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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French (fr)
Inventor
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 JP6515459A priority Critical patent/JPH08505150A/en
Priority to AU59601/94A priority patent/AU690534B2/en
Priority to EP94905516A priority patent/EP0679084A1/en
Priority to US08/464,808 priority patent/US5693643A/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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Abstract

Compounds of formula (I) where X is (a) or (b), R is Het, wherein Het is as defined in the description. These compounds are oxytocin and vasopressin antagonists useful in the treatment of preterm labor, dysmenorrhea, and for the stoppage of labor preparatory to cesarean delivery, timing of parturition, uterine hyperactivity, endometriosis, hypertension, congestive heart failure, hyponatremia and cognitive disorders.

Description

TITLE OF THE INVENTION
HYDANTOIN AND SUCCINIMIDE-SUBSTITUTED DERIVATIVES
OF SPIROINDANYLCAMPHORSULFONYL OXYTOCIN
ANTAGONISTS
FIELD OF THE INVENTION
This application is a continuation-in-part of application Serial No. 07/993,861 , filed December 23, 1992, which is a
continuation-in-part of application Serial No. 07/760,416, filed
September 16, 1991, now abandoned.
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.
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 ethanol.
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). 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.
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.
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 as a result of 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 of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea then current regimens.
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 another purpose of this invention to prepare novel compounds which more selectively inhibit oxytocin. It is still another purpose of this invention to provide a method of antagonizing the functions of oxytocin when oxytocin activity is responsible for causing 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 the present invention are antagonists of oxytocin and bind to the 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.
SUMMARY OF THE INVENTION
The compounds of the present invention and their pharmaceutically acceptable salts and esters are those of the general structural formula:
Figure imgf000006_0001
wherein
X is
Figure imgf000006_0002
a is a single or double bond,
R is
Het, wherein
Het is
a substituted saturated or unsaturated heterocyclic ring wherein said substituents are independently one or more of R1, R2, R3, Alk-R1,
Alk-R2, Alk-R3, -NHC(O)-Alk-R2R3, -NR5-Alk-R2R3 or Alk-R2R3; where Alk is C1-10 alkyl and R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C2-10 alkenyl, methylene, C1-10 alkoxycarbonyl, C1-10 alkoxycarbonyl- C1-10 alkylamino, C1-10 alkoxycarbonylamino, C1-10 alkylamino- C1-10 alkylaminocarbonyl, C1-10 alkylcarbonylamino, -S-R4,
C1-10 alkylcarbonyloxy, C1-10 alkylsulfonyl, C1-10 alkylthio, amino, amino C1-10 alkylcarbonylamino, amino C1-10 alkylamino,
carbonylamino, carbamoyl, carboxyl C1-10 alkylamino, carboxyl, cyano, di-C1 - 10 alkylamino, di-C1-10 alkylamino-C1-10 alkylamino, di-C1-10 alkylamino-C1-10 alkylthio, di-C1-10 alkylamino- C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl,
hydroxyl C1-10 alkylamino, imidazolyl, imidazolyl amino,
imidazolyl C1-10 alkylamino, imidazolyl C1-10 alkylaminocarbonyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, pyrrolidinyl, sulfonyl, tetrazolyl C1-10 alkylcarbonylamino, tetrazolylaminocarbonyl, phosphoryl, phosphoryl C1-10 alkylamino and thiono;
R4 is selected from the group consisting of imidazolyl,
C1-10 alkoxycarbonyl-C1-10 alkyl, di-C1-10 alkylamino-C1-10 alkyl and C1 -5 alkyl; and
R5 is selected from the group consisting of hydrogen and C1 -5 alkyl.
In one embodiment of the instant invention are compounds represented by the formula
Figure imgf000007_0001
wherein X is
Figure imgf000008_0001
a is a single or double bond,
R is
Het, wherein
Het is
a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocycli c or 7 to 10 membered heterobicyclic ring containing 1, 2 or 3 nitrogen atoms, wherein said substituents are independently one or more of R1, R2, R3, Alk-R1, Alk-R2, Alk-R3, -NHC(O)-Alk-R2R3, -NR5-Alk-R2R3 or Alk-R2R3; where Alk is C1-10 alkyl and R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C2-10 alkenyl, methylene, C1-10 alkoxycarbonyl, C1-10 alkoxycarbonyl-C1 -10 alkylamino, C1-10 alkylcarbonylamino, C1-10 alkylsulfonyl, -S-R4, amino, amino-C1-10 alkylcarbonylamino, amino C1-10 alkylamino, carbamoyl, carboxyl C1-10 alkylamino, carboxyl, cyano,
di-C1-10 alkylamino, di-C1-10 alkylamino-C1 -10 alkylamino, di-C1-10 alkylamino-C1-10 alkylthio, di-C1-10 alkylamino- C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, hydroxyl- C1-10 alkylamino, imidazolyl, imidazolyl amino, imidazolyl- C1-10 alkylamino, morpholinyl, thiomorpholinyl, dioxothiomorpho- linyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C1-10 alkylamino and thiono;
R4 is selected from the group consisting of imidazolyl,
C1-10 alkoxycarbonyl-C1 -10 alkyl, di-C1-10 alkylamino-C1-10 alkyl and C1 -5 alkyl; and
R5 is selected from the group consisting of hydrogen and C1 -5 alkyl. In a second embodiment of the instant invention are compounds represented by the formula
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, wherein
a is a single or double bond,
R is
Het, wherein
Het is
a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocyclic ring containing 1 , or 2 nitrogen atoms that is bonded to said bicyclic ring at one of said heterocycli c ring's nitrogen atoms, wherein said substituents are independently one or more of Rl, R2, R3, Alk-R1, Alk-R2, Alk-R3 or Alk-R2R3; and where Alk is C1-10 alkyl and R1, R2 and R3 are independently selected from the group consisting of hydrogen, C2-10 alkenyl, C1-10 alkoxycarbonyl, C1-10 alkoxycarbonyl-C1-10 alkylamino, C1-10 alkoxycarbonylamino, C1-10 alkylamino-C1-10 alkylaminocarbonyl, C1-10 alkylcarbonylamino, C1-10 alkylcarbonyloxy, C1-10 alkylsulfonyl, C1-10 alkylthio, amino, amino-C1 -10 alkylcarbonylamino, carbonylamino,
carboxyl C1-10 alkylamino, carboxyl, carboxyl C1 -10 alkylamino, cyano, di-C1-10 alkylamino, di-C1-10 alkylamino- C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl,
imidazolyl C1-10 alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino, piperizinyl, pyrrolidinyl, sulfonyl, tetrazolyl- C1-10 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:
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 Oxalate
Dihydrochloride Pamoate (Embonate)
Edetate Palmitate
Edisylate Pantothenate
Estolate Phosphate/diphosphate
Esylate Polygalacturonate
Fumarate Salicylate
Gluceptate Stearate
Gluconate Subacetate
Glutamate Succinate
Glycollylarsanilate Tannate
Hexylresorcinate Tartrate
Hydrabamine Teoclate Hydrobromide Tosylate
Hydrocloride Triethiodide
Hydroxynaphthoate Valerate
Iodide
Isethionate
Lactate
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 "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms or any number within this range.
The term "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.
The term "aryl" shall mean phenyl.
The term "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.
Whenever the terms "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., C1-10) 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.
The term "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. Examples of such heterocycli c elements 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,
isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, oxadiazolyl, triazaspirodecane, pyrrolo-isoxazole, pyrrolo-pyrazole, and pyrrolo- pyrrole.
The term "oxo" shall refer to the substituent =O.
The term "thiono" shall refer to the substituent =S.
The term "phosphoryl" shall refer to the substituted
-OPO(OH)2.
The term "oxiranyl" shall refer to the substituent
Figure imgf000012_0001
The term "dioxothiomorpholinyl" shall refer to the
substituent
Figure imgf000012_0002
The term "halogen" shall include iodine, bromine, chlorine and fluorine.
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 term "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.
Because of the known relationship of vasopressin to oxytocin, the compounds of the present invention are also useful as vasopressin antagonists. Vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin
disorders, including their use as diuretics and their use in congestive heart failure.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. 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 intermittant 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 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,
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.
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.
Abbreviations used in the Examples are as follows: TEA = triethylamine
DIEA = diisopropylethylamine
BOP = benzotriazolyloxytris(dimethylamino)
phosphonium hexafluorophosphate
THF = tetrahydrofuran
DMF = dimethylformamide
LAH = lithium aluminum hydride
TFA = trifluoroacetic acid
HPLC Method A = 15 min. linear gradient
95:5 A:B to 0:100 A:B
A = H2O containing 0.1% by vol. TFA
B = CH3CN containing 0.1% by vol. TFA
2.0 mL/min flow rate
12 cm C18 reverse phase column
UV detection (215 nm)
HPLC Method B = 20 min. linear gradient
90:10 A:B to 5:95 A:B
A = H2O containing 0.1% by vol. phosphoric acid
B = CH3CN containing 0.1% by vol. phosphoric acid
2.0 mL/min flow rate
12 cm C18 reverse phase column
UV detection (215 nm)
TLC was performed on 20 cm plates coated with silica gel (250 microns) from Analtech. EXAMPLE A
Endo-(1S)-1'(((2-amino-7,7-dimethylbicyclo(2.2.1)- hept-1-yl)- methyl)- sulfonyl) spiro(1H-indan-1,4'- piperidine)
Figure imgf000017_0001
Di-t-butyl dicarbonate (31g, 0.14 mole available from Aldrich) and bis(2-chloroethyl) amine hydrochloride (21.6g, 0.12 mole Aldrich) were combined in CH2CI2 (250 ml) stirred at ambient temperature and treated with triethylamine (12.8 g, 0.127 mole) added dropwise over 15 minutes. After 1 hour, another 1.5 ml of triethylamine was added. After a total of 2.5 hours, the mixture was poured onto a silica gel column packed with CH2Cl2:hexane (1:1), and eluted with CH2CI2. The combined product fractions were evaporated to dryness in vacuo to give N,N-bis(2-chloroethyl)-t-butyl-carbamate.
To a solution of indene (10.3 g, 89 mmole) in dry tetrahydrofuran (THF, 18 ml) cooled in an ice bath and maintained under a nitrogen blanket was added lithium bis(trimethylsilyl)amide (Aldrich, 177 ml of a 1.0M solution in THF; 177 mmole) over 15 minutes. The mixture was stirred in the cold for 30 minutes, then added over 15 minutes to a solution of N,N-bis(2-chloroethyl)-t- butylcarbamate (21.2 g, 88 mmole) stirred in an ice bath. The mixture was stirred for 2 hours in the cold and for 30 minutes at ambient temperature under nitrogen, then evaporated in vacuo to a foam.
