(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0261693 A1
`(43) Pub. Date:
`Oct. 14, 2010
`Ulmann et al.
`
`US 2010.0261693A1
`
`(54) METHOD FORTREATING CUSHINGS
`SYNDROME
`
`(76) Inventors:
`
`André Ulmann, Paris (FR); Erin
`Gainer, Paris (FR); Francois
`Vuillet, Paris (FR)
`
`Correspondence Address:
`Ohlandt, Greeley, Ruggiero & Perle, LLP
`c/o Charles N.J. Ruggiero and
`Axinn, Veltrop & Harkrider LLP, One Landmark
`Square, 10th Floor
`Stamford, CT 06901-2682 (US)
`
`(21) Appl. No.:
`
`12/738,525
`
`(22) PCT Filed:
`
`Oct. 13, 2008
`
`PCT/EP08/63699
`
`(86). PCT No.:
`S371 (c)(1),
`Apr. 16, 2010
`(2), (4) Date:
`Related U.S. Application Data
`(60) Provisional application No. 60/960,856, filed on Oct.
`17, 2007.
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`A 6LX 3/575
`(2006.01)
`A6IP5/00
`(52) U.S. Cl. ........................................................ 514/179
`(57)
`ABSTRACT
`The invention relates to a method for treating Cushing's Syn
`drome in a patient, which method comprises administering
`the patient with a pharmaceutical composition comprising a
`glucocorticoid receptor antagonist, at least twice a day, or an
`extended-release composition of a glucocorticoid receptor
`antagonist, or a combination of a glucocorticoid receptor
`antagonist and a inhibitor of cortisol synthesis.
`
`1
`
`TEVA1008
`
`

`

`US 2010/0261693 A1
`
`Oct. 14, 2010
`
`METHOD FOR TREATING CUSHINGS
`SYNDROME
`
`0001. The invention relates to a method for treating Cush
`ing's syndrome using glucocorticoid receptor antagonists.
`
`BACKGROUND OF THE INVENTION
`
`0002 Cushing's syndrome of endogenous origin is a hor
`monal disease with an estimated incidence of approximately
`10 per 1 million persons (Meier and Biller, 1997). Cushing's
`syndrome is associated with an increased blood concentration
`of cortisol (hypercortisolism) or the presence in blood of
`glucocorticoid hormone excess over a long period of time.
`Cushing's syndrome is classified as either ACTH dependent
`or non ACTH dependent.
`0003 ACTH dependent Cushing's syndrome is character
`ised by a chronic ACTH hypersecretion which stimulates the
`growth of the adrenal glands and the hypersecretion of corti
`costeroids. The most common underlying cause of ACTH
`dependent Cushing's syndrome is excessive production of
`ACTH by pituitary adenomas known as Cushing's disease.
`Cushing's syndrome resulting from the production of ACTH
`in another location than the pituitary gland is known as
`ectopic Cushing's syndrome. Examples of ectopic sites
`include thymoma, medullary carcinoma of the thyroid, pheo
`chromocytoma, islet cell tumours of the pancreas and Small
`cell carcinoma of the lung.
`0004 ACTH independent Cushing's syndromes are
`caused by adrenal tumors that can be either adenomas or
`carcinomas. Both adrenal adenomas and carcinomas are char
`acterised by chronic cortisol hypersecretion.
`0005 Symptoms of Cushing's syndrome include a char
`acteristic abnormal fat deposition around the neck, thinning
`of the skin, osteoporosis, moon face, weakness, fatigue, back
`ache, headache, impotence, muscle atrophy, increased thirst,
`urination, insulin resistance, dyslipidemia, myopathy, amen
`orrhea, hypertension, weight gain, central obesity, Steroid
`hypersecretion, elevated urinary cortisol excretion and men
`tal status changes, in particular depression (Orth 1995; Dahia
`and Grossman, 1999).
`0006 Effective drug therapies for Cushing's syndrome
`currently are not satisfactory. The oral inhibitors of adrenal
`steroidogenesis are the most commonly used medical agents
`in the treatment of Cushing's syndrome: these include
`metyrapone, ketoconazole, aminoglutethimide, mitotane and
`triloStane.
`0007. In ectopic ACTH secretion, when the tumor cannot
`be found or removed, medical therapy may be used to reduce
`cortisol production (Doppman et al., 1987, Doppman et al.
