(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2016/0067.264 A1
`Newell-Price
`(43) Pub. Date:
`Mar. 10, 2016
`
`US 20160067264A1
`
`(54) MEDICAMENT AND METHOD OF
`DAGNOSIS
`
`(71) Applicant: UNIVERSITY OFSHEFFIELD,
`Sheffield (GB)
`
`(72) Inventor: John Newell-Price, Sheffield (GB)
`
`(73) Assignee: UNIVERSITY OF SHEFFIELD,
`Sheffield (GB)
`
`(21) Appl. No.: 14/941,489
`1-1.
`22) Filed:
`Nov. 13, 2015
`(22) File
`OV. 15,
`Related U.S. Application Data
`(63) Continuation of application No. 13/128.225, filed on
`May 6, 2011, now Pat. No. 9.216,221, filed as appli-
`cation No. PCT/GB2008/003751 on Nov. 7, 2008.
`
`Publication Classification
`
`(51) Int. Cl.
`A 6LX3/575
`A6 IK3I/56
`A 6LX3/5.375
`A6 IK3I/495
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`A613 L/4164
`A613 L/53
`A613 L/45
`A 6LX3/5377
`A613 L/4745
`A613 L/496
`A61K3I/444
`A 6LX3/57
`A613 L/496
`(52) U.S. Cl.
`CPC ............... A61K3I/575 (2013.01); A6IK3I/57
`(2013.01); A61 K3I/56 (2013.01); A61 K
`31/5375 (2013.01); A61K3I/495 (2013.01);
`A61K 31/4164 (2013.01); A61 K31/4196
`(2013.01); A61 K31/415 (2013.01); A61 K
`31/5377 (2013.01); A61K3I/4745 (2013.01);
`A6 IK3I/496 (2013.01); A61 K3I/444
`(2013.01); A61 K3I/513 (2013.01)
`
`ABSTRACT
`(57)
`Disclosed is a diagnostic test to determine Suitable therapeu
`tic intervention of subjects suffering from subclinical Cush
`ing's syndrome SCSI and also agents that antagonise the
`action of cortisol or inhibit excess cortisol production in the
`treatment of conditions such as SCS in the presence of an
`adrenal incidentaloma.
`
`TEVA1079
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`
`1
`
`

`

`Patent Application Publication
`
`Mar. 10, 2016 Sheet 1 of 3
`
`US 2016/0067264 A1
`
`Figure 1
`
`Hs
`
`Hc
`
`Hs
`CO
`-OAc
`
`Ha
`
`Hc
`
`CH,
`CO
`st OA
`
`Hs
`N
`HaC
`
`C
`
`-CsC-CH
`
`O
`
`Hs
`
`CDB-294
`
`Hy
`
`O
`
`CDB-424
`
`9CH3
`Cer
`as OA
`
`H
`
`O
`
`O
`
`Hs
`N
`
`O
`
`mifepristore
`
`O
`-cisc-CH
`
`modernethylated CDE-424
`
`monodemethylated mifepristone
`
`didermethylated CDB-2914
`
`H
`H N
`
`O
`-CEC-CH
`
`O
`didcincthylated inifepristone
`
`Hs
`N
`Hsc?
`
`Gla
`Cat
`an OH
`
`Hs
`HC N
`
`CHs
`Cs
`to OH
`
`Hs
`
`Hc
`
`O
`-CEC-cHOH
`
`O
`
`to-hydroxy CDR-2914
`
`O
`17c-hydroxy CDB-4124
`
`O
`17o-3'-hydroxypropynyl)
`mifeprisone
`
`Hs
`Hic"
`3.