CH2CI2 was added and the resulting mixture poured onto a silica gel column packed with 40% hexane in CH2CI2. The column was eluted with 40% hexane in CH2CI2 followed by CH2CI2, and die product fractions were evaporated to dryness in vacuo to provide l'-(t- butyloxycarbonyl)-spiro(indene-1,4'-piperidine).
1'-(t-Butyloxycarbonyl)spiro(indene-1,4'- piperidine) (16 g, 56 mmole) in ethyl acetate (250 ml) was stirred in an ice bath and saturated with HCl(g) for 30 minutes. The mixture was evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4'-piperidine) hydrochloride. The free base was obtained by slurrying the hydrochloride in aqueous sodium bicarbonate solution and extracting with CH2CI2. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to provide spiro(1H-indene-1,4'piperidine.
Spiro(1H-indene-1,4'piperidine) (308 mg, 1.66 mmol) and (+)-10-camphorsulfonyl chloride (418 mg, 1.66 mmol) were combined in CH2CI2 and treated with triethylamine (0.23 ml). The mixture was stirred at ambient temperature for 15 minutes, then poured onto a silica gel column and eluted with 1 : 1 CH2Cl2:hexane. The product fractions were combined and evaporated to dryness in vacuo to provide (1S)-1'- (((7,7-dimethyl-2-oxobicicylo-(2.2.1)hept-1-yl)methyl)sulfonyl)spiro- (1H-indene- 1,4'-piperidine) as a solid which was recrystallized from petroleum ether and dried overnight in vacuo at ambient temperature.
(1S)-1'-(((7,7-dimethyl-2-oxobicyclo(2.2.1) hept-1-yl)- methyl)sulfonyl)spiro(1H-indene-1,4'- piperidine) (30 g, 0.075 mole) in pyridine (500 mL) was heated in an oil bath to 70°C (internal).
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
hydrochloride were added. After another 30 minutes, the mixture was poured into water (2 L) and extracted 3 times with ethyl acetate (300 mL portions). The organic layers were combined, washed with IN HCl (600 mL total), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. EtOH (abs; ca. 250 mL) was added to the resulting thick syrup and the solution allowed to stand at ambient temperature overnight. The mixture was filtered and the filtrate boiled down to ca. 80 mL. After standing, the mixture was again filtered and boiled down to ca. 20 mL. After a third filtration, the filtered solids were combined to give (1S)-1'-(((7, 7-dimethyl-2-oximinobicyclo(2.2.1)hept-1-yl)- methyl) sulfonyl)spiro(1H-indene-1,4'-piperidine) (28 g).
Freshly prepared, activated Raney Nickel catalyst (ca. 30 g) in water was allowed to settle and the water decanted. Abs. ethanol (300 mL) was added, and the mixture swirled and again allowed to settle. The solvent was decanted. Two more wash- decant cycles with 150 mL of ethanol were similarly carried out. (1S)-1'-(((7,7-dimethyl- 2-oximinobicyclo (2.2.1)hept-1-yl)methyl)sulfonyl)-spiro(1H-indene-1, 4'-piperidine) (30 g) was stirred in a mixture of abs. ethanol (450 mL) and 2-methoxy ethanol (900 mL), nitrogen was bubbled through the suspension/solution, and the Raney Nickel catalyst was added. The mixture was hydrogenated under 50 psi overnight. TLC (9:1
CH2Cl2MeOH, silica gel) showed the reaction to be complete. The catalyst was removed by filtration, and the filtrate evaporated to dryness in vacuo. The crude solid (27 g) was divided into 7 g batches, and each batch was dissolved in methylene chloride (ca. 200 mL) and flash chromatographed on silica (700 g in a 100 mm column, packed and eluted with 8% (v/v) methanol in methylene chloride), taking 200 mL fractions. The exo isomer of the title amine was obtained in fractions ca. 5-7, and the desired endo isomer in fractions ca. 8-16. TLC was on silica, eluted with 8% methanol-methylene chloride, phosphomolybdic acid stain. The combined product fractions were evaporated to dryness to provide the title compound (4.5 g from each 7 g lot, ca. 18 g total) as a colorless solid. EXAMPLE B
1-((7,7-Dimethyl-2-oxo-bicyclo(2.2.1)heptan-1-yl)methanesulfonyl)-4- (2-methylphenyl)piperazine
Figure imgf000020_0001
To a stirred, 0°C solution of 1-(o-tolyl) piperazine hydrochloride (50.0 g; 235 mmol) and TEA (83 mL; 590 mmol) in chloroform (1000 mL) was added (+)-10-camphorsulfonyl chloride (65.5 g; 260 mmol). The solution was stirred at 0°C for 1 h and then at ambient temperature for 3 h. The solution was extracted with 5% aqueous HCl (2 x 500 mL), water (500 mL), and saturated aqueous NaHCO3 (2 x 500 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The resulting solid was recrystallized from methanol to give the title compound, mp 112-114°C (69 g; 75%).
Analysis calculated for (C21H30N2O3S)
C, 64.57; H, 7.74; N, 7.17
Found: C, 64.52; H, 7.68; N, 6.99
TLC: Rt 0.49 (75:25 hexane/ethyl acetate)
HPLC (method A): retention time 10.33 min
FAB MS: m/z 391 (M+ + H)
1H NMR (300 MHz, CDCI3): δ 7.2 (m, 2H), 7.0 (m, 2H), 3.45 (m, 4H), 3.40 (d, J=16 Hz, 1H), 3.0 (m, 4H), 2.57 (m, 1H), 2.40 (dt, Jd=14 Hz, Jt=3 Hz, 1H), 2.30 (s, 3H), 2.10 (m, 2H), 1.96 (d, J=14 Hz, 1H), 1.67 (m, 1H), 1.44 (m, 1H), 1.18 (s, 3H), 0.91 (s, 3H) EXAMPLE 1
(1S)-1-' (((7,7-dimethyl-2-endo-(4-nitrophenyloxycarbonylamino)- bicyclo-(2.2.1)-hept-1-yl)-methyl)- sulfonyl)spiro(1H-indane-1,4'- piperidine)
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
Figure imgf000021_0001
(1S)-1'-(((7,7-dimethyl-2-endo-(4-nitrophenyloxycarbonylamino)- bicyclo-(2.2.1)-hept-1-yl)-methyl))sulfonyl)spiro(1H-indane-1,4'- piperidine) [1.80 mmol] and histidine methyl ester dihydrochloride
[1.90 mmol] were combined in DMF. The reaction mixture was treated with triethylamine [5.90 mmol] and allowed to stir for 2 hours. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in CH2CI2. This CH2CI2 solution was placed on a silica gel column and eluted with 2% methanol in CH2CI2 and then with 95/5/0.5 of CH2Cl2/methanol/ammonium hydroxide. The product fractions were combined and evaporated to dryness in vacuo. A white solid was obtained from ether. The resulting white solid [0.954 mmol] and sodium hydride [0.45 mmol] were combined in ethanol and left to stir for 12 hours. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in CH2CI2. This solution was placed on a silica gel column and eluted with 95/5/0.5 of
CH2Cl2/methanol/ ammonium hydroxide. The product fractions were combined and evaporated to dryness in vacuo. The title compound was obtained as a white solid from ether and dried in vacuo. overnight. m.p.: 146°C-192°C
NMR: Consistent with structure
HPLC: >99% pure
MS: M+H+=566.2 (FAB)
CHN: Calc'd for C30H39N5O4S·0 .05 C4H10O•0.80 H2O;
C, 62.12; H, 7.10; N, 12.00.
Found: C, 62.10; H, 7.02; N, 12.01.
EXAMPLE 3
Figure imgf000023_0001
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 CH2CI2 and then with 3% methanol in CH2CI2. The title compound was obtained as a white solid from ether and dried in vacuo. overnight,
mp: 104°-166°C
NMR: Consistent with structure
HPLE: >97% pure
MS: M+H+=557.2 (FAB)
CHN: Calc'd for C29H40N4O5S·0.50 C4H100·0.10 H2O;
C, 62.51; H, 7.65; N, 9.41.
Found: C, 62.55; H, 7.36; N, 9.04. EXAMPLE 4
Figure imgf000024_0001
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 CH2Cl2/methanol/ammonium hydroxide. For column 2, the elution was done with 5% methanol in CH2CI2 and then with 95/5/0.5 of CH2Cl2/methanol/ammonium hydroxide. A white solid was obtained from ether. This white solid was dissolved in methanol. This solution was treated with oxone [0.284 mmol], which had been dissolved in a small amount of water, and the mixture was stined at ambient temperature for 4 hours. The reaction mixture was concentrated and the resulting residue was partitioned between ethyl acetate and sat'd sodium bicarbonate solution. The ethyl acetate layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column, eluted with 2% methanol in CH2CI2. The product fractions were combined and concentrated. The title compound was obtained as a white solid from ether, and dried in vacuo. overnight. m.p.: 134°-209°C
NMR: Consistent with structure
HPLC: >97% pure
MS: M+H+=592 (FAB)
CHN: Calc'd for C29H41N3O6S2;
C, 58.86; H, 6.98; N, 7.10.
Found: C, 58.55; H, 6.59; N, 7.04.
EXAMPLE 5
Figure imgf000025_0001
The procedure of Example 2 was carried out using the product of Example 1 [0.366 mmol], triethylamine [0.83 mmol], and substituting N-α -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 CH2Cl2/methanol/ammonium hydroxide. For column 2, the elution was done with 2% methanol in CH2CI2. 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 CH2Cl2/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.
m.p.: 99°-158°C
NMR: Consistent with structure
HPLE: >94% pure
MS: M+H+=557.3 (FAB)
CHN: Calc'd for C30H44N4O4S·0 .25 C4H10O·Η2O;
C, 64.11; H, 8.18; N, 9.65.
Found: C, 64.12; H, 8.01; N, 9.32.
EXAMPLE 6
Figure imgf000026_0001
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 CH2Cl2/methanol/ammonium hydroxide. For column 2, the elution was done with 1 % methanol in CH2CI2. The title compound was obtained as a white solid from ether and dried in vacuo, overnight. m.p.: 106°-128°C
NMR: Consistent with structure
HPLE: >94% pure
MS: M+H+=542.3 (FAB)
CHN: Calc'd for C30H43N3O4S;
C, 66.51; H, 8.00; N, 7.76.
Found: C, 66.24; H, 8.10; N, 7.49.
EXAMPLE 7
Figure imgf000027_0001
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 CH2CI2 and then with 5% methanol in CH2CI2. 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
NMR: Consistent with structure
HPLE: >96% pure
MS: M+H+=500 (FAB)
CHN: Calc'd for C27H37N3O4S•0.10 C4H10O·0.4O H2O;
C, 63.99; H, 7.60; N, 8.17.
