SK81998A3 - Compounds having analgesic effects - Google Patents

Abstract

Compounds of formula (I) as well as their pharmaceutically acceptable salts, and pharmaceutical compositions comprising the novel compounds. The novel compounds of formula (I) are useful in the management of pain.

Description

Novel compounds with analgesic effects

Technical field

The invention relates to novel compounds which are substituted 7-membered nitrogen cycles, processes for their preparation, their use and pharmaceutical compositions containing the novel compounds. The compounds of the invention are useful in the treatment and in particular in the treatment of pain.

BACKGROUND OF THE INVENTION

The δ receptor has been found to play a role in many body functions such as the circulatory and pain systems. Therefore, δ receptor ligands may find potential use as analgesics or as antihypertensive agents. Δ receptor ligands also have immunomodulatory activities.

Different populations of opioid receptors (μ, δ and κ) have been identified and all three are evident in the central and peripheral nervous systems of several animal species including humans. When one or more of these receptors were activated, analgesic effects were observed in several animal models.

The currently available selective opioid δ ligands are, with a few exceptions, of a peptide nature and are not suitable for administration by systemic routes. Some non-peptide δ antagonists have been available for some time (see review in Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox. 32: 239-269). These compounds, such as naltrindole, have a rather low (e.g., less than 10-fold) selectivity in binding to the δ receptor over binding to the µ receptor and do not exhibit analgesic activity, a fact that underlines the need to develop highly selective non-peptide ligands.

Recently, a non-peptide δ agonist has been described, BW 373U86 by Chang et al., 1993, J. Pharmacol. Exp. Ther., 267: 852-857., As the first δ selective non-peptide, but exhibits significant affinity for the µ receptor.

The problem underlying the present invention was to find new analgesics having excellent analgesic effects, but also an improved side effect profile over current µ agonists and potential oral efficacy.

The analgesics already identified have many disadvantages in that they have poor pharmacokinetics and are not analgesics in administration by systemic routes. It has also been documented that the preferred compounds described so far exhibit significant adverse effects when administered systemically.

In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine and diarylmethylpiperidine compounds, including BW 373U86 are described, but these hitherto known compounds are structurally different from the compounds of the present invention.

The above deficiency has been solved by the development of new compounds which are 7-membered nitrogen cycles as described below.

SUMMARY OF THE INVENTION

The novel compounds of the invention are defined by the general formula (D

where

A is substituted or unsubstituted aromatic; optionally substituted C ₅ C ₁₀ hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from C, S, N and O, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, _{CH3, (CH2) o CF3,} halogen, CONR ⁵ R ^6, CO 2 R ^5, COR ^5, (CH ₂₎ NR ⁵ R ^6, (CH 2) OCH 3 (CH 2) OSOR ⁵ R ^6, (CH 2) _o SO ₂ R ^5, (CH 2) oSO2NR ^5, (CH 2) ₀ DB ⁵ COR ⁶ and NR ⁵ (CH ₂ ) _o COR ¹ ;

wherein o is 0, 1 or 2, and R ¹ , R ⁵ and R ⁶ are as defined below;

R ¹ is selected from hydrogen, a branched or straight _Ο Γ Ο ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ (alkyl-cycloalkyl) wherein alkyl is C, -C ₂ alkyl and cycloalkyl is C ₃ - C ₆ cycloalkyl; C ₆ -C ₁₀ aryl; and heteroaryl having 5 to 10 atoms selected from C, S, N and O;

R ⁵ and R ⁶ independently represent R ¹ as defined above;

R ² is selected from hydrogen, CH 3, OR ^1, CO 2 R ^1, and CH ₂ CO ₂ R ^1, wherein

R ¹ is as defined above;

B is substituted or unsubstituted aromatic; optionally substituted C _with C ₁₀ hydroaromatic; and a heteroaromatic or haterohydroaromatic group having 5 to 10 atoms selected from C, S, N and O atoms, optionally substituted with 1 to 2 substituents independently selected from hydrogen, CH ₃ , CF ₃ , halogen, (CH ₂ ) _p CONR ⁵ R ⁶ , (CH 2) p NR ⁵ R ^6, (CH 2) _p COR ^5, (CH 2) PCO2R ^5, OR ^5, (CH 2) _p SO ₂ R ^5, and (CH 2) p SO 2 N R ⁵ R ^6; χ wherein p is 0,1,2 or 3 and wherein R ⁵ and R ⁶ are as defined above;

'A

R ³ and R ⁴ independently of one another are selected from

R ^5, (CH _{2) p} -CONR ⁵ R ^6, (CH 2) p NR ⁵ R ^6, (CH 2) _p -CONR ⁵ R ^6, (CH _{2) p,} C0 ₂ R ^5, (CH2) pPh, (CH2) p ( p-OH Ph), (CH 2) p -3-indolyl, (CH ² ) _p PS ⁵ or (CH 2) _p OR ⁵ ;

wherein p is 0, 1, 2, 3 or 4 and wherein R ⁵ and R ⁶ are as defined above.

The present invention also provides pharmaceutically acceptable salts of the compounds of formula (I), isomers, hydrates, isoforms and medicaments thereof.

Preferred compounds of the invention are compounds of formula (I) wherein

A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquininyl, tetrahydroisoquinolinyl, tetrahydrofuranyl and pyrrolidinyl; wherein each A is optionally substituted with 1 to 2 substituents independently selected from hydrogen, CH ₃ , (CH ₂ ) _O CF ₃₁ F, Cl, CONR ⁵ R ⁶ , CO ² R ⁵ , COR ⁵ , (CH 2) _o SOR ⁵ , ( _{CH2) o} SO ₂ R ^5, (CH 2) oSO2NR ^5, (CH ₂₎ NR ⁵ COR ⁶ and NR ⁵ (CH _{2) a} COR ^6; wherein R ⁵ and R ⁶ are as defined below and o is 0 or 1;

R ^1, R ⁵ and R ⁶ independently is selected from hydrogen, straight or branched C _r H ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₄ -C ₈ (alkyl-cycloalkyl) wherein alkyl is 0, - O 2 alkyl and cycloalkyl is C ₃ -C ₆ cycloalkyl, and phenyl;

R ² is hydrogen, methyl, or OR ¹ , wherein R ¹ is as defined above;

B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquininyl, tetrahydroisoquinanyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl,

each B group is optionally substituted with 1 to 2 substituents independently selected from hydrogen, CH ₃ , CF ₃ , halogen, (CH ₁ ) _p CONR ⁵ R ⁶ , (CH ₂ ) _p NR ⁵ R ⁵ , (CH ₂ ) _p COR ^5, (CH _{2) p} CO ₂ ^R and OR ^5;

wherein p is 0 or 1 and wherein R ⁵ and R ⁶ are as defined above;

R ³ and R ⁴ are independently selected from hydrogen, CH 3, CH (Me) 2, CH 2 CH (Me) 2, CH (Me) CH 2 CH 3, (CH 2) PCON ⁵ R ⁶ , (CH 2) _P NR ⁵ R ⁵ , (CH ₂ ) _{p P} R ⁵ R ⁶ , (CH 2) _p CO ₂ R ⁵ , (CH ₂ ) p Ph, (CH 2) p (p-OH Ph), (CH 2) p -3-indolyl, (CH 2) p PS ⁵ and ( CH 2) _p oR ⁵ wherein p is 0, 1,2 or 3 and wherein R ⁵ and R ⁶ are as defined above.

