WO1996022775A1 - Antagonistes tocolytiques des recepteurs de l'oxytocine - Google Patents

Antagonistes tocolytiques des recepteurs de l'oxytocine Download PDF

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Publication number
WO1996022775A1
WO1996022775A1 PCT/US1996/000850 US9600850W WO9622775A1 WO 1996022775 A1 WO1996022775 A1 WO 1996022775A1 US 9600850 W US9600850 W US 9600850W WO 9622775 A1 WO9622775 A1 WO 9622775A1
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alkyl
compound
hydrogen
methyl
mammal
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PCT/US1996/000850
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English (en)
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Peter D. Williams
Roger M. Freidinger
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Merck & Co., Inc.
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Priority to EP96903618A priority Critical patent/EP0805681A4/fr
Priority to AU47638/96A priority patent/AU4763896A/en
Publication of WO1996022775A1 publication Critical patent/WO1996022775A1/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
    • C07D413/04—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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture; such compounds are generally pharmacologically useful as agents in obstetric and gynecologic therapy in mammals. More specifically, the compounds of the present invention can be used in the treatment of preterm labor, dysmenorrhea and for stopping labor preparatory to Caesarean delivery.
  • Tocolytic (uterine-relaxing) agents that are currently in use include ⁇ 2 -adrenergic agonists, magnesium sulfate and ethanol.
  • Ritodrine the leading ⁇ 2 -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 ⁇ 2 -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
  • 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 may be a physiological initiator of labor in several mammalian species including humans. 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 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 than current regimens.
  • An additional use for the present invention is for the stoppage of labor preparatory (i.e., prior) to Caesarean delivery.
  • 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. Additionally, such
  • oxytocin antagonists are useful in inducing contraception in mammals inasmuch as oxytocin antagonists have now been shown to inhibit the release of oxytocin-stimulated luteinizing hormone (LH) by anterior pituitary cells.
  • LH luteinizing hormone
  • Compounds of the present invention are also inhibitors of vasopressin and can bind to the vasopressin receptor. These compounds are useful in inducing vasodilation, treating hypertension, inducing diuresis and inhibiting platelet agglutination.
  • X is selected from CH 2 or O
  • R 1 is selected from hydrogen, mono- or di-C 1-5 alkyl, C 1-5 alkoxy-substituted C 1-5 alkyl, CO 2 H or CONH 2 ;
  • R 2 is selected from hydrogen or C 1-5 alkoxy
  • R 3 is selected from hydrogen, C 1-5 alkyl, di-, tri- or tetra-methyl, C 1-5 alkoxy-substituted C 1-5 alkyl, hydroxy-substituted C 1-5 alkyl, C 1-5 alkoxycarbonyl, CO 2 H or CONH 2 ;
  • R 4 is selected from hydrogen, C 1-5 alkoxycarbonyl, C 1-10 alkyl, C 3-8 cycloalkyl-substituted C 1-5 alkyl, COR 5 , SO 2 R 6 ,
  • R 5 is selected from C 1-10 alkyl, C 1-5 alkoxy or NHCOR 6 ;
  • R 6 is C 1-10 alkyl;
  • R 7 is selected from hydrogen, halogen, amino, mono- or
  • R 8 is selected from hydrogen, C 1 -5 alkyl or halogen
  • R 9 is selected from hydrogen and C 1 -5 alkyl; n is an integer of from 0 to 1 ; and
  • n 1 to 3; provided that when R 1 and R 3 are both simultaneously hydrogen: then
  • R 8 is C 1 -5 alkyl or halogen, and R 2 is C 1 -5 alkoxy, or
  • R 1 and R 3 can both simultaneously be hydrogen, is when one of two things occurs: (a) either R 8 is C 1 -5 alkyl or halogen, and R 2 is C 1 -5 alkoxy; or (b) R 4 is
  • R 1 and R 3 can not both simultaneously be hydrogen.
  • R 1 is selected from hydrogen, C 1 -5 alkyl or CONH 2 ;
  • R 3 is selected from hydrogen, C 1 -5 alkyl, C 1 -5 alkoxy-substituted C 1 -5 alkyl, C 1 -5 alkoxycarbonyl, CO 2 H or CONH 2 ;
  • R 4 is selected from hydrogen, C 1 -5 alkyl, C 3-8 cycloalkyl-substituted C 1 -5 alkyl, COR 5 , SO 2 R 6 or
  • R 5 is C 1 -5 alkyl
  • R 6 is C 1 -5 alkyl
  • R 7 is selected from hydrogen, chlorine, amino, mono- or
  • R 3 is selected from hydrogen, C 1 -5 alkyl, CH 2 OCH 3 , C 1 -5 alkoxycarbonyl, CO 2 H or CONH 2 ;
  • R 4 is selected from hydrogen, methyl, ethyl, isopropyl,
  • R 7 is selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl; where R 1 , R 9 and n are as defined above.
  • R 4 is selected from hydrogen, isopropyl, COCH 3 , SO 2 CH 3 ,
  • R 4 is selected from hydrogen, isopropyl, COCH 3 , SO 2 CH 3 ,
  • R 3 is selected from C 1 -5 alkyl, CH 2 OCH 3 , CO 2 CH 2 CH 3 , CO 2 H or CONH 2 ; where X and R 4 are as defined above.
  • R 3 is C 1 -5 alkyl.
  • R 3 is C 1 -5 alkyl; where X and R 4 are as defined above.
  • R 1 is selected from methyl or CONH 2 ;
  • R 4 is selected from hydrogen, methyl, ethyl, isopropyl,
  • R 1 is C 1 -5 alkyl; and R 4 is selected from hydrogen, methyl, ethyl, isopropyl,
  • Another example of the invention are compounds of the formula
  • R 3 is selected from C 1 -5 alkyl, CH 2 OCH 3 , C 1 -5 alkoxycarbonyl, CO 2 H or CONH 2 ; where X and R 4 are as defined above.
  • R 3 is C 1 -5 alkyl
  • R 4 is selected from hydrogen, isopropyl, COCH 3 , SO 2 CH 3 ,
  • R 7 is selected from hydrogen, chlorine, amino, mono- or di-C 1 -5 alkylamino, C 1 -5 alkyl or C 3-8 cycloalkyl;
  • R 9 is C 1 -5 alkyl; where X, R 2 , R 8 , m and n are as defined above.
  • R 7 is selected from hydrogen, C 1 -5 alkyl and C 3-8 cycloalkyl; and R 9 is methyl; where X, m and n are as defined above.
  • Still another example of the invention are compounds of the formula
  • R 2 is C 1 -5 alkoxy
  • R 4 is selected from C 1 -3 alkoxycarbonyl, C 1 - 10 alkyl,
  • R 5 is selected from C 2- 10 alkyl or NHCOR 6 ;
  • R 8 is selected from C 1 -5 alkyl or halogen; where X, R 6 , R 7 , R 9 , m and n are as defined above.
  • R 7 is selected from hydrogen, C 1-5 alkyl or C 3-8 cycloalkyl;
  • R 8 is selected from methyl, fluorine, chlorine or bromine; and
  • R 9 is hydrogen or methyl; where X, m and n are as defined above.
