WO1997023467A1 - Novel compounds with analgesic effect - Google Patents

Novel compounds with analgesic effect Download PDF

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Publication number
WO1997023467A1
WO1997023467A1 PCT/SE1996/001636 SE9601636W WO9723467A1 WO 1997023467 A1 WO1997023467 A1 WO 1997023467A1 SE 9601636 W SE9601636 W SE 9601636W WO 9723467 A1 WO9723467 A1 WO 9723467A1
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WO
WIPO (PCT)
Prior art keywords
compound
compound according
conr
cor
hydrogen
Prior art date
Application number
PCT/SE1996/001636
Other languages
French (fr)
Inventor
Edward Roberts
Claes Wahlestedt
Original Assignee
Astra Pharma Inc.
Astra Aktiebolag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IL12499796A priority Critical patent/IL124997A0/en
Application filed by Astra Pharma Inc., Astra Aktiebolag filed Critical Astra Pharma Inc.
Priority to JP09523558A priority patent/JP2000502680A/en
Priority to PL96327538A priority patent/PL327538A1/en
Priority to KR1019980704758A priority patent/KR19990076649A/en
Priority to EP96943427A priority patent/EP0873322A1/en
Priority to NZ324888A priority patent/NZ324888A/en
Priority to AU12163/97A priority patent/AU706436B2/en
Priority to EE9800195A priority patent/EE9800195A/en
Priority to SK819-98A priority patent/SK81998A3/en
Priority to BR9612206A priority patent/BR9612206A/en
Publication of WO1997023467A1 publication Critical patent/WO1997023467A1/en
Priority to IS4768A priority patent/IS4768A/en
Priority to NO982863A priority patent/NO982863D0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention is related to novel compounds which are substituted 7-membered nitrogen rings, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds.
  • the novel compounds are used in therapy, and in particular for the treatment of pain.
  • the ⁇ receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the ⁇ receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the ⁇ receptor have also been shown to posess immunomodulatory activities.
  • the problem underlying the present invention was to find new analgesics having excellent analgesic effects, but also with an improved side-effect profile over current ⁇ agonists and potential oral efficacy.
  • Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
  • novel compounds according to the present invention are defined by the general formula (I)
  • A is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH2) 0 CF3, halogen, CONR 5 R 6 , CO 2 R 5 , COR 5 , (CH 2 )oNR 5 R 6 , (CH 2 )oCH3(CH 2 )oSOR 5 R 6 , (CH 2 ) 0 SO 2 R 5 , (CH 2 ) 0 SO 2 NR 5 , (CH 2 )oNR 5 COR 6 and — NR 5 (CH 2 ) 0 COR 1 ; wherein o is 0, 1, or 2, and R , R and R are as defined below respectively;
  • R is selected from hydrogen, a branched or straight C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C -C6 cycloalkyl; Cg-Cio aryl; and heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O;
  • R and R is each and independently as defined for R above;
  • R is selected from hydrogen, CH3, OR , CO2R , and CH CO 2 R wherein R is as defined above; B is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally substituted by 1-2 substituents each and independently selected from hydrogen, CH3, CF3, halogen, (CH2) p CONR R ,
  • Preferred compounds according to the invention are compounds of the formula (I) wherein
  • A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and pyrrolidinyl; wherein
  • each A group being optionally substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH 2 ) 0 CF3, F, Cl, CONR 5 R 6 , CO 2 R 5 , COR 5 , (CH2) ⁇ SOR 5 , (CH2)oSO 2 R 5 , (CH2) 0 SO 2 NR 5 , (CH 2 )oNR 5 COR 6 and NR 5 (CH 2 ) 0 COR 6 ; wherein R 5 and R are as defined below, and o is 0 or 1; R , R and R is each and independently selected from hydrogen, a branched or straight C1-C4 alkyl, C3-C5 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is -C2 alkyl and cycloalkyl is C3-C6 cycloalkyl, and phenyl;
  • R is hydrogen, methyl, or OR wherein R is as defined above;
  • B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl. indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and
  • each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH , CF3, 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 ;
  • R and R are each and independently selected from hydrogen, CH3, CH(Me) 2 ,
  • each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from H, CH3, (CH 2 ) 0 CF3, F, Cl, CONR R , CO 2 R 5 , (CH 2 ) 0 SOR 5 , (CH 2 )oSO 2 R 5 , (CH 2 ) D SO 2 NR 5 R 6 , (CH 2 )oNR 5 COR 6 , and NR (CH ) 0 COR ; wherein R and R are as defined below, and 0 is 0, 1 or 2;
  • R and R is each and independently selected from phenyl, methyl and ethyl; or R and R taken together is -(CH 2 )r- wherein r is 4 or 5;
  • 2 1 R is H, methyl, or OR ;
  • R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R , and R is each and independently as defined forR above;
  • B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and
  • each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, methyl, CF 3 , halogen, (CH 2 ) p CONR 5 R 6 , (CH 2 )pNR 5 R 6 , (CH2) p COR 5 , (CH 2 ) p CO 2 R 5 , and OR 5 ,
  • R " and R are each and independently selected from H, CH3, CH(Me)2, CH 2 CH(Me)2, CH(Me)CH 2 CH 3 (CH 2 ) p CONR 5 R 6 , (CH 2 )pNR 5 R 6 , (CH 2 ) p CONR 5 R 6 . (CH 2 ) p CO 2 R 5 ,
  • R , R , R and R are as defined above.
  • the substituents A and B respectively, may optionally be substituted at any position of the ring.
  • halogen we mean chloro, fluoro, bromo and iodo.
  • aryl we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
  • heteroaryl we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
  • hydroaromatic we mean a partly or fully saturated aromatic ring structure having 5-10 carbon atoms in the ring.
  • heterohydroaromatic we mean a partly or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
  • isomers we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation.
  • orientation we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
  • isoforms we mean compounds of the formula (I) which differ by their crystal lattice, such as crystalline compound and amorphous compounds.
  • prodrug we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug.
  • pharmaceutically acceptable derivatives e.g. esters and amides
  • the novel compounds of the present invention are useful in therapy, especially for the treatment of pain.
  • a further aspect of the invention is the use of a compound of the formula (I) for the manufacture of a medicament for use in any of the diseases disclosed below.
  • the compounds are useful for modulating the analgesic effects acting at the ⁇ opioid receptor subtype, including for modulating side effects seen with agents acting at the ⁇ opioid receptor subtype such as morphine, especially respiratory depression, gut motility and abuse liability.
