WO1995019773A1 - Carbostyril oxytocin receptor antagonists - Google Patents

Carbostyril oxytocin receptor antagonists Download PDF

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Publication number
WO1995019773A1
WO1995019773A1 PCT/US1994/000847 US9400847W WO9519773A1 WO 1995019773 A1 WO1995019773 A1 WO 1995019773A1 US 9400847 W US9400847 W US 9400847W WO 9519773 A1 WO9519773 A1 WO 9519773A1
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Prior art keywords
substituted
optionally
lower alkyl
phenyl
alkoxy
Prior art date
Application number
PCT/US1994/000847
Other languages
French (fr)
Inventor
Roger M. Freidinger
Joseph M. Pawluczyk
Douglas J. Pettibone
Peter D. Williams
Original Assignee
Merck & Co., Inc.
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Publication date
Priority to US07/957,491 priority Critical patent/US5356904A/en
Priority claimed from US07/957,491 external-priority patent/US5356904A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to PCT/US1994/000847 priority patent/WO1995019773A1/en
Publication of WO1995019773A1 publication Critical patent/WO1995019773A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • This invention relates to treatment of preterm labor, stopping labor preparatory to Cesarean delivery and to the treatment of
  • dysmenorrhea through the use of agents that are oxytocin receptor antagonists.
  • the present invention provides a novel use of piperidinyl carbostyril compounds previously known to be useful as vasopressin receptor antagonists.
  • the aforementioned pharmacologic activities are useful in the treatment of mammals.
  • Tocolytic (uterine-relaxing) agents that are currently in use include ⁇ 2-adrenergic agonists, magnesium sulfate and calcium
  • 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) and pulmonary edema.
  • 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 neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
  • Calcium antagonists have been used to inhibit uterine activity of preterm labor but also produce unwanted
  • the compounds used in 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.
  • a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea then current regimens.
  • Additional uses for the present invention are for the stoppage of labor preparatory to Cesarean delivery and to control uterine activity during fetal surgery.
  • compounds of formula I are antagonists of oxytocin and bind to the oxytocin receptor.
  • oxytocin receptor When the oxytocin receptor is bound by the compounds used in 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 utility for the stoppage of labor preparatory to Cesarean delivery.
  • the invention is a method of antagonizing binding of oxytocin to mammalian oxytocin receptors, comprising the step of administering to a mammal in need thereof, in an amount effective to antagonize said binding, an antagonist compound of the formula:
  • R! is hydrogen; nitro; lower alkoxy; lower alkoxycarbonyl; lower alkyl; halogen; amino having one to two substituents selected from the group consisting of lower alkanoyl, lower alkyl, benozyl and phenyl lower alkoxycarbonyl; hydroxy; cyano; carboxy; lower alkanoyloxy; or hydrazinocarbonyl;
  • q is an integer of 1 to 3 and
  • R is a group of the formula
  • R 2 is hydrogen; lower alkoxycarbonyl; phenoxycarbonyl which phenyl ring may be substituted by one to three substituents selected from nitro and an amino having optionally one or two substituents selected from a lower alkanoyl, lower alkyl or benzoyl; phenyl lower alkenylcarbonyl; phenyl lower alkanoyl substituted by amino which in turn is substituted by lower alkoxycarbonyl; alkanoyl; alkenylcarbonyl; phenylsulfonyl substituted by lower alkoxy; a group of the formula
  • R 8 and R 9 are the same or different and are each hydrogen or phenyl substituted by lower alkoxy, lower alkyl, halogen, amino substituted by lower alkyl, lower alkanoyl or nitro; carbonyl substituted by a heterocyclic ring substituted by one to three substituents selected from phenyl lower alkoxycarbonyl, phenyl lower alkoxy, oxo, lower alkyl or lower alkylenedioxy; a group of the formula naphthylcarbonyl; thienyl lower alkanoyl;
  • alkanoyloxy tri-lower alkylammonium, lower alkoxy, or a group of the formula
  • R 32 and R 33 are the same or different and are each hydrogen, lower alkyl, hydroxy-substituted lower alkyl, lower alkanoyl,
  • A is alkylene, k is an integer of 0 or 1 , E is -CO- or -OCO-, R 4 and R 5 are the same or different and are each hydrogen; lower alkyl which may optionally be substituted by hydroxy or cyano; lower alkenyl, lower alkynyl; phenyl lower alkyl; lower alkanoyl which may optionally have one to three substituents of a halogen atom; benzoyl which phenyl ring may optionally be substituted by a member selected from nitro and an amino having optionally one or two substituents selected from lower alkyl, lower alkanoyl or phenyl lower alkoxycarbonyl; phenyl; lower alkoxycarbonyl; lower alkoxycarbonyl lower alkyl wherein the lower alkyl moiety may optionally be substituted by hydroxy or an amino having optionally a phenyl lower alkoxycarbonyl substituent; an amido having optionally a lower alkyl substituent
  • heterocyclic group which may be intervened or not with nitrogen, oxygen, or sulfur, wherein the heterocyclic group may optionally be substituted by a member selected from a phenyl having optionally a substituent selected from a lower alkoxy and a halogen atom, oxo, hydroxy, lower alkenyl, carboxy, phenyl lower alkyl having an optional hydroxy substituent on the lower alkyl moiety, lower alkanoyl lower alkyl having optionally a hydroxy substituent, benzoyl, an amido having optionally a lower alkyl substituent, anilinocarbonyl, benzoyl lower alkyl lower alkylsulfonyl, piperidinyl, pyrimidyl, pyridyl, and lower
  • alkoxycarbonyl carbamoyloxy-substituted lower alkoxy; lower alkylthio-substituted lower alkoxy; alkenyloxy; phenoxy; lower alkanoyloxy; lower alkylsulfonyloxy; lower alkynyl; phenyl lower alkoxy; cycloalkyl;