`
`Ha
`CeO
`OAC
`
`Ha
`N
`
`HC
`
`OCH
`CeO
`*OAt
`
`HO
`aromatic A-ring CDB-2914
`
`O
`
`aromatic A-ring CDB-4; 24
`
`2
`
`

`

`Patent Application Publication
`
`Mar. 10, 2016
`Sheet 2 of 3
`
`US 2016/0067264 A1
`
`Figure 2
`
`
`
`Adrenal Incidentaloma <4cm and lack of supression of
`Serum cortisol on 1 mg overnight dexamethaSone
`suppression or 2 mg/day 48 hour dexamethasone
`Suppression testing Suggesting Sub clinical Cushing's
`syndrome,
`Symptoms: Glycemic disorder or Hypertension
`
`
`
`
`
`8 Weeks MFEPRSTONE
`diagnostic test"
`
`impovement of glycemic disorder or
`Hypertension = glycemic disorder or
`hypertension are related
`to Sub-Clinical Cushing's syndrome
`
`No change of glycemic disorder or
`hypertension-glycemic disorder or
`hypertension are not related to Sub
`Clinical Cushing's syndrome
`
`
`
`Long-term
`mifepristo
`e
`treatment
`
`
`
`Long-term
`treatment
`of other
`glucocortico
`id receptor
`antagonist
`and/or
`inhibitor of
`adrena
`steroidogen
`esis
`
`
`
`No need for adrenalectomy
`or anti-Cortisol treatment
`
`Adrenalectomy
`
`
`
`Long-term Symptomatic
`Treatment of glycemic disorder or
`/hypertension
`
`* Or other glucocorticoid receptor
`antagonist and/or inhibitor of adrena
`steroidogenesis
`
`3
`
`

`

`Patent Application Publication
`
`Mar. 10, 2016 Sheet 3 of 3
`
`US 2016/0067.264 A1
`
`Figure 3
`
`
`
`Adrenal Incidentaloma <4cm and lack of supression of
`serum Cortisol on 1 mg overnight dexamethasone
`suppression or 2 mg/day 48 hour dexamethasone
`Suppression testing Suggesting Sub clinical Cushing's
`syndrome.
`
`Symptoms: Glycemic disorder or Hypertension
`
`8 WeekS MFEPRSTONE
`diagnostic test
`
`-N
`
`improvement of glycemic disorder
`or hypertension
`
`
`
`
`
`
`
`No change of glycemic disorder or
`hypertension
`
`Adrenalectomy
`
`
`
`Non-Surgery
`
`Long-term Symptomatic
`Treatment of glycemic
`disorder or hypertension
`
`* Or other glucocorticoid receptor antagonist
`and/or inhibitor of adrenal steroidogenesis
`
`4
`
`

`

`US 2016/0067264 A1
`
`Mar. 10, 2016
`
`MEDCAMIENT AND METHOD OF
`DAGNOSIS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`0001. This is a continuation of U.S. patent application Ser.
`No. 13/128.225, filed on May 6, 2011, which is the U.S.
`National Stage of PCT Application No. PCT/GB2008/
`003751, filed on Nov. 7, 2008, which was published in
`English under PCT Article 21(2). The prior applications are
`incorporated herein by reference in their entirety.
`
`FIELD
`0002 The invention relates to agents that inhibit the pro
`duction of excess cortisol, or antagonize its effects, in the
`prevention or treatment of conditions such as Subclinical
`Cushing's syndrome SCSI; medicaments and pharmaceuti
`cal compositions comprising the agents, combinations of
`agents; and also to a diagnostic test to determine Suitable
`therapeutic intervention of subjects suffering from SCS.
`
`BACKGROUND
`0003 Cortisol, also called the “stress hormone', is
`secreted by the adrenal glands which are adjacent the kidneys.