Found: C, 63.95; H, 7.37; N, 7.92. EXAMPLE 8
Figure imgf000028_0001
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 CH2CI2 and then with 3% methanol in CH2CI2. For column 2, elution was done with 1 % methanol in CH2CI2. The title compound was obtained as a white solid from ether and dried in vacuo, overnight.
m.p.: 104°-176°C
NMR: Consistent with structure
HPLE: >97% pure
MS: M+H+=615 (FAB)
CHN: Calc'd for C32H46N4O6S·0.10 C4H10O·0 .45 H2O;
C, 61.73; H, 7.66; N, 8.89.
Found: C, 61.68; H, 7.66; N, 8.97. EXAMPLE 9
Figure imgf000029_0001
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-α-methyl ester-α-methyl ester-α-t-butylester [0.308 mmol] for histidine methyl ester dihydrochloride. Chromatographic elution for column 1 was with 5% ether in CH2CI2 and then with 5% methanol in CH2CI2. For column 2, elution was done with 4% methanol in CH2CI2. The title compound was obtained as a white solid from ether and dried in vacuo, overnight.
m.p.: 94°-117°C
NMR: Consistent with structure
HPLE: >93% pure
MS: M+H+=614 (FAB)
CHN: Calc'd for C33H47N3O6S•0.10 C4H10O•0.50 H2O;
C, 63.65; H, 7.84; N, 6.67.
Found: C, 63.68; H, 7.64; N, 6.67. EXAMPLE 10
Figure imgf000030_0001
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 CH2CI2 and then with 5% methanol in CH2CI2. For column 2, elution was done with 4% methanol in CH2CI2. The title compound was obtained as a white solid from ether and dried in vacuo. overnight.
m.p.: 111°-176°C
NMR: Consistent with structure
HPLE: >92% pure
MS: M+H+=615.2 (FAB)
CHN: Calc'd for C35H42N4O4S·0 .50 C4H10O•0.85 H2O;
C, 66.62; H, 7.29; N, 8.49.
Found: C, 66.64; H, 6.93; N, 8.12. EXAMPLE 11
Figure imgf000031_0001
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 CH2CI2 and then with 4% methanol in CH2CI2. For column 2, the elution was done with 99/1/0.1 of
CH2Cl2/methanol/ammonium hydroxide. The title compound was obtained as a white solid from ether and dried in vacuo, overnight. m.p.: 230°-239°C
NMR: Consistent with structure
HPLE: >92% pure
MS: M+H+=486 (FAB)
CHN: Calc'd for C26H35N3O4S·0 .10 C4H10O·0 .20 H2O;
C, 63.84; H, 7.39; N, 8.46.
Found: C, 63.77; H, 7.39; N, 8.50. EXAMPLE 12
Figure imgf000032_0001
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
anhydride (1 mL) and toluene (2 mL), then heated to reflux for 15 minutes while the excess trifluoroacetic anhydride was allowed to boil out. The mixture was then cooled and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (8" column, 0.5" diam.), eluted with 0.5% (100 mL) followed by 1% (100 mL) methanol in methylene chloride. The product fractions were combined and evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate, diluted with hexane, and allowed to stand whereupon the title compound was deposited as a white solid. This material was filtered and dried in vacuo at 90° for eighteen hours,
m.p.: 228.5°-229.5°C
1H-NMR: Consistent with structure, ca. 0.1 mol of ethyl acetate and ca. 0.05 mol of hexane observed
TLC: (2% MeOH in CH2CI2) single component,
Rt=0.66
MS: M+H+=485 (FAB)
CHN: Calc'd for C27H36N2O4S•0.10 C4H8O2•0.05 C6H14; C, 66.83; H, 7.59; N, 5.63.
Found: C, 66.62; H, 7.61; N, 5.51.
EXAMPLE 13
Figure imgf000033_0001
To a 0°C solution of endo-(1S)-1'(((2-amino- 7,7- dimethylbicyclo (2.2.1)-hept-1-yl)-methy1)- sulfonyl)spiro(1H-indan- 1,4'-piperidine) (0.90 g; 2.2 mmol) and diisoprpylethylamine (DIEA) (0.47 mL; 2.7 mmol) in CHCI3 (50 mL) was added iodoacetonitrile
(0.38 grams; 2.3 mmol). The solution was stirred for 1 h at 0°C and then for 18 h at ambient temperature. The mixture was extracted with aqueous NaHCO3 (2 x 25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1 :3 ethyl acetate- hexanes as eluant (TLC Rf = 0.30 in 1:3 ethyl acetate-hexanes; HPLC retention time = 9.30 min). 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 CHCI3 (50 mL) and washed with water (2 x 25 mL). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8
CHCl3:MeOH:NH4OH as eluant (TLC Rf = 0.25 in 92:8:0.8
CHCl3:MeOH:NH4OH; HPLC retention time = 7.20 min; FAB mass spectrum m/z = 446). The purified diamine (0.51 g; 1.1 mmol) was dissolved in CHCI3 and to the solution was added 1,1'-carbonyldi- imidazole (0.19 g; 1.2 mmol). After the solution had been stined for 1 h at ambient temperature, acetic acid (0.63 mL; 11 mmol) was added and the solution was refluxed for 6 h. The reaction was cooled and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the solution was washed with 10% aqueous citric acid (25 mL), water (25 mL), and aqueous NaHCθ3 (25 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:3 EtOAc:CHCl3 as eluant. The title compound was obtained as a white foam from CHCI3 (TLC Rt = 0.27 in 1:4 EtOAc:CHCl3;
HPLC retention time = 10.67 min;
FAB mass spectrum m/z=472; calc for C26H37N3O3S-0.70
CHCI3: C, 57.76; H, 6.84; N, 7.75.
Found: C, 57.84; H, 6.82; N, 7.42;
1H NMR (CDCI3, 300 MHz) δ 7.15-7.25 (m, 4H), 4.39 (ddd, J = 2.3, 5.3, 12.0 Hz, 1H) 1.05 (s, 3H), 1.00 (s, 3H)).
HPLC conditions: 12 cm C18 reverse phase Vydac column; 15 min gradient 95:5 to 0:100 A:B (A = H2O containing 0.1% TFA, B = CH3CN containing 0.1% TFA), flow rate = 2.0 mL/min, detection at 215 nm. EXAMPLE 14
Figure imgf000035_0001
2-Amino-[1-[[(2,3-dihydrospiro[1H-indene-1,4'- piperidin]- 1'-yl)sulfonyl]methyl]-7,7-dimethylbicyclo [2.2.1]hept-2-yl]-4-(methyl- sulfonyl)-but-1-ylamine (250 mg, 0.425 mmole) and thiocarbonyl- diimidazole (76 mg, 0.425 mmole) were combined with 500 mg of anhydrous cesium carbonate in 12 ml of dry N,N'-dimethylformamide at room temperature. The orange suspension was stined for 2 hours, filtered, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and sodium bicarbonate solution. The phases were separated and the organic phase was washed with saturated sodium bicarbonate solution (3 X 40 ml) and brine, then dried (sodium sulfate) and concentrated. The crude product was (250 mg) was obtained as an oil which crystallized on standing in methanol: NMR: Consistent with structure and verifies presence of solvent;
HPLC: > 97% pure at 214 nm;
FAB MS: 594 (M+ + H);
Elem. Anal, calc'd for
C29H43N3O4S3•1.05 CH3OH•0.25H2O:
Calc'd: C, 57.10; H, 7.61; N, 6.65.
Found: C, 57.11; H, 7.21; N, 6.28. EXAMPLE 15
1-[1-[[(2,3-Dihydrospiro[1H-indene-1,4'-piperidin]-1'-yl)sulfonyl]- methyl]-7,7-dimethylbicyclo[2.2.1]hept-2-yl]-2,5-dioxo-3- pynolidineacetic acid
Figure imgf000036_0001
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. The residue was chromatographed on silica gel (10" column, 2"diam.), eluted with 200:10:1:1 CH2Cl2:MeOH:HoAc:H2O. The product obtained by evaporation of the eluate was rechromatographed on silica gel twice, once eluted with 1L each of 1000:10:1 :1, 500:10:1 :1, and 330: 10:1 :1
CH2Cl2:MeOH:HoAc:H2O, and the second time with 600:10:1 :1 of the same solvents. The combined product fractions were evaporated to dryness in vacuo. treated with ether and re-evaporated 3 times, then treated with hexane and evaporated to obtain the title compound as a solid which was dried in vacuo at 400°C for eighteen hours.
M.P. 80-100°C (foam;indistinct)
HPLC: 100%
1H-NMR: Consistent with structure, ca. 0.05 mol of DMF and ca. 0.18 mol of hexane observed.
TLC: (490:10:1:1 CH2Cl2:MeOH:HoAc:H2O) single component, Rt =
0.25.
M.S.: (FAB) M+H @ 543
Analysis for
C29H38N2O•0.05 C3H7NO·0.18 C6H14•0.3 H2O:
Calc'd: C, 64.00; H, 7.37; N, 5.0
Found: C, 64.01; H, 7.30; N, 5.12.
EXAMPLE 16
Figure imgf000037_0001
To a 0°C stined solution of p-nitrophenyl chloroformate (1.37 g; 6.8 mmol) in CHCl3 (100 mL) was added DIEA (1.18 ml; 12.4 mmol) and the product of Example A (2.5 g; 6.2 mmol). The solution was stinred at 0°C for 1 h and then at ambient temperature for 14 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in CHCI3 (100 mL) and washed with 5% aqueous HCl (2 x 50 mL) and aqueous NaHCO3 (100 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The urethane was obtained as a white foam.
TLC: Rt 0.35 (1:3 EtOAc :hexanes)
HPLC (method A): retention time 12.3 min
To a 0°C stined solution of the p-nitrophenyl urethane (2.8 g; 5.0mmol) in DMF (20 mL) was added methyl 1-methyl-4-amino-4- piperidine carboxylate hydrochloride (1.04 gm, 5 mmol) and DIEA (0.87 ml, 5 mmol). The solution was stined for 2 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in CHCI3 (100 mL) and washed with 5% aqueous HCl (2 x 50 mL) and 10 % aqueous Na2CO3 (5 x 100 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The urea was obtained as a foam which was crystallized from EtOAc ( 1.14 gm, 2 mmol).
Analysis calculated for (C31H44N4O4S).1.85 H2O
C 60.61 H 8.22 N 8.84
Found: C 60.58 H 8.02 N 8.80
TLC: Rt 0.2 (95: 5: 0.5 CHCI3: MeOH: NH3OH)
HPLC (method A): retention time 9.17 min
FAB MS: m/z 601 (M+ + H)
To a 0°C stined solution of the urea (1.0 gm, 1.67 mmol) in MeOH ( 50 mL) was added in small portions NaH (dry powder) (0.125 gm, 5 mmol). The solution was stined for 2 hours. The reaction mixture was neutralized with acetic acid and evaporated under reduced pressure. The residue was dissolved in CHCI3 (100 mL) and washed with 5% aqueous HCl (2 x 50 mL) and aqueous NaHCO3 (100 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The title compound was obtained as a foam which was precipitated from EtOAc/ hexanes ( 0.260 gm, 0.5 mmol).
