WO1993017019A1 - 2,6-methano-2h-quinolizin derivative as 5-ht3-receptor antagonist - Google Patents

2,6-methano-2h-quinolizin derivative as 5-ht3-receptor antagonist Download PDF

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Publication number
WO1993017019A1
WO1993017019A1 PCT/US1993/000880 US9300880W WO9317019A1 WO 1993017019 A1 WO1993017019 A1 WO 1993017019A1 US 9300880 W US9300880 W US 9300880W WO 9317019 A1 WO9317019 A1 WO 9317019A1
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WO
WIPO (PCT)
Prior art keywords
treatment
treating
mania
vomiting
migraine
Prior art date
Application number
PCT/US1993/000880
Other languages
English (en)
French (fr)
Inventor
Maurice W. Gittos
Original Assignee
Merrell Dow Pharmaceuticals 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 Merrell Dow Pharmaceuticals Inc. filed Critical Merrell Dow Pharmaceuticals Inc.
Priority to AU36034/93A priority Critical patent/AU675060B2/en
Priority to KR1019940702945A priority patent/KR100287933B1/ko
Priority to JP5514868A priority patent/JPH07504192A/ja
Priority to US08/290,792 priority patent/US5508287A/en
Priority to EP93904797A priority patent/EP0628043A1/en
Publication of WO1993017019A1 publication Critical patent/WO1993017019A1/en
Priority to NO943101A priority patent/NO943101L/no
Priority to FI943872A priority patent/FI105917B/fi

