WO1993007132A1 - 10-acyle-dibenz(b,f(1,4)-oxazepines et leurs analogues prenant la forme de thiazepines et diazepines, utilises comme antagonistes des prostaglandines - Google Patents

10-acyle-dibenz(b,f(1,4)-oxazepines et leurs analogues prenant la forme de thiazepines et diazepines, utilises comme antagonistes des prostaglandines Download PDF

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Publication number
WO1993007132A1
WO1993007132A1 PCT/US1992/006584 US9206584W WO9307132A1 WO 1993007132 A1 WO1993007132 A1 WO 1993007132A1 US 9206584 W US9206584 W US 9206584W WO 9307132 A1 WO9307132 A1 WO 9307132A1
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Prior art keywords
chloro
oxazepine
dibenz
dihydro
oxo
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PCT/US1992/006584
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English (en)
Inventor
Nizal Samuel Chandrakumar
Timothy Joseph Hagen
E. Ann Hallinan
Robert Knol Husa
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G.D. Searle & Co.
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Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to US08/178,283 priority Critical patent/US5449673A/en
Priority to PCT/US1992/006584 priority patent/WO1993007132A1/fr
Publication of WO1993007132A1 publication Critical patent/WO1993007132A1/fr

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    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the present invention generally relates to
  • analgesic agents for the treatment of pain to pharmaceutical compositions containing one or more of these compounds, and to methods of treatment employing these compounds. More particularly, the
  • present invention concerns substituted dibenzoxazepine compounds, pharmaceutical compositions containing one or more of these compounds in combination with a
  • Analgesic compounds are agents which alleviate
  • analgesic compounds include narcotic analgesics, or opiates, compounds which
  • analgesicantipyretic compounds compounds which alleviate pain and reduce fever, such as salicylates.
  • salicylate and salicylate-like agents are also efficacious in relieving pain, they often exhibit undesirable side effects, such as gastrointestinal irritation, as with aspirin, allergic response, as with aspirin, and/or liver toxicity with extended use, as with acetaminophen.
  • the compounds of the present invention are neither opiates nor NSAIDS, and represent another class of compounds which are useful as analgesic agents.
  • dibenzoxazapine derivatives as cholesterol lowering agents.
  • U.S. Patent No. 3,624,104 discloses aralkanoyl derivatives of dibenzoxazepine-N-carboxylic acid
  • U.S. Patent No. 3,989,719 discloses N,N'-diacyl hydrazines.
  • U.S. Patents Nos. 3,917,649 and 3,992,375 (a divisional of U.S. Patent No. 3,917,649) disclose dibenzoxazepine N-carboxylic acid hydrazides compounds.
  • U.S. Patent No. 4,559,337 discloses 8-chlorodibenz-[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-(alkoxy-containing acyl)hydrazide compounds.
  • GB 1 522 003 discloses 1-acyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine compounds.
  • GB 1 331 892 discloses derivatives of
  • 0 193 822 discloses 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-(thio-, sulfinyl- and
  • 0 218 077 discloses 8-chlorodibenz[b,f][1,4]oxazepine10(11H)-carboxylic acid, 2[(substituted phenylsulfinyl)alkanoyl]hydrazide compounds and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(substituted phenylsulfonyl) alkanoyl]hydrazide
  • Prostaglandins Prog. Lioid. Res.. 20(1-4), 453-9 (1981), disclose on Page 454, Lines 11-12, Page 458, Lines 43-44, and in Table 1, two dibenzoxazepine compounds designated SC-19220 and SC-25191, and shown above and below, respectively, which were employed in an investigation of the effects of prostaglandin antagonists on platelet responses to stimulatory and inhibitory prostaglandins.
  • SC-19220 prostaglandin synthesis inhibitors, including SC-19220 (see structure above), and morphine using the writhing test. SC-19220 is discussed on Page 133, Lines 10 and 14-16, in Table II (Page 134), and on Page 135, Lines 16-25, and Page 137, Lines 34-38.
