WO1994014438A1 - Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists - Google Patents

Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists Download PDF

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Publication number
WO1994014438A1
WO1994014438A1 PCT/US1993/012565 US9312565W WO9414438A1 WO 1994014438 A1 WO1994014438 A1 WO 1994014438A1 US 9312565 W US9312565 W US 9312565W WO 9414438 A1 WO9414438 A1 WO 9414438A1
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alkylamino
amino
imidazolyl
mmol
compound
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PCT/US1993/012565
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English (en)
French (fr)
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Kevin Gilbert
Doug W. Hobbs
Daniel F. Veber
Peter D. Williams
Ben E. Evans
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Merck & Co., Inc.
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Priority to EP94905516A priority Critical patent/EP0679084A1/en
Priority to US08/464,808 priority patent/US5693643A/en
Priority to JP6515459A priority patent/JPH08505150A/ja
Priority to AU59601/94A priority patent/AU690534B2/en
Publication of WO1994014438A1 publication Critical patent/WO1994014438A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy.
  • the aforementioned pharmacologic activities are useful in the treatment of mammals. More specifically, the compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to 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 ⁇ 2-adrenergic agonists, magnesium sulfate and ethanol.
  • Ritodrine the leading ⁇ 2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant).
  • Other ⁇ 2-adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine.
  • Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
  • Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
  • oxytocin is 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.
  • the compounds of the present invention can also be useful in the treatment of dysmenorrhea.
  • This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium.
  • a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea then current regimens.
  • compounds of the present invention are antagonists of oxytocin and bind to the oxytocin receptor.
  • oxytocin receptor When the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or pharmacologic effects.
  • These compounds are useful in the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Cesarean delivery.
  • a is a single or double bond
  • imidazolyl C 1-10 alkylamino imidazolyl C 1-10 alkylaminocarbonyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, pyrrolidinyl, sulfonyl, tetrazolyl C 1-10 alkylcarbonylamino, tetrazolylaminocarbonyl, phosphoryl, phosphoryl C 1-10 alkylamino and thiono;
  • R4 is selected from the group consisting of imidazolyl
  • R 5 is selected from the group consisting of hydrogen and C 1 -5 alkyl.
  • a is a single or double bond
  • R4 is selected from the group consisting of imidazolyl
  • R 5 is selected from the group consisting of hydrogen and C 1 -5 alkyl.
  • R 5 is selected from the group consisting of hydrogen and C 1 -5 alkyl.
  • a is a single or double bond
  • carboxyl C 1-10 alkylamino carboxyl, carboxyl C 1 -10 alkylamino, cyano, di-C 1-10 alkylamino, di-C 1-10 alkylamino- C 1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl,
  • imidazolyl C 1-10 alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino, piperizinyl, pyrrolidinyl, sulfonyl, tetrazolyl- C 1-10 alkylcarbonylamino, tetrazolylaminocarbonyl and thiono.
  • salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the following salts:
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
  • alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms or any number within this range.
  • alkenyl shall mean straight or branched chain alkenes, with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
  • aryl shall mean phenyl
  • cycloalkyl shall mean cyclic rings of alkanes, alkenes or alkynes with one or more degrees of unsaturation at any position of the ring, of three to eight total carbon atoms.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) they shall be interpreted as including those limitations given above for "alkyl” and "aryl”.
  • Designated numbers of carbon atoms e.g., C 1-10 ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • heterocyclic or “heterocycle,” as used herein except where noted, represents a stable mono, di, tri or tetra-substituted 5- to 7- membered mono- or bicyclic or stable mono, di, tri or tetra- substituted 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N and O.
  • the heterocycli c ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocycli c elements examples include piperidinyl, piperazinyl, azepinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, 4-piperidonyl, imidizolyl, imidazolinyl, imidazolidinyl, triazolyl, triazolinyl, triazolidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, quinuclidinyl, indolyl, quinolinyl,
  • oxiranyl shall refer to the substituent
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • preterm labor shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
  • cesarean delivery shall mean incision through the abdominal and uterine walls for delivery of a fetus.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent.
