EP0874833A1 - 4,5-dihydronaphth 1,2-c]isoxazoles et leurs derives ayant une activite au niveau du systeme nerveux central - Google Patents

4,5-dihydronaphth 1,2-c]isoxazoles et leurs derives ayant une activite au niveau du systeme nerveux central

Info

Publication number
EP0874833A1
EP0874833A1 EP96944274A EP96944274A EP0874833A1 EP 0874833 A1 EP0874833 A1 EP 0874833A1 EP 96944274 A EP96944274 A EP 96944274A EP 96944274 A EP96944274 A EP 96944274A EP 0874833 A1 EP0874833 A1 EP 0874833A1
Authority
EP
European Patent Office
Prior art keywords
isoxazole
compound according
salts
isomers
applicable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96944274A
Other languages
German (de)
English (en)
Inventor
Nicholas J. Hrib
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Hoechst Marion Roussel Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst Marion Roussel Inc filed Critical Hoechst Marion Roussel Inc
Publication of EP0874833A1 publication Critical patent/EP0874833A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention is directed to certa in nove l compounds and thei r use as pharmaceutical agents having unique central nervous sys tem act ivity .
  • This invention relates to 4, 5-d ⁇ hydronaphth[1, 2- c) isoxazoles and derivatives thereof, and their use as serotonin 5-HTj antagonists, which may be useful for the treatment of anxiety, psychiatric disorders, schizophrenia, nausea, vomiting and the control of drug dependency, of general formula (I) :
  • A is hydrogen, hydroxy
  • R is hydrogen, an alkyl group of 1 to 6 carbons, optionally substituted with hydroxy, alkoxy or amino substitution; aryl or heteroaryl, optionally substituted with halogen, hydroxy or alkoxy; or benzyl optionally substituted with halogen, hydroxy or alkoxy;
  • Z ia nitrogen, CH or C(0H); m is an integer of 1 to 3;
  • X is hydrogen, hydroxy or alkoxy; or a pharmaceutically acceptable additional salt thereof, or " where applicable, a geometric or optical isomer or racemic mixture thereof.
  • the present invention also relates to a process for preparing these compounds, pharmaceutically acceptable addition salts thereof, as well as the pharmaceutical acceptable compositions thereof, and a method of using the compounds as seroton 5-HT, antagonists.
  • a given chemical formula or name shall encompass all stereo and optical isomers where such isomers exist. Additionally, a given chemical formula or name shall encompass the pharmaceutically acceptable additional salts thereof.
  • R t is hydrogen, an alkyl group of 1 to 6 carbons, " optionally substituted with hydroxy, alkoxy or amino substitution; aryl or heteroaryl, optionally substituted with halogen, hydroxy or alkoxy; or benzyl optionally substituted with halogen, hydroxy or alkoxy;
  • n is an integer of 1 or 2;
  • n is an integer of 1 to 3;
  • X is hydrogen, hydroxy or alkoxy.
  • R t is hydrogen, or an alkyl group of 1 to 3 carbons
  • n 1;
  • novel compounds of the present invention and the intermediates thereto may be prepared by the reaction sequence illustrated hereinbelow.
  • the substituents Z, m, n and X are generally as defined above unless otherwise indicated.
  • hydroxyisoxazoles 3 are prepared from oximes 2 in a solvent such as tetrahydrofuran (THF) at a temperature of from about 25 * C to about reflux temperature of the solvent for a period of from about 0.25 to
  • a solvent such as tetrahydrofuran (THF)
  • the hydroxyisoxazoles 3 are converted to chloroisoxazoles 4 via treatment with phosphorous oxychloride in the presence of a suitable base, such as triethylamine, at a temperature of from about 100 * to about 200 * C for a period of from about 0.25 to about 4 hours in a manner similar to that utilized by Adembri ec al . (G. Adembri and P.Tedeschi, Bull. 8ci. F»c. Ch ⁇ m. Ind.
  • the resultant solid was filtered through silica using CH-C1, eluent to provide 6.2g of crude product.
  • This crude product was recrystallized from a minimum of heptane to provide a product as needles, mp of 57-59 * C, homogeneous by thin layer chromatography (TLC) [silica, CH : Clj, R f -0.80).
  • TLC thin layer chromatography
  • IR Infrared
  • CHC1 5 nuclear magnetic resonance
  • NMR nuclear magnetic resonance
  • Mass Spectrum M * «205, El, 70eV
  • Preferred pharmaceutically acceptable addition salts include salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids; as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids
  • organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids.
  • the active compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, waters, chewing gums and the like. These preparations should contain or form at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be from about 4 to about 75% of the weight of the unit. The amount of compound present in such composition is such that a suitable dosage of active compound will be obtained.
  • Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains from about 1.0 to about 300mgs of active compound.