  • R 10 and R 11 are each independently selected from hydrogen, halogen or C 1-6 alkyl
  • R 12 and R 13 are each independently selected from hydrogen
  • R 14 is selected from hydrogen, CO-C 1 -6 alkyl, CO 2 -C 1 -6 alkyl or
  • R 15 , R 16 and R 17 are each independently selected from hydrogen or
  • n is integer from zero to one
  • R 14 is
  • R 15 , R 16 and R 17 are each independently C 1 -6 alkyl
  • R 10 is selected from hydrogen or methyl
  • R 1 1 is selected from hydrogen, bromine or fluorine
  • R 12 is selected from hydrogen or methyl
  • R 13 is selected from hydrogen or CO 2 CH 3 ;
  • R 14 is selected from hydrogen, COCH 3 , CO 2 C(CH 3 ) 3 or
  • R 15 , R 16 and R 17 are each independently selected from hydrogen, methyl, ethyl or 2-propyl;
  • n is integer from zero to one
  • R 14 is
  • R 15 , R 16 and R 17 are each independently selected from methyl, ethyl or 2-propyl;
  • composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of any of the compounds of the instant invention described above to prevent preterm labor in a mammal in need thereof.
  • FIG. 1 Further illustrating the invention is a method of eliciting an oxytocin antagonizing effect in a mammal, comprising the step of administering to said mammal a pharmacologically effective amount of any of the compounds of the instant invention described above.
  • a further illustration of the instant invention are methods of treating preterm labor, stopping labor preparatory to cesarian delivery, and treating dysmenorrhea in a mammal in need thereof, comprising the step of administering to said mammal a
  • Another example of the invention is a method for improving survival of a farm animal neonate comprising controlling timing of parturition to effect delivery of the neonate during daylight hours by administering to a farm animal which is expected to deliver the neonate within 24 hours a pharmacologically effective amount of any of the compounds of the present invention described above.
  • Additional examples of the invention are the use of any of the compounds described above in the preparation of a medicament for the treatment of preterm labor, dysmenorrhea or stoppage of labor prior to cesarian delivery in a mammal in need thereof.
  • More particularly illustrating the invention is a drug which is useful for treating preterm labor, dysmenorrhea or stopping labor prior to cesarian delivery in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds descibed above.
  • Additional illustrations of the instant invention are methods of antagonizing vasopressin from binding to its receptor site, inducing vasodilation, treating hypertension, inducing diuresis and inhibiting platelet agglutination in a mammal in need thereof comprising the step of administering to said mammal a pharmacologically effective amount of any of the compounds of the instant invention described above.
  • salts encompassed within the term "pharmaceutically acceptable salts" 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:
  • Glycollylarsanilate Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
  • 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 (i.e., methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, t-butyl, etc.).
  • aryl shall mean phenyl, napthyl or fluorenyl.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it 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.
  • R 1 in the definition of R 1 , the term “mono- or di-C 1 -5 alkyl” shall mean that the piperidine ring containing the R 1 substituent can be mono- or di-substituted with a C 1 -5 alkyl group.
  • R 1 is di-C 1 -5 alkyl
  • R 1 is di-C 1 -5 alkyl
  • the C 1 -5 alkyl groups can be the same or different.
  • the term "di-, tri- or tetra-methyl" shall mean that the piperidine ring containing the R 3 substituent can be di-, tri- or tetra-substituted with a methyl group.
  • R 3 is dimethyl, trimethyl and
  • 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 the present invention 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.
  • the present invention is also directed to combinations of the compounds of formula I with one or more agents useful in the treatment of oxytocin related disorders such as preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery.
  • the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents used in the treatment of preterm labor, such as antenatal steroids (e.g., dexamethasone).
  • Preferred combinations are simultaneous or
  • the oxytocin antagonist compounds of the present invention are also useful for improving reproductive efficiency in farm animals.
  • farm animals e.g., sheep, cattle, swine, horses and goats
  • the beginning of the estrous cycle is typically marked by behavioral estrus when the female animal accepts the male for mating.
  • Ovulation of the ovarian follicle occurs shortly after onset of estrus and cells in the follicle give rise to the corpus luteum.
  • the cells that form the corpus luteum produce progesterone and they also produce oxytocin.
  • the secretion of oxytocin from the corpus luteum and/or pituitary acts on the uterine endometrium to stimulate the secretion of prostaglandins (in particular PGF) which, in turn, causes the regression of the corpus luteum of the ovary.
  • PGF prostaglandins
  • PGF is, therefore, the luteolytic hormone.
  • destruction of the corpus luteum removes the source of progesterone which is key to the preparation of the uterus for pregnancy.
  • the presence of a viable conceptus i.e., the embryo and its associated membranes
  • the first key signal that the conceptus must produce is the one to prevent regression of the corpus luteum (i.e., the maternal recognition of pregnancy signal).
  • an oxytocin antagonist of the present invention at this critical period after fertilization (i.e., just prior to or during the period of maternal recognition of pregnancy) supplements the natural signal from the conceptus (i.e., maternal recognition of pregnancy) to prolong corpus luteal function.
  • the result is to increase pregnancy rates by enhancing the chances of impregnation through a reduction in embryonic loss.
  • a mated animal for example, a mated ewe, is treated with an oxytocin antagonist compound beginning on between day 10 to day 15 after onset of estrus.
  • the oxytocin antagonist compound is administered to the mated animal for a period of one day to three weeks, preferably one week to three weeks, most preferably one week to two weeks.
  • the compounds of the present invention are also useful for controlling the timing of parturition in farm animals so that delivery of the neonates occurs during the daytime. Approximately 80% of livestock are delivered at night and up to 5 to 10% of newborns die because the deliveries are not monitored properly.
  • An oxytocin antagonist compound of the present invention administered to the mother on the evening before expected delivery delays parturition so that the delivery occurs during the daylight hours. By delaying the timing of parturition, proper monitoring of the delivery and the neonates is ensured, resulting in increased survival rates of the
  • the oxytocin antagonists of the instant invention can also be used to control the timing of estrus in a cycling farm animal by preventing luteal regression.
  • An oxytocin antagonist compound of the instant invention is administered to a cycling farm animal prior to expected estrus to prevent regression of the corpus luteum.
  • Daily administration of the compound retards estrus until administration of the compound ceases.
  • the oxytocin antagonist compound is administered at least 1 day prior to expected estrus.
  • the compounds of the present invention also bind to the vasopressin receptor and are therefore useful as vasopressin antagonists.
  • 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.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.03-6.0 gm/day orally.
  • an effective daily dose when administered orally for the treatment of preterm labor, will be in the range of 0.05 mg/kg to about 100 mg/kg of body weight, preferably, from 0.5 mg/kg to 50 mg/kg, administered in single or divided dose.
  • compositions are preferably provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from 0.01 to about 1.0 mg/minute during a constant rate infusion.
  • 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 intermittant throughout the dosage regimen.
  • 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 conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with 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 incorporated into the mixture.
  • 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 administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • 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, polyhydroxypropylmethacrylamide-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.
  • Boc t-butyloxycarbonyl
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • FAB MS fast atom bombardment mass spectroscopy
  • NCS N-chlorosuccinimide
  • PPTS pyridinium p-toluenesulfonate
  • TMEDA N, N, N', N'-tetramethylethylenediamine
  • TMS-allyl allyltrimethylsilane
  • the compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • Schemes 2 and 7 utilize processes similar to those described by D. L. Comins and co-workers (Tetrahedron Letters, 1989, vol. 30, pp. 5053-5056, Tetrahedron Letters, 1986, vol. 27, pp. 4549-4552) and Schemes 3, 4, and 8 utilize 4-ketopipecolic acid (C.