Particularly preferred compounds of the invention are compounds of formula (I) wherein

wherein the phenyl ring of each A substituent may be optionally and independently substituted with 1 or 2 substituents selected from H, CH ₃₁ (CH ₂ ) _O CF ₃ , F, Cl, CONR ⁵ R ⁶ , CO ² R ⁵ , (CH 2) _o SOR ⁵ , ( CH 2) OSO 2 R ^5, (CH 2) _a SO ₂ NR ^{5 R,} (CH2) ONR ⁵ COR ⁶ and NR ⁵ (CH 2) _a COR ^6; wherein R ⁵ and R ⁶ are as defined below and o is 0, 1 or 2;

R ¹ is selected from hydrogen, methyl, ethyl, CH ₂ CH = CH ₂ or CH ₂ -cyclopropyl;

R ⁵ and R ⁶ are independently selected from phenyl, methyl and ethyl; or R ⁵ and R ⁶ together represent - (CH ₂ ) r -, where 4 or 5;

R ² is H, methyl, or OR ¹ ;

- 6 R ^7, R ^3, R ^s, R ^10, R ^11, R @ ^2, R @ ³ ·, R ^14, R ^'3 and R' ³ independently of one another are R as defined above;

B is selected phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolynyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquininyl, tetrahydroisoquinolinyl, indazolinyl and tetrahydrofuranyl

each B group is optionally substituted with 1 to 2 substituents independently selected from hydrogen, methyl, CF ₃ , halogen, (CH ₂ ) _p CONR ⁵ R ⁶ , (CH 2) PNR ⁵ R ⁶ , (CH 2) _p COR ⁵ , (CH) ₂ ) _p CO ² R ⁵ and OR ⁵ wherein p is 0, 1 or 2 and wherein R ⁵ and R ⁶ are as defined above;

R ³ and R ⁴ are independently selected from H, CH ₃ , CH (Me) ₂ , CH ₂ CH (Me) ₂ , CH (Me) CH ₂ CH ₃ (CH ₂ ) _p CONR ⁵ R ⁶ , (CH ₂ ) ) NR ⁵ R ^6, (CH 2) _p -CONR ^{5 R,} (CH _{2) p} CO ₂ R ^5, (CH2) pPh, (CH2) p (p-OH Ph), (CH2) p-3-indolyl, (CH 2) pSR ⁵ and (CH 2) _p OR ⁵ ;

wherein p is 0, 1, 2 or 3 and wherein R ⁵ and R ⁶ are as defined above.

It is even more preferred to use a compound wherein substituent A is

and wherein R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above.

The substituents A and B may be optionally substituted at any position of the ring.

Halogen means chloro, fluoro, bromo and iodo.

Aryl means an aromatic ring having 6 to 10 carbon atoms such as phenyl and naphthyl.

Heteroaryl means an aromatic ring in which one or more of the 5 to 10 ring atoms are elements other than carbon, such as N, S and O.

Hydroaromatic means a partially or fully saturated aromatic cyclic structure of 5 to 10 ring carbon atoms.

Heterohydroaromatic means a partially or fully saturated aromatic cyclic structure in which one or more of the 5 to 10 atoms in the cycle are elements other than carbon such as N, S and O.

Isomers are compounds of formula (I) which differ in their functional group position or orientation. Orientation means stereoisomers, diastereomers, regioisomers and enantiomers.

Isoforms are compounds of formula (I) which differ in their crystal lattice, such as crystalline compound and amorphous compounds.

Promedicament means pharmacologically acceptable derivatives, for example esters and amides, wherein the resulting biotransformation product of the derivative is an active drug. Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-HilI, Int. Ed. 1992, Biotransformation of Drugs, p. 13-1 5, generally describes said promedicament.

The novel compounds of the invention are used in therapy, in particular for the treatment of pain.

Another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for use in any of the diseases listed below.

The compounds are used to modulate analgesic effects on the µ opioid receptor subtype, including the modulation of side effects seen with agents acting on the opioid µ receptor subtype such as morphine, especially respiratory depression, motility and addiction tendency.

The compounds of the invention are also used as immunomodulators, especially in autoimmune diseases such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumor agents and antiviral agents.

The compounds of the invention are also used in diseases where opioid receptor degeneration or dysfunction is / or is suspected. This may include the use of isotope-labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

The compounds of the invention are used to treat diarrhea, depression, urinary incontinence, various mental illnesses, cough, pulmonary edema, various gastrointestinal disorders, spinal cord injuries and drug addiction, including the treatment of alcoholism, nicotinism, oipioid and other drug addiction, and sympathetic nervous disorders. system such as hypertension.

Methods of preparation

Generalized method

The aldehyde or ketone is exposed to a nucleophile such as a Grignard reagent or organolithium compound to form the corresponding alcohol. This alcohol may then be converted to a suitable temporary group (X) such as an ester, sulfonate or halide, which may then be replaced by nucleophilic groups such as substituted or unsubstituted piperazine. The N- (4) -substituted piperazine derivatives may then be suitably substituted with a variety of groups via their organohalide or equivalent species, or acylated with a number of different acylating compounds. This sequence yields compounds of formula (I).

Generalized method

The amino acid protected at the N position, such as its activated ester, can react with a second amino acid ester. As a result of the action of the acid, it can cyclize to form the piperazinedione. This dione can be reduced by a number of standard methods to the corresponding piperazine (e.g., a reducing agent such as lithium aluminum hydride, conversion to thioamide followed by desulfurization, hydrogenation in the presence of POCl _3, etc.). The piperazine may then be alkylated or acylated at one or more nitrogen, or may subsequently be used in a generalized method A.

Subsequently, functional group deprotection or other modifications may be necessary, these being described for each individual case. Specific examples of the above transformations are given in the experimental section.