  • R 6 and R 7 are the same or different and are each hydrogen, lower alkyl, lower alkanoyl having optionally one to three halogen substituents, carboxy lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl lower alkyl, lower alkenyl, amido-substituted lower alkyl having an optional lower alkyl substituent, or a phenyl lower alkoxycarbonyl, or R 6 and R 7 may bind together with a nitrogen atom to which they bond to form a 5 or 6 membered, saturated or unsaturated heterocyclic group which may be intervened or not with nitrogen, oxygen or sulfur, wherein the
  • heterocyclic group may optionally have a substituent selected from a lower alkoxycarbonyl, lower alkyl, lower alkylthio, or oxo; nitro;
  • halogen lower alkylsulfonyl; lower alkyl which may optionally have one to three substituents selected from a halogen, hydroxy, phenyl and lower alkoxy; cyano-substituted lower alkoxy, pyrrolyl-substituted lower alkoxy; cyano; lower alkoxycarbonyl; amidino; carbamoyl; carboxy; lower alkanoyl; benzoyl; lower alkoxycarbonyl lower alkyl; carboxy lower alkyl; lower alkoxy lower alkyl; lower alkanoyloxy lower alkyl; hydroxyimino; substituted lower alkyl; phenyl; lower alkylthio; lower alkylsulf ⁇ nyl; lower alkenyl optionally having a hydroxy substituent; lower alkylenedioxy, lower alkylsilyl; pyrimidylthio-substituted lower alkoxy; pyrimidylsulfin
  • pyridylsulfonyl-substituted lower alkoxy which pyridyl ring may optionally be substituted by oxo; n is an integer of 1 or 2; m is 0 or an integer of 1 to 3; R 3 is a lower alkyl; R 10 is a group of the formula (
  • R 1 1 and R 12 are the same or different and are each hydrogen, lower alkyl, phenyl lower alkyl, lower alkenyl, benzoyl which may optionally have a lower alkoxy substituent,
  • R 1 1 and R 12 may bind together with the nitrogen atom to which they bond to form a saturated or unsaturated heterocyclic group which may be intervened or not with nitrogen, oxygen or sulfur, wherein the heterocylic group may optionally have a substituent selected from a benzoyl, a lower alkanoyl, phenyl lower alkyl and a phenyl which may optionally be substituted by a lower alkoxy and a lower alkonoyl; the bond between 3 and 4 positions of the carbostyril ring is a single bond or double bond; provided that when R 1 is hydrogen and the k in the formula
  • R 1 1 and R 12 are not simultaneously hydrogen atoms.
  • X is oxygen or sulfur
  • Y is hydrogen or lower alkyl
  • R A is a group of the formula
  • n 1 or 2
  • A is a lower alkylene
  • R 1 is a benzoyl which phenyl may optionally have one to three substituents selected from a lower alkoxy and an amino having optionally a lower alkyl substituent; or R A is a group of the formula
  • R 2A is a group of the formula wherein R 3A is a lower alkoxy; or a 5 or 6 membered heterocyclic ring having 1 to 2 hetero atoms selected from nitrogen, oxygen, or sulfur which may optionally have a substituent selected from lower alkyl, oxo, phenyl optionally having a substituent selected form halogen and a lower alkoxy on the phenyl ring and a phenylthio optionally having a
  • B is a lower alkylene having optionally a hydroxy substituent
  • R 4 is hydrogen and R 5 is tricyclo[3.3.1.1]decanyl, tricyclo[3.3.1.1]-decanyl-lower alkyl, halogen-substituted lower alkyl, lower alkoxy-carbonyl-glower alkanoyloxy-lower alkyl, lower alkanyl, or lower alkenyl, or R 4 and R 5 may bind together with the nitrogen atom to which then bond to form a group of the formula or
  • R 6 is an amino which may optionally be substituted by a lower alkanoyl having optionally one to three halogen substituents; or lower alkoxy having two substituents selected from an aminocarbonyloxy having optionally a lower alkyl substituent or a group of the formula wherein R 7 and R 8 are the same of different and are each hydrogen or lower alkyl;
  • n is an integer of 1 to 3;
  • the bond between the 3 and 4 positions of the carbostyril ring is a single bond or a double bond; provided that when all of R 3A are lower alkoxy or when R 5 is a lower alkanoyl, X is sulfur and that when R 5 is lower alkenyl and X is oxygen, B is a lower alkylene having a hydroxy subsitituent, and further that when R 3A is a heterocyclic group having a lower alkyl or oxo substituent, the heterocyclic group is bound to the phenyl ring at the position other than the hetero atom, or a
  • Salts encompass non-toxic salts of the compounds used in 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.
  • 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 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.
  • 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 conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers 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.
  • 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, corn 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, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, 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.
  • 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.
  • AVP vasopressin
  • Radioligand binding assays for additional subgenera of compounds were additionally performed for each of the following three groups.

Abstract

The invention relates to treatment of preterm labor, stopping labor preparatory to Cesarean delivery and to the treatment of dysmenorrhea through the use of agents that are oxytocin receptor antagonists. The present invention provides a novel use of piperidinyl carbostyril compounds previously known to be useful as vasopressin receptor antagonists. The aforementioned pharmacologic activities are useful in the treatment of mammals.

Description

TITLE OF THE INVENTION
CARBOSTYRIL OXYTOCIN RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
This invention relates to treatment of preterm labor, stopping labor preparatory to Cesarean delivery and to the treatment of
dysmenorrhea through the use of agents that are oxytocin receptor antagonists. The present invention provides a novel use of piperidinyl carbostyril compounds previously known to be useful as vasopressin receptor antagonists. The aforementioned pharmacologic activities are useful in the treatment of mammals.