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Classifications

    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • This invention relates to 5-chloro-2,3-dihydro-2,2- dimethylbenzofuran-7-carboxylie acid-octahydro-3-hydroxy- 5 2,6-methano-2H-quinolizin-8-yl ester, a novel 5-HT 3 -receptor antagonist, its method of preparation, and to its end-use application in the treatment of conditions responsive to 5-HT 3 receptor antagonism such as radio- and chemo-therapeu ⁇ tically-induced nausea and vomiting, • __ ⁇ « • the treatment of
  • the wavy line bonding the oxygen atom of the ester moiety to the 8-position of the octahydro-2,6-methano- 2H-quinolizin moiety indicates that the bonding may be in the endo (trans) or the exo (cis) configuration.
  • the preferred configuration is endo.
  • the pharmaceutically acceptable acid addition salts referred to above can be non-toxic salts with suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; or with organic acids such as organic carboxylic acids r for example, acetic, propionic, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicylic, 2-acetyl- oxybenzoic, nicotinic or isonicotinic; or organic sulfonic acids, for example, methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalene- sulfonic.
  • suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids
  • organic acids such as organic carboxylic acids r for example, acetic, propi
  • Step A' (Alternate to Step A): Using trichlorometh l chloroformate 5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester
  • the racemic mixture can be separated into its separate enantiomers by standard techniques.
  • the compounds of the present invention block the M receptors for 5-hydroxytryptamine (5HT) on afferent sensory neurons otherwise known as 5HT 3 -receptors.
  • the activity of the compounds of this invention against the 5HT 3 -receptor can be assessed by determining their pA 2 values in the isolated rabbit heart as described by J. R. Fozard et al., Eur. J. Pharmacol. 5£, 195-210 (1979).
  • the in ⁇ i ⁇ o 5HT 3 -receptor antagonist activity can be assessed by measurement of the effect of the compound on the Von Bezold- Jarisch reflex induced by 5HT injected intravenously into the rat (see Paintal A. S., Physiol. Rev. 5_3, 159-227 (1973); J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol. 326, 36-44 (1984).
  • the compounds of this invention may be utilized in a variety of treatments.
  • the compounds of the present invention are useful in treating conditions responsive to 5-HT 3 receptor antagonism.
  • conditions responsive to 5-HT 3 receptor antagonism are well known to those skilled in the art.
  • Some examples of these conditions are treating anxiety, psychosis, glaucoma and for stimulating gastric motility (U.S. Patent No. 5,011,846), treatment of panic disorders and/or agoraphobia or obsessive compulsive disorders (Patent No. EP 422,154); treatment of autism or other disorder originating in childhood in which there is mental retardation (Patent No. EP 450,757); treatment of cognitive disorders such as Alzheimer's Disease (U.S. Patent Application Serial No. 806,987); production of orexiogenic effect (U.S. Patent Application Serial No.
  • Patent No. GB 2,193,633 Patent No. GB 2,193,633
  • Patent No. EP 279,114 and GB 2,206,788 treatment of lung embolism
  • Patent No. GB 2,231,265 treatment of cough and/or bronchoconstriction
  • Preferred uses for the compounds of the present invention include the treatment of nauseas- and vomiting, particularly radio- and chemo-therapeutically induced in those patients being treated for cancer, in the treatment of pain associated with migraine and neuralgia, in the
  • Doses administered to patients are within the range of about 0.01 to about 10 mg per kilogram of body- weight, with 35 0.01 to 1 mg per kilogram of body weight being preferred for parenteral administration and 0.25 to 1 mg per kilogram of body weight upon enteral administration.
  • dosage required for the treatment of the foregoing disease states will depend upon such factors as the severity and stage of the particular disease, the age and condition of the patients as such other normal factors taken into consideration by the attending diagnostician.
  • patient means warm-blooded animals such as rats, mice, dogs, cats, guinea pigs, primates and humans.
  • treat means to prevent or alleviate the patient's disease or condition.
  • the compounds of Formula (I) can be administered in various manners to achieve the desired effect.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions.
  • Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
  • the compounds of Formula (I) can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or algenic acid, and a lubricant such as stearic acid or magnesium stearate.
  • binders such as acacia, cornstarch, or gelatin
  • disintegrating agents such as potato starch or algenic acid
  • a lubricant such as stearic acid or magnesium stearate.
  • Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non- aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
  • the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, buffers, etc. as are known in the art.
  • the compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO)
  • DMSO dimethyl sulfoxide
  • transdermal devices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894 incorporated herein. These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces.
  • the active agent may be contained in a plurality of microcapsules distributed throughout the permeable adhesive layer. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or ucosa of the recipient.
  • the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the pharmaceutically active compound is contained in a matrix from which it is delivered in the desired gradual, constant and controlled rate.
  • the matrix is permeable to the release of the compound through diffusion or microporous flow. The release is rate controlling.
  • Such a system, which requires no membrane is described in U.S. Pat. No. 3,921,636 incorporated herein. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is non-porous.
  • the pharmaceutically effective compound dissolves in and diffuses through the matrix itself. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the matrix.
  • compositions of the present invention are prepared in a manner well known perse in the pharmaceutical art and usually comprise one or more active compounds of the invention in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent therefor.
  • the active ingredient will usually be mixed with a carrier, or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container.
  • a carrier or diluent may be solid, semisolid or liquid material which serves as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are well known per se. See Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, incorporated herein, for a description of the preparation of such formulations.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/US1993/000880 1992-02-24 1993-02-03 2,6-methano-2h-quinolizin derivative as 5-ht3-receptor antagonist WO1993017019A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU36034/93A AU675060B2 (en) 1992-02-24 1993-02-03 2,6-methano-2H-quinolizin derivative as 5-HT3-receptor antagonist
KR1019940702945A KR100287933B1 (ko) 1992-02-24 1993-02-03 5-ht3-수용체 길항제로서의 2,6-메타노-2h-퀴놀리진 유도체,이의 제조방법 및 이를 포함하는 약제학적 조성물
JP5514868A JPH07504192A (ja) 1992-02-24 1993-02-03 ５−ｈｔ３受容体拮抗剤としての２，６‐メタノ‐２ｈ‐キノリジン誘導体
US08/290,792 US5508287A (en) 1992-02-24 1993-02-03 2,6-methano-2H-quinolizin derivative as 5-HT3 -receptor antagonist
EP93904797A EP0628043A1 (en) 1992-02-24 1993-02-03 2,6-methano-2h-quinolizin derivative as 5-ht3-receptor antagonist
NO943101A NO943101L (no) 1992-02-24 1994-08-23 2,6-metano-2H-kinolizinderivat som 5-HT3-reseptorantagonist
FI943872A FI105917B (fi) 1992-02-24 1994-08-23 Menetelmä terapeuttisesti aktiivisen 5-kloori-2,3-dihydro-2,2-dimetyylibentsofuraani-7-karboksyylihappo-oktahydro-3-hydroksi-2,6-metano-2H-kinolitsin-8-yyliesterin valmistamiseksi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP92400474 1992-02-24
EP92400474.0 1992-02-24

