WO2024010817A2 - Selective androgen receptor degrader (sard) o-linked ligands and methods of use thereof - Google Patents
Selective androgen receptor degrader (sard) o-linked ligands and methods of use thereof Download PDFInfo
- Publication number
- WO2024010817A2 WO2024010817A2 PCT/US2023/026942 US2023026942W WO2024010817A2 WO 2024010817 A2 WO2024010817 A2 WO 2024010817A2 US 2023026942 W US2023026942 W US 2023026942W WO 2024010817 A2 WO2024010817 A2 WO 2024010817A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- cancer
- subject
- isomer
- compound
- Prior art date
Links
- 229940122793 Selective androgen receptor degrader Drugs 0.000 title claims abstract description 124
- 238000000034 method Methods 0.000 title claims abstract description 115
- 239000003446 ligand Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 265
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 131
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 127
- 239000003098 androgen Substances 0.000 claims abstract description 67
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 58
- 201000004384 Alopecia Diseases 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims abstract description 33
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims abstract description 33
- 108010040003 polyglutamine Proteins 0.000 claims abstract description 32
- 208000007474 aortic aneurysm Diseases 0.000 claims abstract description 31
- 208000002223 abdominal aortic aneurysm Diseases 0.000 claims abstract description 28
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 21
- 206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 16
- 201000010260 leiomyoma Diseases 0.000 claims abstract description 16
- 229920000155 polyglutamine Polymers 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 90
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 81
- 150000003839 salts Chemical class 0.000 claims description 72
- 229910052794 bromium Inorganic materials 0.000 claims description 70
- 229910052731 fluorine Inorganic materials 0.000 claims description 66
- 229910052801 chlorine Inorganic materials 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 239000000203 mixture Substances 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 238000011282 treatment Methods 0.000 claims description 51
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 49
- 229940127557 pharmaceutical product Drugs 0.000 claims description 49
- 125000001188 haloalkyl group Chemical group 0.000 claims description 48
- -1 CH2CFI2OH Chemical group 0.000 claims description 41
- 238000009167 androgen deprivation therapy Methods 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 230000004083 survival effect Effects 0.000 claims description 31
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 30
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 30
- 230000000694 effects Effects 0.000 claims description 29
- 229960004671 enzalutamide Drugs 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 230000015556 catabolic process Effects 0.000 claims description 28
- 238000006731 degradation reaction Methods 0.000 claims description 28
- 230000001965 increasing effect Effects 0.000 claims description 28
- 125000003342 alkenyl group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000002837 carbocyclic group Chemical group 0.000 claims description 25
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 25
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 206010006187 Breast cancer Diseases 0.000 claims description 23
- 229930194542 Keto Natural products 0.000 claims description 23
- 125000000468 ketone group Chemical group 0.000 claims description 23
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 claims description 21
- 208000026310 Breast neoplasm Diseases 0.000 claims description 20
- 229960000853 abiraterone Drugs 0.000 claims description 20
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 20
- 210000002374 sebum Anatomy 0.000 claims description 20
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 19
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 19
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 19
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 19
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 19
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 19
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 18
- 231100000360 alopecia Toxicity 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 229960002074 flutamide Drugs 0.000 claims description 17
- 230000003287 optical effect Effects 0.000 claims description 17
- 206010056292 Androgen-Insensitivity Syndrome Diseases 0.000 claims description 16
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 16
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 15
- 229960000997 bicalutamide Drugs 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 15
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 15
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 15
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 15
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 14
- 206010000496 acne Diseases 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 14
- 230000000683 nonmetastatic effect Effects 0.000 claims description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 14
- 206010005003 Bladder cancer Diseases 0.000 claims description 13
- 208000027747 Kennedy disease Diseases 0.000 claims description 13
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 13
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 13
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 13
- 229940123407 Androgen receptor antagonist Drugs 0.000 claims description 11
- 206010020112 Hirsutism Diseases 0.000 claims description 10
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 10
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 10
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 10
- 201000002528 pancreatic cancer Diseases 0.000 claims description 10
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 10
- 150000003852 triazoles Chemical class 0.000 claims description 10
- 239000003936 androgen receptor antagonist Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 206010068597 Bulbospinal muscular atrophy congenital Diseases 0.000 claims description 8
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 8
- 206010025323 Lymphomas Diseases 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims description 8
- 230000001394 metastastic effect Effects 0.000 claims description 8
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 8
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 claims description 7
- 239000000499 gel Substances 0.000 claims description 7
- 229960004125 ketoconazole Drugs 0.000 claims description 7
- 239000006210 lotion Substances 0.000 claims description 7
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims description 7
- 239000002674 ointment Substances 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 230000001568 sexual effect Effects 0.000 claims description 7
- 230000000699 topical effect Effects 0.000 claims description 7
- ZMGUKFHHNQMKJI-CIOHCNBKSA-N (1e,4z,6e)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(\O)=C\C(=O)\C=C\C1=CC=C(OC)C(OC)=C1 ZMGUKFHHNQMKJI-CIOHCNBKSA-N 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 6
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 6
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 6
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 6
- 206010057644 Testis cancer Diseases 0.000 claims description 6
- 208000008385 Urogenital Neoplasms Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 239000006071 cream Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- YPQLFJODEKMJEF-UHFFFAOYSA-N hydroxyflutamide Chemical compound CC(C)(O)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 YPQLFJODEKMJEF-UHFFFAOYSA-N 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 229960002653 nilutamide Drugs 0.000 claims description 6
- 201000008968 osteosarcoma Diseases 0.000 claims description 6
- 208000006155 precocious puberty Diseases 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 201000003120 testicular cancer Diseases 0.000 claims description 6
- 208000037964 urogenital cancer Diseases 0.000 claims description 6
- 210000004291 uterus Anatomy 0.000 claims description 6
- 208000003200 Adenoma Diseases 0.000 claims description 5
- 206010001233 Adenoma benign Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 201000010208 Seminoma Diseases 0.000 claims description 5
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 201000007455 central nervous system cancer Diseases 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 230000002710 gonadal effect Effects 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 239000002502 liposome Substances 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 210000004303 peritoneum Anatomy 0.000 claims description 5
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- JMEYDSHPKCSIJC-UHFFFAOYSA-N 1-[4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1CCOC1=CC=C(C2CCN(CC2)C=2CCC=3N(C(=NN=3)C(F)(F)F)N=2)C=C1 JMEYDSHPKCSIJC-UHFFFAOYSA-N 0.000 claims description 4
- 201000009273 Endometriosis Diseases 0.000 claims description 4
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 4
- 206010066364 Hypersexuality Diseases 0.000 claims description 4
- 206010033888 Paraphilia Diseases 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 206010047486 Virilism Diseases 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 claims description 4
- 229960000978 cyproterone acetate Drugs 0.000 claims description 4
- 201000001343 fallopian tube carcinoma Diseases 0.000 claims description 4
- 230000003054 hormonal effect Effects 0.000 claims description 4
- BLIJXOOIHRSQRB-PXYINDEMSA-N n-[(2s)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide Chemical compound C([C@H](C)NC(=O)C=1NN=C(C=1)C(C)O)N(N=1)C=CC=1C1=CC=C(C#N)C(Cl)=C1 BLIJXOOIHRSQRB-PXYINDEMSA-N 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000016087 ovulation Effects 0.000 claims description 4
- 201000002628 peritoneum cancer Diseases 0.000 claims description 4
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 claims description 4
- 229960002256 spironolactone Drugs 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- 208000037853 Abnormal uterine bleeding Diseases 0.000 claims description 3
- 201000000736 Amenorrhea Diseases 0.000 claims description 3
- 206010001928 Amenorrhoea Diseases 0.000 claims description 3
- 241000195940 Bryophyta Species 0.000 claims description 3
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 3
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 3
- 208000000571 Fibrocystic breast disease Diseases 0.000 claims description 3
- PAFKTGFSEFKSQG-PAASFTFBSA-N Galeterone Chemical compound C1=NC2=CC=CC=C2N1C1=CC[C@H]2[C@H](CC=C3[C@@]4(CC[C@H](O)C3)C)[C@@H]4CC[C@@]21C PAFKTGFSEFKSQG-PAASFTFBSA-N 0.000 claims description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 3
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 3
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 3
- 206010047791 Vulvovaginal dryness Diseases 0.000 claims description 3
- 231100000540 amenorrhea Toxicity 0.000 claims description 3
- HDTYUHNZRYZEEB-UHFFFAOYSA-N bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether Chemical compound C=1C=C(OCC(O)CCl)C=CC=1C(C)(C)C1=CC=C(OCC(O)CO)C=C1 HDTYUHNZRYZEEB-UHFFFAOYSA-N 0.000 claims description 3
- 208000011803 breast fibrocystic disease Diseases 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 208000002296 eclampsia Diseases 0.000 claims description 3
- 239000006260 foam Substances 0.000 claims description 3
- 229950003400 galeterone Drugs 0.000 claims description 3
- 235000011929 mousse Nutrition 0.000 claims description 3
- 208000025661 ovarian cyst Diseases 0.000 claims description 3
- 201000011461 pre-eclampsia Diseases 0.000 claims description 3
- 230000035935 pregnancy Effects 0.000 claims description 3
- 239000002453 shampoo Substances 0.000 claims description 3
- 239000000344 soap Substances 0.000 claims description 3
- 208000033206 Early menarche Diseases 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 4
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims 1
- 108010080146 androgen receptors Proteins 0.000 abstract description 183
- 102000001307 androgen receptors Human genes 0.000 abstract description 181
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 33
- 201000010099 disease Diseases 0.000 abstract description 26
- 230000035772 mutation Effects 0.000 abstract description 26
- 201000002996 androgenic alopecia Diseases 0.000 abstract description 15
- 201000000585 muscular atrophy Diseases 0.000 abstract description 13
- 230000001717 pathogenic effect Effects 0.000 abstract description 10
- 230000002500 effect on skin Effects 0.000 abstract description 8
- 102000054765 polymorphisms of proteins Human genes 0.000 abstract description 3
- 208000027418 Wounds and injury Diseases 0.000 description 65
- 206010052428 Wound Diseases 0.000 description 61
- 230000002280 anti-androgenic effect Effects 0.000 description 41
- 239000000051 antiandrogen Substances 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 36
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 36
- 210000003491 skin Anatomy 0.000 description 35
- 108020001756 ligand binding domains Proteins 0.000 description 33
- 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 32
- 230000001419 dependent effect Effects 0.000 description 32
- 210000001519 tissue Anatomy 0.000 description 32
- 239000005557 antagonist Substances 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 29
- 210000002966 serum Anatomy 0.000 description 26
- 229940030486 androgens Drugs 0.000 description 24
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 239000000556 agonist Substances 0.000 description 18
- 230000027455 binding Effects 0.000 description 18
- 230000006870 function Effects 0.000 description 18
- 230000012010 growth Effects 0.000 description 18
- 229940088597 hormone Drugs 0.000 description 18
- 239000005556 hormone Substances 0.000 description 18
- 239000003814 drug Substances 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 229960003604 testosterone Drugs 0.000 description 16
- 230000004913 activation Effects 0.000 description 15
- 230000035876 healing Effects 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 14
- 208000025865 Ulcer Diseases 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- 108700012941 GNRH1 Proteins 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 210000002307 prostate Anatomy 0.000 description 13
- 231100000397 ulcer Toxicity 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 210000004209 hair Anatomy 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 230000008506 pathogenesis Effects 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 102000015694 estrogen receptors Human genes 0.000 description 10
- 108010038795 estrogen receptors Proteins 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 10
- 230000003676 hair loss Effects 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108010000817 Leuprolide Proteins 0.000 description 9
- 206010028289 Muscle atrophy Diseases 0.000 description 9
- 230000007423 decrease Effects 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 230000009977 dual effect Effects 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 208000014674 injury Diseases 0.000 description 9
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 8
- 206010027476 Metastases Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 230000003779 hair growth Effects 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 210000004379 membrane Anatomy 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 230000020763 muscle atrophy Effects 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000011200 topical administration Methods 0.000 description 8
- XMAYWYJOQHXEEK-ZEQKJWHPSA-N (2S,4R)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@H]1O[C@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-ZEQKJWHPSA-N 0.000 description 7
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000001413 cellular effect Effects 0.000 description 7
- 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 7
- 208000024963 hair loss Diseases 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 229960004338 leuprorelin Drugs 0.000 description 7
- 230000000670 limiting effect Effects 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000009885 systemic effect Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 230000029663 wound healing Effects 0.000 description 7
- 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 6
- 101150029129 AR gene Proteins 0.000 description 6
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 210000000709 aorta Anatomy 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229960004039 finasteride Drugs 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 6
- 230000003902 lesion Effects 0.000 description 6
- PTQMMNYJKCSPET-OMHQDGTGSA-N mibolerone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 PTQMMNYJKCSPET-OMHQDGTGSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 6
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 208000029402 Bulbospinal muscular atrophy Diseases 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 108010069236 Goserelin Proteins 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 208000004210 Pressure Ulcer Diseases 0.000 description 5
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 5
- 229960002184 abarelix Drugs 0.000 description 5
- 108010023617 abarelix Proteins 0.000 description 5
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229960003473 androstanolone Drugs 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000007547 defect Effects 0.000 description 5
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 230000008439 repair process Effects 0.000 description 5