  • the 3,4-dihydro-2(1H)-quinolinone ring system can be prepared using methods analogous to those described by H. Ogawa and co-workers (Journal of Medicinal Chemistry, 1993, vol. 36, pp.
  • the piperidine nitrogen can be derivatized by alkylation with an alkyl halide, by reductive alkylation with an aldehyde and a reducing agent such as sodium cyanoborohydride, by acylation with an activated carbonyl compound (e.g., carboxylic acid chloride,
  • R 4 substituent is a substituted or unsubstituted picolyl or picolyl N-oxide group
  • a substituted or unsubstitutued pyridinyl ester is converted to an alcohol using a reducing agent such as lithium aluminum hydride.
  • the alcohol is converted to an aldehyde using an oxidizing agent such as manganese dioxide, or converted to a
  • chloromethyl derivative by treatment with a chlorinating agent such as thionyl chloride.
  • a chlorinating agent such as thionyl chloride.
  • the aldehyde can be used to reductively alkylate the free piperidine, or the chloromethyl derivative can be used to alkylate the piperidine, giving compounds of the present invention in which R 4 is a substituted or an unsubstituted picolyl group.
  • Treatment of the chloromethyl derivative with an oxidizing agent such as m-chloroperoxybenzoic acid gives the chloromethylpyridine-N-oxide derivative, which is then used to alkylate the piperidine to provide compounds of the present invention in which R 4 is a substituted or an unsubstituted picolyl N-oxide group.
  • Directed ortho metalation reactions can be used to prepare alkylated aromatics as shown in Scheme 15, which can then be further elaborated to benzoic acid and phenylacetic acid derivatives which are usful for preparing compounds of the present invention in which R 8 is an alkyl group as shown in Schemes 15 and 16.
  • Syntheses of intermediates which are useful for preparing compounds of the present invention in which an alkyl group is substituted at the R 9 position are given in Scheme 17.
  • Pyridine carboxylic acid derivatives can be converted to pyridyl alkyl ketones, which can then be used to reductively alkylate the terminal piperidine ring to give compounds of the present invention in which an alkyl group is substituted at the R 9 position.
  • the pyridyl alkyl ketone derivatives can be reductively aminated with ammonia and the resulting aminoalkyl pyridines can be converted to pyridinylalkyl piperidinols by reaction with 1 ,1-dimethyl-4-piperidinone using a procedure similar to that reported by M. E. Kuehne and co-worker (Journal of Organic Chemistry, 1991 , vol. 56, pp. 2701-2712) followed by ketone reduction, or by reaction with allyltrimethylsilane and aqueous formaldyhyde using a procedure similar to that reported by P. A. Grieco and co-workers (Journal of the American Chemical Society, 1986, vol. 108, pp. 3512-3513).
  • the pyridinylalkyl piperidinols are then used in ether forming reactions to give compounds of the present invention in which R 9 is alkyl as shown in Scheme 17.
  • R 1 , R 3 , R 8 , and R 9 substituents in compounds of the present invention include but are not limited to the specific substitutents given in Schemes 1-17. Also, Schemes 1 -17 serve to exemplify methods for preparation of compounds of the present invention, but other methods and variations of those given, which are familiar to those of ordinary skill in the art, are also useful for preparing compounds of the present invention.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these Examples and the following Tables 1 -12. 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.
  • Tables 1 -12 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.
  • Step 1 1 -t-Butyloxycarbonyl-4-piperidinone (20 g, 0.10 mol), 2-aminobenzyl alcohol (13 g, 0.1 1 mol), and acetic acid (14 mL, 0.22 mol) were dissolved in dry toluene (500 mL). The solution was refluxed under inert atmosphere for 3 h with azeotropic removal of water. The solution was cooled to ambient temperature and concentrated under reduced pressure to one half of the original volume. To the solution was added NaBH 3 CN (20 g, 0.32 mol) and dry THF (300 mL). Acetic acid (10 mL, 0.15 mmol) was added dropwise over a period of about 1 h.
  • the reaction was stirred at ambient temperature for 24 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (750 mL). The EtOAc layer was washed with saturated aqueous NaHCO 3 (3 ⁇ 500 mL) and brine (250 mL). The EtOAc layer was dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using a gradient elution of 15-30% EtOAc- hexanes.
  • Step 2 1-t-Butyloxycarbonyl-4-((2-hydroxymethyl)phenylamino)-piperidine (24 g, 78 mmol) from step 1 above was dissolved in dry THF (250 mL) and cooled to 0°C under an atmosphere of nitrogen. To the solution was added DIEA (41 mL, 0.24 mol) and triphosgene (8.54 g, 28.8 mmol). The reaction was stirred at 0°C for 1h, and then at ambient temperature for 24 h. Ether (250 mL) was added, the mixture was cooled to 0°C and then filtered to remove the hydrochloride salt of DIEA.
  • Step 3 A stirred solution of 1 -(N-t-butyloxycarbonyl-4-piperidinyl)-4H-3,1-benzoxazin-2(1H)-one (19 g, 57 mmol) from step 2 above in EtOAc (500 mL) was cooled to 0°C. HCl gas was bubbled through the solution for 30 min. Stirring was continued at 0°C for 1 h, during which time a precipitate had formed, and the reaction was warmed to ambient temperature for 1 h. The stirred suspension was cooled to 0°C and cold ether (250 mL) was added. The precipitate was collected by filtration and washed with ether.
  • Step 4 To a solution of the hydrochloride salt of 1-(4-piperidinyl)-4(H)-3,1 -benzoxazin-2(1H)-one (150 mg, 0.56 mmol) from Step 3 above in DMF (5 mL) was added 2,4,6-trimethoxy-benzoic acid (120 mg, 0.56 mmol), HOBT (92 mg, 0.60 mmol), and EDC (140 mg, 0.73 mmol). To the stirred solution was added DIEA (0.19 mL, 1.1 mmol) until the reaction was pH 7 as judged by spotting an aliquot on wetted E.
  • Step 1 To a strirred solution of triphenylphosphine (57.2 g, 0.218 mol) and methyl 2,4-dihydroxybenzoate (29.2 g, 0.174 mol) in dry THF (250 mL) at 0°C was added a solution of N-t-butyloxy-4-piperidinol (43.8 g, 0.218 mol) and diethyl azodicarboxylate (37.9 mL, 0.218 mol) in dry THF (150 mL) dropwise over a period of 2 h. The resulting solution was warmed to ambient temperature over 2 h and stirred for an additional 16 h. The solvent was concentrated to half of the original volume under reduced pressure, ether (200 mL) was added, and the mixture was cooled to 0°C for 3 h. The precipitated
  • triphenylphosphine oxide was removed by filtration and washed with cold ether, and the filtrate solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 10-25% EtOAc-hexane. Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoate was obtained as a waxy solid.
  • Step 2 To a solution of methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoate (50 g, 0.14 mol) from Step 1 above and iodomethane (17.4 mL, 0.28 mol) in DMF (300 mL) at 0oC was added NaH (6.55 g of a 60% suspension in mineral oil, 0.164 mol) in several portions over a period of 2 h. The resulting suspension was warmed to ambient temperature and stirred for 18 h. The mixture was quenched with methanol (5 mL) and concentrated under reduced pressure.