Publications (1)

Publication Number Publication Date
WO1993017019A1 true WO1993017019A1 (en) 1993-09-02

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ID=8211614

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/000880 WO1993017019A1 (en) 1992-02-24 1993-02-03 2,6-methano-2h-quinolizin derivative as 5-ht3-receptor antagonist

Country Status (14)

Country Link
EP (1) EP0628043A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JPH07504192A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
KR (1) KR100287933B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AU (1) AU675060B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
CA (1) CA2130563C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
FI (1) FI105917B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
HU (1) HU216831B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
IL (1) IL104821A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
MX (1) MX9300948A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
NO (1) NO943101L (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
NZ (1) NZ249346A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
TW (1) TW226374B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1993017019A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
ZA (1) ZA931146B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6384042B2 (en) 1999-02-18 2002-05-07 Faerber Lothar Systemic use of 5-HT3 receptor antagonists against rheumatic inflammatory processes
US9662325B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9662390B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9675602B2 (en) 2005-03-07 2017-06-13 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9717725B2 (en) 2005-03-07 2017-08-01 The University Of Chicago Use of opioid antagonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0329932A2 (en) * 1988-02-23 1989-08-30 Merrell Pharmaceuticals Inc. Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments
EP0517984A1 (en) * 1991-06-11 1992-12-16 Merrell Dow Pharmaceuticals Inc. Derivatives of amide analogs of certain methano bridged quinolizines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0329932A2 (en) * 1988-02-23 1989-08-30 Merrell Pharmaceuticals Inc. Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments
EP0517984A1 (en) * 1991-06-11 1992-12-16 Merrell Dow Pharmaceuticals Inc. Derivatives of amide analogs of certain methano bridged quinolizines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY vol. 35, no. 2, 24 January 1992, WASHINGTON US pages 310 - 319 D.W. ROBERTSON 'Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships' *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6384042B2 (en) 1999-02-18 2002-05-07 Faerber Lothar Systemic use of 5-HT3 receptor antagonists against rheumatic inflammatory processes
US9662325B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9662390B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9675602B2 (en) 2005-03-07 2017-06-13 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9717725B2 (en) 2005-03-07 2017-08-01 The University Of Chicago Use of opioid antagonists

Also Published As

Publication number Publication date
NO943101D0 (no) 1994-08-23
FI105917B (fi) 2000-10-31
NO943101L (no) 1994-08-23
HU216831B (hu) 1999-09-28
TW226374B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1994-07-11
AU3603493A (en) 1993-09-13
AU675060B2 (en) 1997-01-23
NZ249346A (en) 1995-10-26
IL104821A0 (en) 1993-06-10
IL104821A (en) 1997-01-10
HUT68249A (en) 1995-06-28
JPH07504192A (ja) 1995-05-11
MX9300948A (es) 1993-08-01
KR950700297A (ko) 1995-01-16
FI943872L (fi) 1994-08-23
CA2130563A1 (en) 1993-09-02
KR100287933B1 (ko) 2001-05-02
ZA931146B (en) 1993-09-14
FI943872A0 (fi) 1994-08-23
HU9402436D0 (en) 1994-10-28
EP0628043A1 (en) 1994-12-14
CA2130563C (en) 1997-11-11

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