WO2007095495A2 - Benzodiazepine gcnf modulators for stem cell modulation - Google Patents
Benzodiazepine gcnf modulators for stem cell modulation Download PDFInfo
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- 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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- 210000000130 stem cell Anatomy 0.000 title claims abstract description 18
- 229940049706 benzodiazepine Drugs 0.000 title abstract description 6
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- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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%.
Abstract
A genus of benzodiazepines that modulate Germ Cell Nuclear Factor (GCNF) is disclosed. The compounds are useful to regulate stem cell differentiation and as contraceptives. Other embodiments are also disclosed.
Description
BENZODIAZEPINE GCNF MODULATORS FOR STEM CELL
MODULATION
Field of the Invention
[0001] The invention relates to a genus of benzodiazepines that modulate Germ Cell Nuclear Factor (GCNF) and are therefore useful as contraceptives.
Background of the Invention
[0002] The nuclear orphan receptor Germ Cell Nuclear Factor (GCNF) is one of the 50 members of the nuclear receptor gene superfamily. GCNF appears not to have any close homologues in any species examined thus far. Gene knock-out studies have shown that GCNF is essential for embryonic survival. The function of GCNF also appears to be critical in both oogenesis and spermatogenesis [Chung and Cooney, Int. J.Bioch.Cell Biol. 33, 1141-1146 (2001)]. In a slightly different vein, studies by Gu et al [Mol.Cellular Biol. 25, 1-13 (2005)] indicate that "a GCNF antagonist would be predicted to inhibit the repression of pluripotency genes, leading to maintenance of pluripotency." Additionally, it is known that human preimplantation embryonic stem cells are similar in phenotype to cancer cells. Both types of cells undergo deprogramming to a proliferative stem cell state and become potentially immortal and invasive. Monk et al. [Oncogene 20, 8085-8091 (2001)] have shown that several embryonic genes, as well as OCT4, are expressed in human tumors, but not expressed in normal somatic tissues. It is predicted that these preimplantation embryonic genes can serve as targets in cancer treatment.
[0003] Accordingly, 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.
[0004] General methods for synthesizing benzodiazepines are described in U.S patent 5,962,337, which is incorporated herein by reference.
Summary of the Invention
[0005] The invention relates to benzodiazepines useful for contraception, for regulating stem cell differentiation, and for treating cancerous tumors reexpressing preimplantation embryonic genes.
In one aspect the invention relates to compounds of formula:
R1 and R2 are independently chosen from H, hydroxy, amino, halo, nitro, phenyl, (C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkyl-OH, O-
(C1-C6)alkyl-OH, COOH and C(O)O(C1-C6)alkyl; or taken together,
R1 and R2 form a 5- or 6-membered ring;
R3 is H or (C1-C6)alkyl;
R8 is chosen from H and (C1-C6)alkyl;
R9 is chosen from H, (C1-C1o)hydrocarbon, flouro(C1-C6)alkyl, substituted aryl, heteroaryl and (C1-C6)alkyl substituted with alkoxy, heteroaryl, substituted heteroaryl, substituted aryl, NH2, NH(C1-C6)alkyl, Nf(C1 -C6)alkyl]2 or fluoro alkoxy; or taken together R8 and R9 form a monocyclic or bicyclic carbocycle or heterocycle, said monocyclic or bicyclic carbocycle or heterocycle optionally substituted with (C1- C1o)hydrocarbon, halogen, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(d-C6)alkyl]2 or fluoro alkoxy
Z is a monocyclic, bicyclic or tricyclic carbocycle;
R10 is from one to three substituents independently selected from H, halo, (C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, NH2, NH(CrC6)alkyl, N[(C1-C6)alkyl]2, NO2 and OH; R11 is chosen from :
(i) -Q-T wherein:
Q is chosen from -(CH2Jn-, -O-, -S-, -SO-, -SO2-, -O-(CH2)n-, -(CH2),,- O-,
-S-(CH2)n-, -(CH2VS-, -NH- and -N[(CrC6)alkyl]-, - CHNH(C1 -C6)alkyl and -CHN[(C1-C6)alkyl]2-; and T is chosen from aryl, heteroaryl, substituted aryl and substituted heteroaryl; with the proviso that if Q is chosen from other than -(CH2)-, -O-, -S-, -SO- and -SO2-, then T must be either phenyl or phenyl substituted with halogen; and (ii), H, halo, (CrC6)alkyl, (CrC6)alkoxy, halo(C1-C6)alkyl and halo(Cr C6)alkoxy, with the provisos that, when R11 is H, halo, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or halo(d-C6)alkoxy, then (a) R8 is not H and R9 is not H, (C1-C1o)alkyl or phenethyl, and (b) R8 and R9 taken together do not form a monocyclic carbocycle; and n at each occurrence is O, 1 or 2.
[0006] In another aspect the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound as described herein.
[0007] In another aspect the invention 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.
[0008] In another aspect the invention 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.
[0010] In yet another aspect, 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.
Detailed Description of the Invention
[0011] Throughout this specification the substituents are defined when introduced and retain their definitions.
[0012] In a first aspect the invention relates to compounds of formula I:
[0013] This genus may be broken down into subgenera. In one subgenus, subgenus II, Z is phenyl, R8 is not H, R9 is not H, (C1-C1o)alkyl or phenethyl and R11 is chosen from H, halo, (CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkyl and halo(CrC6)alkoxy. Embodiments of this subgenus include compounds of formula Ha:
Ha
[0014] In some of these embodiments R11 is (C3-C6)alkoxy and R12 is chosen from H, halo, (CrC6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(CrC6)alkoxy. In many examples of this embodiment, R is hydrogen and R is hydrogen or 4-fluoro.
[0015] In a second subgenus of formula III, Z is a tricyclic carbocycle:
[0016] In subgenus III, m is zero or one; and
R4, R5, R6 and R7 are independently chosen from H, hydroxy, amino, halo, nitro, (C1- C6)alkyl, (CrC6)alkoxy, halo(C1-C6)alkyl and halo (Q-C6^lkoxy.
[0017] In a third subgenus IV, Z is phenyl and R11 is -Q-T. Embodiments of genus IV may be described by the general formula
In these compounds R4, R5, R6 and R7 are independently chosen from H, hydroxy, amino, halo, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and 1IaIo(C1- C6)alkoxy, with the proviso that when Q is other than -(CH2)-, -O-, -S-, -SO- and - SO2-, R must be halogen and R must be H or halogen.
