WO2007095495A2 - Modulateurs du gcnf a la benzodiazepine destines a moduler les cellules souches - Google Patents

Modulateurs du gcnf a la benzodiazepine destines a moduler les cellules souches Download PDF

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Publication number
WO2007095495A2
WO2007095495A2 PCT/US2007/061984 US2007061984W WO2007095495A2 WO 2007095495 A2 WO2007095495 A2 WO 2007095495A2 US 2007061984 W US2007061984 W US 2007061984W WO 2007095495 A2 WO2007095495 A2 WO 2007095495A2
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Prior art keywords
alkyl
halo
compound according
alkoxy
chosen
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PCT/US2007/061984
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English (en)
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WO2007095495A3 (fr
Inventor
Andrew Roughten
Yajing Rong
Jorge Quintero
Michael Ohlmeyer
Steven Kultgen
Celia Kingsbury
Koc-Kan Ho
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Pharmacopeia, Inc.
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Publication of WO2007095495A2 publication Critical patent/WO2007095495A2/fr
Publication of WO2007095495A3 publication Critical patent/WO2007095495A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • 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
    • A61P15/16—Masculine contraceptives
    • 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
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to a genus of benzodiazepines that modulate Germ Cell Nuclear Factor (GCNF) and are therefore useful as contraceptives.
  • GCNF Germ Cell Nuclear Factor
  • GCNF Germ Cell Nuclear Factor
  • the compounds of the invention are therefore useful for contraception, for regulating stem cell differentiation, and for treating cancerous tumors reexpressing preimplantation embryonic genes. Both agonists and antagonists are useful in accomplishing the desired utility, albeit by different routes.
  • the invention relates to benzodiazepines useful for contraception, for regulating stem cell differentiation, and for treating cancerous tumors reexpressing preimplantation embryonic genes.
  • the invention relates to compounds of formula:
  • R 1 and R 2 are independently chosen from H, hydroxy, amino, halo, nitro, phenyl, (C 1 - C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-OH, O-
  • R 1 and R 2 form a 5- or 6-membered ring
  • R 3 is H or (C 1 -C 6 )alkyl
  • R 8 is chosen from H and (C 1 -C 6 )alkyl
  • R 9 is chosen from H, (C 1 -C 1 o)hydrocarbon, flouro(C 1 -C 6 )alkyl, substituted aryl, heteroaryl and (C 1 -C 6 )alkyl substituted with alkoxy, heteroaryl, substituted heteroaryl, substituted aryl, NH 2 , NH(C 1 -C 6 )alkyl, Nf(C 1 -C 6 )alkyl] 2 or fluoro alkoxy; or taken together R 8 and R 9 form a monocyclic or bicyclic carbocycle or heterocycle, said monocyclic or bicyclic carbocycle or heterocycle optionally substituted with (C 1 - C 1 o)hydrocarbon, halogen, (C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N[(d-C 6 )alkyl] 2 or fluoro alkoxy
  • Z is a monocyclic, bicyclic or tricyclic carbocycle
  • R 10 is from one to three substituents independently selected from H, halo, (C 1 - C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, NH 2 , NH(C r C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , NO 2 and OH;
  • R 11 is chosen from :
  • Q is chosen from -(CH 2 J n -, -O-, -S-, -SO-, -SO 2 -, -O-(CH 2 ) n -, -(CH 2 ),,- O-,
  • T is chosen from aryl, heteroaryl, substituted aryl and substituted heteroaryl; with the proviso that if Q is chosen from other than -(CH 2 )-, -O-, -S-, -SO- and -SO 2 -, then T must be either phenyl or phenyl substituted with halogen; and (ii), H, halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C r C 6 )alkoxy, with the provisos that, when R 11 is H
  • compositions comprising a pharmaceutically acceptable carrier and a compound as described herein.
  • the invention in another aspect relates to a method of contraception comprising administering to a mammal an amount of a compound as described herein sufficient to suppress gamete production.
  • the gamete may be an oocyte or a sperm cell.