  • the ability of the compounds of the present invention to antagonize oxytocin makes these compounds useful as pharmacologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein oxytocin may be involved. Examples of such disorders include preterm labor and especially dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean delivery.
  • vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin
  • disorders including their use as diuretics and their use in congestive heart failure.
  • the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.3-6.0 gm/day orally.
  • the most preferred doses will range from 0.1 to about 10 mg/ minute during a constant rate infusion.
  • 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 intermittant throughout the dosage regimen.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorp orated 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, 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, polyhydroxypropylmethacrylamidephenol,
  • 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.
  • the compounds of the present invention can be prepared readily according to the following reaction Schemes (in which all variables are as defined before) 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.
  • LAH lithium aluminum hydride
  • A H 2 O containing 0.1% by vol. phosphoric acid
  • Hydroxylamine hydrochloride (30 g) was added in three portions over ca. 20 minutes. After 2 hours, an additional 10 g of hydroxylamine hydrochloride was added (over 10 minutes). At 30, 40, and 50 minutes additional elapsed time, further 3 g lots of hydroxylamine
  • Example A The product of Example A [3.47 mmol] and 4- nitrophenyl chloroformate [3.64 mmol] were combined in THF.
  • the reaction mixture was treated with triethylamine [4.54 mmol] and allowed to stir for 2 hours.
  • the reaction mixture was concentrated to dryness and the resulting residue was purified by a silica gel column, while eluting with 1 % ethyl acetate in methylene chloride.
  • the product fractions were combined and concentrated to dryness in vacuo.
  • the title compound was obtained as a white solid from ether.
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [0.197 mmol], triethylamine [0.54 mmol] and substituting glutamine-t-butyl ester hydrochloride [0.217 mmol] for histidinne methyl ester dihydrochloride. Chromatographic elution for column 1 was with 1% methanol in CH 2 CI 2 and then with 3% methanol in CH 2 CI 2 . The title compound was obtained as a white solid from ether and dried in vacuo. overnight,
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [0.215 mmol], triethylamine [0.55 mmol] and substituting L-methionine methyl ester [0.239 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 96/4/0.4 of CH 2 Cl 2 /methanol/ammonium hydroxide. For column 2, the elution was done with 5% methanol in CH 2 CI 2 and then with 95/5/0.5 of CH 2 Cl 2 /methanol/ammonium hydroxide. A white solid was obtained from ether. This white solid was dissolved in methanol.
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [0.366 mmol], triethylamine [0.83 mmol], and substituting N- ⁇ -Cbz-L-Lysine methyl ester [0.379 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 95/5/0.5 of CH 2 Cl 2 /methanol/ammonium hydroxide. For column 2, the elution was done with 2% methanol in CH 2 CI 2 . A white solid was obtained from ether. This white solid was combined with palladium hydroxide on carbon catalyst in absoute ethanol. The mixture was hydrogenated at 40 p.s.i. overnight.
  • the reaction mixture was filtered and the filtrate was concentrated to dryness.
  • the resulting residue was purified by a silica gel column, eluting with 92/8/0.8 of CH 2 Cl 2 /methanol/ammonium hydroxide.
  • the product fractions were combined and evaporated to dryness.
  • the title compound was obtained as a white solid from ether and was dried in vacuo. overnight.