`1989, Passet al., 1990, Wajchenberget al., 1994, Newell-Price
`etal, 1998). Furthermore, clinical trials showed some efficacy
`using high-dose mifepristone once a day (Nieman et al., 1985;
`Chrousos etal, 1989; vander Lely, 1991, Newfieldetal, 2000;
`Chu et al., 2001). A fractioned dosage of mifepristone was
`successfully given to a young child (Beaufrere et al., 1987).
`0008. However in a long term, such high dosage of mife
`pristone given with long intervals between doses (e.g. once a
`day) triggers a massive secretion of cortisol due to interrup
`tion of the endogenous feedback mechanism. This high level
`
`of cortisol then overwhelms the blockage of the glucocorti
`coid receptors, leading to hypercortisolism (Raux-Demay et
`al, 1990).
`
`SUMMARY OF THE INVENTION
`0009. In order to avoid secretion of cortisol in response to
`the blockade of the glucocorticoid receptor, it is now pro
`posed to give multiple low doses or a Sustained-release low
`dosage of glucocorticoid receptor antagonist, and/or to com
`bine the glucocorticoid receptor antagonist with an inhibitor
`of cortisol synthesis, for treating Cushing's syndrome.
`0010. The invention thus provides a method for treating
`Cushing's syndrome in an adult or an adolescent patient,
`which method comprises administering the patient with a
`pharmaceutical composition comprising a glucocorticoid
`receptor antagonist, at least twice a day.
`0011. The invention also relates to a glucocorticoid recep
`tor antagonist for treating Cushing's syndrome in an adult or
`an adolescent patient by administration of said glucocorticoid
`receptor antagonist at least twice a day.
`0012. The invention also provides a method for treating
`Cushing's syndrome in a patient, which method comprises
`administering the patient with an extended-release composi
`tion of a glucocorticoid receptor antagonist.
`0013 The invention also relates to an extended-release
`composition of a glucocorticoid receptor antagonist for treat
`ing Cushing's syndrome in an adult or an adolescent patient.
`0014. The invention further provides a method for treating
`Cushing's syndrome in a patient, which method comprises
`administering the patient with a glucocorticoid receptor
`antagonist and an inhibitor of cortisol synthesis.
`
`DETAILED DESCRIPTION OF THE INVENTION
`00.15
`Definitions:
`0016. Unless otherwise indicated, the patient to be treated
`may be any human Subject afflicted with Cushing's Syn
`drome, whatever the sex and the age of the subject. The
`patient may be a child, an adolescent (i.e. generally a subject
`who is 12 years old or above), or an adult. The patient to be
`treated is afflicted with Cushing's syndrome, preferably
`caused by ectopic ACTH secretion.
`0017. In the context of the invention, the glucocorticoid
`receptor antagonist may be a steroidal or non-steroidal glu
`cocorticoid receptor antagonist.
`00.18 Examples of steroidal glucocorticoid receptor
`antagonists include, without limitation, mifepristone, cortex
`olone, dexamethasone-oxetanone, 19-nordeoxycorticoster
`one, 19-norprogesterone, cortisol-21-meSylate; dexametha
`Sone-21-mesylate, 11(-(4-dimethylaminoethoxyphenyl)-17
`(-propynyl-17(-hydroxy-4.9-estradien-3one,
`and
`17(-
`hydroxy-17(-19-(4-methylphenyl)androsta-4,9011)-dien-3-
`OC.
`0019. In another preferred embodiment the steroidal glu
`cocorticoid receptor is ulipristal, formerly known as CDB
`2914, is 17O-acetoxy-11 B-4-N,N-dimethylamino-phenyl)-
`19-norpregna-4,9-diene-320-dione, represented below.
`0020. It is a well-known steroid, more specifically a
`19-norprogesterone, which possesses antiprogestational and
`antiglucocorticoidal activity. This compound, and methods
`for its preparation, are described in U.S. Pat. Nos. 4,954,
`490.5, 073,548, and 5,929, 262, and international patent
`applications WO2004/0654.05 and WO2004/078709, all
`incorporated herein by reference.
`
`2
`
`

`

`US 2010/0261693 A1
`
`Oct. 14, 2010
`
`0021. Other steroidal glucocorticoid receptor antagonists
`include metabolites of CDB-2914, as described in Attardi et
`al, 2004, e.g. monodemethylated CDB-2914 (CDB-3877);
`didemethylated CDB-2914 (CDB-3963): 17alpha-hydroxy
`CDB-2914 (CDB-3236); aromatic A-ring derivative of CDB
`2914 (CDB-4183).
