WO2012110768A1 - Therapeutic uses of diarylalkanes such as mitotane - Google Patents
Therapeutic uses of diarylalkanes such as mitotane Download PDFInfo
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- WO2012110768A1 WO2012110768A1 PCT/GB2012/000167 GB2012000167W WO2012110768A1 WO 2012110768 A1 WO2012110768 A1 WO 2012110768A1 GB 2012000167 W GB2012000167 W GB 2012000167W WO 2012110768 A1 WO2012110768 A1 WO 2012110768A1
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- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 title claims description 12
- 229960000350 mitotane Drugs 0.000 title claims description 10
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- -1 amino, hydroxyl Chemical group 0.000 claims abstract description 17
- 230000001404 mediated effect Effects 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 7
- 150000007942 carboxylates Chemical class 0.000 claims abstract description 7
- 241001465754 Metazoa Species 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000003098 androgen Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 5
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 201000004384 Alopecia Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 230000002611 ovarian Effects 0.000 claims description 4
- 206010020112 Hirsutism Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000005676 Adrenogenital syndrome Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 claims description 2
- 206010065371 Hyperthecosis Diseases 0.000 claims description 2
- 206010020880 Hypertrophy Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 2
- 206010068168 androgenetic alopecia Diseases 0.000 claims description 2
- 201000002996 androgenic alopecia Diseases 0.000 claims description 2
- 230000036621 balding Effects 0.000 claims description 2
- 210000002950 fibroblast Anatomy 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 230000003211 malignant effect Effects 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 201000010174 renal carcinoma Diseases 0.000 claims description 2
- 238000007910 systemic administration Methods 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- 102000004316 Oxidoreductases Human genes 0.000 claims 2
- 108090000854 Oxidoreductases Proteins 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 description 16
- 239000002207 metabolite Substances 0.000 description 7
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 5
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 5
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 5
- 238000005259 measurement Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- QGXBDMJGAMFCBF-HLUDHZFRSA-N 5α-Androsterone Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-HLUDHZFRSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 229960003473 androstanolone Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- VFUIRAVTUVCQTF-UHFFFAOYSA-N (17-oxo-5alpha-androstan-3alpha-yl)-beta-D-glucuronic acid Natural products O=C1CCC2C1(C)CCC(C1(CC3)C)C2CCC1CC3OC1OC(C(O)=O)C(O)C(O)C1O VFUIRAVTUVCQTF-UHFFFAOYSA-N 0.000 description 1
- 0 **N(*)c1c(*)c(S)c(*C(c2c(*)[n](**)c3c(*)c(*)c(*)c(*)c23)=O)c(*)c1* Chemical compound **N(*)c1c(*)c(S)c(*C(c2c(*)[n](**)c3c(*)c(*)c(*)c(*)c23)=O)c(*)c1* 0.000 description 1
- QGXBDMJGAMFCBF-BNSUEQOYSA-N 3alpha-hydroxy-5beta-androstan-17-one Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@@H]21 QGXBDMJGAMFCBF-BNSUEQOYSA-N 0.000 description 1
- 241000195940 Bryophyta Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 101150085994 SRD5A2 gene Proteins 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 229940061641 androsterone Drugs 0.000 description 1
- VFUIRAVTUVCQTF-BSOWLZGZSA-N androsterone 3-glucosiduronic acid Chemical compound O([C@H]1C[C@@H]2CC[C@@H]3[C@@H]([C@]2(CC1)C)CC[C@]1([C@H]3CCC1=O)C)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O VFUIRAVTUVCQTF-BSOWLZGZSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 235000011929 mousse Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000037359 steroid metabolism Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/02—Halogenated hydrocarbons
- A61K31/025—Halogenated hydrocarbons carbocyclic
- A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention relates to the use of certain diarylethane derivatives in the treatment of certain medical conditions.
- it relates to the use of diarylethane derivatives in the treatment of medical conditions known to be mediated by the action of the 5a-reductase enzyme.
- 5a-reductase plays an active role in certain androgen-related medical conditions.
- the enzyme is involved in steroid metabolism, and is known to convert the male sex hormone testosterone (1) into the more potent (with respect to binding and transactivation of the androgen receptor) dihydrotestosterone (2).
- 5a-reductase activity also contributes to the inactivation of glucocorticoids, and is therefore expected to have an impact on metabolic function.