[0018] In one subset of subgenus IV, R and R taken together form a bicyclic carbocycle, such as a spiro-attached indane. These compounds may be represented by formula FVa.
[0019] In another subset of subgenus IV, R8 is H; and R9 is chosen from H, (C1- C1o)hydrocarbon and [optionally substituted phenyl](C1-C6)alkyl. In many
embodiments R4 and R5 are H. In many embodiments R9 is (C3-C1o)alkyl; in many others R is
[0020] In many embodiments of the foregoing subgenera II- IV, R1 and R2 are chosen from H, halogen, hydroxy, methoxy, -NH2, -NO2, phenyl and methyl and R3 is H. Examples of such compounds include those of formula
[0021] All of the compounds falling within the foregoing parent genera and their subgenera are useful as GCNF modulators. It may be found upon examination that
species and genera not presently excluded from the claims are not patentable to the inventors in this application. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention. The invention, in a composition aspect, is all compounds of formula I except those that are in the public's possession.
Definitions
[0022] For convenience and clarity certain terms employed in the specification, examples and claims are described herein.
[0023] 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 C20 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.
[0024] C1 to C1o hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylm ethyl, camphoryl and naphthylethyl.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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. For example, [substituted phenyl](C1-C6)alkyl is intended to encompass substituents of formula
in which the wavy line indicates the point of attachment to the parent structure. 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.
[0029] 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. Examples of hetero cycles 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. It is to be noted that heteroaryl is a
subset of heterocycle in which the heterocycle is aromatic. Examples of 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, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl. A nitrogenous heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other hetero atoms.
[0030] 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.
[0031] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine.
[0032] 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. When 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. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double
bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion.
[0033] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
[0034] It will be recognized that 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 3H, 14C, 35S, 18F, 36Cl and 125I, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3H, and carbon-14, i.e., 14C, 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.
[0035] The present invention further provides pharmaceutical compositions comprising as active agents, the compounds described herein.
[0036] As used 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.
[0037] Pharmaceutical 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.
[0038] 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.
[0039] For oral administration, 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). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
[0040] In addition, enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment.
[0041] 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.
[0042] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
[0043] For injection, 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. For transmucosal and transdermal administration, penetrants appropriate to the barrier to be permeated may be used in the composition. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.
[0044] For administration by inhalation, 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. In the case of a pressurized aerosol, 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.
[0045] Pharmaceutical 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.
[0046] 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.
[0047] Depending on the severity and responsiveness of the condition to be treated, 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.
[0048] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound. The term "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. In general, 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.
[0049] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, 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. When the compounds contain an acidic side chain, 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.
[0050] The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an attack The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term "prevent" is not an absolute term. In 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.
[0051] It should be understood that in addition to the ingredients particularly mentioned above, the 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.
[0052] The compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient. Examples of 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.
Chemical Synthesis
[0053] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, 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. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups" Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.
[0054] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference.
[0055] In general, 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
[0056] One method (Procedure A, solid phase synthesis WO97/01560) for preparing compounds of the invention is shown in Scheme 1. A typical solid support
( ' -s- ! ) would be Wang-OH resin (e.g. Advanced ChemTech). The hydroxyl terminus of the resin is esterifϊed with a Fmoc protected amino acid. Alternatively, these Wang- Amino -Acid-Fmoc entities may be commercially obtained (e.g. Advanced ChemTech). Removal of the Fmoc protecting group and subsequent reductive amination of the resulting primary amine with an aldehyde yields the resin bound secondary amine. Acylation of this resin bound amine with excess substituted 2- azidobenzoyl chlorides yields a resin linked N-(2-azidobenzoyl)amino ester that is treated with tri-w-butylphosphine. This mixture is gently stirred and heated to 60-120 0C to yield the resin-linked l,4-benzodiazepin-5-one. Subsequent cleavage of yield the l,4-benzodiazepin-2,5-dione product is accomplished with dilute TFA solutions as illustrated below in a representative example of procedure A (Scheme 1).
Scheme 1
[0057] 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. Wang resin (0.57g at 1.4 mmol/g, 0.8mmol, Advanced ChemTech) was added to a premixed (30 min) mixture of L- Fmoc-2-Furyl- AIa-OH (0.5g, 1.5 equiv., 1.25mmol), pyridine (0.7 mL, 10 equiv.), 2,6-dichlorobenzoyl chloride (0.7 mL, 6 equiv.) and DMA (20 mL) in a shaker vessel. The resin suspension was shaken at RT for 16 h, then the vessel was drained and the resin washed with 20 mL portions of DMF (3x), methanol (3x) and DCM (3x), then dried.
[0059] 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.
[0060] 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).
[0061] 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).
[0062] 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 0C 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).
[0063] 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. The crude product was purified via preparative TLC (50% EtOAc/hexanes ) to yield (iS)-4-[2-(4-chloro-phenylsulfanyl)-benzyi]-3-furan-2-
ylmethyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (22 mg, 17% overall yield) as a 1: 1 mixture of conformational isomers; 1H NMR (CDCI3): δ 8.60 (m, 2H, major and minor), 8.05 (m, 2H, major and minor), 7.55-7.05 (m, 22H, major and minor), 6.95 (m, 2H, major and minor), 6.20 (s, 2H, major), 6.05 (s, IH, minor), 5.90 (s, IH, minor), 5.35 (d, IH, major), 5.00 (m, 2H, minor), 4.55 (t, IH, minor), 4.40 (t, IH, major), 4.20 (d, IH, major), 3.30 (m, IH, minor), 3.05 (d, IH, minor), 2.80 (m, 2H, major); ESI-MS (m/z) 489 [M+H]+
Procedure B
[0064] Compounds of the invention may also be prepared via the route shown in Scheme 2. In a typical example, an amino acid is esterified, alternatively, the amino acid ester may be commercially obtained. A two-step reductive amination of a amino acid ester with a benzylic aldehyde yields the intermediated secondary amine. Acylation of the amine with 2-nitrobenzoyl chloride yields a nitro intermediate that is reduced to the aniline under electron transfer conditions. The aniline- amino -ester intermediate is cyclized with catalytic acid to yield the l,4-benzodiazepin-2,5-dione product adduct. The following is a representative example of procedure B (Scheme 2)
Scheme 2
Amino Acid ester MeOH, TMSCI
Step i
[0065] 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
[0066] 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).