- 210000004761 scalp Anatomy 0.000 description 5
- 208000008742 seborrheic dermatitis Diseases 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 108091008721 AR-V7 Proteins 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 206010011985 Decubitus ulcer Diseases 0.000 description 4
- 206010061216 Infarction Diseases 0.000 description 4
- 208000035901 Ischaemic ulcer Diseases 0.000 description 4
- 102000016387 Pancreatic elastase Human genes 0.000 description 4
- 108010067372 Pancreatic elastase Proteins 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 208000004965 Prostatic Intraepithelial Neoplasia Diseases 0.000 description 4
- 206010071019 Prostatic dysplasia Diseases 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 150000001408 amides Chemical group 0.000 description 4
- 230000003042 antagnostic effect Effects 0.000 description 4
- 230000002238 attenuated effect Effects 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 210000002808 connective tissue Anatomy 0.000 description 4
- 229960002272 degarelix Drugs 0.000 description 4
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 description 4
- 238000002297 emergency surgery Methods 0.000 description 4
- 239000003862 glucocorticoid Substances 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 230000007574 infarction Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 4
- 125000005394 methallyl group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229950006489 mibolerone Drugs 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 238000011474 orchiectomy Methods 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 102000003998 progesterone receptors Human genes 0.000 description 4
- 108090000468 progesterone receptors Proteins 0.000 description 4
- 208000021046 prostate intraepithelial neoplasia Diseases 0.000 description 4
- 230000007420 reactivation Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000008929 regeneration Effects 0.000 description 4
- 238000011069 regeneration method Methods 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229940037128 systemic glucocorticoids Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000004001 thioalkyl group Chemical group 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 206010066882 Metastatic salivary gland cancer Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010039792 Seborrhoea Diseases 0.000 description 3
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 208000002847 Surgical Wound Diseases 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- 206010068168 androgenetic alopecia Diseases 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000006552 constitutive activation Effects 0.000 description 3
- 239000002537 cosmetic Substances 0.000 description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229960004199 dutasteride Drugs 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000001853 liver microsome Anatomy 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229940087857 lupron Drugs 0.000 description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 208000037819 metastatic cancer Diseases 0.000 description 3
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 230000002232 neuromuscular Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 208000022823 partial androgen insensitivity syndrome Diseases 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000000306 recurrent effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 210000001732 sebaceous gland Anatomy 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940033942 zoladex Drugs 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 206010068065 Burning mouth syndrome Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 2
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 2
- 206010056340 Diabetic ulcer Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 101001038388 Glycine max Nodulin-20 Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 101000928259 Homo sapiens NADPH:adrenodoxin oxidoreductase, mitochondrial Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101000896517 Homo sapiens Steroid 17-alpha-hydroxylase/17,20 lyase Proteins 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 description 2
- 206010020864 Hypertrichosis Diseases 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 229940122014 Lyase inhibitor Drugs 0.000 description 2
- 102000004317 Lyases Human genes 0.000 description 2
- 108090000856 Lyases Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 101001038410 Medicago truncatula Early nodulin-20 Proteins 0.000 description 2
- 208000037848 Metastatic bone disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 208000010428 Muscle Weakness Diseases 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- 102000018658 Myotonin-Protein Kinase Human genes 0.000 description 2
- 108010052185 Myotonin-Protein Kinase Proteins 0.000 description 2
- JKWKMORAXJQQSR-MOPIKTETSA-N Nandrolone Decanoate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCC)[C@@]1(C)CC2 JKWKMORAXJQQSR-MOPIKTETSA-N 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 208000009893 Nonpenetrating Wounds Diseases 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 208000009344 Penetrating Wounds Diseases 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 208000010366 Postpoliomyelitis syndrome Diseases 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 208000025844 Prostatic disease Diseases 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 108091005682 Receptor kinases Proteins 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 206010040943 Skin Ulcer Diseases 0.000 description 2
- 102100021719 Steroid 17-alpha-hydroxylase/17,20 lyase Human genes 0.000 description 2
- 102000008221 Superoxide Dismutase-1 Human genes 0.000 description 2
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 2
- 206010053615 Thermal burn Diseases 0.000 description 2
- 208000000558 Varicose Ulcer Diseases 0.000 description 2
- 210000001766 X chromosome Anatomy 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000005299 abrasion Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 150000008052 alkyl sulfonates Chemical group 0.000 description 2
- 208000004631 alopecia areata Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 description 2
- 230000003608 autoimmunological effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000036621 balding Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 229960003996 chlormadinone Drugs 0.000 description 2
- VUHJZBBCZGVNDZ-TTYLFXKOSA-N chlormadinone Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 VUHJZBBCZGVNDZ-TTYLFXKOSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000000306 component Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 229940048820 edetates Drugs 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 230000001815 facial effect Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 2
- 229960003690 goserelin acetate Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000002557 hidradenitis Diseases 0.000 description 2
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 2
- 102000046818 human AR Human genes 0.000 description 2
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 201000010066 hyperandrogenism Diseases 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000002697 lyase inhibitor Substances 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 210000002161 motor neuron Anatomy 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 2
- 229960001935 nandrolone decanoate Drugs 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 230000004942 nuclear accumulation Effects 0.000 description 2
- 230000005937 nuclear translocation Effects 0.000 description 2
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 210000003101 oviduct Anatomy 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000001050 pharmacotherapy Methods 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 235000007586 terpenes Nutrition 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 230000036575 thermal burns Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical class O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical class OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 1
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 1
- 101710181757 1,2-dihydroxy-3-keto-5-methylthiopentene dioxygenase Proteins 0.000 description 1
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical class CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NUGZBVBZIDWZAD-UHFFFAOYSA-N 1h-pyrazole-4-carbonitrile Chemical compound N#CC=1C=NNC=1 NUGZBVBZIDWZAD-UHFFFAOYSA-N 0.000 description 1
- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- SOZGHDCEWOLLHV-UHFFFAOYSA-N 2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=CC=C1C#N SOZGHDCEWOLLHV-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical class OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- PMDYLCUKSLBUHO-UHFFFAOYSA-N 4-amino-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1 PMDYLCUKSLBUHO-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- MDBVIOUGHSKRMT-UHFFFAOYSA-N 4-hydroxy-2-(trifluoromethyl)benzonitrile Chemical compound OC1=CC=C(C#N)C(C(F)(F)F)=C1 MDBVIOUGHSKRMT-UHFFFAOYSA-N 0.000 description 1
- 229940122835 5 Alpha reductase Type II inhibitor Drugs 0.000 description 1
- MTGUYKMVEUMQQY-UHFFFAOYSA-N 5-phenyl-7-(trifluoromethyl)-2,3-dihydro-1h-1,4-diazepine Chemical compound C1CNC(C(F)(F)F)=CC(C=2C=CC=CC=2)=N1 MTGUYKMVEUMQQY-UHFFFAOYSA-N 0.000 description 1
- 108091008715 AR-FL Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101710094863 Acireductone dioxygenase Proteins 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- 108010009551 Alamethicin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101100515517 Arabidopsis thaliana XI-I gene Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 102100023006 Basic leucine zipper transcriptional factor ATF-like 2 Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010006563 Bullous impetigo Diseases 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 102000009058 Death Domain Receptors Human genes 0.000 description 1
- 108010049207 Death Domain Receptors Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 206010016936 Folliculitis Diseases 0.000 description 1
- 208000001034 Frostbite Diseases 0.000 description 1
- 201000000628 Gas Gangrene Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 101000836540 Homo sapiens Aldo-keto reductase family 1 member B1 Proteins 0.000 description 1
- 101000809450 Homo sapiens Amphiregulin Proteins 0.000 description 1
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 description 1
- 101000903615 Homo sapiens Basic leucine zipper transcriptional factor ATF-like 2 Proteins 0.000 description 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 1
- 101600111816 Homo sapiens Sex hormone-binding globulin (isoform 1) Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- FJHHZXWJVIEFGJ-UHFFFAOYSA-N N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C=2OC=NN=2)C=C1 FJHHZXWJVIEFGJ-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 208000006595 Necrotizing Ulcerative Gingivitis Diseases 0.000 description 1
- 102100030569 Nuclear receptor corepressor 2 Human genes 0.000 description 1
- 101710153660 Nuclear receptor corepressor 2 Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010050808 Procollagen Proteins 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010038111 Recurrent cancer Diseases 0.000 description 1
- 206010070308 Refractory cancer Diseases 0.000 description 1
- 108010052090 Renilla Luciferases Proteins 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102300044179 Sex hormone-binding globulin isoform 1 Human genes 0.000 description 1
- 208000026214 Skeletal muscle atrophy Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010042731 Sycosis barbae Diseases 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical class OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010067653 Tropical ulcer Diseases 0.000 description 1
- HDYANYHVCAPMJV-LXQIFKJMSA-N UDP-alpha-D-glucuronic acid Chemical compound C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(NC(=O)C=C1)=O)O)O)OP(O)(=O)OP(O)(=O)O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O HDYANYHVCAPMJV-LXQIFKJMSA-N 0.000 description 1
- HDYANYHVCAPMJV-UHFFFAOYSA-N Uridine diphospho-D-glucuronic acid Natural products O1C(N2C(NC(=O)C=C2)=O)C(O)C(O)C1COP(O)(=O)OP(O)(=O)OC1OC(C(O)=O)C(O)C(O)C1O HDYANYHVCAPMJV-UHFFFAOYSA-N 0.000 description 1
- 239000004164 Wax ester Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- GRAAWEGTURLYKP-MVTMSODMSA-N [(8r,9s,10r,13s,14s,17s)-13-methyl-3-oxo-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl] undecanoate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCCC)[C@@]1(C)CC2 GRAAWEGTURLYKP-MVTMSODMSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 238000010317 ablation therapy Methods 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- LGHSQOCGTJHDIL-UTXLBGCNSA-N alamethicin Chemical compound N([C@@H](C)C(=O)NC(C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)NC(C)(C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NC(C)(C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)CC=1C=CC=CC=1)C(C)C)C(=O)C(C)(C)NC(=O)[C@@H]1CCCN1C(=O)C(C)(C)NC(C)=O LGHSQOCGTJHDIL-UTXLBGCNSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229920000615 alginic acid Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001484 arginines Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 229940054749 avodart Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 238000009412 basement excavation Methods 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical class BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 1
- 229960001573 cabazitaxel Drugs 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 229940097647 casodex Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical class OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical class OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 125000005534 decanoate group Chemical class 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 201000010380 endocervicitis Diseases 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 150000002171 ethylene diamines Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229940002006 firmagon Drugs 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 230000023611 glucuronidation Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- RBNPOMFGQQGHHO-UHFFFAOYSA-N glyceric acid Chemical compound OCC(O)C(O)=O RBNPOMFGQQGHHO-UHFFFAOYSA-N 0.000 description 1
- 150000002315 glycerophosphates Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 230000031774 hair cycle Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 230000003659 hair regrowth Effects 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 239000009331 herbal preparation PC-SPES Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical class CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 108700020746 histrelin Proteins 0.000 description 1
- 229960002193 histrelin Drugs 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-N iodic acid Chemical class OI(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-N 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 108010078259 luprolide acetate gel depot Proteins 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- CFTUQSLVERGMHL-UHFFFAOYSA-N methyl 2-(bromomethyl)prop-2-enoate Chemical compound COC(=O)C(=C)CBr CFTUQSLVERGMHL-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical class CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 229940041676 mucosal spray Drugs 0.000 description 1
- 238000002552 multiple reaction monitoring Methods 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 229960004719 nandrolone Drugs 0.000 description 1
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 150000005480 nicotinamides Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229940099637 nilandron Drugs 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 229940064438 nizoral Drugs 0.000 description 1
- 125000005474 octanoate group Chemical class 0.000 description 1
- 230000037312 oily skin Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical class N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical class OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000001564 phenyl benzoates Chemical class 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- QPMDWIOUHQWKHV-ODZAUARKSA-M potassium;(z)-4-hydroxy-4-oxobut-2-enoate Chemical class [K+].OC(=O)\C=C/C([O-])=O QPMDWIOUHQWKHV-ODZAUARKSA-M 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003658 preventing hair loss Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940072254 proscar Drugs 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 229940034080 provenge Drugs 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000004728 pyruvic acid derivatives Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011472 radical prostatectomy Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 208000020989 salivary duct carcinoma Diseases 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011820 transgenic animal model Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 229940032510 trelstar Drugs 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940097704 vantas Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 229940061389 viadur Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 235000019386 wax ester Nutrition 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229940085728 xtandi Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940051084 zytiga Drugs 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- This disclosure is directed to selective androgen receptor degrader (SARD) compounds, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogemc dermal diseases, spinal (and) bulbar muscular atrophy (SBMA), amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.
