EP1244453A1 - Methode et composition pour traiter la douleur - Google Patents

Methode et composition pour traiter la douleur

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Publication number
EP1244453A1
EP1244453A1 EP00987933A EP00987933A EP1244453A1 EP 1244453 A1 EP1244453 A1 EP 1244453A1 EP 00987933 A EP00987933 A EP 00987933A EP 00987933 A EP00987933 A EP 00987933A EP 1244453 A1 EP1244453 A1 EP 1244453A1
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European Patent Office
Prior art keywords
mmol
chloro
pain
tert
added
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EP00987933A
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German (de)
English (en)
Inventor
Dean Gordon Brown
Thomas Michael Bare
Megan Murphy
Rebecca Ann Urbanek
Wenhua Xiao
Frances Marie Mclaren
Carey Lynn Horchler
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1244453A1 publication Critical patent/EP1244453A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/503—Pyridazines; Hydrogenated pyridazines spiro-condensed
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to the treatment or prevention of pain or nociception.
  • Pain is a sensory experience distinct from sensations of touch, pressure, heat and cold.
  • Pain that is caused by damage to neural structures is often manifest as a neural supersensitivity or hyperalgesia and is termed "neuropathic" pain. Pain can also be “caused” by the stimulation of nociceptive receptors and transmitted over intact neural pathways, such pain is termed “nociceptive” pain. The level of stimulation at which pain becomes noted is referred to as the "pain threshold.”
  • Analgesics are pharmaceutical agents which relieve pain by raising the pain threshold without a loss of consciousness. After administration of an analgesic drug a stimulus of greater intensity or longer duration is required before pain is experienced. In an individual suffering from hyperalgesia an analgesic drug may have an anti-hyperalgesic effect.
  • agents such as local anaesthetics block transmission in peripheral nerve fibers thereby blocking awareness of pain.
  • General anaesthetics reduce the awareness of pain by producing a loss of consciousness.
  • Tachykinin antagonists have been reported to induce antinociception in animals, which is believed to be analogous to analgesia in man (Maggi et al, J. Auton. Pharmacol. (1993) 13, 23-93).
  • non-peptide NK-1 receptor antagonists have been shown to produce such analgesia.
  • the NK-1 receptor antagonist RP 67,580 produced analgesia with potency comparable to that of morphine (Garret et al, Proc. Natl. Acad. Sci. USA (1993) 88, 10208-10212).
  • the opioid analgesics are a well-established class of analgesic agents with morphine- like actions.
  • Synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperi dines; morphinans; and benzomorphans.
  • Pharmacologically these compounds have diverse activities, thus some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g., codeine); still others exhibit mixed agonist-antagonist activity (e.g., nalbuphine); and yet others are partial agonists (e.g. nalorphine).
  • an opioid partial agonist such as nalorphine
  • morphine Whilst an opioid partial agonist such as nalorphine, (the N-alkyl analogue of morphine) will antagonize the analgesic effects of morphine, when given alone it can be a potent analgesic in its own right.
  • opioid analgesics morphine remains the most widely used, but, in addition to its therapeutic properties, it has a number of drawbacks including respiratory depression, decreased gastrointestinal motility (resulting in constipation), nausea and vomiting. Tolerance and physical dependence also limit the clinical uses of opioid compounds. Aspirin and other salicylate compounds are frequently used in treatment to interrupt amplification of the inflammatory process in rheumatoid diseases and arthritis and temporarily relieve the pain.
  • Other drug compounds used for these purposes include phenylpropionic acid derivatives such as Ibuprofen and Naproxen, Sulindac, phenyl butazone, corticosteroids, antimalarials such as chloroquine and hydroxychloroquine sulfate, and fenemates (J. Hosp. Pharm., 36:622 (May 1979)). These compounds, however, are ineffective for neuropathic pain.
  • NMD A receptors are defined by the binding of N-methyl-D-aspartate (NMD A) comprise a receptor/ion channel complex with several different identified binding domains.