All transformations contemplated use reagents (including salts) and solvents known for chemistry and biotransformations carried out in a suitable biological medium to effect these transformations, and include all reaction promoters (e.g., HMPA), and chiral resolutions by chiral salt formation and chiral bio-resolutions.

The best, currently known embodiment of the invention is to use compounds 1, 2, 3, 4, 9 and 10.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more detail by the following examples, which are not to be construed as limiting the invention.

The compounds of Example 1-3 were synthesized as shown in Scheme 1.

Scheme 1

4-f-(1-Homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide (1,2 and 3)

A) P)

I. Preparation of 4-N- (1-Homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide

To a solution of 3-bromoanisole (5.61 g, 30.0 mmol) in dry THF (100 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 mol / L, 20 mL, 32 mmol) under nitrogen at -78 ° C. C. The mixture was stirred for 1 hour. at the same temperature before the addition of 4formyl-N, N-diethylbenzamide (6.15 g; 30.0 mmol) in dry THF (20 mL). The reaction mixture was allowed to warm to room temperature (4 h) and then quenched with ammonium chloride. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate / heptane (1: 1), washed with saturated brine and dried (MgSO 4). ( ¹ H-mopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide (6.15 g, 66%): ¹ H-NMR (400mHz, CDCl ₃ ) δ 1.10 (3H, br, ΟΗ, ΟΗ, Ν- 1.22 (3H, br, CHCl 3 N-), 2.60 (1H, br, OH), 3.24 (2H, br, CH ₃ CH ₂ N-), 3.52 (2 H, br, CH ₃ CH ₂ N-), 3.79 (3H, s, OCH 3), 5.8 (1H, s, CHN), 6.81 (1H, m, ArH), 6.93 (1H, m, ArH), 6.94 (1H, m, ArH), 7.25 (1H, m, ArH), 7.31 (2H, m, ArH), 7.39 (2H, m, ArH); m, ArH).

II. Preparation of 4- (α-Chloro-3-methoxybenzyl) -N, N-diethylbenzamide (Compound A in Scheme 1)

To a solution of 4- (α-hydroxyl-3-methoxybenzyl) -N, N-diethylbenzamide (3.13 g; 10.0 mmol / L) in AcOEt (20 mL) was added 35% hydrochloric acid (20 mL) at 0 ° C. C. The reaction mixture was stirred for 12 hours. at room temperature and extracted with AcOEt. The organic layers were washed with saturated ammonium chloride solution and salt, dried over MgSO ₄ and evaporated to give the crude product which was purified by silica gel column chromatography to give 4- (α-Chloro-3-methoxybenzyl) -N, N-diethylbenzamide (compound A) (1.82 g; 55%): GC-MS: 331, 330, 296, 259, 224, 196, 165, 152, 112;

Example 1

Preparation of 4- (α- (1-Homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide

A mixture of homopiperazine (200 mg; 2.0 mmol / L), 4- (α-chloro-3-methoxybenzyl) N, N-diethylbenzamide (331 mg; 1.0 mmol / L) and K ₂ CO ₃ (276 mg; 2 1.0 mmol / L) in dry acetonitrile (50 mL) after reflux for 2 h. Under nitrogen and cooling to room temperature, the reaction mixture was quenched with 1mol / L aqueous NH ₄ OH and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous NH ₄ Cl solution and saturated brine, dried over MgSO ₄ . Removal of the solvents gave 4- (α- (1-Homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide (compound 1) which was purified on a silica gel column and eluted with MeOH-CH ₂ Cl ₂ (2: 98 10: 90) to give formation of the title compound (254 mg, 64%).

GC-MS (R _t = 17.35 min) 369.30 (M ⁺ +1; 0.4%), 395.30 (M ⁺ ; 1.2); 380.25 (0.9), 337.20 (6.5), 325.25 (27.2), 297.15 (25.8), 251.10 (1.1), 224.10 (3) , 7), 196.10 (26.4),

165.15 (12.8), 152.10 (1676), 112.15 (4.8), 99.20 (100); δ _Η (400 MHz, CDCl ₃ ) 1.10 (brs, 3H), 1.20 (brs, 3H), 1.82 (m, 2H), 2.66 (t, J = 6.0 Hz, 2H 1.72 (m, 2H), 2.97 (t, J = 5.2 Hz, 2H), 3.12 (t, J = 6.0 Hz, 2H), 3.23 (brs, 2H) ), 3.51 (brs, 2H), 3.77 (s, 3H), 4.60 (s, 1H), 5.26 (brs, 1H), 6.72 (m, 1H), 6, 99 (m, 2H), 7.18 (t, J = 8.0Hz, 1H), 7.28 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.0) Hz 2H); ô _c . ₁₃ (100 MHz, CDCl ₃ ) 12.8, 14.2, 29.0, 39.2, 43.3, 46.0, 48.6, 53.0, 53.6, 55.2, 74, 9, 112.3, 113.5, 120.2, 126.7,

127.8, 129.5, 135.9, 144.3, 144.4, 159.7, 171.0.

Its HBr salt: mp 137-140.5 ° C (AcOEt-ether); v _max (Kbr) cm ^-1 3500, 1600, 1288; Anal calcd for C ₂₄ H ₃₃ N ₃ O ₂ .1.5HBr.0.8H ₂ O: C, 54-25; H, 6.85; N, 7.91. Found: C, 54.36; H, 6.89; N, 7.78.

Example 2

Preparation of 4- (α- (4-Methyl-1-homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide (Compound 2)

A mixture of homopiperazine (114 mg; 1.14 mmol / L), 4- (α-chloro-3-methoxybenzyl) -, Ν-diethylbenzamide (compound A) (100 mg; 0.3 mmol / L) and K ₂ CO ₃ (138 mg (1.0 mmol / L) in dry acetonitrile (10 mL) was refluxed for 5 h. under nitrogen. After cooling to room temperature, the reaction mixture was quenched with 1mol / L aqueous NH ₄ OH solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with aqueous NH ₄ Cl solution and saturated brine, and dried over MgSO ₄ . Removal of the solvents gave 4- (α- (4-methyl-1-homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide, which was purified on a silica gel column and eluted with MeOH-CH ₂ Cl ₂ (5: 95 - 10: 90) to give formation of the title compound (82 mg, 67%).