[0067] 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. After removing the volatiles in vacuo, the resulting residue was dissolved in ethyl acetate, washed with 0.5M NaOH, dried over MgSO4, and rotovaced. The column was purified by flash chromatography, using 20% ethyl acetate/hexanes as the mobile phase, to yield 2-[2-(4-chlorophenylthio)-benzylamino]-indan-2-carboxylic acid methyl ester (384mg). 1H NMR (CDCl3): δ 7.51 (d, IH), 7.41-7.36 (m, HH), 3.92 (s, 2H), 3.80 (s, 3H), 3.60 (d, 2H), 3.20 (d, 2H).
[0068] 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 MgSO4, 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). 1H NMR (CDCl3): δ 8.27 (d, IH), 8.03 (dodlH), 7.53 (t, IH), 7.40 (m, 3H), 7.30 (d, IH), 7.21- 7.03 (m, 5H), 6.90 (d, 2H), 6.62 (d, 2H), 4.35 (br s, 2H), 3.82 (s, 3H), 3.40 (br s, 2H).
[0069] Procedure B - Step 3. A solution of potassium carbonate (0.19g) and sodium hydrosulfϊte (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 400C under argon for 48h, cooled to room temperature, diluted with water, and extracted with methylene chloride. The organic layers were combined, dried over MgSO4, and rotovaced. The crude compound was purified by flash chromatography, using 40% ethyl acetate/hexanes as the mobile phase to give 2-{(2-amino-benzoyl)-[2-(4- chlorophenylthio)-benzyl]-amino}-indan-2-carboxylic acid methyl ester (95mg). H NMR (CDCl3): δ 7.77 (d, IH), 7.35 (m, 2H), 7.22 (t, IH), 7.14-7.05 (m, 7H), 6.94
(dd, IH), 6.82 (m, 2H), 6.61 (d, IH), 6.42 (t, IH), 4.69 (s, 2H), 3.79 (d, 2H), 3.78 (t, IH), 3.32 (d, 2H).
[0070] 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 1200C for 2Oh. After removing the solvent in vacuo, the desired compound was purified by flash chromatography, using 40% ethyl acetate/hexanes as the mobile phase to give 4- [2-(4-chloro-phenylsulfanyl)-benzyl]-r,3'-dihydro-spiro[3H-l,4-benzodiazepine-3,2'- [2H]indene]-2,5(lH,4H)-dione (35.3mg). 1H NMR (CDCl3): δ 8.06 (dd, IH), 7.93 (br s, IH), 7.54 (t, IH), 7.49 (d, IH), 7.38-7.20 (m, 7H), 7.16-7.02 (m, 4H), 6.92-6.86 (m, 2H), 5.02 (dd, 2H), 3.08 (m, 3H); ESI-MS (m/z) 511 [M+H]+.
Procedure C
[0071] Another procedure to prepare compounds of the present invention is illustrated in Scheme 3. The overall general scheme was adapted from the literature procedure of Sugimori, T. et al. Tetrahedron, 1998, 54, 7997-8008. The bromobenzene ether starting material was prepared via literature procedures (Chan, D .M. T. et al. Tet. Lett., 1998, 39, 2933-2936 and Evans, D. A. et al. Tet. Lett., 1998, 39, 2937-2940). N-Arylation of phenylalanine with the bromobenzene ether followed by esterification gave a secondary amine that was acylated in poor yield with 2- azidobenzoyl chloride. Aza-Wittig reaction of the resulting azido-amino -ester with tri-H-butylphosphine gave the l,4-benzodiazepin-2,5-dione adduct. The synthesis of (iS)-3-Benzyl-4-[2-(4-chloro-phenyloxy)-phenyl]-3,4-dihydro-lH- benzo[e][l,4]diazepine-2,5-dione in Scheme 3 below is a representative example of this process.
Scheme 3
[0072] 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. 1H NMR (CDCl3): δ 7.63 (dd, IH), 7.31-7.25 (m, 3H), 7.06 (ddd, IH), 6.97 (dd, IH), 6.88 (d, 2H).
[0074] Procedure C- Step 2. N-Arylation of L-Phe with 2-(4-chlorophenoxy)- bromobenzene according to the procedure of Ma, D. et al. (J. Am. Chem. Soc. 1998, 120, 12459-12467) gave (£)-2-[2-(4-Chloro-phenoxy)-phenylamino]-3-phenyl- propionic acid after preparative TLC purification (elution with 50% EtOAc/hexanes ) in 58% yield; 1H NMR (CDCl3): δ 7.42-6.71 (m, 13H), 4.13 (broad s, IH), 3.13 (dd, IH), 3.05 (dd, IH); ESI-MS (m/z) 368 [M+H]+.
[0075] 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). The mixture was stirred at RT under an Ar atmosphere for 2 h, then the solvents were removed and the crude product was purified via Prep TLC (elution with 20% EtOAc/hexanes ) to give (S)-2- [2-(4-Chloro-phenoxy)-phenylamino]-3-phenyl-propionic acid methyl ester in 56% yield; 1H NMR (CDCl3): δ 7.26-6.60 (m, 13H), 4.59 (broad d, IH), 4.17 (broad q, IH), 3.62 (s, 3H) 3.10 (ddd, 2H); ESI-MS (m/z) 382 [M+H]+<
[0076] Procedure C- Step 4. 2-Azido-benzoyl chloride (110 mg) was added to a solution of (iS)-2-[2-(4-Chloro-phenoxy)-phenylamino]-3-phenyl-prop ionic acid methyl ester (77 mg) and pyridine (0.2 mL) in DCM (2 mL). The mixture was stirred at RT for 64 h, then partition between H2O and EA. The layers were separated, and the aqueous phase was extracted twice more with EA. The combined organics were evaporated and purified via prep TLC (15% EtOAc/hexanes ) to give recovered starting material (23 mg) together with (iS)-2-{(2-Azido-benzoyl)-[2-(4-chloro- phenoxy)-phenyl]-amino}-3-phenyl-propionic acid methyl ester (10% yield); 1H NMR (CDCl3): δ 7.30-6.87 (m, 13H), 6.71 (d, IH), 6.50 (d, IH), 6.46 (d, 2H), 5.30- 5.18 (m, IH), 3.69 (s, 3H) 3.53 (ddd, 2H); ESI-MS (m/z) 499 [M-N2+H]+.