BACKGROUND OF THE INVENTION
In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a leading cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents that are currently in use include β2-adrenergic agonists, magnesium sulfate and calcium
antagonists. Ritodrine, the leading β2-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) and pulmonary edema. Other β2-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. Calcium antagonists have been used to inhibit uterine activity of preterm labor but also produce unwanted
cardiovascular side effects. It has been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has accumulated to strongly suggest that the hormone oxytocin is the 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. By these mechanisms, the process of labor (term and preterm) is initiated by a heightened sensitivity of the uterus to oxytocin, resulting in part from 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. 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. In addition, since 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 used in 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. Additional uses for the present invention are for the stoppage of labor preparatory to Cesarean delivery and to control uterine activity during fetal surgery.
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 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.
It has now been found that compounds of formula I, below, are antagonists of oxytocin and bind to the oxytocin receptor. When the oxytocin receptor is bound by the compounds used in 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 utility for the stoppage of labor preparatory to Cesarean delivery.
SUMMARY OF THE INVENTION
The invention is a method of antagonizing binding of oxytocin to mammalian oxytocin receptors, comprising the step of administering to a mammal in need thereof, in an amount effective to antagonize said binding, an antagonist compound of the formula:
Figure imgf000005_0001
wherein
R! is hydrogen; nitro; lower alkoxy; lower alkoxycarbonyl; lower alkyl; halogen; amino having one to two substituents selected from the group consisting of lower alkanoyl, lower alkyl, benozyl and phenyl lower alkoxycarbonyl; hydroxy; cyano; carboxy; lower alkanoyloxy; or hydrazinocarbonyl;
q is an integer of 1 to 3 and
R is a group of the formula
or
Figure imgf000006_0002
Figure imgf000006_0001
wherein
R2 is hydrogen; lower alkoxycarbonyl; phenoxycarbonyl which phenyl ring may be substituted by one to three substituents selected from nitro and an amino having optionally one or two substituents selected from a lower alkanoyl, lower alkyl or benzoyl; phenyl lower alkenylcarbonyl; phenyl lower alkanoyl substituted by amino which in turn is substituted by lower alkoxycarbonyl; alkanoyl; alkenylcarbonyl; phenylsulfonyl substituted by lower alkoxy; a group of the formula
Figure imgf000006_0003
wherein
R8 and R9 are the same or different and are each hydrogen or phenyl substituted by lower alkoxy, lower alkyl, halogen, amino substituted by lower alkyl, lower alkanoyl or nitro; carbonyl substituted by a heterocyclic ring substituted by one to three substituents selected from phenyl lower alkoxycarbonyl, phenyl lower alkoxy, oxo, lower alkyl or lower alkylenedioxy; a group of the formula
Figure imgf000007_0001
naphthylcarbonyl; thienyl lower alkanoyl;
tricyclo [3.3.1.1]decanyl(lower)alkanoyl;
tricyclo[3.3.1.1.]-decanylcarbonyl; or a group of the formula
Figure imgf000007_0002
wherein p is 0 or an integer of 1 to 3, and R13 is hydroxy; alkoxy; alkoxy having one or two substituents selected from hydroxy, lower
alkanoyloxy, tri-lower alkylammonium, lower alkoxy, or a group of the formula
Figure imgf000007_0003
wherein R32 and R33 are the same or different and are each hydrogen, lower alkyl, hydroxy-substituted lower alkyl, lower alkanoyl,
tetrahydropyranyl lower alkyl, phenyl, phenyl lower alkyl wherein the alkyl moiety may optionally be substituted by hydroxy and the phenyl ring may optionally be substituted by a lower alkoxy, or a pyridyl lower alkyl; or R32 and R33 may be bound to nitrogen to form a 5 or 6 membered saturated heterocyclic ring which may be intervened with nitrogen, oxygen or sulfur wherein the heterocyclic group may optionally be substituted by a member selected from carbamoyl, lower alkyl, phenyl lower alkyl, phenyl or hydroxy-substituted lower alkyl; carboxy-substituted alkoxy; halogen-substituted lower alkoxy; lower
alkoxycarbonyl-substituted alkoxy; lower alkanoyloxy-substituted lower alkoxy; lower alkenyloxy substituted lower alkoxy; lower alkoxy lower alkoxy; lower alkylsulfonyloxy-substituted lower alkoxy; benzoyloxy-substituted lower alkoxy; tricyclo[3.3.1.1]decanyl-substituted lower alkoxy; lower alkoxy lower alkoxy substituted by one or two substituents selected from hydroxy and an amino being optionally substituted by lower alkyl; morpholinyl-substituted lower alkoxy; benzimidazolylsulfinyl-substituted lower alkoxy; a group of the formula
Figure imgf000008_0001
wherein A is alkylene, k is an integer of 0 or 1 , E is -CO- or -OCO-, R4 and R5 are the same or different and are each hydrogen; lower alkyl which may optionally be substituted by hydroxy or cyano; lower alkenyl, lower alkynyl; phenyl lower alkyl; lower alkanoyl which may optionally have one to three substituents of a halogen atom; benzoyl which phenyl ring may optionally be substituted by a member selected from nitro and an amino having optionally one or two substituents selected from lower alkyl, lower alkanoyl or phenyl lower alkoxycarbonyl; phenyl; lower alkoxycarbonyl; lower alkoxycarbonyl lower alkyl wherein the lower alkyl moiety may optionally be substituted by hydroxy or an amino having optionally a phenyl lower alkoxycarbonyl substituent; an amido having optionally a lower alkyl substituent; a pyrrolidinyl-substituted carbonyl which pyrrodinyl ring may optionally be substituted by phenyl lower alkoxycarbonyl; amino-substituted lower alkanoyl wherein the lower alkanoyl moiety may optionally be substituted by a member selected from phenyl lower alkoxycarbonyl amino, hydroxy, phenyl optionally having a