Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • 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
  • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
• • 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

Definitions

• PROCESSES ANH INTERMEDIATES FOR PREPARING 1-(2-f2-ISOXAZOL- ⁇ LBENZOFURAN-5-YLOXY1ETHYLAMINO ⁇ -3-PHENOXY-2(S.-OL Background of the Invention
• the present invention relates to certain compounds of the formula I depicted below. More particularly, the invention relates to processes and intermediates for use in the preparation of the compound of formula I.
• the compound of formula I, its pharmaceutically acceptable salts and prodrugs have utility as hypoglycemic and antiobesity agents.
• the compound of the formula I, its pharmaceutically acceptable salts and prodrugs are also useful in increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
• the compound of formula I and its pharmaceutically acceptable salts and prodrugs effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
• the compound of formula I also decreases weight gain when administered to mammals.
• the ability of these compounds to affect weight gain is due to activation of ⁇ -adrenergic receptors which stimulate the metabolism of adipose tissue.
• T h e disease diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia.
• Type II diabetes or non-insulin dependent diabetes
• Type II diabetes or non-insulin dependent diabetes
• Most of the Type II diabetics are also obese.
• ⁇ -Adrenergic receptors can be divided into ⁇ , , ⁇ 2 and ⁇ 3 -subtypes.
• Activation of ⁇ , -receptors invokes increases in heart rate while activation of ⁇ .-receptors induces relaxation of smooth muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors.
• Activation of ⁇ 3 -receptors stimulates lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids), and thereby promotes the loss of fat mass. Compounds that stimulate ⁇ 3 -receptors will have anti- obesity activity.
• compounds which are ⁇ 3 -adrenoceptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is unknown.
• a compound that selectively stimulates ⁇ 3 -receptors, i.e., has little or no ⁇ , or ⁇ 2 -activity will have the desired anti-diabetic and/or anti-obesity activity, but without the undesirable effects of increased heart rate ( ⁇ , -effect) or muscle tremor ( ⁇ 2 -effect).
• ⁇ 3 -adrenoceptor agonists as antidiabetic, hypoglycemic and antiobesity agents has been frustrated, however, by the lack of selectivity of these agents for ⁇ 3 - adrenoceptors over the other two other adrenoceptors, ⁇ , and ⁇ 2 .
• the compound of formula I, its pharmaceutically acceptable salts and prodrugs are selective ⁇ 3 adrenoceptor agonists.
• the compound of formula I, its pharmaceutically acceptable salts and prodrugs are described in co-pending United States Application Serial No. 08/076026, assigned to the assignee of this application and inco ⁇ orated herein in its entirety.
• 'halo' as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
• 'alkyl' as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
• substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
• treating includes preventative treatment.
• compound 1 is treated with phenol in the presence of a base to form compound 2.
• the base for use in this step is selected from the group comprising alkali metal hydrides, such as NaH, and alkali metal alkoxides such as sodium t-butoxide.
• the reaction is effected in an aprotie polar solvent such as DMF or THF.
• the reaction is preferably carried out using NaH in DMF.
• Compound 3 is formed by treating compound 2 with C ⁇ H 5 CH 2 NH(CH 2 ) 2 OH in a (C,-C ⁇ )alkanol.
• a preferred alkanol is ethanol.
• Compound 4 is formed by treating compound 3 with hydrogen in the presence of a hydrogenation catalyst such as Pd(OH) 2 on C or Pd on C in a (C,-C ⁇ ) alkanol such as ethanol or propanol.
• a hydrogenation catalyst such as Pd(OH) 2 on C or Pd on C in a (C,-C ⁇ ) alkanol such as ethanol or propanol.
• the alkanol is ethanol.
• Compound 4 is reacted with a carbonyl compound such as an aldehyde or ketone to form a mixture of compounds 5 & 6.
• Aldehydes useful in the practice of this part of the invention include aliphatic aldehydes, such as acetaldehyde
• Useful ketones may be ⁇ xemplifed by alephatic ketones, e.g., acetone and methyl ethyl ketone; cycloalkyl ketones such as cyclohexanone and arylalkyl ketones such as acetophenone.
• a preferred carbonyl compound is cyclohexanone.
• the reaction is effected in a solvent such as a (C 1 -C ⁇ )alkanol, preferably methanol.
• Compound 5 or 6, or a mixture thereof is treated with compound 7 and an azodicarbonyldialkox.de, such as azodicarbonyl dipropoxide or diethexoxide, or diamine, such as azodicarbonyldipiperidine in the presence of a suitable trialkyl- or triarylphosphine such as (C 4 H 9 ) 3 P or (C 6 H 5 ) 3 P, respectively, or (C ⁇ H 5 ) 3 P supported on a polymer (e.g. (C ⁇ H 5 ) 3 P polymer supported, Aldrich Cat. No.
• an azodicarbonyldialkox.de such as azodicarbonyl dipropoxide or diethexoxide, or diamine, such as azodicarbonyldipiperidine
• a suitable trialkyl- or triarylphosphine such as (C 4 H 9 ) 3 P or (C 6 H 5 ) 3 P, respectively, or (C ⁇ H
• Compound 8 is treated with an aqueous mineral acid to produce compound I.
• Useful mineral acids include HCl, H 2 S0 4 , NaHS0 4 , HBr and H 3 P0 4 .
• the preferred mineral acid is NaHS0 4 .
• the dosage is in the range of about 0.01 to about 50 mg/kg body weight of the subject per day, preferably about 0.1 to about 25 mg/kg body weight per day, administered singly or as a divided dose.
• the optimum dosage tor the individual subject being treated will be determined by the person responsible for the treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage. This will vary according to the particular compound employed and with the subject being treated.
• the active compounds When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the active compounds are administered at a daily dosage of from 0.01 milligram to about 50 milligrams per kilogram of animal body weight, preferably given in divided doses 4 times a day, or in sustained release form.
• the total daily dosage is from about 0.1 milligrams to about 6000 milligrams, preferably from about 1 milligrams to about 1500 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.1 milligrams to about 1500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
• the active compounds are used in combination with a pharmaceutically acceptable carrier or diluent.
• suitable pharmaceutically-acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
• the active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described above.
• the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
• the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
• the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
• a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
• tablets may be coated with shellac, sugar or both.
• a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
• the active compounds may also be administered parenterally.
• parenteral administration the active compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
• Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
• Dispersions can also be prepared in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrrolidone and mixtures thereof in oils as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds.
• injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being the preferred parenteral route in man.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy synngability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
• the active compounds also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e., ungulate animals and poultry.
• Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 10 "3 to 500 ppm of the compound in the feed.
• Animal feed supplements can be prepared by admixing about 75% to 95% by weight of an active compound with about 5% to about 25% by weight of a suitable carrier or diluent.
• Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, commeal, can molasses, urea, bone meal, corncob meal and the like.
• the carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
• the preferred medicated swine, cattle, sheep and goat feeds generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.
• the preferred poultry and domestic pet feeds usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
• the active compound may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought.
• parenteral administration involves injection of a sufficient amount of the active compound to provide the animal with 0.01 to 100 mg/kg/day of body weight of the active ingredient.
• the preferred dosage for swine, cattle, sheep and goats is in the range of from 0.01 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.01 to 35 mg/kg/day of body weight.
• Paste formulations can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, com oil or the like.
• Pellets containing an effective amount ofthe active compound can be prepared by admixing the effective amount of active compound with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
• a diluent such as carbowax, carnuba wax, and the like
• a lubricant such as magnesium or calcium stearate
• the active compounds have several advantageous features. For the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the active compounds provide the means by which this can be accomplished. For the poultrymen and swine raisers, use of the active compounds yields leaner animals which command higher prices from the meat industry.
• GCMS's were taken on a Hewlett Packard 5890 GC in tandem with a Hewlett Packard Model 5971 A Mass Selective Detector using a HP-1 12 m capillary column. Column conditions were as follows: initial temp, 133°C; ramp of 19°C/min; final temp, 310°C.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Child & Adolescent Psychology (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

