temperature and then quenched with aqueous MNaCl and extracted with ethyl acetate ( 2x50ml). The combined organic layers were washed with brine, dried over Mo5O4. Extraction of the solvents gave a crude product, which was purified on a silica gel column eluting with MeOHnN-CNesI2 (0.5:99.5--5:95), obtaining 4 -(α-hydroxyl-α-(4-N-tert-butoxylcarbonylpiperidinyl)-α-(1-naphthyl)methyl)-N,M-diethylbenzamide (compound 4) (760mg, 7495).

T. pl. 121-12476 (SNeosSi");

Mtach cm"! 3402, 2960, 1685, 1626, 1425, 1283, 1160;

Elemental analysis. Calculated for Cz2NaoM2O4 0.50 NgO: С 73.1195; H 7,860; M 5.3395. C 72.8690 was found; H 7.6490; M 52695; bn (400Mhz, SOSIz") 1.03 (width s, ЗН), 1.16 (width s, ЗН), 1.18-1.35 (m, ЗН), 1.95 (m, 1Н) , 2.60 (m, 2H), 2.75 (width s, 2H), 3.15 (width s, 2H), 3.42 (width s, 2H), 4.10 (width s , 2H), 7.10-7.50 (m, 7H), 7.75 (m, ЗН), 8.27 (width s, 1H); bs-iz (100 MHz, SOSIz) 0: 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4, 79.3, 80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128.8, 129.2, 131.4, 135.0, 135.2, 139.4, 146, 5, 154.6, 171.0. (M Preparation of 4-(α-hydroxygt-α-(4-M-tertbutoxylcarbonylpiperidinyl)-2,6-dimethylbenzyl)-M,M-diethylbenzamide (compound 5)

Obtained in the manner described for compound 4, except for the use of 2-bromo-m-xylene (749mg, 7690):

T. pl. 92-96270 (SNeSi");

Mtach (KV) cm"! 3451, 2970, 1690, 1631, 1425, 1165;

Elemental analysis. Calculated for SzoNa2M2O4:0.50 NgO: C 71.5495, H 8.6195; M 5.5695. Found: C 71.70905; H 8.34905; M 5,629. bn (400 MHz, SOSIz) 1.10 (lat.s, ZN), 1.21 (lat.s, ZN), 1.32 (m, 2H), 1.43 (s, 9H), 1.69 ( m, 1H), 1.77 (m, 1H), 2.32 (s, 6H), 2.47 (s, 1H), 2.75 (m, ЗН), 3.25 (width s, 2H ), 3.51 (width, 2H), 4.13 (width, 2H), 6.91 (m, 2H), 7.00 (m, 1NU, 7.26 (d, 9U-8 ,4Hz, 2H), 7.39 (d, 9-8.4Hz, 2H); bs-iz (100MHz, SOS") 6: 12.6, 14.0, 25.0, 27.7, 28, 2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3, 127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7.

Example 1

Preparation of M,M-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (compound 6)

Trifluoroacetic acid (10, Oml).

The reaction mixture was stirred for 16 hours at room temperature and then concentrated. The residue was dissolved in ASOEA (100 ml). The obtained solution was washed with a 1 N solution of Maon, an aqueous solution of MNACI and a saline solution, and dried over Ma5O»x. Removal of the solvents gave the crude product, which was purified on a silica gel column eluting with Meon-SNeCl (20:80) to give (α-phenyl-α-(4-M',M'-diethylamino-carbonylphenyl))-4-methylenepiperidine (compound 6) (632mg, 91905): bn (400MHz, СОСИз) 1.08 (shr.s, ZN), 1.17 (shr.s, ZN), 2.29 (m, 4H), 2.86 (m, 4H), 2.94 (width s, 1H), 3.24 (width s, 2H), 3.47 (width s, 2H), 7.09 (m, 4H), 7, 15 (m, 1H), 7.24 (m, 4H); bs-iz (100 MHz, SOSI") 6: 12.6, 141, 32.7, 32.8, 39.1; 43.2, 47.9,.126.0, 126.4, 127.9, 129.6, 134.9, 135.4, 135.9, 141.7, 143.2, 1711.

Salt of NOA: t. pl. 110-1207C (ASOEI-simple ether-SNesSig2);

Mmtach (KV) cm"! 3440, 2970, 1617, 1438, 1289.

Elemental analysis. Calculated for SgziNgvimgO-1.0 NCI-0.50 СНоСиИ2: 0.25 НО: С 65.3595; H 71290; M 6.4995. Found: С 65,1495; H 7.0890; M 6,559.

Example 2

Preparation of M, M-diethyl-4-(1-naphylpiperidin-4-ylidenemethyl) benzamide (compound 7)

Obtained by the method described in example 1, using compound 4 (226 mg, 7190):

T. pl. 80-85"C (MEON-SNesi");

Mtach (KV) cm" 3052, 2970, 1628, 14391, 1286.

Elemental analysis. Calculated for С27НзоМ2гО-0.20 СНоСи2: С 78.6295; H 7.3795; M 6.7495. Found: C 78.6390; H 7.070; M 6,549. bn (400 MHz, SOSIz") 1.06 (width s, .H), 1.16 (width s, ZN), 2.00 (m, 2H), 2.53 (m, 2H), 2, 64 (width, MN), 2.77 (m, 2H), 2.97 (m, 2H), 3.20 (width, 2H), 3.47 (width, 2H), 7 .26 (m, 5H), 7.43 (m, ЗН), 7.74 (m, 2H), 8.0 (m, 1H); bs-iz (10O0MHz, SOS") b: 12.8, 14.1, 32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5, 125.7 , 125.8, 126.1, 127.1, 127.2, 1291, 131.9, 132.5, 133.8, 135.1, 138.3, 139.8, 142.6, 171.1 .

Example C

Preparation of M,M-diethyl-4-(2,6-dimethylphenylpiperidin-4-ylidenemethyl)benzamide (compound 8)

Obtained in the manner described in example 1, using compound 5 (242mg, 8090).

Noah's salt: breakdown. 211572 (AsOBEgi-simple ether-SNesSig); Mtakh (KVO cm"! 2970, 2725, 1590, 1464, 1290, 1101;

Elemental analysis. Calculated for C25Nz2aM2gO 1.0 NCI-0.50 SnSiI2:0.25 NgO: C 65.9495; H 7.6090; M 6.0395. Found: C 65.9895; H 7.379; M 5,819.

Example 4

Preparation of M,M-diethyl-4-(1-naphthyl-M-allylpiperidin-4-ylidenemethyl)benzamide (compound 9)

A mixture of (a-(1-naphthyl)-a-(4-M'M'-diethylaminocarbonylphenyl))-4-methylenepiperidine (compound 7) (125mg/g), allyl bromide (9mg) and KgCO3 (138mg) in MesmM (1mg ) was stirred for 14 hours at room temperature and then quenched with a solution of MNAOH, extracted with AcOEII (100 ml). The organic phase was washed with an aqueous solution of MNACI and a saline solution, dried over Mod5Ox. Removal of the solvents gave the crude product, which was purified on a silica gel column eluting with Meon-SnNesig (2:98) to give (α-(1-naphthyl)-α-(4-M',M'-diethylaminocarbonylphenyl))-4- methylene-M-allylpiperidine (5Omg, 3690): bn (400MHz, СОСИз) 1.08 (shr.s, ЗН), 1.19 (shr.s, ЗН), 2.08 (m, 2Н), 2, 39 (m, 2H), 2.61 (m, 4H), 3.01 (m, 2H), 3.24 (width, 2H), 3.52 (width, 2H), 5.13 (m, 2H), 5.90 (m, 1H), 7.27 (m, 5H), 7.45 (m, ЗН), 7.80 (m, 2H), 8.04 (m, 1H) ; bs-iz (100MHz, SOS") 0: 12.8, 14.1, 30.9, 32.0, 39.1, 43.2, 54.7, 54.9, 61.5, 117.8 , 125.4, 125.6, 125.8, 126.0, 1271, 128.2, 129.1, 131.8, 132.4, 133.7, 135.0, 138.0, 139.8 , 142.6, 1711.

Salt of NOA: t. pl. 110-1207C (ASOEI-simple ether-SNesSig2);

Mtach (KV) cm"! 3416, 2961, 1620, 1430, 1288;

Elemental analysis. Calculated for SzoNzaM2O-1.0 NCI-0.50 SneSiI»: 0.25 NgO: C 701795; H 7.059; M 5.3795. Found: C 70,1595; H 6.9295; M 5.2495.

Example 5

Preparation of M,M-diethyl-4-(phenyl-M-benzylpiperidin-4-ylidenemethyl)benzamide (compound 10)

It was obtained by the method described in example 4, using compound 6 and benzyl bromide (215 mg, 98905): bn (400 Mhz, SOSI»z) 1.09 (shyr.s, ZH), 1.19 (shyr.s, ZH) , 2.37 (m, 4H), 2.47 (m, 4H), 3.25 (width, 2H), 3.50 (width, 4H), 7.0-7.30 (m , 14H); bs-iz (100 MHz, SOSIz) 6: 12.7, 14.0, 31.6, 39.1, 43.1, 54.9, 55.0, 62.8, 125.9, 126.2, 126.8, 127.8, 128.0, 128.9, 129.6, 129.7, 134.9, 135.0, 136.3, 138.2, 141.9, 143.3, 171.0.

Salt of NOA: t. pl. 230-2457C (ASOEI-simple ether-SNesSig2);

Mtach (KV) cm"! 3423, 2976, 1624, 1434, 1288;

Elemental analysis. Calculated for SzoNzaM2O-1.0 NCI-0.25 SNeaSiI»: 0.25 NgO: C 725595; H 7.259; M 5.5995. Found: C 72.3890; H 7.1695; M 5.5095.

Example 6

Preparation of M,Mdiethyl-4-(M-2,3-epoxypropylphenylpiperidin-4-ylidenemethyl)benzamide (compound 11)

It was obtained according to the method described in example 4, using compound 6 and epibromohydrin (102 mg, 84905) bn (400 MHz, SOCI3) 1.10 (shyr.s, ZN), 1.20 (shyr.s, ZN), 2, 28 (m, 1H), 2.39 (m, 4H), 2.45 (m, 1H), 2.54 (m, 2H), 2.61 (m, 2H), 2.74 (m, 2H ), 3.09 (m, 1H), 3.26 (width, 2H), 3.50 (width, 2H), 7.10 (m, 4H), 7.15 (m, 1H) , 7.25 (m, 4H); bs-iz (100MHz, SOS") 0: 12.8, 14.1, 31.4, 39.1, 43.2, 44.9, 50.1, 55.5, 60.8, 126.0 , 126.4, 127.9, 129.6, 129.7, 135.0, 135.3, 135.7, 141.8, 143.2, 171.1.

Example 7

Preparation of M,M-diethyl-4-(1-cyclopropylmethylphenylpiperidin-4-ylidenemethyl)benzamide (compound 12)

It was obtained by the method described in example 4, using compound 6 and cyclopropyl methyl chloride (104 mg, 8695). bn (400 MHz, SOSIz) 0.20 (m, 2H), 0.59 (m, 2H), 1.04 (m, 1H), 1.14 (lat.s, ZN), 1.24 (lat. s, ZN), 2.48 (d, 2-6.4

Hz, 2H), 2.56 (width s, 4H), 2.80 (width s, 4H), 3.29 (width s, 2H), 3.53 (width s, 2H), 7 ,14 (m, 4H), 7.22 (m, 1H), 7.27 (m,

Academy of Sciences); bsiiz (100MHz, SOS") b: 4.18, 7.3, 12.8, 14.1, 30.3, 39.2, 43.2, 54.3, 62.7, 126.2, 126 .6, 128.0, 129.5, 129.6, 134.1, 135.3, 136.3, 141.5, 142.9, 171.0.

Noah's salt: breakdown. 21007С (АСсСОБИ-simple ether-СНеси");

Mmtach (KVI) cm"! 3027, 2359, 1620, 1439, 958;

Elemental analysis. Calculated for С27НзаМ2О-1.0 НСИ-0.50 СНе2СиИ»: 0.75 НгО: С 66.7395; H 7.64905; M 5.6695. Found: C 66.60; H 7.4595; M 5.7895.

C) Synthesis scheme of the compound of example 8

Example 8 compound was prepared using the following procedure shown in Scheme 2 below.

SCHEME 2

OMe o ml» SO S re svshi p-Vii i - - 5 ( t ( - xx

M M

!

Vos Vos o az o o -e de pana BADy pshe yad

GoK tA i m t sk

SHY g siy still I Kk

Weight and

NK ah

Cryclad E () Preparation of 4-(2-benzofuroyl)-M-tert-bupyoxycarbonylpiperidine (compound 13)

To a solution of 2,3-benzofuran (295mg, 2.5mmol) in dry THF (10ml) at -78"C was added tert-butyllithium (1.5ml, 1.7M, 2.5mmol). After 30 minutes, M- tert-butoxylcarbonyl-M-methyl-M-methoxylisonepecotamide (544mg, 2.0mmol) in THF (2ml), the reaction mixture was heated to room temperature and then quenched with an aqueous solution of MNACI and extracted with ethyl acetate (2x50ml). The combined organic layers were washed with brine solution, dried over Mo 5 O 4 . Removal of the solvents afforded the crude product, which was purified on a silica gel column eluting with Meon-SnNesi" (5:95) to give 4-(2-benzofuroyl)-N-tert-butoxylcarbonylpiperidine (13) (456 mg, 6995): bn (400 MHz, SOSIz) 1.46 (s, 9H), 1.75 (m, 2H), 1.91 (m, 2H), 2.91 (m, 2H), 3.37 (m , 1H), 4.20 (width, 2H), 7.29 (m, 1H), 7.46 (m, 1H), 7.53 (s, 1H), 7.56 (m, 1H) . 123.8, 126.9, 128.2, 151.8, 154.5, 155.5, 192.8. (i) Preparation of 4-(o-hydroxy-4(4-M-tert-butoxylcarbonyl) piperidinyl)-2-benzofuryl)-M,M,-diethylbenzamide (compound 14)

It was obtained by the method described in example 4, using 4-iodo-M,M,-diethylbenzamide (425 mg, 6190):

T. pl. 102-1067C (SNesi");

Mtach (KV) cm" 3362, 2970, 1690, 1617, 1425, 1288, 1160; bn (400MHz, SOSIz) 1.06 (width, ЗН), 1.20 (width, ЗН), 1, 24 (m, 2H), 1.46 (m, 11H), 2.42 (m, 1H), 2.58 (width, 2H), 3.20 (width, 2H), 3.50 (width s, 2H), 4.05 (width s, 2H), 4.37 (s, 1H), 6.70 (s, 1H), 7.16 (m, 2H), 7.23 ( d, U-8.0Hz, 2H), 7.41 (d, 9-7.6HzC, 1H), 7.47 (d, 9-7.6Hz, 1H), 7.58 (d, 9U-8 ,0Hz, 2H); bs-iiz (100MHz, SOS") 0: 12.6, 13.9, 25.5, 26.3, 28.2, 39.0, 43.1, 44.9, 77 ,3, 79.0, 103.3, 110.9, 120.6, 122.5, 123.5, 125.6, 125.8, 127.9, 135.3, 144.0, 154.4 , 154.5, 160.5, 170.9.