  • NMDA itself is a molecule structurally similar to glutamate (Glu) which binds at the glutamate binding suite and is highly selective and potent in activating the NMDA receptor (Watkins (1987); Olney (1989)).
  • non-competitive NMDA antagonists bind at other sites in the NMDA receptor complex (examples are phencyclidine, dizocilpine, ketamine, tiletamine, CNS 1102, dextromethorphan, memantine, kynurenic acid, CNQX, DNQX, 6,7-DCQX, 6,7- DCHQC, R(+)-HA-966, 7-chloro-kynurenic acid, 5,7-DCKA, 5-iodo-7-chloro-kynurenic acid, MDL-28,469, MDL-100,748, MDL-29,951, -689,560, L-687,414, ACPC, ACPCM, ACPCE, arcaine, diethylenetriamine, 1,10-diaminodecane, 1,12-diaminododecane, ifenprodil, and SL- 82.0715). These compounds have been extensively reviewed by Roga
  • Glu neurotoxicity In addition to its physiological function, glutamate (Glu) can be neurotoxic. Glu neurotoxicity is referred to as "excitotoxicity" because the neurotoxic action of Glu, like its beneficial actions, is mediated by an excitatory process (Olney (1990); Choi (1992)). Normally, when Glu is released at a synaptic receptor, it binds only transiently and is then rapidly removed from the receptor by a process that transports it back into the cell. Under certain abnormal conditions, including stroke, epilepsy and CNS trauma, Glu uptake fails and Glu accumulates at the receptor resulting in a persistent excitation of electrochemical activity that leads to the death of neurons that have Glu receptors. Many neurons in the CNS have Glu receptors, so excitotoxicity can cause an enormous amount of CNS damage.
  • Acute excitotoxicity injury can occur as a result of ischemic events, hypoxic events, trauma to the brain or spinal cord, certain types of food poisoning which involve an excitotoxic poison such as domoic acid, and seizure-mediated neuronal degeneration, which can result from persistent epileptic seizure activity (status epilepticus).
  • NMDA receptor one receptor subtype through which Glu mediates a substantial amount of CNS injury, and it is well established that NMDA antagonists are effective in protecting CNS neurons against excitotoxic degeneration in these acute-CNS injury syndromes (Choi (1988); Olney (1990)).
  • Glu receptors In addition to neuronal damage caused by acute insults, excessive activation of Glu receptors may also contribute to more gradual neurodegenerative processes leading to cell death in various chronic neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia, Parkinson's disease and Huntington's disease (Olney (1990)). It is generally considered that NMDA antagonists may prove useful in the therapeutic management of such chronic diseases.
  • PCP also known as "angel dust” acts at a "PCP recognition site" within the ion channel of the NMDA Glu receptor. PCP acts as a non- competitive antagonist that blocks the flow of ions through the NMDA ion channel.
  • NMDA receptor complex The glycine binding site of the NMDA receptor complex is distinguishable from the Glu and PCP binding sites. Also, it has recently been discovered that NMDA receptors occur as several subtypes which are characterized by differential properties of the glycine binding site of the receptor. Many compounds that bind at the NMDA receptor glycine site, useful for the treatment of stroke and neurodegenerative conditions, have been described in U.S. Patents 5,604,227; 5,733,910; 5,599,814; 5,593,133; 5,744,471; 5,837,705 and 6,103,721. Summary of the Invention
  • the invention provides a method for the treatment of pain comprising administering a pain-ameliorating effective amount of any compound according to structural diagram I;
  • R 1 is halo
  • A is CH(R 2 )(CH 2 ) n where n has a value selected from 0, 1 or 2
  • R 2 is selected from C ⁇ -6 alkyl
  • D is selected from a five- or six-membered heteroaryl moiety or a benz-derivative thereof having 1, 2 or 3 ring atoms selected from nitrogen oxygen or sulfur where D is unsubstituted or substituted with one, two or three moieties selected from C 1-3 aIkoxy, halo and cyano.
  • the method comprises administering pain- ameliorating effective amounts of compounds according to structural diagram I wherein: D is selected from pyridyl, furanyl, benz[b]furanyl, thienyl, benz[b]thienyl and pyrazinyl.