  • the invention in another aspect relates to a method for regulating stem cell differentiation comprising exposing the stem cell to an amount of a compound as described herein sufficient to retard stem cell differentiation. [0009] In another aspect the invention relates to a method for reversing stem cell differentiation comprising exposing the stem cell to an amount of a compound as described herein sufficient to reverse stem cell differentiation.
  • the invention relates to a method for treating cancer by exposing a tumor cell reexpressing preimplantation embryonic genes to a compound as described herein in an amount sufficient to inhibit proliferation of the cancer cells.
  • This genus may be broken down into subgenera.
  • Z is phenyl
  • R 8 is not H
  • R 9 is not H
  • R 11 is chosen from H, halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, halo(C r C 6 )alkyl and halo(C r C 6 )alkoxy.
  • Embodiments of this subgenus include compounds of formula Ha:
  • R 11 is (C 3 -C 6 )alkoxy and R 12 is chosen from H, halo, (C r C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C r C 6 )alkoxy.
  • R is hydrogen and R is hydrogen or 4-fluoro.
  • Z is a tricyclic carbocycle:
  • m is zero or one
  • R 4 , R 5 , R 6 and R 7 are independently chosen from H, hydroxy, amino, halo, nitro, (C 1 - C 6 )alkyl, (CrC 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo (Q-C 6 ⁇ lkoxy.
  • Z is phenyl and R 11 is -Q-T. Embodiments of genus IV may be described by the general formula
  • R 4 , R 5 , R 6 and R 7 are independently chosen from H, hydroxy, amino, halo, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and 1IaIo(C 1 - C 6 )alkoxy, with the proviso that when Q is other than -(CH 2 )-, -O-, -S-, -SO- and - SO 2 -, R must be halogen and R must be H or halogen.
  • R and R taken together form a bicyclic carbocycle, such as a spiro-attached indane.
  • a bicyclic carbocycle such as a spiro-attached indane.
  • R 8 is H; and R 9 is chosen from H, (C 1 - C 1 o)hydrocarbon and [optionally substituted phenyl](C 1 -C 6 )alkyl.
  • R 4 and R 5 are H.
  • R 9 is (C 3 -C 1 o)alkyl; in many others R is
  • R 12a is H, -OCH3 or halogen.
  • R 1 and R 2 are chosen from H, halogen, hydroxy, methoxy, -NH 2 , -NO 2 , phenyl and methyl and R 3 is H. Examples of such compounds include those of formula
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl groups are those of C 2 0 or below.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
  • C 1 to C 1 o hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylm ethyl, camphoryl and naphthylethyl.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower- alkoxy refers to groups containing one to four carbons.
  • Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue maybe replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10- membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
  • the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene and naphthalene.
  • the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl, e.g. benzyl, phenethyl and the like.
  • alkyl e.g. benzyl, phenethyl and the like.
  • [substituted phenyl](C 1 -C 6 )alkyl is intended to encompass substituents of formula
  • Heteroaryl-alkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • hetero cycles examples include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydro isoquinoline, benzo furan, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
  • heterocyclyl residues additionally include pip erazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo- pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, lmidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,
  • Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, suboxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or hetero aryloxy.
  • halogen and halo refer to fluorine, chlorine, bromine or iodine.
  • Some of the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereo isomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include 3 H, 14 C, 35 S, 18 F, 36 Cl and 125 I, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples by substituting a readily available radiolabeled reagent for a non-radio labeled reagent. Because of the high affinity for the GCNF active site, radiolabeled compounds of the invention are useful for GCNF assays, and even unlabelled compounds may be used for x-ray crystallographic studies.
  • the present invention further provides pharmaceutical compositions comprising as active agents, the compounds described herein.
  • a "pharmaceutical composition” refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvents thereof, with other chemical components such as physiologically suitable carriers and excipients.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • Compounds described herein can be formulated as pharmaceutical compositions and administered to a mammalian subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal or subcutaneous routes.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylm ethyl- cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
  • enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment.