`0022. Still other steroidal glucocorticoid receptor antago
`nists include metabolites of mifepristone, as described in
`Attardi et al., 2004, e.g. monodemethylated mifepristone,
`didemethylated mifepristone, and 17-O-3'-hydroxy-propy
`nylmifepristone.
`0023 These steroidal glucocorticoid receptor antagonists,
`as well as other derivatives, are represented below.
`
`CH3
`=o
`
`- OAC
`
`CH3
`N
`1
`
`H3C
`
`O
`
`
`
`-continued
`
`1N
`
`O
`
`H
`
`N
`H1
`
`OH
`
`C ---CEC-CH
`
`monodemethylated mifepristone
`
`CH
`
`CO
`
`---OAc
`
`O
`
`didemethylated CDB-2914
`
`CDB-4124
`
`CH
`
`N 1
`HC
`
`OH
`
`---CEC-CH
`
`H
`
`1N
`
`OH
`
`---CEC-CH
`
`O
`
`
`
`mifepristone
`
`O
`
`
`
`CH
`
`didemethylated mifepristone
`
`CH
`
`monodemethylated CDB-2914
`
`17c-hydroxy CDB-2914
`
`3
`
`

`

`US 2010/0261693 A1
`
`Oct. 14, 2010
`
`
`
`-continued
`
`(I)
`
`R2
`
`H
`
`s
`
`HN
`
`N
`
`O 21
`
`--R,
`S
`
`0027 wherein
`0028. R1 is Hand R2 is H or C1,
`0029 or R1 is o-chloro or m-chloro and R2 is H.
`0030. In WO05/087769, incorporated herein by reference,
`Corcept therapeutics described the synthesis and biological
`testing of 150 compounds with a tetracyclic core ring struc
`ture that they term as azadecalins. Preferred azadecalin
`antagonists are compounds of formula II
`0031 (II)
`
`aromatic A-ring CDB-4124
`
`0024. In a most preferred embodiment, the steroidal glu
`cocorticoid receptor antagonist is mifepristone.
`0025. Examples of non-steroidal glucocorticoid receptor
`antagonists include, without limitation, N-(2-4.4.441
`trichlorotrityloxyethyl)morpholine: 1-(24,4',4'-trichlorot
`rityloxyethyl)-4-(2-hydroxyethyl)piperazine
`dimaleate;
`N-(4,4',4'-trichlorotrityl)imidazole; 9-(3-mercapto-1,2,4-
`triazolyl)-9-phenyl-2,7-difluorofluorenone: 1-(2-chlorotri
`tyl)-3,5-dimethylpyrazole: 4-(morpholinomethyl)-A-(2-py
`ridyl)benzhydrol;
`5-(5-methoxy-2-(N-methylcarbamoyl)-
`phenyl)dibenzosuberol:
`N-(2-chlorotrityl)-L-prolinol
`acetate:
`1-(2-chlorotrityl)-1,2,4-triazole;
`1.S.-bis(4,4',4'-
`trichlorotrityl)-1,2,4-triazole-3-thiol: 4.alpha.(S)-Benzyl-2
`(R)-chloroethynyl-1,2,3,4,4-alpha.,9,10,10.alpha.(R)-oc
`tahydro-phenanthrene-2,7-diol (“CP 3.94531), 4.alpha.(S)-
`Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4-alpha.9,10,10.alpha.
`(R)-octahydro-phenanthrene-2,7-diol (“CP-409069), trans
`(1R,2R)-3,4-dichloro-N-methyl-N-2-1 pyrrolidinyl)
`cyclohexylbenzeneacetamide,
`bremazocine,
`ethylketocyclazocine and naloxone.
`0026. In another embodiment, the non-steroidal glucocor
`ticoid antagonist is one of the series synthesized by Corcept
`therapeutics. WO2006/014394, incorporated herein by refer
`ence, reports the synthesis and biological characterization of
`48 novel 5,6-substituted pyrimidine-2,4-dione GR modula
`tors. The most active compounds are compounds of formula
`I
`
`1.
