4-piperazinyl-(8-quinolinyl)-methyl)-benzamides, pharmaceutical composition and method for pain treatment

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

 

The invention relates to new compounds, to a method of production thereof, their use and pharmaceutical compositions containing these new compounds. These new compounds are useful in therapy, in particular for the treatment of pain.

Prior art

δ-Receptor identified as a receptor that plays a role in many body functions, such as cardiovascular and lymphatic and pain systems. Therefore, ligands for δ-receptor can find potential use as analgesics and/or anti-hypertensive agents. It is also shown that ligands for δ-receptor possess immunomodulatory activity.

Identify at least three different groups of opioid receptors (μ, δ and κ) now clearly established, and it is obvious that all three are located in both Central and peripheral nervous systems of many species, including humans. The analgesia observed in various animal models when the activation of one or more than one of these receptors.

With rare exception, currently available selective δ-opioid ligands are peptidic in nature and are not suitable for injection through a system of paths. One of the examples of peptide δ-agonist SNC80 is (E.J. Bilsky et al., Journal of Pharmacology and Experimentl Therapeutics, 273 (1), pp.359-366 (1995)). However, there is still a need for selective δ-agonists, possessing not only high selectivity, but also improved side effect profile.

Thus, the problem underlying the present invention was to search for new analgesics with improved analgesic effects, but also with an improved side effect profile compared to today μ-agonists, as well as with improved system efficiency.

Analgesics, which have been identified and are available in the prior art have many disadvantages, namely that they have poor pharmacokinetics and not have analgesic actions for introduction through a system of paths. Also documented that the preferred connection δagonists described in this prior art, have a strong convulsive effects upon systemic administration.

The inventors have now discovered that some compounds are not specifically disclosed, but included within the scope of WO 98/28270, show unexpectedly superior δ-agonistic properties and efficacy in vivo relative to the compounds disclosed in WO 98/28270, with the systemic administration. Compounds of the present invention demonstrate a significant and unexpectedly on yennie levels agonism in relation to the Delta receptor and metabolic stability.

Summary of the invention

The new compounds of the present invention are defined by formula 1

where

R1selected from the

(1) phenyl;

(2) pyridinyl

(3) thiophenyl

(4) furanyl

(5) imidazolyl

(6) triazolyl

where each phenyl ring of R1and heteroaromatic ring R1it may be possible, and independently optionally substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6of alkyl, NO2, CF3C1-C6alkoxy, chloro, fluorescent, bromo and iodide. Substitution on the phenyl ring and heteroaromatic ring may be in any position on these ring systems.

In the scope of the present invention also includes pharmaceutically acceptable salts of compounds of formula I, as well as their isomers.

In the preferred embodiment of this invention the compounds of formula 1 are in the form of (+)-enantiomer or in the form of (-)-enantiomer.

Under "isomers" the authors of this invention include compounds of formula I which differ in the position of their functional groups and/or orientation. Under "orientation," the authors of izaberete the Oia mean stereoisomers, diastereoisomer, regioisomers and enantiomers.

The new compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain, and so forth. This list, however, should not be interpreted as exhaustive.

Compounds of the present invention are useful as immunomodulators, especially in autoimmune diseases, such as arthritis, skin grafts, transplants of organs and similar surgical needs, when collagenoses, various allergies, for use as antitumor agents, and antiviral agents.

Compounds of the present invention are useful in disease States in which there is degeneration or dysfunction of opioid receptors, either degeneration or dysfunction of opioid receptors involved in the process. In diagnostic techniques and applications related to imaging, such as positron emission tomography (PET), may be also involved the use of labeled isotopes are variants of the compounds of the present invention.

Compounds of the present invention are useful for the treatment of diarrhea, depr the hurt, anxiety, urinary incontinence, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, spinal cord injury and addiction to the excessive use of drugs, including the treatment of abuse of alcohol, nicotine, opioids and other drugs, as well as to treat disorders of the sympathetic nervous system, such as hypertension.

Compounds of the present invention are useful as an analgesic agent for use during General anesthesia and controlled adjustments of anesthesia. Combinations of agents with different properties are often used to balance the effects required to maintain the state of anesthesia (e.g., amnesia, analgesia, muscle relaxation and sedation). In this combination enabled inhalation anesthetics, sleeping pills, anxiolytics, neuromuscular blockers and opioids.

In the scope of the present invention also includes the use of any of the compounds of formula I, above, for the production of drugs for the treatment of any of the conditions discussed above.

Another aspect of the present invention is a method of treatment of a subject suffering from any of the conditions discussed above, whereby a patient in need of such treatment is administered an effective quantity the quantity of compounds of formula I, above. Also in the scope of the present invention include any new intermediate connection, as described in the Diagram below, I, useful in the synthesis of compounds of formula I, above.

Ways to get

Compounds of the present invention can be obtained by following any of the methods described in Schemes I, II, III and IV. These known methods described in J. March, Advanced Organic Chemistry, 4thEdition, John Wiley and sons (1992); Katritsky, A.R., Lan, X. Chem. Soc. Rev., pp.363-373 (1994), which are included in this description by reference.

SCHEME I

P=protective group, such as Bn, Boc, CBz

M=Li, Mg, Zn

X=Br, I

L=Cl, Br, OMs, OTs, I

R1=as defined in formula (I)above.

SCHEME II

P=protective group, such as Bn, Boc, CBz

M=Li, Mg, Zn

X=Br, I

L=Cl, Br, OMs, OTs, I

R1=as defined in formula (I)above.

SCHEME III

P=protective group, such as Bn, Boc, CBz

M=Li, Mg, Zn

X=Br, I

L=Cl, Br, OMs, OTs, I

R1=as defined in formula (I)above.

SCHEME IV

P=protective group, such as Bn, Boc, CBz

M=Li, Mg, Zn

X=Br, I

L=Cl, Br, OMs, OTs, I

R1=as defined in formula (I)above.

Examples

Hereinafter the invention will be described in more detail with OSU the following examples, which should not be construed as limiting the invention.

Example 1

Getting 4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 2)

Compound 2, specified in the header, received, following the methodology of synthesis Scheme 1, below.

Scheme 1

(1) preparation of N,N-diethyl-4-formylbenzoate (compound I)

4-Formylbenzoate acid (11.2 g, 74,6 mmol) and triethylamine (10.4 ml, 75 mmol) was dissolved in tetrahydrofuran (THF) (100 ml) and cooled to -10°C. was Added ISO-butylchloroformate (10.3 ml, 78 mmol), and stirring was continued for 10 minutes at -10°C, after which was added diethylamine (9.7 ml, 94 mmol)and the solution was left to warm to achieve 25°C. After concentration, water treatment and chromatography on silica gel (0-100% EUAs in heptane) received a total of 7.4 g (50%) of compound I.

