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WO2009080675A1 - Dérivés de quinoline ayant une affinité pour le récepteur 5-ht2b - Google Patents

Dérivés de quinoline ayant une affinité pour le récepteur 5-ht2b Download PDF

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WO2009080675A1
WO2009080675A1 PCT/EP2008/067810 EP2008067810W WO2009080675A1 WO 2009080675 A1 WO2009080675 A1 WO 2009080675A1 EP 2008067810 W EP2008067810 W EP 2008067810W WO 2009080675 A1 WO2009080675 A1 WO 2009080675A1
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compound
pain
treatment
mmol
fibrosis
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Gordon Bruton
David Hirst
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel quinoline derivatives which bind to the 5-HT 2B receptor and are capable of interfering with the effects of 5-hydroxytryptamine (5-HT) at the 5-HT 2B receptor; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.
  • 5-HT 5-hydroxytryptamine
  • 5-Hydroxytryptamine is a neurotransmitter important to both the central nervous system (CNS) and as a pivotal mediator of sensory and motor function in the gastrointestinal (Gl) tract, McLean et al., TRENDS in Neurosciences (2006) Vol.30 No.1 , 9-13.
  • CNS central nervous system
  • Gl gastrointestinal
  • serotonin was referred to as 'gut- stimulating factor', Erspamer et al., Nature (1952) Vol.169, 800-801 , and since that time has also become appreciated as a neurotransmitter in the brain.
  • the cell surface receptors via which serotonin exerts its biological effects have been identified by molecular techniques.
  • 5-HT 1 , 5-HT 2, 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 based on gene sequence, pharmacological profile and signal transduction pathways, Robichaud et ai., Annual Reports in Medicinal Chemistry (2000) Vol.36, 11-20.
  • 5-HT 2 receptors are a family of seven transmembrane domain G-protein coupled receptors which can be subdivided into three distinct subtypes: 5-HT 2A , 5-HT 26 and 5- HT 2C , sharing an overall amino acid homology of approximately 50% and the homology within the transmembrane domains being greater than 70%, J. E. Leysen, Current Drug Targets - CNS & Neurological Disorders (2004), Vol.3, 11-26.
  • 5-HT 2B receptors are present on both smooth muscle and nerves and their activation by serotonin can cause direct smooth muscle contraction in the human ileum, Borman et ai, British Journal of Pharmacology (1995) Vol.114, 1525-1527. Furthermore, activation of 5-HT 2B receptors can enhance cholinergic-neuron- mediated contractions in human colon (Borman et al., British Journal of
  • 5-HT 26 receptor antagonists may be of use in the treatment of functional bowel disorders such as Irritable Bowel Syndrome (IBS). Visceral pain is commonly associated with IBS, the most frequent features of which are recurrent abdominal pain and discomfort, altered bowel habits and a strong female predominance.
  • IBS Irritable Bowel Syndrome
  • the definition and criteria for IBS have been formalised by the Rome III criteria, Drossman et al., Journal of Gastrointestinal and Liver Diseases (2006) Vol.15(3), 237-241.
  • the potential usefulness of 5-HT 2B receptors in the treatment of IBS is further supported by the observation that the 5-HT 4 agonist
  • Tegaserod Novartis
  • 5-HT 3 antagonist Alosetron GlaxoSmithKline
  • IBS may also be treated with gabapentin or the tricyclic antidepressant drug amitriptyline.
  • Gabapentin is widely used as a medication to relieve pain and has been shown to reduce rectal sensory thresholds through attenuating rectal sensitivity to distension and enhancing rectal compliance in diarrhoea-predominant IBS patients, Lee et al., Alimentary Pharmacology and Therapeutics (2005), Vol.22, 981-988.
  • 5-HT 2B receptor blockade is involved in migraine since the experimental drug tool m-chlorophenylpiperazine that triggers migraine in selected subjects has affinity for both the 5-HT 2B receptor and the 5-HT 2C receptor, Fozard et al., Naunyn-Schmiedeberg's Arch Pharmacol (1994) Vol. 250, 225-229, as do a number of migraine prophylactic drugs, Kalkman Life Sciences (1994) Vol.54(10), 641-644.
  • 5-HT 2C receptor-knockout mice suggest that the 5-HT 2C receptor may also be involved in obesity and epilepsy, Tecott et al. Nature (1995) Vol.374, 542-546.
  • the 5-HT 2C receptor is closely involved in the weight gain that occurs following treatment with many antipsychotic drugs, for example clozapine and olanzapine, and is likely to contribute directly via the 5-HT 2C antagonistic effects of these drugs, Reynolds et al., Journal of Psychopharmacology (2006) Vol. 20, 15-18.
  • 5-HT 2B receptor activation is also believed to influence mitogenic signalling. This activity is thought to underpin the reason why 5-HT 26 receptor antagonists are likely to provide useful treatments of conditions associated with the development of fibrosis, including valvular heart diseases, pulmonary hypertension and lung and liver fibrosis.
  • the evidence pointing to a link between the 5-HT 26 receptor and the various cardiovascular diseases is summarised by Kaumann & Levy (2006, Pharmacology & Therapeutics, 1 11 , 674-706) and specifically described by Jaffre et al (2004, Circulation, 110, 969-974) and Launay et al (2002, Nature Medicine, 8, 1129-1 135).