GC-MS (R t = 16.19 min) 410.10 (M ⁺ +1, 0.3%) 409.20 (M ⁺ , 0.9), 351.15 (1.7), 324.15 (3.4), 296.15 (5.3), 264.10 (0.2), 237.00 (0.6), 224.05 (3.0), 196.05 (6.2), 152 .00 (5.6), 113.15 (100); δ _Η (400 MHz, CDCl ₃ ) 1.10 (bs, 3H), 1.20 (brs, 3H),

1.79 (m, 2H), 2.38 (s, 3H), 2.59 (m, 2H), 2.65 (m, 4H), 2.72 (t, J = 6.0 Hz, 2H ), 3.24 (brs, 2H), 3.54 (brs, 2H), 3.78 (s, 3H), 4.54 (s, 1H), 6 µ (dt, J = 8.0, 1.2 Hz, 1H), 6.99 (m, 2H), 7.18 (dt, J = 8.0, 1.2 Hz, 1H), 7.27 (dd, J = 8.4, 1) 1.6 Hz, 2H), 7.44 (dd, J = 8.4, 1.6 Hz, 2H); ô _c . ₁₃ (100 MHz, CDCl ₃ ) 12.9, 14.2, 27.7, 39.1, 43.2, 46.9, 52.7,

52.8, 55.2, 56.3, 59.1, 75.3, 11270, 113.7, 120.4, 126.6, 127.9, 129.4, 135.7, 144.7,

144.8, 159.7, 171.1.

Its HBr salt: 1.1. 165-178 ° C (AcOEt-ether); _max (KBr) cm ^-1 3400, 1603, 1286; Anal calculated for Ο ₂ 5Η ₃₅ Ν3Ο ₂ .2,0ΗΒγ.0,6Η ₂ Ο: C, 51.57; H, 6.61: N, 7.22. Found: C, 51.88; H, 6.56; N, 6.92.

Example 3

Preparation of ________ 4- (α- (4-Cyclopropylmethyl-1-homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide (Compound 3)

A mixture of 4- (α- (1-homopiperazinyl) -3-methoxybenzyl) -N ₁ N-diethylbenzamide (compound 1) (119 mg; 0.3 mmol), (chloromethyl) cyclopropane (45 mg; 0.5 mmol), sodium iodide (75 mg; 0.5 mmol) and K ₂ CO ₃ (138 mg; 1.0 mmol) in MeCN (10 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was quenched with 1mol / L aqueous NH ₄ OH solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated NH ₄ Cl solution and saturated brine, dried over MgSO ₄ . After removal of the solvents it was formed

4- (α- (4-cyclopropylmethyl-1-homopiperazinyl) -3-methoxybenzyl) -N, N-diethylbenzamide (compound 3), which was purified on a silica gel column and eluted with MeOH-CH ₂ Cl ₂ (1: 99_ ^ 10) : 90) to give the title compound (125 mg, 93%).

GC-MS (R _t = 25.44 min) 377.15 (0.2%), 365.10 (0.3), 352.25 (0.3), 337.20 (1.9), 323 , 15 (3.2), 296.15 (6.3), 259.10 (0.3), 237.05 (0.3), 224.00 (2.6), 196.10 (7.3) , 153.20 (100), 110.10 (4.6); δ _Η (400 MHz, CDCl ₃ ) 0.33 (m, 2H), 0.69 (m, 2H),

1.11 (m, 3H), 1.20 (m, 4H), 2.11 (m, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.81 (d, J = 6.6 Hz, 2H), 2.9 (m, 2H), 3.13 (brs, 2H), 3.25 (brs, 2H), 3.30 (m, 2H), 3.51 (brs , 2H),

3.79 (s, 3H), 4.59 (s, 1H), 6.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 6.98 (m, 2H) 7.21 (t, J = 8.0 Hz, 1H), 7.3 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H); ô _c . ₁₃ (100 MHz,

CDCl

112.2, 113.8, 120.2, 126.7, 127.8, 129.6, 136.1, 143.6, 143.7, 159.8, 170.9.

Its HBr salt: mp 138-147 ° C (AcOEt-ether); v _max (KBr) ^cm-1 3435, 1606, 1287;

Anal. Calcd. For C ₂₈ H ₃₉ N ₃ O ₂ .1.20HBr.1.40H ₂ O: C, 58.80; H, 7.58; N, 7.35. Found: C, 58.82; H, 7.58; N, 7.24.

Scheme 2

4- (α- (1-Homopiperazinyl) benzyl) -N, N-diethylbenzamide hydrochloride (compound 4)

The compound of Example 4 was synthesized as shown in Scheme 2 above.

B)

I. Preparation of 4- (Phenyl-hydroxymethyl) -N, N-diethylbenzamide

4-Formyl-N, N-diethylbenzamide (19.5 g; 95 mmol) was dissolved in dry THF, cooled to -78 ° C under nitrogen. Phenyl magnesium bromide (104 mL; 1.0 mol in THF) was added dropwise at -78 ° C. The temperature was slowly raised until the reaction was complete (1 h). The reaction was cooled in ammonium chloride The solvent was removed in vacuo, the residue was dissolved in ethyl acetate / heptane, 1: 1, washed with saturated brine and dried (MgSO 4). Evaporation of the solvent in vacuo gave 26.5 g (98%) 4- ( MS: 282, 211, 165, 105, ¹ H NMR: (CDCl ₃ ): δ = 7.38-7.20 (m, 9H), 5.8 (d, J = 3) 5 Hz, 1H), 3.5, 3.2 (2br, 4H), 1.2, 1.05 (2br, 6H).

II. Preparation of 4- (Chloro-phenyl-methyl) -N, N-diethylbenzamide (Compound B in Scheme 2)

4- (Phenyl-hydroxymethyl) -N, N-diethylbenzamide (24.5 g; 93 mmol) was dissolved in dichloromethane (300 mL), dried over 4A molecular sieves and transferred to a dry flask under nitrogen. Thionyl chloride (7.5 mL; 103 mmol) was added at 0 ° C. The solution was stirred at 25 ° C for 1 hour. The solvent was evaporated in vacuo. The residue was dissolved in toluene and the solvent was evaporated again. 4- (Phenylhydroxymethyl) -N, N-diethylbenzamide (compound B) was obtained as an oil (ca. 100%) which crystallized in the freezer. GC-MS (2 peaks): 296, 225, 165, 121 and 300, 266, 229, 195, 165. ¹ H NMR: (CDCl ₃ ): δ = 7.45-7.20 (m, 9H), 6.09 (s, 1H), 3.4 (br. M, 4H), 1.1 (br. M, 6H).

Example 4

Preparation of 4- (α- (1-Homopiperazinyl) -benzyl) -N, N-diethylbenzamide (Compound 4)

This compound was prepared as described in Example 1 (compound 1), but compound A was substituted with compound B.