Analysis calculated for (C31H44N4O4S)•0.3 EtOAc
C 64.98 H 7.86 N 9.41
Found: C 64.65 H 7.76 N 9.46
TLC: Rt 0.35 (95:5:0.5 CHCl3:MeOH:NH4OH)
HPLC (method A): retention time 10.17 min
FAB MS: m/z 569 (M+ + H)
1H NMR (300 MHz, CDCI3): d 7.15-7.25 (m, 4H), 5.8 (s, 1H), 4.49 (m, 1H), 2.3 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H)
EXAMPLE 17
Figure imgf000039_0001
To a 0°C solution of the unsubstituted hydantoin product of Example 11 (1.50 g; 3.09 mmol) and 4-chloromethyl-1-(triphenyl)- methylimidazole (1.39 g; 3.87 mmol) in dry THF (60 mL) under an atmosphere of argon was added NaH (154 mg of a 60% suspension in mineral oil; 3.86 mmol). The mixture was stined at 0°C for 1 h, and then at ambient temperature for 24 h. Several drops of acetic acid were added and the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aqueous NaHCO3 (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 1:1 EtOAc:CHCl3 as eluant. The product (1.40 g; 1.73 mmol) was heated in 10 mL of MeOH containing 10 mL of 6N HCl at 60°C for 6 h. The solvents were removed under reduced pressure and the residue was dissolved in
CHCl3 (100 mL) and washed with aqueous NaHCO3 (2 x 50 mL). The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5:0.5 CHCl3:MeOH:NH4OH as eluant. The purified product was dissolved in MeOH containing 3 equivalents of 6 N HCl and the solvent was removed under reduced pressure. The residue was taken up in water-dioxane and lyophilized to give the HCl salt of title compound as a white powder.
Analysis calculated for (C30H39N5O4S)•2.05 HCl•0.55 H2O
C, 57.40; H, 6.53; N, 10.77
Found: C, 57.44; H, 6.53; N, 10.41
TLC: Rt 0.29 (95:5:0.5 CHCl3:MeOH:NH4OH)
HPLC (method A): retention time 9.43 min
FAB MS: m/z 566 (M+ + H)
1H NMR (300 MHz, CDCI3): δ 8.95 (s, 1H), 7.40 (s, 1H), 7.15-7.25 (m, 4H), 4.75 (m, 2H), 4.55 (m, 1H), 1.03 (s, 3H), 0.97 (s, 3H)
EXAMPLE 18
Figure imgf000041_0001
To a stined solution of the hydantoin (150 mg; 0.309 mmol) in a mixture of 2:1 allyl bromide:tetrahydrofuran (30 mL) was added sodium hydride (12 mg; 60% dispersion in oil). The temperature was then increased to reflux. After 1 hr the solution was cooled, then concentrated. Purification by flash chromatography (5% methanol in methylene chloride) provided the intermediate allyl derivative (158 mg).
The 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%).
Analysis calculated for (C29H41N3O6S)·0.56 H2)
C, 61.13; H, 7.45; N, 7.37
Found: C, 61.15; H, 7.55; N, 7.15 HPLC: (Vydac C18 Column; gradient from 95/5 to 0/100
H2O/CH3CN with 0.1% TFA. 15 min. gradient,
flow rate = 1.5 ml/min.)
Rt = 12.12 min. Purity = 96%
1HNMR: Consistent with structure
FABMS: m/z = 560 (M+ + H)
EXAMPLE 19
Figure imgf000042_0001
To a stined solution of N-methyliminodiacetic acid (220 mg; 1.50 mmol) in DMF (10 mL) was added DIEA (0.575 mL; 3.30 mmol) and BOP (665 mg; 1.50 mmol). The mixture was stined at ambient temperature for 24 h, and then the product of Example A (500 mg; 1.24 mmol) was added. The mixture was strined at ambient temperature for 24 h and then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 10% aqueous citric acid (20 mL) and water (10 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-10% MeOH- CHCI3. The purified monoacid, monoamide was obtained as a white foam. TLC: Rt 0.40 (90:10 CHCl3:MeOH)
HPLC (method A): retention time 9.03 min
FAB MS: m/z 532 (M+ + H)
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
chromatography using 1 :4 EtOAc-hexanes as eluant. The title
compound was obtained as a white foam from ether.
Analysis calculated for (C28H39N3O4S)•0.2 ether•0.1 H2O
C, 65.23; H, 7.83; N, 7.92;
Found: C, 65.10; H, 7.99; N, 7.95;
TLC: Rt 0.29 (1:2 EtOAc :hexanes)
HPLC (method A): retention time 10.57 min
FAB MS: m/z 514 (M+ + H)
lH NMR (300 MHz, CDCI3): δ 7.10-7.25 (m, 4H), 5.20 (ddd, J = 2.2, 5.9, 12.1 Hz, 1H), 3.40 (s, 3H), 2.37 (s, 3H), 1.06 (s, 3H), 0.95 (s, 3H)
EXAMPLE 20
Figure imgf000043_0001
(1S)-1'-(((2-endo-Amino-7,7-dimethylbicyclo-(2.2.1) hept- 1-yl)methyl) sulfonyl)spiro(1H-indane-1,4'-piperidine) (1.5 g, 3.7 mmole), tert-butylbromo acetate (0.8 g, 4.1 mmole), and crushed potassium carbonate (0.57 g, 4.1 mmole) were combined in 80 ml of absolute ethanol and heated at reflux for 12 hours. The reaction mixture was cooled, filtered, and rotoevaporated under reduced pressure. The residual material was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed in succession with saturated sodium bicarbonate solution and brine, then dried
(sodium sulfate), and concentrated to give a semi-solid. The crude product was crystallized from ethyl acetate to give 0.85 g of (1S)-1'- (((2-endo-tert-butyloxycarbonylmethylamino-7,7-dimethylbicyclo- (2.2.1) hept-1-yl)methyl)sulfonyl)spiro(1H-indane-1,4'- piperidine). Concentration of the mother liquors afforded an additional 0.99 g of material.
A solution of 40 ml of methylene chloride containing 0.41 ml of triethylamine and 0.97 g of (1S)-1'-(((2-endo-tert-butyloxy- carbonylmethylamino-7,7-dimethylbicyclo(2.2.1) hept-1-yl)methyl) sulfonyl) spiro(1H-indane-1,4'-piperidine) was stined magnetically in an ice bath and treated in one portion with 0.24 ml of bromoacetyl- bromide. After 1 hour, an additional equivalent each of bromo- acetylbromide and triethylamine were added and the reaction mixture was stined at ambient temperature overnight. The reation mixture was diluted with methylene chloride and washed in succession with sodium bicarbonate solution, 10% citric acid solution, and brine. The dried extracts were concentrated and the residual material was flash
chromatographed on silica gel (15% ethyl acetate- hexane) to give 0.74 g of 2-tert-buty loxy carbony lmethy lamino-N-[1-[[(2,3-dihydro-spiro[1H- indane-1,4'-piperidin]-1'-yl)sulfonyl]methyl]-7,7- dimethyl- bicyclo[2.2.1]hept-2-yl]-bromoacetamide.
A continuous stream of ammonia gas was passed for 10 minutes into an ice cold solution of methanol (32 ml) containing 0.64 g (1.0 mmole) of 2-tert-butyloxycarbonylmethylamino-N-[1-[[(2,3-di- hydrospiro[1H-indane-1,4'-piperidin]-1'-yl)sulfonyl]- methyl]-7,7- dimethylbicyclo[2.2.1]hept-2-yl]-bromoacetamide. The reaction mixture was warmed to room temperature and stined for 1 hour. All volatile components were removed under reduced pressure to give a semi-solid which was partitioned between ethyl acetate and water. The organic phase was washed with water (3X) and brine, then dried
(sodium sulfate) and concentrated. Triturate of the residual material with ether gave 0.32 g of the title compound as an off-white solid: m.p.
>220°C;
NMR: Consistent with structure:
HPLC: > 99% pure at 214 nm;
FAB MS: 500 (M+ + H);
Elem. Analysis calculated for C27H37N3O4S·0.25 H2O:
C, 64.31; H, 7.51; N, 8.34.
Found: C, 64.32; H, 7.34; N, 8.14.
EXAMPLE 21
Figure imgf000045_0001
To an ice cold suspension of trimethylsulfoxonium iodide (610 mg, 2.77 mmole) in 10 ml of dry tetrahydrofuran was added 1.8 ml of 1 ,6M n-butyllithium under nitrogen. After addition was complete the resulting 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. The 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).
To a suspension of 1.7 mmole of sodium hydride in 1.7 ml of dry N,N'-dimethylformamide was added 0.18 mmole of succinimide. After stirring for 15 minutes the reaction mixture became homogeneous and 70 mg (0.17 mmole) of (1S)-1'-(((7,7-dimethyl-2- oxiranebicyclo- [2.2.1]hept-1-yl)methyl)sulfonyl)spiro-(1H-indene-1,4'-piperidine) was added. The reaction mixture was heated at 150°C for 4 hours, then cooled to room temperature, and diluted with ethyl acetate. The organic phase was washed with water and brine, then dried, and concentrated to give 92 mg of crude product. Fl ash column
chromatography on silica gel (30% ethyl acetate-hexane elution) of the crude reaction product afforded the title compound in analytically pure form as a white solid: m.p. 111-115°C;
NMR: Consistent with structure:
HPLC: > 99% pure at 214 nm;
FAB MS: 513 (M+ + H), 621 (M+ + thioglycerol);
Elem. Analysis calculated for C28H36N2O5S•0.75 H2O:
C, 63.90; H, 7.20; N, 5.32.
Found: C, 63.86; H, 7.14; N, 5.10.
EXAMPLE 22
Figure imgf000047_0001
To a 0°C solution of the unsubstituted hydantoin product of Example 11 (1.50 g; 3.09 mmol) and iodoacetonitrile (1.03 g; 6.18 mmol) in dry THF (30 mL) under an atmosphere of argon was added NaH (185 mg of a 60% suspension in mineral oil; 4.64 mmol). The mixture was stined at 0°C for 1 h, and then at ambient temperature for 6 h. The reaction was cooled to 0°C and more iodoacetonitrile (0.52 g; 3.1 mmol) and NaH (124 mg of a 60% suspension in mineral oil; 3.1 mmol) were added. 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 NaHCO3 (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.
