WO2001045637A2 - Novel 4(piperazinyl (8-quinolinyl)metyl)benzamides - Google Patents

Novel 4(piperazinyl (8-quinolinyl)metyl)benzamides Download PDF

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Publication number
WO2001045637A2
WO2001045637A2 PCT/SE2000/002559 SE0002559W WO0145637A2 WO 2001045637 A2 WO2001045637 A2 WO 2001045637A2 SE 0002559 W SE0002559 W SE 0002559W WO 0145637 A2 WO0145637 A2 WO 0145637A2
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WO
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Prior art keywords
compound
quinolinyl
piperazinyl
methyl
diethyl
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PCT/SE2000/002559
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French (fr)
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WO2001045637A3 (en
Inventor
William Brown
Christopher Walpole
Niklas Plobeck
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Astrazeneca Ab
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Publication date
Priority to SK885-2002A priority Critical patent/SK285753B6/en
Priority to JP2001546378A priority patent/JP2003518022A/en
Priority to DK00989096T priority patent/DK1242402T3/en
Priority to BR0016578-6A priority patent/BR0016578A/en
Priority to MXPA02006062A priority patent/MXPA02006062A/en
Priority to DE60006583T priority patent/DE60006583T2/en
Priority to HU0300298A priority patent/HUP0300298A2/en
Priority to CA002393568A priority patent/CA2393568C/en
Priority to EEP200200334A priority patent/EE05035B1/en
Priority to US10/149,911 priority patent/US6784181B2/en
Priority to PL00356797A priority patent/PL356797A1/en
Priority to EP00989096A priority patent/EP1242402B1/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU25643/01A priority patent/AU780714B2/en
Priority to UA2002064508A priority patent/UA72945C2/en
Priority to AT00989096T priority patent/ATE254120T1/en
Priority to SI200030296T priority patent/SI1242402T1/en
Priority to NZ519985A priority patent/NZ519985A/en
Priority to IL15012600A priority patent/IL150126A0/en
Publication of WO2001045637A2 publication Critical patent/WO2001045637A2/en
Publication of WO2001045637A3 publication Critical patent/WO2001045637A3/en
Priority to IL150126A priority patent/IL150126A/en
Priority to BG106806A priority patent/BG65456B1/en
Priority to IS6423A priority patent/IS2194B/en
Priority to NO20022918A priority patent/NO323402B1/en
Priority to HK03100181.6A priority patent/HK1048113B/en

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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/02Drugs for disorders of the nervous system for peripheral neuropathies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56Nitrogen atoms
    • C07D211/58Nitrogen atoms attached in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds.
  • the novel compounds are useful 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 possess immunomodulatory activities.
  • the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current ⁇ agonists, as well as having improved systemic 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 ⁇ agonist compounds, described within the prior art, show significant convulsive effects when administered systemically.
  • novel compounds according to the present invention are defined by the formula I
  • R is selected from
  • each R phenyl ring and R heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched Ci-C ⁇ alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo.
  • the substitutions on the phenyl ring and on the heteroaromatic ring may take place in any position on said ring systems.
  • the compounds of formula I are present as the (+)-enantiomer, or as the (-)-enantiomer.
  • 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.
  • novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
  • Compounds of the invention are 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 in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled 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 diarrhoea, depression, anxiety, urinary incontinence, various mental illnesses, cough, lung oedema, various gastrointestinal 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.
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
  • an effective amount of a compound according to the formula I above is administered to a patient in need of such treatment.
  • the compounds according to the present invention may be prepared by following any one of the procedures described in Schemes I, II, III, and IV. These known procedures are described in J. March, Advanced Organic Chemistry, 4' ' Edition, John Wiley and sons (1992); Katritsky, A.R., Lan, X. Chem. Soc. Rev., pp. 363-373 (1994), which are hereby incorporated by reference. SCHEME I
  • R 1 as defined in formula (I) above SCHEME II
  • R 1 as defined in formula (I) above SCHEME IV
  • 8-Bromoquinoline (3.0 g, 14.4 mmol) was dissolved in dry THF (150 mL) and cooled to -78 °C under nitrogen.
  • s-BuLi (11.1 mL, 1.3 M in pentane, 14.4 mmol) was added dropwise during 5 min (Preparation and reactions with 8-lithioquinoline: Suggs, J. Org. Chem. 1980, 45, 1514.).
  • ⁇ /V-diethyl-4-formylbenzamide (3.5 g, 17.0 mmol) was added dissolved in THF (5 mL). The solution was stirred 1 h, then NH CI (aq.) was added.
  • novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • a preferred route of administration is orally, intravenously or intramuscularly.
  • 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 as 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, citrate, 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
  • 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 finely 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.
  • 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 ⁇ Mbestatin, 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 mini vials 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 (njj) for ligands in displacing specifically bound radioligand 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. Biological data are reported below in Table 1.
  • Radioligand K ⁇ values were determined by performing the binding assays on cell membranes with the appropriate radiohgands at concentrations ranging from 0.2 to 5 times the estimated K ⁇ (up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of K ⁇ and B max from individual expe ⁇ ments were obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site model.
  • Rats were placed in Plexiglas cages on top of a wire mesh bottom which allowed access to the paw, and were left to habituate for 10-15 min. The area tested was the mid-plantar left hind paw, avoiding the less sensitive foot pads. The paw was touched with a series of 8 Von Frey hairs with logarithmically incremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Stoelting, 111, USA).
  • the von Frey hair was applied from underneath the mesh floor pe ⁇ endicular to the plantar surface with sufficient force to cause a slight buckling against the paw, and held for approximately 6-8 seconds. A positive response was noted if the paw was sharply withdrawn. Flinching immediately upon removal of the hair was also considered a positive response. Ambulation was considered an ambiguous response, and in such cases the stimulus was repeated.
  • the animals were tested on postoperative day 1 for the FCA-treated group.
  • the 50% withdrawal threshold was determined using the up-down method of Dixon (1980). Testing was started with the 2.04 g hair, in the middle of the series. Stimuli were always presented in a consecutive way, whether ascending or descending. In the absence of a paw withdrawal response to the initially selected hair, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was chosen.
  • Optimal threshold calculation by this method requires 6 responses in the immediate vicinity of the 50% threshold, and counting of these 6 responses began when the first change in response occurred, e.g. the threshold was first crossed.
  • 0.224.
  • Von Frey thresholds were converted to percent of maximum possible effect (% MPE), according to Chaplan et al. 1994. The following equation was used to compute % MPE:
  • % MPE Drug treated threshold (g) - allodvnia threshold (g) X 100 Control threshold (g) - allodynia threshold (g)
  • Rats were injected (subcutaneously, intraperitoneally, intravenously or orally) with a test substance prior to von Frey testing, the time between administration of test compound and the von Frey test varied depending upon the nature of the test compound.
  • Acetic acid will bring abdominal contractions when administered intraperitoneally in mice. These will then extend their body in a typical pattern. When analgesic drugs are administered, this described movement is less frequently observed and the drug selected as a potential good candidate.