hydroxy substituent, carbamoyl, imidazolyl or a lower alkylthio, and the amino group may optionally have a substituent selected from a lower alkyl optionally having a hydroxy substituent, lower alkenyl, phenyl lower alkyl optionally having a lower alkoxy substituent on the phenyl ring, lower alkylsulfonyl, lower alkanoyl, lower alkylsulfonyl, a phenylsulfonyl which phenyl ring may optionally be substituted by a lower alkyl group, nitro or amino having optionally one or two substituents selected from a lower alkyl and a lower alkanoyl; amido-substituted lower alkyl wherein the lower alkyl moiety optionally has a substituent selected from phenyl optionally having a hydroxy substituent, imidazolyl, carbamoyl or a lower alkylthio, and the amido group may optionally have a lower alkyl substituent; amino-substituted lower alkyl which may optionally be substituted by a lower alkyl or a lower alkanoyl; anilinocarbonyl; piperidinyl which may optionally be substituted by phenyl lower alkyl; cycloalkyl, cycloalkenylcarbonyl; cycloalkylcarbonyl which may optionally have one to three substituents selected from hydroxy and a lower alkanoyloxy; tetrahydropyranyl-substituted lower alkyl wherein the tetrahydropyranyl ring may optionally have one to four substituents selected from hydroxy and a lower alkoxy; lower alkanoyl which is substituted by a 5 or 6 membered saturated heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl wherein the heterocyclic group may have optionally a substituent selected from a lower alkyl and phenyl; piperidinyl- substituted carbonyl which may optionally be substituted by a lower alkanoyl; lower alkanoyloxy lower alkyl; pyridyl-substituted lower alkyl; or an amino acid residue which can form an amido group with its amino group or R4 and R5 may bind together with the nitrogen atom to which they bond to form a 5 or 6 membered saturated or unsaturated
heterocyclic group which may be intervened or not with nitrogen, oxygen, or sulfur, wherein the heterocyclic group may optionally be substituted by a member selected from a phenyl having optionally a substituent selected from a lower alkoxy and a halogen atom, oxo, hydroxy, lower alkenyl, carboxy, phenyl lower alkyl having an optional hydroxy substituent on the lower alkyl moiety, lower alkanoyl lower alkyl having optionally a hydroxy substituent, benzoyl, an amido having optionally a lower alkyl substituent, anilinocarbonyl, benzoyl lower alkyl lower alkylsulfonyl, piperidinyl, pyrimidyl, pyridyl, and lower
alkoxycarbonyl; carbamoyloxy-substituted lower alkoxy; lower alkylthio-substituted lower alkoxy; alkenyloxy; phenoxy; lower alkanoyloxy; lower alkylsulfonyloxy; lower alkynyl; phenyl lower alkoxy; cycloalkyl;
cycloalkyloxy; cycloalkenyloxy; imidazo [4, 5-c]pyridyl-carbonyl lower alkoxy; a group of the formula
Figure imgf000010_0001
wherein k is as defined above, B is a lower alkylene or a group -CO- and R6 and R7 are the same or different and are each hydrogen, lower alkyl, lower alkanoyl having optionally one to three halogen substituents, carboxy lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl lower alkyl, lower alkenyl, amido-substituted lower alkyl having an optional lower alkyl substituent, or a phenyl lower alkoxycarbonyl, or R6 and R7 may bind together with a nitrogen atom to which they bond to form a 5 or 6 membered, saturated or unsaturated heterocyclic group which may be intervened or not with nitrogen, oxygen or sulfur, wherein the
heterocyclic group may optionally have a substituent selected from a lower alkoxycarbonyl, lower alkyl, lower alkylthio, or oxo; nitro;
halogen; lower alkylsulfonyl; lower alkyl which may optionally have one to three substituents selected from a halogen, hydroxy, phenyl and lower alkoxy; cyano-substituted lower alkoxy, pyrrolyl-substituted lower alkoxy; cyano; lower alkoxycarbonyl; amidino; carbamoyl; carboxy; lower alkanoyl; benzoyl; lower alkoxycarbonyl lower alkyl; carboxy lower alkyl; lower alkoxy lower alkyl; lower alkanoyloxy lower alkyl; hydroxyimino; substituted lower alkyl; phenyl; lower alkylthio; lower alkylsulfϊnyl; lower alkenyl optionally having a hydroxy substituent; lower alkylenedioxy, lower alkylsilyl; pyrimidylthio-substituted lower alkoxy; pyrimidylsulfinyl-substituted lower alkoxy; pyrimidylsulfonyl-substituted lower alkoxy; imidazolylthio-substituted lower alkoxy which may optionally have a lower alkyl substituent; imidazolylsulfonyl- subsituted lower alkoxy which may optionally have a lower alkyl substituent; ammonium-lower alkoxy having three substituents selected from lower alkoxy, lower alkenyl and oxo; phenylthio-substituted lower alkoxy which phenyl ring may optionally have a substituent selected from nitro and amino; phenylsulfonyl-substituted lower alkoxy which phenyl ring may optionally have a substituent selected from nitro and an amino having optionally one or two substituents selected from a lower alkanoyl and lower alkyl; pyridylthio-substituted lower alkoxy; or a
pyridylsulfonyl-substituted lower alkoxy which pyridyl ring may optionally be substituted by oxo; n is an integer of 1 or 2; m is 0 or an integer of 1 to 3; R3 is a lower alkyl; R10 is a group of the formula (
Figure imgf000011_0001
wherein k is as defined above and R1 1 and R12 are the same or different and are each hydrogen, lower alkyl, phenyl lower alkyl, lower alkenyl, benzoyl which may optionally have a lower alkoxy substituent,
tricyclo[3.3.1.1]decanyl, a phenyl which may optionally have a lower alkoxy substituent or a cycloalkyl, or R1 1 and R12 may bind together with the nitrogen atom to which they bond to form a saturated or unsaturated heterocyclic group which may be intervened or not with nitrogen, oxygen or sulfur, wherein the heterocylic group may optionally have a substituent selected from a benzoyl, a lower alkanoyl, phenyl lower alkyl and a phenyl which may optionally be substituted by a lower alkoxy and a lower alkonoyl; the bond between 3 and 4 positions of the carbostyril ring is a single bond or double bond; provided that when R1 is hydrogen and the k in the formula
Figure imgf000011_0002
is 0, R1 1 and R12 are not simultaneously hydrogen atoms.