(2) Obtaining N,N-diethyl-4-[hydroxy(8-chinoline)methyl]benzamide (compound II)

8-Bromohydrin (3.0 g, 14.4 mmol) was dissolved in anhydrous THF (150 ml) and cooled to -78°C in nitrogen atmosphere. Was added dropwise sec-utility (emop-BuLi) (11,1 ml, 1.3 M in pentane, 14.4 mmol) over 5 minutes (Preparation and reactions with 8-lithioquinoline: Suggs, J. Org. Chem. 1980, 45, 1514). After another 5 min was added N,N-diethyl-4-formylbenzoate (3.5 g, 17,0 mmol)dissolved in THF (5 ml). This solution paramesh the Wali for 1 h, then added NH4Cl (aqueous). After concentration, water treatment and chromatography on silica gel (0-100% EtOAc in heptane) received a total of 3.5 g (70%) of compound (II).

MS: 334, 262, 234, 215, 204, 178, 156, 129.

An alternative way of obtaining the compound (II) of N,N-diethyl-4-jogesuido (compound IV)

Compound IV (0,67 g, 2.2 mmol) was dissolved in dry THF (25 ml) and cooled to -78°C in nitrogen atmosphere. Was added dropwise n-BuLi (1.3 ml, 1.6 M in hexane, 2.2 mmol) for 5 min after 10 min was added 8-formylphenol (0.17 g, 1.1 mmol) (8 formylphenol received from 8-methylinosine by oxidation with selenium dioxide at 150-155°C for 12 h (Kingsbury, J. Med. Chem. 1993, 3308)), dissolved in THF (1 ml). This solution was stirred for 1 h, then was added NH4Cl (aqueous). After concentration, water treatment and chromatography on silica gel (0-100% EtOAc in heptane) received a total of 0.29 g (78%) of compound (II).

(3) Obtaining 4-[chloro(8-chinoline)methyl]-N,N-diethylbenzamide (compound III).

Compound II (2.0 g, 6.6 mmol) was dissolved in anhydrous CH2Cl2(25 ml) was added SOCl2(of 0.53 ml, 7,3 mmol). This solution was stirred at 25°C for 30 min, and the solvent evaporated in vacuum. Compound III was obtained as oil (-100%) and used in the next reaction without further purification.

MS: 348, 333, 233, 215, 204, 156.

(4) to Obtain N,N-diethyl-4-[1-Pieper is sinil(8-chinoline)methyl]benzamide (compound 1).

The crude product compound III (˜6.6 mmol) and piperazine (2.3 g, 26 mmol) was dissolved in anhydrous MeCN (50 ml) and was heated under reflux for 12 hours the Solvent was removed in vacuo, the residue was dissolved in CH2Cl2and washed with water, and the organic phase was dried (K2CO3) and evaporated in vacuo. After chromatography on silica gel (0-20% Meon in CH2Cl2, 1% NH4OH) has received a total of 1.8 g (68%, stage 2) connection 1. Further purification can be achieved by reverse-phase chromatography (LiChroprep RP-18, 10-50% MeCN in water, 0.1% of TFU) to obtain 1.2 g of colorless product. Salt is the dihydrochloride was obtained by treatment with 2 EQ. HCl in ether.

TPL:180-90°C.

IR (KBr, νmax) 3297, 2982, 2716, 2474, 1611, 1434, 1380, 1288, 1098 cm1.

MS (Amin): 402, 318, 246, 217, 109.

1H NMR (Amin, CDCl3): δ 1.2, 1.1 (2s, 6H), 2.94, 2.51 (2m, 8H), 3.5-3.1 (m, 5H), 6.05 (s, 1H), 8.94-7.20 (m, 10H).

Analysis (C25H30N4Ox3,2 CF3CO2N), N; N: calculated 4,36; found 3,90.

(5) Obtaining 4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 2, specified in the header).

Connection 1 (1.3 g, 3.2 mmol) and triethylamine (of 0.90 ml, 6.4 mmol) was dissolved in MeCN (10 ml). Benzylbromide (of 0.77 ml, 6.4 mmol) was added under stirring at 25°C. After 4 h the solution was concentrated and purified by chromatography on forces is the Kagel (0-5% Meon in CH 2Cl2) or by reverse-phase chromatography (LiChroprep RP-18, 20-80% MeCN in water, 0.1% of TFU). Total received 2.2 g (72%) of compound 2, is specified in the header.

By treatment with 2 EQ. HCl (aqueous) and lyophilization got dihydrochloride salt (3.6 g).

IR (HCI 2, KBr): 2388, 1606, 1434, 1356, 1287 cm-1.

1H NMR (free amine, CDCl3): δ=1.05 (m, 6H), 2.5 (m, 8H), 3.1-3.6 (m, 6H), 6.04 (s, 1H), 7.18-8.98 (m, 15H).

Analysis (C32H38Cl2N4O) C, H, N. an Alternative method of obtaining compounds 2, indicated in the header of the compound III

The crude product compound III (˜13,2 mmol), triethylamine (2.0 ml, 14.5 mmol) and N-benzyl-piperazine (2.6 g, 14.5 mmol) was dissolved in anhydrous MeCN (50 ml) and was heated under reflux for 12 hours was Added an additional amount of N-benzyl-piperazine (0.5 g, 2.8 mmol) and heating was continued for 12 h the Solvent was removed in vacuo, the residue was dissolved in CH2Cl2and washed with water; and the organic phase was dried (K2CO3) and evaporated in vacuo. After chromatography on silica gel (0-10% Meon in CH2Cl2total received 3.5 g (53%) of compound 2, is specified in the header.

Examples 2 and 3

Separation of the enantiomers of compound 2 (compound 3 and 4)

Preparative separation of this compound was carried out on a column Chiralcel OD (50 mm × 50 cm)using a mixture of hexa is/EtOH/diethylamine in the ratio of 85:15:0.1 V as mobile phase. Found that on a column Chiralcel OD (+)-isomer eluted first.

Example 2 (-)4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide (compound 3)

[α]D25: -130° (0,78, Meon)

1H NMR: (CD3OD): δ=1.05 (m, 6H), 3.0-3.6 (m, 14H), 5.90 (s, 1H), 7.22-8.20 (m, 13H), 8.78 (m, 1H), 9.50 (m, 1H).

ANALYSIS: Calculated mass of 3.1 H2O: 61.85; H: 7.17, N: 9.02. Detected With: 61.84, H: 6.60, N: 8.89.

Example 3

(+)4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide (compound 4)

[α]D25: +130° (c 0,69, MeOH)

1H NMR: (CD3OD): δ=1.05 (m, 6N), 3.0-3.6 (m, 14H), 5.90 (s, 1H), 7.22-8.20 (m, 13H), 8.78 (m, 1H), 9.50 (m, 1H).

ANALYSIS: Calculated mass of 3.2 H2O: 61.67, H: 7.18, N: 8.99. Detected With: 61.70; H: 6.46, N: 8.84.

Example 4

Obtaining N,N-diethyl-4-[[4-(4-methylbenzyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 5)

Connection 5 specified in the header, obtained by following the procedure of synthesis Scheme 2, below.

Scheme 2

To a solution of compound 1 (0,80 g, 1,99 mmol) in CH2Cl2(20 ml) was added Et3N (0,83 ml, 5,97 mmol), then the pair-methylbenzylamine (773 mg, 4,18 mmol). This reaction mixture was stirred overnight, and then concentrated under reduced pressure. Purification by reverse-phase chromatography using 10%-30% of CH3CN/N2O.

