UA77672C2 - 4-(phenyl-piperazinyl-methyl)-benzamide derivatives and use thereof for the treatment of pain, anxiety or gastrointestinal disorders, a process for preparation thereof and a pharmaceutical composition based thereon - Google Patents

Abstract

Compounds of general formula I R1 is selected from any one of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, pyrrolyl, triazolyl, thiazolyl, and pyridine N-oxide; R2 is independently selected from ethyl and isopropyl; R3 is independently selected from hydrogen and fluoro; R4 is independently selected from -OH, -NH2 and û NHSO2R5; and R5 is independently selected from hydrogen, -CF3 and C1-C6 alkyl, or salts thereof or separate enantiomers and salts thereof; where each R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the heteroaromatic ring may take place in any position on said ring systems; are disclosed and claimed in the present application, as well as separate enantiomers of the compounds and salts and pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain, anxiety and functional gastrointestinal disorders.

Description

Description of the invention

The presented invention relates to new compounds, the method of their production, their use, and pharmaceutical 2 compositions containing new compounds. The new compounds are useful in therapy, and in particular for the treatment of pain, anxiety and functional gastrointestinal disorders.

Receptor 5 has been identified as playing a role in many body functions, such as the circulatory and pain systems. Ligands for receptor 5 may therefore find potential use as analgesics and/or as antihypertensive agents. Ligands for receptor 5 are also shown to exhibit immunomodulatory activity.

The identification of at least three distinct populations of opioid receptors (M, 5 and K) is now well established and all three are found in the central and peripheral nervous systems of many species, including humans. Analgesia has been observed in various animal models upon activation of one or more of these receptors.

With few exceptions, currently available selective opioid 5-ligands are peptide in nature and unsuitable for administration by systemic routes. One example of a non-peptide 6β-agonist is 5MOS8O0

IVIZKUEU. hey ay, doigpa! oh RIaptpasoodu apa Ehregitepia! Tpegaretsiisv, 273(1), pp. 359-366 (19953). However, there is still a need for selective 5-agonists with not only enhanced selectivity but also an improved side effect profile.

Thus, the problem at the heart of the presented invention was to find new analgesics that have an enhanced analgesic effect, but also with an improved side effect profile compared to M-agonists, and also have enhanced systemic effectiveness.

Analgesics that have been identified and exist in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesics when administered by systemic routes. It has also been documented that the preferred 5-agonist compounds described in the prior art show significant (5) convulsive activity when administered systemically.

We have identified some compounds that exhibit unexpectedly enhanced properties, including enhanced 8-agonist potency, ip mimo potency, pharmacokinetics, bioavailability, ip miigo stability, and/or lower toxicity. with

New compounds according to the presented invention are defined by the formula | - b I (Se)

Shk: | І Z s "m - ! same nie viya - schi Z s NI knock out I bdsavnv one truty

I'm in the middle of nowhere

Mi licks ts

And to V

Well, where is b5?

Ku is chosen from any one of the group "I and Her I ! With and

SI and m

Do not be afraid of the evil of every widow and godmother.

GU (o)

Sq

To press down

I. t; with m

Sh prize ge that UM sh-- m- sh -

What is semididipm oxide: everything - and WHAT - where every heteroaromatic ring is KE! may optionally and independently be additionally substituted with 1, 2, or C b substituents, independently selected from linear and branched S.--Swalkil, halogenated Si-Swalkil, MO",

SEZ, Si-Svalkoxil, chlorine, fluorine, bromine and iodine.

Sh-B2 is independently selected from ethyl and isopropyl;

Kz VZ is independently selected from hydrogen and fluorine;

В" is independently selected from -OH, -МН»о and -МНЗО»В?; a

IN? independently selected from hydrogen, -SEz and Si-Svalkylu, provided that when B? represents ethyl, quince! 99 represents hydrogen, then B cannot be -OH.

GF) Substitutions on the phenyl ring and on the heteroaromatic ring can occur anywhere on the above-mentioned ring systems;

When the phenyl ring B! and heteroaromatic ring B! are substituted, preferred substituents being selected from any one of the group consisting of C3, methyl, iodo, bromine, fluorine and chlorine, of which methyl is preferred. because the next embodiment of the presented invention is, thus, a compound of formula I, where B! defined above, and each phenyl ring K' and heteroaromatic ring B! may be independently additionally substituted by a methyl group;

The next embodiment of the present invention is the compound shown in Fig. 1, where in! represents phenyl, 65 pyrrolyl, furanyl, thienyl or imidazolyl; B2 represents ethyl or isopropyl; IN? represents hydrogen or fluorine; B" represents -MH" or -MNZO"; and B9 represents S.-Svalkyl, optionally with 1 or 2 preferred substituents on the phenyl ring of B and the heteroaromatic ring of B.

An additional embodiment of the present invention is the compound shown in Fig. 1, where Ge represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; b2 represents ethyl or isopropyl; K Z represents pdrogen; K 4 9 represents -MNBO 289; and B5 represents C -Svalkyl, optionally with 1 or 2 preferred substituents on the phenyl ring of B! and heteroaromatic ring B.

Other embodiments of the present invention are the compounds shown in Fig. 1, where a) in! represents phenyl, pyrrolyl, or furanyl; KE? represents ethyl or isopropyl; 2 represents hydrogen or fluorine; and KE" represents 70 -MH", B) c! represents thienyl or imidazolyl; b2 represents ethyl or isopropyl; c represents hydrogen or fluorine; and B" represents -MH"; c) In! represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; IN? represents ethyl or isopropyl; C represents hydrogen or fluorine; BC 7 represents -MNVO 282; and B? represents

S.-Srvalkil; and a) in! represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; K 2 represents ethyl or isopropyl; 3 represents hydrogen or fluorine; in? represents -MNVZO»V; and B5 represents S.-Svalkil, where all t embodiments from a) to a) can, as an option, be replaced by 1 or 2 better substituents on the phenyl ring of B! and heteroaromatic ring B.

The scope of the invention also includes individual enantiomers and salts of compounds of formula I, including salts of enantiomers.

Also within the framework of the presented invention are mixtures of individual enantiomers, such as racemic mixtures, as well as salts of mixtures of individual enantiomers.

