EP0663827A1 - Antagonistes recepteurs d'oxytocine tocolytique - Google Patents

Antagonistes recepteurs d'oxytocine tocolytique

Info

Publication number
EP0663827A1
EP0663827A1 EP93923134A EP93923134A EP0663827A1 EP 0663827 A1 EP0663827 A1 EP 0663827A1 EP 93923134 A EP93923134 A EP 93923134A EP 93923134 A EP93923134 A EP 93923134A EP 0663827 A1 EP0663827 A1 EP 0663827A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
mammal
compound
chr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93923134A
Other languages
German (de)
English (en)
Other versions
EP0663827A4 (fr
Inventor
Ben E. Evans
Douglas W. Hobbs
Joseph M. Pawluczyk
Douglas J. Pettibone
Kenneth E. Rittle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co 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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0663827A1 publication Critical patent/EP0663827A1/fr
Publication of EP0663827A4 publication Critical patent/EP0663827A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy.
  • the aforementioned pharmacologic activities are useful in the treatment of mammals. More specifically, the compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to Caesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.
  • Tocolytic (uterine-relaxing) agents that are currently in use include B2-adrenergic agonists, magnesium sulfate and ethanol.
  • Ritodrine the leading B2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant).
  • Other B2-adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine.
  • Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
  • Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
  • Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may, in addition, be important in the cervical ripening process.
  • the process of labor (term and preterm) is initiated by a heightened sensitivity of the uterus to oxytocin, resulting in part as a result of a well-documented increase in the number of oxytocin receptors in this tissue.
  • This "up-regulation" of oxytocin receptors and enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term.
  • oxytocin By blocking oxytocin, one would block both the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus.
  • a selective oxytocin blocker, or antagonist would likely be more efficacious for treating preterm labor than current regimens.
  • oxytocin at term has major effects only on the uterus, such an oxytocin antagonizing compound would be expected to have few, if any, side effects.
  • the compounds of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating
  • dysmenorrhea then current regimens.
  • An additional use for the present invention is for the stoppage of labor preparatory to Caesarean delivery. It is, therefore, a purpose of this invention to provide substances which more effectively antagonize the function of oxytocin in disease states in animals, preferably mammals, especially in humans. It is another purpose of this invention to prepare novel compounds which more selectively inhibit oxytocin. It is still another purpose of this invention to provide a method of antagonizing the functions of oxytocin in disease states in mammals. It is also a purpose of this invention to develop a method of preventing or treating oxytocin-related disorders of preterm labor and dysmenorrhea by antagonizing oxytocin.
  • compounds of the present invention are antagonists of oxytocin and bind to the oxytocin receptor.
  • oxytocin receptor When the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or pharmacologic effects.
  • These compounds are useful in the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Caesarean delivery.
  • W is hydrogen or acetate
  • Y is -CO-, -SO 2 - -CO(CH 2 ) m - or -(CH 2 ) m -;
  • R is hydrogen, C 1-5 alkyl or C 1 -5 alkoxycarbonylamino
  • R 1 is -CH 3 , -CH(CH 3 ) 2 , C 1-5 alkoxycarbonyl,
  • R 2 is hydrogen, hydroxy, carboxyl, acetyl, nitro, cis or trand oximino, halogen,
  • Het is imidazole or benzimidazole or azimidobenzene, or where R 2 is further defined as -COR 6 , -(CH 2 ) m -NHCOR 7 , -(CH2) m NHCOOR 7 .
  • R 3 is one or two of hydrogen, hydroxyl or C 1-5 alkyl; with the proviso that when R 1 is cyclohexyl, then R 2 and R 3 are limited to being hydroxyl or C 1-5 alkyl;