(M+1) calculated: 507,70,(M+1) observed: 507,20.

IR (NaCl, the free amine) 2969, 2807, 2360, 1628, 1455, 1425, 1286, 1134, 1095 (cm-1).

1H NMR: (CDCl3free amine): δ=1.0, 1.1 (2m, 6H, amide-Me), 2.31 (s, 3H, Ar-Me), 2.5 (m, 8H, piperazine-H), 3.2, 3.5 (2m, amide-CH2), 3.49 (s, 2H, ArCH2N), 6.03 (s, 1H, Ar2CH), 7.06-7.68 (m, 11H, Ar-H), 8.01-8.12 (m, 2H, Ar-H), 8.93 (m, 1H, Ar-H).

Analysis (C32H38Cl2N4O) C, H, N.

Examples 5 and 6

Separation of the enantiomers of compound 5 with the formation of compounds 6 and 7

Preparative separation of this compound was carried out on prepreparation column Chiralcel AD (21 mm × 25 cm)using a mixture of hexane/EtOH/diethylamine in the ratio of 80:20:0.1 V as mobile phase. Found that on a column Chiralcel AD (-)-isomer eluted first.

Example 5

(-)4-[(4-methylbenzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide (compound 6)

[α]D25: -131o(c and 1.0, MeOH)

Example 6

(+)4-[(4-methylbenzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide (compound 7)

[α]D25: +124o(c 1,4, Meon)

Example 7

Getting 4-[{4-[4-(tert-butyl)benzyl]-1-piperazinil}(8-chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 8)

Using a technique similar to the method for obtaining compounds 2, received 8 connection specified in the header. Alkylation was carried out by 4-tert-butylbenzylamine.

(MS) (ES): 549,53 (MH+).

And The (NaCl, the free amine) 2963, 2807, 2360, 1631, 1456, 1425, 1285, 1135, 1094, 1001 (cm-1).

1H NMR; (CDCl3free amine): δ=1.0, 1.2 (2m, 6H), 1.29 (s, 9H), 2.50 (m, 8H), 3.2, 3.5 (2m), 3.50 (s, 2H), 6.04 (s, 1H), 7.16-7.68 (m, 11H), 7.98-8.10 (m, 2H), 8.92 (m, 1H).

Analysis (C36H46Cl2N4O) C, H, N.

Example 8

Obtaining N,N-diethyl-4-[[4-(4-nitrobenzyl)1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 9)

Using a technique similar to the method for obtaining compounds 2, described above, has received the connection 9, is specified in the header. Alkylation was carried out by 4-nitrobenzylamine.

(MS) (ES): 538,04 (MH+).

IR (NaCl, the free amine) 2969, 2809, 2360, 1626, 1518, 1456, 1426, 1343, 1286, 1134, 1095, 1001 (cm-1).

1H NMR: (CDCl3free amine): δ=1.0, 1.2 (2m, 6H), 2.50 (m, 8H), 3.2, 3.5 (2m), 3.60 (s, 2H), 6.05 (s, 1H), 7.18-8.16 (m, 13H), 8.94 (m, 1H).

Analysis (C32H37Cl2N5O3) C, H, N.

Example 9

Getting 4-[{4-[2,4-bis(trifluoromethyl)benzyl]1-1-piperazinil}(8-chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 10)

Connection 10

Following a technique similar to the method for obtaining compounds 2, described above, has received the connection 10, is specified in the header. Alkylation was carried out by 2,4-bis(trifluoromethyl)benzylbromide.

(MS) (ES): 629,08 (MH+).

IR (NaCl, the free amine) 2970, 2811, 2360, 1628, 1456, 142, 1346, 1275, 1170, 1128 (cm-1).

1H NMR: (CDCl3free amine): δ=1.0, 1.2 (2m, 6H), 2.48 (m, 8H), 3.2, 3.5 (2m), 3.71 (s, 2H), 6.06 (s, 1H), 7.20-8.14 (m, 12H), 8.95 (m, 1H).

Analysis (C34H36Cl2F6N4O) C, H, N.

Example 10

Obtaining N,N-diethyl-4-[[4-(4-methoxybenzyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 11)

Using a technique similar to the method for obtaining compounds 2, described above, has received the connection 11, specified in the header. Alkylation was carried out by 4-methoxybenzylamine.

(MS) (ES): 523,45 (MH+).

IR (NaCl, the free amine) 2966, 2806, 2360, 1627, 1510, 1456, 1426, 1286,1246, 1134, 1095 (cm-1).

1H NMR: (CDCl3free amine): δ=1.0, 1.2 (2m, 6H), 2.48 (m, 8H), 3.2, 3.5 (2m), 3.47 (s, 2H), 3.78 (s, 3H), 6.03 (s, 1H), 6.80-7.68 (m, 11H), 8.01-8.12 (m, 2H), 8.93 (m, 1H).

Analysis (C33H40Cl2N4O2) C, H, N.

Example 11

Getting 4-[[4-(2,4-dichlorobenzyl)-1-piperazinil](8-chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 12)

Following a technique similar to the method for obtaining compounds 2, described above, has received the connection 12, is indicated in the header. Alkylation was carried out by 2,4-dichlorobenzamide.

(MS) (ES): 562,45 (MH+).

IR (NaCl, the free amine) 2968, 2810, 2360, 2341, 1627, 1470, 1426, 1285, 1134, 1095 (cm-1).

1H NMR: (CDCl3free the amine): δ =1.0, 1.1 (2m, 6H), 2.5 (m, 8H), 3.2, 3.5 (2m), 3.58 (s, 2H), 6.05 (s, 1H), 7.14-7.70 (m, 10H), 8.06 (m, 2H), 8.94 (m, 1H).

Analysis (C32H36Cl4N4O) C, H, N.

Example 12

Obtaining N,N-diethyl-4-[[4-(2-pyridinylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 13)

Compound 1 (80 mg, 0.20 mmol) was dissolved in Meon (2 ml) with 2-pyridylcarboxylic (39 μl, 0.40 mmol) and the SPLA (1 ál, 0.02 mmol). Added cyanoborohydride sodium (26 mg, 0.40 mmol), and stirring was continued for 48 hours, the Solvent evaporated and the residue was purified by chromatography on silica gel (0-10% Meon in CH2Cl2). Got 38 mg (39%) of product.

(MC)(ES):494,19(MH+).

IR (NaCl, the free amine) 2968, 2809, 2360, 1626, 1455, 1428, 1286. 1134, 1094, 1001 (cm-1).

1H NMR: (CDCl3free amine): δ=1.0, 1.2 (2m, 6H), 2.50 (m, 8H), 3.2, 3.5 (2m), 3.69 (s, 2H), 6.05 (s, 1H), 7.12-7.70 (m, 10H), 8.08 (m, 2H), 8.54 (m, 1H),8.94(m, 1H).

Analysis (C31H37Cl2N5O) C, H, N.

Example 13

Obtaining N,N-diethyl-4-[[4-(3-thienylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 14)

The connection 14 specified in the header, received, following the methodology of synthesis Scheme 3, below.