- SARD selective androgen receptor degrader
- PCa Prostate cancer
- ADT Androgen-deprivation therapy
- LHRH luteinizing hormone releasing hormone
- LHRH antagonists LHRH antagonists
- bilateral orchiectomy a progressive hypertension of prostate cancer
- CRPC castration-resistant prostate cancer
- mCRPC metastatic CRPC
- Patients with CRPC have a median survival of 12-18 months.
- AR androgen receptor
- a critical barrier to progress in treating CRPC is that AR signaling inhibitors such as enzalutamide, bicalutamide, and abiraterone, acting through the LBD, fail to inhibit growth driven by the N-terminal domain (NTD)-dependent constitutively active AR-SV.
- NTD N-terminal domain
- a significant number of CRPC patients are becoming refractory to abiraterone or enzalutamide, emphasizing the need for next generation AR antagonists.
- One embodiment encompasses a selective androgen receptor degrader (SARD) compound represented by the structure of formula I: wherein
- T is I L OH.
- Ri is H, CI-I 3 , CI-bF, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
- Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3 ;
- Z is NO2, CN, COOH. COR, M K'OR. or CONHR;
- X is CH or N
- Ris H alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
- A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, maieimide, NHCOOR, N(R)z, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- this disclosure is directed to a SARD compound represented by the structure of formula IA:
- R is H, ('l l :. CH2F, CHF2, ('!• :. CH 2 CH 3 , or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
- Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
- Z is NO2, CN, COOH, COR, NHCOR or COM IR;
- X is CH or N
- A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, malemnde, NHCOOR, N(R) 2 , NHCOR, COM IR. COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- this disclosure is directed to a SARD compound represented by the structure of formula IB: wherein
- T is H, OH, OR, OCOR, OCHjCi—CHzICi—OIOCH?, CH3, NHCOCH3, or NHCOR;
- Ri is II, CI -fe, CII2F, CI- IF?, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring,
- Y is H, CF3, F, I, Br, Cl, CN, or C(R ) 3;
- Z is NO2, CN, COOH, COR, NUCOR, or CONHR;
- X is CH orN
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
- A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, aiylalkyl, NCS, maleimide, NHCOOR, N(R)? submit NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- Ri is H, CI ⁇ 3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri formr a 3-8 carbocyclic or heterocyclic ring;
- Y is II, CF3, F, I, Br, Cl, CN, or C(R h ;
- Z is NO ? argue CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CFFCHiCl, aryl,
- A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Qy or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aiyd, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N( R) 2, NHCOR, CONHR, COOR or COR; or its optical isomer,
- this disclosure is directed to a SARD compound represented by the structure of formula IIA:
- Ri is H, CH3, CHZF, CHF2, CF 3 , CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
- Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl,
- A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleirnide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its is
- this disclosure is directed to a SARD compound represented by the structure of formula IIB:
- Ri is II, CH3, CH2F , CHF2, CF3, CH2CH3, or CF2CF3; or T and R1 form a 3-8 carbocyclic or heterocyclic ring,
- Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3;
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH orN
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
- A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, C1, Br, I, CN, NO2., hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, N ICOOR . N(R)2., NHCOR, CONHR, COOR or COR; or its iso
- the disclosure encompasses a SARD compound represented by the structure of formula III: wherein
- Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri formr a 3-8 carbocyclic or heterocyclic ring;
- Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3 ;
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
- A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , O'.
- Q 4 each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- this disclosure is directed to a SARD compound represented by the structure of formula III A: wherein
- T is H, OH, OR.
- OCOR OCH 2 C(-CH 2 )C(-O)OCH 3 , CH3, NHCOCH3, or NHCOR;
- Ri is H, Cl b. CU T. CHF2, CF 3 , CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring; Y is 11, CF 3 , F. I, Br, Cl, CN, or C( R ) 3;
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- Ris H alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
- A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q i or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically
- this disclosure is directed to a SARD compound represented by the structure of formula IIIB: wherein
- T is H, OH, OR, OCOR, OCHjCi—CHzlCt—OlOCH?, CH3, NHCOCH3, or NHCOR;
- Ri is H, CHy CH2F, CHF2, CFy CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring,
- Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3 ;
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH orN; Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
- A is a pyrrole, pyrroline, pyrrolidine, pyrazoie, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q J , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer,
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IV: wherein
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- Y is H, CF3, F, I, Br, Cl, CN, or C(R)i;
- Ri is H, CI-I3, CH2F, CHF2, CFs, CH.-CH 3, or CF2CF3;
- T is H, OH, OR. OCOR, OCI l-C( CH -)('( OjOCI h. Cl b. NFICOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
- R is FI, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CFs, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
- Q 2 , Q’, or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Ci, Br, I, CN, NOz, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVA: wherein
- Z is NO2, CN, COOi L COR, NHCOR, or CONHR;
- X is CH or N
- Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH3, CH2F, CHF2, CF 3 , CH2CH3, or CF2CF3;
- T is H, OH, OR. ()( OR. OCH.'Ci CH'lCi O)OCH CH 3, NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
- Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CFs, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hy drate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVB:
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- Y is H, ('!• :. F, I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH 3 , CH2F, CHF2, CF 3 , CH 2 CH 3 , or CF2CF3;
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
- Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula V:
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- Y is H, ('!• :. F, I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH 3 , CH2F, CHF2, CF 3 , CH 2 CH 3 , or CF2CF3;
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
- Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR: or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VA: wherein
- Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
- R is H, Ci h. Ci Nd CHF.'. CF 3 , CH Ci I 3 , or CF.'CN.
- Ris H alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
- O', Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)?., NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VB: wherein
- Z is NOz, CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- Y is I L CL ⁇ IL I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH 3 , CH2F, CHF2, CF 3> CH 2 CH 3 , or CF2CF3;
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
- Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VI: wherein
- Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- ⁇ is H, C F 3 , F, I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH 3 , CH?F, CHF?, CF 3 , CH?CH 3 , or CF?CF 3 ;
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH2CI, CH 2 CH?C1, aryl, F, Cl, Br, I, or OH; and
- Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VIA:
- Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- ⁇ is H, CH. F, I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH 3 , CH?F, CHF?, CF 3 , CH?CH 3 , or CF?CF 3 ;
- Ris H alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH2CI, CH 2 CH?C1, aryl, F, Cl, Br, I, or OH;
- Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VIB:
- Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
- X is CH or N
- ⁇ is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
- Ri is H, CH 3 , CH?F, CHF?, CF 3 , CH?CH 3 , or CF?CF 3 ;
- R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH2CI, CH 2 CH?C1, aryl, F, Cl, Br, I, or OH; and
- Q 2 , Q ⁇ or Q' are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, arylalkyl, NCS, maleinride, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- One embodiment encompasses the SARD compound having at least one of the following properties: binds to the AR through an alternate binding and degradation domain (BDD), e.g, in the NTD, binds to the AR through the AR ligand binding domain (LBD); exhibits AR- splice variant (AR-SV) degradation activity; exhibits AR-full length (AR-FL) degradation activity including pathogenic mutations thereof, exhibits AR-SV inhibitory activity (z.e., is an AR-SV antagonist); exhibits AR-FL inhibitory activity (i.e., is an AR-FL antagonist) including pathogenic mutations thereof, possesses dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions.
- BDD alternate binding and degradation domain
- AR-SV AR-splice variant
- AR-FL AR-full length
- AR-FL exhibits AR-FL inhibitory activity including pathogenic mutations thereof, possesses dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation
- compositions comprising a SARD compound according to this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and a pharmaceutically acceptable carrier.
- the pharmaceutical composition may be formulated for topical use.
- the topical pharmaceutical composition may be a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soaps or bars, emulsion, mousse, aerosol, or shampoo.
- the disclosure encompasses a method of treating prostate cancer (PCa) or increasing survival in a male subject in need of treatment comprising administering to the subject a therapeutically effective amount of a compound defined by formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPI). 44, CPD. 45, or CPD. 13.
- the prostate cancer includes, but is not limited to, advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
- the method may treat a prostate or other cancer that is resistant to treatment with known androgen receptor antagonist(s) or ADT.
- the method may treat enzalutamide resistant prostate cancer.
- the method may treat abiraterone resistant prostate cancer.
- Yet another embodiment encompasses a method of treating prostate or other AR antagonist resistant cancer with a SARD compound of the disclosure wherein the androgen receptor antagonists) is at least one of enzalutamide, bical utamide, abiraterone, ARN-509, ODM-201 , EPI- 001 , AZD-3514, galeterone, ASC-J9, flutamide, hydroxyfl utamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.
- the androgen receptor antagonists is at least one of enzalutamide, bical utamide, abiraterone, ARN-509, ODM-201 , EPI- 001 , AZD-3514, galeterone, ASC-J9, flutamide, hydroxyfl utamide, nilutamide, cyproterone acetate, ketoconazole, or s
- Yet another embodiment encompasses a method of treating prostate or other cancers using a SARD compound of the disclosure wherein the other cancers are selected from breast cancer such as TNBC, testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer.
- the breast cancer is triple negative breast cancer (TNBC).
- the disclosure encompasses a method of reducing the levels of AR-sphce variants in a subject comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the method may comprise further reducing the levels of AR-full length in the subject.
- Another embodiment encompasses a method of treating Spinal (and) Bulbar Muscular Atrophy (SBMA) (also referred to herein as “Kennedy’s disease”) in a subject comprising administering to the subject a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPI). 44, CPD. 45, or CPD. 13 or a compound of another formula of the disclosure.
- SBMA Spinal (and) Bulbar Muscular Atrophy
- Yet another embodiment encompasses a method of: (a) treating acne in a subject; (b) decreasing sebum production in a subject; (c) treating hirsutism in a subject, e.g., female facial hair; (d) treating alopecia in a subject, e.g., androgenic alopecia; (e) treating a hormonal condition in female; (f) treating sexual perversion, hypersexuality', or paraphilias in a subject; (g) treating androgen psychosis in a subject; (h) treating virilization in a subject; (i) treating complete or partial androgen insensitivity 7 syndrome in a subject; (j) increasing or modulating ovulation in an animal; (k) treating of cancer in a subject; or any combination thereof, by administering a compound of this disclosure or a pharmaceutical composition thereof.
- One embodiment encompasses methods of reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject comprising administering a compound according to this disclosure.
- the method may inhibit, degrade, or both the function of the polyglutamine (polyQ) AR polymorphs (polyQ- AR).
- the polyQ- AR may be a short polyQ polymorph or a long polyQ polymorph.
- the method further treats dermal disease.
- the polyQ- AR is a long polyQ polymorph
- the method further treats Kennedy’s disease.
- Another embodiment encompasses methods of treating amyotrophic lateral sclerosis (ALS) in a subject by administering a therapeutically effective amount of the compound of the disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
- ALS amyotrophic lateral sclerosis
- Another embodiment encompasses methods of treating abdominal aortic aneurysm (AAA) in a subject by administering a therapeutically effective amount of the compound of the disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
- AAA abdominal aortic aneurysm
- Yet another embodiment encompasses methods of treating uterine fibroids in a subject by administering a therapeutically effective amount of the compound of this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
- Androgens act in cells by binding to the AR, a member of the steroid receptor superfamily of transcription factors.
- PCa prostate cancer
- AR antagonists such as enzalutamide, bicalutamide or hydroxyfl utamide to disrupt receptor activation has been successfully used in the past to reduce PCa growth.
- All currently available AR antagonists competitively bind AR and recruit corepressors such as NCoR and SMRT to repress transcription of target genes.
- corepressors such as NCoR and SMRT
- Abiraterone resistance mutations include L702H mutations which results in activation of the AR by glucocorticoids such as prednisone, causing resistance to abiraterone because abiraterone is usually prescribed in combination with prednisone. If resistance develops to enzalutamide then often the patient is refractory to abiraterone also and vice versa; or the duration of response is very’ short. This situation highlights the need for a definitive androgen ablation therapy’ to prevent AR reactivation in advanced prostate cancers.