The method of the invention can also be practiced with compounds of formula II
Figure imgf000012_0001
wherein X is oxygen or sulfur;
Y is hydrogen or lower alkyl;
R A is a group of the formula
Figure imgf000012_0002
wherein n is 1 or 2, A is a lower alkylene, and R1 is a benzoyl which phenyl may optionally have one to three substituents selected from a lower alkoxy and an amino having optionally a lower alkyl substituent; or R A is a group of the formula
Figure imgf000012_0003
wherein n is as defined above, and R2A is a group of the formula
Figure imgf000013_0001
wherein R3A is a lower alkoxy; or a 5 or 6 membered heterocyclic ring having 1 to 2 hetero atoms selected from nitrogen, oxygen, or sulfur which may optionally have a substituent selected from lower alkyl, oxo, phenyl optionally having a substituent selected form halogen and a lower alkoxy on the phenyl ring and a phenylthio optionally having a
substituent selected from nitro and amino; lower alkynylthio;
pyrrolidinyl-substituted lower alkylthio; pyrrolidinyl-substituted lower alkylsulfinyl; pyrrolidinyl-substituted lower alkylsulfonyl; a group of the formula
Figure imgf000013_0002
wherein B is a lower alkylene having optionally a hydroxy substituent, R4 is hydrogen and R5 is tricyclo[3.3.1.1]decanyl, tricyclo[3.3.1.1]-decanyl-lower alkyl, halogen-substituted lower alkyl, lower alkoxy-carbonyl-glower alkanoyloxy-lower alkyl, lower alkanyl, or lower alkenyl, or R4 and R5 may bind together with the nitrogen atom to which then bond to form a group of the formula
Figure imgf000013_0003
or
Figure imgf000013_0004
wherein R6 is an amino which may optionally be substituted by a lower alkanoyl having optionally one to three halogen substituents; or lower alkoxy having two substituents selected from an aminocarbonyloxy having optionally a lower alkyl substituent or a group of the formula
Figure imgf000014_0001
wherein R7 and R8 are the same of different and are each hydrogen or lower alkyl;
m is an integer of 1 to 3;
the bond between the 3 and 4 positions of the carbostyril ring is a single bond or a double bond; provided that when all of R3A are lower alkoxy or when R5 is a lower alkanoyl, X is sulfur and that when R5 is lower alkenyl and X is oxygen, B is a lower alkylene having a hydroxy subsitituent, and further that when R3A is a heterocyclic group having a lower alkyl or oxo substituent, the heterocyclic group is bound to the phenyl ring at the position other than the hetero atom, or a
pharmaceutically acceptable salt thereof.
Most preferred compounds for use in the present method are those represented in the following table:
Figure imgf000015_0001
DETAILED DESCRIPTION OF THE INVENTION
Compounds of formula I are prepared as taught in European patent application EP 0 382 185, published August 16, 1990, the entire disclosure of which is incorporated herein by reference. Compounds of formula II are prepared as taught in European patent application
EPO 470 514 A1, published August 2, 1991, the entire disclosure of which is incorporated herein by reference.
Salts encompass non-toxic salts of the compounds used in this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
Acetate Lactobionate
Benzenesulfonate Laurate
Benzoate Malate
Bicarbonate Maleate
Bisulfate Mandelate
Bitartrate Mesylate
Borate Methylbromide
Bromide Methylnitrate
Calcium Edetate Methylsulfate
Camsylate Mucate
Carbonate Napsylate
Chloride Nitrate
Clavulanate N-methylglucamine
Citrate ammonium salt
Dihydrochloride Oleate
Edetate Oxalate
Edisylate Pamoate (Embonate)
Estolate Palmitate
Esylate Pantothenate
Fumarate Phosphate/diphosphate
Gluceptate Polygalacturonate
Gluconate Salicylate Glutamate Stearate
Glycollylarsanilate Sulfate
Hexylresorcinate Subacetate
Hydrabamine Succinate
Hydrobromide Tannate
Hydrochloride Tartrate
Hydroxynaphthoate Teoclate
Iodide Tosylate
Isothionate Triethiodide
Lactate Valerate
The term "pharmacologically 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.
The term "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 "Cesarean delivery" shall mean incision through the abdominal and uterine walls for delivery of a fetus.
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.
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.
Intravenously, the most preferred doses will range from 0.1 to about 10 mg/minute during a constant rate infusion. Advantageously, 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. Furthermore, 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. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
In the methods of the present invention, 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. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, 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, corn 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, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, 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. RADIOLIGAND BINDING ASSAYS
The high affinity binding of [3H] oxytocin (OT)([tyrosyl, 3,5-[3H]OT; 30-60 Ci/mmol; New England Nuclear, Boston, MA) to uterine OT receptors was based on an assay (Fuchs, A-R; Fuchs, F;
Soloff, MS. 1985, J. Clin. Endocrinol. Metab. 60:37) using a crude membrane preparation of uteri taken from diethylstilbestrol dipropionate (DES)-treated (0.3 mg/kg, ip; 18-24) rats. Competition studies were conducted at equilibrium (60 minutes; 22°C) using 1 nM[3H]OT in the following assay buffer: 50 mM Tris-HCl, 5 mM MgCl2, and 0.1% BSA, pH 7.4. Nonspecific binding (10% of the total binding) was determined using 1 μM unlabeled OT and the binding reaction was terminated by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, Inc., Sterling, VA).
The measurement of [3H]vasopressin (AVP) ([phenylalanyl-3,4,5-3H]AVP; 80-90 Ci/mmol; New England Nuclear) binding to a crude membrane preparation of male rat liver (AVP-V1 sites) or kidney medulla (AVP-V2 sites) was determined according to the method of Butlen, et al. (Butlen, D; Guillon, G; Rajerison, R.M.; Jard, S; Sawyer, W.H.; Manning, M. 1978 Mol Pharmacol 14:1006).