  • the tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as ⁇ ucrocrystallme cellulose, gum tragacanth or gelatin; an " excipient such as starch or lactose, a disintegrating agent such as alginic acid, Pri ogel 1 *, corn starch and the like; a lubricant such as magnesium stearate or Sterotex ⁇ ; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added.
  • a binder such as ⁇ ucrocrystallme cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Pri ogel 1 *, corn starch and the like
  • a lubricant such as magnesium stearate or Sterotex ⁇
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings an flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of the aforesaid compound, but may be varied from about 0.5 to about 30% of the weight thereof. The amount of compound m such composition is such that a suitable dosage of active compound will be obtained. Preferred compositions and preparations according to the invention are prepared so that a -parenteral dosage unit contains from about 0.5 to about lOOmgs of active compound.
  • the solutions or suspensions may also include the following components; a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as EDTA
  • buffers such as acetates, citrates or phosphates
  • the compounds of the invention may be useful as 5-HT, antagonists on the coronary chemoreflex for the treatment of anxiety, psychiatric disorders, nausea and vomiting by virtue of their ability to bind to rat entorhinal cortex membranes.
  • 5HT binding sites existed only in the periphery.
  • antagonist drugs such as GR65630, Zacopnde, IC3 205 930 and MDL 72222 (Bemesetron, C, j H Cl 2 N0 2 )
  • 5HT binding sites are also located in selected areas of the brain.
  • the highest levels of 5HT, binding sites have been detected in limbic and dopamine containing brain areas (entorhinal cortex, amygdala, nucleus accumhens and tuberculum olfactorium) (Kllpatrick, G.J. et al .
  • 5HT 5HT
  • antagonists Besides possessing selective binding in dopamine rich areas, 5HT, antagonists have been reported to block behavioral effects associated with certain drugs of abuse (nicotine and morphine) and to be active in behavioral tests predictive of anxiolytic activity. Based on these selective regional binding results and behavioral studies, 5HT, antagonists may have a therapeutic benefit in disease states believed to be associated with excessive dopaminergic activity, i.e., schizophrenia, anxiety and drug abuse.
  • a 0.05M of -Krebs-Hepes buffer, pH 7.4 was prepared as follows:
  • GR38032F was obtained from Research Biochemical Inc. GR38032F was made up to a concentration of 500 ⁇ M in Krebs-Hepes buffer. 50 ⁇ l of Krebs-Hepes were added to each of 3 tubes for determination of nonspecific binding (yields a final concentration of lOO ⁇ M in the 250 ⁇ l assay) .
  • a 50 ⁇ l stock solution was prepared in a suitable solvent and serially diluted with Krebs-Hepes buffer such that when 50 ⁇ l of drug s combined with the total 250 ⁇ l assay, a final concentration from 10 "5 to 10 " *M was attained. Characteristically, seven concentrations may be used for each assay; however, higher or lower concentrations may be used, depending on the potency of the drug.
  • lOO ⁇ l of Tissue suspension lOO ⁇ l of [ ] H]-GR65630; and 50 ⁇ l 500M GR38032F (Vehicle for binding) or appropriate drug concentration
  • Sam le tubes were kept on ice for additions, then vortexed and incubated with continuous shaking for 30 minutes at 37>c.
  • the incubate is diluted with 5 ml of ice-cold Krebs-Hepes buffer and immediately vacuum filtered through Whatman GF/B filters, followed by two 5ml washes with ice-cold Krebes-Hepes buffer. The filters are dried and counted in 10 ml of liquid scintillation cocktail.
  • Specific GR 65630 binding is defined as the difference between the total binding and that bound in the presence of lOO ⁇ M GR38032F.
  • IC 50 values were derived from computer-derived log-probit analysis.
  • This assay evaluates the effect of these compounds as 5-HT, antagonists. They were examined in this assay on the coronary chemoreflex (Bezold-Jarisch) initiated by 5-HT, i n vivo and characterized by leading inhibition of sympathetic outflow and increased activity of the cardiac vagus, leading. to profound bradycardia and hypotension. The values obtained allow for continuous monitoring of arterial pressure and heart rate responses by these compounds over an extended period of time to determine their effecicy for 5 HT, antagonism.
  • the catheters were prepared from Tygon tubing (45cm length, 0.05mm, ID) bonded to Teflon tubing (0.38mm, ID) .
  • the mechanical bonding was achieved by insertion of the Teflon tubing (5mm) into the dilated (ethylene dichloride, 3-4 min.) tip of the Tygon tubing.
  • the junction was then sealed with vinyl glue, the catheters were soaked in cold sterilization solution (Amerse instrument germicide) and flushed thoroughly with saline prior to implantation.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

