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WO1995019773A1 - Carbostyrile utilise comme antagoniste des recepteurs a l'oxytocine - Google Patents

Carbostyrile utilise comme antagoniste des recepteurs a l'oxytocine 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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WO
WIPO (PCT)
Prior art keywords
substituted
optionally
lower alkyl
phenyl
alkoxy
Prior art date
Application number
PCT/US1994/000847
Other languages
English (en)
Inventor
Roger M. Freidinger
Joseph M. Pawluczyk
Douglas J. Pettibone
Peter D. Williams
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/fr
Publication of WO1995019773A1 publication Critical patent/WO1995019773A1/fr

Links

Classifications

    • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne la prévention d'accouchements précoces, l'arrêt de l'accouchement en vue d'une césarienne et le traitement de la dysménorrhée, par l'utilisation d'agents qui sont des antagonistes des récepteurs à l'oxytocine. La présente invention concerne une nouvelle utilisation de composés pipéridinyle carbostyrile, qui étaient connus auparavant comme étant d'utiles antagonistes des récepteurs à la vasopressine. Les activités pharmacologiques susmentionnées sont utiles en thérapie chez les mammifères.
PCT/US1994/000847 1992-10-07 1994-01-19 Carbostyrile utilise comme antagoniste des recepteurs a l'oxytocine WO1995019773A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US07/957,491 US5356904A (en) 1992-10-07 1992-10-07 Carbostyril oxytocin receptor antagonists
PCT/US1994/000847 WO1995019773A1 (fr) 1992-10-07 1994-01-19 Carbostyrile utilise comme antagoniste des recepteurs a l'oxytocine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/957,491 US5356904A (en) 1992-10-07 1992-10-07 Carbostyril oxytocin receptor antagonists
PCT/US1994/000847 WO1995019773A1 (fr) 1992-10-07 1994-01-19 Carbostyrile utilise comme antagoniste des recepteurs a l'oxytocine

Publications (1)

Publication Number Publication Date
WO1995019773A1 true WO1995019773A1 (fr) 1995-07-27

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Cited By (6)

* 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 (ja) * 2001-04-18 2009-12-03 Euro-Celtique Sa ノシセプチン類似体
US7662972B2 (en) 2004-03-05 2010-02-16 Nissan Chemical Industries, Ltd. 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 118, No. 21, issued 16 July 1993, HAYASHI et al., "5-HT Receptor Antagonists, 2. 4-Hydroxy-4-Quinolinecarboxylic Acid Derivatives", Abstract No. 212852j; & J. MED. CHEM., 35(5), 1993, 617-26. *

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 (ja) * 2001-04-18 2009-12-03 Euro-Celtique Sa ノシセプチン類似体
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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