  • the method comprises administering a pain-ameliorating effective amount of a compound according to structural diagram I wherein: R is selected from methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl and sec-butyl.
  • Still more particular embodiments of the invention are those where the method comprises treatment with an exemplary compound specifically disclosed herein.
  • Another aspect of the invention is a method for making compounds in accord with structural diagram I.
  • Suitable pharmaceutically-acceptable salts of compounds of the invention include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, tris(hydroxymethyl)aminomethane, maleate and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salts for example sodium, alkaline earth metal salts for example calcium or magnesium, organic amine salts for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, choline, N,N-dibenzylethylamine or amino acids such as lysine.
  • a B where R is an alkyl group b) preparing a Boc-protected hydrazine by reacting a ketone as prepared in step a), or an aldehyde, according to one of the procedures shown in the following scheme:
  • CMC is l-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate; the "R/H/D” group is the "-A-D” moiety of structural diagram I; and throughout the foregoing process:
  • R 1 is as defined for structural diagram I.
  • the compound can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • Suitable pharmaceutical compositions that contain a compound of the invention may be administered in conventional ways, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • a compound of the invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • a preferred route of administration is orally by tablet or capsule.
  • a pharmaceutical composition of this invention may also contain one or more other pharmacologically-active agents, or such pharmaceutical composition may be simultaneously or sequentially co-administered with one or more other pharmacologically-active agents.
  • Pharmaceutical compositions of this invention will normally be administered so that a pain-ameliorating effective daily dose is received by the subject.
  • the daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • a preferred dosage regime is once daily.
  • a further embodiment of the invention provides a pharmaceutical composition which contains a compound of the structural diagram I as defined herein or a pharmaceutically- acceptable salt thereof, in association with a pharmaceutically-acceptable additive such as an excipient or carrier.
  • a yet further embodiment of the invention provide the use of a compound of the structural diagram I, or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament useful for binding to the NMDA receptor glycine site in a warm-blooded animal such as a human being.
  • Still another embodiment of the invention provides a method of binding a compound of the invention to the NMDA receptor glycine site of a warm-blooded animal, such as a human being, in need of treatment for pain, which method comprises administering to said animal an effective amount of a compound of structural diagram I or a pharmaceutically- acceptable salt thereof.
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” refer to the straight chain moiety.
  • halo means fluoro, chloro, bromo and iodo.
  • aryl means an unsaturated carbon ring or a benz- derivative thereof. Particularly, aryl means phenyl, naphthyl or biphenyl. More particularly aryl means phenyl.
  • heteroaryl or “heteroaryl ring” means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidized to form the N-oxide.
  • heteroaryls examples include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.
  • heterocyclyl or “heterocyclic ring” means, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
  • concentrations were carried out by rotary evaporation in vacuo; operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere; column chromatography (by the flash procedure) was performed on Merck Kieselgel silica- (Art.
  • CDC1 3 is deuterated chloroform
  • CMC is l-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulf onate ;
  • DCM is dichloromethane;
  • DCU is dicyclohexyl urea;
  • DHC is 1,3-dicyclohexylcarbodiimide
  • DMF is N,N-dimethylformamide
  • NMP is N-methylpyrrolidinone
  • THF is tetrahydrofuran, and t.i.d. is three times daily.
  • Example 1 (+/-V 7-Chloro-4-hvdro ⁇ y-2-(3-pyridyleth- 1 - ylV 1 ,2.5.10- tetrahvdropyridazinor4,5-blquinoline-l,10-dione methanesulfonate. N-(l-Aza-2-(3-pyridyl)prop-l-enyl (tert-butoxy)carboxamide. To a stirred solution of tert-butylcarbazate (2.18 g, 16.5 mmol) in THF (40 mL) was added 3-acetylpyridine (2.00 g, 16.5 mmol), followed by 3 drops of concentrated hydrochloric acid.