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Cited By (1)

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Citations (1)

• 1996
  • 1996-08-15 IL IL12362396A patent/IL123623A0/xx unknown
  • 1996-08-15 CA CA002234081A patent/CA2234081A1/en not_active Abandoned
  • 1996-08-15 HU HU9900090A patent/HUP9900090A3/hu unknown
  • 1996-08-15 BR BR9611217A patent/BR9611217A/pt not_active Application Discontinuation
  • 1996-08-15 EP EP96925934A patent/EP0861240A1/en not_active Withdrawn
  • 1996-08-15 WO PCT/IB1996/000803 patent/WO1997016432A1/en not_active Application Discontinuation
  • 1996-08-15 CN CN96198046A patent/CN1201455A/zh active Pending
  • 1996-08-15 CZ CZ981308A patent/CZ130898A3/cs unknown
  • 1996-08-15 PL PL96327997A patent/PL327997A1/xx unknown
  • 1996-08-15 TR TR1998/00710T patent/TR199800710T2/xx unknown
  • 1996-08-15 AU AU66285/96A patent/AU6628596A/en not_active Abandoned
  • 1996-08-15 KR KR1019980703123A patent/KR19990067172A/ko not_active Application Discontinuation
  • 1996-08-15 JP JP9506054A patent/JPH10513480A/ja active Pending
  • 1996-10-29 HR HR60/008,153A patent/HRP960502A2/hr not_active Application Discontinuation
  • 1996-10-30 YU YU57396A patent/YU57396A/sh unknown

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Non-Patent Citations (2)

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