- ADT initial response to androgen deprivation therapy
- PCa disease progression is inevitable and the cancer emerges as castration-resistant prostate cancer (CRPC).
- CRPC castration-resistant prostate cancer
- AR androgen receptor
- AR-SV AR splice variants
- LBD ligand binding domain
- This disclosure describes novel AR antagonists with unique pharmacology that strongly (high potency and efficacy) and selectively bind AR (better than known antagonists in some cases; bind to LBD and/or NTD), antagonize AR, and degrade AR full length (AR-FL) and AR-SV.
- Selective androgen receptor degrader (SARD) compounds possess dual degradation and AR-SV inhibitory functions and hence are distinct from any available CRPC therapeutics. These novel selective androgen receptor degrader (SARD) compounds inhibit the growth of PCa cells and tumors that are dependent on AR-FL and AR-SV for proliferation.
- SARDs have the potential to evolve as new therapeutics to treat CRPCs that are unbeatable with any other antagonists. This unique property of degrading AR-SV has extremely important health consequences for prostate cancer. Till date only one synthetic molecule (EPI-001) and some marine natural products such as the sinkotamides and glycerol ether Naphetenone B, are reported to bind to AR-NTD and inhibit AR function and PCa cell growth, albeit at lower affinity and inability to degrade the receptor. The SARDs reported herein also bind to AR-NTD and inhibit NTD-driven (e.g., ligand independent) AR activity.
- EPI-001 synthetic molecule
- some marine natural products such as the sinkotamides and glycerol ether Naphetenone B
- non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity syndrome (PAIS) associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J. Gastroenterology 20(29):9229), cancer of the ovary', fallopian tubes, or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT was tested in AR-expressing recurrent metastatic salivary gland cancers and was confirmed to have benefit on progression free survival and overall survival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876); Int J.
- pancreatic cancer pancreatic cancer
- lymphoma including mantle cell
- hepatocellular carcinoma Use of a more potent antiandrogen such as a SARD in these cancers may more efficaciously treat the progression of these and other cancers.
- cancers may also benefi t from SARD treatment such as breast cancer (e.g., triple negative breast cancer (TNBC)), testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer.
- TNBC triple negative breast cancer
- PAIS partial androgen insensitivity syndromes
- NSCLC non-small cell lung cancer
- gastric cancer colon cancer
- perianal adenoma or central nervous system cancer.
- TNBC Triple negative breast cancer
- ER estrogen receptor
- PR progesterone receptor
- HER2 receptor kinase a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase.
- ER estrogen receptor
- PR progesterone receptor
- HER2 receptor kinase a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase.
- HER2 receptor kinase lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers.
- chemotherapy is often the initial pharmacotherapy for TNBC.
- AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy.
- ER-positive breast cancer AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors.
- AR in the absence of ER,
- TNBC TNBC
- SARDs which are capable of destroying AR-SVs through a binding site in the NTD of AR would be able to antagonize AR in these TNBC’s and provide an anti-tumor effect.
- antiandrogens such as bicalutamide and flutamide were approved for use in prostate cancer.
- antiandrogens e.g., flutamide, spironolactone, cyproterone acetate, finasteride and chlormadmone acetate
- androgen-dependent dermatological conditions such as androgenic alopecia (male pattern baldness), acne vulgaris, and hirsutism (e.g, in female facial hair).
- Prepubertal castration prevents sebum production and androgenic alopecia but this can be reversed by use of testosterone, suggesting its androgen-dependence.
- the AR gene has a polymorphism of glutamine repeats (polyQ) within exon 1 which when shortened may augment AR transactivation (/. ⁇ ?., hyperandrogenism). It has been found that shortened polyQ polymorphisms are more common in people with alopecia, hirsutism, and acne. Classic antiandrogens are undesirable for these purposes because they are ineffective through dermal dosing and their long-term systemic use raises the risks of untoward sexual effects such as gynecomastia and impotence.
- T and DHT endogeneous androgens testosterone
- DHT dihydrotestosterone
- An emerging concept is the topical application of a SARD to destroy the AR locally to the affected areas of the skin or other tissue without exerting any systemic antiandrogemsm.
- a SARD that does not penetrate the skin or is rapidly metabolized would be preferrable.
- Androgenic alopecia occurs in -50% of Caucasian males by midlife and up to 90% by 80 years old.
- Minoxidil a topical vasodilator
- finasteride a systemic 5alpha reductase type II inhibitor
- Minoxidil a topical vasodilator
- finasteride a systemic 5alpha reductase type II inhibitor
- Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy.
- Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis (The anabolic/androgenic steroid nandrolone exacerbates gene expression modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis.
- Galbiati M Onesto E, Zito A, Crippa V, Rusmmi P, Mariotti R, Bentivoglio M, Bendotti C, Poletti A. Pharmacol. Res. 2012, 65(2), 221-230), but the mechanism through which androgens modify the ALS phenotype is unknown.
- a transgenic animal model of ALS demonstrated improved survival upon surgical castration (i.e., androgen ablation). Treatment of these castrated animals with the androgen agonist nandrolone decanoate worsened disease manifestations. Castration reduces the AR level, which may be the reason for extended survival.
- the survival benefit is reversed by androgen agonist (Androgens affect muscle, motor neuron, and survival in a mouse model of SOD 1 -related amyotrophic lateral sclerosis. Aggarwal T, Polanco MJ, Scaramuzzino C, Rocchi A, Milioto C, Emionite L, Ognio E, Sambataro F, Galbiati M, Poleti A, Pennuto M. Neurobiol.
- an antiandrogen that can block both action of LBD-dependent AR agonists and lower AR protein levels would be therapeutic in ALS.
- Riluzole is an available drug for ALS treatment, however, it only provides short-term effects. There is an urgent need for drugs that extend the survival of ALS patients.
- SARDs could be used in women with uterine fibroids, especially those expressing shorter and longer [CAG](n) repeat alleles, to treat existing uterine fibroids, prevent worsening of fibroids and/or ameliorate carcinogenicity associated with fibroids.
- An abdominal aortic aneurysm is an enlarged area m the lower part of the aorta, the major blood vessel that supplies blood to the body.
- the aorta about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the aorta is the body’s mam supplier of blood, a ruptured abdominal aortic aneurysm can cause life- threatening bleeding.
- treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery can be planned if it's necessary.
- X-linked spinal-bulbar muscular atrophy (SBMA-also known as Kennedy’s disease) is a muscular atrophy that arises from a defect in the androgen receptor gene on the X chromosome. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases.
- the mutation results in a protracted polyglutamine tract added to the N-terminal domain of the androgen receptor (polyQ AR). Binding and activation of this lengthened polyQ AR by endogeneous androgens (testosterone and DHT) results in unfolding and nuclear translocation of the mutant androgen receptor.
- pyrrole, pyrazole, triazole, imidazole, and morpholine based selective androgen receptor degrader (SARD) compounds that may bind to the LBD and/or an alternate binding and degradation domain (BDD) located in the NTD, antagonize AR, and degrade AR thereby blocking ligand-dependent and ligand-independent AR activities.
- BDD alternate binding and degradation domain
- the disclosure encompasses novel selective androgen receptor degrader (SARD) compounds encompassed by Formula I, which inhibit the growth of prostate cancer (PCa) cells and tumors that are dependent on AR full length (AR-FL) including pathogenic and resistance mutations and wildtype, and/or AR splice variants (AR-SV) for proliferation.
- SARD selective androgen receptor degrader
- a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of inhibiting the growth of PCa cells and tumors that are dependent on AR-full length (AR-FL) and/or AR splice variants (AR-SV) for proliferation.
- the SARD compound may not bind to ligand binding domain (LBD).
- a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of causing degradation of a variety of pathogenic mutant variant AR’s and wildtype AR and hence are capable of exerting anti-androgenism is a wide variety of pathogenic altered cellular environments found in the disease states embodied in this disclosure.
- the SARD is orally active.
- the SARD is applied topically to the site of action.
- the SARD compound may bind to the N-terminal domain (NTD) of the AR; to an alternate binding and degradation domain (BDD) of the AR, to both the AR ligand binding domain (LBD) and to an alternate binding and degradation domain (BDD); or to both the N- terminal domain (NTD) and to the ligand binding domain (LBD) of the AR.
- the BDD may be located in the NTD.
- the BDD is located in the AF-1 region of the NTD.
- the SARD compound may be capable of: inhibiting growth driven by the N-tenninal domain (NTD)-dependent constitutively active AR-SV; or inhibiting the AR through binding to a domain that is distinct from the AR LBD.
- the SARD compound may be a strong (i.e., highly potent and highly efficacious) selective androgen receptor antagonist, which antagonizes the AR stronger than other known AR antagonists (e.g., enzalutamide, bicalutamide and abiraterone).
- a strong androgen receptor antagonist e.g., highly potent and highly efficacious selective androgen receptor antagonist, which antagonizes the AR stronger than other known AR antagonists (e.g., enzalutamide, bicalutamide and abiraterone).
- the SARD compound may be a selective androgen receptor antagonist, which targets AR-SVs, which cannot be inhibited by conventional antagonists.
- the SARD compound may exhibit one of several activities including, but not limited to: AR-SV degradation activity'; AR- FL degradation activity; AR-SV inhibitory’ activity (i.e., is an AR-SV antagonist); AR-FL inhibitory activity' (i.e., is an AR-FL antagonist); inhibition of the constitutive activation of AR- SVs; or inhibition of the constitutive activation of AR-FLs.
- the SARD compound may possess dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions; or alternatively possess all four of these activities.
- the SARD compound may also degrade AR-FL and AR-SV.
- the SARD compound may degrade the AR through binding to a domain that is distinct from the AR LBD.
- the SARD compound may possess dual degradation and AR-SV inhibitory functions that are distinct from any available CRPC therapeutics.
- the SARD compound may inhibit the re-activation of the AR by alternate mechanisms such as: intracrine androgen synthesis, expression of AR-SV that lack ligand binding domain (LBD) and AR-LBD mutations with potential to resist antagonists, or inhibit re-activated androgen receptors present in pathogenic altered cellular environments.
- AR-splice variants include, but are not limited to, AR-V7 and ARv567es (a.k.a. AR-V12; S. Sun, etal. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. (2010) 120(8), 2715- 2730).
- AR mutations conferring antiandrogen resistance are: W741L, T877A, and F876L (J. D. Joseph et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. (2013) 3(9), 1020-1029) mutations.
- AR-V7 is a splice variant of AR that lacks the LBD (A. H. Bryce & E. S. Antonarakis. Androgen receptor splice variant 7 in castration-resistant prostate cancer: Clinical considerations. Int J Urol. (2016 Jun 3). doi: 10.1111/iju.13134. [Epub ahead of print]). It is constitutively active and has been demonstrated to be responsible for aggressive PCa and resistance to endocrine therapy .
- the disclosure encompasses novel selective androgen receptor degrader (SARD) compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any’ of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 which bind to the AR through an alternate binding and degradation domain (BDD).
- BDD alternate binding and degradation domain
- the SARDs may’ further bind the AR ligand binding domain (LBD).
- the SARD compounds may be used in treating CRPC that cannot be treated with any other antagonist.
- the SARD compounds may treat CRPC by degrading AR-SVs.
- the SARD compounds may maintain their antagonistic activity in AR mutants that normally convert AR antagonists to agonists.
- the SARD compounds maintain their antagonistic activity to AR mutants W741L, T877A, and F876L (J. D. Joseph el al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN- 509. Cancer Discov. (2013) 3(9): 1020-1029).
- the SARD compounds elicit antagonistic activity within an altered cellular environment in which LBD-targeted agents are not effective or in which NTD-dependent AR activity is constitutively active.
- a of formula I, IA, IB, II, IIA, TIB, III, TITA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom.
- A is a substituted or unsubstituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, morpholine, or other heterocyclic ring.
- A is a five or six-membered heterocyclic ring.
- IVA, IVB, V, VA, VB, VI, ATA, or VIB Q 1 is hydrogen.
- Q 1 is CN.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 1 ! is F.
- IVB, V, VA, VB, VI, VIA, or VIB Q l is NHCOOR.
- Q 1 is N(R)?
- Q ⁇ is CONHR.
- Q 1 is phenyl.
- Q' 1 is 4-fluorophenyl.
- IVA, IVB, V, VA, VB, VI. VIA, or VIB is 4-fluorophenyl.
- VI, VIA, or MB Q 1 is CF?.
- Q 1 is substituted or unsubstituted alkyl.
- IVA, IVB, V 7 , VA, VB, V 7 !, VIA, or VIB Q ! is substituted or unsubstituted cycloalkyl.