Separation of racemic mixtures into individual enantiomers is well known in the art and can be carried out, for example, by separation on a suitable chiral chromatographic column. Preparation of salts is well known in the art, and can be carried out, for example, by mixing a compound of formula | in a suitable solvent with the desired protonic acid and isolation by standard means in the art. Salts of the compounds of the formula include pharmaceutically acceptable salts as well as pharmaceutically unacceptable salts. high school

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

The compounds of the invention are useful as immunomodulators, especially for autoimmune diseases such as arthritis, for skin grafting, organ transplantation and similar surgical needs, for collagen diseases, various cm 3o allergies, for use as antitumor and antiviral agents. -

The compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or included in this paradigm. This may include the use of an isotopically labeled compound of the invention in diagnostic and endoscopy applications such as positron emission tomography (PET). uh-

The compounds of the invention are useful in the treatment of diarrhea, depression, anxiety, and stress-related disorders, such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder; urinary incontinence, various mental illnesses, cough, pulmonary edema, various gastrointestinal disorders such as constipation, functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury , stroke, protection of the heart after myocardial infarction, back injury and physical dependence on 7 drugs, including the treatment of dependence on alcohol, nicotine, opioids and other drugs and for disorders of the sympathetic nervous system, such as hypertension. 1" Compounds of the invention are useful as analgesics for use in general anesthesia and anesthesia monitoring. Combinations of agents with distinct properties are often used to achieve the balance of effects necessary to maintain the state of anesthesia (for example, amnesia, analgesia, muscle relaxation, and sedation), 15 included in this combination are inhalational anesthetics, hypnotics, anxiolytics, neurom' ulcer blockers and opioids. Also, the scope of the invention includes the use of any compound of the formula | above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method of treating a subject suffering from any of the conditions discussed above, wherein an effective amount of a compound of formula I above is administered to a patient in need of such treatment. "from Methods of obtaining

The compounds of the present invention can be prepared using the following general method.

Obtaining phenols:

Examples 1-3 o 25 Compounds of the formula I, where B7 represents -OH, are obtained by the reaction of compounds of the general formula ИЙ о не Іі п т в что о тс и В г і ј є б? and BZ are defined in Fig. and 7 represents OMe, with Bos-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Bos-protecting group under standard conditions to give the compound of formula II

(c) TI in B is also OMe

And co

Mn 70, which is further alkylated under reducing conditions with a compound of the formula B 1-CHO, and then by cleavage of the methyl ether using BVgz in dichloromethane, obtaining a compound of the formula I, where E7 represents -OH.

Obtaining anilines;

Examples 4-6

The compound of the formula I, where B" represents -MH»o, is obtained by the reaction of the compound of the general formula IM s. o M aoF vk: in

Ve And where V? and KZ are defined in Fig. 1, and 7 represents the MO of 2, 3 Bos-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Bos-protecting group under standard conditions, obtaining the compound of the formula U c o M in thio) went to Mo ,

M.

C With see

AND

В В - which is further alkylated under reducing conditions with the compound of the formula ВК !-СНО, and then the reduction of the nitro group using hydrogen and palladium on activated carbon, obtaining the compound of the formula I, where K7 represents - 35. МН". -

Preparation of methylsulfonanilides:

Examples 7-8

The compound of the formula I, where B" represents -"МНЗО"В? is obtained by the reaction of the compound of the general formula MI « o M! -sh i tod. yiv Y )" Vg m where B? and KZ are determined according to item 1 and B" represents MO 2, 3 by Bos-piperazine in acetonitrile in the presence of triethylamine under standard conditions, and then by reduction of the nitro group by hydrogenation using palladium on -I activated carbon as a catalyst, by methanesulfonylation using methanesulfonyl anhydride. in dichloromethane in the presence of triethylamine, and further removal of the Bos-protecting group under standard conditions, (22) obtaining a compound of the formula MIII b MI also As is si o or which is further alkylated under reducing conditions with a compound of the formula K "-CHO, and then reduction of the nitro group , because Using hydrogen and palladium on activated carbon, obtaining a compound of formula I, where B" represents -МНБО2в".

The scope of the invention also includes individual enantiomers and salts of compounds of formula I, including salts of enantiomers.

The compounds of formula I are chiral compounds with a diarylmethylpiperazine group as the stereogenic center, see Figure 1 below. b5 o I: theme ; that

M.

Content 70 The next embodiment of the present invention is thus the (-)-enantiomer of the compound of formula I, as well as the salt of the specified compound.

The next embodiment of the presented invention is thus the (t)-enantiomer of the compound of formula I, as well as the salt of the specified compound.

Examples

The invention is further described in more detail by the following non-limiting examples.

Scheme 1: Preparation of fluorophenols; Examples 1-3 and 48 | 5. яще у: ше и з ко Priknedtje ge)

Kik "5 pera nanvonvvnyanni shko

Hey -- and m

Intermediate 1: 4-(4-fluoro-3-methoxyphenyl)(hydroxy)methylid|-M,M-diisopropyl-benzamide.

M,M-Diisopropyl-4-iodobenzamide (6b, 0g, 14mmol) was dissolved in tetrahydrofuran (200ml) and cooled to -182C under nitrogen. H-Vii (14 ml, 1.3 M solution in hexane, 18 mmol) was added dropwise over 10 minutes at -65 - « -1826. 4-fluoro-3-methoxybenzaldehyde (2.8 g, 14 mmol) was added dropwise to a solution in tetrahydrofuran (bml). From 70 MNASI (aqueous) was added after 30 minutes. After concentration in vacuo, extraction with a mixture of E(Ac/water, drying with magnesium sulfate and evaporation of the organic phase, the residue was purified by chromatography on silica gel (0-7590 1% ECHOAc/heptane), obtaining the desired product (3.9 g, 6090).

TN NMR (SOSIZ) 5 1.0-1.6 (gl, 12Н), 2.65 (а, 9-4Hz, 1Н), 3.4-3.9 (t, 2Н), 3.80 (8 . 1H), 7.25, 7.40 (24, 9-7.5Hz, 4H). -1 Intermediate 2: 4-(4-fluoro-3-methoxyphenyl)(1-piperazinyl)methyl/)-M,M-diisopropylbenzamide.