  • Pharmaceutical compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer.
  • physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated may be used in the composition.
  • penetrants including for example DMSO or polyethylene glycol, are known in the art.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide.
  • a suitable propellant e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e. g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.
  • the compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • the amount of a composition to be administered will, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician.
  • the compounds of the invention may be administered orally or via injection at a dose from 0.001 to 2500 mg/kg per day.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • solvate refers to a compound of Formula I - IV in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent.
  • the solvate is typically dried or azeotroped under ambient conditions.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all eye lodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • preventing refers to administering a medicament beforehand to forestall or obtund an attack
  • prevent is not an absolute term.
  • the term “prevent” is not an absolute term.
  • the medical art it is understood to refer to the prophylactic administration of a drug to substantially dimmish the likelihood or seriousness of a condition, and this is the sense intended herein.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient.
  • a packaging device include metal or plastic foil, such as a blister pack and a nebulizer for inhalation.
  • the packaging device or dispenser may be accompanied by instructions for administration.
  • Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be placed in an appropriate container and labeled for treatment of an indicated condition.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the starting materials are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.
  • Procedure A Preparation of (5)-4- [2-(4-Chloro-phenylsulfanyl)-b enzyl]-3 - furan-2-ylmethyl-3,4-dihydro- lH-benzo [e] [ 1 ,4] diazep ine-2,5-dione [0058] Procedure A - Wang-Fmoc- Amino acid.
  • Procedure A Step 1.
  • the resin-bound N-Fmoc-L-2-Furyl- AIa-OH 0.5 g was suspended in 30% piperidine/DMF (20 mL), agitated for 2 h, then filtered and washed with 20 mL of DMF (3x) and 2% AcOH/DMF.
  • Procedure A Step 2. To the resin-bound AA was added 2-(4-chloro- phenylsulfanyl)-benzaldehyde (0.49 g, 3 equiv) and 2% AcOH/DMF (15 mL). The mixture was shaken at RT for 2 h when sodium cyanoboro hydride (1 M/THF, 6.60 mL, 10 equiv.) was added and shaken for a further 16 h. The resins were drained, and washed with 20 mL portions of DMF (3x) and DCM (3x).
  • Procedure A - Step 3 To a suspension of the resin (0.2g, 0.265mmol), DIEA (0.23 mL, 5 equiv) in DCM (20 mL) was added 2-azido-benzoyl chloride (0.144 g, 3 equiv.). The resin mixture was shaken at RT for 16 h, then the vessel was drained and the resins washed with 20 mL portions of DCM (3x) and xylene (3x).
  • Procedure A - Step 4 The resin-bound azide was transferred to a reaction flask, a stirring bar and anhydrous xylene (20 mL) were added and the suspension was flushed with Ar for 5 min. Tri- «-butylphosphine (0.2 mL, 3 equiv.) was added and the mixture was heated at 60 0 C for 16 h with gentle stirring. Once cooled the mixture was transferred to a shaker vessel, drained and rinsed with toluene (2x) and DCM (3x).
  • Procedure A Step 5. Resin-bound product was suspended in 5% TFA/DCM and shaken at RT for 2 h. The filtrate and washing from 15 mL portions of methanol (1 x) and DCM (Ix) from the resins were collected, combined and evaporated.
  • Procedure B Preparation of 4-[2-(4-chloro-phenylsulfanyi)-benzyl]-r,3'- dihydro-spiro[3H-l,4-benzodiazepine-3,2'-[2H]indene]-2,5(lH,4H)-dione
  • Procedure B Amino acid ester. To a mixture of 2-aminoindan-2- carboxylic acid hydrochloride (0.5g, Acros) in 25mL anhydrous methanol was added chlorotrimethylsilane (1.5mL). After stirring for lOOh at room temperature, the volatiles were removed in vacuo to cleanly yield 2-aminoindan-2-carboxylic acid methyl ester hydrochloride (0.58g).