`Cortisol secretion increases when the body is stressed, either
`physically or psychologically. Cortisol is released from the
`adrenal gland under the regulation of ACTH derived from the
`pituitary gland. There is a circadian rhythm to cortisol release
`with high levels first thing in the morning and very low levels
`around midnight. ACTH and thus cortisol levels begin to rise
`between 2-3 am and peak between 7-9 am gradually falling
`over the day to a nadir between 8 pm and 2 am. Disease
`conditions associated with excess cortisol Secretion include
`Cushing's syndrome also referred to as hypercortisolism or
`hyperadrenocorticism and typically results from excess cor
`tisol production due to a pituitary adenoma. Cushing's Syn
`drome has a complex pathology and symptoms include
`Weight gain, telangiectasia, skin thinning, bruising, insomnia,
`psychiatric disorders or depression, impaired cognition or
`memory, osteopenia or osteoporosis, obesity, persistent
`hypertension, insulin resistance which can lead to impaired
`fasting glucose or impaired glucose tolerance or diabetes
`mellitus, dyslipidemia, metabolic syndrome, coagulation dis
`orders, proximal muscle weakness, hirsutism, amenorrhea.
`Untreated Cushing's disease can result in atherosclerosis,
`heart disease and increased mortality.
`0004. A related disease associated with excess cortisol
`production is subclinical Cushing's syndrome SCS. This
`condition is commonly associated with adrenal incidenta
`loma. Incidentaloma’s are mostly benign non-secreting
`tumours discovered by imaging studies performed for unre
`lated reasons. In approximately 10 to 15% of cases, they
`produce Supraphysiological amounts of cortisol. The levels
`are insufficient to cause clinical features typically associated
`with Cushing's syndrome. SCS is common in the general
`population (~1% or more of those >70y in hospitalized or
`health-screened populations), and contributes to overall car
`diovascular morbidity and mortality. A major problem is that
`management of SCS is not established. Approximately 90%
`of patients with SCS have hypertension; over 60% have
`impaired glucose tolerance or diabetes mellitus, obesity and
`osteoporosis or abnormal biochemical markers of bone turn
`over, 50% have dyslipidemia and abnormalities in hemostatic
`
`parameters. Carotid intima-media thickness is increased and
`atherosclerotic plaques are more frequent in patients than in
`controls.
`0005. In SCS there is the potential to permanently reduce
`these risks, and to improve bone health, by adrenalectomy.
`Only a very limited number of individuals with SCS are
`Subjected to adrenalectomy. In those that have undergone this
`procedure improvements have been found in blood pressure
`(~10 mmHg drop in systolic BP), lipid profiles, fibrinogen
`levels, biochemical markers of bone turnover and glycaemic
`control. However, a problem is deciding whether adrenal
`surgery will be of benefit for a given patient with SCS, and the
`basis for selection for Such permanent and invasive interven
`tion is not established.
`
`SUMMARY
`0006. There is a need to provide a treatment regime for
`controlling SCS and a diagnostic test to determine an appro
`priate treatment regime for a subject suffering from SCS. The
`response of subjects to the administration of these agents will
`also allow an objective means to determine if a Subject Suf
`fering from SCS would benefit from adrenalectomy.
`0007 Glucocorticoid receptor antagonists are known in
`the art. For example mifepristone (11-4-(Dimethylamino)
`phenyl-17-hydroxy-17-1-propynyl)-113, 17 B-estra-4.9-
`dien-3-one), a derivative of the synthetic progestin norethin
`drone, is a potent competitive glucocorticoid and
`progesterone receptor antagonist. Mifepristone is also known
`as RU486. Mifepristone causes glucocorticoidantagonism by
`reducing translocation of the receptor to the nucleus and also
`by antagonising glucocorticoid-dependent transcriptional
`activity. In man the administration of mifepristone at >200
`mg/day blocks central and peripheral glucocorticoid action
`with resultant activation of the HPA axis. Selective, nonste
`roidal glucocorticoid receptor antagonists have been derived
`from RU486 for instance as described by Morgan et al. (2002)
`in J. Med. Chem. 45, 2417-2424, as CP-394.531, and
`CP-409069. A further example is RU43044 which is a selec
`tive glucocorticoid receptor antagonist. Other nonsteroidal
`glucocorticoid receptor antagonist compounds are described
`for example in following patents and patent applications: U.S.
`Pat. No. 6,380,223, U.S. Pat. No. 6,436,986, U.S. Pat. No.