Example 8

Preparation of M,M-diethyl-4-(2-benzofurylpiperidin-4-ylidenemethyl)benzamide (compound 15)

It was obtained by the method described in example 1, using compound 14 (135 mg, 8890): bn (400 MHz, СОСИ3») 1.20 (shyr.s, ZH), 1.24 (shyr.s, ZH), 2, 36 (width s, 2H), 3.00 (width s, 4H), 3.15 (width s, 2H), 3.33 (width s, 2H), 3.56 (width s, 2H), 4.45 (width, 1H), 6.25 (s, 1H), 7.24 (m, 4H), 7.41 (m, 4H); bs-iz (100MHz, SOSIz) b: 12.9, 14.2, 29.6, 32.0, 32.4, 39.3, 43.4, 47.2, 107.4, 111.0, 120.7, 122.7, 124.2, 126.0, 126.5, 128.2, 129.9, 136.1, 139.5, 140.5, 154.4, 156.2, 171, 0.

Noah's salt: breakdown. 21207C (PERSONS-simple ether-SNesi");

Mtach (KVI) cm" 2977, 2801, 1586, 1449, 1257.

C) Synthesis scheme of compounds of examples 9-10

The compounds of Examples 9 and 10 were prepared using the method shown in Scheme 3.

SCHEME Z x x 2 x Y th K: du fi fi ME ! on his V zh yi yi yi n Vos Vos

XE (av) Xe E, (18) Xa E, (20)

He SI) Ha SI, (19) ho (21) o x r g t

M

! . N

X - BE, (22) Example C x - c1, (23) Example 10 () Preparation of 4-(4-fluorobenzoyl)-N-tert-butoxycarbonylpiperidine (compound 18)

A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (compound 16) (2.44g, 10.00mmol), di-tert-butyldicarbonate (2.18g, 10.0mmol) and MgSO3 (1.59g, 15mmol) in HgOo- THF (50/5 ml) was refluxed for 1 hour. The reaction mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with saline, dried over NaCl. Extraction of solvents gave 4-(4-fluorobenzoyl)-M-tert-butoxyl-carbonylpiperidine (OV 701-31, 2.28g, 7490);

T. pl. 80-837C (SNesi");

Mmtach (KV) cm"! 2980, 2842, 1680, 1587, 1416, 1160; bn (400MHz, SOSIz) 1.44 (s, 9H), 1.69 (m, 2H), 1.79 (m, 2H ), 2.87 (m, 2H), 3.34 (m, 1H), 4.13 (width, 2H), 7.12 (m, 2H), 7.95 (m, 2H); (100MHz, SOSIz) 5: 27.4, 28.4, 43.2, 43.4, 79.6, 115.8, 115.9, 130.8, 130.9, 132.2, 154.6 , 164.4, 166.9, 200.4. (i) Preparation of 4-(4-chlorobenzoyl)-N-tert-butoxylcarbonylpiperidine (compound 19)

Obtained by the method described for compound 18, using compound 17 (1.23 g, 8595):

T. pl. 122-12576 (SNeosSi");

Mmtach (KV) cm"! 2970, 2842, 1680, 1582, 1420, 1200; bn (400 MHz, SOSIz) 1.47 (s, 9H), 1.69 (m, 2H), 1.81 (m, 2H ), 2.90 (m, 2H), 3.36 (m, 1H), 4.18 (width, 2H), 7.44 (m, 2H), 7.88 (m, 2H); bs -iz (100 MHz, SOSIz) 6: 28.3; 28.4; 43.2; 43.4; 79.6; 129.0; 129.6; 134.1; 139.4; 154.6; 200 ,7. (her) Preparation of 4-(α-hydroxy-α-(4-M-tert-butoxylcarbonylpiperidinyl)-4-fluorobenzyl)-M,M-diethylbenzamide (compound 20)

Obtained in the manner described for compound 4, using compound 18 and 4-iodo-M,M-diethylbenzamide (454 mg, 4795):

T. pl. 84-867C (SNesSi");

Mmtach (KV) cm"! 3421, 2970, 1685, 1612, 1430, 1288, 1165; bn (400 MHz, SOSIz") 1.13 (width, ЗН), 1.23 (width, ЗН), 1.32 (m, 4H), 1.44 (s, 9H), 2.48 (m, 1H), 2.68 (width s, 2H), 3.26 (width s, 2H), 3 .54 (width s, 2H), 3.57 (s, 1H), 4.11 (width s, 2H), 6.96 (m, 2H), 7.27 (d, 9U-8.0Hz , 2H), 7.44 (m, 2H), 7.47 (d, 9-8.0Hz, 2H); bs-iz (100MHz, SOSI") b: 12.9; 14.0; 26.2 ; 28.2; 39.1; 43.2; 43.6; 44.3; 78.9; 79.1; 114.5; 114.7; 125.75126.1; 127.55127.6; 135 .0; 141.2; 146.9; 154.5; 160.0; 162.5; 170.9. (M Preparation of 4-(a-hydroxy-a-(4-M-tert-butoxylcarbonylpiperidinyl)-4 -chlorobenzyl)-M,M-diethylbenzamide (compound 21)

Obtained in the manner described for compound 4, using compound 19 and 4-iodo-M,M-diethylbenzamide (626 mg, 6395):

T. pl. 100-1057C (SNesSi");

Mtach (KV) cm" 3411, 2970, 1685, 1617, 1425, 1288, 1165, 1092; bn (400 MHz, SOSIz") 1.08 (width, ЗН), 1.20 (width, ЗН) , 1.33 (m, 4H), 1.41 (s, 9H), 2.44 (m, 1H), 2.63 (width s, 2H), 3.22 (width s, 2H), 3.49 (width, 2H), 3.99 (s, 1H), 4.05 (m, 2H), 7.20 (m, 4H), 7.39 (d, 9U-8.0Hz, 2H), 7.44 (d, 9U8.0Hz, 2H); bs-iiz (100MHz, SOSIz") b: 12.5; 13.9; 25.9; 28.1; 39.0; 43.0 ; 44.1; 78.7; 79.0; 125.6; 126.0; 127.2; 127.8; 131.9; 134.8; 1441; 146.6; 154.3; 170.7 .

Example 9

Preparation of M,M-diethyl-4-(4-fluorophenylpiperidine-4-ylidenemethyl)benzamide (compound 22)

It was obtained by the method described in example 1 (compound b), using compound 20.

IN NMR (400 MHz, SOSIz) b 1.12 (ZN, shr.m, CHzCHe-), 1.24 (ZH, shr.m, CHzCHe-), 2.32 (4H, m, piperidine-

SNU), 2.54 (1Н, width m, МН), 2.91 (4Н, m, piperidine-CH-), 3.27 (2Н, width m, СНе2М-), 3.52 (2Н, width m, CH2M-), 7.00 (2H, m, AgH), 7.09 (2H, m, AgH), 7.11 (2H, d, U-8.0Hz, AGN), 7.29 (2H, d, 9U-8.0Hz, AgH).

Example 10

Preparation of M,M-diethyl-4-(4-chlorophenylpiperidine-4-ylidenemethyl)benzamide (compound 23)

It was obtained by the method described in example 1 (compound 6), using compound 21.

IN NMR (400 MHz, SOSIz) b 1.13 (ZN, shr.m, CHzSNeg-), 1.22 (ZN, shr.m, CHzSNeg-), 2.02 (1H, shr.m, MH), 2 .30 (AN, m, piperidine-CH-), 2.90 (4H, m, piperidine-CH-), 3.28 (2H, shr.m, CH2M-), 3.53 (2H, shr.m , CH2M-), 7.04 (2H, d, 9-8.0Hz, AgH), 7.11 (2H, d, 9-8.0Hz, AgH), 7.25 (2H, d, 9U-8 ,0Hz, AgH), 7.30 (2H, d, 9U-8,0Hz, AgH).

Salt of NOA: t. pl. 115-1207C (NgO-SNes"); 14 (KVo) 3337, 2973, 1618, 1431, 1290, 1092 cm".

Elemental analysis. Calculated for SgzNg7SIM2O-1.0 NSI-1.20 NO: С 62.6495; H 6.9596; M 6.3595.

Found: C 62.5395; H 6.9195; M 6,309.

Or) Synthesis scheme of the compound of example 11

SCHEME 4 phi phi SOME, phi S SOM i 5os, ----- I

М M s 09 g that Example 11

Example 11

Preparation of M,M-diethyl-4-(phenyl-M-allylpiperidin-4-ylidenemethyl)benzamide (compound 25) 4-(α-hydroxy-α-(4-M-allylpiperidinyl)benzyl)-M,M-diethyl- benzamide (compound 24) (8 mg) was dissolved in ClCl 3 (1 mL) and treated with thionyl chloride (2 mL) at room temperature. The reaction mixture was refluxed for 2 hours and then concentrated. The residue was dissolved in ethyl acetate (50 ml) and the resulting solution was washed with MNAOH (1 N), an aqueous solution of MNACI and saline, and dried over Md5O»x. Removal of the solvents afforded the crude product, which was purified on a silica gel column eluting with Meon-CNesi" (1:99--5:95) to give (α-phenyl-α-(4-M';M'-diethylaminocarbonylphenyl))- 4-methylene-M-allylpiperidine (compound 25, example 11) (32mg, 4090): bn (400MHz, SOCIz) 1.12 (shr.s, ZN), 1.21 (shr.s, ZN), 2, 43 (m, 4H), 2.55 (m, 4H), 3.08 (d, 2-6.8Hz, 2H), 3.25 (width, 2H), 3.53 (width, 2H), 5.18 (m, 2H), 5.86 (m, 1H), 7.12 (m, 4H), 7.20 (m, 1H), 7.27 (m, 4H).

Salt NS: t. pl. 85-957C (INDIVIDUAL-SNESI");

Mmtach (KV) cm"! 3491, 2971, 1624, 1428, 1289, 1096;

Elemental analysis. Calculated for СгвНзг2М2гО:-НСИ-0.25 НгО.0.25 СНоСи»: С 69.9595; H 7.6095; M 6,219.

Found: C 70.0095; H 7,700; M 6.07905.

Example 12

Preparation of M,M-diethyl-4-(4-chlorophenyl-M-benzylpiperidin-4-ylidenemethyl)benzamide (compound 26) o; si "oyi iy

RI

M,M-diethyl-4-(4-chlorophenyl-M-benzylpiperidine-4-ylidenemethyl)benzamide (110 mg, 9395) was obtained by the method described in example 4, using compound 23 (9 mg) and benzyl bromide (43 mg):

IN NMR (400MHz, SOSIz) b 1.13 (ZN, shr.m, CHzCHe-), 1.23 (ZH, shr.m, CHzCHe-), 2.37 (4H, m, piperidine-

SNU), 2.49 (AN, m, piperidine-CH-), 3.28 (2H, shr.m, CHzSNeM-), 3.53 (4H, shr.m, RYSN»M and CHzSNeM-), 7 .04 (2H, d, U-8.0Hz, AgH), 7.11 (2H, d, U-8.0Hz, AgHN), 7.25 (2H, d, 9U-8.0Hz, AgH), 7.29 (7Н, m, АН).

Salt (SNONSO»N): t. pl. 100-1107C (MeOH); 14 (KVi) 3368, 2977, 1728, 1603, 1433, 1290, 1087 cm;

Elemental analysis. Calculated for SzaNzzSIM2O7:1.50 NgO: С 62.8195; H 6.5190; M 4.3195. Found: C 62.8590; H 6.170; M 42195.

Example 13

Preparation of M,M-diethyl-4-((M-3-methyl-2-butenyl)phenylpiperidine-4-ylidenemethyl]benzamide (compound 27)

BOM Shchi Ff

M

I

It was obtained by the method described in example 4, using 1-bromo-33-methyl-2-butene as an alkylating reagent.

IR (masses, film): NSI salt at 3432, 2976, 1623, 1434 cm'!.

IN NMR: (base) (SOSIz, TM) b 1.10-1.30 (6H, wide OSMSNegSN"), 1.64 (ZN, s, "SSN"z), 1.73 (ZN, s,

ССН"), 2.40 (АН, m, MSНеСН"), 2.52 (АН, m, "ССН"), 3.0 (2Н, d, 9-7.6 Hz, MSН»СН-С) , 3.20-3.60 (4H, width

OSMSNeCH3), 5.28 (1H, m, MCHgCH-C), 7.16-7.45 (9H, m, Ac) m.h.

Elemental analysis. Calculated for SgvNzeM2gO-1.8 NOSI: С 69.7495; H 7.9095; M 5.8195. Found: C 69.7190; H 7.4890; M 5,589.

Example 14

Preparation of M,M-diethyl-4-| (1-cyclohexylpiperidin-4-ylidene)phenylmethyl|benzamide (compound 28)

oh oh oh

A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (ZbmCl, 0.35 mmol) and Ti(OR-i)" (0.17 mL, 0.58 mmol) was sonicated for 1 h and then stirred at room temperature overnight in nitrogen atmosphere. The mixture was diluted with ethanol (5 mL) and then MavVnNa (ZZmg, 87 mmol) was added. The resulting mixture was stirred for 12 hours at room temperature. 2N was added to quench the reaction mixture

MnZ:NgO, and the mixture was filtered through celite. The filtrate was extracted several times with ethyl acetate and the combined organic phases were washed with water and brine and dried over Mag25O»x. Concentration in vacuo and purification by MRI C (silica gel 60, elution with EtOAc:heptane, from 0:100 to 100:0) gave the title compound (24mg, 2090).

T.pl. (NOSE salt): 105-10926.

IR (NSI salt, film) m 3394 (MN), 1620 (SOME) cm".

IN NMR (free amine, 400MHz, SOSIz) b 1.00-1.25 (17Н, m, MSНСНа.СнНгсСНсСНесН», 2хСН3 and СН(ИНСН)С-С), 1.60 (1Н, m, SNСН)С -С), 1.75 (1Н, m, СН(ИСН)С-С), 1.80 (1Н, m, СН(ИСН)С-С), 2.30 (ЗН, m, MSN» and MSN ), 2.60 (2H, m, MON"), 3.20 (2H, shr.s, MSNeSnHz), 3.50 (2H, shr.s, MSNegSnHz), 7.00-7.30 (9H, m, Ac). 136 NMR (free amine, 100 MHz, SOSIz") b: 12.7; 14.1; 25.9; 28.7; 32.0; 39.1; 43.2; 50.7; 50.8; 63.6; 126.0; 126.3; 127.9; 129.7; 129.8; 134.7; 134.9; 136.9; 142.0; 143.4; 171.2.