  • Procedure B Step 1. A mixture of 2-aminoindan-2-carboxylic acid methyl ester hydrochloride (0.58g, 2.54mmol), 2-(4-chlorophenylthio)benzaldehyde (0.7Og, 2.8mmol), and DIEA(0.49mL, 2.8mmol) in absolute ethanol (12mL) was stirred at room temperature overnight. The volatiles were removed in vacuo, and the resulting imine was dissolved in anhydrous methanol (15mL). Sodium borohydride (192mg, 5.08mmol) was added in portions, and the reaction was allowed to stir for 2h.
  • Procedure B Step 2. To a solution of 2-[2-(4-chlorophenylthio)- benzylamino]-indan-2-carboxylic acid methyl ester (164mg, 0.38mmol) and pyridine (125uL) in methylene chloride (3mL) was added 2-nitrobenzoyl chloride (9OuL, Aldrich). After stirring at room temperature for approximately 90 hours, the reaction mixture was diluted with methylene chloride, washed with a saturated sodium bicarbonate solution, dried over MgSO 4 , and the volatiles were removed in vacuo.
  • the compound was purified by flash chromatography, using 35% ethyl acetate/hexanes as the mobile phase to give 2-[[2-(4-chlorophenylthio)-benzyl]-(2- nitrobenzoyl)-amino]-indan-2-carboxylic acid methyl ester (150mg).
  • Procedure B Step 3
  • a solution of potassium carbonate (0.19g) and sodium hydrosulf ⁇ te (0.25 g) in water (2mL) was added to a mixture of 2-[[2-(4- chlorophenylthio)-benzyl]-(2-nitrobenzoyl)-amino]-indan-2-carboxylic acid methyl ester (0.13g) and ethyl viologen dibromide (5mg) in a 8:1 mixture of methylene chloride and water (4mL).
  • the mixture was heated to 40 0 C under argon for 48h, cooled to room temperature, diluted with water, and extracted with methylene chloride.
  • Procedure B Step 4.
  • a solution of 2- ⁇ (2-amino-benzoyl)-[2-(4- chlorophenylthio)-benzyl]-amino ⁇ -indan-2-carboxylic acid methyl ester (56mg) and p-toluenesulfonic acid monohydrate (5mg) in DMSO (5mL) was heated to 120 0 C for 2Oh.
  • Procedure C Preparation of (5)-3-Benzyl-4-[2-(4-chloro-phenyloxy)- phenyl]-3,4-dihydro- lH-benzo [e] [ l,4]diazepine-2,5 -dione [0073] Procedure C- Step 1. The methods of Evans and Chan were used to prepare 2-(4-chlorophenoxy)-bromobenzene in 13% yield. 1 H NMR (CDCl 3 ): ⁇ 7.63 (dd, IH), 7.31-7.25 (m, 3H), 7.06 (ddd, IH), 6.97 (dd, IH), 6.88 (d, 2H).
  • Procedure C- Step 3 Trimethylsilyl diazomethane (0.4 mL, 2M/hexane) was added to a solution of (iS)-2-[2-(4-Chloro-phenoxy)-phenylamino]-3-phenyl- propionic acid (0.13g) in DCM/MeOH (1:1, 6 mL).
  • Procedure C- Step 5 A solution of (iS)-2- ⁇ (2-Azido-benzoyl)-[2-(4-chloro- phenoxy)-phenyl]-amino ⁇ -3-phenyl-propionic acid methyl ester (11 mg) in anhydrous toluene (0.5 mL)is flushed with Ar for 5 min, then tri- «-butylphosphine (8 uL) was added via syringe. The mixture is heated at 60 C for 16 h, allowed to cool and solvents removed. A solution of TF A/H 2 O/THF (1: 1:12.5, 0.5 mL) was added to the crude mixture and stirred overnight at RT.
  • Procedure D Preparation of (S)-3-Benzyl-4-(4'-chloro-biphenyl-3- ylmethyl)-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (xx).