[0077] 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/H2O/THF (1: 1:12.5, 0.5 mL) was added to the crude mixture and stirred overnight at RT. The subsequent mixture was neutralized with 5% sodium bicarbonate and extracted with EA (3x). The organic fractions were combined, evaporated and purified via prep TLC (40% EtOAc/hexanes ) to yield (S)- 3-Benzyl-4-[2-(4-chloro-phenyloxy)-phenyl]-3,4-dihydro-lH-benzo[e][l,4]diazepine- 2,5-dione in 25% yield as a 1.2:1 mixture of conformational isomers; 1H NMR (CD3OD): δ 8.01 (dd, IH, major), 7.89 (dd, IH, minor), 7.78-6.88 (m, 14H, major and minor), 6.02 (d, IH), 4.69 (dd, IH, minor), 4.38 (dd, IH, major), 3.07-2.81 (m, 2H, major and minor); ESI-MS (m/z) 469 [M+H]+.
Procedure D
[0078] Bromo- or iodo- containing l,4-benzodiazepin-2,5-dione adducts were reacted with boronic acids using standard Suzuki reaction protocols. An example of this reaction is illustrated in Scheme 4.
Scheme 4
[0079] 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).
[0080] 4-Chlorophenylboronic acid (33 mg), tris(dibenzylideneacetone)diaplladium (0) (9 mg), cesium fluoride (10 mg) and triphenylarsine (6 mg) were added to 3- benzyl-4-(3-iodo-benzyl)-3,4-dihydro-lH-benzo [e] [l,4]diazepine-2,5-dione (50 mg) in a clear glass vial. A solution of DME/EtOH (4: 1, 1 mL) was added and the mixture was swirled then irradiated at 50 W for 1 h, with additional swirling every 20 min.
The volatiles were removed in vacuo, and the product was purified by prep TLC, using 50% EtOAc/hexanes as the mobile phase to yield the titled compound (27 mg) as a 3:1 mixture of conformational isomers; 1H NMR (CDCI3): δ 8.45 (s, IH, major), 8.25 (s, IH, minor), 8.15 (d, IH, major), 8.054 (d, IH, minor), 7.60-7.15 (m, 26H, major and minor), 6.85 (m, 6H, major and minor), 5.00 (m, 2H, major and minor), 4.80 (d, IH, minor), 4.45 (m, IH, minor), 4.30 (t, IH, major), 4.20 (d, IH, major), 3.50 (m, H, minor), 3.15 (m, IH, minor), 2.65 (m, 2H, major); ESI-MS (m/z) 467 [M+H]+.
Procedure E
[0081] Certain hydroxy-substitited l,4-benzodiazepin-2,5-dione products of the invention were obtained via boron tribromide treatment of the corresponding alkoxy- substituted l,4-benzodiazepin-2,5-dione. Illustrated in Scheme 5 is the low temperature conversion with boron tribromide. Alternatively, this transformation was accomplished with boron tribromide dimethylsulfide complex at 80 C, according to the procedure of Williard, P. G. and Fryhle, C. B. (Williard, P. G. and Fryhle, C. B. Tet. Lett, 1980, 21, 3731-3734) as depicted in Scheme 6.
Scheme 5
OH
O H
H P
N _ . O ,;"" ^, -
\ BBr3, DCM /.
N — N
-78 C to RT O
O v— S
c, cι
[0082] 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. A IM solution of boron tribromide (0.43mmol) was added and the reaction allowed to warm to RT overnight. The reaction was quenched by addition of methanol, the volatiles were removed in vacuo, and the product was purified by flash chromatography, using 1 1 EtOAc/Hexanes as the mobile phase to give 4-[2-(4-chloro-phenylsulfanyl)- benzyl]-9-hydroxy-l\3'-dihydro-spiro[3H-l,4-benzodiazepine-3,2'-[2H]indene]- 2,5(lH,4H)-dione (19.0mg).
1H NMR (CDCl3): δ 7.98 (br s, IH), 7.94 (s, IH), 7.48 (d, 2H), 7.36-7.22 (m, 5H), 7.16-7.00 (m, 6H), 6.90 (br m, IH), 6.80 (dd, IH), 5.03 (br m, 2H), 3.86 (d, IH), 3.24- 3.06 (m, 3H); ESI-MS (m/z) 527/529 [M+H]+.
Scheme 6
[0084] Procedure E, Preparation of (iS)-3-Benzyl-4-[2-(4-hydroxy-phenylsulfanyl)- benzyl]-3 ,4-dihydro- lH-benzo [e] [l,4]diazepine-2,5 -dione (XX)
[0085] An excess of BBr3-DMS (ca. 100 mg) was added to a solution of (5)-3- Benzyl-4- [2-(4-methoxy-phenylsulfanyl)-benzyl]-3,4-dihydro- IH- benzo[e][l,4]diazepine-2,5-dione (9.1 mg) in dichloro ethane under an atmosphere of Ar. The mixture was heated at 80 C for 16 h, allowed to cool the quenched by the addition of MeOH and volatiles removed in vacuo. The product was purified prep TLC (50% EtOAc/hexanes elution) to yield the titled compound (6.4 mg) as a 4:1 mixture of conformational isomers; 1H NMR (CDCl 3): δ 9.40 (s, IH, major), 8.41 (s, IH, minor), 8.18 (dd, IH, major), 8.03 (dd, IH, minor), 7.47 (dt, IH, major), 7.35-
6.72 (m, 13H, major and minor), 6.55 (d, 2H, major), 5.32 (d, IH, major),4.96 (dd, IH, minor), 4.46 (IH, dd, minor), 4.34 (dd, IH, major), 3.74 (d, IH, major), 3.44 (dd, IH, minor), 3.01 (dd, IH, minor), 2.82 (dd, IH, major), 2.70 (dd, IH, major); ESI-MS (m/z) 481 [M+H]+.
Examples
? H
T'"N N p- °
' N ' --J1 O *
Cl
[0086] 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.
[0087] 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.