Analysis calculated for (C28H36N4O4S)•0.35 TFA•0.25 H2O
C, 60.51; H, 6.44; N, 10.22
Found: C, 60.57; H, 6.53; N, 9.85.
TLC: Rt 0.43 (3:2 hexane.EtOAc) HPLC (method A): retention time 11.39 min
FAB MS: m/z 525 (M+ + H)
1H NMR (300 MHz, CDCl3): δ 7.1-7.3 (m, 4H), 4.56 (m, 1H), 4.35
(AB quartet, J = 18 Hz, 2H), 3.95 (AB quartet, J = 16 Hz, 2H), 1.06 (s,
3H), 0.97 (s, 3H)
EXAMPLE 23
Figure imgf000048_0001
To a stined solution of endo-(1S)-1'(((2- amino-7,7- dimethylbicyclo(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan- 1,4'-piperidine (526 mg; 1.31 mmol) in methylene chloride (20 mL) was added diacetyl-L-tartaric anhydride (312 mg; 1.44 mmol), followed by diisopropylethyl amine (0.251 mL; 1.44 mmol). After 18 hr the solution was concentrated, then partitioned between ethyl acetate (200 mL) and 1M HCl (200 mL). The ethyl acetate layer was washed with additional water (2 x 200 mL), then dried over sodium sulfate and concentrated. Partial purification by flash chromatography (10% methanol in methylene chloride) afforded material that was dissolved in methylene chloride (20 mL) and treated with thionyl chloride (0.096 mL; 1.31 mmol). After stirring at room temperature for 18 hr, the solution was concentrated. The intermediate diacetate was obtained by purification of the residue by flash chromatography (10% methanol in methylene chloride). The diacetate described above (1 g; 1.66 mmol) was dissolved in a solution of 3:1 tetrahydrofuran: water (40 mL) then cooled to 0°C. A solution of 30% hydrogen peroxide (0.832 mL; 6.64 mmol) was added followed by lithium hydroxide (80 mg; 3.32 mmol). After stirring at 0°C for 30 min the solution was concentrated. The title compound (492 mg; 73%) was obtained through purification of the residue by flash chromatography (10% methanol in methylene
chloride).
Analysis calculated for (C27H36N2O6S)· 0.35 H2O
C, 62.01; H, 7.07; N, 5.36
Found: C, 62.00; H, 6.86; N, 5.47
HPLC: (Vydac C18 Column; gradient from 95/5 to 0/100
H2O/CH3CN with 0.1% TFA. 15 min. gradient,
flow rate = 1.5 ml/min.)
Rt = 12.5 min. Purity = 100%
1HNMR: Consistent with structure
FABMS: m/z = 517 (M+ + H)
EXAMPLE 24
[1R-[[(2,3-Dihydrospiro[1H-indene-1,4'-piperidin]-1'-yl)sulfonyl]- methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2-propen-1-yl]- 2-5-dioxo-1-imidazolidine
Figure imgf000049_0001
To a stined solution of [1R-[[(2,3-Dihydrospiro[1H-indene- 1,4'-piperidin]-1'-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2- endo-yl]-2,5-dioxo-1-imidazolidine (150 mg; 0.309 mmol) in
tetrahydrofuran (20 mL) was added allyl bromide (27 μL; 0.309 mmol), followed by sodium hydride (12 mg; 60% dispersion in oil). The temperature was increased to reflux. After 4 h the solution was cooled then concentrated. Purification by flash chromatography (5% methanol in methylene chloride) provided the title compound as a white solid (81 mg).
1HNMR: consistent with structure.
M.P.: 101-104°C
HPLC: Rt = 14.7 min; 95%
FABMS: M + 1 at 526
Analysis calculated for C29H39N3O4S + 0.05 CH2CI2 + 0.40 H2O
C, 64.95; H, 7.49; N, 7.82
Found: C, 64.93; H, 7.48; N, 7.43
EXAMPLE 25
[1R-[[(2,3-Dihydrospiro[1H-indene-1,4'-piperidin]-1'-yl)sulfonyl]- methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2-hydroxy-3-[1,1- dimethylaminol-propan-1-yl]- 2,5-dioxo-1-imidazolidine
Figure imgf000050_0001
To a stined solution of [1R-[[(2,3-Dihydrospiro[1H-indene- 1,4'-piperidin]-1'-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2- endo-yl]- 2,5-dioxo-1-imidazolidine (164 mg; 0.338 mmol) in tetrahydrofuran (2 mL) was added bromoepihydrin (1 mL), followed by sodium hydride (12 mg; 60% dispersion in oil). The mixture was then heated to reflux. After 6 hours, the mixture was cooled and concentrated. Purification by flash chromatography (30% ethyl acetate in petroleum ether as eluent) afforded [1R-[[(2,3-Dihydrospiro[1H-indene- 1,4'-piperidin]-1'-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2- endo-yl]-3-[2,3 oxirane-1-propenyl]- 2,5-dioxo-1-imidazolidine as a white foam (141 mg).
To a solution of [1R-[[(2,3-Dihydrospiro[1H-indene-1,4'- piperidin]-1'-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2- endo-yl]-3-[2,3 oxirane-1-propenyl]- 2,5-dioxo-1-imidazolidine (73 mg; 0.135 mmol) in absolute ethanol (2 mL) was added dimethylamine hydrochloride (55 mg; 0.68 mmol) and dusopropylethylamine ((47 μL). After 6 hours at reflux, the solution was cooled and concentrated.
Purification by preparative HPLC afforded the title compound (41 mg). 1HNMR: consistent with structure.
M.P.: 93-97°C
HPLC: Rt = 11.63 min; 99%
FABMS: M + 1 at 587
Analysis calculated for C31H46N4O5S + 0.65 CH2CI2 + 0.20 H2O
C, 58.88; H, 7.45; N, 8.08
Found: C, 58.90; H, 7.46; N, 8.53
EXAMPLE 26
[1R-[[(2,3-Dihydrospiro[1H-indene-1,4'-piperidin]-1'-yl)sulfonyl]- methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2,5-dioxo-3S-[4- aminopropylamido]]-1-succinimide
Figure imgf000052_0001
To a solution of endo-[1S]-1'[[[2-amino-7,7-dimethyl- bicyclo[2.2.1]-hept-1yl]-methyl]-sulfonyl]spiro[1H-indan-1-4'- piperidine] (lg, 2.48 mmol) in methylene chloride (75 mL) was added Boc-(L)-Aspartic acid β-methyl ester (675 mg, 2.72 mmol),
hydroxybenzotriazole (436 mg, 3.22 mmol), and 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride (618 mg, 3.22 mmol). After 4 hours the solution was concentrated, then partitioned between ethyl acetate and 1M NaOH (75 mL each). The organic layer was washed with IM HCl, and brine (75 mL each) then dried over Na2SO4. The solution was filtered and concentrated. Purification by flash chromatography (40% ethyl acetate in petroleum ether as eluent) gave an amide ester intermediate as white foam (1.15g).
The foam was dissolved in dry tetrahydrofuran (100 mL) under nitrogen atmosphere, then cooled to -78 °C. Lithium
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
(gradient from 15% to 20% ethyl acetate in petroleum ether as eluent) afforded a protected aminosuccinimide intermediate as a white foam
(1.1g).
To a solution of the aminosuccinimide (1.46 g, 2.43 mmol) in ethyl acetate (50 mL) was indroduced a stream of HCl gas. After 15 min. the HCl was removed and the solution was washed with IM sodium carbonate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (a gradient from 2% to 10% methanol in methylene chloride as eluent) afforded an intermediate unprotected aminosuccinimide as a white foam (1.12g).
To a solution of the unprotected aminosuccinimide (90 mg, 0.18 mmol) in methylene chloride (15 mL) was added Boc-b-alanine (51 mg, 0.27 mmol), hydroxybenzotriazole (37 mg, 0.27 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol), and dusopropylethylamine (47μL, 0.27 mmol). After stirring at room temperature for 6 hours the mixture was concentrated, then partitioned between ethyl acetate and IM HCl (200 mL each). The ethyl acetate layer was dried over sodium sulfate, then filtered and
concentrated. Purification by preparative HPLC afforded an adduct which was dissolved in methylene chloride (20 mL) and treated with trifluoroacetic acid (8 mL). After 1 hour, the solution was
concentrated, then the product was purified by preparative HPLC to give the title compound (71 mg).
1HNMR: consistent with structure.
HPLC: Rt = 12.2 min; 97%
FABMS: M + 1 at 571
Analysis calculated for C30H42N4O5S + 2.5 trifluoroacetic acid
C, 46.89; H, 5.47; N, 6.83
Found: C, 46.91; H, 5.30; N, 6.77 EXAMPLE 27
[1R-[[(2,3-Dihydrospiro[1H-indene-1,4'-piperidin]-1'-yl)sulfonyl]- methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]-3 endo-[2,5-dioxo-3S- amino-[4-piperidinyl]]-1-succinimide
Figure imgf000054_0001
To a solution of [1R-[[(2,3-Dihydrospiro[1H-indene-1,4'- piperidin]-1'-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2- endo-yl]-3 endo-[2,5-dioxo-[3S-amino]]-1-succinimide (161 mg, 0.32 mmol) in methanol (15 mL) was added Boc-4-piperidinone (77 mg, 0.39 mmol), and sodium cyanoborohydride (61 mg, 0.96 mmol). After stirring at room temperature for 4 hours, the mixture was concentrated and purified by flash chromatography (5% methanol in methylene chloride as eluent).
The residue was redissolved in methylene chloride (10 mL), then treated with trifluoroacetic acid (5 mL). After 2 hours the solution was concentrated. Purification by flash chromatography (10% methanol in methylene chloride as eluent) afforded the title compound (91 mg).
1HNMR: consistent with structure.
HPLC: Rt = 13.2 min; 98%
FABMS: M + 1 at 583 Analysis calculated for C32H46N4O4S + 1.5 trifluoroacetic acid + 1.5 H2O
C, 53.84; H, 6.52; N, 7.18
Found: C, 53.85; H, 6.69; N, 6.79
EXAMPLE 28
[1R-[[4-(2-methylphenyl)piperazin-1-yl)sulfonyl]-methyl]7,7- dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2R-hydroxy-3-[piperazin-1- yl]-propan-1-yn-2,5-dioxo-1-imidazolidine
Figure imgf000055_0001
To a stined solution of [1R-[[4-(2-methylphenyl)piperazin-
1-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]- 2,5- dioxo-1-imidazolidine (120 mg, 0.253 mmol) in dry tetrahydrofuran
(15 mL) was added 2R-(-)-glycidyl tosylate (288 mg, 1.26 mmol), followed by sodium hydride (60% dispersion in oil). The temperature was increased to reflux. After 2 hours the mixture was cooled then concentrated. Purification by preparative TLC (40% ethyl acetate in petroleum ether as eluent) afforded [lR-[[4-(2-methylphenyl)piperazin- 1-yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2S,3 oxirane-1-propenyl]- 2,5-dioxo-1-imidazolidine as a white foam (112 mg).