  • Compounds of the invention are also useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti tumour agents and anti viral agents.
  • Compounds of the invention are useful also in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • An aldehyde or ketone is treated with a nucleophile such as a Grignard or organolithium species to produce the corresponding alcohol.
  • This alcohol may then be converted into a suitable leaving group (X) such as an ester, sulphonate or halide which may in turn be displaced with a nudeophilic species such as a substituted or unsubstituted piperazine.
  • X a suitable leaving group
  • N- (4)-unsubstituted piperazine derivatives may then be suitably substituted with a variety of groups via their organo halide or equivalent species, or acylated with a number of different acylating compounds. This sequence of events will give rise to compounds according to general formula I.
  • N-protected amino acid as its activated ester, may be reacted with a second amino acid ester.
  • this species On treatment with an acid this species may then cyclize to form a piperazinedione.
  • This dione may be reduced via a number of standard methods to the corresponding piperazine (e.g. a reducing agent such as lithium aluminium hydride, by conversion to the thioamide and subsequent desulphurization, hydrogenation in the presence of POCI3 etc.)
  • This piperazine may then be alkylated or acylated on one or more of the nitrogens and/or may be used subsequently in generalized method A.
  • Ar 4-diethylaminocarbonylphenyl (5)
  • Ar 2- naphthyl (6)
  • Ar 4-diethylaminocarbonylphenyl (9)
  • Ar 2-naphthyl (10)
  • novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, intrathecally and intracerebroventricularly.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, cetrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sub
  • Preferred pharmaceutically acceptable salts are the hydrochlorides and citrates.
  • composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid from compositions include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the fmely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art
  • the pharmaceutical compositions is in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • Human 293S cells expressing cloned human ⁇ , ⁇ , and K receptors and neomycin resistance were grown in suspension at 37°C and 5% CC ⁇ in shaker flasks containing calcium-free DMEM 10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 ⁇ g/ml geneticin.
  • Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec. The suspension was spun at lOOOg (max) for 10 min at 4°C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supernatants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again.
  • lysis buffer 50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol
  • the final pellets were resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined by a modified Lowry assay with SDS.
  • Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, 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 had been freshly added 5 ⁇ g/ml aprotinin, 10 ⁇ M bestatin, 10 ⁇ M diprotin A, no DTT).
  • binding buffer 50 mM Tris, 3 mM MgCl 2 , 1 mg/ml BSA (Sigma A- 7888), pH 7.4
  • the radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least 12h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI- soaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 ⁇ l MS-20 scintillation fluid/well.
  • TopCount Packard
  • the specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test peptides was expressed as percentage of control SB.
  • Values of IC50 and Hill coefficient (n ⁇ ) for ligands in displacing specifically bound radiohgand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit.
  • Values of Kj were calculated from the Cheng-Prussoff equation. Mean ⁇ S.E.M. values of IC50, Kj and n ⁇ were reported for ligands tested in at least three displacement curves.
  • Radioligand Kg values were determined by perf orming the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kg (up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kg and Bma from individual experiments were obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site mode B) BIOLOGICAL MODEL (IN VIVO MODEL)

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 EFFECT
Field of the invention
The present invention is related to novel compounds which are substituted 7-membered nitrogen rings, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are used in therapy, and in particular for the treatment of pain.
Background and prior art
The δ receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the δ receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the δ receptor have also been shown to posess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (μ, δ and K) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid δ ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-pepudic δ antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e., < 10-fold) selectivity for the δ receptor vs μ receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non- peptidic δ ligands. Recently, a non-peptidic δ agonist, BW 373U86, was described by Chang et al., 1993, J. Pharmacol. Exp. Ther., 267: 852-857., as the first δ-selective non-peptide with analgesic activity, however, it shows significant affinity for the μ receptor.
Thus, the problem underlying the present invention was to find new analgesics having excellent analgesic effects, but also with an improved side-effect profile over current μ agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine and diarylmethyl- piperidine compounds, including BW 373U86. are disclosed, but these prior art compounds are structurally distinct from the compounds acccording to the present invention.
The problem mentioned above has been solved by developing novel compounds which are 7-membered nitrogen rings, as will be described below.
Outline of the invention
The novel compounds according to the present invention are defined by the general formula (I)
Figure imgf000005_0001
wherein
A is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH2)0CF3, halogen, CONR5R6, CO2R5, COR5, (CH2)oNR5R6, (CH2)oCH3(CH2)oSOR5R6, (CH2)0SO2R5, (CH2)0SO2NR5, (CH2)oNR5COR6 and — NR5(CH2)0COR1; wherein o is 0, 1, or 2, and R , R and R are as defined below respectively;
R is selected from hydrogen, a branched or straight C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C -C6 cycloalkyl; Cg-Cio aryl; and heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O;
R and R is each and independently as defined for R above;
2 1 1 1
R is selected from hydrogen, CH3, OR , CO2R , and CH CO2R wherein R is as defined above; B is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally substituted by 1-2 substituents each and independently selected from hydrogen, CH3, CF3, halogen, (CH2)pCONR R ,
(CH2)pNR5R6, (CH2)pCOR5, (CH2)pCO2R5, OR5, (CH2)pSOR5, (CH2)pSO2R5, and
(CH2)pSO2NR5R6; wherein p is 0, 1 , 2 or 3 and wherein R and R are as defined above;
3 4 R and R is each and independently selected from
R5, (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCONR5R6, (CH2)pCO2R5, (CH2)pPh,
(CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR5 or (CH2)pOR5; wherein p is 0, 1, 2, 3, or 4, and wherein R and R are as defined above.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof.