[0088] To a solution of 2-[2-(4-chlorophenylthio)-benzylamino]-indan-2-carboxylic acid methyl ester (170.4mg) and pyridine (129uL) in methylene chloride (4mL) was added 2-azido-3-methoxy-benzoyl chloride (1 lOmg). After stirring at room temperature for approximately 100 hours, the reaction mixture was diluted with methylene chloride, washed with a saturated sodium bicarbonate solution, dried over MgSO4, and the volatiles were removed in vacuo. 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). To a solution of 2-{(2-azido-3-methoxy- benzoyl)-[2-(4-chloro-phenylsulfanyl)-benzyl]-amino}-indan-2-carboxylic acid methyl ester (47m g) in anhydrous toluene (2.OmL) under argon was added tπ-n- butylphosphine. The mixture was heated to 600C overnight, the volatiles were
removed in vacuo, and the residue was taken up in a 1:1:12.5 solution (2.OmL) of TFA:H2θ:THF. The volatile s were removed in vacuo, and the product was purified by flash chromatography, using 40% EtOAc/Hexanes as the mobile phase to yield 2- {(2-amino-3-methoxy-benzoyl)-[2-(4-chloro-phenylsuncanyl)-benzyl]-amino}-indan- 2-carboxylic acid methyl ester (40mg), rather than the expected cyclized benzodiazepine dione product.
[0089] The title compound was prepared from the aniline-amino-ester above according to the method of Procedure B, Step 4 to give 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 (28.8mg); 1H NMR (CDCl3): δ 7.95 (s, IH), 7.64 (dd, IH), 7.48 (d, IH), 7.36-7.20 (m, 6H), 7.16-7.04 (m, 5H), 6.94 (br s, IH), 5.01 (br m, 2H), 3.92 (s, 3H), 3.88 (m, IH), 3.16 (m, 3H); ESI-MS (m/z) 541 [M+H]+.
H N
,- N
O
Cl
[0090] Example 2. 3-Benzyl-4-[2-(4-chloro-phenyl)-ethyl]-3,4-dihydro-lH- benzo[e][l,4]diazepine-2,5-dione
[0091] The synthesis of the titled compound was accomplished using the Ugi four- component coupling reaction according to the procedure of T. Lindhorst et al, Tetrahedron, 55(1999) 7411-7420. The reactants were phenylacetaldehye, 4- chlorophenethylamine, anthranilic acid, and [(2-isocyano-2-methyl)-propyl-l-]-ethyl- carbonate. The product was isolated in poor yield (1.5%) by flash chromatography, using 25% EtOAc/hexanes, followed by semi-preparative HPLC. A 3.1:1 mixture of conformational isomers; 1H NMR (CDCl3): 68.40 (br s, IH, major and minor), 8.13 (d, IH, major), 7.95 (d, IH, minor), 7.55 (m, IH, major and minor), 7.38-7.14 (m, 8H, major and minor), 7.12-6.92 (m, 3H, major and minor), 4.40 (dd, IH, minor), 4.22 (dd, IH, major and minor), 3.82 (m, IH, major), 3.60 (m, IH, minor), 3.20 (m, IH,
minor), 3.10 (m, IH, major) 2.95-2.42 (m, 4H, major and minor); ESI-MS (m/z) 405/407 [M+H]+.
[0092] 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.
[0093] The thioether (i?)-3-Benzyl-6-chloro-4-[2-(4-chloro-phenylsulfanyl)- benzyl]-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione was oxidized to the sulfoxide and sulfone with 3-chloroperoxybenzoic acid according to literature procedure (Georgiadis, M. P., Couldouros, E.A., J. Org. Chem. 1986, 51, 2725-2727) to yield (i?)-3-benzyl-6-chloro-4-[2-(4-chloro-benzenesuncinyl)-benzyl]-3,4-dihydro- lH-benzo[e][l,4]diazepine-2,5-dione, as a 1 1 mixture of conformational isomers; 1H NMR (CDCl3): δ 9.05 (m, 2H, major and minor), 7.90 (m, 2H, major and minor), 7.60-6.80 (m, 30H, major and minor), 5.10 (m, IH, minor), 4.80 (m, 2H, major), 4.55 (m, IH, major), 4.25 (m, 2H, major and minor), 3.30 (m, IH, minor), 3.00 (m, IH, minor), 2.80 (m, IH, major), 2.60 (m, IH, major); ESI-MS (m/z) 549 [M+H]+ and (R)- 3-benzyl-6-chloro-4-[2-(4-chloro-benzenesulfonyl)-benzyl]-3,4-dihydro-lH- benzo[e][l,4]diazepine-2,5-dione as a 1:1 mixture of conformational isomers; 1H NMR (CDCl3): δ 8.50-7.90 (m, 4H, major and minor), 7.85 (d, 2H, major and minor), 7.60-7.20 (m, 17H, major and minor), 7.20-6.80 (m, HH, major and minor), 5.20 (d, IH, minor), 4.95 (m, 2H, major and minor), 4.50 (m, 2H, major and minor), 4.40 (m, IH, minor), 3.00 (m, IH, minor), 2.80 (m, IH, minor), 2.60 (m, 2H, major); ESI-MS (m/z) 565 [M+H]\
Cl <' xχ
N
;' [ °
\\ , )
Cl
[0094] Example 4. (i?)-3-Benzyl-6-chloro-4-[2-(4-chloro-phenoxy)-benzyl]-l- methyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione.