`6,468,975, US2002/0147336, US 2002/0107235, US2004/
`0014741, US2004/0176595, WO2004/009017, WO 2004/
`110385, WO2004/111015, US2004/0266758, US2004/
`0266831, WO2001/16128 WO2006/084917 and WO2008/
`017658 each of which is incorporated by reference.
`0008. An alternative means to oppose the actions of corti
`Sol is to reduce circulating levels by blocking cortisol synthe
`sis using inhibitors of adrenal Steroidogenesis. Cortisol Syn
`thesis inhibitory properties have been ascribed to several
`drugs. For instance, ketoconazole, was initially developed as
`an anti-fungal therapy. The drug inhibits unselectively the
`synthesis corticosteroids and at higher doses the synthesis of
`testosterone. Recently, the use of ketoconazole in cardiovas
`cular and metabolic diseases has been claimed by e.g. U.S.
`Pat. No. 6,274,582, U.S. Pat. No. 6,642,236. Further
`examples include aminogluthetimide and metyrapone. Ami
`nogluthetimide blocks the conversion of cholesterol to preg
`nenolone by inhibiting desmolase which inhibits the synthe
`sis of many steroids including cortisol. Metyrapone blocks
`cortisol synthesis by inhibition of steroid 11 beta hydroxy
`lase. Other examples include triloStane, etomidate, epostane,
`thiopentone and ketotriloStane.
`
`5
`
`

`

`US 2016/0067264 A1
`
`Mar. 10, 2016
`
`0009. This disclosure relates to a diagnostic test to deter
`mine a Suitable treatment regime for a subject suffering from
`excess cortisol production, for example Subclinical Cushings
`syndrome and also the treatment of the condition by admin
`istration of agents that inhibit the synthesis or activity of
`cortisol, or by Surgical intervention.
`
`BRIEF DESCRIPTION OF THE FIGURES
`0010 FIG. 1 illustrates non-limiting examples of gluco
`corticoid receptor antagonists;
`0011
`FIG. 2 illustrates a non-limiting embodiment of the
`treatment regime herein disclosed; Mifepristone test demon
`strates if diabetes or hypertension are caused by sub-clinical
`Cushing's syndrome or not (are cortisol-dependent or not);
`and
`0012 FIG. 3 illustrates a further embodiment of the treat
`ment regime herein disclosed. Diagnostic Test for Subclinical
`CS-incidentaloma. This test will help to select which patient
`would benefit from adrenalectomy.
`
`DETAILED DESCRIPTION
`0013. According to an aspect of the invention there is
`provided a diagnostic test, to determine a Suitable treatment
`regime for a subject Suffering from or having a pre-disposi
`tion to Subclinical Cushing's syndrome or incidentaloma
`comprising:
`0014 i) obtaining a biological sample from the subject;
`determining the level of cortisol in the subject and com
`paring this to control cortisol levels as a measure of
`Subclinical Cushing's syndrome;
`0015 ii) administering an effective amount of at least
`one agent to the Subject to inhibit the synthesis or activ
`ity of cortisol in the subject; and
`0016 iii) analysing the response of the subject to the
`administration of the agent to determine the improve
`ment or not of the subjects condition.
`0017. In a preferred method of the invention, the diagnos
`tic test aims at developing a clinical decision-making tool to
`inform the critical decision as to whether to proceed to
`adrenalectomy or not, or to use glucorticoid receptor antago
`nists and/or inhibitor of adrenal steroidogenesis.
`0018. In a preferred method of the invention, the diagnos
`tic test aims at developing a clinical decision-making tool to
`inform if hypertension and/or, glucose metabolism impair
`ment, glucose tolerance impairment, diabetes and/or
`osteoporosis are cortisol-dependent.
`0019. In a preferred method of the invention wherein there
`is an improvement in the Subject’s condition, the Subject is
`either administered a unit dose of the agent in a controlled
`regime to maintain control of the Subject's condition or to an
`alternative treatment regime; preferably said alternative treat
`ment regime is Surgical intervention, for example adrenalec
`tomy.