  • methanol 5 mL
  • Step 3 Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoate (35 g, 96 mmol) from Step 2 above was dissolved in MeOH (250 mL) and to the solution was added 2 N NaOH (100 mL, 200 mmol). The stirred mixture was warmed to 70°C for 3 h. The solution was cooled to ambient temperature, concentrated under reduced pressure, cooled to 0°C and 0.5 M aqueous citric acid solution (300 mL) was added. To the suspension was added EtOAc (500 mL) and water (300 mL). The EtOAc layer was separated and the aqueous phase was washed with EtOAc (200 mL).
  • Step 4 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid from step 3 above was coupled to the
  • Example 1 The crude product was purified by pressurized silica gel column chromatography using a gradient elution of 1-4% MeOH-DCM. The title compound was obtained as a white foam by evaporation of a DCM solution under reduced pressure.
  • the solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 2-5% MeOH-DCM.
  • the title compound was obtained as an amorphous solid by lyophilization from acetonitrile-H 2 O.
  • hydrochloride salt of 1 -(1-(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3,1-benzoxazin-2(1H)-one from Example 3 (0.25 g; 0.50 mmol) was mesylated with methanesulfonyl chloride (0.60 mmol) and DIEA (1.1 mmol) in DCM (10 mL) at ambient temperature for 18 h. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous NaHCO 3 (50 mL), dried (MgSO 4 ), and filtered.
  • Step 1 N-t-Butyloxycarbonyl-3-piperidinylmethanol was etherified with ethyl 4-hydroxybenzoate using the procedure given in Step 1 of Example 2. The crude product was purified by pressurized silica gel column chromatography using a gradient elution of 10-25% EtOAc-hexanes. 4-(N-t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoic acid ethyl ester was obtained as an oil.
  • Step 2 4-(N-t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoic acid ethyl ester was saponified with aqueous NaOH in MeOH using the procedure given in Step 3 of
  • Example 2 4-(N-t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoic acid was obtained as a foam by evaporation of a DCM solution.
  • Step 3 4-(N-t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoic acid was coupled to the hydrochloride salt of 1 -(4-piperidinyl)-4(H)-3,1-benzoxazin-2(1H)-one from step 3 of Example 1 using the procedure described in step 4 of Example 1.
  • the crude product was purified by pressurized silica gel column chromatography using a gradient elution of 1 -4% MeOH-DCM.
  • the title compound was obtained as a white foam by evaporation of a DCM solution under reduced pressure.
  • Step 1 1 -(4-Piperidinyl)-1 ,2-dihydro-4(H)-3,1 -benzoxazin-2-one hydrochloride (150 mg, 0.559 mmol) from Step 3 of Example 1 (988 mg, 3.68 mmol) was treated with aqueous sodium carbonate and the resulting free base was extracted into ether. The dried (sodium sulfate) ether layer was evaporated in vacua and the residue evaporated three times from methylene chloride/methanol. The residue was treated with methylene chloride and filtered to remove insoluble material.
  • Step 2 1-(N-Chloro-4-piperidinyl)-4(H)-3, 1-benzoxazin-2(1H)-one from Step 1 above (230 mg, 0.86 mmol) was dissolved in warm ether (30 mL) and the solution was added dropwise to a
  • Step 3 1 -(2-Cyano-4-piperidinyl)-4(H)-3, 1 -benzoxazin-2(1H)-one from Step 2 above (198 mg, 0.77 mmol) was dissolved in methylene chloride (2 mL) and treated with 2,4-dimethoxybenzoyl chloride (170 mg, 0.84 mmol) followed by triethylamine (0.12 mL, 85 mg, 0.85 mmol). The mixture was stirred at ambient temperature for one hour, then chromatographed on silica gel eluted with 1 :9
  • Step 1 Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (3.5 g, 18.1 mmol) was stirred in methylene chloride (30 mL) and treated with di-t-butyl dicarbonate (3.6 g, 16.5 mmol) followed by triethylamine added dropwise to maintain the pH of the mixture (moistened E. Merck colorpHast sticks) in the range 7-8. The mixture was stirred at ambient temperature for 18 h, then washed with 1 N HCl followed by saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give methyl 1 -Boc-4-oxo-3-piperidinecarboxylate.
  • Step 2 Methyl 1-Boc-4-oxo-3-piperidinecarboxylate from Step 1 above (3.86 g, 15 mmol) was combined with 2-aminobenzyl alcohol (1.5 g, 12.2 mmol) and acetic acid ( 1.29 mL, 1.35 g, 22.5 mmol) in methanol (10 mL). Sodium cyanoborohydride (0.94 g, 15 mmol) was added and the mixture was stirred at ambient temperature for 3.5 h. The solvent was removed in vacuo and the residue treated with ethyl acetate ( 100 mL).
  • Step 3 Methyl 1-Boc-4-(2-hydroxymethylphenylamino)-3-piperidine carboxylate from Step 2 above (4.1 g, 1 1.3 mmol) was stirred in THF (40 mL) in an ice bath and treated with triphosgene (1.1 1 g, 3.74 mmol) followed by triethylamine (4.7 mL, 3.41 g, 33.7 mmol). The mixture was stirred at ambient temperature for 18 h, then treated with an additional 0.47 g of triphosgene and 1.9 mL of triethylamine, and stirred an additional 4.5 h. Water was added and the mixture was extracted with ethyl acetate.
  • Step 4 Methyl 1 -Boc-4-(3,1 -benzoxazin-2-one-1 -yl)-3-piperidine carboxylate from Step 3 above (0.6 g, 1.5 mmol) was stirred in ethyl acetate in an ice bath, then saturated with HCl gas and stirred another 15 min in the cold. The mixture was evaporated in vacua.
  • Step 5 Methyl 4-(3,1-benzoxazin-2-one- 1-yl)-3-piperidinecarboxylate hydrochloride from Step 4 above (0.26 g, 0.97 mmol) was stirred in methylene chloride (10 mL), and 2,4-dimethoxybenzoyl chloride (0.19 g, 0.95 mmol) was added followed by triethylamine (0.26 mL, 0.19 g, 1.9 mmol). The mixture was stirred at ambient temperature for 2.5 h, then chromatographed on silica gel eluted with 500:10: 1 CHCl 3 :MeOH:NH 4 OH. The combined product fractions were evaporated to dryness in vacua. The residue was rechromatographed on silica gel eluted with 4:1 EtOAc:hexane and the combined product fractions were evaporated to dryness in vacuo to give the title
  • Step 1 To a solution of 2-methoxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoic acid (3.2 g; 9.1 mmol) from Step 3 of Example 2 in THF was added thionyl chloride (1 mL; 13.7 mmol) and pyridine (2 drops) while under a nitrogen atmosphere. The solution was stirred for 4 hours and then concentrated under reduced pressure to dryness. The residue was suspended in ether and filtered, and the filtrate was concentrated to dryness to yield 2-methoxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoyl chloride.
  • Step 2 A two phase mixture of ether (66 mL) and 40% aqueous potassium hydroxide (20 mL) was cooled to 0°C and N-nitrosomethylurea (6.6 g) was added portionwise over 30 minutes. The resulting yellow diazomethane/ether solution was decanted and dried over potassium hydroxide. The diazomethane/ether solution was decanted and cooled to 0°C. At this point, a solution of 2-methoxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoyl chloride from Step 1 above in THF was added dropwise to the diazomethane/ether solution. The resulting bronze solution was warmed to ambient temperature and stirred for 3 hours.
