WO2002036596A2 - Cycloalkyl[b][1,4]diazepino[6,7,1-hi]indoles et derives - Google Patents

Cycloalkyl[b][1,4]diazepino[6,7,1-hi]indoles et derives Download PDF

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WO2002036596A2
WO2002036596A2 PCT/US2001/046084 US0146084W WO0236596A2 WO 2002036596 A2 WO2002036596 A2 WO 2002036596A2 US 0146084 W US0146084 W US 0146084W WO 0236596 A2 WO0236596 A2 WO 0236596A2
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compound
diazepino
formula
carbon atoms
alkyl
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PCT/US2001/046084
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WO2002036596A3 (fr
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Annmarie Louise Sabb
Robert Lewis Vogel
Gregory Scott Welmaker
Joan Eileen Sabalski
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Wyeth
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to new and known cycloalkyl[b][l,4]- diazepino[6,7,l-hi]indoles and derivatives thereof, processes for their preparation and pharmaceutical compositions containing them which are serotonin 5-hydroxy- tryptamine 2c (5HT c) receptor agonists useful for the treatment or prevention of disorders such as obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, obesity, epilepsy, and spinal cord injury.
  • disorders such as obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, obesity, epilepsy, and spinal cord injury.
  • Obesity is a medical disorder characterized by an excess of body fat or adipose tissue.
  • Comorbidities associated with obesity are Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality.
  • the serotonin 5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptor which is expressed in neurons in many regions of the human central nervous system. [Wilkinson, L. O. and Dourish, C. T.
  • the 5HT 2c receptor (formerly called the 5HT ⁇ c receptor) is a prominent subtype of the serotonin receptor found in the central nervous system of both rats and humans. It is expressed widely in both cortical and subcortical regions. [Julius, D. MacDermott, A. B., Axel, R. Jessell, T. M.
  • Compounds of this invention are 5HT 2 c receptor subtype selective ⁇ agonists which are selective over other monoamine receptors, causes a reduction in food intake and result in a reduction in weight gain.
  • Other therapeutic indications for 5HT 2 c agonists are obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders, epilepsy, and spinal cord injury.
  • This invention provides a method of treatment of obsessive-compulsive disorder, depression or anxiety in a mammal, the method comprising administering to a mammal in need thereof a phannaceutically effective amount of a compound of formula (I):
  • R j and -f ⁇ are independently selected from hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -CH 2 -cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl of 1-6 carbon atoms, -CN, -NH- SO 2 -alkyl of 1-6 carbon atoms, -SO 2 -NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, aroyl and heteroaroyl;
  • R 3 , R 4, R 5 and R 6 are independently selected from hydrogen, C ⁇ -C 6 alkyl, C -C 7 cycloalkyl, -CH -cycloalkyl of 3 to 7 carbon atoms, C ⁇ -C 6 alkoxy or C 3 ⁇ C 6 cycloalkoxy;
  • R is hydrogen or alkyl of 1-6 carbon atoms; R 8 is hydrogen or C ⁇ -C 6 alkyl; and the dashed line indicates an optional double bond; or a pharmaceutically acceptable salt thereof.
  • This invention further provides novel compounds having formula (I) defined above.
  • the fluorinated alkyl and fluorinated alkoxy groups indicate the specified alkyl or alkoxy groups having any amount of fluorine substitution, including, but not limited to, groups such as -CHF 2 , -CF 3 , -C 2 F 5 , -OCF 3 , etc.
  • the compounds of formula (I) can possess one or more asymmetric centres and accordingly the compounds may exist and be isolated in a number of optically active stereoisomeric forms. While shown without respect to stereochemistry in formula (I), this invention encompasses the compounds of formula (I) in any optically active or geometric form or mixtures thereof eg, racemates, enantiomers or diastereoisomers. Standard separation techniques may be used to isolate particular enantiomeric and diastereomeric forms. For example a racemic mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a 'resolving agent' (for example by diastereomeric salt formation or formation of a covalent bond).
  • optically active diastereoisomers may be separated by standard techniques (e.g crystallisation or chromatography) and individual optically active diastereoisomers then treated to remove the 'resolving agent' thereby releasing the single enantiomer of the compound of the invention.
  • Chiral chromatography using a chiral support, eluent or ion pairing agent may also be used to separate enantiomeric mixtures directly.