- 5a-reductase has therefore been targeted in the treatment of several hyperandrogenic conditions, including prostate cancer, female hirsutism, male pattern baldness, and alopecia (both male and female).
- a number of documents have proposed 5a-reductase inhibitors:
- WO 93/23048 describes 5a-reductase inhibitors of formula 7:
- WO 94/11004 describes 5a-red tase inhibitors of formula 10:
- WO 94/18168 describes inhibitors of formula 11.
- WO 95/23143 discloses 5a-reductase inhibitors of formula 19
- WO 96/09046 discloses inhibitor of formula 21 :
- WO 97/30069 discloses 5a-reductase inhibitors of formula 24: O 02/00681 discloses inhibitors of formula 26:
- 1 and X 2 are independently selected from H, halogen, substutituted or unsubstituted amino, hydroxyl, C C 6 alkoxy, substutituted or unsubstituted carboxylate, substituted or unsubstituted d-C 6 alkyl, substutituted or unsubstituted C 2 -C 6 alkenyl, substutituted or unsubstituted C 2 -C 6 alkynyl, or substutituted or unsubstituted aryl; and
- Ar ! and Ar 2 are independently selected from substutituted or unsubstituted aryl.
- a method of treating a human or animal for a 5a-reductase-mediated condition comprising administering a therapeutically effective amount of a compound of formula 30:
- Xi and X 2 are independently selected from H, halogen, substutituted or unsubstituted amino, hydroxyl, C C 6 alkoxy, substutituted or unsubstituted carboxylate, substituted or unsubstituted CrC 6 alkyl, substutituted or unsubstituted C 2 -C 6 alkenyl, substutituted or unsubstituted C 2 -C 6 alkynyl, or substutituted or unsubstituted aryl; and
- An and Ar 2 are independently selected from substutituted or unsubstituted aryl.
- a compound of formula 30 in the preparation of a medicament for the treatment of a 5a-reductase- msdistsd condition in a human or a ' ! '
- Xi and X 2 are independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, CrC 6 alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted aryl; and
- Ar ! and Ar 2 are independently selected from substituted or unsubstituted aryl. The following statements apply to all aspects of the invention.
- the 5a-reductase-mediated condition is a 5a-reductase-mediated condition other than renal carcinoma, astrocytoma, fibroblasts, renal cancer and prostate cancer.
- the 5a-reductase-mediated condition is selected from hirsutism, androgenic alopecia, male-pattern balding, metabolic syndrome, polycystic ovary syndrome, congenital adrenal hyperplasia, prostate hypertrophy, benign and malignant ovarian tumours associated with androgen excess, and ovarian hyperthecosis associated with androgen excess.
- the question of whether a given condition is 5a-reductase-mediated can be readily determined by a skilled practitioner through measurement of 5a-reductase - in activity within the cells relating to the disease. Such measurement may be by, for example, measurement of the ratio of dihydrotestosterone to testosterone within the cells, with an increased ratio relative to the same cells of a healthy subject indicating that the condition is 5a-reductase-mediated. In some cases, increased 5a-reductase activity may be observed through an increase of androgen (or androgen metabolites, such as androsterone glucuronide) levels elsewhere in the body, such as in the circulatory system.
- androgen or androgen metabolites, such as androsterone glucuronide
- Measurement of androgen or androgen metabolite levels may be undertaken by any appropriate method, such as GC-MS.
- treatment of the 5a-reductase mediated condition comprises systemic administration of a medicament comprising the compound.
- the medicament may be formulated for oral, sub-lingual, intravenous, intramuscular, subcutaneous, intradermal, transdermal, intraosseous, intraocular, inhalation, intranasal, perineural, peritoneal, vaginal and/or rectal administration.
- treatment of the 5a-reductase mediated condition comprises topical administration of a medicament comprising the compound.
- the medicament may be formulated as a cream, mousse, gel, topical aerosol spray, or other suitable preparation.
- the treatment is for a human or other mammal. In some further embodiments, the treatment is for a human or primate. In some still further
- the treatment is for a human.
- each of Xi and X 2 is independently selected from hydrogen, halogen, amino (optionally substituted with 1 or 2 C C 4 alkyl groups), nitro, hydroxyl, C C 4 alkoxy, and C C 4 alkyl.
- At least one of Xi and X 2 is not hydrogen. In some further embodiments, both of Xi and X 2 are not hydrogen.