  • N-(l-Aza-2-(3-pyridyl)prop-l-enyl)(tert-butoxy)carboxamide (1.0 g, 4.2 mmol) was dissolved in methyl alcohol (80 mL) and placed in a Parr shaker bottle. To this was added 10% palladium-on-carbon (250 mg) and the reaction was hydrogenated at 40 psi for 24 h. The mixture was filtered through diatomaceous earth, which was washed with methyl alcohol (3 x 100 mL). The combined filtrate and washes were concentrated in vacuo. The resultant oil (ca. 1.0 g) was used in the following reaction without further purification.
  • the reaction mixture was filtered and the collected solids washed with DCM (2 x 150 mL). The combined filtrate and washes were concentrated in vacuo to dryness. The resultant yellow foam was subjected to chromatography (silica gel, 95/5 chloroform/methyl alcohol) to give the title compound as a yellow foam (0.860 g, 41%).
  • Example 2 (+/-)-7-Chloro-4-hvdroxy-2-(4-pyridyleth-l-yl -1.2,5,10- tetraKvdropyridazinor4,5-b1quinoline-1.10-dione methanesulfonate.
  • 4-acetylpyridine (2.00 g, 16.5 mmol), followed by 3 drops of concentrated hydrochloric acid.
  • Example 3 (+/-V7-Chloro-4-hvdroxy-2-(4-pyridylprop-l-yl)-1.2,5,10- tetrahydropyridazinor4.5-b1quinoline-1.10-dione sodium methanesulfonate.
  • N-(l-Aza-2-(2-pyridyl)but-l-enyi ⁇ tert-butoxy)carboxamide (2.25 g, 9.03 mmol) was dissolved in methyl alcohol (90 mL) and placed in a Parr shaker bottle. To this was added 10% palladium-on-carbon (500 mg) and the reaction was hydrogenated at 40 psi for 18 h. The catalyst was filtered on diatomaceous earth, washed with methyl alcohol (2 x 300 mL), and the solvents were removed in vacuo to give a white solid (1.34 g, 70%).
  • Example 1 To a stirred slurry of 7-chloro-4-oxo-2-(pyrrolidinylcarbonyl)hydroquinoline-3- carboxylic acid, Example 1, (1.22 g, 3.82 mmol) in THF (60 mL) was added CMC (1.77 g, 4.20 mmol) and the reaction was stirred for five minutes. To this mixture was added, via dropwise addition, a solution of (+/-)-(tert-butoxy)-N-[(2-pyridylpropyl)amino]carboxamide (2.00 g, 6.23 mmol) and DMAP (0.080 g, 0.65 mmol) in THF (20 mL), and the mixture was stirred at room temperature for 1 hour.
  • Example 5 (+/-)-7-Chloro-4-hvdroxy-2-( ⁇ ropyl- l-(3-pyridyl))-l .2.5, 10- tetrahvdropyridazino 4.5-blquinoline-l,10-dione methanesulfonate. N-(l-Aza-2-(3-pyridyl)prop-l-enyl)(tert-butoxy)carboxamide.
  • N-(l-Aza-2-(3-pyridyl)but-l-enyl)(tert-butoxy)carboxamide (2.00 g, 8.02 mmol) was dissolved in methyl alcohol (60 mL) and placed in a Parr shaker bottle. To this was added 10% palladium-on-carbon (500 mg) and the reaction was hydrogenated at 40 psi for 18 h. The catalyst was filtered on diatomaceous earth, washed with methyl alcohol (2 x 300 mL), and the solvents were removed in vacuo to give a white solid (1.34 g, 73%).
  • Example 1 To a stirred slurry of 7-chloro-4-oxo-2-(pyrrolidinylcarbonyl)hydroquinoline-3- carboxylic acid, Example 1, (1.87 g, 5.80 mmol) in THF (60 mL) was added CMC (2.69 g, 6.35 mmol) and the reaction was stirred for five minutes. To this mixture was added, by dropwise addition, a solution of (+/-)-(tert-butoxy)-N-[(3-pyridylpropyl)amino]carboxamide (1.47 g, 5.80 mmol) and DMAP (0.070 g, 0.58 mmol) in THF (20 mL), and the mixture was stirred at room temperature for 1 hour.