  • 5-HT 2B receptor antagonists are also useful for the treatment of disorders where inappropriate release of 5-HT leads to tissue remodelling. For example, it has been demonstrated in both humans and mice that pulmonary hypertension is associated with a substantial increase in 5-HT 2B receptor expression in pulmonary arteries. These data show that activation of 5-HT 26 receptors is a limiting step in the development of pulmonary arterial hypertension (Launay, J. -M. et al., (2002) Nature Medicine 8(10), 1129-1135) associated with, for example, hypoxic lung disease or hypoxemia. Treatment with 5-HT 26 receptor antagonists would, therefore, be expected to inhibit both the vasconstrictor and vascular cell proliferative actions of 5- HT (Kaumann, AJ & Levy, F. O.
  • 5-HT 26 receptor antagonists are also useful in the treatment of conditions where there is cardiac hypertrophy (Jaffre, F., et al (2004) Circulation, 110, 969-974).
  • cardiac hypertrophy Jaffre, F., et al (2004) Circulation, 110, 969-974.
  • 5-HT exerts a negative influence on hepatic growth and function which can be prevented by 5-HT 26 receptor antagonists, demonstrating their use in the treatment of liver degeneration (Ebrahimkhani, M., et al., 2007, 58th Ann Mtg Am Assoc for the study of Liver Diseases, Abstract 1238).
  • 5-HT 26 receptor antagonists to reduce the profibrogenic activity of 5-HT extends the use of such compounds to disorders associated with fibrosis, such as cardiac valvulopathy (Hoffman, C, et al., 2006, Clinical Neuropharmacol., 29, 80-86).
  • 5-HT 26 receptor antagonists include the treatments of narclopesy or other conditions where increased wakefulness is required (Kantor, S, et al., 2004, Br J Pharmacol., 142, 1332-1342).
  • the present invention provides compounds with affinity for the 5-HT 2B receptor and which are capable of interfering with the affects of serotonin at these receptors.
  • a compound which is 8-[4-(1 ,1-dioxidotetrahydro-2H- thiopyran-4-yl)-1-piperazinyl]-2-methylquinoline: or a pharmaceutically acceptable salt thereof (hereinafter referred to as compounds of formula (I)).
  • the compound is 8-[4-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1- piperazinyl]-2-methylquinoline (E1 ).
  • the compound is 8-[4-(1 ,1-dioxidotetrahydro-2H-thiopyran- 4-yl)-1-piperazinyl]-2-methylquinoline hydrochloride (E2).
  • the compound is 8-[4-(1 ,1-dioxidotetrahydro-2H- thiopyran-4-yl)-1-piperazinyl]-2-methylquinoline dihydrochloride (E3).
  • a method of treatment of fibrosis or a fibrotic condition comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I).
  • the mammal in need of such treatment is human.
  • the human is female.
  • fibrosis refers to the formation or development of excess fibrous connective tissue in an organ or tissue as a reparative or reactive process, as opposed to a formation of fibrous tissue as a normal constituent of an organ or tissue.
  • fibrotic condition refers to a disease or condition mediated by fibrosis. Examples of types of fibrotic conditions and associated conditions include but are not limited to cardiovascular disorders (e.g. valvular heart diseases, conditions associated with cardiac hypertrophy and pulmonary hypertension), lung fibrosis (e.g. after chronic obstructive pulmonary disease), liver fibrosis (e.g.
  • precirrhotic alcoholic liver disease nonalcoholic steatohepatitis/ fatty liver disease and hepatitis C
  • cystic fibrosis such as cystic fibrosis of the pancreas and lungs
  • injection fibrosis such as fibrotic conditions which can occur as a complication of intramuscular injections, especially in children
  • fibrosis which follows organ transplant or other therapeutic regimens, such as anti-cancer treatment with radiation, schleroderma, endomyocardial fibrosis, idiopathic pulmonary fibrosis, mediastinal fibrosis, myleofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, tuberculosis, sickle-cell anemia and rheumatoid arthritis.
  • the fibrotic condition is a cardiovascular disorder (e.g. valvular heart diseases, conditions associated with cardiac hypertrophy and pulmonary hypertension), lung fibrosis (e.g. after chronic obstructive pulmonary disease) or liver fibrosis (e.g. precirrhotic alcoholic liver disease, nonalcoholic steatohepatitis/ fatty liver disease and hepatitis C).
  • a cardiovascular disorder e.g. valvular heart diseases, conditions associated with cardiac hypertrophy and pulmonary hypertension
  • lung fibrosis e.g. after chronic obstructive pulmonary disease
  • liver fibrosis e.g. precirrhotic alcoholic liver disease, nonalcoholic steatohepatitis/ fatty liver disease and hepatitis C.
  • Antagonists of the 5-HT 2B receptor may also be useful in preventing, treating or ameliorating Gl tract disorders, for example IBS.
  • 5-HT 2B receptor antagonists may also be useful in preventing, treating or ameliorating pain, for example inflammatory pain or visceral pain.
  • 5-HT 26 receptor antagonists may be useful in preventing, treating or ameliorating certain CNS disorders including migraine.
  • 5-HT 2B receptor antagonists may also be useful in preventing, treating or ameliorating certain cardiovascular disorders including pulmonary arterial hypertension.
  • a method of treatment of inflammatory pain in mammals comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I).
  • the cause of such inflammatory pain may be osteoarthritis or rheumatoid arthritis.
  • a method of treatment of chronic articular pain associated with osteoarthritis or rheumatoid arthritis in mammals comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I).
  • a method of treatment of visceral pain in mammals comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I).