`0020. In an alternative preferred method of the invention
`wherein the Subjects condition does not improve a treatment
`regime is elected; preferably said alternative treatment
`regime is to avoid unnecessary Surgical intervention, for
`example adrenalectomy; preferably said alternative treatment
`regime is to continue symptomatic treatment for hypertension
`and/or glucose metabolism impairment and/or osteoporosis.
`0021. In a preferred method of the invention wherein there
`is an improvement in the Subjects condition, this means that
`the diagnosis test is positive; preferably this means that hyper
`
`tension and/or glucose metabolism impairment and/or
`osteoporosis are linked to Subclinical Cushing's syndrome or
`incidentaloma; preferably this means that hypertension and/
`or glucose tolerance impairment or diabetes and/or
`osteoporosis are linked to Subclinical Cushing's syndrome or
`adrenal incidentaloma.
`0022. In an alternative preferred method of the invention
`wherein the Subjects condition does not improve, this means
`that the diagnosis test is negative; preferably said this means
`that hypertension and/or glucose metabolism impairment
`and/or osteoporosis are not linked to Subclinical Cushings
`syndrome or adrenal incidentaloma; preferably said, this
`means that hypertension and/or glucose tolerance impairment
`or diabetes and/or osteoporosis are not linked to Subclinical
`Cushing's syndrome or adrenal incidentaloma.
`0023. In a preferred method of the invention said agent is
`a glucocorticoid receptor antagonist.
`0024. The term “glucocorticoid receptor antagonist'
`refers to any agent which partially or completely inhibits (i.e.
`antagonizes) the binding of a glucocorticoid receptoragonist,
`Such as cortisol.
`0025. In a preferred method of the invention said gluco
`corticoid receptor antagonist is mifepristone.
`(0026. The term “mifepristone” also referred to as RU486
`or 17-beta-hydroxy-11-beta-(4-dimethyl-aminophenyl)-17
`alpha-(1-propynyl)-estra-4.9-dien-3-one, refers to a mol
`ecule which belongs to a family of molecules sharing the
`same mechanism of action), including 11-beta-(4dimethy
`laminophenyl)-17-beta-hydrox 17-alpha-(1-propynyl)-estrn
`4.9-dien-3-one), or analogues thereof, which bind to the glu
`cocorticoid receptor, typically with high affinity, and inhibit
`the biological effects initiated/mediated by the binding of
`cortisol to a glucocorticoid receptor.
`0027. In an alternative preferred method of the invention
`said glucocorticoid receptor antagonist is selected from the
`group illustrated in FIG. 1.
`0028. In a most preferred embodiment, the steroidal glu
`cocorticoid receptor antagonist is mifepristone.
`0029. 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 (“CP3.94531), 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)cyclo
`hexylbenzeneacetamide, bremazocine, ethylketocyclaZo
`cine and naloxone.
`0030. 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.
`
`6
`
`

`

`US 2016/0067264 A1
`
`Mar. 10, 2016
`
`(I)
`
`R
`
`H
`
`s
`
`N
`
`O 21
`
`i-R,
`N
`
`0031 wherein
`0032 R1 is Hand R2 is H or Cl,
`0033 or R1 is o-chloro or m-chloro and R2 is H.
`0034. 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
`
`(II)
`
`O O
`V/
`-S
`N
`
`Ol
`
`R
`
`R
`
`(
`
`N
`N
`
`F
`
`0035 wherein
`0036). R1 is F and R2 is pyrrolidine,
`0037 or R1 is t-butyl and R2 is selected from the group
`consisting of H, a phenyl group, and —CH2—O—CH.
`0038. In a further alternative method of the invention said
`agent is an inhibitor of adrenal steroidogenesis.
`0039. In a preferred method of the invention said inhibitor
`of adrenal Steroidogenesis is selected from the group consist
`ing of ketoconazole, metyrapone, aminoglutethimide, trilos
`tane, etomidate, epostane, thiopentone and ketotrilistane.