- Q 1 is substituted or unsubstituted heterocycloalkyl.
- Q 1 is haloalkyl.
- Q 1 is substituted or unsubstituted aryl.
- Q 1 is hydroxyl.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 1 is alkoxy.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ! is OR.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q ! is arylalkyl.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ] is amine.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 1 is amide.
- Q f is COOR.
- fomiuias I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 2 is keto.
- fomiuias I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 2 is NCS.
- VIA, or VIB Q 2 is N(R) 2 .
- Q 2 is CONHR.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB is NHCOR.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 2 is F.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 2 is Cl.
- formulas I, LA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 2 is Br.
- formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB,Q 2 is I.
- formulas I, IA, IB, II, IIA, IIB, III, IILA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 2 is NO2.
- Q 2 is phenyl.
- Q 2 is 4-fluorophenyl.
- Q 2 is CFs.
- Q 2 is substituted or unsubstituted heterocycloalkyl.
- Q 2 is haloalkyl.
- III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q 2 is alkoxy.
- Q 2 is OR.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q' is CN.
- Q 3 is F.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 3 is NCS.
- IVA, IVB, V, VA, VB, VIA, or VIB Q 3 is NCS.
- VI, VIA, or VIB Q ⁇ is NHCOR.
- Q 3 is hydrogen.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 3 is keto.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 3 is keto.
- Q 3 is phenyl.
- Q' is 4-fluorophenyl.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB,Q 3 is substituted or unsubstituted cycloalkyl.
- formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB,Q 3 is substituted or unsubstituted heterocycloalkyl.
- III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q 3 is alkoxy.
- formulas I, LA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q 3 is OR.
- formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q 3 is arylalkyl.
- IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q 3 is COOR.
- Q 3 is COR.
- VA, VB, VI, VIA, or VIB Q 4 is NO2.
- Q 4 is phenyl.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 4 is 4-fluorophenyl.
- VI, VIA, or VIB Q 4 is haloalkyl.
- Q 4 is substituted or unsubstituted aryl.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 4 is substituted or unsubstituted aryl.
- IVA, IVB, V, V A is substituted or unsubstituted aryl.
- Q 4 is arylalkyl.
- IVA, IVB, V, VA, VB, VI, VIA, or VIB Q 4 is amine.
- Q 7 is amide.
- Q 1 is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CHs)3.
- IVA, IVB, V 7 , VA, VB, VI, VIA, or VIB Q 2 is H, CN, CFi, phenyl, 4-fluorophenyl, F, Br, or NHCOOCfCFhh.
- Q 3 is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CH 3 )3.
- Q 4 is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CH 3 )3.
- heterocycle or “heterocyclic ring” group refers to a ring structure comprising in addition to carbon atoms, at least one atom of sulfur, oxygen, nitrogen or any combination thereof, as part of the ring.
- the heterocycle may be a 3-12 membered ring; 4- 8 membered ring; a 5-7 membered ring; or a 6 membered ring.
- the heterocycle is a 5 to 6 membered ring.
- heterocycles include, but are not limited to, piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazole, pyrazine, piperazine or pyrimidine.
- Cs-Cs heterocyclic rings include pyran, dihydropyran, tetrahydropyran, dihydropyrrole, tetrahydropyrrole, pyrazine, dihydropyrazine, tetrahydropyrazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidone, pyrazole, dihydropyrazole, tetrahydropyrazole, triazole, tetrazole, piperidine, piperazine, pyridine, dihydropyridine, tetrahydropyridine, morpholine, thiomorpholine, furan, dihydrofuran, tetrahydrofuran, thiophene, di
- the heterocycle ring may be fused to another saturated or unsaturated cycloalkyl or a saturated or unsaturated heterocyclic ring.
- the substituents include at least one of halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylaniido, dialkylamido, cyano, nitro, CO2H, amino, alkylaniino, dialkylamino, carboxyl, thiol, or thioalkyl.
- cycloalkyl refers to a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms.
- a cycloalkyl group can have one or more carbon-carbon double bonds in the ring so long as the ring is not rendered aromatic by their presence.
- cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C3-C7) cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes.
- Cb-Cs carbocyclic examples include cyclopentane, cyclopentene, cyclohexane, and cyclohexene rings.
- a cycloalkyl group can be unsubstituted or substituted by at least one substituent.
- the cycloalkyl group is a monocyclic ring or bicyclic ring.
- alkyl refers to a saturated aliphatic hydrocarbon, including straight- chained and branched-chained. Typically, the alkyl group has 1-12 carbons, 1 -7 carbons, 1-6 carbons, or 1-4 carbon atoms.
- a branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. The branched alkyl may have an alkyl substituted by a C1-C5 haloalkyl.
- alkyl group may be substituted by at least one of halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, ammo, alkylaniino, dialkydamino, carboxyl, thio or thioalkyl.
- arylalkyl refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined herein.
- An example of an ary lalkyl group is a benzyl group.
- alkenyl refers to an unsaturated hydrocarbon, including straight chain and branched chain having one or more double bonds.
- the alkenyl group may have 2-12 carbons, preferably the alkenyl group has 2-6 carbons or 2-4 carbons.
- Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, cyclohexenyl, etc.
- the alkenyl group may be substituted by at least one halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio, or thioalkyl.
- aryl group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted.
- substituents include, but are not limited to, at least one halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio or thioalkyl.
- Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridmyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
- the aryl group may be a 4-12 membered ring, preferably the aryl group is a 4-8 membered ring. Also the aryl group may be a 6 or 5 membered ring.
- haloalkyl group refers to an alkyl group that is substituted by one or more halogen atoms, e.g., by F, Cl, Br or I.
- a “hydroxyl” group refers to an OH group. It is understood by a person skilled in the art that when T, Q 1 , Q z , Q 3 , or Q 4 , in the compounds of the present disclosure is OR, then R is not OH.
- halogen refers to a halogen, F, Cl, Br or I.
- the compounds and/or its use and/or, its derivative, optical isomer, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal or combinations thereof are provided.
- the methods make use of “pharmaceutically acceptable salts” of the compounds, which may be produced, by reaction of a compound of this disclosure with an acid or base.
- the compounds may be converted into pharmaceutically acceptable salts.
- a pharmaceutically acceptable salt may be produced by reaction of a compound with an acid or base.
- Suitable pharmaceutically acceptable salts of amines may be prepared from an inorganic acid or from an organic acid.
- inorganic salts of amines include, but are not limited to, bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates, or thiocyanates.
- Examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, arahphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, carboxylates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates
- Examples of inorganic salts of carboxylic acids or phenols may be selected from ammonium, alkali metals, and alkaline earth metals.
- Alkali metals include, but are not limited to, lithium, sodium, potassium, or cesium.
- Alkaline earth metals include, but are not limited to, calcium, magnesium, aluminium; zinc, barium, cholines, or quaternary ammoniums.
- organic salts of carboxylic acids or phenols may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, r-butylamines, benethamines (A ; ⁇ benzylphenethylaniine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglammes, JV-methyl-D-glucamines, N,N ’-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolines, piperazines, procaine, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.
- A
- Salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.
- the methods of the disclosure may use an uncharged compound or a pharmaceutically acceptable salt of the compound.
- the methods use pharmaceutically acceptable salts of compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,
- the pharmaceutically acceptable salt may be an amine salt or a salt of a phenol of the compounds of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, ALA,
- the methods make use of a free base, free acid, non charged or non-complexed compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,
- the methods make use of an optical isomer of a compound of formulas I, IA, IB, II, IIA, IIB, 111, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. In one embodiment, the methods make use of an isomer of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
- the methods make use of a pharmaceutical product of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB. In one embodiment, the methods make use of a hydrate of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA,
- the methods make use of a polymorph of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VTB. In one embodiment, the methods make use of a metabolite of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VTB.
- the methods make use of a composition comprising a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, as described herein, or, in another embodiment, a combination of isomer, metabolite, pharmaceutical product, hydrate, polymorph of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
- the term “isomer” includes, but is not limited to, optical isomers, structural isomers, or conformational isomers,
- the term “isomer” is meant to encompass optical isomers of the SARD compound. It will be appreciated by those skilled in the art that the SARDs of the present disclosure contain at least one chiral center. Accordingly, the compounds may exist as optically-active (such as an (/?) isomer or (S) isomer) or racemic forms. Optically active compounds may exist as enantiomer! cal ly enriched mixtures. Some compounds may also exhibit polymorphism. It is to be understood that the present disclosure encompasses any racemic, optically active, polymorphic, or stereroisomeric form, or mixtures thereof Thus, the disclosure may encompass SARD compounds as pure (A’)-isomers or as pure (A)-isomers.
- optically active forms For example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary' phase.
- Compounds may be hydrates of the compounds.
- the term “hydrate” includes, but is not limited to, hemihydrate, monohydrate, dihydrate, or trihydrate.
- the disclosure also includes use of A'-oxides of the ammo substituents of the compounds described herein.
- metabolites of the compounds as herein described means any substance produced from another substance by metabolism or a metabolic process.
- the compounds of this disclosure are prepared according to Example 1.
- a method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, represented by a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
- a compound or its pharmaceutically acceptable salt represented by a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
- a method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, or isomer, represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
- the prostate cancer may be advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (rnCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
- CRPC castration resistant prostate cancer
- rnCRPC metastatic CRPC
- nmCRPC non-metastatic CRPC
- high-risk nmCRPC or any combination thereof.
- the prostate cancer may depend on AR-FL and/or AR-SV for proliferation.
- the prostate or other cancer may be resistant to treatment with an androgen receptor antagonist.
- the prostate or other cancer may be resistant to treatment with enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof.
- the method may also reduce the levels of AR, AR-FL, AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-SV, gene-amplified AR, or any combination thereof.
- this disclosure provides a method of treating enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- this disclosure provides a method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- this disclosure provides a method of treating triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
- the method may further comprise a second therapy such as androgen deprivation therapy (ADT) or LHRH agonist or antagonist.
- ADT androgen deprivation therapy
- LHRH agonists include, but are not limited to, leuprolide acetate.
- the disclosure encompasses a method of treating or inhibiting the progression of prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is at least one of compounds of formula I, I A. IB, II, ll A. IIB, III, Hl A. IIIB, IV, IVA, IVB. V, VA, VB. AT, ATA, or ATB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the disclosure encompasses a method of treating or inhibiting the progression of refractory prostate cancer (PCa) or increasing the survival of a male subject suffering from refractory prostate cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, Ill, IIIA, IIIB, IV, IA r A, IVB, A r , AA, VB, AT, VIA, or ATB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the disclosure encompasses a method of treating or increasing the survival of a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering to the subject a therapeutically effective amount of a SARD wherein the compound is represented by a compound of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, ATA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the method may further comprise administering androgen deprivation therapy to the subject.
- the disclosure encompasses a method of treating or inhibiting the progression of enzalutamide resistant prostate cancer (PCa) or increasing the survival of a male subject suffering from enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a SARI) compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the method may further comprise administering androgen deprivation therapy to the subject.
- the disclosure encompasses a method of treating or inhibiting the progression of tripie negative breast cancer (TNBC) or increasing the survival of a female subject suffering from triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, XT, ATA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the term “increase the survival” refers to a lengthening of time when describing the survival of a male subject.
- the compounds may be used to increase the survival of men with advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC) or high-risk nmCRPC.
- the terms “increase”, increasing” and “increased” may be used interchangeably and refer to an entity becoming progressively greater (as in size, amount, number, or intensity), wherein for example the entity is sex hormone-binding globulin (SHBG) or prostate-specific antigen (PSA).
- SHBG sex hormone-binding globulin
- PSA prostate-specific antigen
- the compounds and compositions of the disclosure may be used for increasing metastasis-free survival (MFS) in a subject suffering from non-metastatic prostate cancer.
- the non- metastatic prostate cancer may be non-metastatic advanced prostate cancer, non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.
- the SARD compounds described herein may be used to provide a dual action.
- the SARD compounds may treat prostate cancer and prevent metastasis.
- the prostate cancer may be refractory prostate cancer: advanced prostate cancer; castration resistant prostate cancer (CRPC); metastatic CRPC (mCRPC); non-metastatic CRPC (nmCRPC); or high-risk nmCRPC.
- the SARD compounds described herein may be used to provide a dual action.
- the SARD compounds may treat TNBC and prevent metastasis.
- Men with advanced prostate cancer who are at high risk for progression to castration resistant prostate cancer are men on ADT with serum total testosterone concentrations greater than 20 ng/dL or men with advanced prostate cancer who at the time of starting ADT had either (1) confirmed Gleason pattern 4 or 5 prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time ⁇ 3 months, (4) a PSA >20 ng/mL, or (5) a PSA relapse in ⁇ 3 years after definitive local therapy (radical prostatectomy or radiation therapy).