Intermediate 1 (3.9g, 11mmol) was dissolved in dry dichloromethane (50ml) and treated with 5OVHg" (0.8v8ml, 11mmol) and at 0 to 259C for 30 minutes. Neutralization of KNSO y) (water) and drying (K»SO)) of the organic phase

F was accompanied by evaporation of the solvent in a vacuum. The residue and EM (1.8ml, 1µmmol) were dissolved in Mesm (50ml) 5p and stirred with Bos-piperazine (2.1g, 1mmol) at 25927 for 12 hours. Concentration in vacuo and chromatography on silica gel (0 to 50950-EOAc in heptane) gave 4.bg. 1.6 g were treated with TR in CH 5Si" (1:71),

Kz was concentrated in vacuo, extracted with CHClCl/K.CO) (aq), dried (K.CO)) and evaporated in vacuo to give Intermediate 2 (1.3g, 8195 from Intermediate 1).

MC (ER) 428.21 (MN).

Example 1: 4-(1-(4-Benzyl-piperazin-1-yl)-1-(4-fluoro-3-hydroxy-phenyl)-methyl-M,M-diisopropyl-benzamide.

Intermediate 2 (0.41g, 0.9bmmol) and triethylamine (0.20ml, 1.4mmol) were dissolved in MesmM (10ml). Benzybromide (0.14 mL, 1.1 mmol) was added with stirring at 2520. After 12 hours, the solution was concentrated and purified by reverse-phase chromatography (GiISpgorger KR-18.10-8096 MesmM in water, 0.195 TEA). 0.53 g of the free base was obtained after extraction with CH 5SiI2/K»CO,) (aq.), drying (K»CO);) and evaporation in a vacuum. Treatment with boron tribromide (4 eq., 1M solution in SNHC) in SNHC at -782C, addition of water, concentration in vacuo and reverse-phase chromatography gave Example 1 as trifluoroacetate (0.35g, 5090).

MS (ER) 504.22 (MN).

IR (mass) 3222, 1677, 1592, 1454, 1346, 1201, 1135 (cm).

TN NMR (СО350О0) 5-11, 1.5 (t, 12Н), 2.3 (t, ЗН), 2.9-3.8 (t, 7Н), 4.33 (в, 2Н),4 .75 (v, 1 H), 6.60 (t, 654 N), 6.83 (t, 1 H), 6.94 (t, 1 H), 7.24 (a, 9-8Gu, 2H ), 7.47 (t, 7H).

Analysis calculated for С34НзвЕМ3О2ох0.8САНоРвО4С: 59.87, Н: 5.82, M: 6.12.

C: 60.06, H: 5.83, M: 6.19 were found.

Example 2: 4-1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophen-3-ylmethyl-pipeoazin-1-yl)-methyl|-M,M-diisopropylbenzamide.

Intermediate 2 (0.43 g, 1.0 mmol) was dissolved in ME (5 mL) with 3-thiophene-carboxaldehyde (0.11 mL, 1.2 mmol) and

HOAc (57 μL, 1.0 mmol) and stirred for 1 hour. Sodium cyanoborohydride (bZmg, 1.0 mmol) was added in portions over b hours and the reaction mixture was stirred at 25 oC for another 12 hours before concentration in vacuo and extraction (dichloromethane/k 2CO3z (aq))). Purification by reversed-phase 70 chromatography as in Example 1 gave 0.32 g (0.62 mmol) as the free base. Treatment with boron tribromide as in Example 1 and chromatography gave Example 2 (0.20 g, 26905) as trifluoroacetate.

MS (ER) 510.17 (MN).

IR (mass) 3281, 1674, 1606, 1454, 1346, 1200, 1135 (cm").

ТН NMR (СО5О0) 5-1.1, 1.5 (t, 12Н), 2.30 (t, 2Н), 2.9-3.7 (t, ТОН), 4.37 (в, 2Н) , 4.75 (v, 1H), 6.60 79 (t, 1H), 6.84 (t, 1H), 6.94 (t, 1H), 7.18 (t, 1H), 7.25 , 7.48 (2.4, 9-8.0 Hz, 4H), 7.55 (t, 1H), 7.65 (t, 1H).

Analysis calculated for СооНзвЕМ2О»зх0.8 САНоРеОдххО.5 Н2О, С:55.16, Н:5.55, M:5.99,

It was revealed, C:55.12, H:B5.39, M:6.07.

Example 3: 4-11-(4-fluoro-3-hydroxy-phenyl)-1-I(4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl|I-methyl)-M, M- action of isopropyl-benzamide.

Using the same method as in Example 2, reaction with 2-imidazole-carboxaldehyde (0.10g, 1.1mmol) followed by treatment with boron tribromide (eq.) gave Example C (0.18g, 2595) as trifluoroacetate.

MS (ER) 494.23 (MN.yu).

IR (MaSII) 3123, 1673, 1592, 1454, 1350, 1201, 1135 (cm'1). high school

TNMR (CO35O0) 5-1.1,1.5 (t, 12H), 2.7-3.8 (t, TON), 3.95 (in, 2H), 5.20 (t, 1H ), 6.70 (t, 1H), 6.94 (t, 1H), 7.02 (t, 1H), 7.32, 7.58 (249, 9U-8.0HZ, 4H), 7, 46 (in, 1H). io)

Analysis calculated for СовНзвЕМ5О»х1.2 САНоЕвОдх0.7 НоО, С: 50.51, Н: 5.14, М: 8.98.

Found, C:50,44, H:B,18, M:9,11.

Scheme 2: Preparation of anilines; Examples 4-6 slk shi che pre no a V tkA ote M o de pen « shine - SHY o no

ZNO ermuiznyuttit an Me. Intermediate 3: 4-(Hydroxy(3-nitrophenyl)methyl|)|-M,M-diisopropylbenzamide. -1 50 Method as for intermediate 1, but after adding n-Vyg and the solution was cannulated into a solution of 3-nitrobenzaldehyde (2.7g, 1mmol) in toluene/tetrahydrofuran (approximately 1:1,100ml) at -782C. Workup and chromatography gave o) intermediate C (2.4g, 3790). "YAN NMR (SOSIz) 5 1.1-1.7 (t, 12), 3.90 (y, 9-3.5Hz, 1H), 3.4-3.9 (t, 2H), 5, 91 (v, 9-3.5Hz, 1H), 7.27, 7.35 (24, 2-8Hz, 4H), 7.51 (t, 1H), 7.71 (t, 1H), 8, 13 (t, 1H), 8.30 (v, 1H). 99 Intermediate 4: M,M-diisopropyl-4-((3-nitrophenyl)(1-piperazinyl)methylIbenzamide gF) Using the same method as for intermediate 2, intermediate C (2.4g, 6b,/mmol) gave Bos-protected intermediate 4 (2.83g, 8195).TPA treatment quantitatively gave intermediate 4,

MS (ER) 425.23 (MN.yu).