Elemental analysis. Calculated for SgoNaoM2OSi: C 69.1795; H 8.0195; M 5.5695. Found: C 69,1795; H 7,820; M 5,189.

Example 15

Preparation of M,M-diethyl-4-Y(M-butyl)phenylpiperidin-4-ylidenemethyl-benzamide (compound 29) by

WITH

It was obtained by the method described in example 4, using 1-iodobutane as an alkylating reagent.

IR (Masi, film): (NSI salt) m-3430, 2967, 2499, 1622, 1433 cm'!.

IN NMR (СОСИ3, TM) b 0.92 (ЗН, t, 9-7.2Hz, СНеСНЗ3), 1.10-1.26 (6Н, width OSMSNeСНВ5), 1.32 (2Н, m,

СНеснН»), 1.53 (2Н, m, СНаСНеоСсН»), 2.42 (6Н, m, МОН»), 2.55 (АН, m, «ССН»g), 3.20-3.60 ( 4Н, width OSMSNoСН 5), 7.10-7.31 (9Н, m, Ag) m.h.

Elemental analysis. Calculated for С27НзавМ2О-НСИ-0.4 SNеосСи". 0.4 NgOo-: C 682495; H 8.0795; M 5.81905.

Found: C 68.2495; H 81290; M 5,899.

Example 16

Preparation of M,M-diephyl-4-|(M-4-methoxybenzyl)phenylpiperidine-4-ylidenemethylibenzamide (compound 30)

what)

More

M

Ome

The title compound (160 mg, 68905) was prepared as described in Example 4, using compound 6 (174 mg) and 4-methoxybenzyl chloride (78 mg):

IN NMR (400 MHz, SOSIzv) b 1.11 (ZN, ext. CHzSNegM-), 1.20 (ZN, ext. CHzSNeg-), 2.38 (AN, m, SSNeC), 2.46 (4H, m . »), 6.83 (2Н, d, 98.0 Hz, АН), 7.05-7.30 (11Н, m, АН).

Salt of NOA: t. pl. 100-1107C (SNesi");

IR (KVh) 3425, 2974, 1618, 1515, 1434, 1255 cm"!.

Elemental analysis. Calculated for SziNzeM2gO»: 1.0 NCI0.35 СНоСи»: C 70.41955 H 71195; M 5,249.

Found: C 70.4695; H 7.10905; M 5,219.

Example 17

Preparation of M,M-diethyl-4-|(M-2,4-dichlorobenzyl)phenylpiperidine-4-ylidenemethyl|benzamide (compound 31) (o;

M. SI

The title compound (206 mg, 8195) was prepared as described in Example 4, using compound 6 (174 mg) and α,2,4-trichlorotoluene (98 mg):

IN NMR (400MGu, SOSIv) b 1.12 (ZN, ext. CHzSNeM-), 1.21 (ZN, ext. CHzSNeM-), 2.39 (4H, m, SSNegS), 2.52 (4H, m ) (12Н, m, АН).

Salt of NOA: t. pl. 95-1107C (SNesSig");

IR (KVo) 3408, 2976, 1620, 1472, 1436, 1288, 1101 cm".

Elemental analysis. Calculated for СзоНзгМ2ОСи2:1.0 НСИ-0.30 СНоСи»: С 63.9195; H 5.9595; M 4.92965.

Found: C 63.8195; H 6.0390; M 4.84965.

Example 18

Preparation of M,M-diethyl-4-|(1-methylpiperidin-4-ylidene)phenylmethyl|benaamide (compound 32) in; eat

Me

M,M-diethyl-4-((piperidin-4-ylidene)phenylmethylbenzamide (0.34g, 1.0mmol) was dissolved in acetonitrile (5ml).

At 2570, potassium carbonate (0.14 g, 1.0 mmol) and methyl iodide (6 µl, 1.0 mmol) were added with stirring.

After 30 minutes, the reaction mixture was evaporated and injected into a silica gel column for purification by chromatography using 0 to 1095 Meons (1095 MNAOH) in SNCl to yield 48 mg of the final product (2895 conversions of the starting material), which was converted to the hydrochloride salt by NCI treatment in simple ether

T. pl. 11072 (schedule).

IR (KVO) (cm"): 2361, 1695, 1487, 1289.

MS (free amine): 362, 318, 219, 189, 165, 144.

IN YAMRE (amine, SOS): b 1.1 (m, 6H, amide-Me), 2.40 (s, ZN, Mem), 2.49, 2.60 (2m, 8H, piperazine-H), 3.40 (m, 4H, amide-CHg), 7.08-7.34 (m, 9H, Agn).

Elemental analysis. Calculated for SgaNzoMgOxHO,1 NgOx3,1 NSI: C 60.3995; H 7.039; M 5.8795. Found:

C 604395; H 6.8496; M 5,459.

Example 19

Preparation of M,M-diethyl-4-((M-tert-butoxycarbonylpiperidin-4-yl)-8-quinolinylhydroxymethyl|benzamide (compound 33) (8)

GO no

Oh and

Bos (To a solution of 4-iodo-M,M-diethylbenzamide (1.52g, 5.0mmol) and 8-bromoquinoline (1.0g) in dry THF (30ml) was added at -787С n-butyllithium (7.0ml, 2 .5M, 17.5mmol). After 10 minutes, M-tert-butoxylcarbonylethyl lysonipecotate (2) (0.77g, 3.0mmol) in THF (5ml) was added dropwise. The reaction mixture was heated to 0"C and then quenched with an aqueous solution of MNACI and extracted with acetate. (2 x 100 mL). The combined organic layers were washed with brine, dried over Ma 5 O"x. Removal of the solvents afforded the crude product, which was purified on a silica gel column eluting with Meon-SNesi" (2:98) to give MT. 0599 (145mg, 9965):

T. pl. 100-1057C;

IR (Massi) 2971, 1686, 1625, 1426, 1167 cm".

Elemental analysis. Calculated for SziNzeMazO4: 0.20 Ng2O: C 71.4395; H 7.6295. Found: C 71.5095; H 7.7590.

IN NMR (400 MHz, SOSIv) 6-1.07 (ZN, ext. CHzSNe-), 1.19 (ZN, ext. CHzSNeM-), 1.24 (1H, m, piperidine-CH-), 1.43 (9Н, с, СН3ОС), 1.65 (1Н, m, piperidine-СН-), 1.89 (2Н, m, piperidine-СН-), 2.52 (1Н, m, piperidine-СН-), 2.64 (1H, ext. piperidine-CH-), 2.78 (1H, ext. piperidine-CH-), 3.22 (2H, ext. CHzCHe-), 3.49 (2H, ext. CHzCHneg- ), 4.16 (2H, ext. piperidine-CH-), 7.24 (2H, d, 9U-8.0Hz, AgHN), 7.35 (1H, dd, 9U-8.0, 4.4Hz , AGN), 7.55 (2H, d, U-8.0Hz,

AGN), 7.58 (1H, d, 9U-8.0Hz, AgH), 7.71 (1H, d, U-8.0Hz, AgH), 7.80 (1H, d, 9U-8.0Hz , AgH), 8.14 (1H, d, 9U-8.0Hz, AgHN), 8.69 (1H, m, AgH), 9.80 (1H, s, OH).

Example 20

Preparation of M,M-diethyl-4-(8-quinolinylpiperidin-4-ylidenemethyl)benzamide (compound 34) (8) ov and Ex

M. ah yi

N

A mixture of the compound of example 19 (45 mg), trifluoroacetic acid (1.00 ml) and trifluoromethanesulfonic acid (1 ml) was refluxed for 8 hours and then concentrated. The residue was dissolved in

AsOEiY (5Oml). The resulting solution was washed with a solution of MaOH, an aqueous solution of MNaS! and saline solution, dried over Ma5O4. Removal of the solvents gave the crude product, which was purified on a silica gel column eluting with MNAOnH (1n)-MeOOnH-CH2Cl (2.5:17.5:80) to give /M,M-diethyl-4-(8-quinolinylpiperidine- 4-ylidenemethyl)benzamide (29mg, 8490):

IN NMR (400 MHz, SOSIz») 6-1.07 (ZN, width m, CHzOHe-), 1.20 (ZH, width m, CHzSnHe-), 2.00 (2H, m, piperidine-

SNU), 2.46 (1Н, с, МН), 2.52 (2Н, m, piperidine-CH-), 2.75 (1Н, m, piperidine-CH-), 2.92 (2Н, m, piperidine-CH-), 3.05 (1H, m, piperidine-CH-), 3.22 (2H, m, SNegM-), 3.49 (2H, m, SNegM-), 7.23 (2H, m, AgH), 7.32 (2H, m, AgH), 7.36 (IN, m, AN), 7.49 (2H, m, AgH), 7.72 (1H, dd, 9-64, 3.2 Hz, AgH), 8.11 (IN, dd, 9U-8.4, 1.6 Hz, AgH), 8.91 (1H, dd, y-4.0, 1.6Gu, AgH).

Salt of NOA: t. pl. х1707C (decomposition);

IR (KVo) 3410, 2973, 1614, 1551, 1436, 1284 cm".

Elemental analysis. Calculated for SovNhoMzO: 2.0 NCI-0.50 СНе2СиИ» 0.75 NgO: C 602395; H 6,399.

Found: C 60.2795; H 6,425.

Example 21

Preparation of M,M-b1Y-diethyl-4-((M-tert-butoxycarbonylpiperidin-4-yl)-3-methoxyphenylhydroxymethylbenzamide (compound 35) o)

OMe no i

Vos

It was obtained by the method of example 19 using 3-bromoanisole, which gave the title compound (226 mg, 2395):

T. pl. 95-1037C;

IR (mass) 3422, 2973, 1684, 1614, 1429, 1289 cm.

Elemental analysis. Calculated for SgeNaoM2O5:0.60 NgO: С 68.6495; H 8, 1895; M 5.52905. Found: C 68.6690; H 7.9890; M 5.64905;

IN NMR (400 MHz, SOSIv) 6-1.07 (ZN, ext. CHzSNegMm-), 1.19 (ZN, ext. CHzSNeM-), 1.31 (4H, m, piperidine-

SNU, 1.А1 (9Н, с, СНЗС), 2.46 (1Н, m, piperidine-CH-), 2.64 (2Н, ext. piperidine-CH-), 3.22 (2H, ext. СНзСНе2М -), 3.49 (2H, ext. CHzCnNeg-), 3.65 (1H, c, OH), 3.72 (ZH, c, OSN"), 4.06 (2H, ext. piperidine-CH- ), 6.69 (1H, m, AgH), 7.01 (1H, d, uU-7.6Hz, AgH), 7.08 (1H, c, AgH), 7.17 (1H, d, 9U -8.0Hz, Ag), 7.21 (2H, d, 9U-8.0Hz, AN), 7.48 (2H, d, u8.0Hz, AN)

Example 22

Preparation of M,M-diethyl-4-(3-methoxyphenylpiperidin-4-ylidenemethyl)benzamide (compound 36) (o)

Ome

AND

NN

It was obtained by the method described in example 1, using compound 21 (100 mg), which gave M,M-diethyl-4-(3-methoxyphenylpiperidin-4-ylidenemethyl)benzamide (75 mg, 9895):

IN NMR (400 MHz, SOSIz) b 1.12 (ZN, ext. CHzSNeM-), 1.23 (ZN, ext. CHzSNaeM-), 2.34 (4H, m, piperidine-CH- ), 2.91 ( 4H, ext. piperidine-CH-), 3.17 (1H, c, MH), 3.27 (2H, ext. CHzCHNaM-), 3.52 (2H, ext. CHzCHNaM-), 3.76 (ЗН , c, OSN"), 6.64 (1H, c, AgH), 6.70 (1H, d, U-8.0Hz, AgH), 6.76 (1H, d, U-7.6Hz, AgH ), 7.15 (2H, d, U-8.0Gu, AgH), 7.22 (1H, m, AgH), 7.29 (2H, d, 9U-8.0Hz, AgH).

Salt of NOA: t. pl. x907C (decomposition);

IR (mass) 2970, 1621, 1430, 1287 cm".

Elemental analysis. Calculated for SgaNzoM2gO»2: NSI-1.70 NgO: С 64.6995; H 7.789; M 6.2995. Found: C 64.8290; H 7.605 M 6.089.

Example 23

Preparation of M,M-diethyl-4-|(M-benzyl)-3-methoxyphenylpiperidine-4-ylidenemethyl)benzamide (compound 37) o); at

Ome co

The method described in example 4 was used, using the compound of example 22 (Zvmg), obtaining

M,M-diethyl-4-((M-benzyl)-3-methoxyphenylpiperidin-4-ylidenemethyl)benzamide (46 mg, 9890):

IN NMR (400 MHz, SOSIz) b 1.12 (ZN, ext. CHzSNeM-), 1.25 (ZN, ext. CHzSNegMm-), 2.38 (4H, m, piperidine-CH- ), 2.48 ( AN, ext. piperidine-CH-), 3.27 (2H, ext. CHzSNegM-), 3.52 (2H, c, RICH2M-), 3.53 (2H, ext. CHzSNeM-),

3.75 (ZH, c, OSH»z), 6.65 (1H, c, AgH), 6.69 (1H, d, U-8.0Hz, AgHN), 6.74 (1H, d, U -7, bHz, AgH), 7.13 (2H, d, y-8.0Gu,

AGN), 7.13-7.32 (8H, m, Agn).

Salt of NOA: t. pl. 100-1107C (SNesi");

IR (Massi) 3421, 2972, 1619, 1430, 1287 cm".

Elemental analysis. Calculated for СзиНзвМ2О»:НСИ-0.40 СНоСи»: С 69.9695; H 7.0795; M 5.2095. Found:

C 69.9495; H 7.069; M 5,159.

Example 24

Preparation of M,M-diethyl-4-((M-tert-butoxycarbonylpiperidin-4-yl)-3-fluorophenylhydroxymethyl|benzamide (compound 38) by

BM Still FI

Oh well

Vos

By the method of example 19 using 3-bromofluorobenzene, the title compound (257 mg, 2795) was obtained:

IN NMR (400MHz, SOSIz) b 1.03 (ZN, ext. CHNasSNegM-), 1.15 (ZN, ext. CHzSNegM-), 1.19-1.29 (4H, m, piperidine-CH-), 1.35 (9H, c, CH3C), 2.39 (1H, m, piperidine-CH-), 2.59 (2H, ext. piperidine-CH-), 3.17 (2H, ext.