  • Step 3 A solution of 2-methoxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)phenyldiazomethyl ketone (930 mg; 2.48 mmol) from Step 2 above in dry methanol (7 mL) was refluxed and a solution of freshly prepared silver benzoate (100 mg) in triethylamine (1 mL) was added portionwise over 45 minutes. The solution was refluxed for an additional 30 minutes, then cooled and filtered.
  • Step 4 To a solution of methyl2-methoxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)phenylacetate (1.37 g; 3.6 mmol) from Step 3 above in 27 mL of THF was added aqueous lithium hydroxide solution (4.5 mL; 1.01M) dropwise. The reaction mixture was stirred for 16 hours and concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and 0.5 M aqueous hydrochloric acid. The organic phase was separated and the aqueous phase was extract with ethyl acetate (2x). The combined organic extracts were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to yield 2-methoxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)phenylacetic acid.
  • aqueous lithium hydroxide solution 4.5 mL; 1.01M
  • Step 5 To a solution of the hydrochloride salt of 1 -(4-piperidinyl)-4(H)-3,1-benzoxazin-2(1H)-one from Step 3 of Example 1 (250 mg; 0.93 mmol) in 8 mL of DMF was added 2-methoxy-4-(N-t- butyloxycarbonyl-4-piperidinyloxy)phenylacetic acid (340 mg; 0.93 mmol) from step 4 above, EDC (213 mg; 1.1 1 mmol), and HOBT (147 mg; 1.09). Triethylamine (0.55 mL) was added to make the solution basic (pH 8-9). After stirring for 18 hours, the solvent was removed under reduced pressure.
  • Step 6 1 -(1-(4-(1 -tert-Butyloxycarbonyl-4-piperidinyloxy)-2-methoxyphenylacetyl)piperidin-4-yl)-4(H)-3, 1 -benzoxazin-2(1H)-one from Step 5 above (0.20 g, 0.35 mmol) was dissolved in ethyl acetate and cooled in an ice bath. Once cool, the solution was saturated with gaseous HCl for 30 minutes. The mixture was evaporated to dryness. Ether was added and removed in vacua three times, and the residue was triturated with ether and filtered to yield the hydrochloride salt of the title compound as a white solid.
  • Step 1 To a well-stirred, 0°C solution of methyl 2,4-dihydroxybenzoate (50 g, 300 mmol) in acetone (1000 mL) was added K 2 CO 3 (150 g, 1000 mmol) and benzyl bromide (39 mL, 330 mmol). The solution was allowed to warm to ambient temperature over 48 h. The mixture was filtered through celite and the filtrate solvent was removed under reduced pressure. The residue was dissolved in EtOAc (1000 mL) and washed with water (250 mL) and saturated aqueous NaHCO 3 (500 mL). The EtOAc layer was dried (MgSO 4 ), filtered, and the EtOAc was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 5: 1 hexanes:EtOAc as eluant. Methyl 4-benzyloxy-2-hydroxybenzoate was obtained as a white powder.
  • Step 2 To a stirred, 0°C solution of methyl 4-benzyloxy-2-hydroxybenzoate (12 g, 46 mmol) from step 1 above in DMF (150 mL) was added NaH (2.76 g of a 60% suspension in mineral oil, 69 mmol) and methyl iodide (7.2 mL, 1 16 mmol). The solution was warmed to ambient temperature and stirred for 18 h. The reaction mixture was poured onto ice and the resulting solution was extracted with ether (3 ⁇ 200 mL). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 4: 1 hexanes:EtOAc as eluant. Methyl 4-benzyloxy-2-methoxybenzoate was obtained as a white powder.
  • Step 3 A round-bottomed flask containing methyl 4-benzyloxy-2-methoxybenzoate (16.48 g, 60 mmol) from step 2 above was purged with argon and 10% palladium on carbon catalyst was added (2 g). Methanol (200 mL) was slowly added followed by HOAc (2 mL). The solution was kept under 1 atm of H 2 and stirred for 24 h. The catalyst was removed by filtration through celite and the filtrate solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1 : 1 hexanes:EtOAc as eluant. Methyl 4-hydroxy-2-methoxybenzoate was obtained as an amorphous solid.
  • Step 4 To a stirred solution of methyl 4-hydroxy-2- methoxybenzoate (11 g, 60 mmol) from step 3 above in THF:H 2 O (100 mL: 10 mL) was added LiOH ⁇ H 2 O (3 g, 71 mmol). The solution was stirred for 24 h and then made acidic (pH 5) by the addition of 10% aqueous HCl. The solution was extracted with CH 2 Cl 2 (3 ⁇ 50 mL). The combined organic layers were dried (MgSO 4 ) and filtered. The filtrate solvent was evaporated under reduced pressure to afford 4-hydroxy-2-methoxybenzoic acid as an amorphous solid.
  • Step 5 1-(4-Piperidinyl)-4(H)-3,1 -benzoxazin-2(1H)-one hydrochloride from Step 3 of Example 1 and 2-methoxy-4-hydroxybenzoic acid from Step 4 above were coupled using the procedure given in step 4 of Example 1.
  • the crude product was purified by pressurized silica gel column chromatography using 98:2 DCM:MeOH as eluant. The title compound was obtained as an amorphous solid.
  • Step 1 To 10 ml of water containing 258 mg of potassium carbonate was added 10 ml of ethyl acetate containing the hydrochloride salt of 1 -(1 -(4-(4-piperidinyloxy)-2-methoxy benzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1H)-one (1.0 g, 1.7 mmol) from Example 3. To this mixture was added 405 mg (1.7 mmol) of N-cyanodiphenyl-imidocarbonate. The reaction mixture was stirred for 2 hr at ambient temperature, diluted with ethyl acetate and the layers were separated.
  • Step 2 A solution of 30 ml of methanol containing 500 mg of N-[1 -(1 -(4-(4-piperidinyloxy)-2-methoxybenzoyl) piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1H)-one]-N-cyano- O-phenylisourea from step 1 above was saturated with ammonia at 0° C. The reaction flask was capped with a septum and the reaction was allowed to stand at ambient temperature overnight. The reaction mixture was cooled and more ammonia was added.
  • Step 2 To a stirred solution of 3-hydroxymethyl-2-methylpyridine (1.00 g, 8.13 mmol) from step 1 above in CH 2 Cl 2 (40 mL) at ambient temperature was added SOCl 2 (9.5 g, 80 mmol). The mixture was stirred for 4 h, and the solvent and excess SOCl 2 were evaporated under reduced pressure. The residue was partitioned between CH 2 Cl 2 (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated, and the aqueous layer was washed with additional CH 2 Cl 2 (2 ⁇ 40 mL).
  • Step 4 To a stirred solution of 1 -(1-(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3,1-benzoxazin-2(1H)-one from Example 3 (6.24 g, 13.4 mmol) in DMF (150 mL) under argon atmosphere was added 3-chloromethyl-2-methylpyridine-N-oxide from Step 3 above (2.33 g, 14.8 mmol) and DIEA (3.5 mL, 20 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. The solvent was removed under reduced pressure.
