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WO1998000406A1 - Procede de traitement du travail preterme - Google Patents

Procede de traitement du travail preterme Download PDF

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Publication number
WO1998000406A1
WO1998000406A1 PCT/US1997/011608 US9711608W WO9800406A1 WO 1998000406 A1 WO1998000406 A1 WO 1998000406A1 US 9711608 W US9711608 W US 9711608W WO 9800406 A1 WO9800406 A1 WO 9800406A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydro
benzodiazepin
methyl
alkyl
oxo
Prior art date
Application number
PCT/US1997/011608
Other languages
English (en)
Inventor
Joseph J. Salata
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 claimed from GBGB9701281.9A external-priority patent/GB9701281D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU35916/97A priority Critical patent/AU3591697A/en
Publication of WO1998000406A1 publication Critical patent/WO1998000406A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides for a method of treating or preventing preterm labor, stopping labor preparatory to vaginal and Cesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.
  • Tocolytic (uterine-relaxing) agents that are currently in use include B2-adrenergic agonists, magnesium sulfate and ethanol.
  • Ritodrine the leading ⁇ 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 neuro- muscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
  • Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
  • IsK or minK channel gene has been cloned from diethylstibestrol (DES) - primed uterine tissue and its expression in Xenopus oocytes results in a slowly activating potassium current that resembles the iKs current constituitively expressed in mammalian cardiac cells.
  • DES diethylstibestrol
  • IKs current or IsK channel highly selective activators or agonists of IKs current or IsK channel have been identified and characterized. These compounds which promote opening of the IsK channel allow effux of positively charged potassium ions (K + ) ions to flow out or exit cells through the cell membrane which produces a hyperpolarization of the transmembrane voltage gradient. This hyperpolarization will prevent or inhibit contraction of excitable smooth muscle cells of the uterus which occur as a direct consequence of membrane depolarization. The inhibition of smooth muscle contraction is beneficial in the treatment of preterm labor or premature uterine contraction.
  • K + positively charged potassium ions
  • the method 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 modulating the IKs current in the uterus, selective, more efficacious treatment of dysmenorrhea will result.
  • An additional use for the present invention is for the stoppage of labor preparatory to vaginal or Cesarean delivery.
  • compounds of the present invention are modulators of DCs current.
  • the IKs current is modulated by the compounds of the present invention, the IKs channel is activated and exerts its biologic or pharmacologic effects.
  • This method is useful in the treatment and prevention of certain gynecological and obstetrical disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. This method would also find usefulness for stoppage of labor preparatory to vaginal or Cesarean delivery.
  • 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 selective modulator of IKs current is presented. Further, a method of stopping labor prior to vaginal or cesarean delivery in a mammal and treatment of dysmenorrhea in a mammal in need thereof comprising administration of a pharmacologically effective amount of a modulator of IKs current is also presented.
  • 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 selective modulator of IKs current is presented. Further, a method of stopping labor prior to cesarean delivery in a mammal and treatment of dysmenorrhea in a mammal in need thereof comprising administration of a pharmacologically effective amount of a modulator of IKs current is also presented.
  • a “selective modulator of IKs” is meant those compounds which when studied in the test disclosed herein have an agonist effect on the IKs current to produce an increase in the efflux of potassium out of the cell and hence an increase in the outward IKs current at a given transmembrane or test voltage at concentrations 1 ⁇ M and should result in treatment which is safe and effective.
  • the invention includes racemic mixtures of these compounds, the separated R and S enantiomers, and preferably, the R enantiomer.
  • A is a 6-membered saturated or unsaturated carbocyclic ring either substituted or unsubstituted wherein the substituents may be 1 or 2 of halo, including floro, chloro, iodo and bormo, Cl-C6 alkyl, either straight, branched chain or cyclic, C1-C6 alkoxy, C1 -C alkylthio, carboxyl, carboxyl-Cl -C6-alkyl, nitro, -CF3, or hydroxy; or a 6- membered heterocyclic ring containing N, or N and O; Y is -NH 2 , NHS0 2 R 1 ,
  • n O or 1;
  • X is O or -CH 2 R
  • R is straight or branched Cj _£ alkyl or Cl-3 alkylamine wherein the amino group is optionally mono- or di-substituted C ] _3 alkyl; or chloro, dichloro, methoxy, or nitroso;
  • R 2 is R or -CONHS0 2 R
  • n O or 1 ;
  • X is O or -CH2R; or a pharmaceutically acceptable salt thereof.
  • the most preferred example of the compounds useful in the method of treatment of this invention is 1 ,3-dihydro-5-2(fluorophenyl) 3-R)-(3'-indol)methyl-l-methyl-2H-l ,4-benzodiazepin-2-one which has the chemical structure
  • the selective modulators of DCs of the present invention have the pharmacological properties required to prevent preterm labor, stop labor prior to vaginal or Cesarean delivery and treat dysmenorrhea in a mammal in need thereof, namely they modulate the IKs current in the uterus and in so doing reduce or eliminate spasms in the uterus which result in these conditions.
  • 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.
  • 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 selectively modulate IKs makes these compounds useful as pharma- cologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein IKs current 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 0.03 to about 1 mg per kg of body weight per day orally.
  • the most preferred doses will range from about 0.0001 to about 10 mg per kg of body weight per day, preferably from about .0001 to about 2 mg per kg of body weight per day, and more preferably by intravenous delivery of from about 0.0003 to about 0.3 mg per kg of body weight per day using constant rate infusion.
  • the dosage and rate of delivery will depend upon the response by the individual patient and the condition of the unborn child when used to prevent preterm labor or to stop or delay delivery.
  • 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 intermittent 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, xanthan 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, polyhydroxypropyl- methacrylamide-phenol, polyhydroxy- ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the 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.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
  • the activity of the compounds described herein is measured by their ability to modulate or gate the IKs current while providing only limited block of the IKs current as determined by the following test protocol.
  • Outward potassium currents are measured in single guinea pig ventricular myocytes using a whole-cell voltage clamp technique described in detail elsewhere (Sanguinetti and Jurkiewicz, 1990, Two components of cardiac delayed rectifier K + current: differential sensitivity to block by Class III antiarrhythmic agents. J. Gen Physiol. 96: 195-215).
  • Myocytes are isolated by enzymatic (collagenase and protease) digestion of Langandorf perfused hearts. Single cells are then voltage clamped using 1 mm square-bore pipettes filled with 0.5 M Kgluconate, 25 mM KC1, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl2, 10 HEPES, 10 glucose: pH 7.2, temp. 35°C.
  • Test depolarizations are applied as voltage steps (5 -7.5 s) to test potentials between -40 and +50 V.
  • IKs is measured as time-dependent current during the pulses and as tail current upon repolarization to -50 mV. Currents are measured during control, then after exposure to drug at two different concentrations.
  • Compounds that produce an increase in IKs current at any test potential are considered selective modulators of IKs.
  • Compounds that produce a decrease in IKs current at any test potential are considered selective blockers of IKs.
  • the compounds described herein as selective modulators of DCs increase IKs current at concentrations 1 ⁇ M.
  • the compounds of this invention are at least 10 times more potent in the modulation blockade of IKs than of blockade of IKs-
  • the NMR spectrum was consistent with the title structure and verified the presence of CH2Q2.
  • the second component eluted was the monomethyl compound B which was obtained as a foam (0.66 g) upon evaporation. Crystallization from hexane/CH2 ⁇ 2 gave analytical material; (m.p. 80°-85°C).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical 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)