CHzSNeM-), 3.28 (1H, c, OH), 3.45 (2H, ext. CHzSNeM-), 4.02 (2H, ext. piperidine-CH-), 6.80 (1H, m, AgH ), 7.15 (ZH, m, Agn), 7.18 (2H, d, 9U-8.0Hz, Agn), 7.39 (2H, d, U-28.0Hz, Agn).

Example 25

Preparation of M,M-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide (compound 39) by

IS

AND

N

M,M-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide (108 mg, 8790) was obtained by the method of example 20 using the compound of example 24 (165 mg):

IN NMR (400 MGu, SOSIz) b 1.08 (ZN, ext. CHzSNegM-), 1.19 (ZN, ext. CHzSNegM-), 2.09 (1Н, с, МН), 2.25 (4Н, m , piperidine-CH-), 2.84 (4H, ext. piperidine-CH-), 3.23 (2H, ext. CHzSNegM-), 3.47, (2H, ext. CHzSiNeM-), 6.74 ( TN, m, AgH), 6.86 (2H, m, AgH), 7.06 (2H, d, U-8.0Gu, AgH), 7.18 (1H, m, AgH), 7.24 ( 2H, d, U-8.0Hz, AgH).

Salt of NOA: t. pl. x707C (decomposition); 14 (mass) 2978, 1605, 1478, 1432, 1290 cm".

Elemental analysis. Calculated for SgzNa7MgOR-HCi- 0.25 SneoCl2:1.50 H2gO: С 61.8995; H 7.0490; M 6,219.

Found: C 61.9795; H 6.9590; M 6,226.

F) Synthesis scheme of the compound of example 26

The compound of example 2 6 was obtained by the method as shown in scheme 5 below.

SCHEME 5

MN AsuSsNSY and sn, ! U -Sh- A Ta 1) manudes,tnE 2) p-VOMi, 7860 and 4 ns M. ren sh I ren" y y E 9 o (z) (t) o i

Vos maosn sn,

M SN.

Foni t 7 sn»

Even in -- A i

Vas M ("3) and (44)

Example 26 () Preparation of 4"-iodoacetanilide (compound 40)

Acetic anhydride (14.09g, 138 mol) was added to a solution of 4-iodanilin (15g, bUmmol) in dry SNS (100ml) at room temperature, and the reaction mixture was then stirred for 2 hours. The gray precipitate formed during the reaction was filtered, washed with ether and collected, the mother liquor was concentrated to dryness and ACSOEI was added, the resulting precipitate was filtered, washed with ether and combined with the previous solid, which is the target product (15.95 g, 88.75).

IN NMR (SOSIz) b: 2.19 (ZN, s, SOSN"), 7.2 (1H, s, shr. -MH), 7.23 (2H, m, Ai), 7.61 (2H, m, Ai). (i) Preparation of 4-(4-acetomidobenzoyl)-N-tert-butoxylcarbonylpiperidine (compound 41)

Manne (1.62 g, 67.5 mmol) was added to a solution of 4"-iodoacetanilide (11.7 g, 45 mmol) in dry THF (200 mL) at 0 °C, and the reaction mixture was stirred for 30 minutes while the temperature rose to room temperature. temperature, then H-Bsh! and (1.6 M in heptane, 54 mmol) was added slowly at -78"C. The mixture was stirred for 15 minutes, then M-tert-butoxylcarbonyl-M'-methyl-

M'-methoxyl-zonipecotamide (6.15 g, 0 mmol) in THF (100 ml). The reaction mixture was heated to room temperature and then quenched with an aqueous solution of MNACI and extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with saturated (aqueous) MNACI, saline solution, dried over Md5O" and concentrated, obtaining a crude product, which was further purified by column chromatography on silica gel using Meon-

SNesi" (0:100 - 5:95), obtaining the target product (9.02g, 8790).

IN H NMR (SOS13z) 6: 1.47 (9H, s (CH3z)z), 1.6-1.8 (4H, m, piperidine), 2.21 (ZN, s, SOSNU"), 2, 9 (2H, m, piperidine), 3.37 (1H, m, COCH-), 4.15 (2H, m, piperidine), 7.64 (2H, m, Ag), 7.86 (1H, s , width, - SOMN), 7.91 (2H, m,

AND). (her) Preparation of 4-(α-hydroxy-4(4-N-tert-butoxylcarbonylpiperidinyl)-3-fluorobenzyl)acetanilide (compound 42)

The title compound (9390) was obtained in the manner described for the preparation of compound 4, but by replacing 1-bromonaphthalene with 3-fluoro-1-iodobenzene.

IN NMR (DMSO-Ob) b: 1.2-1.3 (4H, m, piperidine), 1.37 (9H, s, (CHZz)z), 2.0 (ZH, s, SOCH»Z» ), 2.65 (ZH, ext., piperidine), 3.95 (2H, m, piperidine), 6.98 (1H, m, Ag), 7.21-7.50 (7H, m, Ag) , 9.85 (1H, s, OS-MH). (mM Preparation of M-methyl-4(α-hydroxy-α-(4-M-tert.-butoxylcarbonylpiperidinyl)-3-fluorobenzyl)acetanilide (compound 43)

Tetrabutylammonium hydrosulfate (1.35g, 3.97mmol) was added to a 2M (aqueous) Masson solution (1Oml), then 4-(α-hydroxy-α-(4-M-tert-butoxylcarbonylpiperidinyl)-3-fluorobenzyl)acetanilide ( 825 mg, 1.86 mmol) and methyl iodide (769 mg, 5.44 mmol) in 100 ml of dichloromethane. The reaction mixture was then refluxed for 1 hour and cooled to room temperature. The dichloromethane layer was collected and evaporated to a volume of about 1 ml. Ethyl acetate was added and the precipitate was separated by filtration. The organic phase was washed with brine and dried over Md 5 O 4 , concentrated to give a solid, which was further purified by MRI C using Meon-CNesy' (5:95) to give the pure title compound (77mg, 93905).

IN NMR (SOCIv) 6: 1.2-1.5 (4Н, m, piperidine), 1.42 (9Н, с, (СНЗ3)з), 1.83 (ЗН, С, СОСН»), 2, 52 (1H, m, -CH-C-

OH), 2.70 (2H, m, piperidine), 2.86 (1H, s, shr., -OH), 3.21 (ZH, s, MON"), 4.15 (2H, s, shr. ., piperidine), 6.90 (1H, m, Ap), 7.12-7.60 (7H, m, Ag).

Example 26

Preparation of M-methyl-4-(3-fluorophenylpiperidine-4-ylidenemethyl)acetanilide (compound 44)

To a solution of M-methyl-4-(α-hydroxy-α-(4-M-tert-butoxylcarbonylpiperidinyl)-3-fluorobenzyl)acetanilide (300 mg, 0.657 mmol) in dry dichloromethane (Xml) was added trifluoroacetic acid (5Oml) at room temperature. The reaction mixture was refluxed for 4 hours and then concentrated.

The residue was dissolved in ASOEA (5 mL). The obtained solution was washed with 2N (aqueous) Mahon, (aqueous) MNASI and saline solution, dried over Md5O". Removal of the solvents afforded the crude product, which was purified by MRI C eluting with MeOH-SNexSi»-MNAOH (5:95:1) to give the pure product (17 mg, 7995).

T. pl. 235-237"C (decomposition).

IR (Masi, film) (NSI salt)

Mtakh-2961, 2722, 2480, 1658, 1608, 1580, 1507, 1429, 1381 cm".

IN YAME (SOSIZz) b: 1.89 (ЗН, с, СОСН»), 1.95 (1Н, с, -МН), 2.32 (4Н, m, piperazine), 2.92 (4Н, m, piperazine), 3.26 (ZH, c, M-CH3z), 6.81-7.28 (8H, m, Ag). 136 NMR: (SOSIv): 5 22.4, 33.2, 33.3, 37.0, 48.3, 113.3 (m, C-E), 116.5 (m, C-E), 125.4, 126.6, 129.5, 129.6, 130.9, 133.7, 137.7, 141.2, 142.8, 144.2, 161.3, 163.8, 170, 4.

Elemental analysis: (905)

Calculated for SgiNgozM2BO-NOSI: C 67.28; H 6.45; M 7.47; Found: C 66.88; H 6.44; M 7.16. (P) Synthesis scheme of the compound of example 27

The compound of example 27 was obtained by the method as shown below in scheme 6

SCHEME 5

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ZKU and Byk 9

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She is like a le otu o and SHY JI

ZhK evionutchumayu i tu shany duttia KK -- i

I | Z rya x ze -

Ve and

But yes

Nritlad ate it: () Preparation of M-tert-butoxylcarbonyl-4-piperidone (compound 46)

A mixture of compound 45 (50 g, 0.325 mol) and di-tert-butyldicarb-onate (71 g, 0.325 mol) in 3 mL of dichloromethane was stirred at 0"C, with triethylamine (133 g, 1.32 mol) added dropwise. The mixture was left to warm to room temperature. and stirred for 12 hours. The solvent was evaporated and the crude product was partitioned between water (400 mL) and diethyl ether (400 mL). The aqueous phase was washed with an additional portion of diethyl ether (4000 mL). The combined ether was washed with water (4000 mL) and brine ( 400ml), dried over Mud5O4. Removal of the solvent gave compound 46 as a pale yellow solid (55.3g, 85905). bn (400Mhz, SOCI3) 1.50 (s, 9H), 2.45 (t, 4H, U-6.1Hz), 3.72 (t, 4H, U-6, 1Hz). (i) Preparation of tert-butyl ether of 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylic acid (compound 49)

Methyl 4-(bromomethyl)benzoate (compound 47) (11.2 g, 49 mmol) was dissolved in 25 ml of trimethyl phosphite and refluxed in an atmosphere of M" for 5 hours. Excess trimethylphosphite was removed by co-distillation with toluene to give the crude methyl ester of 4-(dimethoxyphosphorylmethyl)benzoic acid (compound 48). bn (400 MHz, SOSIz) 3.20 (d, 2H, 9U-22Hz), 3.68 (d, ЗН, 10.6 Hz), 3.78 (d, ЗН, 11.2Hz), 3.91 ( s, ZN), 7.38 (m, 2H), 8.00 (d, 2H, U9-8Hz).

The crude product (compound 48) was dissolved in dry THF (200 mL) under M2 atmosphere and cooled to -7870.

Lithium diisopropylamide (32.7 ml, 1.5 M in hexanes, 49 mmol) was added dropwise. The solution was left to warm to room temperature. A solution of compound 46 (9.76 g,

49 mmol in 100 ml of dry THF) and the mixture was stirred in an atmosphere of M" for 12 hours. Water (3300 ml) and ethyl acetate (3000 ml) were added to the reaction mixture and extracted. The aqueous phase was washed with ethyl acetate (2x30 Oml). The combined ethyl acetate layers were dried over Md 5 O»x and evaporated to give the crude product, which was purified by chromatography on silica gel (0-3390 ethyl acetate in hexanes) to give compound 49 as a white solid (5.64 g, 3590). bn (400MHz, SOS") 1.44 (s, 1H), 2.91 (t, 9-5.5Hz, 2H), 2.42 (t, 9-5.5HzC, 2H), 3.37 ( t, 9-5.5Hz, 2H), 3.48 (t, 9.5.5Hz, 2H), 3.87 (s, ЗН), 6.33 (s, 1H), 7.20 (d, 9- 6.7 Hz, 2H), 7.94 (d, 9U-6.7 Hz, 2H). bs-iz (SOSIz) 28.3, 29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6, 166.8 m.h. mtakh (MaSiI) cm"! 3424, 2974, 2855, 1718, 1688, 1606, 1427, 1362, 1276.

Elemental analysis. Calculated for C19H25MO4: C 68.8695, H 7.6095, M 4.2390; Found: C 69195, H 7.69906, M 42595. (its) Preparation of tert-butyl ether 4-bromo-4-I(bromo-(4-methoxycarbonylphenyl)methyl|piperidine-1- carboxylic acid acid (compound 50)

K»CO3 (1.0 g) was added to a solution of compound 49 (5.2 g, 1 mmol) in dry dichloromethane (200 ml). Then, a bromine solution (2.9 g, 114 mmol in 30 mL of OSM) was added dropwise at 0"C, and the mixture was stirred for 1.5 hours at room temperature. CaCO3 was removed by filtration and the solution was evaporated to dryness. The crude product was dissolved in ethyl acetate (200 mL) and washed with water. (200ml) , 0.5M CARRIER (200ml) and brine (200ml), dried over Md5O»x. The solvent was evaporated to give a crude product, which was recrystallized from methanol to give compound 50 as a white solid (6.07g, 7895 ). bn (400 MHz, SOSIz) 1.28 (s, 9H), 1.75 (m, 2H), 1.90 (m, 2H), 2.1 (m, 4H), 3.08 (width 4H), 3.90 (s, ЗН), 4.08 (width, 4H), 5.14 (s, 1H), 7.57 (d, 9-8.4Hz, 2H), 7.98 ( d, 9U-8.4Hz, 2H). bs-iz (400MHz, SOSIv) 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9, 129.0 , 130.3, 130.4, 141.9, 154.4, 166.3 m.h. Mtach (MaSi) cm"! 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243.

Elemental analysis. Calculated for C1i9H25Vi2MOa: C 46.69, H 5.139, M 2.8595. Found: C 46.6495, H 5.165, M 2.899. (m) Preparation of 4-(bromo(4-carboxyphenyl)methylene|piperidine-1 carboxylic acid tert-butyl ether (compound 51)

2.0M Mahon (100ml) was added to a solution of compound 50 (5.4g, 11mmol) in methanol (300ml) at 40°C.

The reaction mixture was stirred for 3 hours at 40°C. The crude salt was isolated by filtration. The solid material was dried overnight under vacuum. The dry salt was dissolved in a 4095 acetonitrile/water mixture and the pH of the solution was adjusted to 2 using concentrated HCl. The target product (7) ( 3, vg, 87905) was isolated in the form of a white powder by filtration. bn (400MHz, SOSIz") 1.45 (s, 9H), 2.22 (dd, 9U-5.5Hz, 6.1Hz, 2H), 2, 64 (dd, 9-5.5Hz, 6.1Hz, 2H), 3.34 (dd, 9sh5.5Hz, 6.1Hz, 2H), 3.54 (dd, 9-5.5Hz, 6.1HuC, 2H), 7.35 (d, 9U-6.7Hz, 2H), 8.08 (d, 9-6.7Hz, 2H). bs-iz (40OMHZ,

SOS") 28.3, 31.5, 34.2, 44.0, 115.3, 128.7, 129.4, 130.2, 137.7, 145.2, 154.6, 170.3 .