  • a complete and typical Writhing reflexe is considered only when the following elements are present: the animal is not in movement; the lower back is slightly depressed; the plantar aspect of both paws is observable.
  • Acetic acid 120 ⁇ L of Acetic Acid is added to 19.88 ml of distilled water in order to obtain a final volume of 20 ml with a final concentration of 0.6% AcOH. The solution is then mixed (vortex) and ready for injection.
  • the AcOH is administered intraperitoneally (i.p.) in two sites at 10 ml/kg (considering the average mice body weight) immediately prior to testing. (iii) Testing
  • mice The animal (mouse) is observed for a period of 20 minutes and the number of occasions (Writhing reflex) noted and compiled at the end of the experiment. Mice are kept in individual "shoe box” cages with contact bedding. A total of 4 mice are usually observed at the same time: one control and three doses of drug.

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  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
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  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Use Of Switch Circuits For Exchanges And Methods Of Control Of Multiplex Exchanges (AREA)
  • Pyridine Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Compounds of general formula (I), wherein R1 is selected from phenyl, pyridinyl, thiophenyl, furanyl and imidazolyl; each phenyl ring and heteroaromatic ring otpionally and independently being further substituted by 1,2 or 3 substituents selected from straight and branched C¿1?-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo; are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

Description

NOVEL COMPOUNDS
Field of the invention
The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
Background and pnor 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 possess 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 peπpheral nervous systems of many species including man. Analgesia has been observed in vaπous animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid δ ligands are peptidic in natuie and are unsuitable for administration by systemic routes One example of a non-peptidic δ-agonist is SNC80 (Bilsky E.J. et al, Journal of Pharmacology and Experimental Therapeutics, 273(1), pp. 359-366 (1995)). There is however still a need for selective δ-agonists having not only improved selectivity, but also an improved side-effect profile.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current μ agonists, as well as having improved systemic 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 δ agonist compounds, described within the prior art, show significant convulsive effects when administered systemically.
We have now found that certain compounds not specifically disclosed by, but included within the scope of WO 98/28270, exhibit surprisingly improved δ-agonist properties and in vivo potency relative to compounds disclosed in WO98/28270, when administered systemically. The compounds of the present invention exhibit significant and unexpected increased levels of delta receptor agonism and metabolic stability.
Outline of the invention
The novel compounds according to the present invention are defined by the formula I
Figure imgf000003_0001
wherein R is selected from
(i) phenyl;
Figure imgf000004_0001
(ii) pyridinyl
Figure imgf000004_0002
(iii) thiophenyl
(iv) furanyl
Figure imgf000004_0003
(v) imidazolyl
Figure imgf000004_0004
(vi) triazolyl where each R phenyl ring and R heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched Ci-Cό alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the phenyl ring and on the heteroaromatic ring may take place in any position on said ring systems.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula I, as well as isomers thereof.
In a preferred embodiment of the invention, the compounds of formula I are present as the (+)-enantiomer, or as the (-)-enantiomer.
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.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are 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 in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled 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 diarrhoea, depression, anxiety, urinary incontinence, various mental illnesses, cough, lung oedema, various gastrointestinal 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. Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment. Also included within the scope of the present invention, is any novel intermediate as described in Scheme I hereinafter useful in the synthesis of compounds of formula I above.
Methods of preparation
The compounds according to the present invention may be prepared by following any one of the procedures described in Schemes I, II, III, and IV. These known procedures are described in J. March, Advanced Organic Chemistry, 4' ' Edition, John Wiley and sons (1992); Katritsky, A.R., Lan, X. Chem. Soc. Rev., pp. 363-373 (1994), which are hereby incorporated by reference. SCHEME I
Figure imgf000007_0001
Figure imgf000007_0003
Figure imgf000007_0002
Figure imgf000007_0004
P=a protecting group such as Bn, Boc, CBz M= Li, Mg, Zn
X=Br, I
L=CI, Br, OMs, OTs, I
R1= as defined in formula (I) above SCHEME II
Figure imgf000008_0001
P=a protecting group such as Bn, Boc, CBz M= Li, Mg, Zn
X=Br, I
L=CI, Br, OMs, OTs, I
R = as defined in formula (I) above SCHEME III
Figure imgf000009_0001
P=a protecting group such as Bn, Boc, CBz M= Li, Mg, Zn
X=Br, I
L=CI, Br, OMs, OTs, I
R1= as defined in formula (I) above SCHEME IV
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000010_0004
P=a protecting group such as Bn, Boc, CBz M= Li, Mg, Zn
X=Br, I
L=CI, Br, OMs, OTs, I
R = as defined in formula (I) above Examples
The invention will now be described in more detail by the following Examples, which are not to be construed as limiting the invention.
Example 1
Preparation of 4-r(4-benzyl-l-piperazinyl)(8-quinolinyl)methyl1-N<N- diethylbenzamide dihydrochloride (compound 2)
The title compound 2 was prepared by following the synthetic procedure of Scheme 1 below.
Scheme 1
Figure imgf000011_0001
Compound 2 (i) Preparation of N^V-diethyl-4-formylbenzamide (compound I).
4-Formylbenzoic acid (11.2 g, 74.6 mmol) and triethylamine (10.4 mL, 75 mmol) was dissolved in THF (100 mL) and cooled to -10 °C. i-Butylchloroformate (10.3 mL, 78 mmol) was added and stirring was continued for 10 minutes at -10 °C before diethylamine ( 9.7 mL, 94 mmol) was added and solution was allowed to reach 25 °C. After concentration, aqueous workup and chromatography on silica (0-100 % EtOAc in heptane), a total of 7.4 g (50 %) compound I was obtained.
(ii) Preparation of N,N-diethyl-4-[hydroxy(8-quinolinyl)methyI]benzamide (compound II)
8-Bromoquinoline (3.0 g, 14.4 mmol) was dissolved in dry THF (150 mL) and cooled to -78 °C under nitrogen. s-BuLi (11.1 mL, 1.3 M in pentane, 14.4 mmol) was added dropwise during 5 min (Preparation and reactions with 8-lithioquinoline: Suggs, J. Org. Chem. 1980, 45, 1514.). After further 5 min, Λ^/V-diethyl-4-formylbenzamide (3.5 g, 17.0 mmol) was added dissolved in THF (5 mL). The solution was stirred 1 h, then NH CI (aq.) was added. After concentration, aqueous workup and chromatography on silica (0-100 % EtOAc in heptane), a total of 3.5 g (70 %) compound II was obtained. MS: 334, 262, 234, 215, 204, 178, 156, 129.