[0095] The titled compound was synthesized according to literature precedent (Tetrahedron. Lett. 2000, 41, 2063-2066) from (i?)-3-benzyl-6-chloro-4-[2-(4-chloro- phenoxy)-benzyl]-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione. A 2.8:1 mixture of conformational isomers; 1H NMR (CDCl3): δ 7.49-6.73 (m, 16H, major and minor), 4.98 (d, IH, major), 4.83 (d, IH, major), 4.82 (d, IH, minor), 4.52 (dd, IH, major), 4.44 (dd, IH, minor), 4.39 (d, IH, minor), 3.48 (dd, IH, major), 3.29 (s, 3H, major), 3.28 (s, 3H, minor), 3.02 (dd, IH, major), 2.52 (dd, IH, minor), 2.30 (dd, IH, minor); ESI-MS (m/z) 531 [M+H]+
[0096] Example 5. (S)-3-Benzyl-4- [4-bromo-2-(4-chloro-benzyl)-2H-pyrazol-3- ylmethyl]-l-methyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione
[0097] 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) and triethylamine (324 uL, 2.32 mmol) were suspended in a 100 mL round-bottomed flask and stirred for 18 h at RT. The suspension was cooled to 00C and treated with polymer-supported borohydride (2.79 g, 6.96 mmol of ca. 2.5 mmol/g resin). After 5
min., the ice bath was removed, the mixture was diluted with anhydrous methanol (2 mL) and stirred for 5 h. The crude suspension was filtered over a glass frit containing a pad of celite and washed with methanol. The filtrate was concentrated to a crude oil/ solid to yield (£)-2-{[4-bromo-2-(4-chloro-benzyl)-2H-pyrazol-3-ylmethyl]- amino}-3-phenyl-propionic acid methyl ester (673 mg, 63%) after flash chromatography (0-30% EtOAc/hexanes ). 1H NMR (CDCl3): δ 7.35-7.10 (m, 10H), 5.16 (s, 2H), 3.82 (d, IH), 3.73 (d, IH); 3.67-3.60 (m, 4H), 3.01 (d, 2H); ESI-MS (m/z) 462/464 [M+H]+
(S)-2-{ [4-Bromo-2-(4-chloro-benzyl)-2H-p yrazol-3 -ylmethyl]-amino } -3 -phenyl- propionic acid methyl ester (50 mg, 109 μmol) was dissolved in anhydrous dichloromethane (0.5 mL) under argon at RT and treated sequentially with diisopropylethylamine (57 μL, 327 μmol) and 2-azidobenzoyl chloride (19.8 mg, 109 μmol; Heterocycles 1998, 47(1), 375-382.). The yellow solution was stirred for 4.5 h and then concentrated in vacuo to give a crude oil from which the desired compound, (iS)-2-{(2-azido-benzoyl)-[4-bromo-2-(4-chloro-benzyl)-2H-pyrazol-3-ylmethyl]- amino}-3-phenyl-propionic acid methyl ester (64 mg, 97%) was isolated by flash chromatography (0-35% EtOAc/hexanes ). 1H NMR (CDCl3); complex due to presence of rotamers: δ 7.46-6.60 (m, 14H), 5.12 (s, 2H), 5.08-3.90 (m, 3H), 3.62 (s, 2H), 3.48 (s, 3H); ESI-MS (m/z) 607/609 [M+H]+.
(iS)-2-{(2-Azido-benzoyl)-[4-bromo-2-(4-chloro-benzyl)-2H-pyrazol-3-ylmethyl]- amino}-3-phenyl-propionic acid methyl ester (37 mg, 60 μmol) was dissolved in anhydrous ethyl acetate (1.5 mL) at RT under argon. Trimethyl phosphine ( 108 μL, 108 μmol of a 1.0 M THF solution) was added and the resulting yellow solution was then treated with H2O (4.3 μL, 241 μmol); 5 min. later a colorless solution was observed. After 6h, the solution was concentrated in vacuo to a crude glass/oil from which the titled compound (13.4 mg) was isolated by flash chromatography (ethyl acetate 10-35% in hexanes + 1-1.5% methanol). An approx. 95:5 mixture of conformational isomers; 1H NMR (CDCl3): δ 8.09 (dd, IH, major), 8.03 (dd, IH, minor), 7.52 (dt, IH, major), 7.36 (s, IH, major), 7.34-7.17 (m, 7H, major and minor), 7.16-7.08 (d, 2H, major and minor), 6.87-6.79 (m, 2H, major and minor), 5.44 (d, IH, minor), 5.22 (dd, 2H, major), 5.12 (d, IH, major), 4.45 (d, IH, minor), 4.36 (d, IH, major), 4.20 (dd, IH, major), 4.12 (dd, IH, minor), 3.53 (s, 3H, major), 3.52 (3H,
minor), 2.64-2.47 (m, 2H, major and minor), 2.62 (dd, IH); ESI-MS (m/z) 563/565 [M+H]+.
Preparations: Synthesis of intermediates.
[0098] Preparation 1. Variously substituted 2-oxy-aryl aldehydes were prepared according to literature methodology (Yeager, G. R. and Schissel, D. N., Synthesis, 1995, 28-30) H ,O
- ., O,
' Ri
R2
Prepared in this manner were:
2-(4-Chloro-phenoxy)-5-methyl-benzaldehyde; 1H NMR (CDCl3): δ 10.41 (s, IH),
7.73 (d, IH), 7.31 (m, 3H), 6.95 (dd, 2H), 6.81 (d, IH), 2.37 (s, 3H),
2-(2-chloro-phenoxy)-benzaldehyde; 1H NMR (CDCl3): δ 10.60 (d, IH), 7.95 (dd,
IH), 7.48 (m, 2 H), 7.30 (m, IH), 7.18 (m, 2H), 7.10 (dd, IH), 6.72 (d, IH),
2-(Pyrazin-2-yloxy)-benzaldehyde; 1H NMR (CDC13): δ 10.23 (s, IH), 8.57 (s, IH),
8.32 (d, IH), 8.07 (d,lH), 7.98 (dd, IH), 7.65 (dt, IH), 7.4(t, IH), 7.2 (d, IH). LCMS:
201 (M+H)+
2-(Pyridin-2-yloxy)-benzaldehyde; 1H NMR (CDC13): δ 10.3 (s, IH), 8.18 (dd, IH),
7.96 (dd, IH), 7.75 (dt,lH), 7.62 (dt, IH), 7.32 (t, IH), 7.16 (d, IH), 7.05 (m, 2H);
ESI-MS (m/z) 200 [M+H]+,
2-(2-Chloro-pyridin-3-yloxy)-benzaldehyde; 1H NMR (CDCB): δ 10.5 (s, IH), 8.25
(dd, IH), 7.92 (dd, IH), 7.52 (dt,lH), 7.38 (dd, IH), 7.25 (m, 2H), 6.75 (d, IH); ESI-
MS (m/z) 234 [M+H]+,
2-(3-chloro-phenoxy)-benzaldehyde,
2-(3,4-dichloro-phenoxy)-benzaldehyde,
2-(4-trifluoromethyl-phenyloxy)-benzaldehyde.
[0099] Preparation 2. Variously substituted 2- phenylsulfanyl benzaldehydes were prepared according to literature procedure (Sivasubramanian, S. and Ravichandran, K. Indian J. Chem. 1991, SOB, 1148-1149).