Elemental analysis. Calculated for SivNg22VIMO: C 545695, H 5.6095, M 3.5395. Found: C 546695, H 5.689, M 3.599. (m) Preparation of 4-(bromo-(4-diethylcarbamoylphenyl)methylene|piperidine-1-carboxylic acid tert-butyl ether (compound 52)

Isobutyl chloroformate (450 mg, 3.3 mmol) was added to a solution of compound 51 (1.0 g, 2.5 mmol) in dry dichloromethane (1 mL) at -20 °C. After 20 minutes at -20 °C, diethylamine (4 mL) was added and the reaction mixture left to warm to room temperature. After 1.5 hours, the solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine and dried over Mo95O4, and the ethyl acetate was removed by evaporation. The crude product was purified by silica gel chromatography (0-6095 ethyl acetate in heptanes) to give the product (compound 52) as white needles (800mg, 7390). bn (400 MHz, SOSIz) 1.13 (lat., ZN), 1.22 (lat., ZN), 1.44 (s, 9H), 2.22 (t, 9-5.5Hz, 2H), 2.62 (t, 9-5.5Hz, 2H), 3.31 (t, 9-5.5Hz, 2H), 9.52 (t, 9-5.5HzC, 2H), 7.27 (d , 9-7.9Hz, 2H), 7.33 (d, 9-7.9Hz, 2H). bs-iiz (400MHz, SOSIz) 12.71, 14.13, 28.3, 31.5, 34.2, 39.1, 43.2, 79.7, 115.9, 126.3, 129, 3, 136.8, 137.1, 140.6, 154.6, 170.5.

Elemental analysis. Calculated for SggNziViM2gOz: C 58.395, H 6.9295, M 6.2195. Found: C 58.6295, H 6.899, M 6.219.

Example 27

Preparation of M,M-diethyl-4-(piperidin-4-ylidene-(3-trifluoromethylphenyl)methylbenzamide (compound 54, Ag-3-trifluoromethylphenyl) (general method)

The Suzuki coupling of compound 52 with various boronic acids followed by deprotection of the substituent was carried out in parallel on a small scale. Reactions and liquid-liquid extraction were carried out in 25x150 mm culture tubes. The methodology of a typical reaction is described below.

To a solution of compound 52 (25 mg, 57 μmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 4.3 μmol) in xylenes (degassed, O0.5 ml) was added 3-trifluorophenylboronic acid (28.5 mg, 150 μmol) in ethanol (degassed, O0.5 ml), then 150 μl of 2M NaClCO3 (aqueous) (3300 μmol). The reaction mixture was left to undergo the reaction at 80"C for 1.5 hours in an Ar atmosphere. The reaction mixture was diluted with water (1 ml) and diethyl ether (ml) and mixed with vortexing. The organic phase was separated and evaporated, obtaining the crude product (compound 9 , Ag-3-trifluoromethylphenyl).

The Vos group was removed by treating the crude product with TFO. After 30 minutes, TFO was evaporated at room temperature, obtaining crude TFO salt. The salt was neutralized with 1 M MNAOH (1.0 M) and extracted with diethyl ether (2 ml). The ether phase was acidified with 4.0 M HCl in dioxane (200 μl) and the HCl salt was extracted with water (2x1 ml). The aqueous solution of the salt was washed with diethyl ether (2xIml) and lyophilized to give the product (compound 54, Ag-3-trifluoromethylphenyl) as a white powder (10mg, 3995).

IN NMR (SOSIZz) (base) b 1.11 (width, ZN), 1.20 (width, ZN), 2.26 (t, 9U-5.6Hz, 2H), 2.31 (t, U-5.6Hz, 2H), 2.88-2.91 (m, 4H), 3.27 (width 2H), 3.52 (width 2H), 7.10-7.47 (m, 8H).

Elemental analysis. Calculated for SgaNoaM2gOgzSix1.80 NgO: С 59.3995; H 6.569; M 5.77905. Found: S

59.3990; H 5.9090; M 5.7 790.

Examples 28-52

According to the method described for compound 54 of example 27, but with the replacement of 3-trifluoromethylphenylboronic acid with the corresponding boronic acids, the following compounds were also obtained.

Example 28

M,M-diethyl-4-(3-nitrophenylpiperidine-4-ylidenemethyl)benzamide (compound 55)

3-nitrophenylboronic acid was used. (8) sub

MO,

What

N

IN NMR (SVSIz) (base) b: 1.11 (width ZN), 1.21 (width ZN), 2.27-2.34 (m, AN), 2.92 (t, y-6 ,0Hz, 4H), 3.26 (width 2H), 3.52 (width 2H), 7.10 (d, U-8.4HzC, 2H), 7.91 (d, 9U-8.4Hz , 2H), 7.40-7.50 (m, 2H), 7.95-8.08 (m, 2H).

Example 29

N,M-diethyl-4-(4-toluylIpiperidin-4-ylidenemethyl)benzamide (compound 56)

p-Toluylboronic acid was used. 0 sleep

M

Nn

IN NMR (SOSIz) (base) b: 1.10 (width ZN), 1.19 (width ZN), 2.29 (s, ZN), 2.26-2.31 (m, 4H), 2.86-2.88 (m, 4H), 3.25 (width, 2H), 3.49 (width 2H), 6.95-7.28 (m, 8H).

Example 30

N,M-decethyl-4-(4-formylphenylpiperidine-4-ylidenemethyl)benzamide (compound 57)

4-formylphenylboronic acid was used. at; sleep

M n

IN NMR (SOSIv) (base) b: 1.10 (width ZN), 1.20 (width ZN), 2.28-2.33 (m, AN), 2.89-2.92 (m , AN), 3.25 (width 2H), 3.50 (width 2H), 7.08-7.79 (m, 8H), 9.95 (s, 1H).

Example 31

N,M-diethyl-4-(3-chloro-4-fluorophenylpiperidine-4-ylidenemethyl)benzamide (compound 58)

3-chloro-4-fluorophenylboronic acid was used. o t Ff F I

SI

M

N

IN NMR (SOSIv) (base) b: 1.10 (width ZN), 1.20 (width ZN), 2.26-2.30 (m, AN), 2.86-2.91 (m , AN), 3.25 (width 2H), 3.50 (width 2H), 6.93-7.30 (m, 7H).

Example 32

M,M-diethyl-4-(fluorophenylpiperidin-4-ylidenemethyl)benzamide (compound 59)

4-fluorophenylboronic acid was used. (in)

E h

M

N

IN NMR (SOSI»z) (base) b: 1.11/ (width ZN), 1.16 (width ZN), 2.25 (s, AN), 2.84 (s, AN), 3 2H .

Example 33

M,M-diethyl-4-(2-fluorophenylpiperidine-4-ylidenemethyl) benzamide (compound 60)

2-fluorophenylboronic acid was used. (8)

IS

M

N

IN NMR (SOS) (base) b: 1.11 (width ZN), 1.15 (width ZN), 2.10 (t, 9-5.2 Hz, 2H), 2.27 (t, Uu "5.2Hz, 2H), 2.83 (m, 4H), 3.20 (width 2H), 3.45 (width 2H), 6.94-7.03 (m, ЗН), 7, 10-7.23 (m, 5H).

Example 34

M,M-diethyl-4-(2,4-dichlorophenylpiperidine-4-ylidenemethyl)benzamide (compound 61)

2,4-dichlorophenylboronic acid was used. (9)

WITH

EOM fi F a

M

Nn

IN NMR (DMSO) (NOI salt) 6: 1.07 (width 6H), 2.24 (t, 2H), 2.50 (t, 2H), 3.10 (t, 2H), 3.30 (t, 2H), 3.31 (width 2H), 3.43 (width 2H), 7.25 (d, 9-8.4Hz, 2H), 7.32 (d, 9-8, АHz , 2H), 7.43 (d, 9U-8.0Hz, 1), 7.47 (d, U-8.0Hz, 1H), 7.68 (s, 1H), 9.20 (width 2H ).

Example 35

M,M-diethyl-4-(3,5-dichlorophenylpiperidine-4-ylidenemethyl)benzamide (compound 62)

3,5-dichlorophenylboronic acid was used. o t F F

SI

M

Nn

IN NMR (DMSO) (NS salt) 6: 1.03 (width 6H), 2.36-2.38 (m, 4H), 3.0-3.2 (m, 4H), 3.2 ( width 2H), 3.38 (width 2H), 7.19 (s, 1H), 7.21 (d, 9-8.0Hz, 2H), 7.29 (d, uU-8.0Hz, 2H), 7.49 (s, 2H), 9.10 (width 2H).

Example 36

M,M-diethyl-4-(3-acetylphenylpiperidine-4-ylidenemethyl)benzamide (compound 63)

3-acetylphenylboronic acid was used.

oh oh sleep

M

N

IN NMR (SOSIz) (base) b: 1.11 (width ZN), 1.20 (width ZN), 2.26 (t, 925.6 Hz, 2H), 2.32 (t, 9-5 ,6Hz, 2H), 2.55 (s, ЗН), 2.92-2.88 (m, 4H), 3.26 (width 2H), 3.51 (width 2H), 7.11 ( d, 9U-8.0Hz, 2H), 7.29 (d, 9U-8.0Hz, 2H), 7.29 (d, u7.2Hz, 1), 7.37 (t, U9-8.0Hz , 1), 7.70 (s, 1H), 7.79 (d, 9-7.2 Hz, 1H).

Example 37

M,M-diethyl-4-(3,5-trifluoromesylphenylpiperidine-4-ylidenemethyl)benzamide (compound 64)

3,5-trifluoromethylphenylboronic acid was used. o) SE, sho

SE,

M

N

IN NMR (DMSO) (carrier salt) 6: 1.06 (lat. ZN), 1.08 (lat. ZN), 2.33 (lat. 2H), 2.41 (lat. 2H), 3, 12 (width 6H), 3.38 (width 2H), 7.24 (d, 9-7.6Hz, 2H), 7.30 (d, U9-7.6Hz, 2H), 7.84 ( s, 2H), 8.00 (s, 2H), 8.9 (width 2H).

Example 38

M,M-diethyl-4-(3-thiophenylpiperidine-4-ylidenemethyl) benzamide (compound 65)

3-thiophenylboronic acid was used. (at)

E.M. Yah I

M

N

IN NMR (DMSO) (NS salt) b: 1.10 (width 6H), 2.44 (t, 2H), 2.58 (t, 2H), 3.10-3.15 (m, AN) , 3.21 (width 2H), 3.44 (width 2H), 6.86 (d, 9-48 Hz, 1H), 7.20 (d, 9-8.0Hz, 2H), 7, 32 (d, 9-8.0Hz, 2H), 7.33 (s, 1H), 7.52 (d, 9-4.8HzC, 1H).

Example 39

M,M-diethyl-4-(2-thiophenylpiperidine-4-ylidenemethyl)benzamide (compound 66)

2-thiophenylboronic acid was used.

Io)

EM and input

WITH

M nn

IN NMR (SOS) (base) 6: 1.12 (width ZN), 1.20 (width ZN), 2.24 (t, 9-25.2Hz, 2H), 2.50 (t, u25 ,2Hz, 2H), 2.85 (t, uU25.6Gu, 2H), 2.92 (t, 955.6Hz, 2H), 3.27 (width 2H), 3.51 (width 2H), 6.75 (d, U-3.6 Hz, 1H), 6.93 (t, U-3.6 HzC, 1), 7.16 (d, U-7.2 Hz, 2H), 7.21 ( d, U-3.6Hz, 1H), 7.30 (d, U-7.2Hz, 2H).

Example 40

M,M-diethyl-4-(4-methylthiophenylpiperidine-4-ylidenemethyl)benzamide (compound 67)

4-methylthiophenylboronic acid was used.

ZMe

M nn

IN NMR (SOSIz) (base) b: 1.11 (width ZN), 1.20 (width ZN), 2.32-2.75 (m, AN), 2.45 (s, ZN), 2.90-2.87 (m, 4H), 3.26 (width 2H), 3.51 (width 2H), 7.01 (d, U-6.0Hz, 2H), 7.10 ( d, 9-6.0Hz, 2H), 7.15 (d, U-6.8Hz, 2H), 7.27 (d, U-6.8Hz, 2H).

Example 41

M,M-diethyl-4-(3-aminophenylpiperidine-4-ylidenemethyl)benzamide (compound 68)

3-aminophenylboronic acid was used.

AT

"yes

MH,

M

Nn

IN NMR (SOSIz) (base) b: 1.11 (width ZN), 1.20 (width ZN), 2.27-2.33 (m, AN), 2.86-2.90 (m , 4H), 3.27 (width 2H), 3.51 (width 2H), 3.57 (width 2H), 3.68 (s, 1H), 6.39 (s, 1H), 6 ... 7.26 (d, U-6.4Hz, 2H).

Example 42

M,M-diethyl-4-(4-trischormethylfecylpiperidine-4-ylidenemethyl)benzamide (compound 69)

4-trifluoromethylphenylboronic acid was used. (in)

CE h with

M

Nn

IN NMR (DMSO) (NS salt) b: 1.05 (width 6H), 2.35 (t, 2H), 2.40 (t, 2H), 3.09 (m, 6H), 3.35 (width 2H), 7.17 (d, 98.0Hz, 2H), 7.28 (d, u-8.0Hz, 2H), 7.35 (d, U-8.0Hz, 2H), 7 .67 (d, 9-8.0 Hz, 2H), 8.71 (width 2H).

Example 43

M,M-diethyl-4-(4-methoxyphenylpiperidine-4-ylidenemethyl)benzamide (compound 70)

4-methoxyphenylboronic acid was used. (o; od

M

N

1TE NMR (SOSIv) (base) b: 1.12 (lat. ZN), 1.19 (lat. ZN), 2.29 (m, 4H), 2.87 (m, 4H), 3.27 ( width 2H), 3.51 (width 2H), 3.77 (s, ЗН), 6.80 (m, 2H), 7.00 (m, 2H), 7.10 (d, U-8 ,4Gu, 2H), 7.26 (d, 9U-8.4Hz).

Example 44

M,M-diethyl-4-(3,4-dichlorophenylpiperidine-4-ylidenemethyl)benzamide (compound 71)

3,4-dichlorophenylboronic acid was used.

o) SI and SI

M

N

IN NMR (SOSIz) (base) b: 1.12 (width ZN), 1.20 (width ZN), 2.28 (t, 9U-5.6 Hz, AN), 2.89 (m, 4H), 3.27 (width 2H), 3.52 (width 2H), 6.8-7.4 (m, 7H).

Example 45

M,M-diethyl-4-(2-trifluoromethylphenylpiperidine-4-ylidenemethyl)benzamide (compound 72)

2-trifluoromethylphenylboronic acid was used. oh new

SE,

M n

IN NMR (SOSIz) (base) b: 1.05 (width ZN), 1.16 (width ZN), 1.95 (m, 2H), 2.35-2.A1 (m, 2H), 2.7-2.9 (m, 4H), 3.20 (width 2H), 3.48 (width 2H), 7.2-7.6 (m, 8H).