Scheme 3

To a solution of compound 1 (500 mg, 0,99 mmol) in methanol (10 ml) was added thiophene-3-carboxaldehyde (104 μl, 1,19 mmol)and then acetic acid (0.1 ml, 1%) is cyanoborohydride sodium (186,6 mg, of 2.97 mmol). This reaction mixture was stirred overnight, then was added 2 n sodium hydroxide and the mixture was extracted with methylene chloride (3x). United methylenechloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography using 10%-30% of CH3CN/N2On (TFU as a buffer), received 258 mg of the desired product (salt TFU).

Purification by HPLC: >99% (215 nm); >95% (254 nm)

(M+1) calculated: 499,25, (M+1) observed: 499,46.

Analysis: calculated for (C30H34N4OS × 2.802HO2F3× 1.80 H2O):: 50,28%; N: 4,79%; N: 6,59%; A: 15,80%; S: OF 3.77%; F: 18,77%. Found: C: 50,28%; N: A 4.83%; N: 6,53%.

1H NMR: 8.95 (dd, 1H, J=4.4, 2.0 Hz), 8.38 (dd, 1H, J=8.0, 2.0 Hz), 8.00 (dd, 1H, J=7.2, 1.6 Hz), 7.84 (dd, 1H, J=8.0, 1.6 Hz), 7.52-7.62 (m, 5H), 7.45 (dd, 1H, J=4.8, 2.8 Hz), 7.20 (dd, 2H, J=8.8, 2.2 Hz), 7.11 (dd, 1H, J=4.8, 1.6 Hz), 5.96 (s, 1H), 4.27 (s, 2H), 3.34-3.44 (m, 2H), 3.22-3.28 (m, 4H), 3.04-3.14 (m, 2H), 2.66-2.88 (m, 4H), 1.04-1.14 (m, 3H), 0.88-0.98 (m, 3H).

Example 14

Obtaining N,N-diethyl-4-[[4-(2-furylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 15)

The connection 15, is specified in the header, received, following the methodology of synthesis Scheme 4, below.

Scheme 4

To a solution of furfuryl alcohol (0,19 ml, 2,24 mmol) and triethylamine (of 0.52 ml, 3.73 mmol) in methylene chloride (4 ml) is 0° With added methanesulfonamide (0.17 ml, 2,24 mmol). This mixture was stirred for 1 h at 0°With, then added compound 1 (300 mg, 0.75 mmol). This reaction mixture was left to warm to room temperature and was stirred overnight, then heated to 45°and was stirred for 1.5 hours. This reaction mixture was left to cool to room temperature and was added 2 n NaOH until the pH was not alkaline. This mixture was extracted with methylene chloride (3x). United methylenechloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography using 10%-25% of CH3CN/H2On (TFU as a buffer), received 197 mg of the desired product (salt TFU).

Purification by HPLC: >99% (215 nm, 254 nm and 280 nm)

(M+1) calculated: 483,63, (M+1) observed: 483,30.

1H NMR: 8.89 (dd, 1H, J=4.4, 1.6 Hz), 8.29 (dd, 1H, J=8.0, 1.6 Hz), 7.97 (dd, 1H, J=7.2, 1.6 Hz), 7.79 (d, 1H, J=7.2 Hz), 7.61 (d, 2H, J=8.0 Hz), 7.52-7.58 (m, 2H), 7.48 (dd, 1H, J=8.0, 4.4 Hz), 7.19 (d, 2H, J=8.0 Hz), 6.56 (d, 1H, J=3.2 Hz), 6.40 (dd, 1H, J=3.2, 2.4 Hz), 6.02 (s, 1H), 4.26 (s, 2H), 3.34-3.44 (m, 2H), 3.16-3.26 (m, 4H), 3.04-3.14 (m, 2H), 2.68-2.86 (m, 4H), 1.06-1.14 (m, 3H), 0.90-0.98 (m, 3H).

Example 15

Obtaining N,N-diethyl-4-[[4-(3-furylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 16)

The connection 16 that is specified in the header, obtained by following the procedure of synthesis Scheme 5, bringing the military below.

Scheme 5

To a solution of 3-furanmethanol (220 mg, 2,24 mmol) and triethylamine (of 0.52 ml, 3.73 mmol) in methylene chloride (4 ml) at 0°With added methanesulfonamide (0.17 ml, 2,24 mmol). This mixture was stirred for 1 h at 0°With, then added compound 1 (300 mg, 0.75 mmol). This reaction mixture was left to warm to room temperature and was stirred overnight, then heated to 45°and was stirred for 3.5 hours. This reaction mixture was left to cool to room temperature and was added 2 n NaOH until the pH was not alkaline. This mixture was extracted with methylene chloride (3x). United methylenechloride extracts were dried over HO2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography using 10%-25% of CH3CN/N2On (TFU as a buffer), received 293 mg of the desired product (salt TFU).

Purification by HPLC: >98% (215 nm and 280 nm); >99% (254 nm).

(M+1) calculated: 483,63, (M+1) observed: 483,34.

Analysis: calculated for (C30H34N4About2× 3.102HO2F3× 1.70 H20):: 50,17%; N: 4,71%; N: 6,46%; A: 18,27%; F: 20,39%. Found: C: 50,14%; N: 4,76%; N, 6.38 Per Cent.

1H NMR: 8.93 (dd, 1H, J=4.4, 2.0 Hz), 8.36 (dd, 1H, J=8.6, 2.0 Hz), 8.00 (dd, 1H, J=7.4, 1.2 Hz), 7.82 (dd, 1H, J=7.6, 1.2 Hz), 7.48-7.66 (m, 6H), 7.19 (d, 2H, J=8.0 Hz), 6.46 (s, 1H), 5.9 (s, 1H), 4.13 (s, 2H), 3.32-3.44 (m, 2H), 3.20-3.28 (m, 4H), 3.04-3.14 (m, 2H), 2.66-2.86 (m, 4H), 1.04-1.14 (m, 3H), 0.88-0.98 (m, 3H).

Example 16

Obtaining N,N-diethyl-4-[[4-(2-thienylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 17)

Connection 17 that is specified in the header, received, following the methodology of synthesis Scheme 6, below.

Scheme 6

To a solution of compound 1 (0,99 mmol) in methylene chloride (10 ml) was added 2-thiophenecarboxaldehyde (190 μl, to 1.98 mmol)and then acetic acid (0.1 ml, 1%). This mixture was stirred for 30 minutes, then added triacetoxyborohydride sodium (0,63 g of 2.97 mmol)and this reaction mixture was stirred over night. This reaction mixture was neutralized with 2 n sodium hydroxide and extracted with methylene chloride (3x). United methylenechloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography using 10%-30% CH3CN/H2O (TFU as a buffer), received 115 mg of the desired product (salt TFU).

Purification by HPLC; >99% (215 nm); >96% (254 nm).

(M+1) calculated: 499,25, (M+1) observed: 499,33.

Analysis: calculated for (C30H34N4OS × 2.502HO2F3× 0.10 H2O):: 53,51%; N: 4,71%; N: 7,13%; A: 12,42%; S: 4,08%; F: 18,14%. Found: C: 53,49%; N: 4,63%; N: ,49%.