- CRPC castration resistant prostate cancer
- PSA prostate specific antigen
- Men with high risk non-metastatic castration resistant prostate cancer may include those with rapid PSA doubling times, having an expected progression-free survival of approximately 18 months or less (Miller K, Moul JW, Gleave M, et al. 2013. “Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer,” Prostate Cane Prost Dis. Feb; 16: 187-192). This relatively rapid progression of their disease underscores the importance of novel therapies for these individuals.
- the methods of the disclosure may treat subjects with PSA levels greater than 8 ng/mL where the subject suffers from high-risk nmCRPC.
- the patient population includes subjects suffering from nmCRPC where PSA doubles in less than 8 months or less than 10 months.
- the method may also treat patient populations where the total serum testosterone levels are greater than 20 ng/mL in a subject suffering from high-risk nmCRPC.
- the serum free testosterone levels are greater than those observed in an orchiechtomized male in a subject suffering from high- risk nmCRPC.
- compositions of the disclosure may further comprise at least one LHRH agonist or antagonist, antiandrogen, anti-programmed death receptor 1 (anti-PD-1) drugs or anti-PD-Ll drugs.
- LHRH agonist includes, but is not limited to, leuprolide acetate (Lupron®) (US 5,480,656; US 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (US 7,118,552; 7,220,247; 7,500,964 hereby incorporated by reference).
- LHRH antagonists include, but are not limited to, degarelix or abarelix.
- Antiandrogens include, but are not limited to, bicalutaniide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, abiraterone, or any combination thereof.
- Anti-PD-1 drugs include, but are not limited to, AMP-224, nivolumab, pembrolizumab, pidihzumab, and AMP-554.
- Anti-PD-Ll drugs include, but are not limited to, BMS-936559, atezolizumab, durvalumab, avelumab, and MPDL3280A.
- Anti-CTLA-4 drugs include, but are not limited to, ipilimumab and tremelimumab.
- Treatment of prostate cancer, advanced prostate cancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningful improvement in prostate cancer related symptoms, function and/or survival.
- Clinically meaningful improvement can be determined by an increase in radiographic progression free survival (rPFS) if cancer is metastatic, or an increase metastasis-free survival (MFS) if cancer is non-metastatic, among others,
- the disclosure encompasses methods of lowering serum prostate specific antigen (PSA) levels in a male subject suffering from prostate cancer, advanced prostate cancer, metastatic prostate cancer or castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount, of a SARD compound, wherein the compound is represented by the structure of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, AT, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the disclosure encompasses a method of secondary hormonal therapy that reduces serum PSA in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, that reduces serum PSA in a male subject suffering from castration resistant prostate cancer.
- CRPC castration resistant prostate cancer
- the disclosure encompasses a method of reducing levels of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), and/or amplications of the AR gene within the tumor in the subject in need thereof comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, I V, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, to reduce the level of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-spiice variant (AR- SV), and/or amplications of the AR gene within the tumor.
- the method may increase radiographic progression free survival (rPFS) or metastasis-free survival (MFS).
- rPFS radiographic progression free survival
- MFS metastasis-free survival
- Subjects may have non-metastatic cancer; failed androgen deprivation therapy (ADT), undergone orchidectomy, or have high or increasing prostate specific antigen (PSA) levels; subjects may be a patient with prostate cancer, advanced prostate cancer, refractory prostate cancer, CRPC patient, metastatic castration resistant prostate cancer (mCRPC) patient, or non-metastatic castration resistant prostate cancer (nmCRPC) patient.
- the refractory may be enzalutamide resistant prostate cancer.
- the nmCRPC may be high-risk nmCRPC.
- the subject may be on androgen deprivation therapy (ADT) with or without castrate levels of total T.
- a subject suffering from castration resistant prostate cancer refers to a subject with at least one of the following characteristics: has been previously treated with androgen deprivation therapy (ADT); has responded to the ADT and currently has a serum PSA > 2 ng/mL or >2 ng/rnL and representing a 25% increase above the nadir achieved on the ADT; a subject which despite being maintained on androgen deprivation therapy is diagnosed to have serum PSA progression, a castrate level of serum total testosterone ( ⁇ 50 ng/dL) or a castrate level of serum total testosterone ( ⁇ 20 ng/dL).
- the subject may have rising serum PSA on two successive assessments at least 2 weeks apart; been effectively treated with ADT; or has a history of serum PSA response after initiation of ADT.
- serum PSA progression refers to a 25% or greater increase in serum PSA and an absolute increase of 2 ng/ml or more from the nadir; or to serum PSA >2 ng/mL, or >2 ng/mL and a 25% increase above the nadir after the initiation of androgen deprivation therapy (ADT).
- ADT androgen deprivation therapy
- nadir refers to the lowest PSA level while a patient is undergoing ADT.
- serum PSA response refers to at least one of the following: at least 90% reduction in serum PSA value prior to the initiation of ADT; to ⁇ 10 ng/mL undetectable level of serum PSA ( ⁇ 0.2 ng/mL) at any time; at least 50% decline from baseline in serum PSA; at least 90% decline from baseline in serum PSA; at least 30% decline from baseline in serum PSA; or at least 10% decline from baseline in serum PSA.
- the methods comprise administering a combination of forms of ADT and a compound of this disclosure.
- forms of ADT include a LHRH agonist.
- LHRH agonist includes, but is not limited to, leuprolide acetate (Lupron®)(US 5,480,656; US 5,575,987; 5,631 ,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (US 7,1 18,552; 7,220,247; 7,500,964 hereby incorporated by reference).
- Lupron® leuprolide acetate
- Zoladex® goserelin acetate
- Forms of ADT include, but are not limited to LHRH antagonists, reversible antiandrogens, or bilateral orchidectomy.
- LHRH antagonists include, but are not limited to, degarelix and abarelix.
- Antiandrogens include, but are not limited to, bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, ARN-509, ODM-201, nilutamide, chlormadinone, abiraterone, or any combination thereof.
- the methods of the disclosure encompass administering at least one compound of the disclosure and a lyase inhibitor (e.g., abiraterone).
- a lyase inhibitor e.g., abiraterone
- the term “advanced prostate cancer” refers to metastatic cancer having originated in the prostate, and having widely metastasized to beyond the prostate such as the surrounding tissues to include the seminal vesicles the pelvic lymph nodes or bone, or to other parts of the body. Prostate cancer pathologies are graded with a Gleason grading from 1 to 5 in order of increasing malignancy. Patients with significant risk of progressive disease and/or death from prostate cancer should be included in the definition and any patient with cancer outside the prostate capsule with disease stages as low as IIB clearly has “advanced” disease. “Advanced prostate cancer” can refer to locally advanced prostate cancer. Similarly, “advanced breast cancer” refers to metastatic cancer having originated in the breast, and having widely metastasized to beyond the breast to surrounding tissues or other parts of the body such as the liver, brain, lungs, or bone.
- refractory may refer to cancers that do not respond to treatment.
- prostate or breast cancer may be resistant at the beginning of treatment or it may become resistant during treatment.
- Refractory cancer may also be referred to herein as “resistant cancer”.
- CRPC growth hormone refractory cancer
- hormone naive, androgen independent or chemical or surgical castration resistant may be the result of AR activation by intracrine androgen synthesis: expression of AR splice variants ( AR- SV) that lack ligand binding domain (LBD); or expression of AR-LBD mutations with potential to resist antagonists.
- AR- SV AR splice variants
- LBD ligand binding domain
- Castration resistant prostate cancer is an advanced prostate cancer which developed despite ongoing ADT and/or surgical castration.
- Castration resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the health of the patient despite prior surgical castration, continued treatment with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitimb (Iressa®), cabozantimb (CometriqTM, also known as XI/184)) or other prostate cancer therapies (e.g, vaccines (sipuleucel- T (Provenge
- Castration resistant prostate cancer may be defined as hormone naive prostate cancer.
- the tumor cells may have the ability to grow' in the absence of androgens (hormones that promote the development and maintenance of male sex characteristics).
- ADT may include orchiectomy; administering luteinizing hormone-releasing hormone (LHRH) analogs; administering luteinizing hormone-releasing hormone (LHRH) antagonists; administering 5a.-reductase inhibitors; administering antiandrogens, administering inhibitors of testosterone biosynthesis, administering estrogens; or administering l7a-hydroxylase/C17,20 lyase (CYP17A1) inhibitors.
- LHRH drugs lower the amount of testosterone made by the testicles.
- LHRH analogs available in the United States include leuprolide (Lupron®, Viadur®, Eligard®), goserehn (Zoladex®), triptorelm (Trelstar®), and histrelin (Vantas®).
- Antiandrogens block the body's ability to use any androgens.
- antiandrogens drugs include enzalutamide (Xtandi®), flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®).
- Luteinizing hormone- releasing hormone (LHRH) antagonists include abarelix (Plenaxis®) or degarelix (Firmagon®) (approved for use by the FD A in 2008 to treat advanced prostate cancer).
- 5a-Reductase inhibitors block the body’s ability to convert testosterone to the more active androgen, 5a- dihydrotestosterone (DHT) and include drugs such as finasteride (Proscar®) and dutasteride (Avodart®).
- Inhibitors of testosterone biosynthesis include drugs such as ketoconazole (Nizoral®).
- Estrogens include diethylstilbestrol or 17P-estradiol.
- 17a-Hydroxylase/C17,20 lyase (CYP17A1) inhibitors include abiraterone (Zytiga®).
- the disclosure encompasses a method of treating antiandrogen-resi stant prostate cancer.
- the antiandrogen may include, but is not limited to, bicalutamide, hydroxyflutamide, flutamide, enzalutamide or abiraterone.
- TNBC Triple Negative Breast Cancer
- TNBC Triple negative breast cancer
- ER estrogen receptor
- PR progesterone receptor
- HER2 receptor kinase a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase.
- ER estrogen receptor
- PR progesterone receptor
- HER2 receptor kinase a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase.
- HER2 receptor kinase lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers.
- chemotherapy is often the initial pharmacotherapy for TNBC.
- AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy.
- ER-positive breast cancer AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors.
- AR in the absence of ER,
- TNBC TNBC
- SARDs of this disclosure which are capable of destroying AR-SVs through a binding site in the NTD of AR would be able to antagonize AR in these TNBC’s and provide an anti-tumor effect.
- Muscle atrophy is characterized by wasting away or diminution of muscle and a decrease in muscle mass.
- post-polio MA is muscle wasting that occurs as part of the post-polio syndrome (PPS).
- PPS post-polio syndrome
- the atrophy includes weakness, muscle fatigue, and pain.
- Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA - also known as Kennedy’s Disease), This disease arises from a defect in the androgen receptor gene on the X chromosome, affects only males, and its onset is in late adolescence to adulthood. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases.
- the mutation results in an extended polyglutamine tract at the N-terminal domain of the androgen receptor (polyQ AR).
- Peripheral polyQ AR anti-sense therapy rescues disease in mouse models of SBMA (Cell Reports 7 , 774-784, May 8, 2014). Further support of use antiandrogen comes in a report in which the antiandrogen flutamide protects male mice from androgen-dependent toxicity' in three models of spinal bulbar muscular atrophy (Renier KJ, Troxell-Smith SM, Johansen JA, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim H, Lieberman AP, Breedlove SM, Jordan CL.
- the disclosure encompasses methods of treating Kennedy’s disease comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI. MA, or MB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the term “androgen receptor associated conditions” or “androgen sensitive diseases or disorders” or “androgen-dependent diseases or disorders” are conditions, diseases, or disorders that are modulated by or whose pathogenesis is dependent upon the activity of the androgen receptor.
- the androgen receptor is expressed in most tissues of the body however it is overexpressed in, inter alia, the prostate and skin.
- ADT has been the mainstay of prostate cancer treatment for many years, and SARDs may also be useful in treating various prostate cancers, benign prostatic hypertrophy, prostamegaly, and other maladies of the prostate.
- the disclosure encompasses methods of treating benign prostatic hypertrophy comprising administering a therapeutically effective amount of at least, one compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, MA, or MB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the disclosure encompasses methods of treating prostamegaly comprising administering a therapeutically effective amount of at least one compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
- the disclosure encompasses methods of treating hyperproliferative prostatic disorders and diseases comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the effect of the AR on the skin is apparent in the gender dimorphism and puberty related dermatological problems common to teens and early adults.