To a solution of [1R-[[4-(2-methylphenyl)piperazin-1- yl)sulfonyl]-methyl]7,7-dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2S,3 oxirane-1-propenyl]- 2,5-dioxo-1-imidazolidine (66 mg, 0.12 mmol) in absolute ethanol (20 mL) was added piperazine (50 mg, 0.58 mmoo). The temperature was increased to reflux. After 2 hours the solution was cooled and concentrated. Purification by flash chromatography
(85:15:1 methylene chloride:methanol:ammonium hydroxide as eluent) afforded the title compound (19 mg).
IHNMR: consistent with structure.
HPLC: Rt = 10.4 min; 95%
FABMS: M + 1 at 517
Analysis calculated for C31H48N6O5S + 0.15 hexanes + 1.2 H2O
C, 58.82; H, 8.12; N, 12.90
Found: C, 58.84; H, 7.76; N, 12.54
EXAMPLE 29
Figure imgf000056_0001
To a solution of endo-(1S)-1'(((2-amino-7,7-dimethyl- bicyclo(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1,4'- piperidine) (3 g, 7.45 mmol) in methylene chloride (150 mL) was added maleic anhydride (876 mg, 8.94 mmol). After stirring for 2 h at room temperature, the mixture was concentrated, then redissolved in acetic anhydride (100 mL). Sodium acetate was added (611 mg, 7.45 mmol), then the temperature was increased to reflux. After 48 h, the mixture was cooled to room temperature, then concentrated. Flash
chromatography using 50% ethyl acetate in petroleum ether afforded 1.5 g of the title compound as a white foam. 1HNMR: consistent with structure.
HPLC: method A, Rt = 14.86 min; 96%
FABMS: M + 1 at 483
Analysis calculated for C27H34N2O4S + 0.35 dioxane
C, 66.43; H, 7.22; N, 5.46
Found: C, 66.45; H, 7.25; N, 5.23
EXAMPLE 30
Figure imgf000057_0001
To a solution of the product of Example 29 (84 mg, 0.17 mmol) in 1 : 1 methylene chloride :diethyl ether (15 mL) was added chloroximidoacetate (32 mg, 0.21 mmol), followed by dusopropylethylamine (37 uL). The mixture was allowed to stir at room temperature for 4 h at which time additional chloroximidoacetate was added (32 mg). After 18 h, the mixture was concentrated and the residue was applied to preparative TLC plates. Two products were obtained as white solids, in 40% overall yield.
1HNMR: consistent with structure.
HPLC: method A, Rt = 14.73 min; 100%
FABMS: M + 1 at 598
Analysis calculated for C31H39N3O7S + 0.55 chloroform
C, 57.21; H, 5.87; N, 6.34
Found: C, 57.18; H, 5.88; N, 6.41 1HNMR: consistent with structure.
HPLC: method A, Rt = 14.99 min; 100% FABMS: M + 1 at 598
Analysis calculated for C31H39N3O7S + 0.20 chloroform
C, 60.29; H, 6.36; N, 6.76
Found: C, 60.27; H, 6.29; N, 6.72
EXAMPLE 31
Figure imgf000058_0001
To a solution of the product of example 29 (109 mg, 0.23 mmol) in acetonitrile (10 mL) was added silver iodide (57 mg, 0.46 mmol), followed by a solution of N-benzyl-N-(trimethylsilylmethyl)- aminoacetonitrile (111 uL, 0.46 mmol) in acetonitrile (10 mL). After stirring at room temperature in the dark for 18 h, the mixture was filtered, then concentrated. The title compound was obtained in 60% yield by preparative TLC using 25% ethyl acetate in petroleum ether as eluent.
1HNMR: consistent with structure.
HPLC: method A, Rt = 12.21 min; 97%
TLC: Rt = 0.2 (20% ethyl acetate in petroleum ether)
Analysis calculated for C36H45N3O4S + 0.45 water
C, 69.30; H, 7.42; N, 6.73
Found: C, 69.34; H, 7.39; N, 7.02 EXAMPLE 32
Figure imgf000059_0001
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).
1HNMR: consistent with structure.
HPLC: method A, Rt = 11.97 min; 97%
TLC: Rt = 0.5 (10% methanol in methylene chloride)
Analysis calculated for C29H39N3O4S + 1.25 trifluoroacetic acid + 0.60 toluene.
C, 59.26; H, 6.28; N, 5.81
Found: C, 59.27; H, 6.26; N, 5.86 EXAMPLE 33
Figure imgf000060_0001
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.
1HNMR: consistent with structure.
HPLC: method A, Rt = 13.48 min (major isomer)
TLC: Rt = 0.5 (40% ethyl acetate in petroleum ether)
FABMS: M + 1 at 525
Analysis calculated for C28H36N4O4S + 0.3 ethyl acetate
C, 63.93; H, 7.02; N, 10.17
Found: C, 63.94; H, 7.09; N, 10.13 EXAMPLE 34
Figure imgf000061_0001
To a solution of the product of Example 33 (40 mg, 0.08 mmol) in 9:1 methanohacetic acid (20 mL) was added zinc dust (10 eq). After stirring at room temperature for 4 h, the mixture was filtered and concentrated. The title compound (15 mg) was obtained through purification by flash chromatography (10% methanol in methylene chloride as eluent).
1HNMR: consistent with structure.
HPLC: method A, Rt = 11.03
FABMS: M + 1 at 527
Analysis calculated for C28H38N4O4S + 0.5 water + 0.25 hexanes
C, 63.59; H, 7.69; N, 10.05
Found: C, 63.61; H, 7.31; N, 9.79
EXAMPLE 35
Figure imgf000062_0001
To a solution of the product of Example 23 (1.03 g, 2 mmol) in dry tetrahydrofuran(100 mL) was added diethylamino dibenzylphosphoramidite (1.78 g, 04 mmol), followed by tetrazole (280 mg, 4 mmol). After 2 h, the solution was cooled to -40°C, then m- chloroperbenzoic acid (1 g, 4 mmol) in methylene chloride (12 mL) was added dropwise. The solution was allowed to warm to 5°C. After 18 h, the mixture was partitioned between aqueous sodium bisulfite and methylene chloride. The methylene chloride layer was dried over sodium sulfate, then concentrated. Flash chromatography (3% methanol in methylene chloride as eluent) allowed the separation of two
phosphorylated intermediates (mono and diphosphorylated adducts) which were hydrogenated separately.
Each of the two phosphorylated intermediates was dissolved in ethanol. Palladium on carbon (10%) was added, then the mixtures were placed under hydrogen atmosphere. After 18 h, the mixtures were filtered and concentrated. The product phosphates were purified by preparative HPLC. mono phosphate:
1HNMR: consistent with structure.
HPLC: method B, Rt = 11.27 min.
FABMS: M + 1 at 597 Analysis calculated for C27H37N2O9S1P1 + 0.65 trifluoroacetic acid + 0.70 dioxane
C, 51.00; H, 5.95; N, 3.83
Found: C, 51.05; H, 6.35; N, 4.21 di phosphate:
1HNMR: consistent with structure.
HPLC: Rt = 10.5 min.
FABMS: M + 1 at 677
Analysis calculated for C27H38N2O12P2S1 + 1.50 dioxane
C, 49.00; H, 6.23; N, 3.46
Found: C, 48.97; H, 6.24; N, 3.43
EXAMPLE 36
Figure imgf000063_0001
To a solution of endo-[lS]-1'[[[2-amino-7,7-dimethyl- bicyclo[2.2.1]-hept-lyl]-methyl]-sulfonyl]spiro[1H-indan-1-4'- piperidine] (4 g, 0.01 mol) in methylene chloride (20 mL) was added Boc-(D)-Aspartic acid beta-benzyl ester (3.32 g, 0.012 mol),
hydroxybenzotriazole (1.62 g, 0.012 mol), and 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 0.012 mmol). After 18 hours the solution was concentrated, then partitioned between ethyl acetate and 1M NaOH (150 mL each). The organic layer was washed with 1M HCl, and brine (150 mL each) then dried over Na2SO4. The solution was filtered then concentrated. Purification by flash chromatography (40% ethyl acetate in petroleum ether as eluent) gave an amide ester intermediate as white foam (3.7 g).
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
chromatography (gradient from 15% to 20% ethyl acetate in petroleum ether as eluent) afforded a protected aminosuccinimide intermediate as a white foam.
To a solution of the Boc protected aminosuccinimide (2.7 g) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL). After 3 h, the mixture was concentrated. Purification by flash chromatography (3% methanol in methylene chloride as eluent) afforded the title compound as a white foam (1.6 g).
1HNMR: consistent with structure.
HPLC: method B, Rt = 11.96 min.
FABMS: M + 1 at 500
Analysis calculated for C27H37N3O4S1 + 0.25 methylene chloride
C, 62.83; H, 7.26; N, 8.07
Found: C, 62.81; H, 7.19; N, 8.08
EXAMPLE 37
Figure imgf000065_0001
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).
1HNMR: consistent with structure.
HPLC: method B, Rt = 14.46 min.
FABMS: M + 1 at 558
Analysis calculated for C29H39N3O6S1 + 0.45 trifluoroacetic acid
C, 58.96; H, 6.53; N, 6.90
Found: C, 59.06; H, 6.72; N, 6.65
EXAMPLE 38
Figure imgf000066_0001
To a solution of the product of Example 37 (200 mg, 0.36 mmol) in dry tetrahydrofuran (15 mL) was added diethylamino dibenzylphosphoramidite (171 mg, 0.54 mmol), followed by tetrazole (75 mg, 1.08 mmol). After 18 h at 9°C, the solution was cooled to -50°C, then m-chloroperbenzoic acid (139 mg) was added and the mixture was allowed to warm to room temperature. After 6 h, the mixture was concentrated, then partitioned between ethyl acetate and aqueous sodium bisulfite. The ethyl acetate was dried over sodium sulfate, then concentrated. Preparative HPLC afforded the intermediate phosphorylated adduct.
The protected phosphate ester obtained above (100 mg) was dissolved in ethanol (10 mL). To this solution was added 10%
palladium on carbon (39 mg), then the mixture was placed under a hydrogen atmosphere at 60 psi. After 18 h, the mixture was filtered then concentrated. Preparative HPLC afforded the title compound. 1HNMR: consistent with structure.
HPLC: method B, Rt = 11.98 min.