Competition assays were conducted at equilibrium (30 minutes at 30°C) using 1 nM [3H] AVP (liver) or 2 nM [3H]AVP
(kidney) in the following assay buffer: 100 mM Tris-HCl, 5 mM MgCl2, 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 μM unlabeled AVP, and the binding reaction was terminated by filtration as described above for the [3H]OT binding assay.
IC50 values were determined for both [3H]OT and
[3H] AVP binding assays by linear regression of the relation log
concentration of compound vs. percent inhibition of specific binding. Data are also shown as the degree (%) of inhibition of specific binding at a given concentration of compound. Example IC50 [3H] OT [3H]AVP-V1
(rat uterus) (rat liver)
1 570 140
2 1100 120
3 2500 320
4 1000 130
5 560 39
Radioligand binding assays for additional subgenera of compounds were additionally performed for each of the following three groups.
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for prevention of preterm labor, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly.

Claims

WHAT IS CLAIMED IS:
1. A method of antagonizing binding of oxytocin to mammalian oxytocin receptors, comprising the step of administering to a mammal in need thereof, in an amount effective to antagonize said binding, an antagonist compound of the formula:
Figure imgf000025_0001
wherein
R1 is hydrogen; nitro; lower alkoxy; lower alkoxycarbonyl; lower alkyl; halogen; amino having one to two substituents selected from the group consisting of lower alkanoyl, lower alkyl, benozyl and phenyl lower alkoxycarbonyl; hydroxy; cyano; carboxy; lower alkanoyloxy; or hydrazinocarbonyl;
q is an integer of 1 to 3 and
R is a group of the formula
Figure imgf000025_0002
wherein
R2 is hydrogen; lower alkoxycarbonyl; phenoxycarbonyl which phenyl ring may be substituted by one to three substituents selected from nitro and an amino having optionally one or two substituents selected from a lower alkanoyl, lower alkyl or benzoyl; phenyl lower alkenylcarbonyl; phenyl lower alkanoyl substituted by amino which in turn is substituted by lower alkoxycarbonyl; alkanoyl; alkenylcarbonyl; phenylsulfonyl substituted by lower alkoxy; a group of the formula χ
Figure imgf000026_0001
wherein
R8 and R9 are the same or different and are each hydrogen or phenyl substituted by lower alkoxy, lower alkyl, halogen, amino substituted by lower alkyl, lower alkanoyl or nitro; carbonyl substituted by a heterocyclic ring substituted by one to three substituents selected from phenyl lower alkoxycarbonyl, phenyl lower alkoxy, oxo, lower alkyl or lower alkylenedioxy; a group of the formula
Figure imgf000026_0002
naphthylcarbonyl; thienyl lower alkanoyl;
tricyclo[3.3.1.1]decanyl(lower)alkanoyl;
tricyclo[3.3.1.1.]-decanylcarbonyl; or a group of the formula
Figure imgf000026_0003
wherein p is 0 or an integer of 1 to 3, and R13 is hydroxy; alkoxy; alkoxy having one or two substituents selected from hydroxy, lower
alkanoyloxy, tri-lower alkylammonium, lower alkoxy, or a group of the formula
Figure imgf000027_0001
wherein R32 and R33 are the same or different and are each hydrogen, lower alkyl, hydroxy-substituted lower alkyl, lower alkanoyl,
tetrahydropyranyl lower alkyl, phenyl, phenyl lower alkyl wherein the alkyl moiety may optionally be substituted by hydroxy and the phenyl ring may optionally be substituted by a lower alkoxy, or a pyridyl lower alkyl; or R32 and R33 may be bound to nitrogen to form a 5 or 6 membered saturated heterocyclic ring which may be intervened with nitrogen, oxygen or sulfur wherein the heterocyclic group may optionally be substituted by a member selected from carbamoyl, lower alkyl, phenyl lower alkyl, phenyl or hydroxy-substituted lower alkyl; carboxy-substituted alkoxy; halogen-substituted lower alkoxy; lower
alkoxycarbonyl-substituted alkoxy; lower alkanoyloxy-substituted lower alkoxy; lower alkenyloxy substituted lower alkoxy; lower alkoxy lower alkoxy; lower alkylsulfonyloxy-substituted lower alkoxy; benzoyloxy - substituted lower alkoxy; tricyclo[3.3.1.1]decanyl-substituted lower alkoxy; lower alkoxy lower alkoxy substituted by one or two substituents selected from hydroxy and an amino being optionally substituted by lower alkyl; morpholinyl-substituted lower alkoxy; benzimidazolylsulfinyl-substituted lower alkoxy; a group of the formula
Figure imgf000027_0002
wherein A is alkylene, k is an integer of 0 or 1 , E is -CO- or -OCO-, R4 and R5 are the same or different and are each hydrogen; lower alkyl which may optionally be substituted by hydroxy or cyano; lower alkenyl, lower alkynyl; phenyl lower alkyl; lower alkanoyl which may optionally have one to three substituents of a halogen atom; benzoyl which phenyl ring may optionally be substituted by a member selected from nitro and an amino having optionally one or two substituents selected from lower alkyl, lower alkanoyl or phenyl lower alkoxycarbonyl; phenyl; lower alkoxycarbonyl; lower alkoxycarbonyl lower alkyl wherein the lower alkyl moiety may optionally be substituted by hydroxy or an amino having optionally a phenyl lower alkoxycarbonyl substituent; an amido having optionally a lower alkyl substituent; a pyrrolidinyl-substituted carbonyl which pyrrodinyl ring may optionally be substituted by phenyl lower alkoxycarbonyl; amino-substituted lower alkanoyl wherein the lower alkanoyl moiety may optionally be substituted by a member selected from phenyl lower alkoxycarbonyl amino, hydroxy, phenyl optionally having a hydroxy substituent, carbamoyl, imidazolyl or a lower alkylthio, and the amino group may optionally have a substituent selected from a lower alkyl optionally having a hydroxy substituent, lower alkenyl, phenyl lower alkyl optionally having a lower alkoxy substituent on the phenyl ring, lower alkylsulfonyl, lower alkanoyl, lower alkylsulfonyl, a phenylsulfonyl which phenyl ring may optionally be