`
`\/
`N Ol
`
`R
`
`R
`
`2
`
`(
`
`N
`N
`
`F
`
`0032 wherein
`0033 R1 is F and R2 is pyrrolidine,
`0034 or R1 is t-butyl and R2 is selected from the group
`consisting of H, a phenyl group, and —CH2—O—CH
`0035. The compounds may be in the form of pharmaceu
`tically acceptable salts, esters, optically active isomers, race
`mates or hydrates.
`0036 Multiple Doses
`0037. In a preferred embodiment, the invention provides a
`method for treating Cushing's syndrome in an adult or an
`adolescent patient, which method comprises administering
`the patient with a pharmaceutical composition comprising a
`glucocorticoid receptor antagonist, at least twice a day.
`0038 Most preferably, the patient is administered with
`pharmaceutical composition comprising a glucocorticoid
`receptor antagonist at least three times a day, e.g. three or four
`times a day.
`0039. Such chronic daily administration of the glucocor
`ticoid receptor antagonist in Subjects with Cushing's Syn
`drome makes it possible to normalize glucocorticoid-depen
`dent parameters through its cortisol-blocking action.
`0040 Preferably the daily dosage is less than about 40
`mg/kg/day, preferably less than about 20 mg/kg/day.
`
`4
`
`

`

`US 2010/0261693 A1
`
`Oct. 14, 2010
`
`0041. The total daily amount of the glucocorticoid recep
`tor antagonist administered may be advantageously inferior
`or equal to 800 mg, preferably inferior or equal to 600 mg.
`still preferably inferior or equal to 400 mg, still more prefer
`ably inferior or equal to 300 mg.
`0042. The composition may be administered by any con
`venient route. The active ingredient may be administered by
`any convenient route, including oral, buccal, parenteral,
`transdermal, vaginal, uterine, rectal, nasal etc. Preferably the
`pharmaceutical composition is Suitable for oral or parenteral
`administration. In a particular embodiment, the composition
`is in the form of an infusion to the patient.
`0043. Extended-Release Form:
`0044. In another embodiment, the invention provides a
`method for treating Cushing's syndrome in a patient, which
`method comprises administering the patient with an
`extended-release composition of a glucocorticoid receptor
`antagonist.
`0045. By extended-release is meant that the active ingre
`dient is released from the formulation and thus made avail
`able for absorption by the body in a sustained manner, this
`being determined by the release rate controlling Substance
`and interactions between the active ingredient, the release
`rate controlling Substance and the media Surrounding the
`formulation (e.g. gastric juice).
`0046 Preferably the daily dosage is less than about 40
`mg/kg/day, preferably less than about 20 mg/kg/day.
`0047. The total daily amount of the glucocorticoid recep
`tor antagonist administered may be advantageously inferior
`or equal to 800 mg, preferably inferior or equal to 600 mg.
`still preferably inferior or equal to 400 mg, still more prefer
`ably inferior or equal to 300 mg.
`0048. The composition may be administered by any con
`venient route. The active ingredient may be administered by
`any convenient route, including oral, buccal, parenteral,
`transdermal, vaginal, intra-uterine, rectal, nasal, etc. Prefer
`ably the pharmaceutical composition is suitable for oral or
`parenteral administration. In a particular embodiment, the
`extended-release composition is Suitable for intradermal
`administration. For instance, the extended-release composi
`tion may be in the form of a patch or an implant. In still
`another embodiment, the extended-release composition is
`suitable for intra-uterine administration.
`0049 Association with an Inhibitor of Cortisol Synthesis:
`0050. The invention further provides a method for treating
`Cushing's syndrome in a patient, which method comprises
`administering the patient with a glucocorticoid receptor
`antagonist and an inhibitor of cortisol synthesis.
`0051. In a preferred embodiment, the inhibitor of cortisol
`synthesis is an adrenolytic agent. Preferably, the inhibitor of
`cortisol synthesis is mitotane. In another preferred embodi
`ment, the inhibitor of cortisol synthesis is metyrapone.
`0052. Other examples of inhibitors of cortisol synthesis
`include, without limitation, aminoglutethimide, Sodium Val
`proate, an enkephalin, an opioid, clonidine, oxytocin, etomi
`date, triloStane, phenyltoin, procaine, Vitamin C, a salicylate,
`cimetidine, and lidocaine, as well as ketoconazole, clotrima
`Zole; N-(triphenylmethyl)imidazole; N-(2-fluoro-9-phenyl
`fluorenyl)imidazole; and N-(2-pyridyldiphenylmethyl)imi
`dazole.