  • Stereospecif ⁇ c synthesis using optically active starting materials and/or chiral reagent catalyst and/or solvents may also be employed to prepare particular diastereoisomers or even a particular enantiomer.
  • alkyl on a group or part of a group, e.g., alkylamino or alkoxy, includes both straight- and branched-chain saturated aliphatic hydrocarbon groups, e.g., methyl, ethyl, propyl, isopropyl and butyl.
  • Halogen is defined as Cl, Br, F or I.
  • cycloalkyl as a group or part of a group (eg cycloalkoxy) are rings of 3-6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • acyl includes alkanoyl of 2-7 carbon atoms, e.g., acetyl and propanoyl.
  • aroyl is defined as an aryl-CO-, where aryl is defined as an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system.
  • aryl groups include phenyl, naphthyl, anthryl, tetrahydronaphthyl and phenanthryl groups
  • Heteroaroyl is defined as heteroaryl-CO- wherein heteroaryl includes mono- or bi-cyclic rings having 5-10 ring members and 1-3 heteroatoms, the same or different, selected from O, N and S, for example thienyl, furanyl, pyrrolyl, pyridinyl or pyrimidinyl.
  • the aroyl group is preferably benzoyl.
  • the heteroaroyl group is preferably thienoyl.
  • Pharmaceutically acceptable salts can be fonned from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
  • organic and inorganic acids for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsul
  • cyclohexyl cycloheptyl or cyclooctyl.
  • R. and R 2 may each be for example independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl of 1- 6 carbon atoms and fluorinated alkoxy of 1-6 carbon atoms.
  • R j and R ⁇ may be each independently selected from hydrogen, alkyl of 1-6 carbon atoms and halogen.
  • R 3 , t, R 5 and R 6 may be for example each independently selected from hydrogen, Ci-C ⁇ alkyl and C ⁇ -C 6 alkoxy.
  • Ri to R 8 may be each independently hydrogen.
  • Preferred aroyl and heteroaroyl groups are respectively benzoyl and thienoyl.
  • a preferred group of compounds of this invention comprises compounds of formula (I) having the structure
  • R ⁇ and R 2 are each independently selected from hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl, -CN, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, and trifluoromethoxy.
  • Another preferred group of compounds of this invention are those of formula I wherein R 7 is hydrogen and Ri to R 6 and R 8 are as defined above, or a pharmaceutically acceptable salt thereof.
  • Another preferred group of compounds of this invention are those of formula I wherein R 2 , R and R are hydrogen and Ri, R 4 to Rg and R 8 are as defined above, or a pharmaceutically acceptable salt thereof.
  • prefened compounds of this invention are those in which R ⁇ -R 6 are each hydrogen.
  • Especially prefened are compounds which are enantiomerically pure stereoisomers of compounds where Rj is hydrogen and the indole ring is reduced or not reduced.
  • Specifcally prefened compounds of this invention are: (a) 1,2,3,4,8,9,10,1 l-Octahydro-[l,4]diazepino[6,5,4-jk]carbazole;
  • the 5HT 2 c receptor agonists of this invention are useful for the treatment or prevention in mammals, preferably in humans, of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, atypical depression, bipolar disorders, anxiety, generalized anxiety disorder, schizophrenia, psychoses, personality disorders, organic mental disorders, behavioral disorders associated with dementia or age-related conditions, aggressivity, drug and alcohol addiction, social phobias, sexual dysfunction, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, bulimia or anorexia nervosa, obesity, epilepsy, and premenstrual tension.
  • disorders involving the central nervous system such as obsessive-compulsive disorder, depression, atypical depression, bipolar disorders, anxiety, generalized anxiety disorder, schizophrenia, psychoses, personality disorders, organic mental disorders, behavioral disorders associated with dementia or age-related conditions, aggressivity, drug and alcohol addiction, social phobias, sexual dysfunction, panic disorder, migraine,
  • This invention also includes methods of utilizing the compounds herein in treatments or preventitive regimens for treatment of central nervous system deficiencies associated with trauma, stroke, neurodegenerative diseases or toxic or infective CNS disorders including, but not limited to, encephalitis or menengitis; or cardiovascular disorders, including thrombosis; gastrointestinal disorders such as malfunction of gastrointestinal motility; and diabetes insipidus.
  • These methods include the improvement or inhibition of further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.
  • This invention includes methods for treating, preventing, modulating, ameliorating or improving the condition of each of these disorders in a mammal in need thereof, the methods comprising administering a therapeutically or pharmaceutically effective amount of a compound of this invention or a pharmaceutically acceptable salt thereof.