  • the visceral pain is associated with irritable bowel syndrome.
  • a method of treatment of irritable bowel syndrome in mammals comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula
  • a method of treatment of headache e.g. migraine
  • which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I).
  • pain refers to any unpleasant sensation that is perceived by the individual and includes, but is not limited to, acute pain, chronic pain, somatic pain (originating from ligaments, tendons, bones, blood vessels or nerves), chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
  • inflammatory pain refers to any kind of pain that results from the inflammation of bodily tissues and includes, but is not limited to, inflammation resulting from soft tissue damage or infection.
  • neurodegenerative pain refers to any kind of pain that results from injury or disease to the nerve tissue itself and includes, but is not limited to: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain conditions include pain associated with normally non- painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • normally non- painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • visceral pain refers to any kind of pain that originates from the body's internal cavities or organs and includes, but is not limited to, pain that originates from the intestines.
  • IBS Irritable Bowel Syndrome
  • Rome III diagnostic criteria where the criteria are fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
  • the Rome III diagnostic criteria for IBS are as follows: - Recurrent abdominal pain or discomfort (where discomfort means an uncomfortable sensation not described as pain) at least 3 days per month in the last 3 months associated with 2 or more of the following:
  • Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool.
  • IBS IBS
  • Abnormal stool frequency greater than 3 bowel movements/day or less than 3 bowel movements/week
  • Abnormal stool form lumpy/hard or loose watery stool
  • - Abnormal stool passage (straining, urgency, or feeling of incomplete bowel movement): Passage of mucous; - Bloating or feeling of abdominal distension.
  • headache refers to any unpleasant sensation that is localised to the individual's head and includes, but is not limited to, migraine, tension headache and cluster headaches.
  • treatment includes the treatment of established disorders and also includes the prophylaxis thereof.
  • prophylaxis is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrence of symptoms in an afflicted subject and is not limited to complete prevention of an affliction.
  • Compounds of the present invention interact with the 5-HT 2B receptor and are capable of interfering with the effects of serotonin at the 5-HT 2B receptor.
  • Such compounds may be competitive antagonists, inverse agonists, or negative allosteric modulators.
  • Compounds of formula (I) exhibit 100 fold selectivity for the 5-HT 26 receptor over certain other serotonin receptors (e.g. 5-HT 2A and 5-HT 2C ).
  • Certain compounds of formula (I) may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds of formula (I) may be used as salts, in which case the salts should be pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19.
  • pharmaceutically acceptable salts includes salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
  • the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 1 1 C, 14C and 18F.
  • Isotopically- labeled compounds of the present invention for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 8F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
  • lsotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • a compound of formula (I) for use in the treatment of fibrosis or a fibrotic condition Gl tract disorders, for example IBS, pain, for example inflammatory pain or visceral pain, headache, for example migraine, cardiovascular disorders including pulmonary arterial hypertension.
  • Gl tract disorders for example IBS
  • pain for example inflammatory pain or visceral pain
  • headache for example migraine
  • cardiovascular disorders including pulmonary arterial hypertension.
  • a compound of formula (I) for use in the treatment of fibrosis or a fibrotic condition there is provided a compound of formula (I) for use in the treatment of fibrosis or a fibrotic condition.
  • a pharmaceutical composition comprising a compound of formula (I), for use in human or veterinary medicine.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), and optionally a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of formula (I) and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 200 mg; and such unit doses will preferably be administered once a day, although administration more than once a day may be required; and such therapy may extend for a number of weeks, months or even years.
  • therapy could be given on demand, prophylactically, or continuously over a period of time until the patient no longer requires treatment.
  • the present invention also provides a process for the preparation of a compound of formula (I) which process comprises:
  • Process (a) may be carried out using a suitable oxidizing agent such as OxoneTM (potassium peroxymonosulfate) or magnesium monoperoxyphthalate.
  • OxoneTM potassium peroxymonosulfate
  • magnesium monoperoxyphthalate magnesium monoperoxyphthalate