4- (cis- (1-homopiperazinyl) -benzyl) -N, N-diethylbenzamide (compound 4) as an oil. GC-MS: 365.30 (M ⁺ , 2.6%), 322.25 (5.7), 295.15 (42.5), 281.20 (22.4), 267.15 (45, 4), 236.10 (0.9), 194.15 (28.8), 165.1 (62.7), 99.20 (100); δ _Η (400 MHz, CDCl ₃ ) 1.08 (brs, 3H), 1.18 (brs, 3H), 1.69 (m, 2H), 2.56 (s, 1H), 2.62 (m 4H), 2.85 (m, 2H), 2.97 (m, 2H), 3.23 (brs, 2H), 3.50 (brs, 2H), 4.63 (s, 1H), 7 16 (m, 1H); 7.26 (m, 4H);

7.40 (d, J = 8Hz, 2H); 7.44 (d, J = 8.0Hz, 2h); Ô _c . ₁₃ (100 MHz, CDCl ₃ ) δ: 12.6, 14.0, 30.7, 39.0, 43.1, 46.9, 49.6, 52.9, 56.1, 74.9, 126.4, 126.7, 127.6, 127.7, 128.3, 135.5, 142.9, 144.8, 171.0.

Its HCl salt (compound 4): 1.1. 155-165 ° C (AcOEt-ether); the _CAX (KBr) ^cm-1 3418, 1628, 1591, 1074; Anal, calcd for ^{C 3} H _{3 3} .N 0.2,50HCI, 0,90H ₂ 0: C, 58.42; H, 7.52; N, 8.89. Found: C, 58.35; H, 7.52; N, 8.62.

Scheme 3

4- (α- (1-Homopiperazinyl) aryl) -N, N-diethylbenzamide hydrochloride (compounds 9 and 10)

(5) a. (6)

Ar = 4-diethylaminocarbonylphenyl (5) Ar = 2-naphthyl (6)

0 SOCI ₂ Ϊ) kx K / Ar homopiperazine I Cl (7) a (8) Ar = 4-diethylaminocarbonylphenyl (7)

Ar = 2-naphthyl (8)

(9) and (10)

Ar = 4-Diethylaminocarbonylphenyl (9)

Ar = 2-naphthyl (10)

The compounds of Examples 5-10 were synthesized as shown in Scheme 3 above.

C)

I. Preparation of 4-iodo-N, N-diethylbenzamide (Compound C in Scheme 3)

To a solution of 4-iodobenzoyl chloride (13.3 g; 50 mmol) in dry dichloromethane (50 mL) was slowly added diethylamine (30 mL) at 0 ° C. After the addition, the reaction mixture was warmed to room temperature and stirred for one hour at room temperature and then quenched with aqueous K ₂ CO _{3 solution} , extracted with diethyl ether (2 x 200 mL). The organic phases were washed with saturated brine, dried over MgSO ₄ . Evaporation of the solvents gave the crude product, which was purified on a silica gel column and eluted with MeOH-CH ₂ Cl ₂ (1:99) to give 4-iodo-N, N -diethylbenzamide (14.5 g; 95%). GC-MS: 303.00 (M *, 20.2%), 302.00 (52.1), 231.85 (7.6), 230.85 (100), 203.85 (1.1) .

II. Preparation of Di- (4-N, N-Diethylaminocarbonylphenyl) methanol (Compound 5)

To a solution of 4-iodo-N, N-diethylbenzamide (1.51 g; 5.0 mmol) in dry THF (10 mL) was slowly added t-butyllithium (5 mL, 1.7 mol / L, 8.5 mmol). ) at - 78 ° C. After 10 min, 4-formyl-N, N-diethylbenzamide (1.03 g; 5.0 mmol) in THF (5 mL) was added dropwise. The reaction mixture was warmed to room temperature and then quenched with aqueous NH ₄ Cl solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated brine, dried over MgSO ₄ . Removal of solvents gave the crude product, which was purified on a silica gel column and eluted with MeOH-CH ₂ Cl ₂ (1:99 5: 95) to give di- (4-N, N-diethylaminocarbonylphenyl) methanol (75 mg; 38%). GC-MS: 382.20 (M ⁺ , 2.9%),

364.15 (4.4), 310.05 (34.2), 283.15 (40.2), 204.05 (15.6), 154.55 (13.9), 119.05 (100) ); δ _Η (400 MHz, CDCl ₃ ) 1.06 (brs, 6H), 1.19 (brs, 6H), 3.20 (brs, 4H), 3.48 (brs, 4H), 5.26 (s 1 H, 5.66 (s, 1 H), 7.21 (d, J = 8.0 Hz, 4H), 7.31 (d, J = 8.0 Hz, 4H); 3 _{C. 13} (100 MHz, CDCl ₃ ) δ: 12.5, 13.9, 39.0, 43.0, 74.5, 125.9, 126.2, 135.3, 145.3, 171.0.

III. Preparation of 4- (α-chloro-4-N, N-diethylaminocarbonylbenzyl) -N, N-diethylbenzamide (Compound 7)

1S

To a solution of di- (4-N, N-diethylaminocarbonylphenyl) methanol (400 mg; 1.05 mmol) in dry dichloromethane (10 mL) was added dropwise thionyl chloride (1.0 mL; 13.7 mmol) at room temperature. . The reaction mixture was stirred at room temperature for one hour. Evaporation of the solvents gave 4- (α-chloro-4-N, N-diethylaminocarbonylbenzyl) -N, N-diethylbenzamide which was used directly in the next step: δ _Η (400 MHz, CDCl ₃ ) 1.16 (brs, 12 H) 3.38 (brs, 8H), 6.15 (s, 1H), 7.35 (d, J = 8.0Hz, 4H), 7.44 (d, J = 8.0Hz, 4H) ); Ô _c . ₁₃ (100 MHz, CDCl ₃ ) δ: 13.1, 39.1, 42.5, 62.7, 126.3, 127.5, 136.2, 141.3, 170.3.

Example 5

Preparation ____________ 4- (α- (1-Homopiperazinyl) -N, N-diethylaminocarbonylbenzyl-N ₁ -diethylbenzamide hydrochloride (compound 9)

This compound was prepared as described for Compounds 1 and 4.

GC-MS: 407.20 (1.5%), 394.25 (9.3), 366.15 (12.4), 293.15 (4.1), 265.15 (11.6), 165.15 (19.1), 99.10 (100); δ _Η (400 MHz, CDCl ₃ ) 1.11 (brs, 6H), 1.21 (brs, 6H), 1.69 (m, 2H), 2.36 (brs, 1H), 2.63 (m 4H), 2.97 (m, 2H), 3.00 (m, 2H), 3.25 (brs, 4H), 3.52 (brs, 4H), 4.63 (s, 1H), 7 27 (d, J = 8.4Hz, 4H), 7.43 (d, J = 8.4Hz, 4H); Ô _c . ₁₃ (100 MHz, CDCl ₃ ) δ; 12.8, 14.1, 30.9, 39.1, 43.2, 47.1, 49.7, 53.0, 56.4, 74.9, 126.5, 127.7, 135, 8, 144.5, 171.1.