- each of ⁇ and Ar 2 is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted triphenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted thiazc!y!, substituted or unsubstituted oxazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted
- each of A ⁇ and Ar 2 is independently selected from phenyl, naphthyl, anthracenyl and triphenyl, optionally substituted with one or more substituents selected from halogen, amino (optionally substituted with 1 or 2 d-C 4 alkyl groups), nitro, hydroxyl, C C 4 alkoxy, and C C alkyl.
- a ⁇ and Ar 2 are isomeric.
- a and Ar 2 consist of the same aromatic group selected from phenyl, naphthyl, anthracenyl and triphenyl, each optionally independently substituted with one or more substituents selected from halogen, amino (optionally substituted with 1 or 2 C C 4 alkyl groups), nitro, hydroxyl, C C 4 alkoxy, and C C 4 alkyl.
- a ⁇ and Ar 2 have the same substituents. It will be understood that the locations of the substituents on Ar and Ar 2 may be the same or different. In some embodiments, A ⁇ and Ar 2 are identical.
- the compound of formula 30 comprises a compound of formula
- X 2 , X 3 and X4 are each independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, d-C 6 alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted aryl; and m and n are each independently an integer from 0 to 5.
- At least one, at least two, at least three, or all of Xi , X 2 , X 3 and X 4 is not hydrogen. !n some further embodiments, both Xi and X ? are halogens. In some still further embodiments, X, and X 2 are selected from fluorine and chlorine. In some still further embodiments, and X 2 are identical.
- both X 3 and X 4 are halogens, and m and n are each greater than zero. In some still further embodiments, X 3 and X 4 are selected from fluorine and chlorine. In some still further embodiments, X 3 and X 4 are identical.
- the positions of X 3 and X4 on the respective phenyl rings may be the same or different.
- the positions of X 3 and X 4 on the respective phenyl rings are the same or different.
- X 3 is located at the ortho- position
- the compound of formula 31 is mitotane (32):
- Mitotane (o, -dichlorodiphenyldichloroethane) was discovered in 1949 and has been known for some time in the treatment of adrenocortical carcinoma (ACC) (Hahner & Fassnacht, "Mitotane for adrenocortical carcinoma treatment", Current Opinion in Investigational Drugs, 2005, 6(4):386-394). More recent data has supported the use of mitotane in adjuvant treatment of ACC. However, the present inventors have surprisingly found that mitotane acts as an inhibitor of 5a-reductase.
- the degree of the decrease in these ratios was similar to that observed in patients treated with the established 5a-reductase type 2 inhibitor finasteride, and also similar to urinary steroid metabolite exretion patterns observed in patients with inactivating mutations in the SRD5A2 gene encoding 5a-reductase type 2.
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Abstract
The present invention provides a compound of formula (30) for use in the treatment of a 5α-reductase-mediated condition in a human or animal: where X1 and X2 are independently selected from H, halogen, substutituted or unsubstituted amino, hydroxyl, C1-C6 alkoxy, substutituted or unsubstituted carboxylate, substituted or unsubstituted C1-C6 alkyl, substutituted or unsubstituted C2-C6 alkenyl, substutituted or unsubstituted C2-C6 alkynyl, or substutituted or unsubstituted aryl; and Ar1 and Ar2 are independently selected from substutituted or unsubstituted aryl.
Description
THERAPEUTIC USES OF DIARYLALKANES SUCH AS MITOTANE
The invention relates to the use of certain diarylethane derivatives in the treatment of certain medical conditions. In particular, it relates to the use of diarylethane derivatives in the treatment of medical conditions known to be mediated by the action of the 5a-reductase enzyme.
It is well known that 5a-reductase plays an active role in certain androgen-related medical conditions. The enzyme is involved in steroid metabolism, and is known to convert the male sex hormone testosterone (1) into the more potent (with respect to binding and transactivation of the androgen receptor) dihydrotestosterone (2). Furthermore, 5a-reductase activity also contributes to the inactivation of glucocorticoids, and is therefore expected to have an impact on metabolic function.
5a-reductase has therefore been targeted in the treatment of several hyperandrogenic conditions, including prostate cancer, female hirsutism, male pattern baldness, and alopecia (both male and female). A number of documents have proposed 5a-reductase inhibitors:
WO 89/11282 suggests a number of steroidal analogues of general formula 3:
R'AOC(CH2)n
WO 93/13124 describes inhibitors of formula 4:
WO 93/17014 describes inhibitors of formula 6:
WO 93/23048 describes 5a-reductase inhibitors of formula 7:
8
WO 94/0012 describes inhibitors of formula 9:
WO 94/11004 describes 5a-red tase inhibitors of formula 10:
10
WO 94/18168 describes inhibitors of formula 11.