1H NMR: 8.91 (dd, 1H, J=4.0, 1.6 Hz), 8.30 (dd, 1H, J=8.8, 1.6 Hz), 7.96 (dd, 1H, J=7.4, 1.4 Hz), 7.81 (d, 1H, J=7.2 Hz), 7.62 (d, 2H, J=8.0 Hz), 7.46-7.58 (m, 3H), 7.20 (d, 2H, J=8.0 Hz), 7.14-7.22 (m, 1H), 7.00 (dd, 1H, J=5.2, 3.6 Hz), 6.03 (s, 1H), 4.38 (s, 2H), 3.34-3.44 (m, 2H), 3.14-3.22 (m, 4H), 3.06-3.12 (m, 2H), 2.74-2.88 (m, 4H), 1.04-1.14 (m, 3H), 0.88-0.98 (m, 3H).

Example 17

Obtaining N,N-diethyl-4-[[4-(2-imidazolidinyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 18)

The connection 18, is listed in the header, received, following the methodology of synthesis Scheme 7, below.

Scheme 7

To a solution of compound 1 (0,99 mmol) in methanol (10 ml) was added 2-imidazolecarboxaldehyde (114 mg, 1,19 mmol)and then acetic acid (0.5 ml, 5%). This mixture was stirred for 3 hours, then added cyanoborohydride sodium (186,6 mg of 2.97 mmol)and this reaction mixture was stirred over night. This reaction mixture was neutralized with 2 n sodium hydroxide and extracted with methylene chloride (3x). United methylenechloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography using 10%-30% CH3CN/H2O (TFU as a buffer), received salt TFU. The HCl salt was obtained using HCl/ether. Output: 60,3 mg of the desired product (HCl salt).

Purification by HPLC: >95% (215 nm); >93% (254 nm).

(M+1) calculated: 83,29, (M+1) observed: 483,19.

1H NMR: 9.12-9.22 (m, 1H), 8.54-at 8.62 (m, 1H), 8.08-8.16 (m, 1H), 7.98-8.04 (m, 1H), 7.60-7.86 (m, 4H), 7.38-7.46 (m, 2H), 7.22-7.32 (m, 2H), 6.32 (s, 1H), 4.11 (s, 2H), 2.94-3.40 (m, 12H), 0.88-1.12 (m, 6H).

Example 18

Obtaining N,N-diethyl-4-[[4-(4-imidazolidinyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 19)

Connection 19 specified in the header, obtained by following the procedure of the synthesis of Scheme 8, below.

Scheme 8

To a solution of 434 (400 mg, 0,99 mmol) and 4-imidazolecarboxaldehyde (95,5 mg, 0,99 mmol) in methylene chloride (10 ml) at room temperature was added acetic acid (0.1 ml). This mixture was stirred for 5 hours, then added triacetoxyborohydride sodium (632 mg, 2,98 mmol). This reaction mixture was stirred overnight and neutralized with 2 n sodium hydroxide. This mixture was extracted with methylene chloride (3x). United methylenechloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography, using 15% of CH3CN/H2On (TFU as a buffer), received 103 mg of the desired product (salt TFU).

Purification by HPLC: >99% (215 nm, 254 nm and 280 nm).

(M+1) calculated: 483,28, (M+1) observed: 482,96.

Analysis: calculated for (C29H34N6O × 3.802HO2F3�D7; 0.80 H2O):: 47,25%; N: 4,27%; N: 9.03 PER CENT; A: 16,17%; F: 23,28%. Found: C: 47,31%; N: 4,40%; N: 8,87%.

1H NMR: 8.99 (dd, 1H, J=4.4, 1.2 Hz), 8.76 (d, 1H, J=1.2 Hz), 8.39 (dd, 1H, J=8.8, 1.2 Hz), 7.93 (dd, 1H, J=7.2, 1.6 Hz), 7.86 (dd, 1H, J=8.0, 1.6 Hz), 7.71 (d, 2H, J=8.8 Hz), 7.60 (dd, 1H, J=8.8, 4.4 Hz), 7.56 (dd, 1H, J=8.0, 7.2 Hz), 7.40 (s, 1H), 7.27 (d, 2H, J=8.8 Hz), 6.12 (s, 1H), 3.74 (s, 2H), 3.38 (q, 2H, J=6.4 Hz), 3.10-3.25 (m, 6H), 3.06 (q, 2H, J=7.2 Hz), 2.75-2.90 (m, 2H), 1.08 (t, 3H, J=6.4 Hz), 0.92 (t, 3H, J=7.2 Hz).

Example 19

Obtaining N,N-diethyl-4-[[4-(3-triazolylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 20)

The connection 20 that is specified in the header, obtained by following the procedure of synthesis Scheme 9 below.

Scheme 9

To a solution of 434 (200 mg, 0.50 mmol) in dimethylformamide (10 ml) at room temperature was added potassium carbonate (275 mg, 1,99 mmol)and then N-formamido-2-(chloromethyl)acetamide (170 mg, 1,24 mmol). This reaction mixture was heated to 60°and was stirred for 2 hours, then the temperature was raised to 140°and was stirred for 3 hours. This reaction mixture was left to cool to room temperature and added water. This mixture was extracted with ethyl acetate (3x). United an ethyl acetate extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Using purification by reverse-phase chromatography, using 20% CH3CN/H2O (TFU in image quality is as buffer), received 21 mg of the desired product (salt TFU).

Purification by HPLC: >99% (215 nm, 254 nm and 280 nm).

(M+1) calculated: 484,28, (M+1) observed: 483,92.

Analysis: calculated for (C28H33N7About × 3.302HO2F3× 3.30 H2O):: 45,20%; N: 4,70%; N: 10.66 PERCENT; A: 18,97%; F: 20,46%. Found: C: 45,12%; N: 4,60%; N: 10,84.

1H NMR: 8.94 (dd, 1H, J=4.4, 1.6 Hz), 8.38 (s, 1H), 8.33 (dd, 1H, J=8.0, 1.2 Hz), 7.93 (d, 1H, J=7.2 Hz), 7.85 (d, 1H, J=7.2 Hz), 7.65 (d, 2H, J=8.8 Hz), 7.51-7.58 (m, 2H), 7.23 (d, 2H, J=8.8 Hz), 6.15 (s, 1H), 4.21 (s, 2H), 3.40-3.50 (m, 2H), 3.10-3.30 (m, 8H), 2.90-3.10 (m, 2H), 0.90-1.30 (m, 6H).

The pharmaceutical composition

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

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

The dosage will depend on the route of administration, severity of disease, age and weight of the patient, and other factors normally considered by the attending physician when determining an individual mode and dose level as the most appropriate for a particular patient.

For the manufacture of pharmaceutical compositions of the compounds according to this invention, inert, pharmaceutically acceptable carriers can be either solid or fluid is mi. Preparations in the form of solid dosage forms include powders, tablets, dispersible granules, capsules, starch capsules and suppositories.

A solid carrier can be one or more than one substance, which can also serve as diluents, corrigentov, solubilizing agents, lubricants, suspendida agents, bonding agents or loosening agents for tablets; it can also be an encapsulating material.

In powders, the carrier is a finely powdered solid substance that is mixed with finely ground active ingredient. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape desired size.