  • Example 7 (+/- -7-Chloro-4-hvdroxy-2-(butyl-l-(4-pyridyl))-1.2.5,10- tetrahydropyridazinor4,5-b1quinoline-l,10-dione. 1 -4-(Pyridyl)butan- 1-one. 4-Pyridinecarboxaldehyde dimethylacetal (Sheldrake P.W., Synth. Commun. 1993
  • the title compound was prepared from l-(4-pyridyl)butan-l-one as a starting material in a manner analogous to the procedure described in Example 5. Conversion to the free base was achieved by titration with 1 N sodium hydroxide until the pH was neutral. The resultant precipitate was collected by vacuum filtration, washed with diethyl ether and dried in vacuo to give the title compound as an off-white solid (29%).
  • Example 8 (+/-)-7-Chloro-4-hvdroxy-2-( ⁇ ro ⁇ yl-(2-meth yl-l-(4-pyridyl))- 1.2,5, 10- tetrahy dropyridazino [4,5 -b] quinoline- 1 , 10-dione methanesulfonate .
  • Example 9 (+/-)-7-Chloro-4-hvdroxy-2-(propyl-(2-methyl- l-(2- ⁇ yridyl ⁇ )-l.2.5.10- tetrahydropyridazino[4.5-b]quinoline-l,10-dione methanesulfonate.
  • Example 10 (+/-)-7-Chloro-4-hvdroxy-2-(pentyl- l-(4-pyridyl))- 1 ,2,5, 10- tetrahvdropyridazino[4,5-blquinoline- 1 , 10-dione methanesulfonate. N-l-Aza-2-(4-pyridyl)hex-l-enyl)(tert-butoxy)carboxamide.
  • the title compound was prepared from N-l-aza-2-(4-pyridyl)hex-l-enyl)(tert- butoxy)carboxamide in a manner analogous to the procedure described in Example 7 to give the title compound as an off-white powder.
  • Example 11 (+/-)-7-Chloro-4-hvdroxy-2-(3-methyl-l-(2-pyridyl)butyl))-l,2,5,10- tetrahvdropyridazino[4,5-blquinoline-1.10-dione methanesulfonate. 3-Methyl-l(2-pyridyl)butan-l-one.
  • N-(l-Aza-4-methyl-2-(2-pyridyl)-pent-l-enyl)(tert-butoxy)carboxamide (3.0 g, 10.8 mmol) was dissolved in methyl alcohol (90 mL) and placed in a Parr shaker bottle. To this was added 10% palladium-on-carbon (500 mg) and the reaction was hydrogenated at 40 psi for 18 h. The catalyst was filtered on diatomaceous earth, washed with methyl alcohol (2 x 300 mL), and the solvents were removed in vacuo to give an oil.
  • Example 1 To a stirred slurry of 7-chloro-4-oxo-2-(pyrrolidinylcarbonyl)hydroquinoline-3- carboxylic acid, Example 1, (2.28 g, 7.11 mmol) in THF (80 mL) was added CMC (3.44 g, 8.12 mmol) and the reaction was stirred for five minutes.
  • the ether was decanted away and to the brown oil was added water (10 mL). After a short time, a precipitate formed and was collected by vacuum filtration. The precipitate was washed with diethyl ether and then sonicated in 20 mL of 4/1 diethyl ether/methyl alcohol for fifteen minutes. The material was filtered, washed with diethyl ether and dried in vacuo to give the title compound (1.0 g, 30%) as an off-white powder (m.p. > 204-207 °C).
  • Example 12 (+/-)-7-Chloro-4-hvdroxy-2-(3-methyl-l-(4-pyridvDbutyl)-l,2.5,10- tetrahydropyridazino[4,5-bl quinoline- 1 , 10-dione.
  • the title compound was prepared using 4-cyanopyridine and isobutyl magnesium bromide as starting materials in a manner analogous to the procedure described in Example 11.