  • SC-19220 Trimethoquinol
  • Br. J. Pharmac. 71, 169-175 (1980) disclose the study of the effects of several compounds, including SC-19220 (see structure above), on contractions of the rat stomach longitudinal muscle to several prostanoids. SC-19220 is discussed on Page 175, Paragraph 1, Page 170, Paragraph 4, in Table 1 and Figure 2, on Page 172, Paragraph 2, and on Page 174, Paragraphs 1 and 2.
  • SC-19220 (see structure above) was employed in this study and is discussed on Page 615 (abstract). Page 616, Line 30, Page 617, Lines 13-18, in Figures 4 and 5, and on Page 618, Lines 23-26.
  • Compounds of the present invention have been found to exhibit activity as prostaglandin E 2 antagonists.
  • the present invention provides compounds having a structure of Formula I
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen, lower alkyl, hydroxy, oxytrimethylsilyl or a glycyl ester or R 1 and R 2 together or R 3 and R 4 together form oxygen;
  • W represents oxygen, sulfur, sulfoxide, sulfone or NR 8 wherein R 8 is hydrogen or lower alkyl;
  • R 5 represents hydrogen, halogen, or trifluoromethyl
  • R 6 represents hydrogen, halogen or OR 7 wherein R 7 is hydrogen or lower alkyl
  • p represents an integer of from 0 to 5;
  • X represents -(CH 2 ) s - wherein s is an integer of from 1 to 5, sulfur, sulfoxide, sulfone, oxygen or -NH-; r represents an integer of from 0 to 5; and
  • Y represents hydrogen or aryl.
  • DSC differential scanning calorimetry
  • lower alkyl as used herein means a saturated hydrocarbon radical having from one to six carbon atoms, within which includes from one to three carbon atoms, which can be a straight or branched chain. Representative of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
  • aryl as used herein means 5- and 6- membered single-ring aromatic radicals which may include from zero to four heteroatoms, within which includes from zero to two heteroatoms.
  • Representative aryls include phenyl, thienyl, furanyl, pyridinyl, imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl,
  • 13 C NMR means 13 Carbon Nuclear Magnetic Resonance.
  • flash chromatography is a form of column chromatography, which is known by those of skill in the art, and which is described in J. Org. Chem. 1978, 43,2923.
  • analgesia means the reduction, or absence, of sensibility to pain
  • animal as used herein includes mammals and nonmammals, and further includes humans and non-human mammals.
  • Boc as used herein means t-butyloxycarbonyl.
  • DCC dicyclohexylcarbodiimide.
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • DMAP dimethylaminopyridine
  • DSC Differential Scanning Calorimetry
  • composition means a product which results from the combining of more than one ingredient.
  • ED 50 dose means that dose of a compound or drug which produced a defined biological effect, such as producing analgesia, in 50% of the animals to which the compound or drug was administered.
  • EtoAc ethyl acetate.
  • Et ethyl (-CH 2 CH 3 ).
  • Et 3 N as used herein means triethylamine.
  • Gly as used herein means the amino acid glycine.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • halo or halogen as used herein means chlorine (Cl), bromine (Br), fluorine (F) and/or iodine (I).
  • hydroxy as used herein means the group -OH.
  • M1 H NMR Proton Nuclear Magnetic Resonance
  • abbreviation "i.g.” as used herein mean that a compound or drug was administered into the stomach.
  • administered parenterally as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular,
  • intraarterial intrathecal
  • intracapsular intracapsular
  • intraorbital intracardiac, intradermal. intraperitoneal, transtracheal, subcutaneous,
  • subcuticular, intraarticulare subcapsular
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication,
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, as defined directly above, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a -chemical compound or pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium
  • gelatin e.g., kaolin, kaolin, kaolin, kaolin, kaolin, talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin,
  • propylene glycol (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium
  • hydroxide and aluminum hydroxide (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
  • pharmaceutically-acceptable salts refers to non-toxic salts of the compounds of the present invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid, or which are prepared by reacting the free acid with a suitable base.
  • Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, clavulanate and the like salts and alkali metal salts such as sodium and potassium and alkaline earth salts, such as calcium and magnesium.
  • phenyl as used herein means the group C 6 H 5 -, derived from benzene.
  • side chain as used herein, means functionalization of the N-10 position of the molecule.