Preferred compounds according to the invention are compounds of the formula (I) wherein
A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and pyrrolidinyl; wherein
each A group being optionally substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH2)0CF3, F, Cl, CONR5R6, CO2R5, COR5, (CH2)σSOR5, (CH2)oSO2R5, (CH2)0SO2NR5, (CH2)oNR5COR6 and NR5(CH2)0COR6; wherein R5 and R are as defined below, and o is 0 or 1; R , R and R is each and independently selected from hydrogen, a branched or straight C1-C4 alkyl, C3-C5 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is -C2 alkyl and cycloalkyl is C3-C6 cycloalkyl, and phenyl;
2 1 1
R is hydrogen, methyl, or OR wherein R is as defined above;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl. indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and
Figure imgf000007_0001
each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH , CF3, halogen, (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCOR5, (CH2)pCO2R5, and OR5;
wherein p is 0 or 1 , and wherein R and R are as defined above;
3 4 R and R are each and independently selected from hydrogen, CH3, CH(Me)2,
CH2CH(Me)2, CH(Me)CH2CH (CH2)pCON5R6, (CH2)pNR5R6, (CH2)pCONR5R6
(CH2)pCO2R5, (CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR5, and
(CH2) OR , wherein p is 0, 1, 2, or 3, and wherein R and R are as defined above. Especially preferred compounds according to the invention are compounds of the formula (I) wherein
Figure imgf000008_0001
Figure imgf000008_0002
wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from H, CH3, (CH2)0CF3, F, Cl, CONR R , CO2R5, (CH2)0SOR5, (CH2)oSO2R5, (CH2)DSO2NR5R6, (CH2)oNR5COR6, and NR (CH )0COR ; wherein R and R are as defined below, and 0 is 0, 1 or 2;
R .1 i •s selected from hydrogen, methyl, ethyl, CH2CH=CH , or CH2-cyclopropyl;
R and R is each and independently selected from phenyl, methyl and ethyl; or R and R taken together is -(CH2)r- wherein r is 4 or 5;
2 1 R is H, methyl, or OR ;
XI n8 -.9 _,10 „11 -.12 „13 n14 „15 ,D16. , .- . . ., J C J
R ,R ,R ,R ,R ,R ,R ,R ,R , and R , is each and independently as defined forR above; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and
Figure imgf000009_0001
each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, methyl, CF3, halogen, (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCOR5, (CH2)pCO2R5, and OR5,
wherein p is 0, 1, or 2, and wherein R and R are as defmed above;
3 4
R" and R are each and independently selected from H, CH3, CH(Me)2, CH2CH(Me)2, CH(Me)CH2CH3 (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCONR5R6. (CH2)pCO2R5,
(CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR5, and (CH2)pOR:':
wherein p is 0, 1, 2, or 3, and wherein R and R are as defined above.
Even more preferred is to use a compound where the A substituent is
Figure imgf000009_0002
9 10 11 12 and wherein R , R , R and R , are as defined above. The substituents A and B respectively, may optionally be substituted at any position of the ring.
By "halogen" we mean chloro, fluoro, bromo and iodo.
By "aryl" we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
By "heteroaryl" we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By "hydroaromatic" we mean a partly or fully saturated aromatic ring structure having 5-10 carbon atoms in the ring.
By "heterohydroaromatic" we mean a partly or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By "isomers" we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By "orientation" we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By "isoforms" we mean compounds of the formula (I) which differ by their crystal lattice, such as crystalline compound and amorphous compounds.
By "prodrug" we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int Ed. 1992, "Biotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated. The novel compounds of the present invention are useful in therapy, especially for the treatment of pain.
A further aspect of the invention is the use of a compound of the formula (I) for the manufacture of a medicament for use in any of the diseases disclosed below.
The compounds are useful for modulating the analgesic effects acting at the μ opioid receptor subtype, including for modulating side effects seen with agents acting at the μ opioid receptor subtype such as morphine, especially respiratory depression, gut motility and abuse liability.
Compounds of the invention are also useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti tumour agents and anti viral agents.
Compounds of the invention are useful also in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension. Methods of preparation
Generalized Method A
An aldehyde or ketone is treated with a nucleophile such as a Grignard or organolithium species to produce the corresponding alcohol. This alcohol may then be converted into a suitable leaving group (X) such as an ester, sulphonate or halide which may in turn be displaced with a nudeophilic species such as a substituted or unsubstituted piperazine. N- (4)-unsubstituted piperazine derivatives may then be suitably substituted with a variety of groups via their organo halide or equivalent species, or acylated with a number of different acylating compounds. This sequence of events will give rise to compounds according to general formula I.
Generalized Method B
An N-protected amino acid, as its activated ester, may be reacted with a second amino acid ester. On treatment with an acid this species may then cyclize to form a piperazinedione. This dione may be reduced via a number of standard methods to the corresponding piperazine (e.g. a reducing agent such as lithium aluminium hydride, by conversion to the thioamide and subsequent desulphurization, hydrogenation in the presence of POCI3 etc.) This piperazine may then be alkylated or acylated on one or more of the nitrogens and/or may be used subsequently in generalized method A.
Deprotection of functional groups or further modifications may then be necessary, these are described for each individual case. Specific examples for the above transformations are given in the experimental. All transformations contemplated use reagents (including salts) and solvents known to the art of chemistry and to biotransformations carried out in a suitable biological medium to bring about these transformations and includes all reaction enhancing agents (e.g. HMPA), and chiral resolutions using chiral salt formation and chiral biological resolutions.
The best mode of carrying out the invention known at present is to use the 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.
EXAMPLES
The compounds according to Examples 1-3 were synthesized as shown in Scheme 1 below.
Scheme 1
4-(α-(l-HomopiDerazinyl)-3-methoxybenzyl)-N.N-diethylbenzamide (1.2 and 3).
Figure imgf000014_0001
cyclopropylmethyl chloride
Figure imgf000014_0002
A)
L Preparation of 4-(α-Hvdroxyl-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 M, 20 mL, 32 mmol) under nitrogen at -78°C The mixture was stirred for 1 hr at the same temperature prior to the addition of 4- formyl-N,N-diethyl-benzamide (6.15 g, 30.0 mmol) in dry THF (20mL). The reaction mixture was allowed to warm up to r.t (4 h), and then quenched with ammonium chloride (aq.). The solvent was removed in vacuo, the residue dissolved in ethyl acetate/heptane, 1:1, washed with brine and dried (MgSO4). Evaporation of solvent in vacuo gave a crude product, which was purified by column chromatography on silica gel to afford 4-(α- hydroxyl-3-methoxybenzyl)-N,N-diethylbenzamide (6.15 g, 66%): H-NMR (400 MHz, CDC13) δ 1.10 (3 H, br, CH3CH2N-), 1.22 (3 H, br, CH3CH2N ), 2.60 (IH, br, OH), 3.24 (2 H, br, CH3CH2N-), 3.52 (2 H, br, CH3CH2N ), 3.79 (3H, s, OCH3), 5.80 (IH, s, CHN), 6.81 (1 H, , ArH), 6.93 (1 H, , ArH), 6.94 (IH, m, ArH), 7.25 (1 H, m, ArH), 7.31 (2H, m, ArH), 7.39 (2 H, m, ArH).