  • This invention also provides processes for preparing compounds of formula (I) which processes comprise one of the following: a) reacting a compound of formula (A)
  • R" is a protecting group with a compound of fonnula (B) wherein R 3 , R 4 , R 5 and R 6 are as defined above followed by removal of the protecting group to give a compound of formula (I) wherein R 8 is hydrogen and the optional double bond is present; or b) reducing a compound of formula (I) wherein the optional double bond is present to give a compound of formula (I) wherein the optional double bond is absent; or c) reducing a compound of formula (C)
  • Ri, R , R , R , R 5 , R 6 , and R 7 are as defined above and R" is a protecting group followed by removal of the protecting group to give a compound of formula (I) wherein the optional double bond is absent; or d) reducing a compound of formula (D)
  • Ri, R 2 , R , Ri , R 5 , R 6 , and R 7 are as defined above and the dashed line indicates an optional double bond; wherein (i) R' is alkoxy; to give a compound of formula (I) wherein R 8 is methyl;
  • R' is C ⁇ -C 5 alkyl; to give a compound of formula (I) wherein R 8 is -CH 2 -(d-C 5 alkyl); or e) alkylating a compound of formula (I) wherein R 8 is hydrogen with an alkylating agent containing the group -R 8 wherein R 8 is C ⁇ -C 6 alkyl to give a compound of formula (I) wherein R 8 is C ⁇ -C 6 alkyl; or f) removing a protecting group from a compound of formula (I) in which at least one substituent carries a protecting group to give a compound of formula (I); or g) converting a basic compound of formula (I) to a salt thereof by reaction with a pharmaceutically acceptable acid; or h) converting a compound of formula (I) having one or more reactive substituent groups to a different compound of formula (I); or i) isolating an isomer of a compound of formula (I) from a mixture thereof.
  • a substituted or unsubstituted isatoic anhydride is allowed to react with substituted or unsubstituted glycine hydrochloride or an ester of the same in an organic base such as pyridine or triethylamine, to give either open-chain intermediate I or the benzodiazepinedione II.
  • Intermediate I can be converted to intermediate II by heating in the presence of an acid, such as acetic acid.
  • the benzodiazepinedione II is reduced to the benzodiazepine III using a reducing agent such as lithium aluminum hydride or a borane-tefrahydrofuran complex.
  • the secondary nitrogen atom in III is protected using a protecting group, such as an amide by reacting III with an acylating agent, such as acetic anhydride, in the presence of a base, such as triethylamine, to give an acylated benzodiazepine IV.
  • a protecting group such as an amide
  • an acylating agent such as acetic anhydride
  • a base such as triethylamine
  • the hydrazines NI are allowed to react with substituted or unsubstituted cycloalkanones in acid, such as acetic acid, to give the fused indoles NIL
  • acid such as acetic acid
  • the fused indoles Nil can be treated with a base, such as ⁇ aOH, in a polar solvent, such as water or an alcohol, or with an acid, such as hydrochloric acid, to give the fused indoles NIII, which are products of this invention.
  • fused indoles NIII can be reduced, such as by catalytic hydrogenation over a catalyst, such as palladium on charcoal, in an organic solvent, such as ethanol, in the presence of a trace of acid, such as trifluoroacetic acid, to give fused indolines IX which are products of this invention.
  • a catalyst such as palladium on charcoal
  • an organic solvent such as ethanol
  • a trace of acid such as trifluoroacetic acid
  • fused indoles NIII can be reduced with a reducing agent, such as borane/THF or sodium cyanoborohydride in the presence of an acid, such as trifluoracetic acid or acetic acid to give fused indolines IX which are products of this invention.
  • a reducing agent such as borane/THF or sodium cyanoborohydride
  • Fused indolines IX are diastereoisomeric mixtures that can be resolved using chiral HPLC or chiral resolving agents to give stereo isomers X and XI and enantiomers thereof, which are products of this invention.
  • fused indoles VII can be reduced, such as by catalytic hydrogenation over a catalyst, such as palladium on charcoal, in an organic solvent, such as ethanol, in the presence of a trace of an acid, such as trifluoroacetic acid, to give fused indolines XII.