Example 4: 4-(1-(3-Amino-Phenyl)-1-(4-benzyl-piperazin-1-yl)-methyl-M,M-diisopropyl-benzamide. 60 Reaction 7 (0.40g, 0, 94mmol) with benzibromide as in Example 1 followed by digestion (H »5, 4000 psi) with 1095 Ra/C (5Omg) in EUN (25ml) and 2H NOI (1.2ml, 2.4mmol) for 2 hours. Purification by reversed-phase chromatography using the same conditions as in Example 1 gave Example 4 (0.20g, 30905) as trifluoroacetate.

MC (ER) 485.40 (MN). b5 IR (MasSi) 3414, 1673, 1605, 1455, 1345, 1201, 1134 (cm"). "H NMR (СО3О0) 5-1,1,1,5 (t, 12Н), 2,3 (t, 2H),

2.9-3.8 (t, 8H), 4.31 (8, 2H), 4.47 (in, 1H), 7.02 (t, 1H), 7.21-7.52 (t, 12H).

Analysis calculated for C34NaoMlOx1.2 САНоРвОдх0О.5 НоО, С:56.04, Н:5.70, M-7.30.

C:56.06, H:5.67, M1:7.41 were found.

Example 5: 4-(1-(3-Amino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,M-diisopropyl-benzamide.

The reaction of intermediate 4 (0.40 g, 0.94 mmol) with 3-thiophene-carboxaldehyde, as in Example 2, was followed by hydrogenation (No, 30 psm) with 1095 Ra/C (5 Ωg) in EUN (25 mL) and 2H NS (1.Oml, 2.0 mmol) for 12 hours. Purification by reversed-phase chromatography using the same conditions as in Example 1 gave Example 5 (0.13g, 2095) as ditrifluoroacetate. 70 MS (ER) 491.28 (MN).

IR (Mass) 3408, 1673,1605, 1455, 1345, 1201,1134 (cm"). "YAN NMR (СО3500) 5-1.1, 1.5 (t, 12Н), 2.3 (t, 2Н ), 2.9-3.8 (t, 8H), 4.35 (v, 2H), 4.44 (v, 1H), 6.98 (t, 1H), 7.16-7.32 ( t, 6H), 7.49 (a, U-8Gu, 2H), 7.55 (t, 1H), 7.64 (t, 1H).

Analysis calculated for SooNzvaM.O5Zx1.3 S.NoReOdhO,6 HO, C:51.48, H:5.28, M:7.02. 19 Found, C:51.51, H:B5.20, M:7.01.

Example 6: 4-11-(3-Amino-phenyl)-1-(4-[1H-imidazol-2-ylmethyl)-piperazin-1-yl|-methyl)-N,M-diisopropyl-benzamide.

Using the same procedure as in Example 2, reaction of intermediate 4 with 2-imidazolecarboxaldehyde (0.10g, 1.1mmol) followed by hydrogenation gave Example 6 (45mg, 795) as ditrifluoroacetate

MC (ER) 475.30 (MN).

IR (2x TEA, Mass) 3351, 1674, 1621, 1455, 1349, 1202, 1134 (cm").

TN NMR (2xTEA, SOZOO) 5-1.1, 1.5 (t, 12H), 2.9-3.8 (t, 8H), 4.35 (in, 2H), 4.44 (in, 1H), 6.98 (t, 1H), 7.16-7.32 (t, 6H), 7.49 (a, 9-Hz, 2H), 7.55 (t, 1H), 7.64 (t, 1H).

Analysis calculated for SovNzvaMeOx1.6 S. NoRvOdkh0O.8 HO, C: 48.39, H: 5.05, M: 9.84. high school

It was found that C:48.43, H:B5.06, M1:9.85.

Scheme 3: Preparation of methylsulfonanilides; Examples 7-8 o); "А, | Е" ee pyulobiy A SA (А о, 2 pos. aleraznn

And 2 l-vo, TNE (375) would ASM, TEA se is that A, | . r a I and - ak c. in. that Kv KO, that

OK

AHA, and - . 4-furan-2-carboxaldehyde

Odessa mon nam vnatavyunth gnatas, yun, 205, ri e | "

Ai n

HO az 70 no von M. Vodn; no) from Example CO that Example 8 Са 1" in su

Intermediate 5: M,M-diisopropyl-4-3-Nmethylsulfonyl)amino|phenyl 1-piperazinyl)methyl|benzamide.

Intermediate C gave Bos-protected Intermediate 4 as described for Intermediate 4 above. Vos-protected Intermediate 4 (1.21 g, 2.3 mmol) was hydrogenated with hydrogen at 30 psi with 1095 Ra/C (15 Ωg) in ASON (25 mL) for 12 h. Evaporation in a vacuum and extraction with CH»SiI»/K»SO, (aq.) gave 1.1 g (2.3 mmol) of intermediate aniline, which was dissolved in MeCM/CH Si» (1:1.10 ml). EBM (0.48 ml, 3.4 mmol), then methanesulfonyl hydride (0.41 g,

Me, 2.4 mmol) was added at 09C. After heating to room temperature, the reaction mixture was treated for 20 hours by extraction with CH3SO4/brine. Purification by chromatography on silica gel (0-595 Meon/CH»osSi») gave

Vos-protected Intermediate 5 (1.3g, 9790). The processing of ТРА in SNoСИ" quantitatively gave Intermediate 5. about MC (ER) 473.16 (MN).

Example 7:

M,M-Diisopropyl-4-(1-(3-methanesulfonylamino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl|-benzamide. 52 Method of reductive amination as in example 2 Intermediate 5 (0.20g, 0.4Zmmol) gave Example 7 (9Omg, 2695)

HF) as ditrifluoroacetate. The dihydrochloride was obtained after extraction of the free base (CH 2SiO/K»CO) (aq.) and treatment with 2 equiv. NSI (water). about MC (ER) 569.21 (MN).

IR (free base, Mass) 1604, 1455, 1340, 1151 (cm". bo TN YAMERE (free base, SOSIz) 5-0.9-1.7 (t, 12Н), 2.5 (t, 8Н) , 2.85 (8, ЗН), 3.55 (8, 2Н), 3.8 (t, 2Н), 4.22 (в, 1Н), 7.00-7.40 (t, 12Н).