11
WO 95/23143 discloses 5a-reductase inhibitors of formula 19
19
WO 95/31453 discloses inhibi
2
20
WO 96/09046 discloses inhibitor of formula 21 :
WO 97/30069 discloses 5a-reductase inhibitors of formula 24:
O 02/00681 discloses inhibitors of formula 26:
26
It can be seen that existing 5a-reductase inhibitors are generally steroidal in structure, or are based upon modified indoles. There remains a need for an alternative class of 5o reducatase inhibitors.
According to a first aspect of the present invention there is provided a compound of formula 30 for use in the treatment of a 5a-reductase-mediated condition in a human or animal:
30
where 1 and X2 are independently selected from H, halogen, substutituted or unsubstituted amino, hydroxyl, C C6 alkoxy, substutituted or unsubstituted carboxylate, substituted or unsubstituted d-C6 alkyl, substutituted or unsubstituted C2-C6 alkenyl, substutituted or unsubstituted C2-C6 alkynyl, or substutituted or unsubstituted aryl; and
Ar! and Ar2 are independently selected from substutituted or unsubstituted aryl.
According to a second aspect of the invention, there is provided a method of treating a human or animal for a 5a-reductase-mediated condition, comprising administering a therapeutically effective amount of a compound of formula 30:
30
where Xi and X2 are independently selected from H, halogen, substutituted or unsubstituted amino, hydroxyl, C C6 alkoxy, substutituted or unsubstituted carboxylate, substituted or unsubstituted CrC6 alkyl, substutituted or unsubstituted C2-C6 alkenyl, substutituted or unsubstituted C2-C6 alkynyl, or substutituted or unsubstituted aryl; and
An and Ar2 are independently selected from substutituted or unsubstituted aryl.
According to a third aspect of the invention, there is provided the use of a compound of formula 30 in the preparation of a medicament for the treatment of a 5a-reductase- msdistsd condition in a human or a ' ?!'
30
where Xi and X2 are independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, CrC6 alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted aryl; and
Ar! and Ar2 are independently selected from substituted or unsubstituted aryl. The following statements apply to all aspects of the invention.
In some embodiments, the 5a-reductase-mediated condition is a 5a-reductase- mediated condition other than renal carcinoma, astrocytoma, fibroblasts, renal cancer and prostate cancer.
In some embodiments, the 5a-reductase-mediated condition is selected from hirsutism, androgenic alopecia, male-pattern balding, metabolic syndrome, polycystic ovary syndrome, congenital adrenal hyperplasia, prostate hypertrophy, benign and malignant ovarian tumours associated with androgen excess, and ovarian hyperthecosis associated with androgen excess.
In general, the question of whether a given condition is 5a-reductase-mediated can be readily determined by a skilled practitioner through measurement of 5a-reductase
- in activity within the cells relating to the disease. Such measurement may be by, for example, measurement of the ratio of dihydrotestosterone to testosterone within the cells, with an increased ratio relative to the same cells of a healthy subject indicating that the condition is 5a-reductase-mediated. In some cases, increased 5a-reductase activity may be observed through an increase of androgen (or androgen metabolites, such as androsterone glucuronide) levels elsewhere in the body, such as in the circulatory system. Measurement of androgen or androgen metabolite levels may be undertaken by any appropriate method, such as GC-MS. !n some embodiments, treatment of the 5a-reductase mediated condition comprises systemic administration of a medicament comprising the compound. In such cases, the medicament may be formulated for oral, sub-lingual, intravenous, intramuscular, subcutaneous, intradermal, transdermal, intraosseous, intraocular, inhalation, intranasal, perineural, peritoneal, vaginal and/or rectal administration.
Alternatively or additionally treatment of the 5a-reductase mediated condition comprises topical administration of a medicament comprising the compound. In such cases, the medicament may be formulated as a cream, mousse, gel, topical aerosol spray, or other suitable preparation.