  • Fused indolines XII are diastereoisomeric mixtures which can be resolved using chiral HPLC to give separated diastereoisomers which can then be treated with an inorganic base, such as ⁇ aOH in a polar solvent, such as water or methanol at elevated temperatures, such as 50-100 °C, to remove the acyl group giving diastereoisomers X and XI which are products of this invention.
  • Enantiomers of X and XI can also be obtained by chiral salt resolution of racemic fused indolines X and XI using a resolving agent, such as benzoyltartaric acid, in an organic solvent, such as isopropyl alcohol.
  • fused indoles VII can be reduced with a reducing agent, such as lithium aluminum hydride or a borane-THF complex to give XIII which are compounds of this invention.
  • a reducing agent such as lithium aluminum hydride or a borane-THF complex
  • the acylation steps of this invention are understood to include reactions of the appropriate compound with any acylating agent and reaction conditions known in the art.
  • Useful in these steps are acylating agents include acid halides and esters or anhyrides of the appropriate aliphatic carboxylic acid.
  • Useful acid halides include acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, etc.
  • Acid anhydrides include acetic anhydride and benzoic anhydride.
  • alkylation steps herein are understood to include any relevant alkylating agents and conditions known in the art. These include, but are not limited to the use of alkyl halides, such as methyl iodide, or alkyl tosylates or aldehyde alkylating agents in the presence of an applicable reducing agent.
  • Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, . malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfomc, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known pharmaceutically acceptable acids.
  • the processes herein will be understood to include an optional additional step of forming a salt form of the products via standard addition reactions with any pharmaceutically acceptable organic or inorganic acid.
  • the cells were allowed to grow to confluence in large culture dishes with intermediate changes of media and splitting. Upon reaching confluence, the cells were harvested by scraping. The harvested cells were suspended in half volume of fresh physiological phosphate buffered saline (PBS) solution and centrifuged at low speed (900 x g). This operation was repeated once more. The collected cells were then homogenized with a polytron at setting #7 for 15 sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA.
  • PBS physiological phosphate buffered saline
  • the homogenate was centrifuged at 900 x g for 15 min to remove nuclear particles and other cell debris. The pellet was discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min. The resulting pellet was resuspended in a small volume of Tris.HCl buffer and the tissue protein content was determined in aliquots of 10-25 microliter ( ⁇ l) volumes.
  • Bovine Serum Albumin (BSA) was used as the standard in the protein determination by the method of Lowry et al., (J. Biol. Chem., 193:265 (1951).
  • the volume of the suspended cell membranes was adjusted with 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mM pargyline and 4 mM CaCl 2 to give a tissue protein concentration of 1-2 mg per ml of suspension.
  • the preparation membrane suspension (many times concentrated) was aliquoted in 1ml volumes and stored at -70 C until used in subsequent binding experiments.
  • Binding measurements were performed in a 96 well microtiter plate format, in a total volume of 200 ⁇ l. To each well was added: 60 ⁇ l of incubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4 mM CaCl 2 ; 20 ⁇ l of [ 125 I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).
  • the dissociation constant, KD of [ 125 I] DOI at the human serotonin 5HT 2 c receptor was 0.4 nM by saturation binding with increasing concentrations of [ 125 I] DOI.
  • the reaction was initiated by the final addition of 100.0 ⁇ l' of tissue suspension containing 50 ⁇ g of receptor protein. Nonspecific binding is measured in the presence of 1 ⁇ M unlabeled DOI added in 20.0 ⁇ l volume. Test compounds were added in 20.0 ml. The mixture was incubated at room temperature for 60 min. The incubation was stopped by rapid filtration. The bound ligand-receptor complex was filtered off on a 96 well unifilter with a Packard ® Filtermate 196 Harvester.
  • the bound complex caught on the filter disk was dried in a vacuum oven heated to 60°C and the radioactivity measured by liquid scintillation with 40 ⁇ l Microscint-20 scintillant in a Packard TopCount ® equipped with six (6) photomultiplier detectors.
  • Specific binding is defined as the total radioactivity bound less the amount bound in the presence of 1 ⁇ M unlabeled DOI. Binding in the presence of varying concentrations of test drugs is expressed as percent of specific binding in the absence of drug. These results are then plotted as log % bound vs log concentration of test drug. Non linear regression analysis of data points yields both the IC50 and the Ki values of test compounds with 95 > confidence limits. Alternatively, a linear regression line of decline of data points is plotted, from which the IC50 value can be read off the curve and the K value determined by solving the following equation:
  • Ki IC50 1+L/KD where L is the concentration of the radioactive ligand used and the KD is the dissociation constant of the ligand for the receptor, both expressed in nM.