  • Process (b) may be carried out by reaction of a compound of formula (III) with a compound of formula (IV) in the presence of suitable reagents such as tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl, sodium t-butoxide and 1 ,4-dioxane.
  • suitable reagents such as tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl, sodium t-butoxide and 1 ,4-dioxane.
  • Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'- trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.
  • an acid such as hydrochloric acid in 1 ,4-dioxane or trifluoroacetic acid in dichloromethane
  • reductively e.g. hydrogenolysis of a benzyl group or reductive removal of a 2',2',2'- trichloroethoxycarbonyl group using zinc in acetic acid
  • Other suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis (e.g.
  • Step (i) typically comprises analogous conditions to those described above for process (b).
  • Step (ii) typically comprises a deprotection reaction in the presence of a strong acid such as hydrochloric acid, or TFA, and a suitable solvent such as methanol or DCM.
  • a strong acid such as hydrochloric acid, or TFA
  • a suitable solvent such as methanol or DCM.
  • Step (iii) typically comprises reaction of a compound of formula (VII) with a compound of formula (VIII) in the presence of suitable reagents such as acetic acid, sodium triacetoxyborohydride and a suitable solvent such as 1 ,2-dichloroethane.
  • suitable reagents such as acetic acid, sodium triacetoxyborohydride and a suitable solvent such as 1 ,2-dichloroethane.
  • Step (i) typically comprises reacting a compound of formula (V) with a compound of formula (VIII) in an analogous manner to that described for Step (iii) in Scheme 1.
  • Step (ii) typically comprises an oxidation reaction in an analogous manner to that described for process (a) above.
  • Step (iii) typically comprises a deprotection reaction in an analogous manner to that described for Step (ii) in Scheme 1.
  • Toluene (60 mL) and crotonaldehyde (5.01 ml_, 60.5 mmol) were added to a solution of 2-bromoaniline (5.2 g, 30.2 mmol) in aqueous 6M HCI (200 mL) at 100 0 C for 2 hours. The mixture was then allowed to cool to room temperature. The aqueous layer was separated and neutralised with 6M NaOH solution (200 mL).
  • METHOD 3 1 1 -dimethylethyl-4-(2-methyl-8-quinolinyl)-1 -piperazinecarboxylate (intermediate 2) (3.43 g, 10.5 mmol) was taken up in dichloromethane (80 mL) and cooled in an ice- bath. Trifluoroacetic acid (20 mL) was added slowly and the reaction was left to stir for 30 minutes before the ice-bath was removed. After a total of 90 minutes the solvent was removed under reduced pressure and the residue was taken up in dichloromethane (100 mL) and saturated NaHCC>3 (200 mL) was added slowly. The organic layer was separated and the aqueous was extracted with further dichloromethane (100 mL).
  • the filtrate was transferred to a separating funnel and the ethyl acetate layer was isolated, dried over MgSO 4 , filtered and concentrated in vacuo to afford a first batch of the crude product as a pale yellow solid.
  • the solid initially isolated by filtration was suspended in ethyl acetate (100 mL) and shaken vigorously with water (30 mL).
  • the ethyl acetate layer was isolated, dried over MgSO 4 , filtered and concentrated in vacuo to afford a second batch of crude product as a white solid.
  • Toluene was heated to boiling point, 40 mL of this was added to the first batch of crude product, this was reheated to boiling point and swirled until all the material had dissolved.
  • Adherent SH-SY5Y cells stably expressing the recombinant human 5-HT 2A , 5-HT 2B or 5-HT 2C were maintained in culture at 37°C under 5% CO 2 in Dulbecco's Modification of Eagle's Medium supplemented with 10% dialysed foetal calf serum and 400 micrograms geneticin.
  • the cloning of human 5-HT 2A and 5-HT 2C receptors (previously denoted as 5-HT 2 and 5-HT 1c receptors respectively) is described by Saltzman et al., Biochemical and Biophysical Research Communications (1991 ) Vol.181 No.3, 1469- 1478.
  • SH-SY5Y cells are commercially available from the American Type Culture Collection (ATCC), catalogue number CRL-2266.
  • SH-SY5Y cells separately expressing 5-HT 2A , 5-HT 2B or 5-HT 2C receptors, were seeded into black walled clear-base 384-well plates at a density of 16,000 cells per well and cultured overnight at 37°C under 5% CO 2 . Media was aspirated off and cells were then incubated with Tyrode's medium (in mM; NaCI 145, KCI 2.5, HEPES 10, Glucose 10, MgCI 2 1.2, CaCI 2 1.5) containing the cytoplasmic calcium indicator, Fluo- 4 in the acetylmethyl form (4 mM) and 25OuM Brilliant Black (Molecular Devices) at 37°C for 60 min.
  • Tyrode's medium in mM; NaCI 145, KCI 2.5, HEPES 10, Glucose 10, MgCI 2 1.2, CaCI 2 1.5
  • the loaded cells were then incubated for 30 min at 37°C with either buffer (agonist mode) or compound (antagonist mode).
  • the plates were then placed into a FLIPR (Molecular Devices, UK) to monitor cell fluorescence ( ⁇ ex 488nm, ⁇ em 540nm) before and after the addition of various compounds (in agonist mode) or a pre-determined concentration of 5-HT (approximately 4xEC50) for testing in antagonist mode.
  • Functional Ki values were calculated from IC50 values in accordance with the following equation:
  • the functional pKi (fpKi) values can then be calculated from the negative Iog10 of the fKi values.
  • Example 1 was also tested in the 5HT 2C assay and displayed a plC50 value ⁇ 5.0.
  • Example 2 was tested in the 5HT 2A and 5HT 2C assays and displayed a plC50 value ⁇ 5.0.