  • terapéuticaally-effective amount means an amount of a compound, material, or composition which is an effective dose for eliminating or ameliorating pain in an animal, or for producing some other desired therapeutic effect, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • TLC Thin
  • trifluoromethyl as used herein means a -CF 3 group.
  • the present invention provides compounds comprising a structure of Formula I, as described above, and pharmaceutically-acceptable salts, esters and amides thereof.
  • the compounds of the present invention comprise a class of substituted dibenzoxazepine compounds in which the 2-, 5- and/or 8-position and/or the side chain is substituted.
  • Compounds within the present invention have been shown to exhibit activity as prostaglandin E 2 antagonists.
  • invention contemplates all such compounds, including cis- and trans- geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Certain compounds of the present invention may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,
  • palmitate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate mesylate
  • the compounds of the invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention.
  • salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine-, ethanolamine,
  • the present invention provides pharmaceutically-acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of Formula I, as described hereinabove, formulated together with one or more pharmaceutically- acceptable carriers.
  • the pharmaceutical compositions of the invention may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal or vaginal administration.
  • the present invention provides a method for eliminating or ameliorating pain in an animal, and methods for treating central nervous system disorders, including convulsions and ischemia, and asthma, enuresis, arrhythmia, diarrhea,
  • dysmenorrhea and osteoporosis in an animal comprising administering a therapeutically-effective amount of a compound of Formula I, as described hereinabove, to the animal.
  • the most preferred embodiment of the present invention is the compound described in Example 17 below.
  • prostaglandin E 2 antagonists prostaglandin antagonists of the E 2 series.
  • Compounds within the present invention, and the pharmaceutical compositions comprising one or more of these compounds, are useful as analgesic agents for the elimination or amelioration of pain in animals.
  • these compounds and compositions would be useful in treating convulsions, ischemia and other central nervous system disorders, as well as osteoporosis, dysmenorrhea, asthma, enuresis, arrhythmia, urinary incontinence, gastric
  • the compounds of the present invention may be prepared by the methods illustrated in the following general reaction schemes, or by modifications thereof, using readily-available starting materials, reagents and conventional synthesis procedures. Unless otherwise specified, the various substituents of the compounds and materials present in the general reaction schemes are defined in the same manner as they are defined above in Formula I.
  • a particular enantiomer of a compound of the present invention may be prepared by chiral synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional
  • the compounds of this invention may be prepared by the methods illustrated in the following reaction schemes.
  • the heterocycle can be reacted with phosgene to form the carbamoyl chloride.
  • This material can then be reacted with a vinyl stannane in the presence of a palladium catalyst to form the ⁇ , ⁇ -unsaturated amides, or reacted with an alkyne in the presence of a palladium
  • the silyl protecting groups can then be removed by tetrabutyl ammonium fluoride.
  • the heterocycle can be reacted with an appropriate acid chloride to form the amide.
  • the alcohol can be esterified with a N-protected amino acid followed by removal of the
  • compositions comprising such compounds.
  • Example 4 a mixture of 2.12 g (10 mmol) of [[1-methyl-1-[2-propynyl]pentyl]oxy]trimethylsilane and 2.91 g (10 mmol) of tri-n-butyltin hydride contained in a Pyrex round-bottomed flask was irradiated under argon with a General Electric sunlamp for 2 hours at room temperature (a circulating water bath is required) and then at about 55°C (heat generated by lamp) for 2 hours. The resulting product was used directly in Example 4 below.
  • Example 4 Example 4
  • the compound 7 was prepared according to the procedure for the synthesis of 3.
  • the 3-methyl-3-trimethylsilyloxy 1-octyne (48 mmol) was treated with tributyl tinhydride to yield 7 (66 %).
  • the compound 10 was prepared according to the procedure for the synthesis of 3.
  • the 1-octyn-3-ol 23 mmol was treated with tributyl tinhydride to yield 10 (95%).
  • triphenylphosphine-palladium (II) 100 mg, 0.13 mmol
  • copper iodide 100 mg
  • the Writhing Assay is one of the most widely-used experimental procedures for measuring the analgesic activity of different narcotic and nonnarcotic
  • analgesic agents and involves the continuous
  • mice analgesic activity in mice, as shown by the results of the Writhing Assay presented in Table I below.