  • Ethyl 2,4-dimethylnicotinate prepared by the method of Ohno, et al., Journal of the American Chemical Society (1979), vol. 101 , pp. 7036-7040,was converted in three steps to 3-chloromethyl-2,4-dimethylpyridine N-oxide using procedures analogous to those given in steps 1-3 of Example 17.
  • Step 1 To a stirred solution of 3-methyl-2-phthalimidopyridine (A. E. Moormann et al., Synthetic Communications (1987), vol. 17, pp. 1695-1699; 0.50 g; 2.1 mmol) in CH 2 Cl 2 (20 mL) was added N-bromosuccinimide(0.37 g; 2.1 mmol). The solution was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure and the crude 3-bromomethyl-2-phthalimidopyridine was dissolved in DMF (10 mL).
  • Step 2 To a solution of 1 -(1-(4-(l -(2-phthalimido-3-pyridy_methyl)-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3.1-benzoxazin-2(1H)-one from Step 1 above (0.90 g; 1.3 mmol) in EtOH (10 mL) was added hydrazine (0.083 mL; 2.6 mmol). The reaction mixture was stirred at ambient temperature for 72 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1 % TFA. The fractions containing product were lyophilized to give the TFA salt of the title compound as an amorphous solid.
  • the organic phase was dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure.
  • the residue was purified by pressurized silica gel column chromatography using 5% methanol in methylene chloride as eluant.
  • the product was further purified by preparative reverse phase HPLC using an acetonitrile: water gradient containing TFA.
  • the TFA salt of the title compound was obtained as a white amorphous solid by lyophilization.
  • Example 29 using a procedure analogous to that given in step 3 of
  • Example 1 The hydrochloride salt of the title compound was obtained as an amorphous solid.
  • the title compound was prepared from 1 -(1-(4-(4-piperidinyloxy)-2-methoxy-5-bromobenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one of Example 30 using a procedure analogous to that given in Example 4.
  • the title compound was purified by pressurized silica gel column chromatography using 98:2 CH 2 Cl 2 :MeOH as eluant and was obtained as an amorphous solid by evaporation from EtOAc-CH 2 Cl 2 under reduced pressure.
  • Step 1 To a stirred, 0°C solution of 1 - ⁇ 1 -[4-hydroxy-2-methoxybenzoyl]-piperidin-4-yl ⁇ -4H-3,1 -benzoxazin-2(1H)-one (0.40 g, 1.0 mmol) from Example 14 and triphenylphosphine (0.58 g, 2.2 mmol) in dry THF (15 mL) was added a solution of DEAD (0.35 mL, 2.2 mmol) and N-Boc-cis-2-methoxycarbonyl-4-hydroxypiperidine (0.54 g, 2.1 mmol; prepared by the method given in, J. Org. Chem. (1991 ) vol.
  • the title compound was prepared from 1 -(1-(4-(trans-2-methoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one of Example 33 using a procedure analogous to that given in Example 4.
  • the title compound was purified by pressurized silica gel column chromatography using 98:2
  • Step 1 To a solution of LDA (44 mmol) in THF (150 mL) at -78oC was added N-Boc-4-piperidinone (8.0 g, 40 mmol) in THF (50 mL) over a period of 30 min. The solution was stirrred at -78°C for 3 h, and iodomethane (5.8 g, 40 mmol) was added. The resulting solution was stirred at -78°C for 2 h and then warmed to ambient temperature for 18 h. The mixture was diluted with saturated aqueous NH 4 CI (150 mL), the layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic phases were dried
  • Step 2 To a stirred solution of N-Boc-3-methyl-4-piperidinone (3.4 g, 12.7 mmol) from step 1 above in MeOH (30 mL) at 0°C was added sodium borohydride (0.48 g, 12.7 mmol) over a period of 30 min. The mixure was was warmed to ambient temperature and stirred for 18 h. The mixture was diluted with water (100 mL) and extracted with CH 2 Cl 2 (3x 30 mL). The combined organic layers were dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 100:0 to 90:10
  • Step 3 N-Boc-3-methyl-4-hydroxypiperidine from step 2 above was coupled to methyl 2-methoxy-4-hydroxybenzoate from step 3 of Example 14 using Mitsunobu conditions as given in step 1 of
  • Example 2 Methyl 4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoate was purified by pressurized silica gel column chromatography using a gradient elution of 100:0 to 90: 10 hexanes:EtOAc and was obtained as an amorphous solid.
  • Step 4 Methyl 4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoate from step 3 above was saponified using the procedure given in step 3 of Example 2. 4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoic acid was obtained as an amorphous solid.
  • Step 5 4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoic acid from step 4 above was coupled to 1-(4-piperidinyl)-4H-3,1 -benzoxazin-2( 1H)-one hydrochloride from step 3 of Example 1 using the procedure given in step 4 of Example 1. 1 -(1 -(4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3, 1-benzoxazin-2(1H)-one was obtained as an amorphous solid.
  • Example 35 was converted to 1 -(1-(4-(3-methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one using the procedure given in step 3 of Example 1.
  • the hydrochloride salt of the title compound was obtained as an amorphous solid.
  • Example 36 1-(1-(4-(3-Methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one from Example 36 was converted to 1-(1 -(4-(N-acetyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one using the procedure given in
  • Example 4 The title compound was obtained as an amorphous solid. Analysis calculated for C 29 H 35 N 3 O 6 , 0.5 H 2 O
  • Step 1 Methyl 4-hydroxy-2-methoxybenzoate (10 g, 55 mmol) from step 3 of Example 14 and l -fluoro-3,5-dichloropyridinium trifluoromethanesulfonate (21 g, 66 mmol) were refluxed in
  • the title compound was prepared from 1 -(1-(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one of Example 39 using the procedure given in step 3 of Example 1.
  • the hydrochloride salt of 1 -(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one was obtained as an amorphous solid.
  • Step 1 Ethyl propionylacetate (25 g, 0.17 mol), hexan-2,4-dione (12.5 g, 0.11 mol), and ammonium acetate (51 g, 0.66 mol) were combined and heated with stirring at 1 10°C for 96 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with water (2x 150 mL) and brine (100 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8 hexanes:EtOAc as eluant.
  • Step 2 To a solution of ethyl 2,4-diethyl-6-methylnicotinate (0.55 g, 2.5 mmol) from step 1 above in THF (65 mL) at 0oC was added LAH (2.5 mL of a 1.0 M solution in THF; 2.5 mmol). The mixture was stirred at ambient temperature for 18 h and then quenched by the sequential addition of ethyl acetate (0.1 mL), water (0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.28 mL). The solids were removed by filtration through celite and the filtrate solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 99: 1
  • Step 3 To a solution of 2,4-diethyl-3-hydroxymethyl-6-methylpyridine (0.35 g, 2.0 mmol) from step 2 above in CH 2 Cl 2 (15 mL) was added thionyl chloride (0.9 g, 8 mmol) dropwise. The mixture was stirred at ambient temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between CH 2 Cl 2 (50 mL) and saturated aqueous NaHCO 3 (50 mL). The organic phase was dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 85: 15 hexanes:EtOAc as eluant. 3-Chloromethyl-2,4-diethyl-6-methylpyridine was obtained as an
  • Step 4 To a solution of 3-chloromethyl-2,4-diethyl-6-methylpyridine (0.32 g, 1.6 mmol) from step 3 above in CHCl 3 (25 mL) was added MCPBA (0.70 g of a 50% by weight mixture; 2.0 mmol) and the mixture was stirred at ambient temperature for 18 h. The solution was extracted with saturated aqueous NaHCO 3 (2 ⁇ 20 mL), dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure.