Abstract

La présente invention concerne un procédé utile dans le traitement du travail préterme et de la dysménorrhée, et permettant d'interrompre le travail en préparation à un accouchement par césarienne.
PCT/US1997/011608 1996-07-02 1997-06-27 Procede de traitement du travail preterme WO1998000406A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35916/97A AU3591697A (en) 1996-07-02 1997-06-27 Method for the treatment of preterm labor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US2113896P 1996-07-02 1996-07-02
US60/021,138 1996-07-02
GB9701281.9 1997-01-22
GBGB9701281.9A GB9701281D0 (en) 1997-01-22 1997-01-22 Method for the treatment of preterm labor

Publications (1)

Publication Number Publication Date
WO1998000406A1 true WO1998000406A1 (fr) 1998-01-08

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Country Status (2)

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AU (1) AU3591697A (fr)
WO (1) WO1998000406A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047882A1 (fr) * 1997-04-21 1998-10-29 Takeda Chemical Industries, Ltd. 4,1 benzoxazepines, leurs analogues et leur utilisation comme agonistes de la somatostatine
US7582624B2 (en) 2002-09-20 2009-09-01 Arrow Therapeutics Limited Benzodiazepine derivatives and pharmaceutical compositions containing them

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047882A1 (fr) * 1997-04-21 1998-10-29 Takeda Chemical Industries, Ltd. 4,1 benzoxazepines, leurs analogues et leur utilisation comme agonistes de la somatostatine
US6352982B1 (en) 1997-04-21 2002-03-05 Takeda Chemical Industries, Ltd. 4,1-benzoxazepines, their analogues, and their use as somatostatin agonists
US7582624B2 (en) 2002-09-20 2009-09-01 Arrow Therapeutics Limited Benzodiazepine derivatives and pharmaceutical compositions containing them
US8119630B2 (en) 2002-09-20 2012-02-21 Arrow Therapeutics Limited Benzodiazepine derivatives and pharmaceutical compositions containing them

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AU3591697A (en) 1998-01-21

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