  • mice Charles River male albino mice, weighing 20 to 30 grams were used in this assay.
  • test compound 0.1 mg per 10 g of body weight of a 0.025% w/v solution of PBQ was injected
  • mice which were given saline in place of a test compound of the
  • each mouse was individually placed into a glass beaker for observation, and the number of writhes occurring during the following tenminute period was counted.
  • test compound was considered to have produced analgesia in a mouse if, in accordance with the
  • the standard initial screening dose of a test compound employed in this assay was 30 mpk per gram of body weight for both routes of administration. If this initial screening dose of the test compound produced analgesia in seven of ten mice, then the effect of additional doses of the test compound on the writhing response was evaluated, and then the ED 50 dose was generally calculated. (The slopes of the dose-response curves for all test compounds analyzed were compared as described by Tallarida and Murray, Manual of
  • test compounds As prostaglandin E 2 antagonists, a
  • prostaglandin antagonism assay was conducted, as described below, to determine the ability of these compounds to inhibit prostaglandin E 2 -induced
  • ileums were then quickly removed from the guinea pigs and placed in a modified Tyrode solution, a solution which is known to those of skill in the art, containing one-half of the usual amount of magnesium ions.
  • test solutions/ suspensions Solutions or suspensions containing an initial amount of a test compound in modified Tyrode solution ("test solutions/ suspensions") were then separately substituted for the tissue bath.
  • prostaglandin E 2 were again injected into the test solutions/suspensions.
  • a second prostaglandin E 2 dose response curve was then generated for PGE 2 in the presence of a test compound.
  • a dose ratio of EC 50 doses (that dose of a compound or drug which is necessary to elicit a 50% maximal biological response and, thus, which is necessary to elicit a 50% reduction in the contractions of the guinea pig ileum segments in this assay) was then calculated from the results of each test in a manner known by those of skill in the art.
  • a concentration of test compound was determined to be "active” if it produced a dose ratio significantly greater than that obtained in a series of blank treatments. Duplicate tests were conducted on each concentration of test compound.
  • the pA 2 value (a statistical constant which is a common measure of expressing the potency of a
  • the compounds of the present invention, and the pharmaceutical compositions comprising one or more of these compounds in combination with a pharmaceutically- acceptable carrier, are useful in treating pain in animals.
  • a physician or veterinarian of ordinary skill in the art can readily determine whether or not a particular patient is in pain.
  • compositions of the present invention which will typically comprise one or more of the compounds of Formula I as an active ingredient in admixture with one or more pharmaceutically-acceptable carriers and, optionally, with one or more other compounds, drugs or materials, are employed
  • compositions will be suitably selected by methods which are
  • compositions of the present invention may be specially formulated for oral
  • administration in solid or liquid form for parenteral injection, and/or for rectal or vaginal administration. They may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally,
  • administration are orally and parenterally, the most preferred mode of administration is orally.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient,
  • compositions, and mode of administration without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the severity of the pain, the duration of the
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required to alleviate or ameliorate a particular patient's pain.
  • the physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required to alleviate or ameliorate a particular patient's pain.
  • the physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required to alleviate or ameliorate a particular patient's pain.
  • a suitable daily dose of a compound of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • dosage levels in the range of from about .001 mg to about 10 g, more preferably from about 1 mg to about 1000 mg, of active compound (a compound of Formula I) per kilogram of body weight per day are administered to a mammalian patient.
  • active compound a compound of Formula I
  • dosage levels in the range of from about .001 mg to about 10 g, more preferably from about 1 mg to about 1000 mg, of active compound (a compound of Formula I) per kilogram of body weight per day are administered to a mammalian patient.
  • the total daily usage of the compounds of Formula I, or the pharmaceutical compositions comprising such compounds will be determined by an attending physician or
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • composition a pharmaceutical formulation (composition) .