Its HCl salt: mp 158-164 ° C (AcOEt-ether); v _max (KBr) ^cm-1 3498, 1627, 1047; Anal, Calc. for C ₂₈ H ₄₀ N ₄ O ₂ H ₂ .2,70HCI.0,30H; C, 59.16; H, 7.68; N, 9.86. Found: C, 59.25; H, 7.66; N, 9.63.

IV. Preparation of 4- (α-hydroxy-2-naphthylmethyl) -N, N-diethylbenzamide (Compound 6)

This compound was prepared as described for Compounds 1 and 4.

GC-MS: 333.20 (M ⁺ , 58.2%), 333.20 (100), 316.15 (2.6), 261.10 (88.3), 21

5.05 (18.8), 155.05 (54.8), 127.10 (29.0); δ _Η (400 MHz, CDCl ₃ ) 0.93 (brs, 3H), 1.11 (brs, 3H), 3.08 (brs, 2H), 3.38 (brs, 2H), 4.80 (brs , 1H), 5.73 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.30 ( dd, J = 8.4, 1.6 Hz, 1H), 7.37 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.70 (m, 2H), 7.74 (s, 1 H); ô _c . ₁₃ (100 MHz, CDCl ₃ ) δ: 12.5, 13.8, 39.0, 43.0, 75.0, 124.7, 124.8, 125.5, 125.7, 126.0, 126, 3, 127.3, 127.6, 127.7, 132.4, 132.4, 132.7, 135.2, 141.3, 145.2, 171.1.

V. Preparation of 4- (α-chloro-2-naphthyl) -N, N-diethylbenzamide (Compound 8)

This compound was prepared as described for Compounds 1 and 4.

Used directly in next step: δ _Η (400 MHz, CDCl ₃ ) 1.15 (brs, 6H), 3.38 (brs, 4H), 6.28 (s, 1H), 7.35 (m, 2H) 7.47 (m, 5H); 7.80 (m, 4H).

Example 6

Preparation of 4- (α- (1-homopiperazinyl) -2-naphthylmethyl-N, N-diethylbenzamide hydrochloride (Compound 10)

This compound was prepared as described for Compounds 1 and 4.

GC-MS: 415.15 (M ⁺ , 1.0%), 400.20 (0.6), 356.20 (4.0), 345.25 (14.8),

317.15 (15.7), 244.00 (7.7), 215.15 (44.4), 99.15 (100); δ _Η (400 MHz, CDCl ₃ ) 1.07 (brs, 3H), 1.17 (brs, 3H), 1.69 (m, 2H), 2.63 (brs, 1H), 2.67 (m 4H), 2.86 (m, 2H), 2.98 (m, 2H), 3.20 (brs, 2H), 3.48 (brs, 2H), 4.80 (s, 1H), 7 30 (d, J = 8.0Hz, 2H), 7.42 (m, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.61 (m, 1H), 7 .78 (m, 4H); ô _c . ₁₃ (100 MHz, CDCl ₃ ) δ: 12.7, 14.0, 30.9, 39.0 43.1, 47.0, 49.6, 53.0, 56.2 75.0, 125, 5, 125.7,

125.8, 126.4, 126.5, 127.4, 127.6, 127.7, 128.1, 132.5, 133.2, 135.5, 140.6, 144.7, 171.0.

Its HCl salt: mp 165-172 ° C (AcOEt-ether); v _max (KBr) ^cm-1 3462, 1612, 1106; Anal, Calc. for C ₂₇ H ₃₃ N ₃ O. 2.0HC. 1,60H ₂ O: C, 62.69; H, 7.44; N, 8.12. Found: C, 62.80; H, 7.37; N, 8.03.

Pharmaceutical compositions

The compounds of the invention may be administered orally, intramuscularly, subcutaneously, intraperitoneally, intratoracially, intravenously, intrathecally and intracerebroventricularly.

The dosage will depend on the route of administration of the drug, the severity of the disease, the age and weight, and other factors usually considered by the physician, in determining the individual diet and the most appropriate dosage for the patient.

For preparing pharmaceutical compositions from the compounds of the invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, and suppositories.

The solid carrier may be one or more substances which may function as diluents, flavoring agents, solvents, lubricants, suspending agents, binders, or tablet disintegrants; it may also be a material for encapsulation.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed to the desired size and shape.

To prepare lace compositions, a low melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredients are dispersed therein, for example by mixing. The molten homogeneous mixture is poured into a suitable shape mold and allowed to solidify.

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

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, carbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycolylarzaninate, hexylrelaraminate, hexylrelaraminate, hexylrehydrochloride , hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandeate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, trietiodide, benzatin, chloroprocaine, choline, deiethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

Preferred pharmaceutical salts are hydrochlorides and citrates.

The term composition includes the composition of the active ingredient with the encapsulating material as the carrier providing the capsule in which the active ingredient (with or without carriers) is surrounded by the carrier which is thus associated therewith.

Similarly, lace is included.

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

The liquid of the composition includes solutions, suspensions and emulsions. Sterile water or water-propylene glycol solutions of the active ingredients may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid mixtures can also be formed in a solution of an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers and thickeners as desired. Aqueous suspensions for oral use can be prepared by dispersing the finely divided active ingredient in water along with viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspending agents known in the pharmaceutical art.

Preferably, the pharmaceutical composition is in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, for example, packaged tablets, capsules and powders in vials or ampoules. The dosage unit form may also be a capsule, suppository, or tablet itself, or it may be any suitable quantity of any of these packaged forms.

Biological assessments

A) In vitro model Cell culture

Human 293S cells expressing cloned human μ, δ and κ receptors and neomycin resistance were grown in suspension at 37 ° C and 5% CO ₂ in shake flasks containing calcium-free DMEM 10% FBS; 5% BCS; 0.1% pluronic F68 and 600 pg / ml geneticin.