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [0.33 mmol], triethylamine [0.88 mmol], and substituting L-leucine methyl ester [0.35 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 95/5/0.5 of CH 2 Cl 2 /methanol/ammonium hydroxide. For column 2, the elution was done with 1 % methanol in CH 2 CI 2 . The title compound was obtained as a white solid from ether and dried in vacuo, overnight. m.p.: 106°-128°C
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [0.23 mmol], triethylamine [0.73 mmol], and substituting sarcosine ethyl ester [0.29 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 1% ether in CH 2 CI 2 and then with 5% methanol in CH 2 CI 2 . For column 2, elution was done with 25% ethyl acetate in hexane. The title compound was obtained as a white solid from ether and dried in vacuo. overnight, m.p.: 89°-152°C
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [1.16 mmol], triethylamine [1.56 mmol], and substituting methyl(2-amino-3-(t-Boc-amino)) propanoate [1.27 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 5% ether in CH 2 CI 2 and then with 3% methanol in CH 2 CI 2 . For column 2, elution was done with 1 % methanol in CH 2 CI 2 . The title compound was obtained as a white solid from ether and dried in vacuo, overnight.
  • Example 2 The procedure for Example 2 was carried out using the product of Example 1 [0.27 mmol], triethylamine [0.76 mmol], and substituting glutamic acid- ⁇ -methyl ester- ⁇ -methyl ester- ⁇ -t-butylester [0.308 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 5% ether in CH 2 CI 2 and then with 5% methanol in CH 2 CI 2 . For column 2, elution was done with 4% methanol in CH 2 CI 2 . The title compound was obtained as a white solid from ether and dried in vacuo, overnight.
  • Example 2 The procedure of Example 2 was carried out using the product of Example 1 [0.22 mmol], triethylamine [0.60 mmol], and substituting D-tryptophan methyl ester [0.24 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 1% ether in CH 2 CI 2 and then with 5% methanol in CH 2 CI 2 . For column 2, elution was done with 4% methanol in CH 2 CI 2 . The title compound was obtained as a white solid from ether and dried in vacuo. overnight.
  • Example 12 The procedure of Example 12 was carried out using the product of Example 1 [1.38 mmol], triethylamine [3.40 mmol], and substituting glycine methyl ester hydrochloride [1.54 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 1 % ether in CH 2 CI 2 and then with 4% methanol in CH 2 CI 2 . For column 2, the elution was done with 99/1/0.1 of
  • Succinic anhydride (12 mg, 0.12 mmols) and endo-(1S)-1'- (((2-amino-7,7-dimethylbicyclo-(2.2.1)-hept-1-yl)methyl)sulfonyl)- spiro(1H-indane-1,4'-piperidine) (50 mg, 0.12 mmols) were combined in a mixture of THF (1 mL) and methylene chloride (1 mL) and stirred at ambient temperature for eighteen hours. The solvents were removed under vacuum and the residue was treated with trifluoroacetic
  • the purified cyanomethylated amine (0.80 g; 1.8 mmol) was dissolved in 2-methoxyethanol (15 mL) and to the stirred solution was added Raney nickel alloy (2.5 grams) followed by 6N NaOH solution (2.0 mL, 12 mmol). The mixture was heated to 80°C on a steam bath and then stirred at ambient temperature for 14 h. The catalyst was removed by filtration through Celite and washed with EtOAc. The filtrate solvents were removed under reduced pressure and the residue was taken up in CHCI 3 (50 mL) and washed with water (2 x 25 mL). The organic phase was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8
  • 2-Carboxymethylsuccinic anhydride (3-carboxymethyl- tetrahydrofuran-2,5-dione) was prepared from tricarballylic acid as described in J. Org. Chem. 46 2866 (1981).
  • 2-Carboxymethylsuccinic anhydride (0.93g, 5.88 mmols) and endo-(1S)-1'-(((2-amino-7,7- dimethylbicyclo-(2.2.1)-hept-1-yl)methyl)sulfonyl)- spiro(1H-indene- 1,4'-piperidine) (2.4g, 5.97 mmols) were combined in DMF (20 mL) and stined at ambient temperature for eighteen hours.
  • the DMF was removed under vacuum and the residue was treated with IN HCl and extracted with methylene chloride.
  • the methylene chloride layers were combined, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo.