  • R 4 is hydrogen, C 1-5 alkyl, or C 6-10 cycloalkyl;
  • R 5 is hydrogen or acetyl
  • R 6 is ;
  • R 8 is hydrogen or C 1-5 alkyl
  • R 9 is hydrogen or C 1-5 alkyl
  • R 10 is-CH 3 , , ,
  • R 11 is -CH 3 ,
  • R 12 is hydrogen, C 1-5 alkyl or C 1-5 alkoxy
  • n is an integer of from 0 to 5;
  • m has a value of from 1 to 5.
  • salts and esters refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the following salts:
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
  • alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range.
  • alkenyl shall mean straight or branched chain alkenes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
  • alkynyl shall mean straight or branched chain alkynes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
  • aryl shall mean phenyl, naphthyl or fluorenyl.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g. aralkoxyaryloxy) they shall be interpreted as including those limitations given above for "alkyl” and "aryl”.
  • Designated numbers of carbon atoms e.g. C 1 -10 ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • preterm labor shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
  • the term "dysmenorrhea” shall mean painful menstruation.
  • the term “Caesarean delivery” shall mean incision through the abdominal and uterine walls for delivery of a fetus.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • the ability of the compounds of formula I to antagonize oxytocin makes these compounds useful as pharmacologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein oxytocin may be involved. Examples of such disorders include preterm labor and especially dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean delivery.
  • vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin disorders, including their use as diuretics and their use in congestive heart failure.
  • the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention, when used for the indicated effects will range between about 0.3-6.0 gm/day orally.
  • the most preferred doses will range from 0.1 to about 10 mg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be used.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate,
  • carboxymethylcellulose polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, zanthan gum and the like.
  • the compounds of the present invention can also be any organic compound having the same side chain length.
  • the compounds of the present invention can also be any organic compound having the same side chain length.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- methacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • LAH lithium aluminum hydride
  • TLC was performed on 20 cm plates coated with silica gel (250 microns) from Analtech.
  • Example 1 70 mg (0.220 mmol) of the product of Example 1 was dissolved in 5 ml DMF and the solution treated with 39.3 mg (0.242 mmol) of imidazole-4-acetic acid-hydrocloride followed by 32.7 mg (0.242 mmol) of 1-hydroxybenzotriazole hydrate (HBT) and 46.4 mg (0.242 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC). The pH was adjusted to 9.5 with triethylamine and the mixture stirred at 25°C or 4 hours.
  • HBT 1-hydroxybenzotriazole hydrate
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride
  • Example 2 85 mg (0.267 mmol) of the product of Example 1 was dissolved in 5 ml DMF and the solution treated with 72.3 mg (0.294 mmol) of N-t-butyloxycarbonyl-L-glutamine followed by 39.7 mg (0.294 mmol) of 1-hydroxybenzotriazole hydrate (HBT) and 56.3 mg (0.294 mmol of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The pH was adjusted to 9.5 with 55 ⁇ l (0.395 mmol) of triethylamine (Et3N) and the mixture stirred at 25°C for 1.5 hours.
  • HBT 1-hydroxybenzotriazole hydrate
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • Example 2 60 mg (0.188 mmol) of the product of Example 1 was dissolved in 3 ml DMF and the solution treated with 36.6 mg (0.226 mmol) of benzoimidazole-5-carboxylic acid followed by 30.5 mg (0.226 mmol) of 1-hydroxybenzotriazole hydrate (HBT) and 43.3 mg (0.226 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). The pH was adjusted to 9.5 with 63.0 ⁇ l (0.453 mmol) of triethylamine and the mixture stirred at 25°C for 20 hours.