Alternative route to prepare compound II from N^V-diethyl-4-iodobenzamide (compound IV)
Compound IV (0.67 g, 2.2 mmol) was dissolved in dry THF (25 mL) and cooled to -78 °C under nitrogen. n-BuLi (1.3 mL, 1.6 M in hexane, 2.2 mmol) was added dropwise during 5 min. After further 10 min, 8-formylquinoline (0.17 g, 1.1 mmol) (8-formylquinoline was made from 8-methylquinoline by oxidation with selenium dioxide at 150-155 °C for 12 h ( Kingsbury, J. Med. Chem. 1993, 3308.) was added dissolved in THF (1 mL). The solution was stirred 1 h, then NHtCl (aq.) was added. After concentration, aqueous workup and chromatography on silica (0-100 % EtOAc in heptane), a total of 0.29 g (78 %) compound II was obtained. (iii) Preparation of 4-[chloro(8-quinolinyl)methyl]-N^V-diethyIbenzamide (compound III).
Compound II (2.0 g, 6.6 mmol) was dissolved in dry CH2C12 (25 mL) and SOCl2 (0.53 mL, 7.3 mmol) was added. The solution was stirred at 25 °C for 30 min and the solvent was evaporated in vacuo. Compound III was obtained as an oil (-100%) and used in the next reaction without further purification. MS: 348, 333, 233, 215, 204, 156.
(iv) Preparation of N,N-diethyl-4-[l-piperazinyI(8-quinolinyI)methyl]benzamide (compound 1).
The crude product compound III (~ 6.6 mmol) and piperazine (2.3 g, 26 mmol) was dissolved in dry MeCN (50 mL) and heated at reflux 12 h. The solvent was removed in vacuo, the residue dissolved in CH2C12 and washed with water and the organic phase dried (K2CO3) and evaporated in vacuo. After chromatography on silica (0-20 % MeOH in CH2C12, 1% NlLjOH), a total of 1.8 g (68 %, 2 steps) compound 1 was obtained. Further purification could be achieved by reverse phase chromatograpy (LiChroprep RP-18, 10-50 % MeCN in water, 0.1 % TFA) to give 1.2 g colorless product. The dihydrochloride salt was made by treatment with 2 eq. HCl in ether.
Mp: 180-90 °C.
IR (KBr, vmax) 3297, 2982, 2716, 2474, 1611, 1434, 1380, 1288, 1098 cm"1. MS (amine): 402, 318, 246, 217, 109.
1H NMR (amine, CDC13): δ 1.2, 1.1 (2s, 6H), 2.94, 2.51 (2m, 8H), 3.5-3.1 (m, 5H), 6.05 (s, 1H), 8.94-7.20 (m, 10H).
Anal. (C25H30N4O x 3.2 CF3CO2H) C, N; H: calcd, 4.36; found, 3.90.
(v) Preparation of 4-r(4-benzyl-l-piperazinyl)(8-quinolinyl)methyl1-N./V- diethylbenzamide dihydrochloride (the title compound 2) Compound 1 (1.3 g, 3.2 mmol) and triethylamine (0.90 mL, 6.4 mmol) was dissolved in MeCN (10 mL). Benzyl bromide (0.77 mL, 6.4 mmol) was added with stirring at 25 °C. After 4 h the solution was concentrated and purified by chromatography on silica (0-5 % MeOH in CH2Cl2j or by reverse phase chromatograpy (LiChroprep RP-18, 20-80 % MeCN in water, 0.1 % TFA). A total of 2.2 g (72 %) of the title compound 2 was obtained. Treatment with 2 eq. HCl (aq.) and freeze drying gave the dihydrochloride salt (3.6g).
IR (2X HCl, KBr) : 2388, 1606, 1434, 1356, 1287 (cm-1).
1H NMR (free amine, CDC13) δ = 1.05 (m, 6H), 2.5 (m, 8H), 3.1-3.6 (m, 6H), 6.04 (s, 1H), 7.18 -8.98 (m, 15H).
Anal. (C32H38Cl2N4O) C, H, N.
Alternative procedure to prepare the title compound 2 from compound III
The crude product compound III (~ 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol) and N- benzyl-piperazine (2.6 g, 14.5 mmol) was dissolved in dry MeCN (50 mL) and heated at reflux 12 h. More N-benzyl-piperazine (0.5 g, 2.8 mmol) was added and heating continued for 12 h. The solvent was removed in vacuo, the residue dissolved in CH C12 and washed with water and the organic phase dried (K2CO3) and evaporated in vacuo. After chromatography on silica (0-10 % MeOH in CH2C12), a total of 3.5 g (53 %) of the title compound 2 was obtained.
Examples 2 & 3
Separation of the enantiomers of compound 2 (compounds 3 and 4)
The preparative separation of this compound was done on a Chiralcel OD column (50mm X 50 cm) using Hexane / EtOH / Diethylamine 85:15:0.1 as the mobile phase. On the Chiralcel OD column, the (+)-isomer was found to elute first. Example 2
(-)4-r(4-benzyl-l-piperazinyl)(8-quinolinyl)methyll-N,N-diethylbenzamide (compound 3) s [ ]D 25: -130° (c 0.78, MeOH)
1H NMR: (CD3OD): δ= 1.05 (m, 6H), 3.0-3.6 (m, 14H), 5.90 (s, 1H), 7.22 -8.20 (m,
13H), 8.78 (m, 1H), 9.50 (m, 1H).
ANALYSIS:Calc.w.3.1 H2O, C: 61.85, H: 7.17, N: 9.02..Found C: 61.84, H: 6.60, N: 8.89 o Example 3
(+)4-r(4-benzyl-l-piperazinyl)(8-quinolinyl)methvn-N,N-diethylbenzamide (compound 4)
[α]D 25: +130° (c 0.69, MeOH)
1H NMR: (CD3OD): δ= 1.05 (m, 6H), 3.0-3.6 (m, 14H), 5.90 (s, 1H), 7.22 -8.20 (m, 13H), 8.78 (m, 1H), 9.50 (m, 1H).
ANALYSIS: Calc.w.3.2 H2O, C: 61.67, H: 7.18, N: 8.99.. Found C: 61.70, H: 6.46, N: 8.84
Example 4 Preparation of NN-diethyl-4-rr4-(4-methylbenzyl)-l-piperazinyl1(8- quinolinyl)methyl1benzamide(compound 5
The title compound 5 was prepared by following the synthetic procedure of Scheme 2 below. Scheme 2
Figure imgf000016_0001
Compound 1 _
Compound 5
To a solution of compound 1 (0.80g; 1.99 mmol) in CH2C12 (20ml) was added Et3N (0.83ml; 5.97mmol) followed by p-methyl benzyl bromide (773mg; 4.18mmol). The reaction mixture was stirred overnight and was then was concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN H2O.
(M+l) calculated: 507.70, (M+l) observed: 507.20
IR (NaCI, free amine) 2969, 2807, 2360, 1628, 1455, 1425, 1286, 1134, 1095 (cm-1). 1H NMR (CDCI3, free amine) δ = 1.0, 1.1 (2m, 6H, amide-Me), 2.31 (s, 3H, Ar-Me), 2.5 (m, 8H, piperazine-H), 3.2, 3.5 (2m, amide-CH2), 3.49 (s, 2H, ArCH2N), 6.03 (s, IH, Ar2CH), 7.06-7.68 (m, 11H, Ar-H), 8.01-8.12 (m, 2H,Ar-H), 8.93 (m, IH, Ar-H). Anal. (C32H38Cl2N4O) C, H, N.