  • Ketanserin 94.8 (70.7 - 127.0) nM Mianserin 2.7 (1.9 - 3.8) nM
  • CHO cells transfected with the cDNA expressing the human 5-HT 2 c receptor were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and non-essential a ino acids. Upon reaching confluence the cells were harvested using PBS/EDTA and plated in 24 well plates at an initial density of 2.5 x 10 5 cells per well. One (1) ml of maintenance medium containing l ⁇ Ci/ml myo-[ 3 H] inositol was added to each well.
  • DMEM Dulbecco's modified Eagle's medium
  • the cells were washed once with 0.5 ml DMEM containing 25 mM HEPES and 10 mM LiCl, then preincubated with the medium for 30 min (antagonists were included in this period if tested). At the end of the preincubation, the medium was removed, the cells were then incubated with test, compounds (in presence of antagonists if needed) for 30 min. The reaction was terminated by removal of the incubation solution and addition of 0.5 ml ice-cold 5% PCA, followed by 15 to 30 min incubation on ice. 200 ⁇ l of 0.5 M Tes/1.5 M K 2 CO 3 was added to each well to neutralize to pH 7, and plates were left on ice for another 15 to 30 min to precipitate all salts. The liquid and solid phases were separated by centrifugation.
  • IPi [ 3 H]inositol monophosphate
  • the results obtained in this standard pharmacological test procedures demonstrate that the compounds of this invention are 5HT 2 c receptor agonists useful for the treatment of diseases involving the central nervous system such as obsessive- compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, obesity, epilepsy, and spinal cord injury.
  • the compounds of this invention can be formulated neat or with one or more pharmaceutical carriers or excipients for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
  • the pharmaceutical carrier may be solid or liquid.
  • This invention includes pharmaceutical compositions comprising a therapeutically or pharmaceutically effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and one or more phannaceutically acceptable carriers or excipients.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material, h powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient, h tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpynolidine, low melting waxes and ion exchange resins.
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a phannaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds of this invention can also be administered orally either in liquid or solid composition form.
  • the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the terms “pharmaceutically effective amount” or “therapeutically effective amount” means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, prevention or amelioration of the cause or symptoms of the malady or condition, or an increase in rate of treatment, prevention or amelioration of such conditions.
  • a meaningful patient benefit i.e., treatment, prevention or amelioration of the cause or symptoms of the malady or condition, or an increase in rate of treatment, prevention or amelioration of such conditions.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated.
  • Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other pharmaceutical agents useful for treating or preventing the malady or condition in question or coexisting conditions or symptoms.
  • the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 ⁇ g/kg - 750 ⁇ g/kg. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • daily dosages may be utilized from between about 0.5 ⁇ g/day to about 70,000 ⁇ g/day. More preferably, daily oral administration may include dosages from about 5mg to about 500 mg, preferably from about 10 mg to about 200 mg, more preferably from about 10 mg to about 150 mg. Intravenous administration will be at a daily dose range of from about 0.5 mg to about 75 mg, preferably from about 1 mg to about 50 mg.
  • Acetic anhydride (0.60 mL) was added dropwise to a stined suspension of 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine (950 mg, 6.4 mmol) in anhydrous ether (25 mL). After refluxing for four hours, the reaction mixture was filtered to remove a solid. Evaporation of the filtrate gave a residue which was purified by chromatography on silica gel eluting with 5% methanol in ethyl acetate. Evaporation of the product fractions gave an oil. The solid removed by filtration above contained a mixture of starting material and product by thin layer chromatography.
  • Example 1 The product of Example 1 (506 mg, 2.23 mmol) was dissolved in anhydrous THF and treated with 1M BH • THF (50 mL). The stined reaction mixture was heated in an oil bath at 75-85 °C under a nitrogen atmosphere while trifluoroacetic acid was added gradually. After adding a total of 10 mL of trifluoroacetic acid and heating for 6 h, the reaction mixture was cooled to room temperature, treated with 6N HC1 and stined at room temperature overnight. The white solid which appeared was treated with cone. HC1 (20 ml), warmed, swirled, and the volatiles were evaporated under reduced pressure. The white residue was suspended in methanol and evaporated two times to break up borane complexes.