  • HBT 1-hydroxybenzotriazole hydrate
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • the pH of the solution was adjusted to 9.5 with 49 ⁇ l (0.350 mmol) of triethylamine and the reaction stirred at 25°C for 1 hour.
  • a second portion consisting of 13.0 mg (0.081 mmol) of indole-5-carboxylic acid, 12.0 mg (0.089 mmol) HBT, 15.0 mg (0.078 mmol) EDC, and 22.1 ⁇ l (0.159 mmol) of triethylamine was added and the reaction stirred at 25°C for 1 hour.
  • Example 1 55 mg (0.173 mmol) of the product of Example 1 was dissolved in 2 ml DMF and the solution was treated with 33.9 mg (0.208 mmol) of benzotriazole-5-carboxylic acid followed by 28.1 mg (0.208 mmol) of 1-hydroxybenzotriazole hydrate (HBT) and 39.9 mg (0.208 mmol of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). The pH of the solution was adjusted to 9.5 with 66.6 ⁇ l (0.478 mmol) of triethylamine and the reaction stirred at 25°C for 18 hours.
  • HBT 1-hydroxybenzotriazole hydrate
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • Nonspecific binding (10% of the total binding) was determined using 1 ⁇ M unlabeled OT and the binding reaction was terminated by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, Inc.,
  • IC 50 the concentration of tested compound that inhibits 50% of OT was reported, unless otherwise noted.
  • AVP Vasopressin
  • Competition assays were conducted at equilibrium (30 minutes at 30°C) using 1 nM [ 3 H]AVP (liver) or 2 nM [ 3 H] AVP (kidney) in the following assay buffer: 100 mM Tris-HCl, 5 mM MgCl 2 , 0.1% BSA, 50 mM phenylmethylsulfonylfluoride, and 50 mg/ml bacitracin, pH 8.0.
  • Nonspecific binding (5-10% of the total binding) was determined using 10 ⁇ M unlabeled AVP, and the binding reaction was terminated by filtration as described above for the [ 3 H]OT binding assay.
  • IC 50 values were determined for both [ 3 H]OT and [ 3 H]AVP binding assays by linear regression of the relation log concentration of compound vs. percent inhibition of specific binding.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés ayant la formule X-Y-Z-R1, dans laquelle X représente (I) ou (II); W représente hydrogène ou acétate; Y représente -CO-, -SO2- -CO(CH2)m- ou -(CH2)m-; Z représente N, O, S, -CHR-, -CR=CH-, -CH=, -(CH2)m- ou -CHCHOH-; R représente hydrogène, C1-5 alkyle, C1-5 alcoxycarbonylamino ou quinuclidinylaminocarbonylamino; R1 représente -CH3, -CH(CH3)2, C1-5 alcoxycarbonyle, aryle, cycloalkyle inférieur et hétérocyclique substituté par R2 et/ou R3, -NR4R5 ou -NCOR6; R2 représente hydrogène, hydroxy, carboxyle, acétyle, nitro, halogène, mono-, di- ou tri-C1-3 alkyle indényle spirocyclique, N-spiroindanepipéridinyle, O-R où R est tel que défini ci-dessus, O-Het où Het représente imidazole ou benzimidazole ou azimidobenzène, ou lorsque R2 est défini par -COR6, -(CH2)m-NHCOR7, -(CH2)mNHCOOR7, -(CH2)m-NR8R9, -(CH2)m-NHCO-(CH2)mR7, -(CH2)m-NHCO-CHR7R7, -(CH2)m-NHCO-CH=CHR7, -(CH2)m-CO-O-R7, -(CH2)m-CO-O-(CH2)mR7, -(CH2)m-CO-O-CHR7R7, -(CH)m-CO-O-CH=CHR7, -NHSO2R- où R est tel que défini ci-dessus, NHSO2R7, -(CH2)m-O-R10, -SO2R10, -COR11, aryle alkyle inférieur, alkyle sulfonylalkyle, alkylsulfonylalkylamido, R3 représente un ou deux des éléments suivants: hydrogène, hydroxyle ou C1-5 alkyle; R4 représente hydrogène, C1-5 alkyle ou C6-10 cycloalkyle; R5 représente hydrogène ou acétyle; R6 représente (A) ou (B); R7 représente alkyle carbamate alkyle, aryle alkyle ou hétérocyclylalkyle substitué par R12, hydrogène, C1-4 alkyle, NSO2R12 ou NHO-C1-4 alkyle; R8 représente hydrogène ou C1-5 alkyle; R9 représente hydrogène ou C1-5 alkyle; R10 représente -CH3, alkaryle, alkarylalkyle ou azimidobenzene; R11 représente -CH3, aralkyle ou hétérocyclylalkyle; R12 représente hydrogène, C1-5 alkyle ou C1-5 alcoxy; et m est un nombre entier compris entre 0 et 5. De tels composés sont utiles en tant qu'antagonistes de l'oxytocine et de la vasopressine.
EP93923134A 1992-10-07 1993-09-27 Antagonistes recepteurs d'oxytocine tocolytique. Withdrawn EP0663827A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US95793892A 1992-10-07 1992-10-07
US957938 1992-10-07
PCT/US1993/009152 WO1994007496A1 (fr) 1992-10-07 1993-09-27 Antagonistes recepteurs d'oxytocine tocolytique