  • Procedure E Preparation of 4-[2-(4-Chloro-phenylsulfanyl)-benzyl]-9- hydroxy- 1 ',3 '-dihydro-spiro [3H- l,4-benzodiazepine-3,2'-[2H]indene]-2,5( IH, 4H)- dione [0083] A solution of 4-[2-(4-chloro-phenylsulfanyl)-benzyl]-9-methoxy- l',3'- dihydro-spiro[3H-l,4-benzodiazepine-3,2'-[2H]indene]-2,5(lH,4H)-dione (Example X, 23.2mg) in 2mL methylene chloride was cooled to -78°C under argon.
  • Example 1 4-[2-(4-Chloro-phenylsulfanyl)-benzyl]-9-methoxy-r,3'- dihydro-spiro[3H-l,4-benzodiazepine-3,2'-[2H]indene]-2,5(lH,4H)-dione.
  • This compound was prepared in a manner similar to Procedure B, except that 2-azido-3-methoxy-benzoyl chloride was used instead of the nitrobenzoyl chloride in Step 2.
  • the compound was purified by flash chromatography, using 40% ethyl acetate/hexanes as the mobile phase to give 2- ⁇ (2-azido-3-methoxy-benzoyl)-[2-(4-chloro-phenylsulfanyl)-benzyl]-amino ⁇ -indan-2- carboxylic acid methyl ester (60mg).
  • Example 3 Sulfur oxidation. Preparation of (R)-3-Benzyl-6-chloro-4-[2-(4- chloro-b enzene sulfinyl)-benzyl]-3,4-dihydro- lH-benzo [e] [ 1 ,4]diazep ine-2, 5-dione and (R)-3-Benzyl-6-chloro-4-[2-(4-chloro-benzenesulfonyl)-benzyl]-3,4-dihydro-lH- benzo[e][l,4]diazepine-2,5-dione.
  • L-Phenylalanine methyl ester hydrochloride 500 mg, 2.32 mmol
  • 4-Bromo- l-(4-chlorobenyl)-lH-pyrazole-5-carbaldehyde 695 mg, 2.32 mmol, Maybridge
  • 3 A molecular sieves 500 mg, ground, oven-dried
  • anhydrous methanol 5 niL
  • triethylamine (324 uL, 2.32 mmol
  • Preparation 5 Variously substituted azido benzoyl chlorides were prepared according to literature methods from commercially available anthranilic acids. The exception, 2-amino-4-methoxy-benzoic acid, was prepared following literature precedent. Illustrated in Scheme 7 is the preparation of 2-amino-4-methoxy-benzoic acid, via an oxidation/reduction pathway, and the subsequent manipulation to the desired azido benzoyl chloride. The azide was formed via a two-step procedure involving a diazonium chloride intermediary. The product acid chloride was prepared from the acid with oxalyl chloride.
  • Preparation 5 - step 4 A catalytic amount of DMF (ca. 100 uL) was added to a suspension of 2-azido-4-methoxy-benzoic acid (1.93 g) and oxalyl chloride (0.96 mL) in DCM (20 mL). The addition of DMF caused gas evolution. The mixture was stirred for 2 h at RT, until no solid remained, then the solvents were removed in vacuo to give 2-azido-4-methoxy-benzoyl chloride in 80% yield.
  • Preparation 6 - Step 1 Commercially available 4-(4-chloro-phenyl)-4-oxo- butyric acid (Aldrich) was converted to 4-(4-chloro-phenyl)-butyric acid by WoIfF- Kishner reduction (AIi, F. E. et al. J. Med Chem., 1982, 25, 947-952).
  • Preparation 7 Many benzaldehydes were prepared via standard chemical manipulation of the oxidation state of commercially available alcohols, acids, esters or nitriles. The preparation of 8-chloro-dibenzofuran-4-carbaldehyde from borane reduction and Swern oxidation from 8-chloro-dibenzofuran-4-carboxylic acid highlights this approach.
  • Preparation 8 Benzylic ethers were prepared via substitution reactions.
  • the synthesis of 2-(4-chloro-phenoxymethyl)-benzaldehyde is illustrate as an example.