  • the resultant material was precipitated from aqueous solution by the addition of saturated aqueous sodium chloride. The precipitate was collected by vacuum filtration, washed with diethyl ether and dried in vacuo to give the title compound as an off-white solid (30%).
  • the title compound was prepared using 3-methoxy-4-cyanopyridine (LaMatting J.L., et al J. Org. Chem. 46, 4179-82, 1981) and methyl magnesium bromide as starting materials in a manner analogous to the procedure described in Example 11, to give the title compound as an off-white powder (31%).
  • Example 14 (+/-)-7-Chloro-4-hvdroxy-2-(l-(2-methoxypyrid-5-yl))ethyl-l,2,5,10- tetrahydropyridazino[4,5-b1quinoline-l,10-dione methanesulfonate.
  • the hydrazone starting material was made in a manner analogous to the process of Example 11 using 2-chloro-3-cyanopyridine and methylmagnesium bromide (1.4 M in toluene/THF) as a white foam (90%).
  • the aqueous layer was adjusted to a pH of 8 with sodium hydroxide (aqueous, 10 N) and further extracted with ethyl acetate. The ethyl acetate layers were combined, dried over Na 2 SO 4 and concentrated to give a yellow foam. This material was chromatographed (SiO 2 , DCM/methyl alcohol; gradient run from 100/0 to 90/10) to give the title compound as a yellow foam (1.60 g, 88%).
  • Example 18 (+/- -7-chloro-4-hvdroxy-2-(furan-2-ylethyl)- 1.2,5, 10- tetrahydropyridazino[4,5-blquinoline-l,10-dione.
  • Example 19 7-Chloro-4-hvdroxy-2-( 1 -(thien-3-yl)ethyl)- 1 ,2,5 , 10-tetrahvdropyridazino [4.5- blquinoline-l.lO-dione.
  • Example 20 7-Chloro-4-hvdroxy-2-(l-(benz[blthien-3-vDethylV1.2.5.10- tetrahydropyridazinor4.5-b1quinoline-l,10-dione.
  • the title compound was synthesized by the method of Example 17 using 2-acetyl-3- methylbenzothiophene as the starting material.
  • Example 21 7-Chloro-4-hydroxy-2-(l-(benz[b1thien-2-vnethyl)-1.2,5,10- tetrahydropyridazino[4,5-blquinoline- 1 , 10-dione.
  • the title compound was synthesized by the method of Example 2 using 2- acetylbenzothiophene as the starting material.
  • Test A Inhibition of binding of [ 3 H1-MDL105.519: Binding of compounds to the NMDA receptor glycine site may be assessed by measuring the ability of test compounds to inhibit the binding of tritiated MDL105,519 to brain membranes bearing the receptor.
  • Rat Brain Membranes The rat brain membranes used in the experiments were obtained from Analytical Biological Services Inc., and were prepared substantially in accordance with the method of B.M. Baron et al, J. Pharmacol. Exp. Ther. 250, 162 (1989).
  • Dawley rats was homogenized in 0.32 M sucrose and centrifuged at low speed to separate cellular membranes from other cellular components. The membranes were then washed 3 times using deionized water, followed by treatment with 0.04% Triton X-100. Finally, membranes were washed six times in 50 mM Tris citrate buffer, pH 7.4, and frozen at -80 °C until use.
  • [ 3 H]MDL105,519 72 Ci/mmol
  • Cold MDL105,519 was purchased from Sigma/RBI. Binding assays were performed substantially in accordance with the protocol of B.M. Baron et al, J. Pharmacol. Exp. Ther. 279, 62 (1996), as follows.
  • the Formalin test is an assay that assesses the capacity of a compound to inhibit formalin-induced nociceptive behaviors in rats (D. Dubuisson, et al, Pain 4, 161-174 (1977); H. Wheeler-Aceto et al, Psychopharmacology 104, 35-44 (1991); TJ. Coderre, et al, Pain 54, 43-50 (1993)).
  • a first phase response caused by acute nociception to the noxious chemical
  • EDs 0 is the dose of compound which produces 50% inhibition of nociceptive response in the first or second phase response.