π. Preparation of 4-(α-Chloro-3-methoxybenzyl)-N ^-dιethylbenzamide (compound A in Scheme 1)
To a solution of 4-(α-hydroxyl-3-methoxybenzyl)-N,N-diethylbenzamide (3.13 g. 10.0 mmol), in AcOEt (20mL) was added 35% hydrochloric acid (20 mL) at 0° C. The reaction mixture was stirred for 12 hr at r.t and extracted with AcOEt. The organic layers was washed with saturated ammonium chloride solution and brine, dried over MgSO4 and evaporated to give a crude product, which was purified by column chromatography on silica gel to afford 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-(l-Homopiperazinvπ-3-methoxτbenzγl)-N.N-diethylbenzamide (compound 1)
A mixture of homopiperazine (200 mg, 2.0 mmol), ^(α-chloro-S-methoxybenzyl^NJ^- diethylbenzamide (331 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) in dry acetonitrile (50 mL) was refluxed for 2 hr under nitrogen, after cooling down to r.t., the reaction mixture was quenched with IN aqueous NH4OH solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous NH4C1 and brine, dried over MgSO4. Removal of solvents gave 4-<α-(l-homopiperazinyl)-3- memoxybenzyl)-N,N-diethylbenzamide (compound 1), which was purified by silica gel column eluting with MeOH-CH2Cl2 (2 : 98 → 10 : 90) to provide the title compound (254 mg, 64%).
GC-MS (R, = 17.35 min) 396.30 (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 (16.6), 1 12.15 (4.8), 99.20 (100); κ (400 MHz, CDC13) 1.10 (brs, 3H), 1.20 (brs, 3H), 1.82 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.72 (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, IH), 5.26 (brs, IH), 6.72 (m, IH), 6.99 (m, 2H), 7.18 (t, J=8.0 Hz, IH), 7.28 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H); δc.,3 (100 MHz, CDC13) 12.8, 14.2, 29.0, 39.2. 43.3. 46.0, 48.6, 53.0, 53.6, 55.2, 74.9, 1 12.3, 113.5, 120.2, 126.7, 127.8, 129.5, 135.9. 144.3, 144.4, 159.7, 171.0.
Its HBr salt: m.p. 137- 140.5°C (AcOEt-Ether); v. ( KBr) cm"1 3500, 1600, 1288; Λnα/.Calcd.for C24H33N3O2 .1.5HBr.0.8H2O: 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-l-homopiperazinyl)- 3- methoxτbenzvO-N.N- diethylbenzamide (compound 2)
A mixture of homopiperazine (114 mg, 1.14 mmol), 4-<α-chloro-3-methoxybenzyl)-N,N- diethylbenzamide (compound A)(100 mg, 0.3 mmol) and K2CO3 (138 mg, 1.0 mmol) in dry acetonitrile (10 mL) was refluxed for 5 hr under nitrogen, after cooling down to r.t, the reaction mixture was quenched with IN aqueous NH4OH solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous NH4C1 and brine, dried over MgSO4. Removal of solvents gave 4-(α-(4-methyl-l- homopiperazinyl)-3-methoxybenzyl)-N,N-dieώylbenzamide, which was purified by silica gel column eluting with MeOH-CH2Cl2 (5 : 95 - 10 : 90) to provide the title compound (82 mg, 67%).
GC-MS (R,= 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); OH (400 MHZ, CDC13) 1.10 (brs, 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, IH), 6.72 (dt, J=8.0, 1.2 Hz, IH), 6.99 (m, 2H), 7.18 (dt, J=8.0, 1.2 Hz, IH), 7.27 (dd, J=8.4, 1.6 Hz, 2H), 7.44 (dd, J=8.4, 1.6 Hz, 2H); δc.13 (100 MHz, CDC13) 12.9, 14.2, 27.7, 39.1, 43.2, 46.9, 52.7, 52.8, 55.2, 56.3, 59.1, 75.3, 1 12.0, 113.7, 120.4, 126.6, 127.9, 129.4, 135.7, 144.7, 144.8, 159.7, 171.1.
Its HBr salt: m.p. 165-178°C (AcOEt- Ether); v∞ (KBr) cm"1 3400, 1603, 1286; Λw /.Calcd.for C25H35N3O2.2.0HBr .0.6H2O: 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«Cvclopropylmethyl-l»homopin<>raπnvi)-3-methoxybenzyl)- N.N-diethylbenzamide (compound 3)
A mixture of 4-(α-(l-homopiperaz yl)-3-methoxybenzyl)-NJ^-diethylbenzamide (compound 1) (119 mg, 0.3 mmol), (chloromethyl)cyclopropane (45 mg, 0.5 mmol), sodium iodide (75 mg, 0.5 mmol) and K2CO3 (138 mg, 1.0 mmol) in MeCN (10 mL) was refluxed for 2 hr. after cooling down to r.L, the reaction mixture was quenched with IN aqueous NH4OH solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous NH4C1 and brine, dried over MgSO4. Removal of solvents gave 4-(α-(4-cyclopropylmethyI- 1 -homopiperazinyl 3- methoxybenzyl)-N,N-diethylbenzamide (compound 3), which was purified by silica gel column eluting with MeOH-CH2Cl2 (1 : 99 → 10 : 90) to provide the title compound (125 mg, 93%).
GC-MS (Rt= 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); oH(400 MHz, CDCl3) 0.33 (m, 2H), 0.69 (m, 2H), 1.11 (m, 3H), 1.20 (m, 4H), 2.1 1 (m, 2H), 2.69 (t, J=6.4 Hz, 2H), 2.81 (d, J=6.6 Hz, 2H), 2.90 (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, IH), 6.75 (ddd, J=8.4, 2.4, 1.2 Hz, IH), 6.98 (m, 2H), 7.21 (t, J=8.0 Hz, IH), 7.30 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H); δc.ι3 (100 MHz, CDC13) 4.6, 6.5, 12.8, 14.1, 24.9, 39.1, 43.3, 48.8, 52.4, 52.5, 55.2, 55.5, 62.3, 74.9, 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: m.p. 138-147°C (AcOEt-Ether); v^ (KBr) cm'1 3435, 1606, 1287:
Λnα/.Calcd.for C28H39N3O2.1.20HBr . 1.40H2O: C, 58.80; H, 7.58; N, 7.35. Found: C, 58.82; H, 7.58: N, 7.24.