Examples 5 & 6 Separation of the Enantiomers of compound 5 to give compounds 6 and 7
The preparative separation of this compound was done on a semi preparative Chiralcel AD column (21 mm X 25 cm) using Hexane / EtOH / Diethylamine 80:20:0.1 as the mobile phase. On the Chiralcel AD column, the (-)-isomer was found to elute first. Example 5
(-)4-rr4-(4-methvIbenzyl)-l-piperazinyl1(8-quinolinyl)methvn-N,N-diethvIbenzamide (compound 6) [α]D 25:: -131° (c 1.0, MeOH)
Example 6
(+)4-rr4-(4-methylbenzyl)-l-piperazinvn(8-quinolinyl)methyl1-N,N-diethylbenzamide (compound 7) [α]D 25: +124° (c 1.4, MeOH)
Example 7
Preparation of 4-r{4-r4-(tgrt-butyl)benzyl1-l-piperazinyl}(8-quinolinyl)methyl1-N,N- diethylbenzamide dihydrochloride (compound 8)
Figure imgf000017_0001
By procedure analogous to the preparation of compound 2, the title compound 8 was prepared. Alkylation was performed with 4-tert-butylbenzylbromide. MS (ES) 549.53 (MH+). IR (NaCl, free amine) 2963, 2807, 2360, 1631, 1456, 1425, 1285, 1135, 1094, 1001 (cm ).
1H NMR (CDC13, free amine) δ = 1.0, 1.2 (2m, 6H), 1.29 (s, 9H), 2.50 (m, 8H), 3.2, 3.5 (2m), 3.50 (s, 2H), 6.04 (s, IH), 7.16-7.68 (m, 11H), 7.98-8.10 (m, 2H), 8.92 (m, IH). Anal. (C36H46Cl2N4O) C, H, N.
Example 8
Preparation of NN-diethyl-4-IT4-(4-nitrobenzyl)-l-piperazinvπ(8- quinolinyl)methyl"|benzamide dihydrochloride (compound 9)
Figure imgf000018_0001
Compound 9
By procedure analogous to the preparation of compound 2 above, the title compound 9 was prepared. Alkylation was performed with 4-nitrobenzylbromide.
MS (ES) 538.04 (MH+).
IR (NaCl, free amine) 2969, 2809, 2360, 1626, 1518, 1456, 1426, 1343, 1286, 1134,
1095, 1001 (cm-1).
1H NMR (CDCI3, free amine) δ = 1.0, 1.2 (2m, 6H), 2.50 (m, 8H), 3.2, 3.5 (2m), 3.60
(s, 2H), 6.05 (s, IH), 7.18-8.16 (m, 13H), 8.94 (m, IH).
Anal. (C32H37Cl2N5O3) C, H, N.
Example 9
Preparation of 4-ri4-r2,4-bis(trifluoromethyl)benzyll-l-piperazinyl|(8- quinolinyl)methvn- VN-diethylbenzamide dihydrochloride (compound 10)
Figure imgf000020_0001
Compound 10
By following the procedure analogous to the preparation of compound 2 above, the title compound 10 was prepared. Alkylation was performed with 2,4- bis(trifluoromethyl)benzylbromide.
MS (ES) 629.08 (MH+).
IR (NaCl, free amine) 2970, 2811,2360, 1628, 1456, 1426, 1346, 1275, 1170, 1128
(cm ).
1H NMR (CDC13, free amine) δ = 1.0, 1.2 (2m, 6H), 2.48 (m, 8H), 3.2, 3.5 (2m), 3.71 (s, 2H), 6.06 (s, IH), 7.20-8.14 (m, 12H), 8.95 (m, IH). Anal. (C34H36Cl2F6N4O) C, H, N Example 10
Preparation of N/V-diethyl-4-[T4-(4-methoxybenzyl)-l-piperazinvH(8- quinolinvDmethyllbenzamide dihydrochloride (compound 11)
Figure imgf000021_0001
By procedure analogous to the preparation of compound 2 above, the title compound 11 was prepared. Alkylation was performed with 4-methoxybenzylchloride. MS (ES) 523.45 (MH+). IR (NaCl, free amine) 2966, 2806, 2360, 1627, 1510, 1456, 1426, 1286, 1246, 1134, 1095 (cm-1).
1H NMR (CDC13, free amine) δ = 1.0, 1.2 (2m, 6H), 2.48 (m, 8H), 3.2, 3.5 (2m), 3.47 (s, 2H), 3.78 (s, 3H), 6.03 (s, IH), 6.80-7.68 (m, 11H), 8.01-8.12 (m, 2H), 8.93 (m, IH). Anal. (Css^oClz^Oz) C, H, N.
Example 11 Preparation 4-rr4-(2,4-dichlorobenzyl)-l-piperazinyll(8-quinolinyl)methyll-/V V- diethylbenzamide dihydrochloride (compound 12)
Figure imgf000022_0001
Compound 12
By following the procedure analogous to the preparation of compound 2 above, the title compound 12 was prepared. Alkylation was performed with 2,4-dichlorobenzylchloride.
MS (ES) 562.45 (MH+). IR (NaCl, free amine) 2968, 2810, 2360, 2341, 1627, 1470, 1426, 1285, 1134, 1095
(cm ).
1H NMR (CDC13, free amine) δ = 1.0, 1.1 (2m, 6H), 2.5 (m, 8H), 3.2, 3.5 (2m), 3.58 (s,
2H), 6.05 (s, IH), 7.14-7.70 (m, 10H), 8.06 (m, 2H), 8.94 (m, IH). Anal. (C32H36CI4N4O)
C, H, N.
Example 12 Preparation of N,N-diethyl-4-rr4-(2-pyridinylmethyl)-l-piperazinyll(8- quinolinvDmethyllbenzamide dihydrochloride (compound 13)
Figure imgf000023_0001
Compound 1 (80 mg, 0.20 mmol) was dissolved in MeOH (2 mL) with
2-pyridylcarboxaldehyde ( 39 μL, 0.40 mmol) and HOAc (1 μL, 0.02 mmol). Sodium cyanoborohydride (26 mg, 0.40 mmol) was added and stirring continued for 48 h. Solvent was evaporated and residue purified by chromatography on silica (0-10 % MeOH in CH2C12). 38 mg (39 %) product was obtained. MS (ES) 494.19 (MH+).
IR (NaCl, free amine) 2968, 2809, 2360, 1626, 1455, 1428, 1286, 1134, 1094, 1001 (cm-1). 1H NMR (CDC13, free amine) δ = 1.0, 1.2 (2m, 6H), 2.50 (m, 8H), 3.2, 3.5 (2m), 3.69 (s, 2H), 6.05 (s, IH), 7.12-7.70 (m, 10H), 8.08 (m, 2H), 8.54 (m, IH), 8.94 (m, IH). Anal. (C3,H37Cl2N5O) C, H, N.