  • Sodium hydride mediated coupling of 4-chlorophenol with 2-bromomethyl- benzonitrile yields a nitrile intermediate that was converted to the aldehyde with DIBAL.
  • the assay is a transactivation assay in which a chimeric protein consisting of lhe GCNF ligand binding domain (LBD) fused to the DNA binding region of the estrogen receptor alpha (ERa) stimulates transcription of an estrogen response element-lucif erase reporter gene construct in the presence of the appropriate ligand.
  • the fusion protein is comprised of lhe estrogen receptor alpha (ERa) NH-terminal region, containing domains A - D, fused to the GCNF LBD. with the fusion point located in the flexible (hinge) region.
  • the fusion protein thus contains sequences responsible for DNA recognition, nuclear localization and receptor dimeri/ation that are derived from ERa and sequence elements responsible for ligand recognition that are derived from GCNF.
  • CHO Kl Chinese hamster ovary cells were stably transfected with both the ER-luciferase reporter construct and DNA encoding the Chimeric GCNF receptor. Cells were grown in DMEM/F 12 without phenol red supplemented with 1 OOU/ml penicillin, lOO ⁇ g/ml streptomycin, 2mM glutamine and 5% charcoal-treated bovine calf serum.
  • the GCNF antagonist assay is similar to the agonist assay, except that test wells contain, in addition to the test compound, an agonist that was identified using the agonist assay.
  • Compounds 1-107 exhibited binding EC50's below 7 ⁇ M and efficacy greater than 50%.
  • Compounds 108-197 exhibited binding EC50's below 60 ⁇ M and efficacy less than 50%.

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Abstract

La présente invention concerne un genre de benzodiazépines qui module le facteur nucléaire de cellules germinales (GCNF). Les composés servent à réguler la différentiation des cellules souches et servent également de contraceptif. L'invention a également trait à d'autres modes de réalisation.
PCT/US2007/061984 2006-02-13 2007-02-12 Modulateurs du gcnf a la benzodiazepine destines a moduler les cellules souches WO2007095495A2 (fr)

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CN105461589A (zh) * 2008-05-05 2016-04-06 赛诺菲-安万特 酰基氨基取代的稠合环戊烷羧酸衍生物及它们作为药物的用途
CN105693634A (zh) * 2016-03-17 2016-06-22 清华大学 化合物及其用途
AU2017232206B2 (en) * 2011-12-28 2019-09-12 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
CN112851561A (zh) * 2021-01-29 2021-05-28 南京艾美斐生物医药科技有限公司 一种nr6a1蛋白受体抑制剂及其制备和应用
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2023174374A1 (fr) * 2022-03-16 2023-09-21 江苏恒瑞医药股份有限公司 Composé hétérocyclique fusionné, son procédé de préparation et son utilisation médicale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678784A (en) * 1984-04-11 1987-07-07 Mcneilab, Inc. Method for the treatment of LHRH diseases and conditions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678784A (en) * 1984-04-11 1987-07-07 Mcneilab, Inc. Method for the treatment of LHRH diseases and conditions

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CN105461589A (zh) * 2008-05-05 2016-04-06 赛诺菲-安万特 酰基氨基取代的稠合环戊烷羧酸衍生物及它们作为药物的用途
AU2019275607B2 (en) * 2011-12-28 2021-06-24 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
AU2017232206B2 (en) * 2011-12-28 2019-09-12 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
AU2017232206C1 (en) * 2011-12-28 2020-03-26 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
CN105693634B (zh) * 2016-03-17 2018-12-11 清华大学 化合物及其用途
CN105693634A (zh) * 2016-03-17 2016-06-22 清华大学 化合物及其用途
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
CN112851561A (zh) * 2021-01-29 2021-05-28 南京艾美斐生物医药科技有限公司 一种nr6a1蛋白受体抑制剂及其制备和应用
WO2023174374A1 (fr) * 2022-03-16 2023-09-21 江苏恒瑞医药股份有限公司 Composé hétérocyclique fusionné, son procédé de préparation et son utilisation médicale

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