Scheme 2 4-(α-(l-Homopiperazinyl)benzyl)-N -diethylbenzamide hydrochloride (compound
Homopiperazine
Figure imgf000019_0001
Figure imgf000019_0002
(4)
The compound according to Example 4 was synthesized as shown in Scheme 2 above.
B )
I. Preparation of 4-(Phenyl-hvdroxymethτl )-N.N-diethylbenzamide
4-Formyl-N,N-diethyl-tenzamide (19.5 g, 95 mmol) was dissolved in dry THF, cooled to -78° C under nitrogen. Phenyl magnesium bromide (104 mL, 1.0M in THF) was added dropwise at -78° C. The temperature was allowed to rise slowly until reaction complete (1 h). The reaction was quenched with ammonium chloride (aq.). The solvent was removed in vacuo, the residue dissolved in ethyl acetate/heptane, 1:1, washed with brine and dried (MgSO4). Evaporation of solvent in vacuo gave 26.5 g (98%) of 4-(phenyl- hydroxymethyl)-N,N-diethylbenzamide. MS: 282, 211, 165, 105, H NMR: (CDCI3): δ = 7.38-7.20 (m, 9H), 5.80 (d, J=3.5Hz, 1 H), 3.5, 3.2 (2br.s, 4H), 1.2, 1.05 (2br. s, 6H). π. Preparation of 4-(Chloro-phen yl-methvD-N.N-diethylbenzamide (compound B in Scheme 2)
4-(Phenyl-hydroxymethyl)-N,N-diethylbenzamide (24.5 g, 93 mmol) was dissolved in dichloromethane (300mL), dried with 4A molecular sieves, and transferred to a dry flask under nitrogen. Thionyl chloride (7.5 mL, 103 mmol) was added at 0° C. Solution stirred at 25° C for 1 h. Solvent evaporated in vacuo. Residue dissolved in toluene and solvent evaporated again.4-(Chloro-phenyl-methyl)-N,N-diethylbenzamide (compound B) was obtained as an oil (~ 100%) which crystallized in the freezer. GC-MS (2 peaks): 296, 225, 116655,, 112211 aanndd 330000,, 226666,, 222299,, 119955,, 116655. *H NMR: (CDC13): δ = 7.45-7.20 (m, 9H), 6.09 (s, IH), 3.4 (br. m, 4H), 1.1 (br. m, 6H).
Example 4 Preparation of 4-(α-(l-Homopiperazinyl)benzγQ-N.N-diethylbenzaιnide (compound 4)
This compound was prepared as described for Example 1 (compound 1), but substituting compound A for compound B.
4-(α-(l-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), 165.15 (62.7), 99.20 (100); 6H (400 MHZ, CDC13) 1.08 (brs, 3H), 1.18 (brs, 3H), 1.69 (m, 2H), 2.56 (s, IH), 2.62 (m, 4H), 2.85 (m, 2H), 2.97 (m, 2H), 3.23 (brs, 2H), 3.50 (brs, 2H), 4.63 (s, IH), 7.16 (m, IH), 7.26 (m, 4H), 7.40 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H); δc-n (100 MHz, CDC13) 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): m.p. 155-165 °C (AcOEt-Ether); v.^ (KBr) cm'1 3418, 1628, 1591, 1074; A/ω/. Calcd. for C23H31N3O.2.50HC1.0.90H2O: C, 58.42; H, 7.52; N, 8.89. Found: C, 58.35; H, 7.52; N, 8.62.
Scheme 3
4-(α-(l-Homopiperazinyl)aryl)-N.N-diethylbenzamide hydrochloride (compounds 9 and 10).
Figure imgf000021_0001
(5) and (6)
Ar=4-diethylaminocarbonylphenyl (5) Ar=2- naphthyl (6)
Figure imgf000021_0002
(9) and (10)
Ar=4-diethylaminocarbonylphenyl (9) Ar=2-naphthyl (10)
The compounds according to Examples 5-10 were synthesized as shown in Scheme 3 above. C)
I. Preparation of 4-Iodo-N.N-diethvIbenzamide (compound C in Scheme 3)
To a solution 4-iodobenzoyl chloride (13.3 g, 50 mmol) in dry dichloromethane (50 mL) was slowly added diethylamine (30 mL) at 0 °C. After addition, the reaction mixture was warmed to r.t. and stirred for one hour at r.t., and then quenched with aqueous K2CO3 solution, extracted with diethyl ether (2 x 200 mL). The organic phases were washed with brine, dried over MgSO4. Evaporation of solvents gave the crude product, which were puried by silica gel column eluting with MeOH-CH2Cl2 (1 : 99) to provide 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 M, 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 dropwise added, the reaction mixture was warmed to r.L and then quenched with aqueous NH4C1 solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4. Removal of solvents gave a crude product, which was purified by silica gel column eluting with MeOH-CH2d2 (1 : 99 → 5 : 95) to provide Di-(4-N,N- diethylaminocarbonylρhenyl)methanol (725 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); OH (400 MHz, CDC13) 1.06 (brs, 6H), 1.19 (brs, 6H), 3.20 (brs, 4H), 3.48 (brs, 4H), 5.26 (s, IH), 5.66 (s, IH), 7.21 (d, J=8.0 Hz, 4H), 7.31 (d, J=8.0 Hz, 4H); Oc.i3 (100 MHz, CDC13) δ: 12.5, 13.9, 39.0, 43.0, 74.5, 125.9, 126.2, 135.3, 145.3, 171.0. HI. Preparation of 4-(α-chloro-4-N.N-diethylaminocarbonylbenzyl)-N.N- diethylbenzamide (compound 7)
To a solution of di-(4-N,N-diethylaminocarbonylphenyl)methanol (400 mg, 1.05 mmol) in dry dichloromethane (10 mL) was dropwise added thionyl chloride (1.0 mL, 13.7 mmol) at r.t. The reaction mixture was stirred for one hour at r.t Evaporation of solvents gave 4-(α- chloro-4-N,N-diethylaminocarbonylbenzyl)-N^-diethylbenzamide, which was used directly in the next step: i (400 MHz, CDC13) 1.16 (brs, 12 H), 3.38 (brs, 8H), 6.15 (s, IH), 7.35 (d, J=8.0 Hz, 4H), 7.44 (d, J=8.0 Hz, 4H); δc.ι3 (100 MHz, CDC13) δ: 13.1, 39.1, 42.5, 62.7, 126.3, 127.5, 136.2, 141.3, 170.3.