Example 13
Preparation of NN-diethyl-4-[T4-(3-thienylmethyl)-l-piperazinvπ(8- quinolinvDmethyllbenzamide (compound 14) The title compound 14 was prepared by following the synthetic procedure of Scheme 3 below.
Scheme 3
Figure imgf000024_0001
Compound 1
Compound 14
To a solution of compound 1 (500mg; 0.99 mmol) in methanol (10ml) was added thiophene 3-carboxaldehyde (104ul; l!9mmol) followed by acetic acid (0.1ml; 1%) and sodium cyano borohydride (186.6mg; 2.97mmol). The reaction mixture was stirred overnight, then sodium hydroxide 2N was added and the mixture extracted with methylene chloride (3X). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave 258mg of desired product (TFA salt). HPLC purity: >99% (215nm); >95% (254nm)
(M+l) calculated: 499.25, (M+l) observed: 499.46
Anal: calculated for (C3oH34N4OS X 2.80 C2HO2F3 X 1.80 H2O): C:50.28%; H:4.79%; N:6.59%; 0:15.80%; S:3.77%; F: 18.77% found: C:50.28%; H:4.83%; N:6.53% HNMR: 8.95(dd, IH, J=4.4, 2.0Hz), 8.38(dd, IH, J=8.0, 2.0Hz), 8.00(dd, IH, J=7.2, 1.6Hz), 7.84(dd, IH, J=8.0, 1.6Hz), 7.52-7.62(m, 5H), 7.45(dd, IH, J=4.8, 2.8Hz), 7.20(dd, 2H, J=8.8, 2.2Hz), 7.11(dd, IH, J=4.8, 1.6Hz), 5.96(s, IH), 4.27(s, 2H), 3.34-3.44(m, 2H), 3.22-3.28(m, 4H), 3.04-3.14(m, 2H), 2.66-2.88(m, 4H), 1.04-1.14(m, 3H), 0.88-0.98(m, 3H)
Example 14 Preparation of N/V-dieth yl-4- \\4- (2-f uran ylmethyl) - 1 -piperazin yll (8- quinolinvDmethvnbenzamide (compound 15)
The title compound 15 was prepared by following the synthetic procedure of Scheme 4 below.
Scheme 4
Figure imgf000025_0001
Compound 1
Compound 15
To a 0°C solution of furfurylalcohol (0.19ml; 2.24 mmol) and triethylamine (0.52ml; 3.73mmol) in methylene chloride (4ml) was added methanesulfonyl chloride (0.17ml; 2.24mmol). The mixture was stirred 1 hour at 0°C, then compound 1 (300mg; 0.75mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight, then heated to 45°C and stirred for 1 Vi hours. The reaction mixture was allowed to cool to room temperature and NaOH 2N was added untill pH was basic. The mixture was extracted with methylene chloride (3X). The combined methylene chloride extracts were dried over Na2SO , filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-25% CH3CN/H2O (TFA as the buffer) gave 197mg of desired product (TFA salt).
HPLC purity: >99% (215nm, 254nm and 280nm) (M+l) calculated: 483.63, (M+l) observed: 483.30
1HNMR: 8.89(dd, IH, J=4.4, 1.6Hz), 8.29(dd, IH, J=8.0, 1.6Hz), 7.97(dd, IH, J=7.2, 1.6Hz), 7.79(d, IH, J=7.2Hz), 7.61(d, 2H, J=8.0Hz), 7.52-7.58(m, 2H), 7.48(dd, IH, J=8.0, 4.4Hz), 7.19(d, 2H, J=8.0Hz), 6.56(d, IH, J=3.2Hz), 6.40(dd, IH, J=3.2, 2.4Hz), 6.02(s, IH), 4.26(s, 2H), 3.34-3.44(m, 2H), 3!6-3.26(m, 4H), 3.04-3.14(m, 2H), 2.68-2.86(m, 4H), 1.06-1.14(m, 3H), 0.90-0.98(m, 3H)
Example 15
Preparation of N V-diethyl-4-[T4-(3-furanylrnethyl)-l-piperazinyl1(8- quinolinyl)methyl]benzamide(compound 16)
The title compound 16 was prepared by following the synthetic procedure of Scheme 5 below.
Scheme 5
Figure imgf000026_0001
Compound 1 Compound 16
To a 0°C solution of 3-furanmethanol (220mg; 2.24 mmol) and triethylamine (0.52ml; 3.73mmol) in methylene chloride (4ml) was added methanesulfonyl chloride (0.17ml; 2.24mmol). The mixture was stirred 1 hour at 0°C, then compound 1 (300mg; 0.75mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight, then heated to 45°C and stirred for 3 Vi hours. The reaction mixture was allowed to cool to room temperature and NaOH 2N was added untill pH was basic. The mixture was extracted with methylene chloride (3X). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-25% CH3CN/H2O (TFA as the buffer) gave 293mg of desired product (TFA salt).
HPLC purity: >98% (215nm and 280nm); >99% (254nm) (M+l) calculated: 483.63, (M+l) observed: 483.34 Anal.: calculated for (C30H34N4O2 X 3.10 C2HO2F3 X 1.70 H2O): C:50.17%; H:4.71%; N:6.46%; O:18.27%; F:20.39% found: C:50.14%; H:4.76%; N:6.38% 1HNMR: 8.93(dd, IH, J=4.4, 2.0Hz), 8.36(dd, IH, J=8.6, 2.0Hz), 8.00(dd, IH, J=7.4, 1.2Hz), 7.82(dd, IH, J=7.6, 1.2Hz), 7.48-7.66(m, 6H), 7.19(d, 2H, J=8.0Hz), 6.46(s, IH), 5.97(s, IH), 4.13(s, 2H), 3.32-3.44(m, 2H), 3.20-3.28(m, 4H), 3.04-3.14(m, 2H), 2.66- 2.86(m, 4H), 1.04-1.14(m, 3H), 0.88-0.98(m, 3H)
Example 16 Preparation of NN-diethyl-4-[T4-(2-thiophenvImethyl)-l-piperazinyll(8- quinolinvOmethyllbenzamide dihydrochloride (compound 17)
The title compound 17 was prepared by following the synthetic procedure of Scheme 6 below.