FABMS: M + 1 at 638 Analysis calculated for C29H40N3O9P1S1 + 1.5 water + 0.6 dioxane
C, 52.55; H, 6.71; N, 5.86
Found: C, 52.53; H, 6.42; N, 5.84
EXAMPLE 39
Figure imgf000067_0001
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.
1HNMR: consistent with structure.
HPLC: method B, Rt = 11.05 min.
FABMS: M + 1 at 594
Analysis calculated for C32H43N5O4S1 + 2.40 trifluoroacetic acid
C, 50.96; H, 5.28; N, 8.07
Found: C, 50.92; H, 5.45; N, 8.14 EXAMPLE 40
Figure imgf000068_0001
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.
1HNMR: consistent with structure.
HPLC: method B, Rt = 12.64 min.
FABMS: M + 1 at 571
Analysis calculated for C31 H46N4O4S 1 + 0.55 water
C, 64.11; H, 8.18; N, 9.65
Found: C, 64.07; H, 8.08; N, 9.49
EXAMPLE 41
Figure imgf000068_0002
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.
1HNMR: consistent with structure.
HPLC: method B, Rt = 13.82 min.
FABMS: M + 1 at 588
Analysis calculated for C31H45N3O4S2 + 1.3 TFA + 0.05 dioxane
C, 54.82; H, 6.36; N, 5.68
Found: C, 54.76; H, 6.37; N, 5.84
EXAMPLE 42
Figure imgf000069_0001
To a solution of the product of Example 36 (25 mg, 0.05 mmol) in acetonitrile (5 mL) was added N-alpha-N-im-bis-Boc-L- Histidine (21mg, 0.06 mmol), followed by BOP reagent (26 mg, 0.06 mmol) and dusopropylethylamine (7.8 mg, 0.06 mmol). After 18 h at room temperature the mixture was concentrated. Preparative HPLC afforded the Boc protected intermediate, which was dissolved in TFA (5 mL). After 2.5 h, the mixture was concentrated. The title compound was purified by preparative HPLC. 1HNMR: consistent with structure.
HPLC: method B, Rt = 10.00 min.
FABMS: M + 1 at 637
Analysis calculated for C33H44N6O5S1 + 2.20 TFA + 1.75 water
C, 48.87; H, 5.45; N, 9.14
Found: C, 48.86; H, 5.47; N, 8.96
EXAMPLE 43
Figure imgf000070_0001
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.
*HNMR: consistent with structure.
HPLC: method B, Rt = 9.80 min.
FABMS: M + 1 at 656
Analysis calculated for C33H49N5O5S1 + 2.5 TFA + 1.45 water
C, 47.19; H, 5.67; N, 10.14
Found: C, 47.19; H, 5.62; N, 10.13 EXAMPLE 44
Figure imgf000071_0001
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.
1HNMR: consistent with structure.
HPLC: method B, Rt = 11.99 min.
FABMS: M + 1 at 698
Analysis calculated for C35H51N706S 1 + 1.7 TFA + 0.1 dioxane
C, 51.74; H, 5.99; N, 10.89
Found: C, 51.72; H, 6.13; N, 11.01
EXAMPLE 45
1 -((7,7-Dimethyl-2-Oximino-Bicyclo(2.2.1)Heptan-1-yl)-Methane- sulfonylV4-(2-Methylphenyl)-3-Piperazine
Figure imgf000072_0001
To a stined solution of 1-((7,7-dimethyl-2-oxo-bicyclo- (2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (65.0 g; 166 mmol) in pyridine (250 mL) was added hydroxylamine hydrochloride (35.0 g; 0.504 mol). The solution was heated to 70°C for 18 h. The solvent was removed under reduced pressure, the residue was taken up in chloroform (500 mL) and washed with aqueous
NaHCO3 (2 x 200 mL), water (100 mL), and 5% aqueous HCl (2 x 200 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The title compound crystallized from ethyl acetate, giving off-white needles (57 g; 84%), mp 174- 175°C.
TLC: Rt 0.40 (75:25 hexane-ethyl acetate)
HPLC (method A): retention time 9.98 min
FABMS: M + 1 at 406
Analysis calculated for C21H31N3O3S
C, 62.19; H, 7.71; N, 10.36
Found: C, 62.29; H, 7.63; N, 10.15
1H NMR (300 MHz, CDCI3): δ 7.90 (br s, 1H), 7.18 (m, 2H), 7.02 (m, 2H), 3.47 (m, 4H), 4.43 (d, J=14.4 Hz, 1H), 3.00 (m, 4H), 2.92 (d, J=14.4 Hz, 1H), 2.4-2.6 (m, 2H), 2.31 (s, 3H), 2.09 (d, J=16.9 Hz, 1H), 1.95 (m, 2H), 1.80 (m, 1H), 1.32 (m, 1H), 1.08 (s, 3H), 0.87 (s, 3H) EXAMPLE 46
1-((7,7-Dimethyl-2-Endo-Amino-Bicyclo(2.2.1)Heptan-1-yl)Methane- sulfonyl)-4-(2-Methylphenyl)- 3-Piperazine
Figure imgf000073_0001
To a stined solution of 1-((7,7-dimethyl-2-oximino- bicyclo(2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)- piperazine (35.0 g; 86 mmol) in 2-methoxyethanol (500 mL) containing Raney Nickel alloy (105.0 g) was added sodium hydroxide solution (17.2 g; 430 mmol dissolved in 75 mL) dropwise over 30 min. During the addition heat and gas was evolved. The mixture was stined at ambient temperature for 16 h, at which time TLC indicated complete consumption of starting oxime and a ca. 4:1 mixture of endo (lower Rt) and exo (higher Rt) amine products. The mixture was filtered through Celite and the filtercake was washed with methanol and ethyl acetate. The solvents were removed under reduced pressure and the resulting solid was dispersed in water and filtered. The dried solid was purified by pressurized silica gel column chromatography, using a 93:3 to 94:6 A:B gradient elution (A=chloroform, B=5% NH4θH/MeOH). The title compound was obtained as a white foam (24 g; 70%). EXAMPLE 47
Figure imgf000074_0001
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.
To a stined solution of the hydantoin (120 mg, 0.253 mmol) in dry tetrahydrofuran (15 mL) was added 2R-(-)-glycidyl tosylate (288 mg, 1.26 mmol), followed by sodium hydride (60% dispersion in oil). The temperature was increased to reflux. After 2 hours the mixture was cooled then concentrated. Purification by preparative TLC (40% ethyl acetate in petroleum ether as eluent) afforded [lR-[[4-(2-methylphenyl)piperazin-l-yl)sulfonyl]-methyl]7,7- dimethylbicyclo[2.2.1]hept-2-endo-yl]-3-[2S,3 oxirane-1-propenyl]- 2,5- dioxo-1-imidazolidine as a white foam (112 mg).
1HNMR: consistent with structure.
HPLC: method A; Rt = 13.4 min; 98%
Analysis calculated for C27H38N4O5S + 0.25 methylene chloride
C, 59.30; H, 7.03; N, 10.15
Found: C, 59.64; H, 7.10; N, 9.79 EXAMPLE 48
Figure imgf000075_0001
To a solution of 1-((7,7-dimethyl-2-endo-amino-bicyclo- (2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)-3-piperazine (103 mg, 0.286 mmol) in methylene chloride (15 mL) was added diacetyl tartaric anhydride (71 mg, 0.315 mmol). After stirring for 1 h at room temperature, the mixture was concentrated, then dissolved in acetic anhydride (20 mL). Sodium acetate (47 mg, 0.572 mmol)was added, then the mixture was heated to 70°C. After 40 h, the mixture was cooled to room temperature, then concentrated. Flash
chromatography using 20% ethyl acetate in petroleum ether as eluent afforded 61 mg of the title compound as a white foam.
1HNMR: consistent with structure.
HPLC: method A; Rt = 14.16 min; 98%
FABMS: M + 1 at 590
Analysis calculated for C29H39N3O8S + 0.15 hexanes + 1.15 ethyl acetate
C, 58.71; H, 7.15; N, 6.01
Found: C, 58.71; H, 6.91; N, 5.98 EXAMPLE 49
Figure imgf000076_0001
To a solution of the product of Example 48 (20 mg, 0.033 mmol) in 3:1 tetrahydrofuran: water (10 mL) at 0°C was added hydrogen peroxide (4 eq), followed by lithium hydroxide (2 eq). After stirring at room temperature for 40 min, the mixture was concentrated. Flash chromatography using 10% methanol in methylene chloride as eluent afforded 14 mg of the title compound as a white foam.
1HNMR: consistent with structure.
HPLC: method A; Rt = 11.4 min; 97%
FABMS: M + 1 at 506
Analysis calculated for C25H35N3O6S + 0.25 chloroform + 0.20 water
C, 56.26; H, 6.67; N, 7.79
Found: C, 56.27; H, 6.55; N, 7.53
EXAMPLE 50
Figure imgf000076_0002
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.
1HNMR: consistent with structure.
HPLC: method A; Rt = 10.82 min; 98%
Analysis calculated for C25H36N4O4S + 0.25 hexanes + 0.50 methylene chloride.
C, 58.68; H, 7.39; N, 10.14
Found: C, 58.73; H, 7.23; N, 10.22
EXAMPLE 51
Figure imgf000077_0001
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.
1HNMR: consistent with structure.
TLC: Rt = 0.4 (10% methanol in methylene chloride)
FABMS: M + 1 at 547
Analysis calculated for C27H37N4O6S + 0.95 trifluoroacetic acid C, 53.08; H, 5.85; N, 8.57
Found: C, 52.97; H, 6.08; N, 8.17
TABLE
In addition to those compounds specifically exemplified above, additional compounds of the present invention are set forth in tabular form below. These compounds are synthesized by use of the synthetic routes and methods described in the above Schemes and Examples and variations thereof well known to those of ordinary skill in the art, and not requiring undue experimentation. All variables listed in the Tables below are with reference to the following generic structure:
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
TABLE (CONT'D)
Figure imgf000085_0001
EXAMPLE 52
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). IC50 (the concentration of tested compound that inhibits 50% of OT) was reported, unless otherwise noted.
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-Vi 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.
Example Result For [3H]OT
29 70% inhib. @ 1000 nM
32 29 nM
38 4.9 nM
44 1.0 nM
48 67 nM
49 68 nM
While the invention has been described and illustrated with reference to certain prefened 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 prefened 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 as is reasonable.