Example 5
Preparation of 4-(α-( 1 -Homopiperazin yl )-4-N J*J-dieth ylaminocarbony I benz yl)-N.N- 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); OH (400 MHz, CDC13) 1.11 (brs, 6H), 1.21 (brs, 6H), 1.69 (m, 2H), 2.36 (brs, IH), 2.63 (m, 4H), 2.97 (m, 2H), 3.00 (m, 2H), 3.25 (brs, 4H), 3.52 (brs, 4H), 4.63 (s, IH), 7.27 (d, J=8.4 Hz, 4H), 7.43 (d, J=8.4 Hz, 4H); δ π (100 MHz, CDC13) 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: m.p. 158-164 °C (AcOEt-Ether); v^ (KBr) cm"1 3498, 1627, 1047; Λm*/.Calcd.for
Figure imgf000023_0001
. 2.70HC1 . 0.30H2O: C, 59.16; H, 7.68; N, 9.86. Found: C, 59.25; H, 7.66; N, 9.63. IV. Preparation of 4-(α-hydroxγ-2-naphthylmethyl)-N S-diethylbenzamide (compound 6)
This compound was prepared as described for compounds 1 and 4.
GC-MS: 333.20 (M+, 58.2%), 332.20 (100), 316.15 (2.6), 261.10 (88.3), 215.05 (18.8), 155.05 (54.8), 127.10 (29.0); 6H (400 MHz, CDC13) 0.93 (brs, 3H), 1.1 1 (brs, 3H), 3.08 (brs, 2H), 3.38 (brs, 2H), 4.80 (brs, IH), 5.73 (s, IH), 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, IH), 7.37 (m, 2H), 7.63 (d, J=8.4 Hz, IH), 7.70 (m, 2H), 7.74 (s, IH); δc.13 (100 MHz, CDC13) 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, 132.7, 135.2, 141.3, 145.2, 171.1.
V. Preparation of 4-(α-chloro-2-naphthγl)-N.N-diethylbenzamide (compound 8)
This compound was prepared as described for compounds 1 and 4.
Used directly in the next step: κ% (400 MHz, CDC13) 1.15 (brs, 6H), 3.38 (brs, 4H), 6.28 (s, IH), 7.35 (m, 2H), 7.47 (m, 5H), 7.80 (m, 4H).
Example 6
Preparation of 4-(α-(l-Homopiperazinyl)-2-naphthylmethγl)-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« (400 MHz, CDC13) 1.07 (brs, 3H), 1.17 (brs, 3H), 1.69 (m, 2H), 2.63 (brs, IH), 2.67 (m, 4H), 2.86 (m, 2H), 2.98 (m, 2H), 3.20 (brs, 2H), 3.48 (brs, 2H), 4.80 (s, IH), 7.30 (d, J=8.0 Hz, 2H), 7.42 (m, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.61 (m, IH), 7.78 (m, 4H); δc-ι3 (100 MHz, CDC13) 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: m.p. 165-172 °C (AcOEt-Ether); v^ (KBr) cm"1 3462, 1612 , 1106; Λrtfl/.Calcd.for C27H33N3O . 2.0HC1 . 1.60H2O: C, 62.69; H, 7.44; N, 8.12. Found: C, 62.80; H, 7.37; N, 8.03.
Pharmaceutical compositions
The novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, intrathecally and intracerebroventricularly.
The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, cetrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannata, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc.
Preferred pharmaceutically acceptable salts are the hydrochlorides and citrates.
The term composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid from compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the fmely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art
Preferably the pharmaceutical compositions is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
Biological evaluation
A) IN VITRO MODEL Cell culture
Human 293S cells expressing cloned human μ, δ, and K receptors and neomycin resistance were grown in suspension at 37°C and 5% CC^ in shaker flasks containing calcium-free DMEM 10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 μg/ml geneticin.
Membrane preparation
Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec. The suspension was spun at lOOOg (max) for 10 min at 4°C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supernatants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pellets were resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined by a modified Lowry assay with SDS.
Binding assays
Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mM MgCl2, 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 had been freshly added 5 μg/ml aprotinin, 10 μM bestatin, 10 μM diprotin A, no DTT). Aliquots of 100 μl (for μg protein, see Table 1) were added to iced 12x75 mm polypropylene tubes containing 100 μl of the appropriate radioligand (see Table 1) and 100 μl of test peptides at various concentrations. Total (TB) and nonspecific (NS) binding were determined in the absence and presence of 10 μM naloxone respectively. The tubes were vortexed and incubated at 25°C for 60-75 min, after which time the contents are rapidly vacuum-filtered and washed with about 12 ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl2) through GF/B filters (Whatman) presoaked for at least 2h in 0.1% polyethyleneimine. The radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least 12h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI- soaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 μl MS-20 scintillation fluid/well.
Data analysis
The specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test peptides was expressed as percentage of control SB. Values of IC50 and Hill coefficient (nπ) for ligands in displacing specifically bound radiohgand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. Values of Kj were calculated from the Cheng-Prussoff equation. Mean ± S.E.M. values of IC50, Kj and nπ were reported for ligands tested in at least three displacement curves.
Receptor saturation experiments
Radioligand Kg values were determined by perf orming the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kg (up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kg and Bma from individual experiments were obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site mode B) BIOLOGICAL MODEL (IN VIVO MODEL)
The well characterized hot plate test (Jolicoeur et al., 1991, "Neurobehavioral evidence for kappa agonist activity of the morphinan derivation 14-b-methyl 8-oxacyclorphan ΪBC(3016)]": Pharmacol. Biochem. Behav. 38: 401-405.) and tail flick test (D'Amour, F.E. and Smith, D.L. (1941): "A method for determining 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 spinal adrenergic analgesia: reversal by mo hine and naloxone"; J. Pharm. Exp. Ther. 340: 972-977) were used to evaluate the effectiveness of compounds of the present invention as potent analgesics.

