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
• 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 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.
• 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)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Hospice & Palliative Care (AREA)
• Otolaryngology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1993
  • 1993-02-03 KR KR1019940702945A patent/KR100287933B1/ko not_active IP Right Cessation
  • 1993-02-03 WO PCT/US1993/000880 patent/WO1993017019A1/en active IP Right Grant
  • 1993-02-03 NZ NZ249346A patent/NZ249346A/en not_active IP Right Cessation
  • 1993-02-03 CA CA002130563A patent/CA2130563C/en not_active Expired - Lifetime
  • 1993-02-03 HU HU9402436A patent/HU216831B/hu unknown
  • 1993-02-03 EP EP93904797A patent/EP0628043A1/en not_active Withdrawn
  • 1993-02-03 JP JP5514868A patent/JPH07504192A/ja active Pending
  • 1993-02-03 AU AU36034/93A patent/AU675060B2/en not_active Expired
  • 1993-02-18 ZA ZA931146A patent/ZA931146B/xx unknown
  • 1993-02-19 TW TW082101189A patent/TW226374B/zh not_active IP Right Cessation
  • 1993-02-22 IL IL10482193A patent/IL104821A/xx not_active IP Right Cessation
  • 1993-02-22 MX MX9300948A patent/MX9300948A/es unknown
• 1994
  • 1994-08-23 FI FI943872A patent/FI105917B/fi not_active IP Right Cessation
  • 1994-08-23 NO NO943101A patent/NO943101D0/no unknown

Non-Patent Citations (1)

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