In some embodiments, the treatment is for a human or other mammal. In some further embodiments, the treatment is for a human or primate. In some still further
embodiments, the treatment is for a human. In some embodiments, each of Xi and X2 is independently selected from hydrogen, halogen, amino (optionally substituted with 1 or 2 C C4 alkyl groups), nitro, hydroxyl, C C4 alkoxy, and C C4 alkyl.
In some embodiments, at least one of Xi and X2 is not hydrogen. In some further embodiments, both of Xi and X2 are not hydrogen.
In some embodiments, Xi and X2 are both members of the same class selected from halogen, amino (optionally substituted with 1 or 2 C C4 alkyl groups), nitro, hydroxyl, (- C4 alkoxy, and C C4 alkyl. In some further embodiments, Xi and X2 are both
halogen. Alternatively or additionally, in some further embodiments, X, and X2 are identical. In some still further embodiments, X = X2 = CI.
In some embodiments, each of Α and Ar2 is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted triphenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted thiazc!y!, substituted or unsubstituted oxazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted purinyl, substituted or unsubstituted dibenzopyrrolyl, and substituted or unsubstituted dibenzofuranyl. In some further embodiments, each of A^ and Ar2 is independently selected from phenyl, naphthyl, anthracenyl and triphenyl, optionally substituted with one or more substituents selected from halogen, amino (optionally substituted with 1 or 2 d-C4 alkyl groups), nitro, hydroxyl, C C4 alkoxy, and C C alkyl.
In some embodiments, A^ and Ar2 are isomeric.
In some embodiments, A and Ar2 consist of the same aromatic group selected from phenyl, naphthyl, anthracenyl and triphenyl, each optionally independently substituted with one or more substituents selected from halogen, amino (optionally substituted with 1 or 2 C C4 alkyl groups), nitro, hydroxyl, C C4 alkoxy, and C C4 alkyl. In some further embodiments, A^ and Ar2 have the same substituents. It will be understood that the locations of the substituents on Ar and Ar2 may be the same or different. In some embodiments, A^ and Ar2 are identical.
In some embodiments, the compound of formula 30 comprises a compound of formula
31 :
31
where X2, X3 and X4 are each independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, d-C6 alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted C C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted aryl; and m and n are each independently an integer from 0 to 5.
In some further embodiments, at least one, at least two, at least three, or all of Xi , X2, X3 and X4 is not hydrogen. !n some further embodiments, both Xi and X? are halogens. In some still further embodiments, X, and X2 are selected from fluorine and chlorine. In some still further embodiments, and X2 are identical.
In some further embodiments, both X3 and X4 are halogens, and m and n are each greater than zero. In some still further embodiments, X3 and X4 are selected from fluorine and chlorine. In some still further embodiments, X3 and X4 are identical.
In some further embodiments, m and n are each selected from the range 1 to 3. In some still further embodiments, m and n are identical. In some still further embodiments, m = n = 1 .
In cases where 1≤ m≤ 4 and/or 1≤ n≤ 4, the positions of X3 and X4 on the respective phenyl rings may be the same or different. In some still further embodiments where m = n = 1 , the positions of X3 and X4 on the respective phenyl rings are the same or different. For example, the following combinations are possible:
In some still further embodiments, X3 is located at the ortho- position, and X4 is located at the para- position.
ln some embodiments, X, = X2 = X3 = X4 = CI.
In some embodiments, the compound of formula 31 is mitotane (32):
32
Mitotane (o, -dichlorodiphenyldichloroethane) was discovered in 1949 and has been known for some time in the treatment of adrenocortical carcinoma (ACC) (Hahner & Fassnacht, "Mitotane for adrenocortical carcinoma treatment", Current Opinion in Investigational Drugs, 2005, 6(4):386-394). More recent data has supported the use of mitotane in adjuvant treatment of ACC. However, the present inventors have surprisingly found that mitotane acts as an inhibitor of 5a-reductase.
Patients receiving mitotane for the treatment of adrenocortical carcinoma were tested for the presence of androgen metabolites in urine, using gas chromatography - mass spectrometry (GC-MS). It was found that the 24h urinary excretion of 5a-reduced glucocorticoids and androgen metabolites significantly increased during mitotane treatment, resulting in an increase in the ratios of 5a-tetrahydrocorticosol (5a-THF) over tetrahydrocorticosol (THF) and of the 5a-reduced androgen metabolite androsterone (An) over the δβ-reduced androgen metabolite etiocholanolone (Et). The degree of the decrease in these ratios was similar to that observed in patients treated with the established 5a-reductase type 2 inhibitor finasteride, and also similar to urinary steroid metabolite exretion patterns observed in patients with inactivating mutations in the SRD5A2 gene encoding 5a-reductase type 2.