  • compositions of the present invention comprise a compound of the present invention together with one or more pharmaceutically-acceptable carriers thereof and, optionally, with other
  • Each carrier must be “acceptable” in the sense of being compatible with the other
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating
  • sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants include: (l) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine
  • EDTA tetraacetic acid
  • sorbitol sorbitol
  • tartaric acid tartaric acid
  • phosphoric acid and the like.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or
  • formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • amount of active ingredient (compound of Formula I) which can be combined with a carrier is conveniently presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an a
  • inventions may also be administered as a bolus
  • the active ingredient (compound of Formula I) is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • binder for example, gelatin or hydroxypropylmethyl cellulose
  • lubricant for example, lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or
  • hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile, injectable medium
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
  • the oral compositions can also include adjuvants such as wetting agents,
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example,
  • cellulose aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body
  • Formulations of the present invention which are suitable for vaginal administration also include
  • pessaries pessaries, tampons, creams, gels, pastes, foams or spray formulations containing-such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body.
  • dosage forms can be made by dissolving, dispersing or otherwise incorporating a compound of the present invention in a proper medium, such as an elastomeric matrix material.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Opthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions,
  • suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol,
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable dosage forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the injectable materials can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or in other sterile injectable mediums just prior to use.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.
  • compositions of the present invention may also be used in the form of veterinary formulations, including those adapted for the
  • oral administration for example, drenches (aqueous or non-aqueous solutions or
  • administration for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension or, when appropriate, by intramammary injection where a suspension or
  • solution is introduced into the udder of the animal via its teat; (3) topical application, for example, as a cream, ointment or spray applied to the skin; or (4) intravaginally, for example, as a pessary, cream or foam.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés substitués de dibenzoxazépine de formule (I), qui sont utiles comme agents analgésiques antidouleur, et compositions pharmaceutiques comprenant une quantité thérapeutiquement efficace d'un composé relevant de la formule (I), combiné avec un vecteur pharmaceutiquement acceptable. L'invention porte aussi sur un procédé, permettant d'éliminer ou d'atténuer la douleur chez l'animal, qui inclut l'administration à l'animal d'une quantité thérapeutiquement efficace d'un composé de formule (I).
PCT/US1992/006584 1991-10-01 1992-08-13 10-acyle-dibenz(b,f(1,4)-oxazepines et leurs analogues prenant la forme de thiazepines et diazepines, utilises comme antagonistes des prostaglandines WO1993007132A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/178,283 US5449673A (en) 1992-08-13 1992-08-13 10,11-dihydro-10-(3-substituted-1-oxo-2-propyl, propenyl or propynyl)dibenz[b,f][1,4] oxazepine prostaglandin antagonists
PCT/US1992/006584 WO1993007132A1 (fr) 1991-10-01 1992-08-13 10-acyle-dibenz(b,f(1,4)-oxazepines et leurs analogues prenant la forme de thiazepines et diazepines, utilises comme antagonistes des prostaglandines

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US76991391A 1991-10-01 1991-10-01
US07769,913 1991-10-01
PCT/US1992/006584 WO1993007132A1 (fr) 1991-10-01 1992-08-13 10-acyle-dibenz(b,f(1,4)-oxazepines et leurs analogues prenant la forme de thiazepines et diazepines, utilises comme antagonistes des prostaglandines

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5354746A (en) * 1993-06-01 1994-10-11 G. D. Searle & Co. Squaric acid derivatives of substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5354747A (en) * 1993-06-16 1994-10-11 G. D. Searle & Co. 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- and/or 10-substituted dibenzoxazepine and dibenzthiazepine compounds, pharmaceutical compositions and methods of use