  • the residue was treated with toluene (100 mL) and trifluoroacetic anhydride (5mL), and the resulting mixture was heated to reflux for 2-4 min while the excess trifluoroacetic anhydride was allowed to boil out. Reflux was continued for 10 min, and the mixture was then cooled and evaporated to dryness in vacuo.
  • allyl hydantoin described above (105 mg; 0.20 mmol) was dissolved in a solution of 1:1 pyridine:toluene (12 mL). While stirring at room temperature, osmium tetraoxide (51 mg; 0.20 mmol) was added. After 8 hr 10 mL of a saturated aqueous solution of sodium bisulfite was added. The solution was allowed to stir for 1 hr, then diluted with ethyl acetate (50 mL). The ethyl acetate was separated, dried over sodium sulfate, then concentrated. Purification of the residue by flash chromatography (10% methanol in methylene chloride) afforded the title compound (39 mg; 35%).
  • the purified monoacid, monoamide (150 mg; 0.282 mmol) was heated to reflux in a solution of THF (5 mL) and acetic anhydride (1 mL) for 14 h. The solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column
  • reaction mixture was stined at ambient temperature for 2 hours, re-cooled to 0°C, and treated with a tetrahydrofuran solution (6 ml) containing 620 mg (1.55 mmole) of (1S)-1'-(((7,7-dimethyl-2- oxobicyclo[2.2.1]hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'- piperidine). The reaction mixture was then stined at ambient temperature overnight.
  • reaction mixture was concentrated under reduced pressure to a volume of 6 ml and chromatographed on silica gel (hexane-ethyl acetate, 4:1) separating unreacted starting material and affording 390 mg of (1S)-1'-(((7,7-dimethyl-2-oxiranebicyclo- [2.2.1]hept-1-yl)methyl)sulfonyl) spiro-(1H-indene-1,4'-piperidine).
  • the mixture was stined at 0°C for 1 h, and then at ambient temperature for 14 h. Several drops of acetic acid were added and the dark brown mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aqueous NaHCO 3 (2 x 50 mL). The organic phase was dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 7:3 hexane :EtO Ac as eluant, and then by preparative reverse phase HPLC using a water- acetonitrile gradient containing 0.1% TFA. The title compound was obtained as a lyophilized powder.
  • hexamethyldisilylazide (3.64 mL, 1M solution in tetrahydrofuran) was added dropwise. After 4 hours, a saturated solution of ammonium chloride was added, and the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water (75 mL each). The ethyl acetate layer was dried over sodium sulfate, then concentrated. Purification by flash chromatography
  • Example 31 To a solution of the product of Example 31 (50 mg, 0.081 mmol) in ethanol (15 mL) was added palladium black (5 mg), followed by acetic acid (1 drop). After stirring at room temperature under an atmosphere of hydrogen for 18 h, the mixture was filtered then concentrated. The title compound was obtained by preparative HPLC (20 mg).
  • Example 29 To a solution of the product of Example 29 (660 mg, 1.37 mmol) in 1:1 tetrahydrofuran: diethyl ether (200 mL) was added an ethereal solution of diazomethane (approximately 5 eq.). After stirring at room temperature for 1 h, acetic acid (2 drops) was added, then the mixture was concentrated. The title compound (717 mg) was obtained as a 3:1 mixture of diastereomers by flash chromatography using 40% ethyl acetate in petroleum ether as eluent.
  • the foam (2.12 g, 0.003 mol) was dissolved in dry tetrahydrofuran (25 mL) under nitrogen atmosphere, then cooled to -78°C.
  • Lithium hexamethyldisilylazide (7 mL, IM solution in tetrahydrofuran) was added dropwise. After 4 hours, a saturated solution of ammonium chloride was added, and the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water (150 mL each). The ethyl acetate layer was dried over sodium sulfate, then concentrated. Purification by flash
  • Example 36 To a solution of the product of Example 36 (24 mg, 0.05 mmol) in acetonitrile (1 mL) was added gly colic acid (9 mg, 0.06 mmol), followed by benzotriazolyl-N-oxy-tris(dimethylamino)- phosonium hexafluorophosphate (26 mg, 0.06 mmol) and dusopropylethylamine (7.8 mg, 0.06 mmol). After 18 h, the mixture was concentrated. The title compound was obtained after purification by preparative HPLC (17 mg).