substituted by a lower alkyl group, nitro or amino having optionally one or two substituents selected from a lower alkyl and a lower alkanoyl; amido-substituted lower alkyl wherein the lower alkyl moiety optionally has a substituent selected from phenyl optionally having a hydroxy substituent, imidazolyl, carbamoyl or a lower alkylthio, and the amido group may optionally have a lower alkyl substituent; amino-substituted lower alkyl which may optionally be substituted by a lower alkyl or a lower alkanoyl; anilinocarbonyl; piperidinyl which may optionally be substituted by phenyl lower alkyl; cycloalkyl, cycloalkenylcarbonyl; cycloalkylcarbonyl which may optionally have one to three substituents selected from hydroxy and a lower alkanoyloxy; tetrahydropyranyl-substituted lower alkyl wherein the tetrahydropyranyl ring may optionally have one to four substituents selected from hydroxy and a lower alkoxy; lower alkanoyl which is substituted by a 5 or 6 membered saturated heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl wherein the heterocyclic group may have optionally a substituent selected from a lower alkyl and phenyl; piperidinyl- substituted carbonyl which may optionally be substituted by a lower alkanoyl; lower alkanoyloxy lower alkyl; pyridyl-substituted lower alkyl; or an amino acid residue which can form an amido group with its amino group or R4 and R5 may bind together with the nitrogen atom to which they bond to form a 5 or 6 membered saturated or unsaturated
heterocyclic group which may be intervened or not with nitrogen, oxygen, or sulfur, wherein the heterocyclic group may optionally be substituted by a member selected from a phenyl having optionally a substituent selected from a lower alkoxy and a halogen atom, oxo, hydroxy, lower alkenyl, carboxy, phenyl lower alkyl having an optional hydroxy substituent on the lower alkyl moiety, lower alkanoyl lower alkyl having optionally a hydroxy substituent, benzoyl, an amido having optionally a lower alkyl substituent, anilinocarbonyl, benzoyl lower alkyl lower alkylsulfonyl, piperidinyl, pyrimidyl, pyridyl, and lower
alkoxycarbonyl; carbamoyloxy-substituted lower alkoxy; lower alkylthio-substituted lower alkoxy; alkinyloxy; phenoxy; lower alkanoyloxy; lower alkylsulfonyloxy; lower alkynyl; phenyl lower alkoxy; cycloalkyl;
cycloalkyloxy; cycloalkenyloxy; imidazo [4, 5-c]pyridyl-carbonyl lower alkoxy; a group of the formula
Figure imgf000029_0001
wherein k is as defined above, B is a lower alkylene or a group -CO- and R6 and R7 are the same or different and are each hydrogen, lower alkyl, lower alkanoyl having optionally one to three halogen substituents, carboxy lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl lower alkyl, lower alkenyl, amido-substituted lower alkyl having an optional lower alkyl substituent, or a phenyl lower alkoxycarbonyl, or R6 and R7 may bind together with a nitrogen atom to which they bond to form a 5 or 6 membered, saturated or unsaturated heterocyclic group which may be intervened or not with nitrogen, oxygen or sulfur, wherein the
heterocyclic group may optionally have a substituent selected from a lower alkoxycarbonyl, lower alkyl, lower alkylthio, or oxo; nitro;
halogen; lower alkylsulfonyl; lower alkyl which may optionally have one to three substituents selected from a halogen, hydroxy, phenyl and lower alkoxy; cyano-substituted lower alkoxy, pyrrolyl-substituted lower alkoxy; cyano; lower alkoxycarbonyl; amidino; carbamoyl; carboxy; lower alkanoyl; benzoyl; lower alkoxycarbonyl lower alkyl; carboxy lower alkyl; lower alkoxy lower alkyl; lower alkanoyloxy lower alkyl; hydroxyimino; substituted lower alkyl; phenyl; lower alkylthio; lower alkylsulfinyl; lower alkenyl optionally having a hydroxy substituent; lower alkylenedioxy, lower alkylsilyl; pyrimidylthio-substituted lower alkoxy; pyrimidylsulfinyl-substituted lower alkoxy; pyrimidylsulfonyl-substituted lower alkoxy; imidazolylthio-substituted lower alkoxy which may optionally have a lower alkyl substituent; imidazolylsulfonyl- subsituted lower alkoxy which may optionally have a lower alkyl substituent; ammonium-lower alkoxy having three substituents selected from lower alkoxy, lower alkenyl and oxo; phenylthio-substituted lower alkoxy which phenyl ring may optionally have a substituent selected from nitro and amino; phenylsulfonyl-substituted lower alkoxy which phenyl ring may optionally have a substituent selected from nitro and an amino having optionally one or two substituents selected from a lower alkanoyl and lower alkyl; pyridylthio-substituted lower alkoxy; or a
pyridylsulfonyl-substituted lower alkoxy which pyridyl ring may optionally be substituted by oxo; n is an integer of 1 or 2; m is 0 or an integer of 1 to 3; R3 is a lower alkyl; R10 is a group of the formula
Figure imgf000030_0001
wherein k is as defined above and R1 1 and R12 are the same or different and are each hydrogen, lower alkyl, phenyl lower alkyl, lower alkenyl, benzoyl which may optionally have a lower alkoxy substituent, tricyclo[3.3.1.1]decanyl, a phenyl which may optionally have a lower alkoxy substituent or a cycloalkyl, or R1 1 and R12 may bind together with the nitrogen atom to which they bond to form a saturated or unsaturated heterocyclic group which may be intervened or not with nitrogen, oxygen or sulfur, wherein the heterocylic group may optionally have a substituent selected from a benzoyl, a lower alkanoyl, phenyl lower alkyl and a phenyl which may optionally be substituted by a lower alkoxy and a lower alkonoyl; the bond between 3 and 4 positions of the carbostyril ring is a single bond or double bond; provided that when R1 is hydrogen and the k in the formula
Figure imgf000031_0001
is O, R1 1 and R12 are not simultaneously hydrogen atoms and including the pharmaceutically acceptable salts of the compounds of the formula I.