Analysis calculated for SzoNlaoMaO352x2.6 NOSI, C:54.30, N:b,47, M:8.44.

Found, C:54.33, H:6.20, M:8.32. 65 Example 8: 4-(4-13-furylmethyl)-1-piperazinyl(3-(methylsulfonyl)amino|phenyl)-M,M-diisopropyl-benzamide.

Using the same method as for Intermediate 7, Intermediate 5 (0.21g, 0.45mmol) gave Example 8 (8Omg,

32905) as a free base.

MS (ER) 553.23 (MN.yu).

IR (free base, Mass) 1604, 1455, 1340, 1151 (cm".

TN YAMERE (free base, SOSI3) 5-1.0-2.6 (t, 20 N), 2.91 (v, ZN), 3.40 (v, 2H), 4.22 (85, 1 N ), 6.39 (in, 1

H), 7.06-7.42 (t, 11H).

Analysis calculated for SzoNloMaO4Zx2.8 NOSI, C:55.03, 11:6:59, M:8.56.

Found, C:54.93, H:B5.93, M:8.49.

Scheme 4: Obtaining examples 9-11 then I R

KA, OO, (in preposition cho

Maya! Ge 29 I applied Fr

Example 9: 4-(3-aminophenyl((4-(3-thienylmethyl)-1-piperazinyl|methyl)-M,M-diethylbenzamide.

M,M-diethyl-4-((3-nitrophenyl)(1-piperazinyl)umethyl|Ibenzamide (obtained analogously to intermediate (4) in Scheme 2) (0.85g, 2.1mmol) was dissolved in Meon (5ml) with C -thiophenecarboxaldehyde (0.4OmL, 4.3mmol) and MeOHAs (bomCl, 1.0mmol) and stirred for 1 hour. Sodium cyanoborohydride (135mg, 2.1mmol) was added portionwise over 6 hours and the reaction mixture was stirred at 2592 12 h before working up by concentration in vacuo and extraction (dichloromethane/k 25СбО3 (aq)).Purification by chromatography on silica gel gave F

Z-thienylmethyl derivative (0.45g, 4390). Hydrogenation of the product (0.30g, 0.bimole) and reverse phase chromatography afforded the title compound (0.17g, 3595) as tris-trifluoroacetate. M

MC (ER) 463.34 (MN).

IR (Mass) 3418, 1673, 1600, 1461, 1200, 1135 (cm"). 3.11 (t, 2H), 3.24-3.66 (t, 10 hours), 4.47 (in, 2H), 4.62 (8, 1H), 7.21 (t, 1H), 7.31 (p, 1H), 7.39-7.56 (t, 5H), 7.61-7.68 (t, ЗН), 7.77 (t, 1H). "

Example 10: 4-(3-aminophenyl)(4-benzyl-1-piperazinyl)methyl)-M,M-diethylbenzamide. -sh c N,N-diethyl-4-((3-Nitrophenyl)(1-piperazinyl)umethylbenzamide (1.77, 4.33mmol) and triethylamine (1.2ml, 8.bmmol) were dissolved in MesmM (10ml). Benzybromide (0.5 bml, 4.7 mmol) was added with stirring at 25 290. )» After 12 hours, the solution was concentrated in vacuo. Extraction (dichloromethane/k 52CO3 (aq)) and purification by silica gel chromatography gave the benzylated product (1.4g, 2.9mmol). Hydrogenation (hydrogen, 40 psig) with 1095 Pa/sC (100 mg) in EOH (25 mL) and 2H HCl (2.5 mL, 5 mmol) for 4 h, then concentration in vacuo and reverse-phase chromatography gave title compound as tris-trifluoroacetate (0.9g, 26905). -1 MC (ER) 457.26 (MN).

IR (Mass)) 3422, 1672, 1603, 1458, 1209, 1133 (cm).

Me. ТН NMR (СО3О0) 5-1.1,1.2 (t, 6Н), 2.3 (t, 2Н), 2.9-3.6 (t, ТОН), 4.33 (в, 2Н) , 4.49 (in, 1H), 5.48 (z, -I 20 2NU, 7.01 (t, 1H), 7.24-7.34 (t, 5H), 7.47 (t, 5H ), 7.52 (a, 9-7.5 Hz, 2H).

Example 11: 4-((4-benzyl-1-piperazinyl)/3-(methylsulfonyl)amino|phenyl)dimethyl)-M,M-diethylbenzamide. The product from Example 10 (0.35 g, 0.1 mmol) and triethylamine (0.12 ml, 0.84 mmol) were dissolved in MesmM (1 ml) and methanesulfonic anhydride (0.14 g, 0.04 mmol) was added at 09C. After stirring for 10 minutes at 25°C, the solution was concentrated in vacuo and purified by reverse phase chromatography to give the title compound as 59 bis-trifluoroacetate (0.23g, 40905). gF) MS (ER) 535.21 (MN). d) IR (mass) 3479, 1673, 1604, 1458, 1337, 1200, 1150 (cm"). "YAN NMR (СО3О0) 5-1.18, 1.31 (t, 6Н), 2.41 (t , 2H), 2.98 (in, 3H), 3.13 (t, 2H), 3.28-3.65 (t, 8H), 4.44 vo (8, 2H), 4.57 (in , 1H), 5.57 (9, 9-2Hz, 2H), 7.15 (t, 1H), 7.30 (t, 1H), 7.37 (t, 1H), 7.42 (t, 2H), 7.54-7.60 (t, 6H), 7.63 (t, 2H).

Pharmaceutical compositions

The novel compounds of the present invention can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly, and by injection into joints.

The preferred route of administration is oral, intravenous or intramuscular.

The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient and other factors that the doctor usually takes into account when determining the individual regimen and dose level that is most acceptable for a particular patient.

To obtain pharmaceutical compositions from the compounds of the present invention, "inert, pharmaceutically acceptable carriers can be solid or liquid. Solid forms of preparations include powders, tablets, granules capable of dispersion, capsules, wafers, and suppositories.

The solid carrier may be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binding agents, or tablet disintegrants; it can also be capsule material.

In powders, the carrier is a highly dispersed solid material, which is mixed with a highly dispersed active component, in tablets, the active component is mixed with a carrier that has the necessary binding properties, in a suitable proportion and compressed to the desired size and shape.