Claims

WHAT IS CLAIMED IS:
A compound of the formula
Figure imgf000088_0001
or a pharmaceutically acceptable salt thereof, wherein
X is
Figure imgf000088_0002
a is a single or double bond,
R is
Het, wherein
Het is
a substituted saturated or unsaturated heterocyclic ring wherein said substituents are independently one or more of R1, R2, R3, Alk-R1,
Alk-R2, Alk-R3, -NHC(O)-Alk-R2R3, -NR5-Alk-R2R3 or Alk-R2R3; where Alk is C1-10 alkyl and R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C2-10 alkenyl, methylene, C1-10 alkoxycarbonyl, C1-10 alkoxycarbonyl- C1-10 alkylamino, C1-10 alkoxycarbonylamino, C1-10 alkylamino- C1-10 alkylaminocarbonyl, C1-10 alkylcarbonylamino, -S-R4, C1-10 alkylcarbonyloxy, C1-10 alkylsulfonyl, C1-10 alkylthio, amino, amino C1-10 alkylcarbonylamino, amino C1-10 alkylamino,
carbonylamino, carbamoyl, carboxyl C1-10 alkylamino, carboxyl, cyano, di-C1-10 alkylamino, di-C1-10 alkylamino-C1-10 alkylamino, di-C1-10 alkylamino-C1-10 alkylthio, di-C1-10 alkylamino- C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl,
hydroxyl C1-10 alkylamino, imidazolyl, imidazolyl amino,
imidazolyl C1-10 alkylamino, imidazolyl C1-10 alkylaminocarbonyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, pynolidinyl, sulfonyl, tetrazolyl C1-10 alkyl-carbonylamino, tetrazolylaminocarbonyl, phosphoryl, phosphoryl C1-10 alkylamino and thiono;
R4 is selected from the group consisting of imidazolyl,
C1-10 alkoxycarbonyl-C1-10 alkyl, di-C1-10 alkylamino-C1-10 alkyl and C1 -5 alkyl; and
R5 is selected from the group consisting of hydrogen and C1 -5 alkyl.
2. The compound as claimed in Claim 1 , wherein
Het is
a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocycli c or 7 to 10 membered heterobicyclic ring containing 1, 2 or 3 nitrogen atoms, and R1 , R2 and R3 are
independently selected from the group consisting of hydrogen, halogen, C2-10 alkenyl, methylene, C1-10 alkoxycarbonyl,
C1-10 alkoxycarbonyl-Cl-io alkylamino, C1-10 alkylcarbonylamino, C1-10 alkylcarbonyloxy, C1-10 alkylsulfonyl, -S-R4, amino,
amino-C1 - 10 alkylcarbonylamino, amino C1-10 alkylamino,
carbamoyl, carboxyl C1 -10 alkylamino, carboxyl, cyano,
di-C1-10 alkylamino, di-C1-10 alkylamino-C1-10 alkylamino, di-C1-10 alkylamino-C1-10 alkylthio, di-C1-10 alkylamino- C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl,
hydroxyl C1-10 alkylamino, imidazolyl, imidazolyl amino,
imidazolyl C1-10 alkylamino, morpholinyl, thiomorpholinyl,
dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C1-10 alkylamino and thiono.
3. The compound as claimed in Claim 2, wherein said bicyclic ring is bonded to one of said heterocycli c or heterobicyclic ring's nitrogen atoms.
4. The compound as claimed in Claim 3, wherein X is
Figure imgf000090_0001
and R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C2-10 alkenyl, C1-10 alkoxycarbonyl,
C1-10 alkoxycarbonyl-C1-10 alkylamino, C1-10 alkylcarbonylamino, C1-10 alkylsulfonyl, -S-R4, amino, amino-C1-10 alkylcarbonylamino, amino C1-10 alkylamino, carbamoyl, carboxyl, cyano,
di-C1-10 alkylamino, di-C1-10 alkylamino-C1 -10 alkylamino, di-C1-10 alkylamino-C1-10 alkylthio, guanidinyl, hydroxyl,
hydroxyl C1-10 alkylamino, imidazolyl, imidazolyl amino,
imidazolyl C1-10 alkylamino, morpholinyl, thiomorpholinyl,
dioxothiomorpholinyl, indolyl, oxo, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C1-10 alkylamino and thiono.
5. The compound as claimed in Claim 3, wherein Het is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, pynolyl, dihydropynolyl, pyrrolidinyl, piperazinyl, triazaspirodecane, pynolo-isoxazole, pynolo-pyrazole and pynolo- pyrrole.
6. The compound as claimed in Claim 1 , wherein X is
Figure imgf000091_0001
R is
Het, wherein
Het is
a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocycli c ring containing 1, or 2 nitrogen atoms that is bonded to said bicyclic ring at one of said heterocycli c ring's nitrogen atoms, wherein said substituents are independently one or more of R1, R2, R3, Alk-R1, Alk-R2 ,Alk-R3 or Alk-R2R3; and
where Alk is C1-10 alkyl and R1, R2 and R3 are independently selected from the group consisting of hydrogen, C2- 10 alkenyl,
C1-10 alkoxycarbonyl, C1-10 alkoxycarbonyl-C1 - 10 alkylamino, C1-10 alkoxycarbonylamino, C1-10 alkylamino- C1 - 10 alkylaminocarbonyl, C1-10 alkylcarbonylamino,
C1-10 alkylcarbonyloxy, C1-10 alkylsulfonyl, C1-10 alkylthio, amino, amino-C1-10 alkylcarbonylamino, carbonylamino,
carboxyl C1-10 alkylamino, carboxyl, cyano, di-C1-10 alkylamino, di-C1-10 alkylamino C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl, imidazolyl C1-10 alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino, piperizinyl, pynolidinyl, sulfonyl,
tetrazolyl C1-10 alkylcarbonylamino, tetrazolylaminocarbonyl and thiono.
7. The compound as claimed in Claim 6, wherein a is a single bond, and R1 , R2 and R3 are independently selected from the group consisting of hydrogen, C2-10 alkenyl, C1-10 alkoxycarbonyl, C1-10 alkoxycarbonyl-C1-10 alkylamino, C1-10 alkylcarbonylamino, C1-10 alkylcarbonyloxy,
C1-10 alkylsulfonyl, amino, amino-C1-10 alkylcarbonylamino, carbonylamino, carboxyl, cyano, di-C1-10 alkylamino,
di-C1-10 alkylamino-C1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl, imidazolyl C1-10 alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino, piperazinyl, sulfonyl and thiono.
8. The compound as claimed in Claim 7, wherein Het is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, pynolyl, dihydropynolyl, pynolidinyl and piperazinyl.
9. The compound as claimed in Claim 2, wherein X is
Figure imgf000092_0001
and R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C2- 10 alkenyl, C1-10 alkoxycarbonyl,
C1-10 alkoxycarbonyl-C1-10 alkylamino, C1-10 alkylcarbonylamino, C1-10 alkylcarbonyloxy, C1-10 alkylsulfonyl, -S-R4, amino,
amino-C1-10 alkylcarbonylamino, amino C1-10 alkylamino,
carbamoyl, carboxyl, cyano, di-C1-10 alkylamino,
di-C1-10 alkylamino-C1-10 alkylamino, di-C1-10 alkylamino- C1-10 alkylthio, guanidinyl, hydroxyl, hydroxyl C1-10 alkylamino, imidazolyl, imidazolyl amino, imidazolyl C1-10 alkylamino,
morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C1-10 alkylamino and thiono.
10. The compound as claimed in Claim 9, wherein
R1, R2 and R3 are independently selected from the group consisting of hydrogen, C1-10 alkylcarbonyloxy, amino, hydroxyl, oxo, phosphoryl and oxiranyl.
11. The compound as claimed in Claim 5, selected from the group consisting of
Figure imgf000093_0001
Figure imgf000094_0001
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in Claim 1, sufficient to antagonize oxytocin from binding to its receptor site.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in Claim 1 sufficient to prevent preterm labor in a mammal in need thereof.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in Claim 1, sufficient to stop labor preparatory to cesarian delivery.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in Claim 1, sufficient to treat dysmenonhea.
16. A method of antagonizing oxytocin from binding to its receptor site in a mammal, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
17. 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 the compound as claimed in Claim 1.
18. A method of stopping labor preparatory to cesarian delivery in a mammal in need thereof, comprising the step of
administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
19. A method of treating dysmenonhea in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
20. A compound of the formula
Figure imgf000095_0001
or a pharmaceutically acceptable salt thereof, wherein
X is
Figure imgf000096_0001
a and b represent a single or double bond,
R is selected from the group consisting of
Figure imgf000096_0002
R2 is selected from the group consisting of -AlkR5R6,
-NH-C(O)-Alk-R7R8, -N(R4)-Alk-R7R8,
amino C1-10 alkylcarbonylamino, piperidinylamino,
oxiranyl C1-10 alkyl, imidazolylamino, C1-10 alkoxycarbonyloxy, hydroxyl, phosphoryl, -S-R9, C1-10 alkylcarbonyloxy and
C1-10 alkylcarbonylamino;
Alk is C1-10 alkyl; R3 is selected from the group consisting of hydrogen, hydroxyl, phosphoryl, C1-10 alkylcarbonyloxy and C1-10 alkoxycarbonyl;
R4 is selected from the group consisting of hydrogen, benzyl and C1-10 alkyl;
R5 and R6 are independently selected from the group consisting of hydroxyl, di-C1-10 alkylamino, piperazinyl, halogen, phosphoryl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl,
hydroxyl C1-10 alkylamino, cyano and -SCH3;
R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, hydroxyl C1-10 alkyl, C1-10 alkylcarbonylamino, amino, phosphoryl, imidazolyl, di-C1-10 alkylamino, guanidinyl, C1-10 alkoxycarbonyl, carboxyl and C1-10 alkoxycarbonylamino;
R9 is selected from the group consisting of di-C1-10 alkylamino- C1 -10 alkyl, imidazolyl and C1-10 alkoxycarbonyl-C1-10 alkyl;
provided that R5 and R6 cannot both be hydroxyl.
PCT/US1993/012565 1991-09-16 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists WO1994014438A1 (en)

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JP6515459A JPH08505150A (en) 1992-12-23 1993-12-23 Hydantoin- and succinimide-substituted derivatives of spiroindanyl camphorsulfonyloxytocin antagonists
AU59601/94A AU690534B2 (en) 1992-12-23 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists
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

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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
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Cited By (9)

* Cited by examiner, † Cited by third party
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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 (en) * 1995-02-27 1996-08-28 F. Hoffmann-La Roche Ag Dioxopyrrolo-pyrrole derivatives
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WO2003064402A1 (en) * 2002-01-31 2003-08-07 Pfizer Limited Treatment of male sexual dysfunction
KR100829262B1 (en) * 2002-01-31 2008-05-13 화이자 인코포레이티드 Treatment of male sexual dysfunction
CN100500658C (en) * 2002-01-31 2009-06-17 辉瑞大药厂 Pharmaceutical composition of male sexual dysfunction
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
JPH08505150A (en) 1996-06-04
AU690534B2 (en) 1998-04-30

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