Example 46

N,M-diethyl-4-(3-toluylpiperidin-4-ylidenemethyl)benzamide (compound 73)

m-tolylboronic acid was used. there is a dream

M

N

IN NMR (SOSI»z) (base) b: 1.11 (lat. ZN), 1.19 (lat. ZN), 2.28 (s, ZN), 2.29 (m, AN), 2, 89 (m, 4H), 3.27 (width 2H), 3.51 (width 2H), 6.8-7.3 (m, 8H).

Example 47

M,M-diethyl-4-(2-methoxyphenylpiperidine-4-ylidenemethyl)benzamide (compound 74)

2-Methoxyphenylboronic acid was used. o) n SHHI Ff

Ome

M n

IN NMR (SOSIz) (base) 6: 1.09 (width ZN), 1.18 (width ZN), 2.10 (sq., U-4.8Hz, 2H), 2.31 (sq., U :4.8Hz, 2H), 2.8-2.9 (m, 4H), 3.25 (width 2H), 3.50 (width 2H), 3.68 (s, ЗН), 6, 83-6.90 (m, 2H), 7.0 (d, 1H), 7.15-7.25 (m, 5H).

Example 48

M,M-diethyl-4-(3-formylphenylpiperidine-4-ylidenemegyl) benzamide (compound 75)

3-formylphenylboronic acid was used.

what a dream

M n

IN NMR (SOSIv) (base) b: 1.15 (width ZN), 1.20 (width ZN), 2.26-2.34 (m, 4H), 2.90-2.92 (m , AN), 3.28 (width 2H), 3.2 (width 2H), 7.11-7.31 (m, 8H), 9.96 (s, 1H).

Example 49

N,M-diethyl-4-(2-naphthylpiperidin-4-ylidenemethyl)benzamide (compound 76)

2-naphthylboronic acid was used. oh oh

N

IN NMR (SOSIv) (base) b: 1.11 (width ZN), 1.20 (width ZN), 2.35-2.39 (m, AN), 2.91-2.96 (m , AN), 3.27 (width 2H), 3.51 (width 2H), 7.16-7.40 (m, 5H), 7.42-7.44 (m, 2H), 7, 57 (c, 1H), 7.72-7.79 (m, 2H).

Example 50

M,M-diethyl-4-(2-formylphenylpiperidine-4-ylidenemethyl)benzamide (compound 77)

2-formylphenylboronic acid was used. at

ШШШШШШ F sno . M

N

IN NMR (SVSIz) (base) b: 1.09 (width ZN), 1.18 (width ZN), 1.70-2.10 (m, 2H), 2.40-2.49 (m , 2H), 2.76-2.84 (m, 2H), 2.85-2.97 (m, 2H), 3.23 (width 2H), 3.48 (width 2H), 7, 13-7.40 (m, 6H), 7.53-7.55 (m, 1H), 7.90 (d, 9-7.6Hz, 1), 10.27 (s, 1H).

Example 51

M,M-diethyl-4-(4-acetylphenylpiperidine-4-ylidenemethyl) benzamide (compound 78)

Pacetylphenylboronic acid was used. (in)

M

N

IN NMR (SOSIz) (base) b: 1.11 (width ZN), 1.20 (width ZN), 2.30-2.35 (m, 4H), 2.56 (s, ZN), 2.92 (m, 4H), 3.27 (width 2H), 3.52 (width 2H), 7.10-7.30 (m, 6H), 7.87 (d, 9-7 2Hz, 2H).

Example 52

M,M-diethyl-4-(3-trifluoromethylphenylpiperidine-4-ylylenemethyl)benzamide (compound 79)

3-trifluoromethylphenylboronic acid was used.

(c) t g

SE,

M.

N

IN NMR (SOS) (base) b: 1.11 (width ZN), 1.20 (width .H), 2.26 (t, 9U-5.6Hz, 2H), 2.31 (t, U-5.6Hz, 2H), 2.88-2.91 (m, 4H), 3.27 (width 2H), 3.52 (width 2H), 7.10-7.47 (m, 8H).

Example 53

Preparation of M,M-diethyl-4-(|1-(2,6-diaminohexanoyl)piperidin-4-ylidene|ifenylmethyl)benzamide (compound 80) o)

M children

MH,

II-Boc-lysine (Sb) (0.938 g, 1.0 mmol) was dissolved in dry tetrahydrofuran (3 mL) in a nitrogen atmosphere at -1576. M-methylmorpholine (0.11 mL, 1.0 mmol) was added, then isobutyl chloroformate (0 ,1Zml, tmmol). After stirring for 10 minutes, N,M-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (compound 6) (0.35g, 1.0mmol) in tetrahydrofuran (ml) was added and the temperature was allowed to rise to 25°C for 2 hours

The reaction mixture was evaporated on silica gel. MRI C on silica gel (from 0 to 10095 ethyl acetate in heptane) gave

Oh Ag.

The product (0.40 g, 0.5 mmol) was dissolved in methylene chloride (100 ml) and treated with trifluoroacetic acid (3 ml) for 30 minutes, then the volatile components were evaporated. The residue was dissolved in acetic acid (25 ml) and subjected to hydrogenolysis for 1.5 hours with hydrogen (atm) over palladium on charcoal (1095, 0.10 g). The solvent was evaporated and the residue was purified by chromatography on a short reverse phase column (AP-18), eluting with 0-3095 acetonitrile in water. The free amine was extracted with a 595% solution of potassium carbonate, methylene chloride, yielding 123 mg, and then treated with two equivalents of hydrochloric acid in a methanol/water mixture.

Lyophilization gave the dihydrochloride salt.

IN NMR (free amine, COzOb): b-1.0-1.7 (m, 16H, amide-Me, piperidine-H, lysine-H), 2.3-2.7 and 3.0-4, 5 (m, 11H, amide-H, piperidine-H, lysine-H), 4.8 (s, AN, 2 MH"), 7.10-7.50 (m, 9H, Agn).

Elemental analysis. Calculated for SgoNaoMaOgh2.4 NgOHX2 NOI: C 58.76905; H 7.969; M 9.4390. Found: C 58.70; H 7.5195; M 9,339.

Example 54

Preparation of phosphonooxymethyl ether /4-((4-diethylcarbamoylphenyl)phenylmethylene|piperidine-1-carboxylic acid (compound 81)

Go) oo

M

And I about o7to-v-on he

M,M-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (compound b) (0.62g, 1.9mmol) was dissolved in methylene chloride (10ml) and 1,8-bisdiaminonaphthalene (0.42g, 2.0mmol) was added ). The solution was cooled to 0 °C and chloromethyl chloroformate (0.25 g, 2.0 mmol) in methylene chloride (ml) was added dropwise. After standing for 2 hours at 25 °C, an additional portion of 1,8-bisdiaminonaphthalene (0.21 g, 1, 0 mmol), then chloromethyl chloroformate (0.12 g, 1.0 mmol). After a total holding time of 4 hours, the solution was washed with 1M HCl, saline, dried (MH) and evaporated, obtaining 0.62 g. The residue was dissolved in toluene (25 ml), silver dibenzyl phosphate (0.81 g, 2.1 mmol) was added and the mixture was heated for three hours at 807C.

The solution was filtered, then washed with 595% potassium carbonate solution, saline, dried (KgSO3) and evaporated. MRI C on silica gel (0 to 10095 ethyl acetate in heptane) gave 0.66 bg (0.96 mmol, 5495). The residue was dissolved in ethyl acetate (50 ml) and subjected to hydrogenolysis (atm. hydrogen) with palladium on carbon (10905, 0.3 g) for 2 hours. After filtering and evaporating the solvent, the product was treated with two equivalents of sodium hydroxide in a methanol/water mixture. Lyophilization gave the disodium salt of the product as a white solid.

IN NMR (020): 6-1.03, 1.20 (2 m, 6H, amide-Me), 2.34 (m, 4H, piperidine-H), 3.19-3.61 (m, 8H , amine-CH", piperidine-nH), 5.44 (d, U-13Hz, 2H, OSNHgO), 7.18-7.36 (m, 9H, AgH).

Compounds 80 and 81, respectively, are suitable prodrugs of compounds of formula (1). (c) Synthesis scheme of compounds of examples 55-57

Compounds of examples 55, 56, and 57 were obtained according to the method presented below in scheme 7.

SCHEME 7 (e)

More:

Vg o

Y in m x; pere o v - mordolin (82) bolo pigernknya m) v I piropidny (89) (51) thing / 3-E-RI-V(ОНО)

RfI(OUMa2SOZ 2. But about E in fi

Y V o - morpholine (85); Example 55

E - pyleridine (86); Example 56

Y V yah pyrrolidine (87); Example 57 () Preparation of tert-butyl 4-(bromo|I4-(morpholinocarbonyl/phenyl|methylene)-1-piperidinecarboxylate (compound 82)

Oxalyl chloride (0.38ml, 2.0M, 0.75mmol) was added dropwise at room temperature to a solution of compound 51 obtained according to scheme b (0.25g, 0.625mmol) and freshly distilled triethylamine (O.bml) in dichloromethane (12ml). The solution was stirred for 10 minutes at room temperature, and the solvent and excess reagents were removed in vacuo to give the chloride as a crude product, which was used in the next step without further purification.

Morpholine (5 mg, 0.65 mmol) was added to a solution of hydrogen chloride (0.65 mmol) and triethylamine (0.5 mL) in dichloromethane (5 mL). The reaction mixture was left to react for one hour at room temperature. The solvent was then removed in vacuo. The crude product was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was washed with ethyl acetate and the combined layers of ethyl acetate were washed with 2M MMA (2x25ml), 2M HCl (2x25ml), saline (1x25ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give the product (compound 82) (294 mg, yield 97905).

IN NMR SOSI»z (400 MGu) 1.44 (s, 9H), 2.21 (t, U-5.6Hz, 2H), 2.62 (t, 9-5.6Hz, 2H), 3.31 (t, 9-5, 6Hz, 2H), 3.52 (t, 9U-5.6Hz, 2H), 3.69 (width, 8H), 7.91 (d, U-6.4Hz, 2H ), 7.37 (d, 9-6.4Hz, 2H). (its Preparation of tert-butyl 4-(bromo-I4-(piperidinocarbonyl)phenyl|methylene)-1-piperidinecarboxylate (compound 83)

The same procedure was used as described for compound 82, but using piperidine instead of morpholine.

IN NMR SOS" (400MG) 1.44 (s, 9H), 1.51 (width, 2H), 1.66 (width, 4H), 2.21 (t, 9U-25.6Hz, 2H) , 2.62 (t, U-5.6Hz, 2H), 3.31 (t, 9U-5.6Hz, 2H), 3.33 (width, 2H), 3.52 (t, 9U-5 ,6Hz, 2H), 3.68 (width, 2H), 7.26 (d, uU-8.4Hz, 2H), 7.35 (d, u8.4hz, 2). (her) Preparation of tert-butyl A(bromo-I4(tetrahydro-1H-1-pyrrolylcarbonyl)phenyl|methylene)-1-piperidinecarboxylate (compound 84)

The same procedure was used as described for compound 82, but using pyrrolidine instead of morpholine.

IN NMR COsSdz (400 MGu) 1.44 (s, 9H), 1.87 (k, U-6.8Hz, 2H), 1.95 (k, U-6.6Hz, 2H), 2.20 (t , u-5.6Hz, 2H), 2.62 (t, uU-5.6Hz, 2H), 3.91 (t, uU-25.6Hz, 2H), 3.43 (t, U-6, 8Hz, 2H), 3.52 (t, 5.6Hz, 2H), 3.63 (t, 9-6.8Hz, 2H), 7.27 (d, y-8.0Hz, 2H), 7, 47 (d, u9-8.0Hz, 2H).

Example 55

Preparation of 4-|(3-fluorophenyl)piperidin-4-ylmethylphenylmorpholin-4-ylmethanone (compound 85)

3-Fluorophenylboronic acid (25 mg, 0.18 mmol) in ethanol ( degassed, 0.5 ml), then 150 μl of 2M Ma»5O:4 (aqueous) (300 μmol). The reaction mixture was left to react at 80°C for 2 hours in an argon atmosphere. The reaction mixture was diluted with water (1 mL) and diethyl ether (mL) and mixed with vortexing. The organic phase was separated and evaporated, obtaining a crude product that was used without additional cleaning.

The Vos group was removed by treating the crude product with TFO. After 30 minutes at room temperature, TFO was evaporated, obtaining crude TFO salt. The salt was neutralized with 1M MNAOH (1.0M) and extracted with diethyl ether (2x1ml). The ether phase was acidified with 4.0 M NOSI in dioxane (200 μl) and the salt of NSI was extracted with water (2x1 ml). The aqueous salt solution was washed with diethyl ether (2xIml) and lyophilized, obtaining the product in the form of a white powder.

IN NMR COsSdz (400MGI) b 2.67 (m, 4H), 3.19 (m, 4H), 3.45 (width, 2H), 3.68 (width, 6H), 6.75 (d , 9U-9.6Hz, 1H),

6.85 (d, U-8.0Hz, 1H), 6.95 (m, 1H), 7.11 (d, U-7.6Hz, 2H), 7.25 (s, 1H), 7, 35 (d, 9-7, 6Hz, 2H).

Example 56

Preparation of 4-|(3-fluorophenyl)piperidin-4-ylmethyl I|phenylpiperidin-4-ylmethanone (compound 86)

The method described for the preparation of compound 85 was used, but using compound 83 as a starting material.

IN NMR SOSI" (400 MGu) b 1.51 (width, 2H), 1.65 (width, AN), 2.60 (width, AN), 3.14 (width, 4H), 3, 33 (width, 2H), 3.68 (width, 2H), 6.67 (d, 9U-8.0Hz, 1), 6.86 (d, 9U-8.0Hz, 1H), 6, 93 (t, U-8.0Hz, 1H), 7.08 (d, 9U-8.4Hz, 2H), 7.25 (s, 1H), 7.32 (d, 9-8.4Hz, 2H ).

Example 57

Preparation of 4-|(3Z-fluorophenyl)piperidin-4-ylmethylylphenylpyrrolidin-1-ylmethanone (compound 87)

The method described for the preparation of compound 85 was used, but using compound 84 as a starting material.