  • the protected phosphate ester obtained above (100 mg) was dissolved in ethanol (10 mL). To this solution was added 10%
  • Example 29 To a solution of the product of Example 29 (24 mg, 0.05 mmol) in methylene chloride (0.5 mL) was added methanol (0.5 mL), followed by histamine dihydrochloride (18 mg, 0.1 mmol) and dusopropylethylamine (26 mg, 0.2 mmol). After 18 h at room temperature the mixture was concentrated. The title compound was purified by preparative HPLC.
  • Example 29 To a solution of the product of Example 29 (48 mg, 0.1 mmol) in methylene chloride (2 mL) was added methanol (2 mL), followed by dimethylaminoethylamine (18 mg, 0.2 mmol). After 18 h at room temperature the mixture was concentrated. The title compound was purified by preparative HPLC.
  • Example 29 To a solution of the product of Example 29 (48 mg, 0.1 mmol) in methylene chloride (0.5 mL) was added methanol (0.5 mL), followed by dimethylaminoethyl mercaptan hydrochloride (28 mg, 0.2 mmol) and dusopropylethylamine (26 mg, 0.2 mmol). After 18 h at room temperature the mixture was concentrated. The title compound was purified by preparative HPLC.
  • Example 36 To a solution of the product of Example 36 (100 mg, 0.2 mmol) in DMF (10 mL) was added N-alpha-Boc-L-arginine hydrochloride (75 mg, 0.24 mmol), followed by hydroxybenzotriazole (35 mg, 0.24 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.24 mmol). After 18 h at room temperature the mixture was concentrated. Preparative HPLC afforded the Boc protected intermediate, which was dissolved in 50% TFA in methylene chloride (6 mL). After 18 h, the mixture was concentrated. The title compound (67 mg) was purified by preparative HPLC.
  • Example 43 To a solution of the product of Example 43 (approx. 0.4 mmol) in methylene chloride (5 mL) was added dusopropylethylamine until the pH was approximately 8.5. Acetyl chloride (31 mg) was added. After 18 h at room temperature the mixture was concentrated. The title compound (138 mg) was purified by preparative HPLC.
  • example 2 The procedure of example 2 was carried out using the product of example 46 [1.38 mmol], triethylamine [3.40 mmol], and substituting glycine methyl ester hydrochloride [1.54 mmol] for histidine methyl ester dihydrochloride.
  • the intermediate hydantoin was purified by flash chromatography using 5% methanol in methylene chloride as eluent.
  • Example 36 The procedure of Example 36 was followed, where the product of example 46 was used in place of endo-[lS]-1'[[[2-amino-7,7- dimethylbicyclo[2.2.1]-hept-1yl]-methyl]-sulfonyl]spiro[1H-indan-1-4'- piperidine], and Boc-(L)-Aspartic acid beta-methyl ester was used instead of Boc-(D)-Aspartic acid beta-benzyl ester.
  • Example 50 To a solution of the product of Example 50 (50 mg, 0.102 mmol) in methylene chloride (15 mL) was added glycolic acid (12 mg, 0.15mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (29 mg, 0.15 mmol) and 1-hydroxy- benzotriazole (21 mg, 0.15 mmol). After stirring at room temperature for 18 h, the mixture was concentrated. The title compound was purified by preparative HPLC.
  • DES dipropionate-treated rats.
  • Competition studies were conducted at equilibrium (60 minutes; 22°C) using 1 nM[ 3 H]OT in the following assay buffer: 50 mM Tris-HCl, 5 mM MgCl 2 , and 0.1 % BSA, pH 7.4.