`0053 Preferably the glucocorticoid receptor antagonist is
`mifepristone and the inhibitor of cortisol synthesis is mito
`tane, metyrapone, aminoglutethimide, fluconazole or keto
`conazole.
`
`0054 Preferably the daily dosage is less than about 40
`mg/kg/day, preferably less than about 20 mg/kg/day.
`0055. The total daily amount of the glucocorticoid recep
`tor antagonist administered may be advantageously inferior
`or equal to 800 mg, preferably inferior or equal to 600 mg.
`still preferably inferior or equal to 400 mg, still more prefer
`ably inferior or equal to 300 mg.
`0056. The composition may be administered by any con
`venient route. The active ingredients may be administered by
`any convenient route, including oral, buccal, parenteral,
`transdermal, vaginal, uterine, rectal, nasal, etc. Preferably the
`pharmaceutical composition is Suitable for oral or parenteral
`administration. In a particular embodiment, the composition
`is in the form of an infusion to the patient.
`0057 Routes of Administration:
`0.058
`For a brief review of present methods for drug deliv
`ery, see, Langer, Science 249:1527-1533 (1990), which is
`incorporated herein by reference. Methods for preparing
`administrable compounds are known or are apparent to those
`skilled in the art and are described in more detail in, for
`example, Remington's Pharmaceutical Science, 17th ed.,
`Mack Publishing Company, Easton, Pa. (1985), which is
`incorporated herein by reference, and which is hereinafter
`referred to as “Remington.”
`0059 For solid compositions, conventional non toxic
`Solid carriers may be used which include, for example, phar
`maceutical grades of mannitol, lactose, starch, magnesium
`Stearate, Sodium saccharine, talcum, cellulose, glucose,
`Sucrose, magnesium, carbonate, and the like. For oral admin
`istration, a pharmaceutically acceptable nontoxic composi
`tion is formed by incorporating any of the normally employed
`excipients, such as those carriers previously listed.
`0060 Oral solid dosage forms are preferentially com
`pressed tablets or capsules. Compressed tablets may contain
`any of the excipients described above which are diluents to
`increase the bulk of the active ingredient so that production of
`a compressed tablet of practical size is possible. Binders,
`which are agents which impart cohesive qualities to pow
`dered materials are also necessary. Starch, gelatine, Sugars
`Such as lactose or dextrose, and natural and synthetic gums
`are used. Disintegrants are necessary in the tablets to facilitate
`break-up of the tablet. Disintegrants include starches, clays,
`celluloses, algins, gums and crosslinked polymers. Lastly
`Small amounts of materials known as lubricants and glidants
`are included in the tablets to prevent adhesion to the tablet
`material to Surfaces in the manufacturing process and to
`improve the flow characteristics of the powder material dur
`ing manufacture. Colloidal silicon dioxide is most commonly
`used as a glidant and compounds such as talc or Stearic acids
`are most commonly used as lubricants. Procedures for the
`production and manufacture of compressed tablets are well
`known by those skilled in the art (See Remington).
`0061 Capsules are solid dosage forms using preferentially
`either a hard or soft gelatine shell as a container for the
`mixture of the active ingredient and inert ingredients. Proce
`dures for production and manufacture of hard gelatin and soft
`elastic capsules are well known in the art (See Remington).
`0062 Buccal forms or devices are also useful, such as
`those described in U.S. patent application 20050208129,
`herein incorporated by reference. U.S. patent application
`20050208129 describes a prolonged release bioadhesive
`mucosal therapeutic system containing at least one active
`principle, with an active principle dissolution test of more
`than 70% over 8 hours and to a method for its preparation.
`
`5
`
`

`

`US 2010/0261693 A1
`
`Oct. 14, 2010
`
`Said bioadhesive therapeutic system comprises quantities of
`natural proteins representing at least 50% by weight of active
`principle and at least 20% by weight of said tablet, between
`10% and 20% of an hydrophilic polymer, and compression
`excipients, and comprising between 4% and 10% of an alkali
`metal alkylsulphate to reinforce the local availability of active
`principle and between 0.1% and 1% of a monohydrate sugar.