  • Step 5 3-Chloromethyl-2,4-diethyl-6-methylpyridine-N-oxide from step 4 above and 1 -(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one from Example 40 were reacted using the procedure given in step 4 of
  • Example 17 The crude product was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of 1 -(1-(4-(1-(N-oxo-2,4-diethyl-6-methyl-3-pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one was obtained by lyophilization from CH 3 CN-H 2 O containing aqueous HCl. Analysis calculated for C 37 H 45 FN 4 O 6 , 0.7 HCl, 2.3 H 2 O
  • Step 1 Ethyl 2-ethyl-4-methylnicotinate was prepared in a manner analogous to that reported for ethyl 2,4-dimethylnicotinate by Ohno et al., J. Am. Chem. Soc. (1979) vol. 101 , p. 7036.
  • Ethyl propionylacetate 25 g, 0.17 mol
  • acetaldehyde (10.6 g, 0.24 mol)
  • acetaldehyde-ammonia complex (1 1.7 g, 0.09 mol
  • Steps 2-5 Ethyl 2-ethyl-4-methylnicotinate from step 1 above was converted to 3-chloromethyl-2-ethyl-4-methylpyridine-N-oxide in three steps using procedures analogous to those given in steps 1 -3 in Example 17, and 3-chloromethyl-2-ethyl-4-methylpyridine-N-oxide was used to alkylate 1 -(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)-piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one from Example 40 using a procedure analogous to that given in step 4 of Example 17.
  • the crude product was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of 1 -(1-(4-(1-(N-oxo-2-ethyl-4-methyl-3-pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one was obtained by lyophilization from CH 3 CN-H 2 O containing aqueous HCl. Analysis calculated for C 35 H 41 FN 4 O 6 , 2.5 HCl, 0.95 H 2 O
  • Step 1 Ethyl propionylacetate, pentan-2,4-dione, and ammonium acetate were reacted to give ethyl 2-ethyl-4,6-dimethylnicotinate using a procedure analogous to that given in step 1 of Example 42.
  • Steps 2-5 Ethyl 2-ethyl-4,6-dimethylnicotinate from step 1 above was converted to 3-chloromethyl-4,6-dimethyl-2-ethylpyridine-N-oxide in three steps using procedures analogous to those given in steps 2-4 of Example 42, and 3-chloromethyl-4,6-dimethyl-2- ethylpyridine-N-oxide was used to alkylate 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)- one from Example 40 using a procedure analogous to that given in step 4 in Example 17.
  • the crude product was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of 1 -(1 -(4-( 1 -(N-oxo-2-ethyl-4,6-dimethyl-3-pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one was obtained by lyophilization from CH 3 CN-H 2 O containing aqueous HCl. Analysis calculated for C 36 H 43 FN 4 O 6 , 2.5 HCl, 1.4 H 2 O
  • Step 1 Ethyl propionylacetate, pentan-2,4-dione, and ammonium acetate were reacted to give ethyl 2-ethyl-4,6-dimethylnicotinate using a procedure analogous to that given in step 1 of Example 42.
  • Steps 2-4 Ethyl 2-ethyl-4,6-dimethylnicotinate from step 1 above was converted to 3-chloromethyl-4,6-dimethyl-2-ethylpyridine in two steps using procedures analogous to those given in steps 2 and 3 of Example 42, and 3-chloromethyl-4,6-dimethyl-2-ethylpyridine was used to alkylate 1 -(1-(4-(4-piperidinyloxy)-5-fluoro-2- methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one from Example 40 using a procedure analogous to that given in step 4 in Example 17.
  • the crude product was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of 1 -(1-(4-(1 -(2-ethyl-4,6-dimethyl-3-pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)-piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one was obtained by
  • the title compound was prepared from 1 -(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one of Example 40 and 3-chloromethyl-2-methylpyridine-N-oxide from step 3 of Example 17 using the procedure given in step 4 of Example 17.
  • the title compound was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of the title compound was obtained as an amorphous solid by lyophilization from CH 3 CN-H 2 O containing aqueous HCl. Analysis calculated for C 33 H 37 FN 4 O 6 , 2.4 HCl, 0.25 H 2 O
  • Ethyl 2-isopropylnicotinate was converted in three steps to 3-chloromethyl-2-isopropylpyridine-N-oxide using procedures analogous to those given in steps 1 -3 in Example 17.
  • the title compound was prepared from 1 -(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one of Example 40 and 3-chloromethyl-2-isopropylpyridine-N-oxide using the procedure given in step 4 of Example 17.
  • the title compound was purified by pressurized silica gel column chromatography using
  • EXAMPLE 48 1 -(1 -(4-( 1 -(N-oxo-2-isopropyl-6-methyl-3-pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2( 1 H)-one
  • Ethyl 2-isopropyl-6-methylnicotinate was prepared using a procedure analogous to that given in step 1 of Example 43 using ethyl 3-oxo-4-methylpentanoate in place of ethyl propionylacetate.
  • Ethyl 2-isopropyl-6-methylnicotinate was converted in three steps to 3-chloromethyl-2-isopropyl-6-methylpyridine-N-oxide using procedures analogous to those given in steps 1 -3 in Example 17.
  • Ethyl 2,4,6-trimethylnicotinate was prepared using a procedure analogous to that given in step 1 of Example 42 using ethyl acetoacetate in place of ethyl propionylacetate. Ethyl 2,4,6-trimethylnicotinate was converted in three steps to 3-chloromethyl-2,4,6-trimethylpyridine-N-oxide using procedures analogous to those given in steps 1 -3 in Example 17.
  • the title compound was prepared from 1 -(1 -(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyI)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one of Example 40 and 3-chloromethyl-2,4,6-trimethylpyridine-N-oxide using the procedure given in step 4 of Example 17.
  • the title compound was purified by pressurized silica gel column
  • Ethyl 2,6-diethyl-4-methylnicotinate from step 1 of Example 42 was converted in three steps to 3-chloromethyl-2,6-diethyl-4-methylpyridine-N-oxide using procedures analogous to those given in steps 1 -3 in Example 17.
  • the title compound was prepared from 1 -(1 -(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1H)-one from Example 3 and 3-chloromethyl-2,6-diethyl- 4-methylpyridine-N-oxide using the procedure given in step 4 of Example 17.
  • the title compound was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of the title compound was obtained as an amorphous solid by lyophilization from CH 3 CN-H 2 O containing aqueous HCl.
  • the title compound was prepared from 1 -(1 -(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1 H)-one from Example 3 and 3-chloromethyl-4,6-dimethyl-2-ethylpyridine-N-oxide from Example 44 using the procedure given in step 4 of Example 17.
  • the title compound was purified by pressurized silica gel column chromatography using 97:3:0.3 CH 2 Cl 2 :MeOH:NH 4 OH as eluant.