  • Nonspecific binding (10% of the total binding) was determined using 1 ⁇ M unlabeled OT and the binding reaction was terminated by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, Inc., Sterling, VA).
  • IC 50 the concentration of tested compound that inhibits 50% of OT was reported, unless otherwise noted.
  • AVP [ 3 H]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-Vi sites) or kidney medulla (AVP-V2 sites) was determined according to the method of Butlen, et al. (Butlen, D; Guillon, G;

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PCT/US1993/012565 1991-09-16 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists WO1994014438A1 (en)

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EP94905516A EP0679084A1 (en) 1992-12-23 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists
US08/464,808 US5693643A (en) 1991-09-16 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists
JP6515459A JPH08505150A (ja) 1992-12-23 1993-12-23 スピロインダニルショウノウスルホニルオキシトシンアンタゴニストのヒダントイン及びスクシンイミド置換誘導体
AU59601/94A AU690534B2 (en) 1992-12-23 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0728758A1 (de) * 1995-02-27 1996-08-28 F. Hoffmann-La Roche Ag Dioxopyrrolo-pyrrolderivate
EP0751773A1 (en) * 1994-03-24 1997-01-08 Merck & Co. Inc. Tocolytic oxytocin receptor antagonists
WO2003064402A1 (en) * 2002-01-31 2003-08-07 Pfizer Limited Treatment of male sexual dysfunction
US7744616B2 (en) 2005-10-15 2010-06-29 Stryker Ireland, Ltd. Surgical sagittal saw blade with angled teeth and chip catchment and reciprocating saw blade with broached teeth
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445974A2 (en) * 1990-03-05 1991-09-11 MERCK SHARP & DOHME LTD. Spirocyclic antipsychotic agents
US5091387A (en) * 1990-03-02 1992-02-25 Merck & Co., Inc. Spirocyclic oxytocin antagonists

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Publication number Priority date Publication date Assignee Title
DE69223573D1 (de) * 1991-09-16 1998-01-29 Merck & Co Inc Hydantoin und Succinimid-substituierte Spiroindanylcamphorsulfonyl als Oxytocin-Antagonisten

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091387A (en) * 1990-03-02 1992-02-25 Merck & Co., Inc. Spirocyclic oxytocin antagonists
EP0445974A2 (en) * 1990-03-05 1991-09-11 MERCK SHARP & DOHME LTD. Spirocyclic antipsychotic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0751773A1 (en) * 1994-03-24 1997-01-08 Merck & Co. Inc. Tocolytic oxytocin receptor antagonists
EP0751773A4 (en) * 1994-03-24 1997-07-16 Merck & Co Inc TOCOLYTIC OXYTOCIN RECEPTOR ANTAGONISTS
EP0728758A1 (de) * 1995-02-27 1996-08-28 F. Hoffmann-La Roche Ag Dioxopyrrolo-pyrrolderivate
US5686459A (en) * 1995-02-27 1997-11-11 Hoffmann-La Roche Inc. Dioxopyrrolo pyrrole derivatives
WO2003064402A1 (en) * 2002-01-31 2003-08-07 Pfizer Limited Treatment of male sexual dysfunction
KR100829262B1 (ko) * 2002-01-31 2008-05-13 화이자 인코포레이티드 수컷의 성 기능 부전을 치료하는 방법
CN100500658C (zh) * 2002-01-31 2009-06-17 辉瑞大药厂 用于男性性功能障碍的治疗的药物组合物
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7744616B2 (en) 2005-10-15 2010-06-29 Stryker Ireland, Ltd. Surgical sagittal saw blade with angled teeth and chip catchment and reciprocating saw blade with broached teeth

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CA2151821A1 (en) 1994-07-07
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EP0679084A1 (en) 1995-11-02
JPH08505150A (ja) 1996-06-04
AU5960194A (en) 1994-07-19

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