For preparation of compositions in the form of suppositories first melted low-melting wax such as a mixture of glycerides of fatty acids and cocoa butter, and dispersed therein an active ingredient, for example, by stirring. Then, this molten homogeneous mixture is poured into molds of suitable size and leave to cool and harden.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethyl cellulose, a low-melting in the IC, cocoa butter and the like.

Pharmaceutically acceptable salts are the acetate, bansilalpet, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, pamoate (embonate), Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannat, tartrate, teoclate, triethiodide, benzathine salt, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred pharmaceutically acceptable salts are hydrochloride and bitartrate. Salt hydrochloride are particularly preferred.

The term "composition" should include the preparation of the active ingredient with encapsulating material as a carrier, forming a capsule in which the active component (with other carriers or without them) is surrounded by carrier, which, thus, is in connection with him. In this way enabled starch capsules.

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

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

Aqueous solutions for oral administration can be produced by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers, and thickening agents as desired. Aqueous suspensions for oral administration can be produced by dispersing finely ground active component in water with viscous material, such as natural and synthetic resins, gums, methylcellulose, sodium carboxymethyl cellulose and other suspendresume agents known in the field of pharmaceutical preparations.

Preferably the pharmaceutical compositions are in a standard dosage form. In this form, the composition is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, the package contains discrete quantities of preparation is tov, for example packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form may be a capsule, a starch capsule or tablet itself, or it may be a suitable number of any of these packaged forms.

BIOLOGICAL ASSESSMENT

Model in vitro

Cell culture

The 293S cells expressing the cloned μ-, δ- and κreceptors of man and resistance to neomycin, were grown in suspension at 37°C and 5% CO2in katalozhnyh flasks containing free calcium modified Dulbecco Wednesday Needle (DMEM), 10% FBS, 5% BCS, 0.1% pluronic (Pluronic F-68 and 600 μg/ml of geneticin.

The preparation of membranes

Cells were besieged and resuspendable in the buffer for lysis (50 mm Tris, pH 7.0, 2.5 mm EDTA with phenylmethylsulfonyl (PMSF)added immediately prior to use up to 0.1 mm 0.1 M initial solution in ethanol), incubated on ice for 15 min, then homogenized using a transmitter station for 30 seconds. The suspension was centrifuged at 1000 g (max) for 10 min at 4°C. the Supernatant was kept on ice, and precipitation resuspendable and centrifuged as described above. Supernatant from both zentrifugenbau were combined and centrifuged at 46000 g (max) for 30 minutes Precipitation resuspendable cold Proc. of the s-buffer (50 mm Tris/Cl, pH 7.0) and centrifuged. The final precipitation resuspendable in the buffer to membranes (50 mm Tris, Of 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in a dry ice/ethanol and stored at -70°s to use. Protein concentration was determined by the modified analysis by Lowry with sodium dodecyl sulfate (SDS).

Analyses linking

The membrane was subjected to thawing at 37°C, cooled on ice, passed 3 times through a needle of the 25 size and was diluted in binding buffer (50 mm Tris, 3 mm MgCl21 mg/ml bovine serum albumin (BSA) (Sigma A-7888), pH 7.4, which was stored at 4°after filtration through a 0.22 m filter and to which was added a freshly prepared 5 mg/ml Aprotinin, 10 μm of bestatin, 10 μm diprolene And (without DTT). Aliquots of 100 µl (µ g protein, see Table 1) was added to a chilled on ice polypropylene tubes 12×75 mm containing 100 μl of each of the radioactive ligand (see Table 1) and 100 μl of the test peptides at various concentrations. Overall (OS) and nonspecific (NS) binding was determined in the absence and presence of 10 μm naloxone, respectively. The tubes were shaken and incubated at 25°for 60-75 min, and after this time the contents were rapidly filtered under vacuum and washed with approximately 12 ml/tube chilled on ice buffer dstmask (50 mm Tris, pH 7.0, 3 mm MgCl2through filters GF/B (Whatman), pre-soaked for at least 2 h in 0.1% polyethylenimine. Radioactivity (disintegrations per minute, dpm), remaining on the filters was measured using a beta counter after soaking the filters for at least 12 hours in mini-vials containing 6-7 ml of scintillation fluid. If the analysis were placed in 96-well tablets with deep wells, filtration was carried out through 96-well standard filters soaked in PEI, which was washed 3×1 ml buffer for washing and dried in an oven at 55°C for 2 h Filter plates were counted in a TopCount (Packard) after adding 50 μl of scintillation fluid MS-20 per well.

Data analysis

Specific binding (SS) was calculated as OS-NS and SS in the presence of various test peptides were expressed in percentage of control of the SS. The values of the IC50and hill coefficient (Hill) (nHfor ligand substitution specific bound radioactive ligand was calculated on the basis of the graphs in logarithmic scale or programs to draw the curve by points, such as Ligand, GraphPad Prism, SigmaPlot or ReceptorFit. Values of Kiwas calculated based on the equation of Cheng-Prussoff. Values are mean ± mean square error (RMSE) IC50Toiand nHpresented to testere the s ligands in at least three curves replacement. Biological data are presented below in Table 1.

14,16
Table 1.
Summary table of biological data.
Example No.HDELTAHDELTAThe RAT BRAINThe MOUSE BRAINMLMRLM
EC50% EMAXEC50% EMAXEC50% EMAX10000% rem.100000% rem.10000% rem.100000% rem.
120,6920,76and 97.7320,99106,4327,1491.34053,5566
131,033the 1.44101,1817,7111,9625,77112,681,66771,6671062,667
140,1810,7688,6514,26102,0220,49106,4804913,584,5
150,7870,7988,99108,8116,01109,850681086
161,5092,3999,3630,83100,524,298,410,546,59,564,5
171,0913,0395,6649,47105,9175,192,470a 21.55,575
181,545,8593,82452,31111,01429,56average 108.41
1918,75185,2497,882807,4756,351365,8248,68

Experiments on saturation of the receptor

Values Forδ radioactive ligands were determined by analyses on binding to cell membranes with the appropriate radioactive ligands at concentrations in the range from 0.2 to 5-fold from an estimated valueδ (up to 10-fold, if the necessary number of radio is active ligand is available). Specific binding of the radioactive ligand was expressed in pmol/mg of membrane protein. Values Forδ andmaxfrom individual experiments obtained on the basis of nonlinear mappings specific bound (SS) vs. nm free (C) radioactive ligand from the individual experiment according to the constitutive model.

DETERMINATION of the MECHANICAL ALLODYNIA USING TEST VON FREY

Testing was carried out between 08:00 and 16:00 h, using the method described by Chaplan et al. (1994). Rats were placed in Plexiglas cages on the upper surface of the bottom of the wire mesh, which provided access to the foot, and left for addiction 10-15 minutes the Test area was the middle of the sole of the left hind legs, avoiding less sensitive pads of the foot. The paw was affected by a series of 8 hairs Von Frey logarithmically incremental stiffness(0,41, 0,69, 1,20, 2,04, 3,63, 5,50, 8,51 and 15,14 g; Stoelting, III, USA). Hair Von Frey was applied from below the mesh floor perpendicular to the surface of the sole with sufficient force to cause slight bending against the legs, and held for about 6-8 seconds. A positive response was noted when the paw was sharply jerk away. Wince immediately after removal of the hair is also considered a positive response. The movement was considered uncertain answer, and in such cases timul repeated.