2. A method of antagonizing binding of oxytocin to mammalian oxytocin receptors, comprising the step of administering to a mammal in need thereof, in an amount effective to antagonize said binding, an antagonist compound of the formula:
Figure imgf000031_0002
wherein X is oxygen or sulfur; Y is hydrogen or lower alkyl;
RA is a group of the formula
Figure imgf000032_0001
wherein n is 1 or 2, A is a lower alkylene, and R1 is a benzoyl which phenyl may optionally have one to three substituents selected from a lower alkoxy and an amino having optionally a lower alkyl substituent; or RA is a group of the formula
Figure imgf000032_0002
wherein n is as defined above, and R2A is a group of the formula
Figure imgf000032_0003
wherein R3A is a lower alkoxy; or a 5 or 6 membered heterocyclic ring having 1 to 2 hetero atoms selected from nitrogen, oxygen, or sulfur which may optionally have a substituent selected from lower alkyl, oxo, phenyl optionally having a substituent selected form halogen and a lower alkoxy on the phenyl ring and a phenylthio optionally having a
substituent selected from nitro and amino; lower alkynylthio;
pyrrolidinyl-substituted lower alkylthio; pyrrolidinyl-substituted lower alkylsulfinyl; pyrrolidinyl-substituted lower alkylsulfonyl; a group of the formula
Figure imgf000033_0001
wherein B is a lower alkylene having optionally a hydroxy substituent, R is hydrogen and R5 is tricyclo[3.3.1.1]decanyl, tricyclo[3.3.1.1]decanyl-lower alkyl, halogen-substituted lower alkyl, lower alkoxycarbonyl-lower alkanoyloxy-lower alkyl, lower alkanyl, or lower alkenyl, or R4 and R5 may bind together with the nitrogen atom to which then bond to form a group of the formula or
Figure imgf000033_0002
Figure imgf000033_0003
wherein R6 is an amino which may optionally be substituted by a lower alkanoyl having optionally one to three halogen substituents; or lower alkoxy having two substituents selected from an aminocarbonyloxy having optionally a lower alkyl substituent or a group of the formula
Figure imgf000033_0004
wherein R7 and R8 are the same of different and are each hydrogen or lower alkyl;
m is an integer of 1 to 3;
the bond between the 3 and 4 positions of the carbostyril ring is a single bond or a double bond; provided that when all of R3A are lower alkoxy or when R5 is a lower alkanoyl, X is sulfur and that when R5 is lower alkenyl and X is oxygen, B is a lower alkylene having a hydroxy subsitituent, and further that when R3A is a heterocyclic group having a lower alkyl or oxo substituent, the heterocyclic group is bound to the phenyl ring at the position other then the hetero atom, or a
pharmaceutically acceptable salt thereof.
3. A method of antagonizing binding of oxytocin to mammalian oxytocin receptors, comprising the step of administering to a mammal in need thereof, in an amount effective to antagonize said binding, an antagonist compound of the formula:
Figure imgf000034_0001
wherein X is CO or SO2;
R is unsubstituted or substituted phenyl where said substituents are Rl or R2; naphthyl; indolyl; P-CH2-C6H4-OCH3; P-CH2C6H4-NH2; p-CH2-C6H4-NHAc; or camphor-10-yl;
R1 is halogen, nitro, cyano, lower alkoxycarbonyl, phenyl, hydroxy, O-(CH2)3N=Pth where Pth is phthaloyl, O-(CH2)3NHCOCH3 or lower alkoxy; and
R2 is hydrogen, hydroxy; or lower alkoxy which may be substituted wherein said substituent is carbonylamine which may be substituted by lower alkyl; or 5 membered heterocyclic rings having 1 nitrogen heteroatom and where said substituent is phenyl or oxo; and the pharmaceutically acceptable salts thereof.
4. A method of preventing preterm labor in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of a compound as claimed in Claim 1.
5. A method of stopping labor prior to Cesarean delivery in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of a compound as claimed in Claim 1.
6. A method of treating dysmenorrhea in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of a compound as claimed in Claim 1.
PCT/US1994/000847 1992-10-07 1994-01-19 Carbostyril oxytocin receptor antagonists WO1995019773A1 (en)

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GB2326410A (en) * 1997-06-18 1998-12-23 Merck & Co Inc Tocolytic Oxytocin Receptor Antagonists
JP2009280603A (en) * 2001-04-18 2009-12-03 Euro-Celtique Sa Nociceptin analog
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US8067415B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756497A (en) * 1996-03-01 1998-05-26 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists
GB2326410A (en) * 1997-06-18 1998-12-23 Merck & Co Inc Tocolytic Oxytocin Receptor Antagonists
JP2009280603A (en) * 2001-04-18 2009-12-03 Euro-Celtique Sa Nociceptin analog
US8946492B2 (en) 2004-03-05 2015-02-03 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US8022089B2 (en) 2004-03-05 2011-09-20 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US8138213B2 (en) 2004-03-05 2012-03-20 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US8492311B2 (en) 2004-03-05 2013-07-23 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US7662972B2 (en) 2004-03-05 2010-02-16 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US10045969B2 (en) 2004-03-05 2018-08-14 Nissan Chemical Industries, Inc. Isoxazoline-substituted benzamide compound and pesticide
US10596157B2 (en) 2004-03-05 2020-03-24 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US10874645B2 (en) 2004-03-05 2020-12-29 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US8067415B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2

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