  • First phase responses may be inhibited by compounds that act peripherally and by compounds that act centrally.
  • Second phase response are inhibited by centrally active compounds.
  • % inhibition of nociceptive response 100 x (number of responses in vehicle group - number of responses in compound group)
  • Test C Neuropathic pain model (Chronic Constriction Injury):
  • the anti-hyperalgesic properties of a compound may be tested with the Chronic Constriction Injury ("CCI") model.
  • CCI Chronic Constriction Injury
  • the test is a model for neuropathic pain associated with nerve injuries that can arise directly from trauma and compression, or indirectly from a wide range of diseases such as infection, cancer, metabolic conditions, toxins, nutritional deficiencies, immunological dysfunction, and musculoskeletal changes.
  • a unilateral peripheral hyperalgesia is produced in rats by nerve ligation (G.J. Bennett, et al, Pain 33, 87-107 (1988)).
  • Sprague-Dawley rats 250-350 g are anesthetized with sodium pentobarbital and the common sciatic nerve is exposed at the level of the mid thigh by blunt dissection through the biceps femoris.
  • a section of nerve (about 7 mm), proximal to the sciatic trifucation, is freed of tissue and ligated at four positions with chromic gut suture.
  • the suture is tied with about 1 mm spacing between ligatures. The incision is closed in layers and the animals are allowed to recuperate.
  • Thermal hyperalgesia is measured using a paw- withdrawal test (K. Hargreaves, et al, Pain 32, 77-88 (1988)).
  • mice are habituated on an elevated glass floor.
  • a radiant heat source is aimed at the mid-plantar hindpaw (sciatic nerve territory) through the glass floor with a 20 second cut-off used to prevent injury to the skin.
  • the latencies for the withdrawal reflex in both hind paws are recorded.
  • Injured paws with ligated nerves show shorter paw withdrawal latencies compared to the uninjured or sham operated paws.
  • Responses to test compounds are evaluated at different times after oral administration to determine the onset and duration of compound effect.
  • groups of CCI rats receive either vehicle or the test compound orally three times daily for 5 days. Paw withdrawal latencies are measured each day 10 min before and 2 or 3 hr. after the first daily dose.
  • Compound efficacy is expressed as mean percentage decrease of hyperalgesia compared to that of vehicle-treated animals, calculated as follows: (Mean of vehicle group - Mean of compound group) I QQ (Mean of vehicle group).

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Abstract

L'invention concerne une méthode de traitement de la douleur qui consiste à administer une quantité effective d'un composé de la formule (I) dans laquelle R1, A et D sont tels que définis dans le mémorandum descriptif. Elle concerne également des compositions pharmaceutiques contenant une quantité effective d'un composé de la formule (I) pouvant atténuer la douleur.
EP00987933A 1999-12-23 2000-12-19 Methode et composition pour traiter la douleur Withdrawn EP1244453A1 (fr)

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US20050070544A1 (en) * 2000-09-29 2005-03-31 Astrazeneca Ab 1,2,5,10-tetrahydropyridazino{4,5-b}quinoline-1,10-diones and their use for the treatment of pain
AU2001292499A1 (en) * 2000-09-29 2002-04-08 Astrazeneca Ab 7-chloro-4-hydroxy-2-(2-pyridylethyl)-1,2,5,10- tetrahydropyridazino(4,5-b)quinoline-1,10-dione and the use thereof for the treatment of pain
ATE327235T1 (de) * 2000-09-29 2006-06-15 Astrazeneca Ab 1,2,5,10-tetrahydropyridazino 4,5-böchinolin-1, 0-dione und ihre anwendung in der behandlung von schmerzen
SE0403172D0 (sv) * 2004-12-23 2004-12-23 Astrazeneca Ab Manufacturing process
CA2689137C (fr) * 2007-05-29 2017-05-02 Intrexon Corporation Ligands diacylhydrazine chiraux destines a moduler l'expression de genes exogenes par le biais d'un complexe recepteur de l'ecdysone

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