Preparation of membranes

Cells were pelleted and suspended in lysis solution (50 mmol / L Tris pH 7.0; 2.5 mmol / L EDTA; with PMSF added just prior to use to 0.1 mmol / L from a 0.1 mol / L stock solution in ethanol), incubated on ice for 15 min, then homogenized on polytrone for 30 sec. The suspension was centrifuged at 1000 g (max) for 10 min at 4 ° C. The supernatant was discarded on ice and the pellets suspended and centrifuged as before. Supernatants from both spins were combined and centrifuged at 46000 g (max) for 30 min. The pellets were suspended in cold Tris buffer (50 mmol / L, Tris / Cl, pH 7.0) and centrifuged again. The resulting pellets were suspended in membrane buffer (50 mmol / L Tris; 0.32 mol / L sucrose; pH 7.0). Aliquots (1 mL) in polypropylene tubes were frozen in dry ice / ethanol and stored at -70 ° C. Protein concentration was determined by a modified Lowry method with SDS.

Binding tests

The membranes were thawed at 37 ° C, cooled on ice, pushed 3 times through needle 25, and diluted into binding buffer (50 mM Tris; 3 mM MgCl ₂ ; 1 mg / ml BSA (Sigma A-7888); pH 7.4, which was stored at 4 ° C after filtration through a 0.22 m filter and to which freshly added 5 µg / ml aprotinin, 10 pmol / L bestatin, 10 µπιοΙ / L diprotin A, bet DTT). 100 μΙ aliquots (per μg protein, see Table 1) were added to 12 x 75 mm ice-cold polypropylene tubes containing 100 μΙ of the respective radioligand (see Table 1) and 100 µl of test peptides at different concentrations. Total (TB) and non-specific (NS) binding were determined in the absence and presence of 10 pmol / L naloxone. The tubes were vortexed and incubated at 25 ° C, 60-75 min, after which time their contents were vacuum filtered and washed with approximately 12 mL / wash buffer (50 mmol / L Tris; pH 7.0; 3 mmol). L MgCl ₂ ) cooled on ice, through GF / B filters (Whatman) moistened for at least 2 hours in 0.1% polyethylene linine. The radioactivity (dpm) captured on the filters was measured by a beta counter after comparing the filters for at least 12 hours in mini-containers containing 6-7 ml of scintillation fluid. If the assay is done in a 96-well deep well plate, filtration is performed through a 96-well ultrafilter soaked in PEI, which is washed in 3 x 1 ml wash buffer and oven dried at 55 ° C for 2 hours. Filter plates were measured in TopCount (Packard) after adding 50 μΙ of MS-20 scintillation fluid per well.

Data analysis

Specific binding (SB) was calculated as TB-NS, and SB in the presence of various test peptides was expressed as a percentage of control SB. Values

IC ₅₀ and Hill coefficient (n _H ) for ligands displacing specifically bound radioligand were calculated from program graphs such as Ligand, GraphPad Prism, SigmPlot or

ReceptorFit. K values ₍ calculated from the Cheng-Prussoff equation. Mean + / 24 of the standard deviation IC ₅₀ , K i and _H values were reported for ligands tested in at least three displacement curves.

Receptor saturation experiments

The K _s values _{of the} radioligand were determined by cell membrane binding assays with appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated K _s value (up to 10 times if the required amounts of radioligand are adequate). The specific bound radioligand was expressed as pmole / mg membrane protein. The Κ _δ and B _max values from individual experiments were obtained by non-linear regression of specifically bound (B) versus nmol / L free (F) radioligand from the individual according to the one-site model.

B) biological model (in vivo model)

A well characterized hot plate assay (Jolicoeur et al., 1991), Neurobehavioral evidence for kappa agonist activity of the morphinan derivative of 14-b-methyl 8-oxacyclophan BC (3016): Pharmcol. Biochem. Behav. 38: 401-405.) And the tail flick test (D'Amour, FE and Smith, DL (1941): A method for determining the loss of pain sensation !, J. Pharmacol. Exp. Ther. 72: 74-79; Nance , P.

A. and Sanyor, J. (1987): Substance P-induced long-term blockade of switched adrenergic anlgesia: reversal b morphine and naloxone; J. Pharm. Exp. Ther. 340: 972-977) were used to determine the efficacy of the compounds of this invention as possible analgesics.

Claims (24)