WO1994025456A1 (fr) * 1993-04-30 1994-11-10 G.D. Searle & Co. Composes de dibenzoxazepine substitues en position 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- et/ou 10-, compositions pharmaceutiques et methodes d'utilisation
WO1994029286A1 (fr) 1993-06-16 1994-12-22 G.D. Searle & Co. Dibenzoxazepine et dibenzothiazepine analgesique
US5382578A (en) * 1991-10-31 1995-01-17 G. D. Searle & Co. Methods for treating convulsions and ischemia with substituted dibenzoxazepine compounds
US5393747A (en) * 1991-05-03 1995-02-28 G. D. Searle & Co. Substituted dibenzoxazepine compounds for the treatment of convulsions, ischemia and other diseases responsive to prostaglandin-E2 antagonists
US5441950A (en) * 1994-06-09 1995-08-15 G. D. Searle & Co. Substituted dibenzoxazepine and dibenzthiazepine carbamate compounds, pharmaceutical compositions and methods of use
US5449675A (en) * 1994-06-09 1995-09-12 G. D. Searle & Co. Substituted dibenzoxazepine and dibenzthiazepine urea compounds, pharmaceutical compositions and methods of use
US5512561A (en) * 1993-10-07 1996-04-30 G. D. Searle & Co. Aryl substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5604220A (en) * 1993-10-07 1997-02-18 G. D. Searle & Company Tartaric acid derivatives of substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5677296A (en) * 1993-11-03 1997-10-14 G.D. Searle & Co. Carbamic acid derivatives of substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
WO2008099907A1 (fr) 2007-02-16 2008-08-21 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour trouble de la miction

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0012385A1 (fr) * 1978-12-06 1980-06-25 Chugai Seiyaku Kabushiki Kaisha Dibenz(b,f)(1,4)oxazépines, procédé pour leur préparation et compositions pharmaceutiques
US4559336A (en) * 1985-02-25 1985-12-17 G.D. Searle & Co. 8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0012385A1 (fr) * 1978-12-06 1980-06-25 Chugai Seiyaku Kabushiki Kaisha Dibenz(b,f)(1,4)oxazépines, procédé pour leur préparation et compositions pharmaceutiques
US4559336A (en) * 1985-02-25 1985-12-17 G.D. Searle & Co. 8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5393747A (en) * 1991-05-03 1995-02-28 G. D. Searle & Co. Substituted dibenzoxazepine compounds for the treatment of convulsions, ischemia and other diseases responsive to prostaglandin-E2 antagonists
US5382578A (en) * 1991-10-31 1995-01-17 G. D. Searle & Co. Methods for treating convulsions and ischemia with substituted dibenzoxazepine compounds
US5719140A (en) * 1993-04-30 1998-02-17 G.D. Searle & Co. 2, 3-, 4-, 5-, 6-, 7-, 8-, 9- and /or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
WO1994025456A1 (fr) * 1993-04-30 1994-11-10 G.D. Searle & Co. Composes de dibenzoxazepine substitues en position 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- et/ou 10-, compositions pharmaceutiques et methodes d'utilisation
US5354746A (en) * 1993-06-01 1994-10-11 G. D. Searle & Co. Squaric acid derivatives of substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5461047A (en) * 1993-06-16 1995-10-24 G. D. Searle & Co. 2-,3-,4-,5-,6-,7-,8-,9- and/or 10-substituted dibenzoxazepine and dibenzthiazepine compounds, pharmaceutical compositions and methods of use
WO1994029286A1 (fr) 1993-06-16 1994-12-22 G.D. Searle & Co. Dibenzoxazepine et dibenzothiazepine analgesique
US5354747A (en) * 1993-06-16 1994-10-11 G. D. Searle & Co. 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- and/or 10-substituted dibenzoxazepine and dibenzthiazepine compounds, pharmaceutical compositions and methods of use
US5512561A (en) * 1993-10-07 1996-04-30 G. D. Searle & Co. Aryl substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5604220A (en) * 1993-10-07 1997-02-18 G. D. Searle & Company Tartaric acid derivatives of substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5677296A (en) * 1993-11-03 1997-10-14 G.D. Searle & Co. Carbamic acid derivatives of substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5441950A (en) * 1994-06-09 1995-08-15 G. D. Searle & Co. Substituted dibenzoxazepine and dibenzthiazepine carbamate compounds, pharmaceutical compositions and methods of use
US5449675A (en) * 1994-06-09 1995-09-12 G. D. Searle & Co. Substituted dibenzoxazepine and dibenzthiazepine urea compounds, pharmaceutical compositions and methods of use
US5504077A (en) * 1994-06-09 1996-04-02 G. D. Searle & Co. Substituted dibenzoxazepine and dibenzthiazepine carbamate compounds, pharmaceutical composition and methods of use
US5661146A (en) * 1994-06-09 1997-08-26 G.D. Searle & Co. Substituted dibenzoxazepine urea compounds, pharmaceutical compositions and methods of use
WO2008099907A1 (fr) 2007-02-16 2008-08-21 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour trouble de la miction

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