The TESTING PROTOCOL

Animals were tested on the 1st day after the operation for the group treated with FCA. 50%threshold otdergivanija was determined using the direct method of Dixon (1980). Testing started from 2.04 g of hair, in the middle of the series. Incentives always gave consistent manner, either ascending or descending. In the absence of a response in the form of otdergivanija paws on the source selected hair gave a stronger incentive; if otdergivanija paws were chosen following a weaker stimulus. To calculate the optimal threshold values this way, you need 6 responses in the immediate vicinity of the 50%threshold, and counting these 6 answers began when he appeared the first change of the response, that is, when the threshold is first crossed. In cases where the threshold value was outside the range of incentives, respectively, were established values 15,14 (normal sensitivity) or 0,41 (maximum allodynia). The resulting picture of positive and negative responses were made to the table using legend: X=no otdergivanija; O=OTDELENIE, and 50%threshold otdergivanija was interpolable, using the formula:

50% g threshold = 10(Xf+kδ)/10000

where Xf=the value of the last IP is risovannogo hairs Von Frey (logarithmic units); k= - valued (Chaplan et al. (1994)) for pictures of positive/negative responses; and δ=value of the difference between stimuli (logarithmic units). Here δ=0,224.

Threshold Von Frey translated into a percentage of the maximum possible response (% MBO) according Chaplan et al., 1994. For computing % MBO used the following equation:

% MBO=Threshold drug treatment (g) - threshold-allodynia (g) × 100

The control threshold (g) - threshold-allodynia (g)

The introduction of the TEST SUBSTANCE

Before testing for Von Frey rats were injected with (subcutaneously, intraperitoneally, intravenously or orally) the test substance, the time between the introduction of the test compounds and test Von Frey depended on the nature of the tested compounds.

The WRITHING TEST

Acetic acid when administered to mice intraperitoneally will cause contraction of the abdomen. Then their body would be a typical way to stretch. When injected painkillers, described the movement see less often, and this medication is chosen as a potential good candidate.

The Writhing reflex is considered complete and typical only when the following items are included: the animal is not in motion; lower back slightly lowered; visible plantar side of both legs.

(1) Preparation of solutions

Acetic who Isleta (Asón): 120 µl of acetic acid is added to a fall of 19.88 ml of distilled water to obtain a final volume of 20 ml at a final concentration of 0.6% of the Asón. Then this solution is stirred (to shake), and it is ready for injection.

Connection (medicine). Each connection and get dissolved in the most appropriate media according to standard methods.

(2) infusion

Compound (drug) administered orally, intraperitoneally (I.P. Pavlova.), subcutaneously (s.c.) or intravenously (i.v.) in the dose of 10 ml/kg (given an average body weight of mice) for 20, 30 or 40 minutes (respectively, the class of compound and its characteristics) before testing. When the connection takes Central: intraventricular (i.c.v.) or vnutriobolochechnoe (i.t), injected volume of 5 ál.

Asón injected intraperitoneally (I.P. Pavlova.) in two places in the dose of 10 ml/kg (given an average body weight of mice) directly before testing.

(3) Testing

Animal (mouse) is followed over a period of 20 minutes and at the end of the experiment celebrate and compile the number of cases (Writhing reflex). Mice kept in individual cages "Shoe box" with contact bedding. Usually see only 4 mice at the same time: one control and three doses of the medication.

Protocol for determination of GTP in the rat brain

Cell culture

A. the 293S Cells expressing the cloned κ-, δ- and μreceptors of human and resistant to neomycin, were grown in suspension at 37°C and 5% CO2in katalozhnyh flasks containing modi is yserowany Dulbecco Wednesday Needle (DMEM) without calcium, 10% of the fetal cow serum (FBS), 5% BCS, 0.1% pluronic F-68 and 600 μg/ml of geneticin.

B. the Brains of the rats were weighed and washed in ice-cold phosphate-saline buffer solution (PBS) containing 2.5 mm EDTA (ethylenediaminetetraacetic acid), pH 7.4). Brains homogenized using a Politron within 30 seconds (rats) in ice-cold buffer for lysis (50 mm Tris (Tris-(hydroxymethyl)-aminomethane), pH 7.0, 2.5 mm EDTA with 0.5 mm phenylmethylsulfonyl (PMSF), which is added immediately before use, preparing it from 0.5 M initial solution in a mixture of DMSO (dimethyl sulfoxide):ethanol).

Obtaining membranes

Cells were besieged by centrifugation and resuspendable in the buffer for lysis (50 mm Tris, pH 7.0, 2.5 mm EDTA with 0.1 mm PMSF, which is added immediately before use, preparing it from 0.1 M initial solution in ethanol), incubated on ice for 15 minutes, then homogenized using a Politron within 30 seconds. The suspension was centrifuged at 1000 g (max) for 10 minutes at 4°C. the Supernatant was kept on ice and precipitation resuspendable and centrifuged as described above. The supernatant from two zentrifugenbau combined and centrifuged at 46000 g (max) for 30 minutes. Precipitation resuspendable in cold Tris-buffer (50 mm Tris/Cl, pH 7.0) and centrifuged. The final precipitation resuspending the Ali in the buffer to membranes (50 mm Tris, of 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in a mixture of dry ice/ethanol and stored at -70°before applying. Protein concentration was determined using the modified analysis by Lowry with sodium dodecyl sulfate.

Tests on linking

Membranes were thawed at 37°C, cooled on ice, missed 3 times through a needle of the 25-th size and diluted in buffer for binding (50 mm Tris, 3 mm MgCl21 mg/ml bovine serum albumin (BSA) (Sigma A-7888), pH 7.4, which was stored at 4°after filtration through 0.22 μm filter and which before the experiment was added 5 μg/ml Aprotinin, 10 μm of bestatin, 10 μm diprolene A (diprotin A)without DTT (dithiothreitol). Aliquots of 100 µl was added to ice polypropylene tubes (12×75 mm)containing 100 μl of each radioligand and 100 μl of test compounds at various concentrations. Total (TV) and nonspecific (NS) binding was determined in the absence and presence of 10 μm naloxone, respectively. The tubes were shaken and incubated at 25°for 60-75 minutes, after which the contents were quickly filtered under vacuum and washed with chilled ice buffer for washing in an amount of about 12 ml/tube (50 mm Tris, pH 7.0, 3 mm MgCl2through GF/B filters (Whatman)pre-soaked for at least 2 hours in 0.1%is polyethylenimine. Radioactivity (disintegrations per minute)remaining on the filters was measured using the counter beta-particles after soaking the filters for at least 12 hours in mini-vials containing 6-7 ml of scintillation fluid. If the test was performed in 96-well tablets with deep wells, the filtering is performed via 96-well universal filters soaked in polyethylenimine, which was rinsed with buffer for washing (3×1 ml) and dried in a drying Cabinet at 55°C for 2 hours. The radioactivity of the filter-plates was measured with TopCount (Packard) after adding 50 μl per well of scintillation fluid MS-20.