IN NMR SOSIz (400 MGu) 5 1.84-1.89 (m, 2H), 1.90-1.98 (m, 2H), 2.60-2.63 (m, 4H), 3.13- 3.17 (m, 4H), Z.A1 (t, y-6.8Hz, 2H), 3.62 (t, 9-6.8Hz), 6.73 (d, 9U-8.9Hz, 1H ), 6.86 (d, 9-7.2Hz, 1H), 6.93 (m, 1H), 7.10 (d, U-8.0Hz, 2H), 7.25 (s, 1H), 7.45 (d, 9-8.0Hz, 2H). (H) Synthesis scheme of compounds of examples 58-68

Compounds of examples 58-68 were obtained according to the method shown below in schemes 8 (a)-(c)

SCHEME 8 (8)

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YaefRyZ (98); Sh. 87 97 () Preparation of 4-Ibromo-(4-ethoxycarbonyl-aminophenyl)methyl|piperidine-1-carboxylic acid tert-butyl ether (compound 88)

Diphenylphosphorylazide (0.192g, 0.70mmol) and triethylamine (0.1ml, 0.7mmol) were added to a mixture of compound 51 obtained according to scheme b (0.25g, 0.625mmol) in toluene (5ml). After stirring the mixture in an argon atmosphere at 95°C for two hours, an excess of anhydrous ethanol (2ml) and triethylamine (O0.Tml) were added, and the solution was stirred at 957°C for an additional 5 hours. After cooling to room temperature, the reaction mixture was partitioned between water and diethyl ether The ether layer was washed with water, dried over magnesium sulfate and evaporated under vacuum, obtaining the product (compound 88) in the form of a reddish

brown foam (Z0Omg, output 9995).

IN NMR (400MGu) (SOS) 1.30 (t, 9-7.2Hz, ЗН), 1.44 (s, 9Н), 2.22 (t, 9-6.0Hz, 2Н), 2.60 (t, 9-6.0Hz, 2H), 3.91 (t, u-6.0Hz, 2H), 3.51 (t, U-6.0Hz, 2H), 4.21 (kv, 9- 7.2Hz, 2H), 6.58 (s, 1H), 7.19 (d, U-8.4Hz, 2H), 7.33 (d, 9-8.4Hz, 2H). (i) Preparation of 4-((4-ethoxycarbonylaminophenyl)-(3-fluorophenyl)methyl|piperidine-1-carboxylic acid tert-butyl ether (compound 92)

The Suzuki coupling of four vinyl bromides (compounds 88-91) with 3-fluorophenylboronic acid was carried out in parallel. Reactions and liquid-liquid extractions were carried out in 25 mm x 150 mm culture tubes. The methodology of a typical reaction is described below.

To a solution of compound 88 (0.30g, 0.625mmol) and tetrakis(triphenylphosphine)palladium(0) (50mg) in toluene (degassed, 0.5ml) was added 3-fluorophenylboronic acid (0.182g, 1.3mmol) in ethanol (degassed, 0.5 l), then 0.75 ml of 2 M MagSO (aqueous) (1.5 mmol). The reaction mixture was left to undergo the reaction at 80"C for 3 hours in an argon atmosphere. The reaction mixture was diluted with water and diethyl ether and mixed with vortexing. The organic phase was separated and evaporated, obtaining a crude product. The crude product was purified by chromatography on silica gel (0-5095 EAs in hexanes), giving the product (compound 92) as a white powder (0.166 g, yield 5890).

IN NMR (400 MHz) (SOSiz) b 1.25 (t, 9-7.2 Hz, ZN), 1.44 (s, 9H), 2.27-2.33 (m, AN), 3.41- 3.44 (m, AN), 4.20 (kv, at 7.2Hz, 2H), 6.52 (s, 1H), 6.76 (d, 9-10Hz, 2H), 6.85-6 .89 (m, 2H), 7.01 (d, uU-8.8Hz, 2H), 7.19-7.23 (m, 1H), 7.28 (d, u8.8Hz, 2H).

Example 58

Preparation of 4-((3-fluorophenyl)piperidin-4-ylmethyl|phenylcarbamic acid ethyl ester (compound 96)

Extraction of the BOC protective group was carried out on a small scale in parallel in test tubes (13 mm x 1!0 mm). A typical technique is described below.

The BOC group was removed by treating compound 92 (50 mg, 0.11 mmol) with NCI in dioxane (4.0 M, 2 ml). The mixture was stirred at room temperature for 30 minutes. The solvent and NSI were removed in vacuo to give the product compound 96 as a white powder after lyophilization (40 mg, yield 99965).

IN NMR (400MGu) (SOSIv) 6 1.28 (t, 9-7.2Hz, ZN), 2.27-2.31 (m, 4H), 2.85-2.91 (m, 4H), 4.19 (kv, 9-7.2Hz, 2H), 6.50 (s, 1H), 6.76 (d, 9U-10Hz, 1H), 6.85-6.89 (m, 2H), 7.01 (d, 9-8.8Hz, 2H), 7.19-7.23 (m, 1H), 7.28 (d, 9-8.8Hz, 2H).

Example 59

Preparation of 4-|((3-fluorophenyl)piperidin-4-ylmethyl|phenylmethylcarbamic acid ethyl ester (compound 100)

Alkylation of amide nitrogen was carried out on a small scale in parallel in test tubes (13 mm x 1!00 mm). A typical technique is described below.

To a solution of compound 92 (5O0mg, 0.11mmol) in dichloromethane (1.5ml) was added methyl iodide (31mg, 0.22mmol), aqueous sodium hydroxide (1.0ml, 2M) and tetrabutylammonium sulfate (44mg, 0.1mmol). The solution was refluxed for one hour. After cooling to room temperature, the dichloromethane layer was separated and evaporated. Ether was added to the residue and white tetrabutylammonium iodide was filtered off. The ether was removed in vacuo to give crude compound 100 as a light oil. The BOC group was removed by treating NS in dioxane as described above to give the product as a white powder after lyophilization (17 mg, yield 4290).

IN NMR (400MHz) (SOSiv) b 1.23 (t, 9-7.2Hz, Z), 2.27-2.33 (m, 4H), 2.85-2.91 (m, 4H), 3.26 (s, ZN), 4.15 (sq, at 7.2Hz, 2H), 6.78 (d, 9-10Hz, 1H), 6.85-6.89 (m, 2H), 7 .05 (d, U-8.0 Hz, 2H), 7.14 (d, 9-8.0 Hz, 2H), 7.19-7.23 (m, 1H).

Example 60

Preparation of 4-((1-benzylpiperidin-4-yl)-(3-fluorophenyl)methyl I|phenylcarbamic acid ethyl ester (compound 116)

Benzylation of compound 100 was carried out on a small scale in parallel in test tubes (13 mm x 100 mm). A typical technique is described below.

Compound 100 in the form of a free base was obtained by adding ammonium hydroxide (1M, 0.5 ml) to an aqueous solution of compound 100 (0.04 mmol) and extracted into ether. The ether was removed in vacuo to give an oil which was dissolved in dichloromethane and treated with benzyl bromide (0.14ml, 0.5M in dichloromethane) and triethylamine (0.05ml). The solution was stirred at room temperature for 5 hours. The solvent was removed under vacuum.

The product was dissolved in a mixture of water/acetonitrile/HCl (2:1:0.5M) and lyophilized, obtaining the product compound 108 in the form of a white powder.

IN NMR (400MHz) (SOSiz) b 1.28 (t, 9-7.2Hz, ZN), 2.33-2.36 (m, AN), 2.38-2.46 (m, 4H), 3.51 (s, 2H), 4.19 (sq, u-7.2Hz, 2H), 6.50 (s, 1H), 6.78 (d, 9U-10Hz, 1), 6.85- 6.89 (m, 2H), 7.05 (d, 9U-8.0 Hz, 2H), 7.19-7.30 (m, 7H).

Examples 61-68

The following compounds were also obtained by synthetic routes described in Schemes 8 (a)-(c).

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In a more acceptable embodiment of the invention, which is known now, compounds 6, 7, 9, 10, 12, 26, 27, 34, 39, 44, 58, 59, 62, 69, 71, 104, 106 and 109 are used.

Pharmaceutical compositions

New compounds according to the present invention can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intramucosally, intracerebroventricularly, and by injection into joints.

A more acceptable method of administration is oral, intravenous or intramuscular,

The dose will depend on the method of administration, the severity of the disease, the age and weight of the patient, and other factors that are usually considered by the treating physician when determining the individual regimen and dose of the drug most suitable for a particular patient.

In order to obtain pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Preparations in solid form include powders, tablets, dispersible granules, capsules, sachets and suppositories.

The solid carrier can be one or more substances that can act as diluents, corrigents, solubilizers, lubricants, suspending agents, binding agents or agents that disintegrate tablets; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid material mixed with a finely divided active component. In tablets, the active component is mixed with a carrier that has the necessary binding properties in suitable proportions and pressed to obtain the desired shape and size.

To obtain compositions in the form of suppositories, a low-melting wax, such as a mixture of glycerides of fatty acids and cocoa butter, is first melted and the active ingredient is dispersed in it, for example, by stirring. The molten homogeneous mixture is then poured into molds of the usual size and left to cool and harden.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, and the like.

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, ethylenediaminetetraacetate, edsylate, estolate, hesylate, fumarate, glucoptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine , hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate phosphate/diphosphate, polygalacturonate, salicylate , stearate, subacetate (basic acetic acid salt), succinate, sulfate, tannate, tartrate, theoclate, triethiodide, benzathine salt, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

More acceptable pharmaceutically acceptable salts are hydrochlorides and citrates.

The term composition refers to a ready-to-use formulation of an active ingredient with an encapsulating material as a carrier, which provides the formation of a capsule in which the active ingredient (with or without other carriers) is surrounded by a carrier, which is thus in association with it. Similarly, sachets are included.

Tablets, powders and capsules can be used as solid dosage forms suitable for oral administration.

Compositions in liquid form include solutions, suspensions and emulsions. Examples of liquid preparations suitable for parenteral administration include solutions of active compounds in sterile water or a water-propylene glycol mixture. Liquid compositions can also be made in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable dyes, correctors, stabilizers and thickeners, if necessary. Aqueous suspensions for oral use can be prepared by dispersing the finely divided active ingredient in water together with a viscous material such as natural and synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical formulation industry.

More acceptable pharmaceutical compositions are single dosage forms. In this form, the composition is divided into unit doses containing a suitable amount of the active component. A single dosage form can be a packaged drug, and the package contains discrete amounts of drugs, for example, packaged tablets, capsules and powders in bottles or ampoules. The unit dosage form may also be a capsule, sachet or tablet or it may be a suitable number of any of these packaged forms.

Biological assessment

A) IP migo model

Cell culture

Human 2935 cells expressing cloned human |, b, and ge receptors and resistant to neomycin were grown in suspension at 37°C in an atmosphere with 595 CO. In shake flasks containing OMEM (Dulbecco's modified Eagle medium), which does not contain calcium, 1095 FTS, 595 VS5, 0.195 pluronic

E-68 and 600 μg/ml geneticin.

Membrane preparation

Cells were collected as a pellet after centrifugation and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTU with FMSOF added immediately before use to 0.1 mM of 01 M stock solution in ethanol), incubated on ice for 15 minutes, then homogenized with a polytron for 30 seconds. The suspension was centrifuged at 10,009 (tah) for 10 minutes at 4°C. The supernatant was kept on ice and the pellet was resuspended and centrifuged as above. The supernatants from the two centrifugations were combined and centrifuged at 460,009 (tah) for 30 minutes. The pellet was resuspended in cold Tris buffer (50mM Tris/Cl, pH 7.0) and centrifuged again. The final pellet was resuspended in membrane buffer (50mM Tris, 0.32M sucrose, pH 7.0). Aliquots (ml) in polyethylene tubes were frozen in the dry ice/ethanol system and stored at -70"C until use.

Protein concentrations were determined by a modified I-omg assay with DSN.

Binding analysis

Membranes were thawed at 37"C, cooled on ice, passed three times through a 25" needle and diluted in binding buffer (5X0mM Tris, 3mM Masig, 1mg/ml ABC (bidta A-7888), pH 7.4/ which was stored at 4"C after filtering through a 0.22 m filter and to which 5 μg/ml of fresh aprotinin, 10 μM bestatin, 10 μM diprotin A without DTT was added). Aliquots of 100 μl (per μg of protein, see Table 1) were added to polypropylene tubes cooled on ice, 12x75 mm in size, containing 100 μl of a suitable radioactive ligand (see Table 1) and 1 μl of the tested peptides at different concentrations.

Total (33) and nonspecific (NS) binding was determined in the absence and presence of 10 μM naloxone, respectively. The tubes were vortexed and incubated at 25°C for 60-75 minutes, after which time the contents were quickly filtered under vacuum and washed with about 12ml/tube of ice-cold washing buffer (50mM Tris, pH 7.0, 3mM Massi»g) through the filters CE/B (Whatman), presoaked for at least 2 hours in 0.195 polyethyleneimine Radioactivity (disintegrations per minute) remaining on the filters was measured with a beta counter after soaking the filters for at least 12 hours in mini-ampules containing 6-7 ml of scintillation liquid. If the analysis was performed in 96-well plates, filtration was performed through a 96-well single filter pre-soaked in PEA, washed with Хх! wash buffer and dried in an oven at 55"C for 2 hours.

The radioactivity of the filter for the tablet was counted in TorSotspa (Raskagi) after adding 50 μl of scintillation liquid M5-20/well.

Data analysis

Specific binding (C3), which is calculated as 33-NH and C3 in the presence of various test peptides, was expressed as a percentage of C3 from the control. ICho values and Hill's coefficient (pn) for the ligands and in the displaced specifically bound radioactive ligand were calculated using a logarithmic plot or a curve plotting program such as Iidapa, StgarpRaiRizt, BidtaRioi, or Reseruogrii. Values K; were calculated using the Spepd-Rgizzoii equation. The values of the mean values are the root mean square error for

ISvo, K; and pn were given for the tested ligands at least on the basis of three displacement curves.

Experiments on receptor saturation

The values of Kb of the radioactive ligand were determined by performing a binding analysis on cell membranes with suitable radioactive ligands at concentrations ranging from 0.2 to 5 times the estimated Kb concentration (up to 10 times, if such quantities of the required radioactive ligand are possible). Specific binding of the radioactive ligand was expressed as pmol/mg membrane protein. The values of Kb and

Vtakh from separate experiments was obtained from the nonlinear dependence of specifically bound (B) ligand on nM of free (E) radioactive ligand from a separate experiment according to the single-site model.

B) Biological model (ip mimo model)

Mechano-allodynia in the rat induced by Freund's complete adjuvant (paf) and a sciatic nerve cuff

Animals

Male Zrgadoe-bSamieu rats (Spapez Vimeg, 5BI-Sopviapi, Sapada) were used, weighing 175-200g at the time of surgery. they were housed in groups of three individuals in boxes that were thermostatically maintained at 207C and a daily light/dark cycle of 12:12 was established, and the rats were provided with free access to food and water. After placing in the boxes, the animals were left to acclimatize for at least 2 days before surgery. The experiments were approved by Medes! Empisa! Sottinee for animal research.