`0040. In a preferred method of the invention said inhibitor
`of adrenal steroidogenesis is ketoconazole.
`0041. In a preferred method of the invention said inhibitor
`of adrenal steroidogenesis is metyrapone.
`0042. In a preferred method of the invention said agent is
`a combination of cortisol lowering agents; preferably a com
`bination of a glucocorticoid receptorantagonistandan inhibi
`tor of adrenal steroidogenesis.
`0043. According to an aspect of the invention there is
`provided an agent that inhibits the synthesis or activity of
`cortisol for use in the prevention or treatment of subclinical
`Cushing's syndrome.
`
`0044. In a preferred embodiment of the invention subclini
`cal Cushing's syndrome is caused by an adrenal incidenta
`loma.
`0045. According to an aspect of the invention there is
`provided an agent that inhibits the synthesis or activity of
`cortisol for use in the prevention or treatment of incidenta
`loma.
`0046. In a preferred embodiment of the invention agent is
`a glucocorticoid receptor antagonist.
`0047. In a preferred embodiment of the invention said
`glucocorticoid receptor antagonist is mifepristone.
`0048. In an alternative preferred embodiment of the inven
`tion said glucocorticoid receptor antagonist is RU-43044.
`Org 34517, Org 34850, or Org 34116.
`0049. In a most preferred embodiment, the steroidal glu
`cocorticoid receptor antagonist is mifepristone.
`0050 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 (“CP3.94531), 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)cyclo
`hexylbenzeneacetamide, bremazocine, ethylketocyclaZo
`cine and naloxone.
`0051. 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
`
`(I)
`
`HN
`
`O 21
`
`i-R,
`N
`
`0052 wherein
`0053 R1 is Hand R2 is H or C1,
`0054 or R1 is o-chloro or m-chloro and R2 is H.
`0055. In WO05/087769, incorporated herein by reference,
`Corcept therapeutics described the synthesis and biological
`testing of 150 compounds with a tetracyclic core ring struc
`
`7
`
`

`

`US 2016/0067264 A1
`
`Mar. 10, 2016
`
`ture that they term as azadecalins. Preferred azadecalin
`antagonists are compounds of formula II
`
`O O
`VW
`15
`
`Ol
`
`R
`
`R
`
`(
`
`N
`N
`
`F
`
`0056 wherein
`0057 R1 is F and R2 is pyrrolidine,
`0058 or R1 is t-butyl and R2 is selected from the group
`consisting of H, a phenyl group, and —CH2—O—CH.
`0059. In an alternative embodiment of the invention said
`agent is an inhibitor of adrenal steroidogenesis.
`0060. In a preferred embodiment of the invention said
`inhibitor of adrenal steroidogenesis is selected from the group
`consisting of ketoconazole, metyrapone, aminoglutethim
`ide, triloStane, etomidate, epostane, thiopentone and ketot
`riloStane.
`0061. In a preferred embodiment of the invention said
`agent is a combination of agents that inhibit the synthesis or
`activity of cortisol; preferably a combination of a glucocor
`ticoid receptor antagonist and an inhibitor of adrenal Ste
`roidogenesis.
`0062 According to a further aspect of the invention there
`is provided a pharmaceutical composition comprising: a glu
`cocorticoid receptor antagonist, an inhibitor of adrenal Ste
`roidogenesis and an excipient.
`0063. The compositions of the invention are administered
`in effective amounts. An "effective amount” is that amount of
`a composition that alone, or together with further doses, pro
`duces the desired response. For example, a dose of 100-300
`mg mifepristone or more preferably 200 mg mifepristone
`twice daily is administered to provide partial blockade of
`glucocorticoid receptor activity. Such amounts will depend,
`of course, on the particular condition being treated, the sever
`ity of the condition, the individual patient parameters includ
`ing age, physical condition, size and weight, the duration of
`the treatment, the nature of concurrent therapy (if any), the
`specific route of administration and like factors within the
`knowledge and expertise of the health practitioner. These
`factors are well known to those of ordinary skill in the art and
`can be addressed with no more than routine experimentation.