- the hyperandrogenism of puberty stimulates terminal hair growth, sebum production, and predisposes male teens to acne, acne vulgaris, seborrhea, excess sebum, hidradenitis suppurativa, hirsutism, hypertrichosis, hyperpilosity, androgenic alopecia, male pattern baldness, and other dermatological maladies.
- antiandrogens theoretically should prevent the hyperandrogenic dermatological diseases discussed, they are limited by toxicities, sexual side effects, and lack of efficacy when topically applied.
- the SARDs of this disclosure potently inhibit ligand-dependent and ligand-independent AR activation, and (in some cases) have short biological half-lives in the serum, suggesting that topically formulated SARDs of this disclosure could be applied to the areas affected by acne, seborrheic dermatitis, and/or hirsutism without risk of systemic side effects.
- the disclosure encompasses methods of treating acne, acne vulgaris, seborrhea, seborrheic dermatitis, hidradenitis supporativa, hirsutism, hypertrichosis, hyperpilosity, or alopecia comprising administering a therapeutically effective amount of a compound of formulas I, TA, IB, II, II A, IIB, III, IIIA, IIIB, IV, IV.A, IVB, ⁇ r , V A, VB, VI, VIA, or VI B, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- the compounds and/or compositions described herein may be used for treating hair loss, alopecia, androgenic alopecia, alopecia areata, alopecia secondary to chemotherapy, alopecia secondary to radiation therapy, alopecia induced by scarring or alopecia induced by stress.
- hair loss or “alopecia” refers to baldness as in the very common type of male-pattern baldness. Baldness typically begins with patch hair loss on the scalp and sometimes progresses to complete baldness and even loss of body hair. Hair loss affects both males and females.
- the disclosure encompasses methods of treating androgenic alopecia comprising administering a therapeutically effective amount of a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- SARDs of this disclosure may also be useful in the treatment of hormonal conditions in females which can have hyperandrogenic pathogenesis such as precocious puberty, early puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, and/or vaginal dryness.
- pathogenesis such as precocious puberty, early puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ova
- the disclosure encompasses methods of treating precocious puberty or early puberty, dysmenorrhea or amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, hyper-androgenic diseases (such as polycystic ovary syndrome (PCOS)), fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary’ syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, or vaginal dryness comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- PCOS polycys
- SARDs of this disclosure may also find utility in treatment of sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization, androgen insensitivity syndromes (AIS) (such as complete AIS (CAIS) and partial AIS (PAIS)), and improving ovulation in an animal.
- AIS AIS
- CAIS complete AIS
- PAIS partial AIS
- the disclosure encompasses methods of treating sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization androgen, insensitivity syndromes, increasing or modulating or improving ovulation comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, TUB, IV, IVA, IVB, V, VA, VB, VI, VI A, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- SARDs of this disclosure may also be useful for treating hormone-dependent cancers such as prostate cancer, breast cancer, testicular cancer, ovarian cancer, hepatocellular carcinoma, urogenital cancer, etc.
- the breast cancer is triple negative breast cancer.
- local or systemic SARD administration may be useful for treatment of precursors of hormone-dependent cancers such as prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP).
- PIN prostatic intraepithelial neoplasia
- ASAP atypical small acinar proliferation
- the disclosure encompasses methods of treating breast cancer, testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, precursors of prostate cancer, or AR related or AR expressing solid tumors, comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- a precursor of prostate cancers may be prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP).
- the tumor may be hepatocellular carcinoma (HCC) or bladder cancer.
- Serum testosterone may be positively linked to the development of HCC.
- ADT enzalutamide, bicalutamide and flutamide and androgen deprivation therapies
- antiandrogens have been successfully tested in breast cancer (enzalutamide; Breast Cancer Res (2014) 16(1): R7), non- small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J Gastroenterology 20(29): 9229), cancer of the ovary, fallopian tubes, or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT was tested in AR-expressing recurrent metastatic salivary gland cancers and was confirmed to have benefit on progression free survival and overall survival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876); Int J Endocrinol (2015), Article ID 384860 ), pancreatic cancer, lymphoma (including mantle cell), and hepatocellular carcinoma.
- a more potent antiandrogen such as a SARD in these cancers may treat the progression of these and other cancers.
- Other cancers may also benefit from SARD treatment such as testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, breast cancer, brain cancer, skin cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, perianal adenoma, or central nervous system cancer.
- SARD treatment such as testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, breast cancer, brain cancer, skin cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, perianal adenoma, or central nervous system cancer.
- NSCLC non-small cell lung cancer
- SARDs of this disclosure may also be useful for treating other cancers containing AR such as breast, brain, skin, ovarian, bladder, lymphoma, liver, kidney, pancreas, endometrium, lung (e.g, NSCLC), colon, perianal adenoma, osteosarcoma, CNS, melanoma, hypercalcemia of malignancy and metastatic bone disease, etc.
- AR e.g, breast, brain, skin, ovarian, bladder, lymphoma, liver, kidney, pancreas, endometrium, lung (e.g, NSCLC), colon, perianal adenoma, osteosarcoma, CNS, melanoma, hypercalcemia of malignancy and metastatic bone disease, etc.
- the disclosure encompasses methods of treating hypercalcemia of malignancy, metastatic bone disease, brain cancer, skin cancer, bladder cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, central nervous system cancer, gastric cancer, colon cancer, melanoma, amyotrophic lateral sclerosis (ALS), and/or uterine fibroids comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD.
- the lung cancer may be non-small cell lung cancer (NSCLC).
- NSCLC non-small cell lung cancer
- SARDs of this disclosure may also be useful for the treating of non-hormone-dependent cancers.
- Non-hormone-dependent cancers include liver, salivary’ duct, etc.
- the SARDs of this disclosure are used for treating gastric cancer. In another embodiment, the SARDs of this disclosure are used for treating salivary duct carcinoma. In another embodiment, the SARDs of this disclosure are used for treating bladder cancer. In another embodiment, the SARDs of this disclosure are used for treating esophageal cancer. In another embodiment, the SARDs of this disclosure are used for treating pancreatic cancer. In another embodiment, the SARDs of this disclosure are used for treating colon cancer. In another embodiment, the SARDs of this disclosure are used for treating non-small cell lung cancer. In another embodiment, the S ARDs of this disclosure are used for treating renal cell carcinoma.
- AR plays a role in cancer initiation in hepatocellular carcinoma (HCC). Therefore, targeting AR may be an appropriate treatment for patients with early stage HCC. In late- stage HCC disease, there is evidence that metastasis is suppressed by androgens.
- the SARDs of this disclosure are used for treating hepatocellular carcinoma (HCC).
- Locati et al. in Head & Neck, 2016, 724-731 demonstrated the use of androgen deprivation therapy (ADT) in AR-expressing recurrent/metastatic salivary gland cancers and confirmed improved progression free survival and overall survival endpoints with ADT.
- ADT androgen deprivation therapy
- the SARDs of this disclosure are used for treating salivary gland cancer.
- AAA Abdominal Aortic Aneurysm
- An abdominal aortic aneurysm is an enlarged area in the lower part of the aorta, the major blood vessel that supplies blood to the body.
- the aorta about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the aorta is the body's main supplier of blood, a ruptured abdominal aortic aneurysm can cause life- threatening bleeding.
- treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery’ can be planned if it's necessary.
- Wounds and/or ulcers are normally found protruding from the skin or on a mucosal surface or as a result of an Infarction in an organ.
- a wound may be a result of a soft tissue defect or a lesion or of an underlying condition.
- wound denotes a bodily injury with disruption of the normal integrity of tissue structures, sore, lesion, necrosis, and/or ulcer.
- ser refers to any lesion of the skin or mucous membranes and the term “ulcer” refers to a local defect, or excavation, of the surface of an organ or tissue, which is produced by the sloughing of necrotic tissue.
- “Lesion” generally includes any tissue defect.
- “Necrosis” refers to dead tissue resulting from infection, injury, inflammation, or infarctions. All of these are encompassed by the term “wound,” which denotes any wound at any particular stage in the healing process including the stage before any healing has initiated or even before a specific wound like a surgical incision is made (prophylactic treatment).
- wounds which can be treated in accordance with the present disclosure are aseptic wounds, contused wounds, incised wounds, lacerated wounds, non- penetrating wounds (?. ⁇ ?. wounds in which there is no disruption of the skin but there is injury to underlying structures), open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, subcutaneous wounds, etc.
- sores include, but are not limited to, bed sores, canker sores, chrome sores, cold sores, pressure sores, etc.
- ulcers include, but are not limited to, peptic ulcer, duodenal ulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer, submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, veneral ulcer, e.g., caused by gonorrhoea (including urethritis, endocervicitis and proctitis).
- peptic ulcer duodenal ulcer
- gastric ulcer gouty ulcer
- diabetic ulcer hypertensive ischemic ulcer
- stasis ulcer ulcus cruris
- sublingual ulcer sublingual ulcer
- submucous ulcer symptomatic ulcer
- trophic ulcer tropical ulcer
- veneral ulcer e.g., caused by gonorrhoea (including urethritis, endocervicitis and proctitis).
- Conditions related to wounds or sores which may be successfully treated according to the disclosure include, but are not limited to, burns, anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae, folliculitis, impetigo contagiosa, impetigo bullosa, etc. It is understood, that there may be an overlap between the use of the terms “wound” and “ulcer,” or “wound” and “sore” and, furthermore, the terms are often used at random.
- the kinds of wounds to be treated according to the disclosure include also: i) general wounds such as, e.g., surgical, traumatic, infectious, ischemic, thermal, chemical and bullous wounds, li) wounds specific for the oral cavity such as, e.g., post-extraction wounds, endodontic wounds especially in connection with treatment of cysts and abscesses, ulcers and lesions of bacterial, viral or autoimmunological origin, mechanical, chemical, thermal, infectious and lichenoid wounds; herpes ulcers, stomatitis aphthosa, acute necrotising ulcerative gingivitis and burning mouth syndrome are specific examples; and iii) wounds on the skin such as, e.g., neoplasm, burns (e.g.
- tissue loss Another way of classifying wounds is by tissue loss, where: i) small tissue loss (due to surgical incisions, minor abrasions, and minor bites) or ii) significant tissue loss.
- tissue loss due to surgical incisions, minor abrasions, and minor bites
- tissue loss ii) significant tissue loss.
- the later group includes ischemic ulcers, pressure sores, fistulae, lacerations, severe bites, thermal burns and donor site wounds (in soft and hard tissues) and infarctions.
- Other wounds include ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns, or donor site wounds.
- Ischemic ulcers and pressure sores are wounds, which normally only heal very slowly and especially in such cases an improved and more rapid healing is of great importance to the patient. Furthermore, the costs involved in the treatment of patients suffering from such wounds are markedly reduced when the healing is improved and takes place more rapidly.
- Donor site wounds are wounds which e.g., occur in connection with removal of hard tissue from one part of the body to another part of the body e.g., in connection with transplantation.
- the wounds resulting from such operations are very painful and an improved healing is therefore most valuable.
- the wound to be treated is selected from the group consisting of aseptic wounds, infarctions, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, and subcutaneous wounds.
- the disclosure encompasses methods of treating a subject suffering from a wound comprising administering to the subject a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, TITA, IIIB, IV, IVA, IVB, V, VA, VB, AT, ATA, or ATB, or any of compounds CPD, 9, CPD. 44, CPD. 45, or CPD. 13, pharmaceutically acceptable salt thereof, or a pharmaceutical compostion thereof.
- the disclosure encompasses methods of treating a subject suffering from a burn comprising administering to the subject a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, AT, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- skin is used in a very broad sense embracing the epidermal layer of the skin and in those cases where the skin surface is more or less injured also the dermal layer of the skin. Apart from the stratum corneum, the epidermal layer of the skin is the outer (epithelial) layer and the deeper connective tissue layer of the skin is called the dermis.
- the skin Since the skin is the most exposed part of the body, it is particularly susceptible to various kinds of injuries such as, e.g., ruptures, cuts, abrasions, burns and frostbites or inj uries arising from various diseases. Furthermore, much skin is often destroyed in accidents. However, due to the important barrier and physiologic function of the skin, the integrity of the skin is important to the well-being of the individual, and any breach or rupture represents a threat that must be met by the body in order to protect its continued existence.
- injuries on the skin may also be present in all kinds of tissues (i.e., soft and hard tissues). Injuries on soft tissues including mucosal membranes and/or skin are especially relevant in connection with the present disclosure.
- Regeneration may be defined as a biological process whereby the architecture and function of lost tissue are completely renewed.
- Repair is a biological process whereby continuity of disrupted tissue is restored by new tissues which do not replicate the structure and function of the lost ones.
- the body provides mechanisms for healing inj ured skm or mucosa in order to restore the integrity of the skin barrier or the mucosa.