`0063 For parenteral administration, fluid unit dosage
`forms are prepared utilizing the compounds and a sterile
`vehicle, water being preferred. The active ingredient, depend
`ing on the vehicle and concentration used, can be either Sus
`pended or dissolved in the vehicle. In preparing solutions the
`compound can be dissolved in water for injection and filtered
`sterilized before filling into a suitable vial or ampoule and
`sealing. Advantageously, adjuvants such as a local anesthetic,
`preservative and buffering agents can be dissolved in the
`vehicle. To enhance the stability, the composition can be
`frozen after filling into the vial and the water removed under
`vacuum. The dry lyophilized powder is then sealed in the vial
`and an accompanying vial of water for injection is Supplied to
`reconstitute the liquid prior to use. Parenteral Suspensions can
`be prepared in Substantially the same manner except that the
`compounds are Suspended in the vehicle instead of being
`dissolved and sterilization cannot be accomplished by filtra
`tion. The compound can be sterilized by exposure to ethylene
`oxide before suspending in the sterile vehicle. Advanta
`geously, a Surfactant or wetting agent is included in the com
`position to facilitate uniform distribution of the active ingre
`dient.
`0064. Additionally, a suppository can be employed to
`deliver the active ingredient. The active compound can be
`incorporated into any of the known Suppository bases by
`methods known in the art. Examples of Such bases include
`cocoa butter, polyethylene glycols (carbowaxes), polyethyl
`ene Sorbitan monostearate, and mixtures of these with other
`compatible materials to modify the melting point or dissolu
`tion rate. These Suppositories can weigh from about 1 to 2.5
`gm.
`0065 Transdermal delivery systems comprising a pen
`etration enhancer and an occlusive backing are of use to
`deliver the active ingredient. Examples of penetration
`enhancers include dimethyl sulfoxide, dimethyl acetamide
`and dimethylformamide.
`0066 Systems comprising polymeric devices which
`slowly release or slowly erode and release within the body to
`provide continuous Supplies of the active ingredient are also
`of use.
`0067. The below example illustrates the invention without
`limiting its scope.
`
`Example
`
`0068 Case-Study:
`0069. A 53 year-old female subject, first presented with
`clinical symptoms of Cushing's syndrome in August 2006,
`and she was diagnosed with Cushing's syndrome secondary
`to ectopic ACTH secretion in March 2007. She received 200
`mg mifepristone, three times a day (in the morning, at noon,
`and in the evening) for 2.5 weeks before dose reduction for 1
`week to 400 mg (200 mg twice a day).
`0070 The administration of mifepristone rapidly
`improved (after 2 weeks of treatment) general clinical conse
`quences of hypercortisolism: glycemia returned to normal,
`insulin was stopped and dose of metformin decreased by two.
`
`The dose of enalapril previously administered for hyperten
`sion was decreased from 30 mg to 10 mg.
`
`REFERENCES
`0071 Attardi et al., Journal of Steroid Biochemistry &
`Molecular Biology, 2004, 88: 277-288
`0072 Beaufrere et al. The Lancet, Jul. 25, 1987, page
`217
`0.073 Chrousos et al., “Clinical applications of RU486,
`a prototype glucocorticoid and progestin antagonist in:
`Adrenal and hypertension' Eds F. mantero, B A Scog
`gins, R. Takeda, E G Biglieri, J W Funder, Raven Press
`(NY), 1989, pp. 273-84
`0074 Chu et al., 2001, J. Clin Endocrinol Metab,
`86:3568-73
`0075 Dahia and Grossman, 1999, Endocr. Rev. 20:136
`55
`0.076 Doppman et al., 1987, Radiology, 163:501-3
`0.077 Doppman et al., 1989, Radiology, 172:115-24
`0078 Meier and Biller, 1997, Endocrinol Metab Clin
`North Am 26:741-762
`0079 Newell-Price et al., 1998, Endocr Rev. 19:647-72
`0080 Newfield et al., 2000: J Clin Endocrinol Metab,
`2000, 85:14-21
`0081 Nieman et al., 1985: J Clin Endocrinol Metab,
`1985, 61:536-40
`0082) Orth, 1995, N. Engl. J. Med. 332:791-803
`0.083
`Pass et al., 1990, Ann Thorac Surg, 50:52-7
`I0084. Raux-Demay et al., 1990; J Clin Endocrinol
`Metab, 1990, 70:230-33
`I0085 vander Lely, 1991, Ann Intern Med, 114:143-144
`I0086 Wajchenberg et al., 1994, Endocr Rev. 15:752-87
`1. A method for treating Cushing's syndrome in an adult or
`an adolescent patient, which method comprises administer
`ing the patient with a pharmaceutical composition compris
`ing a glucocorticoid receptor antagonist, at least twice a day.