Scheme 6
NaBH(OCOCH3)3; CH3C02H; CH2CI2
Figure imgf000027_0003
Figure imgf000027_0002
Figure imgf000027_0001
Compound 1 Compound 17
To a solution of compound 1 (0.99 mmol) in methylene chloride (10ml) was added 2-thiophenecarboxaldehyde (190ul; 1.98mmol) followed by acetic acid (0.1ml; 1%). The mixture was stirred 30 minutes then sodium triacetoxyborohydride (0.63g; 2.97mmol) was added and the reaction mixture stirred overnight. The reaction mixture was neutralized with sodium hydroxide 2N and extracted with methylene chloride (3X). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave 115mg of desired product (TFA salt). HPLC purity: >99% (215nm); >96% (254nm) (M+l) calculated: 499.25, (M+l) observed: 499.33
Anal.: calculated for (C30H34N4OS X 2.50 C2HO2F3 X 0.10 H2O): C:53.51%; H:4.71%; N:7.13%; 0:12.42%; S:4.08%; F:18.14% found: C:53.49%; H:4.63%; N:7.49% 1HNMR: 8.91(dd, IH, J=4.0, 1.6Hz), 8.30(dd, IH, J=8.8, 1.6Hz), 7.96(dd, IH, J=7.4, 1.4Hz), 7.81(d, IH, J=7.2Hz), 7.62(d, 2H, J=8.0Hz), 7.46-7.58(m, 3H), 7.20(d, 2H, J=8.0Hz), 7.14-7.22(m, IH), 7.00(dd, IH, J=5.2, 3.6Hz), 6.03(s, IH), 4.38(s, 2H), 3.34- 3.44(m, 2H), 3!4-3.22(m, 4H), 3.06-3.12(m, 2H), 2.74-2.88(m, 4H), 1.04-1.14(m, 3H), 0.88-0.98(m, 3H)
Example 17 Preparation of N,N-diethyl-4-|T4-(2-imidazolylmethyl)-l-piperazinyl~l(8- quinolinvDmethyllbenzamide dihydrochloride (compound 18) The title compound 18 was prepared by following the synthetic procedure of Scheme 7 below.
Scheme 7
Figure imgf000028_0001
Compound 1
Compound 18
To a solution of compound 1 (0.99 mmol) in methanol (10ml) was added 2-imidazolecarboxaldehyde (U4mg; 1.19mmol) followed by acetic acid (0.5ml; 5%). The mixture was stirred 3 hours then sodium cyanoborohydride (186.6mg; 2.97mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was neutralized with sodium hydroxide 2N and extracted with methylene chloride (3X). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave the TFA salt. The HCl salt was made using HCl/ether. Yield: 60.3mg of desired product (HCl salt). HPLC purity: >95% (215nm); >93% (254nm) (M+l) calculated: 483.29, (M+l) observed: 483.19
1HNMR: 9.12-9.22(m, IH), 8.54-8.62(m, IH), 8.08-8.16(m, IH), 7.98-8.04(m, IH), 7.60- 7.86(m, 4H), 7.38-7.46(m, 2H), 7.22-7.32(m, 2H), 6.32(s, IH), 4.1 l(s, 2H), 2.94-3.40(m, 12H), 0.88-1.12(m, 6H).
Example 18
Preparation of N,N-diethyl-4-r[4-(4-imidazolylmethyl)-l-piperazinvn(8- quinolinyl)methyl~|benzamide dihydrochloride (compound 19)
The title compound 19 was prepared by following the synthetic procedure of Scheme 8 below.
Scheme 8
NaBH(OCOCH3)3; CHjjCOgH; CH2CI2
Figure imgf000030_0003
Figure imgf000030_0001
Compound 1
Figure imgf000030_0002
Compound 19
To a room temperature solution of 434 (400mg; 0.99 mmol) and 4-imidazole carboxaldehyde (95.5mg; 0.99mmol) in methylene chloride (10ml) was added acetic acid (0.1ml). The mixture was stirred for 5 hours then sodium triacetoxyborohydride (632mg; 2.98mmol) was added. The reaction mixture was stirred overnight and was neutralized with sodium hydroxide 2N. The mixture was extracted with methylene chloride (3X). The combined methylene chloride extracts were dried over Na2SO , filtered and concentrated under reduced pressure. Purification by reverse phase chromatography using 15% CH3CN/H2O (TFA as the buffer) gave 103mg of desired product (TFA salt).
HPLC purity: >99% (215nm, 254nm and 280nm)
(M+l) calculated: 483.28, (M+l) observed: 482.96
Anal.: calculated for (C29H34N6O X 3.80 C2HO2F3 X 0.80 H2O): C:47.25%; H:4.27%;
N:9.03%; 0:16.17%; F:23.28% found: C:47.31%; H:4.40%; N:8.87
'HNMR: 8.99(dd, IH, J=4.4, 1.2Hz), 8.76(d, IH, J=1.2Hz), 8.39(dd, IH, J=8.8, 1.2Hz),
7.93(dd, IH, J=7.2, 1.6Hz), 7.86(dd, IH, J=8.0, 1.6Hz), 7.7 l(d, 2H, J=8.8Hz), 7.60(dd, IH,
J=8.8, 4.4Hz), 7.56(dd, IH, J=8.0, 7.2Hz), 7.40(s, IH), 7.27(d, 2H, J=8.8Hz), 6.12(s, IH)
3.74(s, 2H), 3.38(q, 2H, J=6.4Hz), 3.10-3.25(m, 6H), 3.06(q, 2H, J=7.2Hz), 2.75-2.90(m,
2H), 1.08(t, 3H, J=6.4Hz), 0.92(t, 3H, J=7.2Hz)
Example 19
Preparation of N,N-diethvI-4-IT4-(3-triazolylmethyl)-l-piperazinvπ(8- quinolinvDmethvnbenzamide dihydrochloride (compound 20)
The title compound 20 was prepared by following the synthetic procedure of Scheme 9 below.
Scheme 9
Figure imgf000031_0001
Compound 1
Figure imgf000031_0002
Compound 20
To a room temperature solution 434 (200mg; 0.50 mmol) in dimethylformamide (10ml) was added potassium carbonate (275mg; 1.99mmol), followed by N-formamido-2- (chloromethyl)acetamidine (170mg; 1.24mmol). The reaction mixture was heated to 60°C and stirred for 2 days, then the temperature was raised to 140°C and stirred for 3 hours. The reaction mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethylacetate (3X). The combined ethylacetate extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography using 20% CH3CN/H2O (TFA as the buffer) gave 21mg of desired product (TFA salt). HPLC purity: >99% (215nm, 254nm and 280nm) (M+l) calculated: 484.28, (M+l) observed: 483.92
Anal.: calculated for (C28H33N7O X 3.30 C2HO2F3 X 3.30 H2O): C:45.20%; H:4.70%; N: 10.66%; 0: 18.97%; F:20.46% found: C:45.12%; H:4.60%; N: 10.84 'HNMR: 8.94(dd, IH, J=4.4, 1.6Hz), 8.38(s, IH), 8.33(dd, IH, J=8.0, 1.2Hz), 7.93(d, IH, J=7.2Hz), 7.85(d, IH, J=7.2Hz), 7.65(d, 2H, J=8.8Hz), 7.51-7.58(m, 2H), 7.23(d, 2H, J=8.8Hz), 6.15(s, IH), 4.21(s, 2H), 3.40-3.50(m, 2H), 3.10-3.30(m, 8H), 2.90-3.10(m, 2H), 0.90-1.30(m, 6H) Pharmaceutical compositions
The novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
A preferred route of administration is orally, intravenously or intramuscularly.