Freund's experimental technique is a complete adjuvant

Rats were first anesthetized in the chamber with halothane, after which TOmcl PAF was injected subcutaneously in the dorsal area of the left foot, between the second and third outer toes. The animals were then left to recover from anesthesia while being observed in the cage.

Cuff for the sciatic nerve

Animals were prepared according to the method described by Mozsopi apa Khydeg (1996). Rats were anesthetized intraperitoneally with a mixture of ketamine/xylazine (2 ml/kg) and placed on their right side, and an incision was made across and along the axis of the lateral side of the left thigh. The upper quadriceps muscles were dissected separately using a needle to release the sciatic nerve, around which a plastic cuff was placed (PE-60 tube, length 2 mm). The wound was then sutured in two layers with 3-0 vicryl and silk sutures.

Determination of mechano-allodynia using the Egeu mop test

The tests were carried out between 08:00 and 16:00 using the method described by SPariap et al. (1994).

Rats were placed in Plexiglas cages on top of a wire mesh base that provided access to the paw, and were left to habituate for 10-15 minutes. The tested area was the mid-plantar part of the left hind foot, which prevented the use of less sensitive foot pads. The paw was touched with hairs from a group of 8 Egeu mops with logarithmically increasing stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; bioepo , IP, BOTH). An Egeu mop bristle was applied from below the mesh floor perpendicular to the plantar surface with a force sufficient to cause the bristle to flex slightly relative to the tarsus, and this force was maintained for approximately 6-8 seconds. A positive corresponding reaction was noted if the paw was sharply withdrawn. Shivering immediately after hair removal was also considered a positive response. Movement of the rat was considered as an unclear response, and in such cases the stimulus was repeated.

Test protocol

Animals were tested on postoperative day 1 for the PAF-treated group and on postoperative day 7 for the sciatic nerve cuff group. 5095 withdrawal threshold was determined using Dixon's "up-down" method (1980). The tests started with a hair of 2.04 g, the average in the series. Stimulations were always performed sequentially, regardless of whether they increased or decreased. In the absence of a corresponding paw withdrawal reaction to the initially selected hair, a stronger stimulus was given; in the case of withdrawal of the paw, the next, weaker stimulus was chosen. Calculating the optimal threshold in this way would require 6 matching responses in the immediate vicinity of the 5095 threshold, and the counting of these matching responses would begin when the first change in the matching response occurred, for example, when the threshold was first crossed. In cases where the thresholds were found outside the stimuli, values of 25.14 (normal sensitivity) or 0.41 (maximum allodynia) were estimated, respectively. The obtained results of positive and negative corresponding reactions are presented in the form of tables using the standard method, X- without pulling away, O- pulling away and 5095 threshold of pulling away was interpolated using the formula: 5095 threshold, g-1О1ka/10000 where chi is the value of the last hair of the Egeu mop, which was used (0d-units); K is the tabular value (from Spariap et al. (1994)) for the results of positive/negative corresponding reactions and 4 is the average difference between the stimuli (I0d units). Here a-0.224.

Thresholds of the Egeu mop were converted into a percentage of the maximum possible effect (956 MME) according to Spariap eii ai., 1994. For the framework of both otsivtkaroskovmyaalbvake equations:

MM - the threshold of (g) allodynia c hyaoo the threshold of (g) control - the threshold of (g) allodynia

Introduction of the test substance

Rats were injected (subcutaneously, intraperitoneally, or administered orally) with the test compound prior to the Egeeu mop test, the time between the introduction of the test compound and the Egeeu mop test varied depending on the nature of the test compound.

The following abbreviations have the following meanings:

Ac - acetyl

Ag - aryl

I-VOC - tertiary butoxycarbonyl

And-Vy - tertiary butyl

Eg - ethyl

IRg - isopropyl

Me - methyl

RI - phenyl

Ri - propyl g. 2 room temperature

TFO - trifluoroacetic acid

THF - tetrahydrofuran

TMEDA -M,M,M'M'-tetramethylethylenediamine.

Claims (22)

1. The compound of the general formula (I) А В З в д2 Я в! And) where B! selected from hydrogen, branched or unbranched C1-C8-alkyl, C1-C8-alkenyl, C3-C8-cycloalkyl, Ca-C8-(alkylcycloalkyl), where alkyl is C1-C8-alkyl, and cycloalkyl is C3-C8 -cycloalkyl; S-Cio-aryl or heteroaryl having from 5 to 10 atoms selected from C, 5, M and O; where aryl or heteroaryl may be optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CHbz, -(CHNo)pC3, halogen, -SOMA»UV", -COOH", -СОН», -««CHg )рМ AB, "СНг)рСНа(СНо)рз Ов, -(СНг)р5О" in and "СНг)р5О2МА", where R. B", each independently, as defined above for P", and p is 0, 1 or 2; (C1-C0-alkyl)-(C1-C0-aryl) or (C1-C0-alkyl)heteroaryl, wherein heteroaryl moieties have from 5 to 10 atoms selected from C, 5, M, and O, and wherein the aryl or heteroaryl may be optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CH33, -(CH3)aCE3, halogen, -SOMA?VU, -SOOVU, -SOVU, -«(SNag)aMAeVU, - (SnazaSNai(SNg)yavOV VU, -«(SNg)а5О» В, -(СНg)а5О2МВ and -««SNag) pOv", where B" and ER", each independently, are as defined above for P", and 4 is equal to 0, 1 or 2; and o) 18 in action 22 A / M cove 21 in 25 in 8 24 o -B 23 B where B/!8, B!Z. d2o Dg!, deg, De. some | c25. each independently, represent hydrogen, C1-Cv-alkyl or Ci-Cv-alkenyl; B2 and 23, each independently, represent hydrogen or Ci-Cv-alkyl; A is chosen from c 6) some Y 2 13 yini wai g o 1 2 (F) works MI 2 1 and in shk sho in, 1 2 d' in) 7: "Z M ate! 1 in o, 2 2 o 1 7 de B8, VU . independently substituted in any position of the phenyl ring 1 or 2 by substituents 2! and 27, which, each independently, are selected from hydrogen, CH3, -(CHg)ace3, halogen, - СсОоМвевВ, -СООНе, -СОНВе, -(СнгуМмвевВ, "СНг)уСсна(СНнгу Ов, -(СНг) БО" and -"CHn)5O2MAV, where P and B", each independently, are as defined above for EC", and r is 0, 1 or 2; O is a C5-Ce-hydroaryl or heterohydroaromatic radical having 5 or 6 atoms selected from C, 5, M and 0; C5-Cv-cycloalkyl or heterocycloalkyl having 5 or 6 atoms selected from C, 5, Mi 0; and where each 0 can optionally be replaced by a substitute 2! and 77 as defined above; B is a substituted or unsubstituted aromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atoms selected from C, 5, M and O, and optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, СНз, -"СНгСЕз, halogen, -"СНгиСОМеВУ, - (СнгнмАВУ, -(Снг Сов, -(СНгиСООв, -ОВ, -(СНгиБОВ, -(СНгО»Во and ""СНг5О2МА?В, where B) and VEB, each independently as defined above for EE", and Her is 0, 1, 2 or 3; and B" and PE5, each independently as defined above for E", as well as pharmaceutically acceptable salts of compounds of the formula ( I) and their isomers, hydrates, isoforms and prodrugs. 2. The compound of the formula (I) according to claims 1, where A is chosen from v o) Ak 7: her Z B 1 o al IYI 2 M-z3 RAI A o 1 u 12 Y 2 Sha M 7 o Ii A, O di 2 in 2 Y " o Mo 1 7 16 in, in 2 M 17 in 7! iv) 2 2 o 1 2 where B8, VU, VO, V, d'?, VZ, dya, B"5, V!E Her B!", each independently, are as defined above for P", and where the phenyl ring of each substituent A may be optionally and independently substituted at any position of the phenyl ring 1 or 2 by substituents 2! and 27, which, each independently, are selected from hydrogen, CH3, -(CHg)ace3, halogen, - СсОомвеВ, -СООНе, -СОНВе, -"СНгуМвевВ, "СНг)усНа(СНнгу Ов, -(СНг) BO» and -"CHn)5O2MAV, where P and B", each independently, are as defined above for PE", and r is 0, 1 or 2; O is selected from morpholine, piperidine, and pyrrolidine; KE", Bl and Z, each independently selected from hydrogen, branched or unbranched C1-C4-alkyl, C3-C5-cycloalkyl, C4-C-(alkylcycloalkyl), where alkyl is C1-C5-alkyl, and cycloalkyl is C3-C5-cycloalkyl; Ce-Cio-aryl or heteroaryl having from 5 to 6 atoms selected from C, 5, M and O; and wherein the aryl or heteroaryl may be optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CH3, -(CHNa)pCE3, halogen, -"SOMA?VU, -SOOVU, -SOVU, ""CHNa)vM ВВ, - (СнгарсНзиз(СНг)в5ов5вУ, -"СНаг)р5О»2В5 and "СНг)р5О2МА", where В and EE", each independently, are as defined above for В", and p is equal to 0, 1 or 2; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl inda, pyrrolidinyl, indenyl each of which is optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CHz, CEz, halogen, -««СНгзаСОМАВУ, -««СНаг)аМАВУ, -«СНг)аСОВ?, -С(СНаг)аСО "B" and -ORVU, where 4 is equal to 0 or 1, and where B" and B are as defined above; B2 and 23 are each independently hydrogen or methyl. 3. The compound of formula (I) according to claim 2, where A is 8 o ra and Y 9 V 1 2 where is E8 and RE? both are ethyl, and where the phenyl ring is optionally and independently substituted at any position of the phenyl ring with two substituents 2 and 27, each independently selected from hydrogen, CH3, -(CH3)αC3, halogen, -SOMAEV", -SOOVYA, -SOVe, -(SnguMmvev", -(SngaSNau(SnguzOvVe, -(СНg) bo» and - (Sng)О2М eV", where R and B", each independently, such as defined above for PE", and r is 0, 1 or 2; B' is selected from hydrogen, methyl, ethyl, -"CHNaCH-CnHe, -CHNo-cyclopropyl, -"CHn-aryl or CNeo-heteroaryl, and the heteroaryl parts have from 5 up to 6 atoms selected from C, 5, Mi 0; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl and indazolinyl, each of which is optionally and independently substituted with 1 or 2 substituents independently selected from hydrogen, CH»z, SEz, halogen, - (СнгасСОоМмезве, -(СНг)аМААУ, -«(СНг)заСОВ», -(СНг)аСО»В and -ОВ?, where 4 is equal to 0 or 1, and where В and P are as defined above; B2 and 23 are each independently hydrogen or methyl. 4. Compound of formula (I) according to claim 1, which is: 9) Sho MI N . (0 Shot M N . at sleep y y t iny M n . o "o what M i o OA M what o . ше M о TO Ф о) OA () І n .- (6) E ше і N .- (c) SI TO Y NN o Sho M kN and SI Sho M still (c) She M S, about M y she eh M Io o Sho M Y i SI (0) yo i Me v) o eh M i N ! c) Ш ОМе и N . (o) TO I OME ko (o) "Os E AD N N Son veshod: and about their di MO, M N o sn, Oi M N o sno t g M N . o E ne si M N o E She M N 6) AH yes E M n . o SI new Si M N ! o s Ada M n . c) EBM sn. at); M - N . o SE, Ha SE, M N . o EM -- - 5 МН ; o Z M N o) 5Me shov M N . o sho MN, MN c) SE, oo M N . (c) . OMe es g M N F) si sho SI M N o u s SE" M N o Od sn. M N . o u r OMe M N . especially M N . (o) Shen M N . about; t sno M H (c) (c) M N . o "o SE, M N . N E shk She and also m N Go) E that M nn de K represents morpholine, piperidine or pyrrolidine, E M zroi M N . ssh eh Y NN oyu She su She su I She Yi y . t E (in) M : She N (TZ cho (in) M More ; N ; KI h ! and -o and She and nn N E c) Phi Fu Yi n 5. The compound according to claim 1, which is chosen from (c) aut M MN kabaa 2 MN, and o . rah M M A oil av Me, o-esoN on 6. The compound according to any of the previous items in the form of its hydrochloride, sulfate, tartrate or citrate salt. 7. The compound according to any of items 1 - b for use in therapy. 8. The compound of claim 7, wherein the therapy is pain relief. 9. The compound according to claim 7, wherein the therapy is aimed at gastrointestinal disorders. 10. The compound of claim 7, wherein the therapy is directed at spinal injuries. 11. The compound according to claim 7, wherein the therapy is aimed at a disturbance of the sympathetic nervous system. 12. The compound according to any one of claims 1 - 7, which is further distinguished by the fact that it is labeled with an isotope. 13. Isotope-labeled compound of formula (I) according to claim 1. 14. Diagnostic agent, which includes the compound of formula (I) according to claim 1. 15. A pharmaceutical composition that includes a compound of formula (I) according to claim 1 as an active ingredient together with a pharmacologically and pharmaceutically acceptable carrier. 16. The method of obtaining the compound of the formula (I) according to claim 1, which includes a) interaction of the ketone of the formula (I) (o; X vk V M 1 and () where B", B? and C are as defined in formula (I) in claim 1, and X is a leaving group with an organometallic reagent of the formula (|) or ( K) AND M. () or h M "(yu where A and B are as defined in formula (I) in claim 1, and M represents a metal group; and where the interaction is optionally carried out in the presence of a solvent, with the formation of a compound of the formula ( n) A B on 2 in B? M 1 A (where A, B, B", B? and 23 are as defined in formula (I) in claim 1, and where B can also be tert-butoxycarbonyl; p ) dehydration of the compound of formula (n) to obtain the compound of formula (I) according to claim 1. 17. The compound of the formula A B (c) 5i 2 in d? Vos (n) where A, B, R: and EZ are as defined in formula (I) in claim 1. 18. The compound of formula (P) according to claim 17, where A is (o, Ak 7: M to 7 where RZ and 2? both represent an ethyl group, and 2! and 72 are as defined in claim 1. 19. Compound according to claim 18, which is: о объя и Вос (о) Meshe no Me Я Vos Я F EM h o viv); Y Vos o E o no her Vos o SI she no i Vos : o o no M 2 o o S what) or Y Vos Shee Vos and her - OME Vos 20. A method of treating pain, which comprises administering an effective amount of a compound of formula (I) according to claim 1 to a subject in need of pain relief. 21. A method of treating gastrointestinal disorders, which includes administering an effective amount of the compound of formula (I) according to claim 1 to a subject suffering from said gastrointestinal disorder. 22. A method of treating back injuries, which includes administering an effective amount of the compound of formula (I) according to claim 1 to a subject suffering from said back injury.