`It is generally preferred that a maximum dose of the indi
`vidual components or combinations thereof be used, that is,
`the highest safe dose according to Sound medical judgment. It
`will be understood by those of ordinary skill in the art, how
`ever, that a patient may insist upon a lower dose or tolerable
`dose for medical reasons, psychological reasons or for virtu
`ally any other reasons.
`0064. In the case of treating SCS the desired response is
`the symptomatic treatment of the consequences of the dis
`ease. This may involve only the partial improvement of the
`symptomatic consequences of the disease, although more
`
`preferably, it involves complete improvement of the symp
`tomatic consequences of the disease. This can be monitored
`by routine methods. More particularly improvements in SCS
`can be monitored by any one of the following indicia:
`0065 Blood pressure: The difference in blood pressure
`compared to baseline, in Systolic and/or diastolic blood pres
`sure (BP) (resting and ambulatory) Glucose homeostasis:
`Homeostasis model assessment of insulin resistance
`(HOMA-IR), and the insulin Sensitivity Index (ISI) as calcu
`lated from oral glucose tolerance test: insulin and glucose at
`-15, 0, 30, 60 and 120 minutes, with oral glucose 75 g at time
`0 (except for those on insulin therapy, whose investigation
`will be limited to basal and 120 minute plasma glucose) and
`2-hour glucose tolerance during a 75g oral glucose tolerance
`teSt.
`Lipid profiling: The difference in fasting lipids post
`0.066
`treatment.
`0067. DEXA scan with measurement of total and abdomi
`nal fat mass: The difference in total and abdominal fat mass
`post treatment compared to baseline.
`0068 Bone Markers: Excess cortisol will suppress serum
`osteocalcin, a marker of bone formation, and thus the effect of
`antagonism of glucocorticoids or lowering cortisol is an
`increase in this marker, and give insight as to the effect on
`bone health. The other bone turnover markers are bone alka
`line phosphatase, C-telepopeptide I (CTX-I) and N-terminal
`propeptide of type 1 procollagen (P1NP) are expected to
`decrease.
`0069. Urine steroid profile:The difference in urinary ste
`roid profile post treatment.
`(0070 Quality of Life: The difference between in depres
`Sion, quality of life and fatigue questionnaires.
`0071. The pharmaceutical compositions used in the fore
`going methods preferably are suitable for oral administration
`and contain an effective amount of an agent according to the
`invention for producing the desired response in a unit of
`weight or volume suitable for administration to a patient. The
`response can, for example, be measured by determining
`decrease of disease symptoms.
`0072 The doses of the agent according to the invention
`administered to a Subject can be chosen in accordance with
`different parameters, in particular in accordance with the
`mode of administration used and the state of the Subject.
`Other factors include the desired period of treatment, sub
`ject's body mass index, ACTH or cortisol (in plasma, urine or
`salivary) levels. In the event that a response in a Subject is
`insufficient at the initial doses applied, higher doses (or effec
`tively higher doses by a different, more localized delivery
`route) may be employed to the extent that patient tolerance
`permits.
`0073. Other protocols for the administration of agents will
`be known to one of ordinary skill in the art, in which the dose
`amount, schedule and mode of administration and the like
`vary from the foregoing. The administration of compositions
`to mammals other than humans, (e.g. for testing purposes or
`Veterinary therapeutic purposes), is carried out under Substan
`tially the same conditions as described above. A Subject, as
`used herein, is a mammal, preferably a human, and including
`a non-human primate, cow, horse, pig, sheep,goat, dog, cat or
`rodent.