PATENT CLAIMS A compound of formula I A is substituted or unsubstituted aromatic; optionally substituted C ₅ C ₁₀ hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from C, S, N and O, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, _{CH3, (CH2) o CF3,} halogen, CONR ⁵ R ^6, CO 2 R ^5, COR ^5, (CH ₂₎ NR ⁵ R ^6, (CH2) 0CH3 (CH2) 0SOR ⁵ R ^6, (CH 2) ₀ SO ₂ R ^5, (CH 2) 0SO2NR ^5, (CH 2) ₀ DB ⁵ COR ⁶ and NR ⁵ (CH ₂ ) _o COR ¹ ; wherein o is 0,1 or 2, and R ¹ , R ⁵ and R ⁶ are as defined below; R ¹ is selected from hydrogen, a branched or straight Ο, -C alkyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ (alkyl-cycloalkyl) wherein alkyl is C _r C ₂ alkyl and cycloalkyl is C ₃ -C ₆ cycloalkyl; C ₆ -C ₁₀ aryl; and heteroaryl having 5 to 10 atoms selected from C, S, N and O; R ⁵ and R ⁶ independently represent R ¹ as defined above; R ² is selected from hydrogen, CH 3, OR ^1, CO 2 R ^1, and CH ₂ CO ₂ R ¹ wherein R ¹ is as defined above; B is substituted or unsubstituted aromatic; optionally substituted C ₅ C ₁₀ hydroaromatic; and a heteroaromatic or haterohydroaromatic group having from 5 to 10 atoms selected from C, S, N and O atoms, optionally substituted with 1 to 2 substituents independently selected from hydrogen, CH ₃ , _CF3, halogen, (CH _{2) p} -CONR ⁵ R ^6, (CH 2) p NR ⁵ R ^6, (CH 2) _p COR ^5, (CH2) pCO2R ^5, OR ^5, (CH 2) _p SO ₂ R ^5, and (CH ₂ ) _p SO ₂ NR ^{6 with} R ⁶ ; wherein, p is 0, 1, 2 or 3 and wherein R ⁵ and R ⁶ are as defined above; R ³ and R ⁴ independently of one another are selected from R ⁵ , (CH ₂ ) _p CONR ⁵ R ⁶ , (CH ₂ ) _p NR ⁵ R ⁶ , (CH 2) _p CONR ⁵ R ⁶ , (CH ₂ ) _p CO ₂ R ⁵ , (CH ₂ ) _p Ph, (CH 2) p ( p-OH Ph), (CH 2) p -3-indolyl, (CH 2) PSR ⁵ or (CH 2) _p OR ⁵ ; wherein p is 0, 1, 2, 3 or 4 and wherein R ⁵ and R ⁶ are as defined above; as well as the pharmaceutically acceptable salts of the compounds of formula I, isomers, hydrates and isoforms thereof. A compound of formula I according to claim 1, wherein A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquininyl, tetrahydroisoquinolinyl, tetrahydrofuranyl and pyrrolidinyl; wherein each A is optionally substituted with 1 to 2 substituents independently selected from hydrogen, CH ₃ , (CH ₂ ) _O CF ₃ , F, Cl, CONR ⁵ R ⁶ , CO ² R ⁵ , COR ⁵ , (CH 2) _o SOR ⁵ , (CH2) 0SO2R ^5, (CH 2) _a SO ₂ NR ^5, (CH 2) 0NR ⁵ COR ⁶ and NR ⁵ (CH 2) _a COR ^6; wherein R ⁵ and R ⁶ are as defined below and o is 0 or 1; R ^1, R ⁵ and R ⁶ independently is selected from hydrogen, straight or branched C _r C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₄ -C ₈ (alkyl-cycloalkyl) wherein alkyl is C _r C ₂ alkyl and cycloalkyl is C ₃ -C ₆ cycloalkyl, and phenyl; R ² is hydrogen, methyl, or OR ¹ , wherein R ¹ is as defined above; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquininyl, tetrahydroisoquinanyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, each the group is optionally substituted with 1 to 2 substituents independently selected from hydrogen, CH ₃ , CF ₃ , halogen, (CH ₂ ) _p CONR ⁵ R ⁶ , (CH ₂ ) _p NR ^with R ⁶ , (CH 2) _p COR ⁵ , (CH ₂₎ ) _p CO ₂ R ⁵ and OR ⁵ ; wherein p is 0 or 1 and wherein R ⁵ and R ^a are as defined above; R ³ and R ⁴ are independently selected from hydrogen, CH 3, CH (Me) 2, CH2CH (Me) 2, CH (Me) CH2CH31 (CH2) PCON ^p R ^6, (CH 2) _p NR ⁵ R ^6, (CH 2) pCONR ^{5 R,} (CH 2) _p CO ₂ R ⁵ , (CH 2) p Ph, (CH 2) p (p-OH Ph), (CH 2) p -3-indolyl, (CH 2) p SR ⁵ and (CH 2) _p OR ⁵ where p is 0, 1, 2 or 3 and wherein R ⁵ and R ⁵ are as defined above. wherein the phenyl ring of each A substituent may be optionally and independently substituted with 1 or 2 substituents selected from H, CH ₃ , (CH ₂ ) _O CF ₃ , F, Cl, CONR ⁵ R ⁶ , CO ² R ⁵ , (CH 2) _o SOR ⁵ , (CH 2) oSO ² R ⁵ , (CH 2) ₀ SO ₂ NR ⁵ R ⁶ , (CH 2) o NR ⁵ COR ⁶ and NR ⁵ (CH 2) _o COR ⁶ ; wherein R ⁵ and R ^e are as defined below and o is 0, 1 or 2; R ¹ is selected from hydrogen, methyl, ethyl, CH ₂ CH = CH ₂ or CH ₂ -cyclopropyl; R ⁵ and R ⁵ are independently selected from phenyl, methyl and ethyl; or R ⁵ and R ⁶ together represent - (CH ₂ ) r -, where 4 or 5; R ² is H, methyl, or OR ¹ ; R ⁷ , R ³ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹³ independently represent R ¹ as defined above; B is selected phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolynyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquininyl, tetrahydroisoquinolinyl, indole, tetrahydroisoquinolinyl; or 2 substituents independently selected from hydrogen, methyl, _CF3, halogen, (CH _{2) p} -CONR ⁵ R ^6, (CH 2) p NR ⁵ R ^a, (CH 2) _p COR ^5, (CH _{2) p} CO 2 R ^5, OR ^5, wherein p is 0, 1 or 2 and wherein R ⁵ and are as defined above R®; R ³ and R ⁴ are independently selected from H, CH 3, CH (Me) 2, CH 2 CH (Me) 2, CH (Me) CH 2 CH 3 (CH 2) p CONR ⁵ R ⁶ , (CH 2) _p NR ⁵ R ®, ( CH 2) pCONR ⁵ R ⁵ , (CH 2) _p CO ₂ R ⁵ , (CH ₂ ) p Ph, (CH 2) p (p-OH Ph), (CH 2) p -3-indolyl, (CH 2) p PS ⁵ and (CH 2) _P OR ⁵ ; wherein p is 0, 1, 2 or 3 and wherein R ⁵ and R ⁵ are as defined above. The compound of claim 3, wherein A is defined as abzbo and wherein R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined in claim 3. A compound according to any one of claims 1 to 4, in the form of its hydrochloride salt. A compound of formula I according to claim 1 which is a compound A compound of formula I according to claim 1 which is a compound A compound of formula I according to claim 1 which is a compound A compound of formula I according to claim 1 which is a compound A compound of formula I according to claim 1 which is a compound Wherein R is 4-diethylaminocarbonylphenyl. A compound of formula I according to claim 1, which is a compound wherein R is 2-naphthyl. A compound according to any one of claims 1 to 11 for use in therapy. The compound of claim 12, wherein the therapy is pain management. The compound of claim 12, wherein the therapy is directed to gastrointestinal disorders. The compound of claim 12, wherein the therapy is directed to spinal injuries. The compound of claim 12, wherein the therapy is directed to disorders of the sympathetic nervous system. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for use in the treatment of pain. Use of a compound according to any one of claims 1 to 1 for the manufacture of a medicament for use in the treatment of gastrointestinal disorders. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for use in the treatment of spinal injuries. A compound according to any one of claims 1 to 11, characterized in that it is isotopically labeled. Use of a compound according to claim 20 as a diagnostic agent. 22. A pharmaceutical composition comprising a compound of formula I according to claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier. A process for the preparation of a compound of formula I according to claim 1, characterized in that A) (i) the aldehyde or ketone is exposed to a nucleophilic agent to form the corresponding alcohol; (ii) the alcohol is converted to a suitable group, which is then replaced by a nucleophile; and (iii) the N- (4) -substituted piperazine derivative is substituted via its organo halide or equivalent species, or B) (i) The N-protected amino acid ester is reacted with a second amino acid ester and subsequently exposed to an acid to form a piperazinedione; (ii) the dione is reduced to the corresponding piperazine: and (iii) the piperazine is alkylated or acylated at one or more nitrogen. A method of treating pain, characterized in that an effective amount of a compound according to any one of claims 1 to 11 is administered to a subject in need of pain management.