To obtain a suppository composition, a low-melting wax, such as a mixture of glycerides of fatty acids and cocoa butter/5, 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 convenient size and allowed 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.

Salts include, but are not limited to, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable boles within the scope of the present invention include: acetate, benzenesulfonate, benzoate, bicarbonate, hydrotartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edsylate, estolate, hesylate, fumarate, glucoptate, gluconate, glutamate, glycoliarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, sodium phosphate /diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide, benzathine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum salts, io) calcium, lithium, magnesium, potassium, sodium and zinc.

Examples of pharmaceutically unacceptable salts within the framework of the present invention include: hydroiodide, perchlorate and tetrafluoroborate. Pharmaceutically unacceptable salts can be used due to their superior physical and/or chemical properties, such as crystallinity.

Preferred pharmaceutically acceptable salts are hydrochlorides, sulfates, and hydrotartrates. Hydrochlorides and sulfates are particularly preferred. "at

The term composition includes the formulation of an active ingredient with an encapsulating material as a carrier, providing a capsule in which the active ingredient (with or without other carriers) is a carrier that is thus in combination therewith. Similarly, wafers are included. uh-

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

Liquid forms of compositions include solutions, suspensions and emulsions. Sterile aqueous or aqueous propylene glycol solutions of the active compounds may be mentioned as examples of liquid preparations suitable for parenteral administration. Liquid compositions can also be formed in solution in a water-polyethylene glycol solution.

Aqueous solutions for oral use can be prepared by dissolving the active ingredient in water and adding suitable coloring agents, flavoring agents, stabilizers and thickeners as needed. Aqueous suspensions for oral use can be prepared by dispersing the highly dispersed active ingredient in water 45 together with a viscous material such as natural synthetic gums, resins, methylcellulose, -I sodium carboxymethylcellulose and other suspending agents known in the art of pharmaceutical compositions.

Sh- Predominantly pharmaceutical compositions are in single dosage form. In this form, the composition is divided into

He" unit doses containing acceptable amounts of the active component. A single dosage form can be a 50-pack drug, the package contains discrete amounts of drugs, for example, packaged tablets, capsules, and powders in glasses or ampoules. The unit dosage form may also be a capsule, wafer, or

With the tablet itself or with it may be an acceptable number of any of these packaged forms.

Biological assessment

IP miigo model. 55 Cell culture

A. Human 2935 cells expressing cloned human M-, 5-, and K-receptors and resistance to o neomycin were grown in suspension at 372C and 5965 CO" in shake flasks containing calcium-free medium OMEM1095 ЕВ5 (germ serum calves), 595 VS5, 0.195 Rishopis E-68, and bO0Omkg/ml geneticin.

B. Mice and rat brains were weighed and washed in ice-cold PBS (containing 2.5 mM EOTA, pH 7.4). 60 brains were homogenized with a polytron for 15 s (mice) or 30 s (rats) in ice-cold lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EOTA, with phenylmethylsulfonyl fluoride added immediately before use to 00.5 M mM with 00.5 M stock solution in mixtures of DMSO ethanol).

Obtaining membranes

Cells were pelleted and resuspended in lysis buffer (50mM Tris, pH7.0, 2.5mM EOTA, with RMB5BE added 65 immediately before use to 0.1mM of 0.1M stock solution in ethanol), incubated on ice for minutes, homogenized with a polytron during ZOs. The suspension was centrifuged at 1000 g (max) for 10 minutes at 42C. The supernatant was kept on ice and the pellet was resuspended and centrifuged as before. Supernatants from both centrifugations were combined and centrifuged at 46000 g (max) for 30 minutes. Granules were resuspended in cold Tris buffer (50 mM Tris/Cl, pH7.0) and centrifuged again. The final granules were resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH7.0). Aliquots (Iml) in polypropylene tubes were frozen in a mixture of dry ice/ethanol and stored at -709C until use.

Protein concentration was determined by a modified Lowry assay with sodium dodecyl sulfate.

Binding assays

Membranes were thawed at 372C, cooled on ice, passed three times through a 25-gauge needle, and diluted 70 with binding buffer (50 mM Tris, 3 mM MOSi 5, Tmg/ml B5A (bovine serum albumin) (Zidta

A-7888), pH7 4, which was stored at 42C after filtration through a 0.22m filter, and to which 5μg/ml aprotinin, 10μM bestatin, 10μM diprotin A, without OTT was added immediately before use). Aliquots of 100 μl were added to ice-cooled 12x75 mm polypropylene tubes containing 100 μl of an acceptable radioligand and 100 μl of the tested compound at various concentrations. Total (33) and nonspecific (NS) binding was determined 72 in the absence and presence of 10 μM naloxone, respectively. The tubes were shaken and incubated at 252C for 60-75 minutes, after which the contents were quickly filtered under vacuum and washed with approximately 12ml/tube of ice-cold wash buffer (50MM Tris, pH7.0, 3mM MCl) through CP/V filters (UUPaiytap) pre-impregnated for at least 2 hours in 0.195 polyethyleneimine. The radioactivity (art) remaining on the filters was measured with a beta counter after impregnation of the filters for at least 12 hours in mini beakers containing 7 ml of scintillation liquid. If the assay is performed in 96-well deep plates, filtration is performed on 96-well REI-impregnated unifilters that were washed with 3 x 1 ml of wash buffer and dried in an oven at 552 for 2 hours. Filter plates were counted with a TorSoishpi (Raskaga) counter after adding 5 Ωcl

MO-20 scintillation liquid/cell. rya Functional analyzes see

Agonistic activity of compounds is measured by determining the degree to which the compound-receptor complex activates (C binding of STR with (z-proteins to which receptors are attached). In the STR binding assay, ZTPM5 is combined with test compound 5. and cell membranes NEK-2935, expressing cloned human opioid receptors or from homogenized rat and mouse brains. Agonists stimulate the binding of STRIA in these membranes. The s zo ECvo and Eudco values of the compounds are determined by dose-response curves. Right shifts of the dose-response curve delta- antagonist naltrinadol is performed to test whether the agonistic activity is mediated by delta receptors. c.