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 as 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, citrate, 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, tannate, 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 bitartrates. The hydrochloride salts are particularly preferred.
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 finely 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
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% CO2 in shaker flasks containing calcium-free DMEM10% 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 μMbestatin, 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 mini vials 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 (njj) for ligands in displacing specifically bound radioligand 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. Biological data are reported below in Table 1.
Figure imgf000038_0001
Table 1. Summary of biological data.
Receptor saturation experiments
Radioligand Kδ values were determined by performing the binding assays on cell membranes with the appropriate radiohgands at concentrations ranging from 0.2 to 5 times the estimated Kδ (up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kδ and Bmax from individual expeπments were obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site model.
DETERMINATION OF MECHANO-ALLODYNIA USING VON FREY TESTING
Testing was performed between 08:00 and 16 OOh using the method described by Chaplan et al. (1994). Rats were placed in Plexiglas cages on top of a wire mesh bottom which allowed access to the paw, and were left to habituate for 10-15 min. The area tested was the mid-plantar left hind paw, avoiding the less sensitive foot pads. The paw was touched with a series of 8 Von Frey hairs with logarithmically incremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Stoelting, 111, USA). The von Frey hair was applied from underneath the mesh floor peφendicular to the plantar surface with sufficient force to cause a slight buckling against the paw, and held for approximately 6-8 seconds. A positive response was noted if the paw was sharply withdrawn. Flinching immediately upon removal of the hair was also considered a positive response. Ambulation was considered an ambiguous response, and in such cases the stimulus was repeated.
TESTING PROTOCOL
The animals were tested on postoperative day 1 for the FCA-treated group. The 50% withdrawal threshold was determined using the up-down method of Dixon (1980). Testing was started with the 2.04 g hair, in the middle of the series. Stimuli were always presented in a consecutive way, whether ascending or descending. In the absence of a paw withdrawal response to the initially selected hair, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was chosen. Optimal threshold calculation by this method requires 6 responses in the immediate vicinity of the 50% threshold, and counting of these 6 responses began when the first change in response occurred, e.g. the threshold was first crossed. In cases where thresholds fell outside the range of stimuli, values of 15.14 (normal sensitivity) or 0.41 (maximally allodynic) were respectively assigned. The resulting pattern of positive and negative responses was tabulated using the convention, X = no withdrawal; O = withdrawal, and the 50% withdrawal threshold was interpolated using the formula:
50% g threshold = 10(Xf + V / 10,000
where Xf = value of the last von Frey hair used (log units); k = tabular value (from Chapl et al. (1994)) for the pattern of positive / negative responses; and δ = mean differen between stimuli (log units). Here δ = 0.224. Von Frey thresholds were converted to percent of maximum possible effect (% MPE), according to Chaplan et al. 1994. The following equation was used to compute % MPE:
% MPE = Drug treated threshold (g) - allodvnia threshold (g) X 100 Control threshold (g) - allodynia threshold (g)
ADMINISTRATION OF TEST SUBSTANCE
Rats were injected (subcutaneously, intraperitoneally, intravenously or orally) with a test substance prior to von Frey testing, the time between administration of test compound and the von Frey test varied depending upon the nature of the test compound.
WRITHING TEST
Acetic acid will bring abdominal contractions when administered intraperitoneally in mice. These will then extend their body in a typical pattern. When analgesic drugs are administered, this described movement is less frequently observed and the drug selected as a potential good candidate.
A complete and typical Writhing reflexe is considered only when the following elements are present: the animal is not in movement; the lower back is slightly depressed; the plantar aspect of both paws is observable.
(i) Solutions preparation
Acetic acid (AcOH): 120 μL of Acetic Acid is added to 19.88 ml of distilled water in order to obtain a final volume of 20 ml with a final concentration of 0.6% AcOH. The solution is then mixed (vortex) and ready for injection.
Compound (drug): Each compound is prepared and dissolved in the most suitable vehicle according to standard procedures.
(ii) Solutions administration The compound (drug) is administered orally, intraperitoneally (i.p.) , subcutaneously (s.c.) or intravenously (i.v.)) at 10 ml/kg (considering the average mice body weight) 20, 30 or 40 minutes (according to the class of compound and its characteristics) prior to testing. When the compound is delivered centrally: Intraventricularly (i.e. v.) or intrathecally (i.t.) a volume of 5 μL is administered.
The AcOH is administered intraperitoneally (i.p.) in two sites at 10 ml/kg (considering the average mice body weight) immediately prior to testing. (iii) Testing
The animal (mouse) is observed for a period of 20 minutes and the number of occasions (Writhing reflex) noted and compiled at the end of the experiment. Mice are kept in individual "shoe box" cages with contact bedding. A total of 4 mice are usually observed at the same time: one control and three doses of drug.

Claims

Claims
1. A compound according to formula I
Figure imgf000043_0001
wherein
R is selected from (i) phenyl;
Figure imgf000043_0002
(ii) pyridinyl
Figure imgf000043_0003
(iii) thiophenyl
Figure imgf000044_0001
(iv) furanyl
Figure imgf000044_0002
(v) imidazolyl and
N-NH
(vi) triazolyl
where each phenyl ring and heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched Ci-C alkyl, NO2, CF3, Ci-C alkoxy, chloro, fluoro, bromo, and iodo;
as well as pharmaceutically acceptable salts thereof and isomers thereof.
2. A compound according to claim 1, wherein the optional substituent(s) on the aromatic or the heteroaromatic ring(s) is selected from anyone of NO2, iso-butyl, CF3, methoxy, methyl, or chloro.
