EP0679084A1 - Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists - Google Patents

Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists

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Publication number
EP0679084A1
EP0679084A1 EP94905516A EP94905516A EP0679084A1 EP 0679084 A1 EP0679084 A1 EP 0679084A1 EP 94905516 A EP94905516 A EP 94905516A EP 94905516 A EP94905516 A EP 94905516A EP 0679084 A1 EP0679084 A1 EP 0679084A1
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EP
European Patent Office
Prior art keywords
alkylamino
amino
imidazolyl
mmol
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP94905516A
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German (de)
English (en)
French (fr)
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EP0679084A4 (ja
Inventor
Kevin Gilbert
Doug W. Hobbs
Daniel F. Veber
Peter D. Williams
Ben E. Evans
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Merck and Co Inc
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Merck and Co Inc
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Publication of EP0679084A1 publication Critical patent/EP0679084A1/en
Publication of EP0679084A4 publication Critical patent/EP0679084A4/xx
Withdrawn legal-status Critical Current

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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
  • Het is a substituted saturated or unsaturated heterocycHc ring wherein said substituents are independently one or more of Rl, R2, R3, Alk-Rl,
  • 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 heterocycHc or 7 to 10 membered heterobicyclic ring containing 1 , 2 or 3 nitrogen atoms, wherein said substituents are independently one or more of Rl, R2, R3, Alk-Rl, Alk-R2, Alk-R3, -NHC(0)-Alk-R2R3, -NR5-Alk-R2R3 0 r Alk-R2R3 ; where Alk is Cl-10 alkyl and Rl, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C2-10 alkenyl, methylene, Cl-10 alkoxycarbonyl, Cl-10 alkoxycarbonyl-Cl-l ⁇ alkylamino, Cl-10 alkylcarbonylamino, Cl-10 alkylsulfonyl, -S-R4, amino, amino-Cl-10 alkylcarbon
  • Het is a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocycHc ring containing 1 , or 2 nitrogen atoms that is bonded to said bicyclic ring at one of said heterocycHc ring's nitrogen atoms, wherein said substituents are independently one or more of Rl, R2, R3, Alk-Rl, Alk-R2, Alk-R3 or Alk-R2R3 ; and where Alk is Cl-10 alkyl and Rl, R2 and R3 are independently selected from the group consisting of hydrogen, C2-10 alkenyl, Cl-10 alkoxycarbonyl, Cl-10 alkoxycarbonyl-Ci-10 alkylamino, Cl-10 alkoxycarbonylamino, Cl-10 alkylamino-Ci-io alkylaminocarbonyl, Cl-10 alkylcarbonyl ⁇ amino, Cl-10 alkylcarbonyloxy, Cl-10 alkylsulfon
  • 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., Cl-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 heterocycHc 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 heterocycHc 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 heterocycHc ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocycHc elements examples include piperidinyl, piperazinyl, azepinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, 4-piperidonyl, imidizolyl, imidazolinyl, imidazolidinyl, triazolyl, triazolinyl, triazolidinyl, mo ⁇ holinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, oxadiazolyl, triazaspirodecane, pyrrolo-iso
  • oxiranyl shall refer to the substituent o / ⁇
  • dioxothiomo ⁇ holinyl shall refer to the
  • 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.
  • 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.
  • 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 inco ⁇ 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.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention can be prepared readily according to the following reaction Schemes (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.
  • TFA B CH3CN containing 0.1% by vol. TFA 2.0 mL/min flow rate 12 cm Cl8 reverse phase column
  • 25 B CH3CN containing 0.1% by vol. phosphoric acid 2.0 mL/min flow rate 12 cm Cl8 reverse phase column UV detection (215 nm)
  • Di-t-butyl dicarbonate 31g, 0.14 mole available from Aldrich
  • 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 triethyl ⁇ amine was added. After a total of 2.5 hours, the mixture was poured onto a silica gel column packed with CH2 ⁇ 2:hexane (1:1), and eluted with 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).
  • l'-(t-Butyloxycarbonyl)spiro(indene-l,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.
  • 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.
  • 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.
  • 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 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.
  • 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-oc-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.
  • 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 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
  • Succinic anhydride (12 mg, 0.12 mmols) and endo-(lS)-l'- (((2-amino-7,7-dimethylbicyclo-(2.2.1 )-hept- 1 -yl)methyl)sulfonyl)- spiro(lH-indane-l,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 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 8O0C on a steam bath and then st ⁇ red 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 (MgS04), filtered and concentrated under reduced pressure.
  • the purified diamine (0.51 g; 1.1 mmol) was dissolved in CHCI3 and to the solution was added l,l'-carbonyldi- imidazole (0.19 g; 1.2 mmol).
  • 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-(lS)-l'-(((2-amino-7,7- dimethylbicyclo-(2.2.
  • 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 (lS)-l'-(((7,7-dimethyl-2- oxobicyclo[2.2.1 ]hept- 1 -yl)methyl)sulf onyl)spiro( 1 H-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 (lS)-l'-(((7,7-dimethyl-2-oxiranebicyclo- [2.2.1 ]hept- 1 -yl)methyl)sulf onyl) spiro-( 1 H-indene- 1 ,4'-piperidine).
  • 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). iHNMR: consistent with structure.
  • 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. iHNMR: consistent with structure.
  • 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]-l'[[[2-amino-7,7- dimethylbicyclo[2.2.1 ]-hept- 1 yl] -methyl] -sulfonyl] spiro[ 1 H-indan- 1 -4'- piperidine], and Boc-(L)-Aspartic acid beta-methyl ester was used instead of Boc-(D)-Aspartic acid beta-benzyl ester.
  • iHNMR consistent with structure.
  • AVP [3H]Vasopressin
  • AVP-Vi sites 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 ⁇ M 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.

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EP94905516A 1992-12-23 1993-12-23 Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists Withdrawn EP0679084A1 (en)

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US5464788A (en) * 1994-03-24 1995-11-07 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists
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US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
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AU690534B2 (en) 1998-04-30
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