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Abstract

La présente invention concerne la 8-[4-(1,1 -dioxydotétrahydro-2H-thiopyran-4-yl)-1- pipérazinyl]-2-méthylquinoline ou l'un de ses sels pharmaceutiquement acceptables (composés représentés par la formule (I)) qui se lient au récepteur 5-HT2B et sont capables d'interférer avec les effets de la 5-hydroxytryptamine (5-HT) au niveau du récepteur 5-HT2B. L'invention concerne également des compositions les contenant et l'utilisation thérapeutique de tels composés.
PCT/EP2008/067810 2007-12-20 2008-12-18 Dérivés de quinoline ayant une affinité pour le récepteur 5-ht2b Ceased WO2009080675A1 (fr)

Applications Claiming Priority (2)

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GB0724931.1 2007-12-20
GBGB0724931.1A GB0724931D0 (en) 2007-12-20 2007-12-20 Novel compounds

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WO2009080675A1 true WO2009080675A1 (fr) 2009-07-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104592109A (zh) * 2015-01-19 2015-05-06 湖南华腾制药有限公司 一种8-溴喹啉衍生物的制备方法
WO2016030445A1 (fr) * 2014-08-29 2016-03-03 Anamar Ab Aminoguanidines de formule (i) à utiliser dans le traitement de la fibrose

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736544A (en) * 1994-03-11 1998-04-07 Eli Lilly And Company Naphthylpiperazinyl compounds useful for treating 5HT2B receptor mediated conditions
WO2005026125A1 (fr) * 2003-09-12 2005-03-24 Glaxo Group Limited Composes de quinoleine et compositions pharmaceutiques contenant ceux-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736544A (en) * 1994-03-11 1998-04-07 Eli Lilly And Company Naphthylpiperazinyl compounds useful for treating 5HT2B receptor mediated conditions
WO2005026125A1 (fr) * 2003-09-12 2005-03-24 Glaxo Group Limited Composes de quinoleine et compositions pharmaceutiques contenant ceux-ci

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030445A1 (fr) * 2014-08-29 2016-03-03 Anamar Ab Aminoguanidines de formule (i) à utiliser dans le traitement de la fibrose
CN104592109A (zh) * 2015-01-19 2015-05-06 湖南华腾制药有限公司 一种8-溴喹啉衍生物的制备方法

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