3. A compound according to claim 1 or 2, selected from any one of • 4-[(4-benzyl-l-piperazinyl)(8-quinolinyl)methyl]-/V,N-diethylbenzamide dihydrochloride (compound 2); • N,N-diethyl-4-[[4-(4-methylbenzyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide (compound 5);
• 4-[{4-[4-(tert-butyl)benzyl]-l-piperazinyl}(8-quinolinyl)methyl]-N,N- diethylbenzamide dihydrochloride (compound 8);
• Λ7N-diethyl-4-[[4-(4-nitrobenzyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 9);
4-[{4-[2,4-bis(trifluoromethyl)benzyl]-l-piperazinyl}(8-quinolinyl)methyl]-Λ,N- diethylbenzamide dihydrochloride (compound 10);
• /V,N-diethyl-4-[[4-(4-methoxybenzyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 11);
• 4-[[4-(2,4-dichlorobenzyl)-l-piperazinyl](8-quinolinyl)methyl]-Λ?,N-diethylbenzamide dihydrochloride (compound 12);
• Λ7,N-diethyl-4-[[4-(2-pyridinylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 13);
• Λ7/-diethyl-4-[[4-(3-thienylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide (compound 14);
• Λ^,/V-diethyl-4-[[4-(2-furanylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide (compound 15);
• NN-diethyl-4-[[4-(3-furanylmethyl)-l-piperazinyl](8- quinolinyl)methyl]benzamide(compound 16); 44
• Λf,N-diethyl-4-[[4-(4-methylbenzyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide (compound 5);
• 4-[{4-[4-(tert-butyl)benzyl]-l-piperazinyl}(8-quinolinyl)methyl]-N,Λ/- diethylbenzamide dihydrochloride (compound 8);
• N,N-diethyl-4-[[4-(4-nitrobenzyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 9);
• 4-[{4-[2,4-bis(trifluoromethyl)benzyl]-l-piperazinyl}(8-quinolinyl)methyl]-Λ7/- diethylbenzamide dihydrochloride (compound 10);
• N,/V-diethyl-4-[[4-(4-methoxybenzyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 11);
• 4-[[4-(2,4-dichlorobenzyl)-l-piperazinyl](8-quinolinyl)methyl]-Λ/,N-diethylbenzamide dihydrochloride (compound 12);
• NN-diethyl-4-[[4-(2-pyridinylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 13);
• /V,N-diethyl-4-[[4-(3-thienylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide (compound 14);
• NN-diethyl-4-[[4-(2-furanylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide (compound 15);
• N,N-diethyl-4-[[4-(3-furanylmethyl)-l-piperazinyl](8- quinolinyl)methyl]benzamide(compound 16); 45
• Λ^,Λ^-diethyl-4-[[4-(2-thiophenylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 17);
• N,N-diethyl-4-[[4-(2-imidazolylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 18);
• /V-diethyl-4-[[4-(4-imidazolylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 19); and
Λ^N-diethyl-4-[[4-(3-triazolylmethyl)-l-piperazinyl](8-quinolinyl)methyl]benzamide dihydrochloride (compound 20).
4. A compound according to any one of claims 1-3, which compound is present as the (+)-enantiomer.
5. A compound according to anyone of claims 1-3, which compound is present as the (-)-enantiomer.
6. A compound according to any of the preceding claims, in form of its hydrochloride, sulfate, tartrate or citrate salts.
7. A compound according to claim 4, selected from any one of
(+)4-[(4-benzyl-l-piperazinyl)(8-quinolinyl)methyl]-N,N-diethylbenzamide; and
(+)4-[[4-(4-methylbenzyl)-l-piperazinyl](8-quinolinyl)methyl]-Λ^,N-diethylbenzamide 46
8. A compound according to claim 5, selected from any one of
(-)4-[(4-benzyl-l-piperazinyl)(8-quinolinyl)methyl]-N,N-diethylbenzamide; and
(-)4-[[4-(4-methylbenzyl)-l-piperazinyl](8-quinolinyl)methyl]-N,/V-diethylbenzamide .
9. A compound according to any of claims 1-8 for use in therapy.
10. A compound according to claim 9, wherein the therapy is pain management.
11. A compound according to claim 9, wherein the therapy is directed towards gastrointestinal disorders.
12. A compound according to claim 9, wherein the therapy is directed towards spinal injuries.
13. A compound according to claim 9, wherein the therapy is directed to disorders of the sympathetic nervous system.
14. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of pain.
15. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of gastrointestinal disorders. 47
16. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of spinal injuries.
17. A pharmaceutical composition comprising a compound of the formula I according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.
18. A method for the treatment of pain, whereby an effective amount of a compound of the formula I according to claim 1 is administered to a subject in need of pain management.
19. A method for the treatment of gastrointestinal disorders, whereby an effective amount of a compound of the formula I according to claim 1, is administered to a subject suffering from said gastrointestinal disorder.
20. A method for the treatment of spinal injuries, whereby an effective amount of a compound of the formula I according to claim 1, is administered to a subject suffering from said spinal injury.
PCT/SE2000/002559 1999-12-20 2000-12-15 Novel 4(piperazinyl (8-quinolinyl)metyl)benzamides WO2001045637A2 (en)

Priority Applications (23)

Application Number Priority Date Filing Date Title
AU25643/01A AU780714B2 (en) 1999-12-20 2000-12-15 Novel compounds
JP2001546378A JP2003518022A (en) 1999-12-20 2000-12-15 New compounds
UA2002064508A UA72945C2 (en) 1999-12-20 2000-12-15 A compound (variants), a pharmaceutical composition, a method for treatment (variants)
MXPA02006062A MXPA02006062A (en) 1999-12-20 2000-12-15 Novel compounds.
DE60006583T DE60006583T2 (en) 1999-12-20 2000-12-15 NEW CONNECTIONS
HU0300298A HUP0300298A2 (en) 1999-12-20 2000-12-15 4-[piperazinyl-(8-quinolinyl)metyl]benzamide derivatives, their use and pharmaceutical compositions containing them
CA002393568A CA2393568C (en) 1999-12-20 2000-12-15 Diarylmethylpiperazines
EEP200200334A EE05035B1 (en) 1999-12-20 2000-12-15 1- [Phenyl- (8-quinolinyl) methyl] piperazine derivatives and their use in medicine
US10/149,911 US6784181B2 (en) 1999-12-20 2000-12-15 Piperazine-containing compounds useful in the treatment of pain
PL00356797A PL356797A1 (en) 1999-12-20 2000-12-15 Novel compounds
EP00989096A EP1242402B1 (en) 1999-12-20 2000-12-15 Novel compounds
SK885-2002A SK285753B6 (en) 1999-12-20 2000-12-15 Benzamide derivatives, pharmaceutical composition containing the derivatives and their use
DK00989096T DK1242402T3 (en) 1999-12-20 2000-12-15 New connections
BR0016578-6A BR0016578A (en) 1999-12-20 2000-12-15 Compound, use of it, pharmaceutical composition, and, methods for the treatment of pain, for the treatment of gastrointestinal disorders and for the treatment of spinal damage.
AT00989096T ATE254120T1 (en) 1999-12-20 2000-12-15 NEW CONNECTIONS
SI200030296T SI1242402T1 (en) 1999-12-20 2000-12-15 Novel compounds
NZ519985A NZ519985A (en) 1999-12-20 2000-12-15 Opioid receptor ligands for treating pain and gastrointestinal disorders
IL15012600A IL150126A0 (en) 1999-12-20 2000-12-15 Novel 4(piperazinyl(8-quinolinyl)methyl) benzamides
IL150126A IL150126A (en) 1999-12-20 2002-06-10 4-(piperazinyl(8-quinolinyl)methyl)benzamides, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments for therapy
BG106806A BG65456B1 (en) 1999-12-20 2002-06-10 Piperazine quinolinemethyl benzamides, a pharmaceutical composition containing them, and use thereof as medicaments
IS6423A IS2194B (en) 1999-12-20 2002-06-14 Compounds containing piperazine that are useful for the treatment of pain
NO20022918A NO323402B1 (en) 1999-12-20 2002-06-18 New connections
HK03100181.6A HK1048113B (en) 1999-12-20 2003-01-07 Novel compounds

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US8129393B2 (en) 2004-08-02 2012-03-06 Astrazeneca Ab Diarylmethyl piperazine derivatives, preparations thereof and uses thereof
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