H ,0
' Ri
R2
Prepared in this manner were:
2-(2-Chloro-phenylsulfanyl)-benzaldehyde; 1H NMR (CDCl3): δ 10.40 (d, IH), 7.95
(dd, IH), 7.51-7.24 (m, 6H), 7.14 (dd, IH),
2-(4-Fluoro-phenylsulfanyl)-benzaldehyde; 1H NMR (CDCl3) δ 10.39 (d, IH), 7.85
(dd, IH), 7.49-7.30 (m, 4H), 7.12 (Id, 2H), 6.96 (dd, IH); 19F NMR: δ -105.3,
2-(2,4-Difluoro-phenylsulfanyl)-benzaldehyde; 1H NMR (CDCl3): δ 10.33 (d, IH),
7.85 (dd, IH), 7.59-6.90 (m, 6H); 19F NMR: δ -95.4, -100.4,
2-Phenylsulfanyl-benzaldehyde,
2-/>-Tolylsulfanyl-benzaldehyde,
2-(4-Methoxy-phenylsulfanyl)-benzaldehyde,
2-(2-Fluoro-phenylsulfanyl)-benzaldehyde,
2-(2,4-Dichloro-phenylsulfanyl)-benzaldehyde,
[00100] Preparation 3. 3-(4-Chloro-phenylsulfanyl)-benzaldehyde and 4-(4-Chloro- phenylsulfanyl)-benzaldehyde were prepared according to the patent procedure of US 5403934.
Cl r I O
^S"" V H
[00101] Preparation 4. The procedure of J.C. Bussolari, D.C. Rehborn, Org. Letters, 1999, 1, (7) 965-967 was used to prepare 5-(4-chloro-phenyl)-thiophene-2- carboxaldehyde.
[00102] 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.
Scheme 7
[00103] Preparation 5 - step 1. 4-Methoxy-2-nitro-benzoic acid was prepared in 71% yield from 4-methoxy-l-methyl-2-nitro-benzene according to literature procedure (Augeri, D. J. et al, J. Med. Chem., 1998, 41, 4288-4300). 1H NMR (CDCl3): δ 7.93 (d, IH), 7.17 (s, IH), 7.11 (d, IH), 3.92 (s, 3H).
[00104] Preparation 5 - step 2. The nitro intermediate was reduced according to literature procedure (Boojamra, C. G. et al. J. Org. Chem, 1997, 62, 11240-1256) to quantitatively give 2-amino-4-methoxy-benzoic acid. 1H NMR (CDCI3): δ 7.84 (d, IH), 6.26 (d, IH), 6.10 (s, IH), 3.80 (s, 3H).
[00105] Preparation 5 - step 3. 2-Azido-4-methoxy-benzoic acid was prepared in 86% yield according to the literature procedure of Lamara, K. et al. (Lamara, K. etal.
Tetrahedron, 1994, 50, (18), 5515-5526). 1H NMR (CDCl3): δ 8.11 (d, IH), 6.76 (dd, IH), 6.71 (d, IH), 3.90 (s, 3H).
[00106] 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. 1H NMR (CDCl3): δ 8.20 (d, IH), 6.78 (dd, IH), 6.72 (d, IH), 3.93 (s, 3H).
[00107] Similarly prepared in this manner were:
2-Azido-3-methoxy-benzoyl chloride; 1H NMR (CDCl3): δ 7.58 (dd, IH), 7.18 (t, IH),
7.09 (dd, IH), 3.95 (s, 3H),
2-Azido-5-methoxy-benzoyl chloride; 1H NMR (CDCl3): δ 7.60 (2, IH), 7.20 (d, 2H),
3.86 (s, 3H),
2-Azido-6-methoxy-benzoyl chloride; 1H NMR (CDCl3) δ 7.20-6.95 (m, 3H), 3.90 (s,
3H),
2-Azido-3-nitro-benzoyl chloride; 1H NMR (CDCl3): δ 8.30 (dd, IH), 8.13 (dd, IH),
7.50 (t, 2H),
2-Azido-3,6-dichloro-benzoyl chloride; 1H NMR (CDCl3): δ 7.40 (d, IH), 7.20 (d,
IH).
[00108] Preparation 6. The alkyl aldehydes employed in the invention were prepared from commercially available substrates. The synthesis of 4-(4-chloro-phenyl)- butyraldehyde as a typical example is illustrated below in Scheme 8.
Scheme 8
Step 3
[00109] 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).
[00110] Preparation 6 - Step 2. To a 00C solution of 4-(4-chloro-phenyl)-butyric acid (2.5g), N,O-dimethylhydroxylamine hydrochloride (1.84g), HOBt (2.Og), and DIEA (6.6mL) in methylene chloride (14OmL) was added EDCI (3.6g). The reaction was allowed to warm to room temperature, diluted with methylene chloride, washed with 0.5M NaOH, dried over MgSO4, and reduced in vacuo. The product was purified by flash chromatography using 55% Et2θ/hexanes as the mobile phase to yield 4-(4-chloro-ρhenyl)-N-methoxy-N-methyl-butyramide (2.7g).
[00111] Preparation 6 - Step 3. A solution of 4-(4-chloro-phenyl)-N-methoxy-N- methyl-butyramide (2.Og) in anhydrous Et2O under argon was cooled to -78°C, and a solution of LiAlH4 (IM, 8.7mL) was added. After 50 minutes, the reaction was quenched with the sequential addition of 0.3SmL H2O, 0.33mL 15% NaOH, and ImL H2O. The reaction was warmed to room temperature, filtered, and the filtrate was reduced in vacuo to yield 4-(4-chloro-phenyl)-butyraldehyde (1.9Og).
[00112] 3-(4-Chlorophenyl)-propionaldehyde was prepared in this manner, but starting from commercially available 3-(4-chlorophenyl)-propionic acid at step 2.
[00113] 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. 1H NMR (CDCl3): δ 10.55 (s, IH), 8.15 (m, IH), 7.95 (m,
2H), 7.50 (m, 3H).
[00114] 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. 1H NMR (CDCl3): δ 10.20 (s, IH), 7.90 (d, IH), 7.75 (d, IH), 7.65 (t, IH), 7.55 (t, IH), 7.25 (d, 2H), 6.95 (d, 2H), 5.50 (s, 2H).
[00115] Preparation 9. 2-Phenoxy-3-pyridinecarboxaldehyde was prepared according to literature reference: Eur. Pat. Appl. (1987), 64 pp. EP 243012 A2.