  • the hydrochloride salt of the title compound was obtained as an amorphous solid by lyophilization from CH 3 CN-H 2 O containing aqueous HCl. Analysis calculated for C 36 H 44 N 4 O 6 , 2.5 HCl, 0.05 H 2 O
  • 100 mg of the compound of Example 22 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • Uterine tissue was taken from nonpregnant adult Sprague-Dawley rats (Taconic Farms, Germantown, NY) pretreated (18-24 h) with diethylstilbestrol propionate (DES; 300 ⁇ g/kg, i.p.). Uterine tissue (full thickness) was also taken with informed consent from nonlabor pregnant women undergoing cesarean section at 38 to 39 weeks gestation (Oregon Health Sciences Center, Portland, OR). Liver and kidney medulla samples were taken from male rats and from human surgical and early
  • [3H]AVP rat liver, 0.21 nM; rat kidney, 0.27 nM; human liver, 0.27 nM; human kidney, 1.4 nM.
  • Computer analysis of the saturation assays by EBDA/LIGAND [McPherson, G.A.: Kinetic, Ebda, Ligand, Lowry: A Collection of Radioligand Binding Analysis Programs, Elsevier Science Publishers, Amsterdam (1985)] indicated that both radioligands apparently bound to single sites in all tissues examined.
  • the final protein concentration for the various tissues in each assay ranged from 150 to 300 ⁇ g/ml [Lowry, P.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J.; J. Biol. Chem., 193:265-275 (1951)].
  • IC50 values were determined for the [ 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. Data is either reported as a given percentage of inhibition at a specified concentration, or if an IC50 was calculated, as a nanomolar concentration.
  • Representative compounds of the present invention were found to have IC50 values for the human oxytocin receptor in the range of 2 nM to 1 ,000 nM.
  • the oxytocin antagonistic effect of the compounds of the present invention can be further evaluated according to the in vitro and/or in vivo functional assays described in detail in D.J. Pettibone et al., Drug Devel.Res. 1993, 30, 129-142.
  • oxytocin antagonist compounds of the instant invention useful for treating oxytocin-related conditions such as preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery, are shown below in Tables 1 through 12.

Abstract

L'invention concerne des composés de la formule (I) dans laquelle X est choisi entre CH2 et O, à condition que lorsque R1 et R3 représentent l'un et l'autre simultanément hydrogène, alors (a) R8 représente alkyle C¿1-5? ou halogène, et R?2¿ représente alcoxy C¿1-5?, ou (b) R?4¿ représente (II); ainsi que leurs sels pharmaceutiquement acceptables. Ces composés sont utiles chez les mammifères en tant qu'antagonistes des récepteurs de l'oxytocine, dans le traitement du travail avant terme, de la dysménorrhée et de l'arrêt du travail avant l'accouchement par césarienne.
PCT/US1996/000850 1995-01-24 1996-01-19 Antagonistes tocolytiques des recepteurs de l'oxytocine WO1996022775A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2310660A (en) * 1996-03-01 1997-09-03 Merck & Co Inc Benzoxazinone oxytocin receptor antagonists
GB2326410A (en) * 1997-06-18 1998-12-23 Merck & Co Inc Tocolytic Oxytocin Receptor Antagonists
US6900200B2 (en) 2001-04-12 2005-05-31 Wyeth Tricyclic hydroxy carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US6977254B2 (en) 2001-04-12 2005-12-20 Wyeth Hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US7022699B2 (en) 2001-04-12 2006-04-04 Wyeth Cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators
US7064120B2 (en) 2001-04-12 2006-06-20 Wyeth Tricyclic pyridyl carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US7109193B2 (en) 2001-04-12 2006-09-19 Wyeth Tricyclic diazepines tocolytic oxytocin receptor antagonists
US7115639B2 (en) 2001-06-18 2006-10-03 Applied Research Systems Ars Holding N.V. Pyrrolidine oxadiazole- and thiadiazole oxime derivatives being oxytocin receptor antagonists
US7189754B2 (en) 2001-03-20 2007-03-13 Applied Research Systems Ars Holding Nv Pyrrolidine ester derivatives with oxytocin modulating activity
US7202239B2 (en) 2001-04-12 2007-04-10 Wyeth Cyclohexylphenyl carboxamides tocolytic oxytocin receptor antagonists
US7211601B2 (en) 2000-03-27 2007-05-01 Applied Research Systems Ars Holding N.V. Pharmaceutically active pyrrolidine derivatives
US7312358B2 (en) 2000-10-17 2007-12-25 Laboratoires Serono Sa Pharmaceutically active sulfanilide derivatives
US7326700B2 (en) 2001-04-12 2008-02-05 Wyeth Cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US7468385B2 (en) 2001-12-20 2008-12-23 Laboratoires Serono Sa Triazoles as oxytocin antagonists

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WO1995002405A1 (fr) * 1993-07-16 1995-01-26 Merck & Co., Inc. Benzoxasinone et benzopyrimidinone piperidinyle utiles comme antagonistes tocolytiques du recepteur de l'oxytocine

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TW199153B (fr) * 1990-08-07 1993-02-01 Dtsuka Seiyaku Kk
CA2116334A1 (fr) * 1992-07-02 1994-01-20 Hidenori Ogawa Antagoniste de l'oxytocine
AU1698997A (en) * 1996-01-16 1997-08-11 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists

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WO1995002405A1 (fr) * 1993-07-16 1995-01-26 Merck & Co., Inc. Benzoxasinone et benzopyrimidinone piperidinyle utiles comme antagonistes tocolytiques du recepteur de l'oxytocine

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2310660A (en) * 1996-03-01 1997-09-03 Merck & Co Inc Benzoxazinone oxytocin receptor antagonists
GB2326410A (en) * 1997-06-18 1998-12-23 Merck & Co Inc Tocolytic Oxytocin Receptor Antagonists
US7211601B2 (en) 2000-03-27 2007-05-01 Applied Research Systems Ars Holding N.V. Pharmaceutically active pyrrolidine derivatives
US7312358B2 (en) 2000-10-17 2007-12-25 Laboratoires Serono Sa Pharmaceutically active sulfanilide derivatives
US7189754B2 (en) 2001-03-20 2007-03-13 Applied Research Systems Ars Holding Nv Pyrrolidine ester derivatives with oxytocin modulating activity
US7109193B2 (en) 2001-04-12 2006-09-19 Wyeth Tricyclic diazepines tocolytic oxytocin receptor antagonists
US7064120B2 (en) 2001-04-12 2006-06-20 Wyeth Tricyclic pyridyl carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US7022699B2 (en) 2001-04-12 2006-04-04 Wyeth Cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators
US7202239B2 (en) 2001-04-12 2007-04-10 Wyeth Cyclohexylphenyl carboxamides tocolytic oxytocin receptor antagonists
US6977254B2 (en) 2001-04-12 2005-12-20 Wyeth Hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US6900200B2 (en) 2001-04-12 2005-05-31 Wyeth Tricyclic hydroxy carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US7326700B2 (en) 2001-04-12 2008-02-05 Wyeth Cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US7115639B2 (en) 2001-06-18 2006-10-03 Applied Research Systems Ars Holding N.V. Pyrrolidine oxadiazole- and thiadiazole oxime derivatives being oxytocin receptor antagonists
US7468385B2 (en) 2001-12-20 2008-12-23 Laboratoires Serono Sa Triazoles as oxytocin antagonists

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CA2210138A1 (fr) 1996-08-01
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AU4763896A (en) 1996-08-14

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