`2. The method of claim 1, wherein the patient is adminis
`tered with pharmaceutical composition comprising a gluco
`corticoid receptor antagonist at least three times a day.
`3. The method of claim 1, wherein the total daily amount of
`the glucocorticoid receptor antagonist administered is pref
`erably less than about 20 mg/kg/day.
`4. The method of claim 1, wherein the total daily amount of
`the glucocorticoid receptor antagonist administered is infe
`rior or equal to 800 mg.
`5. The method of claim 4, wherein the total daily of the
`glucocorticoid receptor antagonist administered is inferior or
`equal to 600 mg.
`6. The method of claim 1, wherein the glucocorticoid
`receptor antagonist is a steroidal glucocorticoid receptor
`antagonist.
`7. The method of claim 6, wherein the steroidal glucocor
`ticoid receptor antagonist is selected from the group consist
`ing of mifepristone, monodemethylated mifepristone, didem
`ethylated
`mifepristone,
`17-CL-3'-hydroxy-propynyl
`mifepristone, ulipristal (CDB-2914), CDB-3877, CDB
`3963, CDB-3236, CDB-4183, cortexolone, dexamethasone
`oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone,
`cortisol-21-meSylate; dexamethasone-21-mesylate, 11(-(4-
`dimethylaminoethoxyphenyl)-17(-propynyl-17(-hydroxy-4,
`9-estradien-3one, and 17(-hydroxy-17(-19-(4-methylphe
`nyl)androsta-4,9011)-dien-3-one.
`8. The method of claim 7, wherein the steroidal glucocor
`ticoid receptor antagonist is mifepristone.
`
`6
`
`

`

`US 2010/0261693 A1
`
`Oct. 14, 2010
`
`9. The method of claim 1, wherein the glucocorticoid
`receptor antagonist is a non-steroidal glucocorticoid receptor
`antagonist.
`10. The method of claim 9, wherein the non-steroidal glu
`cocorticoid receptor antagonist is selected from the group
`consisting of N-(2-4.4.441-trichlorotrityloxyethyl)mor
`pholine: 1-(24,4',4'-trichlorotrityloxyethyl)-4-(2-hydroxy
`ethyl)piperazine dimaleate; N-(4,4',4'-trichlorotrityl)imi
`dazole;
`9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-
`difluorofluorenone: 1-(2-chlorotrityl)-3,5-dimethylpyrazole;
`4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol; 5-(5-meth
`oxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol; N-(2-
`chlorotrityl)-L-prolinol acetate: 1-(2-chlorotrityl)-1,2,4-tria
`Zole;
`1.S.-bis(4,4',4'-trichlorotrityl)-1,2,4-triazole-3-thiol:
`4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4-alpha.,9.
`10,10.alpha.(R)-octahydro-phenanthrene-2,7-diol
`(“CP
`3.94531), 4.alpha. (S)-Benzyl-2(R)-prop-1-ynyl-1,2.3.4.4.
`alpha.9,10,10.alpha.(R)-octahydro-phenanthrene-2,7-diol
`(“CP-409069), trans-(1R,2R)-3,4-dichloro-N-methyl-N-
`2-1 pyrrolidinyl)cyclohexylbenzeneacetamide, bremazo
`cine, ethylketocyclazocine, naloxone compounds of formula
`I
`
`wherein
`R1 is Hand R2 is H or Cl,
`or R1 is o-chloro or m-chloro and R2 is H.
`or compounds of formula II
`
`(II)
`
`O. O
`V/
`1. S
`N
`
`Ol
`
`R
`
`R2
`
`/
`
`N
`N
`
`F
`
`(I)
`
`wherein
`R1 is F and R2 is pyrrolidine,
`or R1 is t-butyl and R2 is selected from the group consist
`ing of H, a phenyl group, and
`—CH, O CH
`11. The method of claim 1, wherein the pharmaceutical
`composition is Suitable for oral administration.
`12. The method of claim 1, wherein the pharmaceutical
`composition is Suitable for parenteral administration.
`13. The method of claim 1, wherein the composition is in
`the form of an infusion to the patient.
`14. The method of claim 1, wherein the composition is
`Suitable for buccal, intradermal and nasal administration.
`15-38. (canceled)
`
`7
`
`