Claims
1. A compound of formula 30 for use in the treatment of a 5a-reductase-mediated condition in a human or animal:
30
where and X2 are independently selected from H, halogen, substutituted or unsubstituted amino, hydroxyl, C Cs alkoxy, substutituted or unsubstituted carboxylate, substituted or unsubstituted CrC6 alkyl, substutituted or unsubstituted C2-C6 alkenyl, substutituted or unsubstituted C2-C6 alkynyl, or substutituted or unsubstituted aryl; and
Ar! and Ar2 are independently selected from substutituted or unsubstituted aryl.
2. The compound of claim 1 for use in the treatment of a 5o reductase-mediated condition other than renal carcinoma, astrocytoma, fibroblasts, renal cancer and prostate cancer in a human or animal.
3. The compound of claim 2 for use in the treatment of a 5a-reductase-mediated condition selected from hirsutism, androgenetic alopecia, male-pattern balding, metabolic syndrome, polycystic ovary syndrome, congenital adrenal hyperplasia, prostate hypertrophy, benign and malignant ovarian tumours associated with androgen excess, and ovarian hyperthecosis associated with androgen excess.
4. The compound of any preceding claim, wherein treatment of the 5a-reductase mediated condition comprises systemic administration of a medicament comprising the compound.
5. The compound of any one of claims 1 to 3, wherein treatment of the 5a- reductase mediated condition comprises topical administration of a medicament comprising the compound.
6. The compound of any preceding claim, wherein each of and X2 is independently selected from hydrogen, halogen, amino (optionally substituted with 1 or 2 C C4 alkyl groups), nitro, hydroxyl, C1-C4 alkoxy, and C1-C alkyl.
7. The compound of any preceding claim, wherein at least one of X! and X2 is not hydrogen.
8. The compound of any preceding claim, wherein ΧΊ and X2 are both members of the same class selected from halogen, amino (optionally substituted with 1 or 2 C C4 alkyl groups), nitro, hydroxyl, C C4 alkoxy, and CrC4 alkyl.
9. The compound of any preceding claim, wherein Xi and X2 are identical.
10. The compound of claim 9, wherein Xi = X2 = CI.
1 1. The compound of any preceding claim, wherein each of Ar, and Ar2 is independently selected from phenyl, naphthyl, anthracenyl, triphenyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, furyl, thiophenyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, purinyl, dibenzopyrrolyl, and dibenzofuranyl, any of which may be substituted or unsubstituted.
12. The compound of any claim 11 , wherein each of An and Ar2 is independently selected from phenyl, naphthyl, anthracenyl and triphenyl, optionally substituted with one or more substituents selected from halogen, amino (optionally substituted with 1 or 2 C C4 alkyl groups), nitro, hydroxyl, C C alkoxy, and C C4 alkyl.
13. The compound of any preceding claim, wherein An and Ar2 are isomeric.
1 . The compound of any preceding claim, wherein the compound has a formula 31 :
31
where X2, X3 and X4 are each independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, d-C6 alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted aryl; and m and n are each independently an integer from 0 to 5.
The compound of claim 14, wherein both X and X2 are halogens.
The compound of claim 14 or claim 15, wherein both X3 and X4 are halogens and m and n are each greater than zero.
The compound of any one of claims 14 to 16, wherein m
The compound of any one of claims 1 to 17, wherein
19. The compound of any preceding claim, wherein the compound is mitotane (32):
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| GBGB1102913.9A GB201102913D0 (en) | 2011-02-18 | 2011-02-18 | Novel therapeutic |
| GB1102913.9 | 2011-02-18 |
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| PCT/GB2012/000167 WO2012110768A1 (en) | 2011-02-18 | 2012-02-17 | Therapeutic uses of diarylalkanes such as mitotane |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111830169A (en) * | 2020-07-24 | 2020-10-27 | 中山大学 | Compound for diagnosing polycystic ovarian syndrome and application thereof |
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Cited By (1)
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|---|---|---|---|---|
| CN111830169A (en) * | 2020-07-24 | 2020-10-27 | 中山大学 | Compound for diagnosing polycystic ovarian syndrome and application thereof |
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