[00116] The following compounds were prepared according to the Procedure indicated in the table with the appropriate building blocks (Table 1). Key to Procedures: A, solid phase prep
B, solution phase prep - stepwise
C, N-phenyl analogues solution phase
D, Suzuki reaction
GCNF Assay
[00117] 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.
[00118] Chinese hamster ovary (CHO Kl) 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, lOOμg/ml streptomycin, 2mM glutamine and 5% charcoal-treated bovine calf serum.
Agonist Assay
[00119] Stock solutions of compounds are stored as iOrnM dilutions in 100% DMSO. Compounds are serially diluted in 100% DMSO, and then the serial dilutions are diluted in culture medium to 1.5X the desired final concentration and 1.5% DMSO Thirty microliters of each compound dilution is then transferred in duplicate
to a Costar white solid bottom 384-well plate. Cells are harvested by trypsinizing, and the cells are diluted in cell culture medium to 3.3x105 cells/ml. Fifteen microliters of the resulting cell suspension is then added to each test well, and assay plates are incubated at 37°C, 5% CO2 for 16h. After incubation, 45 μl of Bright-Glo (Promega Corp., Madison, WI) is added to each well, and luminescence is measured using a ViewLux UltraHTS Microplate Imager (PerkinElmer Life Sciences, Boston, MA).
Antagonist Assay
[00120] 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.
[00121] Compounds 1-107 exhibited binding EC50's below 7 μM and efficacy greater than 50%. Compounds 108-197 exhibited binding EC50's below 60 μM and efficacy less than 50%.
[00122] Although the invention has been described in detail for the purpose of illustration, it is understood that such detail is solely for that purpose, and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the following claims.
Claims
1. A compound of formula:
R and R are independently chosen from H, hydroxy, amino, halo, nitro, phenyl, (C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (d-C6)alkyl-OH, O-
(C1-C6)alkyl-OH, COOH and C(O)O(C1-C6)BIlCyI; or taken together,
R1 and R2 form a 5- or 6-membered ring;
R3 is H or (C1-C6)alkyl;
R8 is chosen from H and (C1-C6)alkyl;
R9 is chosen from H, (C1-C1o)hydrocarbon, flouro(C1-C6)alkyl, substituted aryl, heteroaryl and (C1-C6)alkyl substituted with alkoxy, heteroaryl, substituted heteroaryl, substituted aryl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2 or fluoro alkoxy; or taken together R8 and R9 form a monocyclic or bicyclic carbocycle or heterocycle, said monocyclic or bicyclic carbocycle or heterocycle optionally substituted with (Q-
C10)hydrocarbon, halogen, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(d-C6)alkyl]2 or fluoroalkoxy
Z is a monocyclic, bicyclic or tricyclic carbocycle;
R10 is from one to three substituents independently selected from H, halo, (Q- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, NH2, NH(C1-C6)alkyl,
N[(C1-C6)alkyl]2, NO2 and OH;
R > i i is chosen from
(i) -Q-T wherein
Q is chosen from -(CH2Jn-, -O-, -S-, -SO-, -SO2-, -O-(CH2)n-, -(CH2),,- O-,
-S-(CH2)n-,-(CH2)n-S-, -NH-, -NKQ-QOalkyl]-, -CHNH(C1- C6)alkyl - and -CHN[(CrC6)alkyl]2- T is chosen from aryl, heteroaryl, substituted aryl and substituted heteroaryl, with the proviso that if Q is chosen from other than -(CH2)-, -O-, -S-, -SO- and -SO2-, then T must be either phenyl or phenyl substituted with halogen; and (ii) H, halo, (CrC6)alkyl, (CrC6)alkoxy, halo(C1-C6)alkyl and halo(Cr C6)alkoxy, with the provisos that (a) R8 is not H and R9 is not H, (C1- C1o)alkyl or phenethyl, and (b) R8 and R9 taken together do not form a monocyclic carbo cycle; and n at each occurrence is zero, one or two.
2. A compound according to claim 1 wherein Z is phenyl and R .11 is chosen from H, halo, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy.
3. A compound according to claim 2 of formula
R11 is (C3-C6)alkoxy and
R12 is chosen from H, halo, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-Cs)alkoxy.
4. A compound according to claim 1 wherein Z is a tricyclic carbocycle.
5. A compound according to claim 1 wherein Z is phenyl and R 11 is -Q-T
6. A compound according to claim 5 of formula:
R4, R5, R6 and R7 are independently chosen from H, hydroxy, amino, halo, nitro, (C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy, with the proviso that when Q is other than -(CH2)-, -O-, -S-, -SO- and -SO2-, R6 must be halogen and R7 must be H or halogen.
7. A compound according to claim 6 wherein Q is chosen from -(CH2)-, -O-, -S-, -SO- and -SO2-.
8. A compound according to claim 7 wherein taken together R8 and R9 form a bicyclic carbocycle, the compound having the formula:
9. A compound according to claim 7 wherein R8 is H; and
R9 is chosen from H, (C1-C1o)hydrocarbon and [optionally substituted phenyl](C1- C6)alkyl.
10. A compound according to claim 9 wherein R4 and R5 are H.
11. A compound according to claim 9 wherein R9 is (C3-C1o)alkyl.
12. A compound according to claim 9 wherein R9 is
13. A compound according to any of claims 1-12 wherein R and R are chosen from H, halo, hydroxy, methoxy, -Ntfe, -NO2, phenyl and methyl.
14. A compound according to any of claims 1-12 wherein R3 is H.
15. A compound according to any of claims 7-12 wherein Q is S.
16. A compound according to claim 10 of formula
7. A compound according to claim 8 of formula
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 1-12, 16 or 17.
19. A method of contraception comprising administering to a mammal an amount of a compound according to any of claims 1-12, 16 or 17 sufficient to suppress gamete production.
20. A method for regulating stem cell differentiation comprising exposing said stem cell to an amount of a compound according to any of claims 1-12, 16 or 17 sufficient to retard stem cell differentiation.
21. A method for reversing stem cell differentiation comprising exposing said stem cell to an amount of a compound according to any of claims 1-12, 16 or 17 sufficient to reverse stem cell differentiation.
22. A method for treating or preventing a cancerous tumor, the method comprising administering to a patient in need thereof a compound according to any of claims 1-12, 16 or 17 in an amount sufficient to inhibit proliferation of cancerous cells.
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