The procedure for the brain of rats STR "o

Rat brain membranes are thawed at 372C, passed three times through a 25-gauge needle with a blunt end and diluted in binding buffer (50mM Hepes, 20mM Mmaon, 100mM Masi, mM EOTA, 5mM Masi), -

With RN, add fresh: to them OTT, 0.195 VZA (cow's serum albumin)). 120 μM of the final SOR is added by M dilutions of the membranes. Values of EKso and Emax of the compounds are estimated by 10-point dose-response curves obtained in ZbOmkl with an acceptable amount of membrane protein (2O0μg/cell) and 100,000-130,000 drt TRU per cell (0.11-0.14nM). The main and maximum stimulated binding are determined in the absence and presence of ZmkM ZMO-80

The results of the analysis - c Specific binding (C3) was calculated as 33-HC, and the NW in the presence of various test compounds was expressed as a percentage of the control NW. The values of ICso and the Hill coefficient (n) for ligands when replacing a specifically bound radioligand were calculated according to the plan of logit transformation or curve fitting programs, as

Idapa, SgarpRaa Rgizt, ZidtaRioi, or Keserioggii. Values K; were calculated using the Cheng-Prusoff equation.

The values - the standard error of the values of ICeo, K and p, were presented for the tested ligands in at least three substitution curves, the biological activity of the compounds of the presented invention is shown in table 2. c.

F t z

Studies of receptor saturation

The values of the K5 radioligand were determined by carrying out binding analyzes on cell membranes with acceptable radioligands at a concentration ranging from 0.2 to 5 times the estimated Kb (up to 10 times if the amount of the required radioligand is real). The specific binding of the radioligand was expressed in μmol/mg membrane protein. име) The values of Ke and Vauxsz from separate experiments were obtained by nonlinear fitting of the specifically bound (3) against

NM of free (B) radioligands from individual according to the single-site model. 60 Determination of mechano-allodynia using Von Frey testing

Testing was carried out between 08:00 and 16:00 using the | method described Spariap ei ai. (1994).

Rats were placed in Plexiglas cages on top of a wire mesh bottom that allowed access to the paw and allowed to habituate for 10–15 min. The testing area was the middle of the sole of the left hind paw, excluding the less sensitive paw pads. The paws were touched with von Frey series 8 villi of logarithmically 65 increasing stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Zioeiipo, NO , OZA).

Von Frey villi were applied from under the mesh floor perpendicular to the sole surface with sufficient force to cause a weak kicking motion relative to the paw, and held for approximately 6-8s. A positive reaction was noted if the paw was quickly withdrawn. Shivering immediately after hair removal was also considered a positive reaction. Displacement was regarded as a questionable response, and in such cases the stimulation was repeated.

Test protocol

Animals were tested on postoperative day 1 for the ESA-treated group. 50905 withdrawal threshold was determined using Dixon's up-down method (1980). Testing began with villi of 2.04 g, in the middle of the series.

Stimuli were always presented sequentially, ascending or descending. In the absence of withdrawal of the paw and reaction to the initially selected hairs, stronger stimulation was used; in the case of withdrawal of the paw, then weaker stimulation was applied. The optimal calculation of the threshold by this method requires 6 reactions in the immediate vicinity of the 5095 threshold, and the calculation of these reactions would start when the first reaction change occurred, for example, the threshold was first crossed. In cases where the thresholds fell out of the limits of stimulation, values of 15.14 (normal sensitivity) or 0.41 (maximum allodynic) were set accordingly. The formed picture of positive and negative reactions was tabulated using marks, there is no X-crossing; 7/5 Og-break-off, and 5095 threshold of break-off were interpolated using the formula: 5096 H-THRESHOLD-TOSKvUT0.000 where Chi-value of the last used Von Frey villi (logarithmic units); K-table value

Ivid Spariap ei ai. (1994)3| for a picture of positive/negative reactions; and 5-value of the difference between stimulations (log units). Here it is 5-:0.224.

Von Frey's thresholds were converted into percentages of the maximum possible action (96 MMD) According to Spariap eg! oh 19941.

The following equation was used to calculate 96 MMDs: "mmd- Threshold for processing and treatment) - threshold for allodynia (gay Po)

Control threshold (g) - apodinia threshold (gu

Application of the test substance p

Rats were injected (subcutaneously, intraperitoneally, intravenously or orally) with the test substance before the von Frey test, the time between the application of the test compound and the von Frey test being varied depending on the nature of the test compound.

Writting's test

Acetic acid will induce abdominal contractions when administered intraperitoneally in mice. with

This will further extend to their body in a typical painting. When analgesics are used, this described movement is observed less often and the drug is chosen as a potential good candidate. -

The complete and typical Writting reflex is considered only when the following elements are present: the animal does not move; Ge) the lower part of the back is weakly depressed; aspect of the soles of both paws is prominent. In this assay, compounds of the present invention demonstrate significant inhibition of Writting reactions following oral dosing of 1-100 μmol/kg. i- () Obtaining solutions

Acetic acid (AcOH): 120 μl of acetic acid is added to 19.88 ml of distilled water to obtain a final volume of 20 ml with a final concentration of 0.695 AsOH. The solution is then mixed (by shaking) and prepared for injection. "

Compound(s): Each compound is prepared and dissolved in the most suitable vehicle by standard methods. w c (i) Application of solutions

The compound(s) are administered orally, intraperitoneally (ip), subcutaneously (ps) or intravenously (iv) at )" 1 bml/kg (taking into account the average body weight of mice) in 20, 30 or 40 minutes (according to the class of the compound and its characteristics) before testing. When the compound is administered centrally: intraventricularly (iv) or intrathecally (it), a volume of 5 μl is used. - and AsoOnH are used intraperitoneally (i.p.) in two stages at 1 Oml/kg (taking into account the average body weight of mice) immediately before testing.

She(s) Testing b Animals (mice) are observed for 20 minutes and the number of cases (Writting reflex) is recorded and compiled at the end of the experiment. Mice are kept in separate cages with contact bedding. A total of 4 mice are usually observed at the same time: one control and three with a dose of drugs. with For indications of anxiety and similar anxiety, the effectiveness is established in the conflict test

Heller-Seifter on rats.