  • Example 2 The residue was partitioned between ethyl acetate and aqueous NaOH. The organic phase was separated, dried (MgSO 4 ), and evaporated under reduced pressure to give a liquid residue which was purified by column chromatography on silica gel eluting with 10-20% methanol in methylene chloride. Evaporation of the pure fractions gave the product of Example 2 (80 mg) as an oil. The oil was dissolved in ether and treated with 1M HC1 in ether to precipitate the dihydrochloride salt of the product of Example 2 (58 mg), mp: 265-269 °C.
  • 6-Methylisatoic anhydride (10.0 g, 56 mmol) ethyl glycinate hydrochloride (9J7g, 1.25 equiv.) and anhydrous pyridine (200 mL) were combined and heated under reflux 3.5h in a nitrogen atmosphere.
  • the pyridine was removed by evaporation under reduced pressure to give an oil.
  • the oil was dissolved in acetic acid (15 mL) and heated under reflux for 6 h.
  • the volatiles were removed under reduced pressure to give a residue which was triturated methanol and filtered to recover 3.63 g of 6-methyl-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione as a yellow solid.
  • 6-Methyl-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione (9.3 g, 49 mmol) was suspended in anhydrous T ⁇ F (150 L) under a nitrogen atmosphere. To the suspension was added 1M B ⁇ in THF (200 mL, 4 equiv.) and the reaction mixture was heated under reflux for 25 h. The reaction was quenched by the careful addition of 6N HCl
  • Example 1 2,3,4,5-tetrahydro-7-methyl- 1,4-benzodiazepine (5.47 g, 34 mmol) was allowed to react with acetic anhydride (3.67 g, 34 mmol) in the presence of triethylamine (4 equiv.) in ether (500 mL) to give 7.29 g of Intermediate E as a yellow oil.
  • Zinc powder (3.27 g, 3 equiv.) was sonicated in water (10 mL) for 35 min.
  • the ice bath was removed and stirring was continued for 1 hr.
  • the reaction mixture was filtered through a sintered glass funnel to remove zinc, the yellow filtrate was evaporated under reduced pressure (oil pump vacuum) to give a residue.
  • Example 10 The product of Example 10 (223 mg, 0.8mmol) was dissolved in glacial acetic acid with stirring and the solution was cooled in an ice/water bath. Solid sodium cyanoborohydride (75 mg) was added portionwise with stirring. The ice bath was removed and the reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 3 h. The volatiles were removed under reduced pressure to give a colorless oil which was partitioned between 2.5 N NaOH and ethyl acetate. The organic phase was washed with saturated NaCl solution, then water and dried (MgSO 4 ). The dried solution was filtered and the filtrate was evaporated under reduced pressure to give a pale yellow oil (206 mg).
  • reaction mixture was filtered into a flask containing cyclooctanone (7 g) and was heated at 110-120°C for 3 h.
  • the acetic acid was removed by evaporation under reduced pressure and the residue was partitioned between 2.5 N
  • Example 12 The product of Example 12 (370 mg, 1.45 mmol) was dissolved in trifluoroacetic acid (10 mL) under a nitrogen atmosphere and cooled in an ice/water bath. 1.5 M BH in THF (7 mL) was added over 4 minutes. The cooling bath was removed and the reaction mixture was stined for an additional 45 min. The reaction was quenched by the careful addition of water. Then 2.5 N NaOH was added followed by 50% aqueous NaOH until the reaction mixture remained basic The product was extracted into methylene chloride and was purified on silica gel eluting with 3-15% methanol in methylene chloride. Evaporation of the volatiles under reduced pressure gave an oil which crystallized to give the title compound as a yellow solid (238 mg), mp: 58-63 °C.

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Abstract

La présente invention concerne des composés de cycloalkyl[1,4] diazépino[6,7,1-hi] indole représentés par la formule (I) ou un sel pharmaceutiquement acceptable de ces derniers ainsi que des procédés et des compositions pharmaceutiques dans lesquels on les utilise pour traiter ou prévenir des troubles tels que les troubles obsessionnels-compulsifs, la dépression, l'anxiété, la schizophrénie, la migraine, les troubles du sommeil, les troubles de l'alimentation, l'obésité, l'épilepsie et le traumatisme médullaire. Formule (I)
PCT/US2001/046084 2000-11-03 2001-11-01 Cycloalkyl[b][1,4]diazepino[6,7,1-hi]indoles et derives WO2002036596A2 (fr)

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