Claims

Claims
1. A compound of the general formula (I)
Figure imgf000031_0001
wherein
A is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH2)0CF3, halogen, CONR R6, CO2R5, COR5, (CH2)oNR5R6, (CH2)0CH3(CH2)oSOR5R6, (CH2)0SO2R5, (CH2)0SO2NR5, (CH2)oNR5COR6 and — NR5(CH2)0COR1; wherein 0 is 0, 1, or 2, and R , R and R are as defined below respectively;
R is selected from hydrogen, a branched or straight Ci-Cβ alkyl, C3-C8 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is -C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; Cβ-Cio aryl; and heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O;
R and R is each and independently as defined for R above;
2 1 1 1
R is selected from hydrogen, CH3, OR , CO2R , and CH2CO2R wherein
R is as defined above; B is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally substituted by 1-2 substituents each and independently selected from hydrogen, CH3, CF3, halogen, (CH2)pCONR R ,
(CH2)pNR5R6, (CH2)pCOR5, (CH2)pCO2R5, OR5, (CH2)pSOR5, (CH2)pSO2R5, and
(CH2)pSO2NR5R6; wherein p is 0, 1 , 2 or 3 and wherein R and R are as defined above;
3 4
10 R and R is each and independently selected from
R5, (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCONR5R6, (CH2)pCO2R5, (CH2)pPh,
(CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR5 or (CH2)pOR5; wherein p is 0, 1, 2, 3, or 4, and wherein R and R are as defined above;
i5 as well as pharmaceutically acceptable salts of the compounds of the formula (I), isomers, hydrates, isoforms and prodrugs thereof.
2. A compound of the formula I according to claim 1 , wherein 0
A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and pyrrolidinyl; wherein
25 each A group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH3, (CH2)0CF3, F, Cl, CONR5R6, CO2R5, COR5, (CH2)oSOR5, (CH2)oSθ2R5, (CH2)oSO2NR5, (CH2)oNR5COR6 and NR5(CH2)0COR6; wherein R5 and R are as defined below, and o is 0 or 1 ;;
30 R , R and R is each and independently selected from hydrogen, a branched or straight C1-C4 alkyl, C3-C5 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is Cι-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl, and phenyl;
2 1 1
R is hydrogen, methyl, or OR wherein R is as defined above;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and
Figure imgf000033_0001
each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH , CF3, halogen, (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCOR5, (CH2)pCO2R5, and OR5,
wherein p is 0 or 1 , and wherein R and R are as defined above;
3 4
R and R are each and independently selected from hydrogen, CH3, CH(Me) ,
CH2CH(Me)2, CH(Me)CH2CH3 (CH2)pCON5R6, (CH2)pNR5R6, (CH2)pCONR5R6 ,
(CH2)pCO2R5, (CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR5, and
(CH2)pOR , wherein p is 0, 1, 2, or 3, and wherein R and R are as defined above. 3. A compound according to claim 2, wherein
A is selected from
Figure imgf000034_0001
Figure imgf000034_0002
wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from H, CH3, (CH2)0CF3, F, Cl, CONR R , CO2R5, (CH2)0SOR5, (CH toSC^R5, (CH2)0SO2NR5R6, (CH2)oNR5COR6, and NR (CH )0COR ; wherein R and R are as defined below, and 0 is 0, 1 or 2;
R is selected from hydrogen, methyl, ethyl, CH2CH=CH , or CH2-cyclopropyl;
R and R is each and independently selected from phenyl, methyl and ethyl; or R and R taken together is -CH2r- wherein r is 4 or 5;
2 1 R is H, methyl, or OR ;
R ,R ,R ,R ,R ,R ,R ,R ,R , and R , is each and independently as defined for R above; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and
Figure imgf000035_0001
each B group being optionaUy substituted by 1-2 substituents independently selected from hydrogen, methyl, CF3, halogen, (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCOR5, (CH2)pCO2R5, and OR5,
wherein p is 0, 1, or 2, and wherein R and R are as defmed above;
3 4
R and R are each and independently selected from H, CH3, CH(Me)2, CH2CH(Me)2, CH(Me)CH2CH (CH2)pCONR5R6, (CH2)pNR5R6, (CH2)pCONR5R6, (CH2)pCO2R5,
(CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR5, and (CH2)pOR5
wherein p is 0, 1, 2, or 3, and wherein R and R are as defined above.
4. A compound according to claim 3, wherein
A is defined as
Figure imgf000035_0002
9 10 11 12 and wherein R , R , R and R , are as defined in claim 3. 5. A compound according to any of claims 1-4, in form of its hydrochloride salt
A compound of the formula (I) of claim 1, which compound is
Figure imgf000036_0001
7. A compound of the formula (I) of claim 1 , which compound is
Figure imgf000036_0002
8. A compound of the formula (I) of claim 1, which compound is
Figure imgf000037_0001
9. A compound of the formula (I) of claim 1, which compound is
Figure imgf000037_0002
10. A compound of the formula (I) of claim 1, which compound is
Figure imgf000038_0001
wherein R is 4-diethylaminocarbonylphenyl.
11. A compound of the formula (I) of claim 1 , which compound is
Figure imgf000038_0002
wherein R is 2-naphtyl.
12. A compound according to any of claims 1 - 11 , for use in therapy. 13. A compound according to claim 12, wherein the therapy is pain management
14. A compound according to claim 12, wherein the therapy is directed towards gastrointestinal disorders.
15. A compound according to claim 12, wherein the therapy is directed towards spinal injuries.
16. A compound according to claim 12, wherein the therapy is directed to disorders of the sympathetic nervous system.
17. Use of a compound according to any of claims 1-11 for the manufacture of a medicament for use in the treatment of pain.
18. Use of a compound according to any of claims 1-1 1 for the manufacture of a medicament for use in the treatment of gastrointestinal disorders.
19. Use of a compound according to any of claims 1 - 1 1 for the manufacture of a medicament for use in the treatment of spinal injuries.
20. A compound according to any of claims 1-11, further characterized in that it is isotopically labelled.
21. Use of a compound according to claim 20 as a diagnostic agent
22. A pharmaceutical composition comprising a compound of the formula I according to claim 1 as an active ingredient together with a pharmaceutically acceptable carrier. 23. A process for the preparation of a compound according to the formula (I) of claim 1, whereby
A) (i) An aldehyde or ketone is treated with a nucleophile, giving the corresponding alcohol;
(ii) the alcohol is converted into a suitable leaving group, which in turn is displaced with a nucleophile; and
(iii) a N-(4)-unsubstituted piperazine derivative is substituted via its organo halide or equivalent species, or acylated; or
B)
(i) A N-protected amino acid ester is reacted with a second amino acid ester, and thereafter treated with an acid, giving a piparazinedione;
(ii) the dione is reduced to the corresponding piperazine: and
(iii) the piperazine is alkylated or acylated on one or more of the nitrogens.