For the indication of a functional gastrointestinal disorder, the effectiveness can be established by the analysis (described by Soshipro ZM ei a), in Ategisap docsgpaI oi RNuzioiyudu - Savigoipievipa! 8 And imeg Rnuzioiodu. o 282(2):0307-16,2002 Rabi, on rats. at

Claims (1)

The formula of the invention 1. Compound of formula b5 o WHAT) 2. , with t | pooe rt | IS | in. - nya 2 i t C 70 VI : where B is selected from any substituent from the group: (I) phenyl (ii) pyridinyl Y A TM. c (ii) thienyl o 78 (im) furanyl c: gu t gai (Se) (m) imidazolyl i- NN, is . h- yes m. (mi) triazolyl « НН, e - - s u m--І i» o, (mii) pyrrolyl z i -i "M H - pn (mii) thiazolyl (2) 8, - 50 i MI g" () pyridyl-M-oxide . selected from CE3, methyl, iodine, bromine, fluorine and chlorine, B2 independently selected from ethyl and isopropyl; BZ independently selected from hydrogen and fluorine; and E? independently selected from hydrogen, -SEz and S.-Svalkylu, because either its salts or its individual enantiomers and their salts. 2. Compound according to claim 1, where in! represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; 2 represents ethyl or isopropyl; VZ represents hydrogen or fluorine; B" represents -МН" or -МНгоОоВ; and B? represents S.-Svalkil. Q. The compound according to claim 1, where in! represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; b2 represents ethyl or 9-isopropyl; 3 represents hydrogen; Ge represents -MHZO»V?; and B5 represents S.-Svalkil. 4. The compound according to claim 1, where the heteroaromatic rings are substituted by CE with, methyl, iodine, bromine, fluorine or chlorine. 5. The compound according to claim 1, where the heteroaromatic rings are substituted with methyl. 6. The compound according to claim 1, selected from the group: 4-(1-(4-benzylpiperazin-1-yl)-1-(4-fluoro-3-hydroxyphenyl)-methyl-N,M-diisopropylbenzamide; 4- (1-(4-fluoro-3-hydroxyphenyl)-1-(4-thiophen-3-ylmethylpiperazin-1-yl)-methyl|-M,M-diisopropylbenzamide; 411-(4-fluoro-3-hydroxyphenyl)- 1-I(4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl|I-methyl)-M,M-diisopropylbenzamide; 4-(1-(3-aminophenyl)-1-(4-benzylpiperazine) -1-yl)-methyl/|-M,M-diisopropylbenzamide; 4-(11-(3-aminophenyl)-1-(4-thiophen-3-ylmethylpiperazin-1-yl)-methyl/|-M,M -diisopropylbenzamide; 4-11-(3-aminophenyl)-1-I4-"1H-imidazol-2-ylmethyl)-piperazin-1-yl|-methyl)-M,M-diisopropylbenzamide; M,M-diisopropyl-4 -(1-(3-methanesulfonylaminophenyl)-1-(4-thiophen-3-ylmethylpiperazin-1-yl)-methyl|-benzamide; 4-(4-(3-furylmethyl)-1-piperazinyl|x/3- Cmethylsulfonyl)amino|phenyl)-M,M-diisopropylbenzamide; 4-(3-aminophenyl)(4-(3-thienylmethyl)-1-piperazinyl|methyl)-M,M-diethylbenzamide; 4-(3-aminophenyl)( 4-benzyl-1-piperazinyl)methyl|-N,M-diethylbenzamide and 4-((4-benzyl-1-piperazinyl)(3-(methylsul (phenyl)amino|phenylmethyl)-M,M-diethylbenzamide. 7. The compound according to any of the previous items in the form of its hydrochloride, dihydrochloride, sulfate, tartrate, ditrifluoroacetate or citrate. 8. The method of obtaining the compound of the formula I, where B" represents -OH, which includes the reaction of the compound of the general formula II with (I) with eE2 i ez i i Abel iks Ne - where B? and KZ are determined according to claim 1, and K7 represents OMe, with Bos-piperazine in acetonitrile in the presence of |se) triethylamine under standard conditions, and then removal of the Bos-protecting group under standard conditions, with their obtaining compounds of the formula PI Go; (I) - in: I z i A -oi M no i» -m H which is further alkylated under reducing conditions with a compound of the formula VK 1-CHO, and then cleavage of the methyl ether using BVgz in dichloromethane to obtain a compound of the formula II, where B represents - ON. -I 9. The method of obtaining the compound of the formula I, where 7 represents -MH", which includes the reaction of the compound of the general formula IM with M - and I: i ez nya Iz nin still schu g it it Ve o de B? and KZ are determined according to claim 1, and EC? represents MO o, with Bos-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Bos-protecting group under standard conditions, to give the compound of formula U 60 b5 (c) (M) 2 years . with t: | Shk i 9 shk» dru y y "Mo, c y I which is further alkylated under reducing conditions with a compound of the formula E !-CHO, and then reduction of the nitro group using hydrogen and palladium on activated carbon to obtain a compound of the formula I, where is EK? represents -MH". 10, The method of obtaining the compound of formula I, where КВ 7 represents -МНЗО 285, which includes the reaction of the compound of the general formula MI (c) ; (M) and A . . . with | . in nya rei She lev Ve de V? and KZ are defined according to claim 1, and BK" represents MO", with Bos-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by reduction of the nitro group by hydrogenation using palladium on activated carbon as a catalyst, methanesulfonylation using methanesulfonyl anhydride. o); dichloromethane in the presence of triethylamine, and then removal of the Vos-protecting group under standard conditions, with the obtaining of the compound of the formula МИЙ о ; MI) sch zo ge A ., with Sho y | She shk | - te) regen ny in she -mMnNIOsSN in 7 with compound I and "which is further alkylated under reducing conditions with a compound of the formula E!-CHO, and then reduction of the nitro group using hydrogen and palladium on activated carbon to obtain a compound of the formula I, where ВЕ? represents no c - МНЗО»VU. у» 11. A compound according to any of claims 1-7 for use in therapy. 12. Use of the compound of formula I according to claim 1 for the production of a medication for use in the treatment of pain, anxiety, and functional gastrointestinal disorders. 13. A pharmaceutical composition containing a compound of formula I according to claim 1 as an active ingredient together with a pharmacologically and pharmaceutically acceptable carrier. -I 14. A method of treating pain, wherein a subject in need of pain therapy is administered an effective amount of a compound of the formula | according to claim 1. Me, 15. A method of treating functional gastrointestinal disorders, in which an effective amount of the compound of formula I according to claim 1 is administered to a subject suffering from -I 20 of the specified functional gastrointestinal disorder according to claim 1. d" Official Bulletin " Industrial property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 1, 15.01.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) name) 60 b5