4,5-dihydronaphth[1,2-c]isoxazoles et leurs dérivés, de formule générale (I), dans laquelle A, X et n sont tels que définis dans la description. Ces composés sont utiles comme antagonistes 5-HT3 de la sérotonine. Ces composés sont utiles pour traiter l'anxiété, les troubles psychiatriques, la nausée, les vomissements et la toxicomanie.
EP96944274A 1996-01-05 1996-12-12 4,5-dihydronaphth 1,2-c]isoxazoles et leurs derives ayant une activite au niveau du systeme nerveux central Withdrawn EP0874833A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US58331996A 1996-01-05 1996-01-05
US583319 1996-01-05
PCT/US1996/019569 WO1997025317A1 (fr) 1996-01-05 1996-12-12 4,5-dihydronaphth[1,2-c]isoxazoles et leurs derives ayant une activite au niveau du systeme nerveux central

Publications (1)

Publication Number Publication Date
EP0874833A1 true EP0874833A1 (fr) 1998-11-04

Family

ID=24332609

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96944274A Withdrawn EP0874833A1 (fr) 1996-01-05 1996-12-12 4,5-dihydronaphth 1,2-c]isoxazoles et leurs derives ayant une activite au niveau du systeme nerveux central

Country Status (14)

Country Link
EP (1) EP0874833A1 (fr)
JP (1) JP3161737B2 (fr)
KR (1) KR100308748B1 (fr)
CN (1) CN1214046A (fr)
AR (1) AR005347A1 (fr)
AU (1) AU710059B2 (fr)
BR (1) BR9612578A (fr)
CA (1) CA2241845C (fr)
HU (1) HUP9903706A3 (fr)
IL (1) IL125197A0 (fr)
NO (1) NO983100L (fr)
NZ (1) NZ325587A (fr)
WO (1) WO1997025317A1 (fr)
ZA (1) ZA9725B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2540846A2 (fr) 2007-05-18 2013-01-02 CESL Limited Procédé de récupération de métal précieux à partir d'un minerai sulfuré ou concentré ou autre matériau

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050131051A1 (en) * 2000-08-21 2005-06-16 Shaomeng Wang 2-3-disubstituted quinuclidiness as modulators of monoamine transporters and theraperutic and diagnostic methods based thereon
MXPA04008626A (es) * 2002-04-02 2004-12-06 Janssen Pharmaceutica Nv Derivados de amino isoxazolina sustituidos y su uso como antidepresivos.
AR040967A1 (es) 2002-08-12 2005-04-27 Janssen Pharmaceutica Nv Derivados de isoxazolina triciclicos c- sustituidos y su uso como anti- depresivos
JP4478571B2 (ja) 2002-08-15 2010-06-09 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 縮合複素環式イソオキサゾリン誘導体及び抗うつ薬としてのそれらの使用
MY134287A (en) 2002-08-21 2007-11-30 Janssen Pharmaceutica Nv C6- and c9-substituted isoxazoline derivatives and their use as anti-depressants
ES2759949T3 (es) 2009-10-29 2020-05-12 Bristol Myers Squibb Co Compuestos heterocíclicos tricíclicos
EP3507278B1 (fr) 2016-09-02 2021-01-27 Bristol-Myers Squibb Company Composés hétérocycliques tricycliques substitués
US11046646B2 (en) 2017-08-09 2021-06-29 Bristol-Myers Squibb Company Alkylphenyl compounds
US11059784B2 (en) 2017-08-09 2021-07-13 Bristol-Myers Squibb Company Oxime ether compounds
KR102002633B1 (ko) 2018-07-19 2019-07-22 김태효 완충이격부가 구비된 논슬립 발의류
KR102429797B1 (ko) 2019-12-31 2022-08-05 주식회사 제이패션 기능성 무재봉 덧신 및 이를 제조하는 제조방법

Family Cites Families (3)

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DE2119977A1 (en) * 1971-04-23 1971-12-16 Teikoku Hormone Manufacturing Co , Ltd, Tokio Antiphlogistic and antisecretory napththisoxazoles - from 1-hydroxyim - 2-carbonyl derivs by intramolecular condensation
DE69021645T2 (de) * 1989-05-19 1996-02-22 Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J. N-(aryloxyalkyl)heteroarylpiperidine und -heteroarylpiperazine, Verfahren zu ihrer Herstellung und ihre Verwendung als Medikamente.
WO1994010162A1 (fr) * 1992-10-23 1994-05-11 Merck Sharp & Dohme Limited Ligands pour les sous-types de recepteurs de dopamine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9725317A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2540846A2 (fr) 2007-05-18 2013-01-02 CESL Limited Procédé de récupération de métal précieux à partir d'un minerai sulfuré ou concentré ou autre matériau

Also Published As

Publication number Publication date
ZA9725B (en) 1997-07-07
NO983100D0 (no) 1998-07-03
JP3161737B2 (ja) 2001-04-25
BR9612578A (pt) 1999-07-27
CA2241845A1 (fr) 1997-07-17
AU1412697A (en) 1997-08-01
HUP9903706A2 (hu) 2000-08-28
AU710059B2 (en) 1999-09-09
NO983100L (no) 1998-09-04
NZ325587A (en) 1999-02-25
HUP9903706A3 (en) 2000-09-28
IL125197A0 (en) 1999-03-12
KR100308748B1 (ko) 2001-12-12
WO1997025317A1 (fr) 1997-07-17
CA2241845C (fr) 2002-10-01
CN1214046A (zh) 1999-04-14
KR19990077033A (ko) 1999-10-25
JPH11510816A (ja) 1999-09-21
AR005347A1 (es) 1999-04-28

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