Functional tests

Agonistic activity of the compounds is measured by determining the extent to which a complex receptor-connection activates the binding of GTP (GTP-independent) with G-proteins associated with the receptor. In the test for binding of GTP GTP[γ]35S combine with the tested compounds and membranes from cells HEK-293S, expressing the cloned opioid receptors of the man, or from homogenized brain of rats and mice. Agonists stimulate the binding of GTP[γ]35S in these membranes. Values EU50(the concentration at which an effect equal to 50% of maximum) and Emax(the maximum effect that can cause the connection is s) compounds determined from curves dose-response. Shifts curve to the right the dose-response Delta-antagonist with naltrindole (naltrindole) carried out to confirm that the agonistic activity mediated through δ-receptors. For functional tests with δ-receptors in human EC50(low) measured when δreceptors person used in the test, expressionlist at low levels compared with those used to determine the EU50(high). The values of Emaxdetermined relative to the standard δ-agonist SNC80, that is, a value above 100% is a compound which has a better efficiency than SNC80.

Procedure for GTP in the rat brain

Membranes of rat brain thawed at 37°passed 3 times through a needle with a blunt end 25-th size and diluted with buffer to bind GTPγS (50 mm N-2-hydroxyethylpiperazine-N'-2-econsultancy acid (Hepes), 20 mm NaOH, 100 mm NaCl, 1 mm EDTA, 5 mm MgCl2pH to 7.4, add fresh 1 mm DTT, 0.1% of BSA (dithiothreitol). In the end it solutions membranes add 120 µm guanozintrifosfata (GDP). EU50and Emaxcompounds evaluated according to 10-point curves dose-response is made in 300 μl with the appropriate amount of membrane protein (20 μg/well) and 100000-130000 the number of disintegrations per minute GTPγ35S per well (0,11-0,14 nm). Basal and maximal stimulated binding determined in the absence and in the presence of the tvii 3 μm SNC80.

Data analysis

Specific binding (SB) was calculated as TB-NS and SB in the presence of various test compounds was expressed as percentage of control SB. The values of the IC50and the hill coefficient (nHfor ligand substitution is specifically linked radioligand was calculated from the logit graphs or by using constructing a curve through points programs, such as Ligand, GraphPad Prism, SigmaPlot or ReceptorFit. Values (constants of inhibition) was calculated by the equation of Cheng-Prussoff. The average value of the ± standard error values IC50, Kiand nHpresents for ligands tested in at least three curves replacement.

Table 2.
The effectiveness of the preferred compounds of WO 9723466
WO 9723466EC50in the rat brain (nm)
Example 50445,50
Example 51Not defined
The connection 64Not defined
The connection 33520,7
The connection 34386,9
The connection 37423,3
The connection 41>30000
The connection 45492
Compound 38 247,6
The connection 42Not defined
The connection 51>90000
The connection 54357,04

Table 3. The effectiveness of the compounds according to the invention
Example No.StructureEC50in the rat brain [nm]
to 12.28
20,99
74,54
18,61
4,18

Example No.StructureEU50in the rat brain [nm]
81,96
10.31
30,83
17,70/td>
49,47

Example No.StructureEC50in the rat brain [nm]
14,26
14,16

1. 4-(Piperazinil(8-chinoline)methyl)benzamide formula I

where R1selected from the

(1) phenyl;

(2) pyridinyl

(3) thiophenyl

(4) furanyl

(5) imidazolyl

and

(6) triazolyl

where each phenyl ring may be optionally and independently substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6of alkyl, NO2, CF3C1-C6alkoxy, chloro, fluorescent, bromo and iodide; and their pharmaceutically acceptable salts and their isomers.

2. The compound according to claim 1, where possible(s) Deputy(s) on the aromatic or heteroaromatic Kohl is e(s) selected(s) any of the NO 2, isobutyl, CF3, methoxy, methyl or chlorine.

3. The compound according to claim 1 or 2, selected from any of the

4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 2);

N,N-diethyl-4-[[4-(4-methylbenzyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 5);

4-[{4-[4-(tert-butyl)benzyl]-1-piperazinil}(8-chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 8);

N,N-diethyl-4-[[4-(4-nitrobenzyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 9);

4-[{4-[2,4-bis(trifluoromethyl)benzyl]-1-piperazinil}(8-chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 10);

N,N-diethyl-4-[[4-(4-methoxybenzyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 11);

4-[[4-(2,4-dichlorobenzyl)-1-piperazinil](8-chinoline)methyl]-N,N-diethylbenzamide dihydrochloride (compound 12);

N,N-diethyl-4-[[4-(2-pyridinylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 13);

N,N-diethyl-4-[[4-(3-thienylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 14);

N,N-diethyl-4-[[4-(2-furylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 15);

N,N-diethyl-4-[[4-(3-furylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide (compound 16);

N,N-diethyl-4-[[4-(2-thienylmethyl)-1-PIP is retinyl](8-chinoline)methyl]benzamide dihydrochloride (compound 17);

N,N-diethyl-4-[[4-(2-imidazolidinyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 18);

N,N-diethyl-4-[[4-(4-imidazolidinyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 19) and

N,N-diethyl-4-[[4-(3-triazolylmethyl)-1-piperazinil](8-chinoline)methyl]benzamide dihydrochloride (compound 20).

4. The compound according to any one of claims 1 to 3, which is in the form of (+)-enantiomer.

5. The compound according to any one of claims 1 to 3, which is in the form of (-)-enantiomer.

6. The compound according to any one of claims 1 to 5 in the form of its salts are hydrochloride, sulfate, tartrate or citrate.

7. The compound according to claim 4, selected from any of (+)4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide and (+)4-[[4-(4-methylbenzyl)-1-piperazinil](8-chinoline)methyl]-N,N-diethylbenzamide.

8. The compound according to claim 5, selected from any of (-)4-[(4-benzyl-1-piperazinil)(8 chinoline)methyl]-N,N-diethylbenzamide and (-)4-[[4-(4-methylbenzyl)-1-piperazinil](8-chinoline)methyl]-N,N-diethylbenzamide.

9. The compound according to any one of claims 1 to 8 for use in the treatment of pain.

10. The compounds of formula I according to claim 1 for the production of medicines for use in the treatment of pain.

11. The pharmaceutical composition exhibiting δ-agonistic properties, containing a compound of the formula I according to claim 1 as an active ingredient together with pharmaceutically and supplied with the ski acceptable carrier.

12. A method of treating pain, wherein the subject in need of pain administered an effective amount of the compounds of formula I according to claim 1.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to the field of chemistry, particularly the proton pump inhibitors

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

New compounds // 2258703

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I):

wherein R1 is taken among phenyl or pyridinyl and wherein each phenyl ring R1 or pyridinyl ring R1 can be substituted additionally and independently with chlorine, fluorine, bromine and iodine atom at any position of indicated ring, and also to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition based on these compounds eliciting δ-agonistic activity and to a method for pain treatment. Invention provides preparing new compounds of the formula (I) used in applying for pain treatment and for manufacturing drugs for this purpose.

EFFECT: valuable medicinal properties of new compounds.

8 cl, 3 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

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