`0074. When administered, the agents of the invention are
`applied in pharmaceutically-acceptable amounts and in phar
`maceutically-acceptable compositions. The term “pharma
`ceutically acceptable” means a non-toxic material that does
`
`8
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`US 2016/0067264 A1
`
`Mar. 10, 2016
`
`not interfere with the effectiveness of the biological activity
`of the active ingredients. Such preparations may routinely
`contain salts, buffering agents, preservatives, compatible car
`riers, and optionally other therapeutic agents. When used in
`medicine, the salts should be pharmaceutically acceptable,
`but non-pharmaceutically acceptable salts may conveniently
`be used to prepare pharmaceutically-acceptable salts thereof
`and are not excluded from the scope of the invention. Such
`pharmacologically and pharmaceutically-acceptable salts
`include, but are not limited to, those prepared from the fol
`lowing acids: hydrochloric, hydrobromic, Sulphuric, nitric,
`phosphoric, maleic, acetic, Salicylic, citric, formic, malonic,
`Succinic, and the like. Also, pharmaceutically-acceptable
`salts can be prepared as alkaline metal or alkaline earth salts,
`Such as sodium, potassium or calcium salts. The composi
`tions also may contain, optionally, Suitable preservatives,
`Such as: benzalkonium chloride; chlorobutanol; parabens and
`thimerosal. The agents of the invention can exist in different
`forms, such as acids, esters, salts and tautomers, for example,
`and the invention includes all variant forms of the agents.
`0075 Compositions may be combined, if desired, with a
`pharmaceutically-acceptable carrier. The term “pharmaceu
`tically-acceptable carrier as used herein means one or more
`compatible solid or liquid fillers, diluents or encapsulating
`Substances which are Suitable for administration into a
`human. The term “carrier in this context denotes an organic
`or inorganic ingredient, natural or synthetic, with which the
`active ingredient is combined to facilitate the application,
`e.g. liposome based. The components of the pharmaceutical
`compositions also are capable of being co-mingled with the
`molecules of the present invention, and with each other, in a
`manner Such that there is no interaction which would substan
`tially impair the desired pharmaceutical efficacy.
`0076. The compositions may conveniently be presented in
`unit dosage form and may be prepared by any of the methods
`well-known in the art of pharmacy. All methods include the
`step of bringing the active agent into association with a carrier
`which constitutes one or more accessory ingredients. In gen
`eral, the compositions are prepared by uniformly and inti
`mately bringing the active compound into association with a
`liquid carrier, a finely divided solid carrier, or both, and then,
`if necessary, shaping the product.
`0077 Compositions suitable for oral administration may
`be presented as discrete units, such as capsules, tablets, loz
`enges, each containing a predetermined amount of the active
`compound. Other compositions include Suspensions in aque
`ous liquids or non-aqueous liquids such as syrup, elixir or an
`emulsion or as a gel. Compositions may be administered as
`aerosols and inhaled.
`0078 Compositions suitable for parenteral administration
`conveniently comprise a sterile aqueous or non-aqueous
`preparation of agent which is preferably isotonic with the
`blood of the recipient. This preparation may be formulated
`according to known methods using Suitable dispersing or
`wetting agents and Suspending agents. The sterile injectable
`preparation also may be a sterile injectable solution or Sus
`pension in a non-toxic parenterally-acceptable diluent or Sol
`vent, for example, as a Solution in 1,3-butane diol. Among the
`acceptable solvents that may be employed are water, Ringer's
`Solution, and isotonic sodium chloride solution. In addition,
`sterile, fixed oils are conventionally employed as a solvent or
`Suspending medium. For this purpose any bland fixed oil may
`be employed including synthetic mono- or di-glycerides. In
`addition, fatty acids such as oleic acid may be used in the
`
`preparation of injectables. Carrier formulation suitable for
`oral, Subcutaneous, intravenous, intramuscular, etc. adminis
`trations can be found in Remington's Pharmaceutical Sci
`ences, Mack Publishing Co., Easton, Pa.
`0079 According to a further aspect of the invention there
`is provided a method of treating Subclinical Cushing's Syn
`drome comprising administering an effective amount of at
`least one agent that inhibits the synthesis or activity of corti
`Sol.
`0080 According to a further aspect of the invention there
`is provided a method of treating Sub