24. A method for the treatment of pain, whereby an effective amount of a compound according to any of claims 1-11 is administered to a subject in need of pain management
PCT/SE1996/001636 1995-12-22 1996-12-11 Novel compounds with analgesic effect WO1997023467A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6200978B1 (en) * 1998-03-05 2001-03-13 Pfizer Inc. Compounds as delta opioid agonists
EP1181279A1 (en) * 1999-05-12 2002-02-27 Torrey Pines Institute For Molecular Studies Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof
EP1408037A1 (en) * 1995-12-22 2004-04-14 AstraZeneca AB Novel diarylmethylpiperazine and diarylmethylphenyl compounds with analgesic effect
US7799337B2 (en) 1997-07-21 2010-09-21 Levin Bruce H Method for directed intranasal administration of a composition
US8412336B2 (en) 2008-12-29 2013-04-02 Autonomic Technologies, Inc. Integrated delivery and visualization tool for a neuromodulation system
US8473062B2 (en) 2008-05-01 2013-06-25 Autonomic Technologies, Inc. Method and device for the treatment of headache
US8494641B2 (en) 2009-04-22 2013-07-23 Autonomic Technologies, Inc. Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism
US9320908B2 (en) 2009-01-15 2016-04-26 Autonomic Technologies, Inc. Approval per use implanted neurostimulator

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2186295C2 (en) 1999-10-27 2002-07-27 Беллакем Ою Cyclic-action plant for utilization of wastes containing polymer compounds
EE9900336A (en) 1999-10-27 2000-10-16 Bellakem OÜ Cycle operation for the disposal of waste containing polymeric compounds

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0166302A2 (en) * 1984-06-19 1986-01-02 POLI INDUSTRIA CHIMICA S.p.A. "1-[Bis-(4-fluorophyl)methyl]-4-(3-phenyl-2-propenyl)-hexahydro-1H-1,4-diazepine, preparation thereof and compositions containing it
EP0283310A1 (en) * 1987-03-18 1988-09-21 Sankyo Company Limited N-Benzhydryl-substituted heterocyclic derivatives, their preparation and their use
EP0289227A1 (en) * 1987-04-24 1988-11-02 Syntex Pharmaceuticals Ltd. Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives
GB2210366A (en) * 1987-09-30 1989-06-07 American Home Prod Substituted cycloalkanols
WO1993015062A1 (en) * 1992-02-03 1993-08-05 The Wellcome Foundation Limited Opioid diarylmethylpiperazines and piperidines
WO1995004051A1 (en) * 1993-07-30 1995-02-09 The Wellcome Foundation Limited Piperazine compounds used in therapy

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0166302A2 (en) * 1984-06-19 1986-01-02 POLI INDUSTRIA CHIMICA S.p.A. "1-[Bis-(4-fluorophyl)methyl]-4-(3-phenyl-2-propenyl)-hexahydro-1H-1,4-diazepine, preparation thereof and compositions containing it
EP0283310A1 (en) * 1987-03-18 1988-09-21 Sankyo Company Limited N-Benzhydryl-substituted heterocyclic derivatives, their preparation and their use
EP0289227A1 (en) * 1987-04-24 1988-11-02 Syntex Pharmaceuticals Ltd. Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives
GB2210366A (en) * 1987-09-30 1989-06-07 American Home Prod Substituted cycloalkanols
WO1993015062A1 (en) * 1992-02-03 1993-08-05 The Wellcome Foundation Limited Opioid diarylmethylpiperazines and piperidines
WO1995004051A1 (en) * 1993-07-30 1995-02-09 The Wellcome Foundation Limited Piperazine compounds used in therapy

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1408037A1 (en) * 1995-12-22 2004-04-14 AstraZeneca AB Novel diarylmethylpiperazine and diarylmethylphenyl compounds with analgesic effect
US6809202B2 (en) 1996-11-07 2004-10-26 Torrey Pines Institute For Molecular Studies Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof
US9302096B2 (en) 1997-07-21 2016-04-05 Bruce H. Levin Apparatus for treating cerebral neurovascular disorders including headaches by neural stimulation
US8224438B2 (en) 1997-07-21 2012-07-17 Levin Bruce H Method for directed intranasal administration of a composition
US9381349B2 (en) 1997-07-21 2016-07-05 Bhl Patent Holdings Llc Apparatus for treating cerebral neurovascular disorders including headaches by neural stimulation
US7799337B2 (en) 1997-07-21 2010-09-21 Levin Bruce H Method for directed intranasal administration of a composition
US6200978B1 (en) * 1998-03-05 2001-03-13 Pfizer Inc. Compounds as delta opioid agonists
EP1181279A4 (en) * 1999-05-12 2002-09-25 Torrey Pines Inst Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof
EP1181279A1 (en) * 1999-05-12 2002-02-27 Torrey Pines Institute For Molecular Studies Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof
US8473062B2 (en) 2008-05-01 2013-06-25 Autonomic Technologies, Inc. Method and device for the treatment of headache
US8412336B2 (en) 2008-12-29 2013-04-02 Autonomic Technologies, Inc. Integrated delivery and visualization tool for a neuromodulation system
US8781574B2 (en) 2008-12-29 2014-07-15 Autonomic Technologies, Inc. Integrated delivery and visualization tool for a neuromodulation system
US9554694B2 (en) 2008-12-29 2017-01-31 Autonomic Technologies, Inc. Integrated delivery and visualization tool for a neuromodulation system
US9320908B2 (en) 2009-01-15 2016-04-26 Autonomic Technologies, Inc. Approval per use implanted neurostimulator
US8494641B2 (en) 2009-04-22 2013-07-23 Autonomic Technologies, Inc. Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism
US8886325B2 (en) 2009-04-22 2014-11-11 Autonomic Technologies, Inc. Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism

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TW360641B (en) 1999-06-11
MX9804797A (en) 1998-10-31
CZ176798A3 (en) 1998-09-16
NO982863L (en) 1998-06-19
AU706436B2 (en) 1999-06-17
PL327538A1 (en) 1998-12-21
EE9800195A (en) 1998-12-15
IS4768A (en) 1998-06-10
EP0873322A1 (en) 1998-10-28
NO982863D0 (en) 1998-06-19
CA2239162A1 (en) 1997-07-03
KR19990076649A (en) 1999-10-15
AU1216397A (en) 1997-07-17
BR9612206A (en) 1999-07-13
ZA9610355B (en) 1997-06-23
IL124997A0 (en) 1999-01-26
CN1209126A (en) 1999-02-24
SK81998A3 (en) 1998-11-04
JP2000502680A (en) 2000-03-07
SE9504662D0 (en) 1995-12-22

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