Publications (2)

Publication Number Publication Date
EP0663827A1 true EP0663827A1 (fr) 1995-07-26
EP0663827A4 EP0663827A4 (fr) 1995-11-15

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Application Number Title Priority Date Filing Date
EP93923134A Withdrawn EP0663827A4 (fr) 1992-10-07 1993-09-27 Antagonistes recepteurs d'oxytocine tocolytique.

Country Status (5)

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EP (1) EP0663827A4 (fr)
JP (1) JPH08502474A (fr)
AU (1) AU5292393A (fr)
CA (1) CA2143117A1 (fr)
WO (1) WO1994007496A1 (fr)

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EP0714299B1 (fr) * 1993-07-16 2002-04-24 Merck & Co. Inc. Benzoxazinone et benzopyrimidinone piperidinyle utiles comme antagonistes tocolytiques du recepteur de l'oxytocine
WO1995002587A1 (fr) * 1993-07-16 1995-01-26 Merck & Co., Inc. Derives de piperazinylcamphre substitues en tant qu'antagonistes de l'ocytocine
US5464788A (en) * 1994-03-24 1995-11-07 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists
US5707985A (en) * 1995-06-07 1998-01-13 Tanabe Seiyaku Co. Ltd. Naphthyl-, quinolyl- and isoquinolyl- sulfonamide derivatives as cell adhesion modulators
WO1998046569A1 (fr) * 1997-04-11 1998-10-22 Sumitomo Pharmaceuticals Co., Ltd. Derives de benzene
GB9819860D0 (en) 1998-09-12 1998-11-04 Zeneca Ltd Chemical compounds
DK1307430T3 (da) 2000-07-05 2006-01-30 Ortho Mcneil Pharm Inc Ikke-peptidsubstituerede spirobenzoazepiner som vasopressin-antagonister
CN1768041A (zh) 2003-04-04 2006-05-03 麦克公司 作为黑皮质素－4受体激动剂的酰化螺哌啶衍生物
EP1633719B1 (fr) 2003-06-17 2009-10-07 Janssen Pharmaceutica N.V. Spirobenzazepines substituees
DE102005000666B3 (de) * 2005-01-04 2006-10-05 Sanofi-Aventis Deutschland Gmbh Sulfonylpyrrolidine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DK2078022T3 (da) 2006-09-22 2012-02-13 Janssen Pharmaceutica Nv Spirobenzazepiner anvendt som vasopressinantagonister
CN101541807A (zh) 2006-09-22 2009-09-23 詹森药业有限公司 用作血管升压素拮抗剂的螺环苯并氮杂
DE602007006990D1 (de) 2006-12-07 2010-07-15 Hoffmann La Roche Spiropiperidinderivate als antagonisten des via-rezeptors
WO2008077811A1 (fr) * 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Dérivés de spiropipéridine
US8084609B2 (en) * 2006-12-22 2011-12-27 Hoffman-La Roche Inc. Spiropiperidine derivatives
US20100022572A1 (en) 2008-07-18 2010-01-28 Kowa Company, Ltd. Novel spiro compound and medicine comprising the same
CA2792539C (fr) * 2010-03-11 2017-04-18 Megumi Maruyama Derive d'amine n-acyle cyclique ou son sel pharmaceutiquement acceptable
US11717499B2 (en) * 2011-06-28 2023-08-08 Sandra Eve Reznik Administration of N,N-dimethylacetamide for the treatment of preterm birth
JP5715605B2 (ja) * 2011-09-14 2015-05-07 大日本住友製薬株式会社 Ｎ−アシル環状アミン誘導体またはその医薬上許容される塩からなる医薬
WO2014024993A1 (fr) * 2012-08-09 2014-02-13 国立大学法人京都大学 Dérivé de pipérazine et utilisation de celui-ci

Citations (2)

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EP0486280A2 (fr) * 1990-11-13 1992-05-20 Merck & Co. Inc. Dérivés de piperidinylcamphresulfonyl comme antagonistes d'oxytocine

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EP0486280A2 (fr) * 1990-11-13 1992-05-20 Merck & Co. Inc. Dérivés de piperidinylcamphresulfonyl comme antagonistes d'oxytocine

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JPH08502474A (ja) 1996-03-19
WO1994007496A1 (fr) 1994-04-14
EP0663827A4 (fr) 1995-11-15
AU5292393A (en) 1994-04-26
CA2143117A1 (fr) 1994-04-14

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