- the repair process for even minor ruptures or wounds may take a period of time extending from hours and days to weeks.
- the healing can be very slow and the wound may persist for an extended period of time, i.e., months or even years.
- Burns are associated with reduced testosterone levels, and hypogonadism is associated with delayed wound healing.
- the disclosure encompasses methods for treating a subject suffering from a wound or a burn by administering at least one SARD compound according to this disclosure.
- the SARD may promote resolving of the burn or wound, participates in the healing process of a burn or a wound, or, treats a secondary complication of a burn or wound.
- the treatment of burns or wounds may further use at least one growth factor such as epidermal growth factor (EGF), transforming growth factor-a (TGF-a), platelet derived growth factor (PDGF), fibroblast growth factors (FGFs) including acidic fibroblast growth factor (a-FGF) and basic fibroblast growth factor (P-FGF), transforming growth factor-P (TGF-3) and insulin like growth factors (IGF-1 and IGF-2), or any combination thereof, which promote wound healing.
- EGF epidermal growth factor
- TGF-a transforming growth factor-a
- PDGF platelet derived growth factor
- FGFs fibroblast growth factors
- a-FGF acidic fibroblast growth factor
- P-FGF basic fibroblast growth factor
- TGF-3 transforming growth factor-P
- IGF-1 and IGF-2 insulin like growth factors
- a SARD as described herein may be administered orally or topically at a dosage of about 0.1-10 mg per day.
- Therapeutic effectiveness is measured as effectiveness in enhancing wound healing as compared to the absence of the SARD compound.
- Enhanced wound healing may be measured by known techniques such as decrease in healing time, increase in collagen density', increase in hydroxyproline, reduction in complications, increase in tensile strength, and increased cellulanty of scar tissue.
- reducing the pathogenesis is to be understood to encompass reducing tissue damage, or organ damage associated with a particular disease, disorder or condition.
- the term may include reducing the incidence or severity of an associated disease, disorder or condition, with that in question or reducing the number of associated diseases, disorders or conditions with the indicated, or symptoms associated thereto.
- compositions means either the compound or pharmaceutically acceptable salt of the active ingredient with a pharmaceutically acceptable carrier or diluent.
- a “therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.
- administering refers to bringing a subject in contact with a compound of the present disclosure.
- administration can be accomplished in vitro, i.e., in a test tube, or in vivo, i.e., in cells or tissues of living organisms, for example humans.
- the subjects may be a male or female subject or both.
- the mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.
- compositions of the disclosure can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, mtraventricularly, intracranially, intra vaginal ly, by inhalation, rectally, or intratum orally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces.
- compositions may be administered topically to body surfaces, and are thus formulated in a form suitable for topical administration.
- Suitable topical formulations include gels, ointments, creams, lotions, drops and the like.
- the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
- Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for sy stemic delivery of active ingredients.
- formulations suitable for oral or topical administration are preferred.
- the compounds of formulasl, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 may be administered topically.
- topical administration refers to application of the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 (and optional carrier) directly to the skin and/or hair.
- the topical composition can be in the form of solutions, lotions, salves, creams, ointments, liposomes, sprays, gels, foams, roller sticks, and any other formulation routinely used in dermatology.
- Topical administration is used for incidations found on the skin, such as hirsutism, alopecia, acne, and excess sebum.
- the dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable carrier in an amount of from about 0.01 to 50 w/w %, and more typically from about 0.1 to 10 w/w %.
- the dermatological preparation will be applied to the affected area from 1 to 4 times daily.
- Dermatologically acceptable refers to a carrier which may be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically “site of action”, it refers to a site where inhibition of androgen receptor or degradation of the androgen receptor is desired.
- the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, maybe used topically to relieve alopecia, especially androgenic alopecia. Androgens have a profound effect on both hair growth and hair loss. In most body sites, such as the beard and pubic skin, androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing follicle size.
- Hair growth on the scalp does not require androgens but, paradoxically, androgens are necessary' for the balding on the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decline in the duration of anagen and in hair follicle size. Androgenic alopecia is also common in women where it usually presents as a diffuse hair loss rather than showing the paterning seen in men.
- the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can be applied topically to the scalp and hair to prevent, or treat balding. Further, the compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD 45, or CPD. 13 can be applied topically in order to induce or promote the growth or regrowth of hair on the scalp.
- the disclosure also encompasses topically administering a compound of formula I, I A. IB, II, II A, I IB, III, I II A, I IIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to treat or prevent the growth of hair in areas where such hair growth in not desired.
- a compound of formula I, I A. IB, II, II A, I IB, III, I II A, I IIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to treat or prevent the growth of hair in areas where such hair growth in not desired.
- One such use will be to alleviate hirsutism.
- Hirsutism is excessive hair growth in areas that typically do not have hair (e.g., a female face
- the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 may also be used topically to decrease sebum production.
- Sebum is composed of triglycerides, wax esters, fatty acids, sterol esters and squalene. Sebum is produced in the acinar cells of the sebaceous glands and accumulates as these cells age. At maturation, the acinar cells lyse, releasing sebum into the luminal duct so that it may be deposited on the surface of the skin.
- the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, 111 B, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can be used to treat a variety of dermal diseases such as acne or seborrheic dermatitis.
- the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, TUB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can also be used to achieve a cosmetic effect. Some consumers believe that they are afflicted with overactive sebaceous glands. They feel that their skin is oily and thus unattractive.
- indiviuals may use the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, XT, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to decrease the amount of sebum on their skin. Decreasing the secretion of sebum will alleviate oily skin in mdvi duals afflicted with such conditions.
- compositions comprising at least one of the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
- Such dermatological compositions will contain from 0.001% to 10% w/w% of the cornpound(s) in admixture with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 w/w % of the compounds.
- Such compositions will typically be applied from 1 to 4 times daily.
- the reader’s attention is directed to Remington’s Pharmaceutical Science, Edition 17, Mark Publishing Co., Easton, PA for a discussion of how to prepare such formulations.
- compositions of the disclosure may also include solid preparations such as cleansing soaps or bars. These compositions are prepared according to methods known in the art.
- Formulations such as aqueous, alcoholic, or aqueous-alcoholic solutions, or creams, gels, emulsions or mousses, or aerosol compositions with a propellant may be used to treat indications that arise where hair is present.
- the composition can also be a hair care composition.
- hair care compositions include, but are not limited to, shampoo, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition, or a lotion or gel for preventing hair loss.
- the amounts of the various constituents in the dermatological compositions are those conventionally used in the fields considered.
- Medicinal and cosmetics containing the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 will typically be packaged for retail distribution (i.e., an article of manufacture). Such articles will be labeled and packaged in a manner to instruct the patient how to use the product. Such instructions will include the condition to be treated, duration of treatment, dosing schedule, etc,
- Antiandrogens such as finasteride or flutamide
- SARD selective androgen receptor degrader
- Such SARD compound would exhibit potent but local inhibition of AR activity, local degradation of AR activity, would not penetrate to the systemic circulation of the subject, or would be rapidly metabolized upon entry into the blood, limiting systemic exposure.
- the active ingredient may be mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- the carrier or diluent may be a solid carrier or diluent for solid formuations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
- Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g, corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcry stalline cellulose), an acrylate (e.g, polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
- a gum e.g, corn starch, pregeletanized starch
- a sugar e.g., lactose, mannitol, sucrose, dextrose
- a cellulosic material e.g., microcry stalline cellulose
- an acrylate e.g, polymethylacrylate
- any of the usual pharmaceutical media may be employed.
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like.
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
- the active agent in a “vectorized” form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
- Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient.
- a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
- a tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent.
- Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
- a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
- a sugar for example sucrose
- Such accessory ingredients may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
- Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution).
- Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
- the formulations may be presented in unit-dose or multi-dose form.
- Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, mtra -abdominal (e.g, intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired admini strati on modal ity .
- Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, mtra -abdominal (e.g, intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired admini strati on modal ity .
- Nasal and other mucosal spray formulations can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
- Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
- Transdennal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
- a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
- formulations of this disclosure may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
- formulations may be of immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
- the physician wall determine the actual dosage and duration of treatment.
- the physician will determine the actual dosage and duration of treatment, which wiil be most suitable for an individual and can vary with the age, weight, genetics and/or response of the particular individual.
- the methods of the disclosure comprise administration of a compound at a therapeutically effective amount.
- the theraperutically effective amount may include various dosages.
- a compound of this disclosure is administered at a dosage of 1-3000 mg per day.
- a compound of this disclosure is administered at a dose of 1 -10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 15-60 mg per day, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day.
- a compound of this disclosure is administered at a dosage of 25 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 40 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 50 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 67.5 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 75 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 80 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 100 mg per day.
- a compound of this disclosure is administered at a dosage of 125 mg per day.
- a compound of this disclosure is administered at a dosage of 250 mg per day.
- a compound of this disclosure is administered at a dosage of 300 mg per day.
- a compound of this disclosure is administered at a dosage of 500 mg per day.
- a compound of this disclosure is administered at a dosage of 600 mg per day.
- a compound of this disclosure is administered at a dosage of 1000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 1500 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 2000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 2500 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 3000 mg per day. [0227] The methods may comprise administering a compound at various dosages.
- the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.
- the compound may be administered at a dosage of 0.1 mg/kg/day.
- the compound may administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.
- the pharmaceutical composition may be a solid dosage form, a solution, or a transdermal patch.
- Solid dosage forms include, but are not limited to, tablets and capsules.
- the reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (19: 1 to 9: 1) as eluent to afford 30mg (11.7%) of the titled compound as off-white oil.
- Log P is the log of the octanol-water partition coefficient, commonly used early in drug discovery efforts as a rough estimate of whether a particular molecule is likely to cross biological membranes.
- Log P was calculated using ChemDraw Ultra version is 12.0.2.1016 (Perkin-Elmer, Waltham, Massachusetts 02-451). Calculated Log P values are reported in Table 1 in the column labeled ‘Log P (-0.-4 to +5.6)’, Lipinski’s rule of five is a set of criteria intended to predict oral bioavailability.
- One of these criteria for oral bioavailability is that the Log P is between the values shown in the column heading (“0.4 (relatively hydrophilic) to +5.6 (relatively lipophilic) range), or more generally stated ⁇ 5.
- the compounds tested exhibit acceptable water solubility.
- HEK-293 cells were transfected with the indicated receptors and GRE-LUC and CMV-renilla luc. Cells were treated 24 hours after transfection and luciferase assay performed 48 hours after transfection. The SARD compounds did not inhibit transactivation of receptors other than AR until 10 pM. The experimental method is described below,
- HEK-293 cells were plated at 120,000 cells per well of a 24 well plate in DME + 5% csFBS. The cells were transfected using Lipofectamine (Invitrogen, Carlsbad, CA) with 0.25 pg GRE-LUC, 0.01 pg CMV-LUC (renilla luciferase) and 25 ng of the AR The cells were treated 24 h after transfection and the luciferase assay performed 48 h after transfection. Transactivation results were based on measured luciferase light emissions and reported as relative light unit intensity' (RLU).
- RLU relative light unit intensity'
- ICso antagonist mode
- Har-LBD (633-919) was cloned into pGex4t.1. Large scale GST- tagged AR-LBD was prepared and purified using a GST column. Recombinant AR-LBD was combined with [ 3 H]mibolerone (PerkmElmer, Waltham, MA) in buffer A (10 Mm Tris, Ph 7.4, 1.5 Mm disodium EDTA, 0.25 sucrose, 10 Mm sodium molybdate, 1 Mm PMSF) to determine the equilibrium dissociation constant (Ka) of [’H]mibolerone.
- buffer A (10 Mm Tris, Ph 7.4, 1.5 Mm disodium EDTA, 0.25 sucrose, 10 Mm sodium molybdate, 1 Mm PMSF
- Protein was incubated with increasing concentrations of [ 3 H]mibolerone with and without a high concentration of unlabeled mibolerone at 4°C for 18 h in order to determine total and non-specific binding. Non-specific binding was then subtracted from total binding to determine specific binding and non-linear regression for the ligand binding curve with one site saturation was used to determine the Kd of mibolerone.
- LNCaP or ADI androgen receptor degradation (fill! length AR): The compounds were tested for their effect on full length AR protein expression.
- LNCaP or ADI cells expressing full length AR were plated at 750,000-1 ,000,000 cells/well of a 6 well plate in growth medium (RPMI + 10% FBS). Twenty four hours after plating, the medium was changed to RPMI + 1% csFBS without phenol red and maintained in this medium for 2 days. The medium again was changed to RPMI + 1% csFBS without phenol red and cells were treated with SARDs (1 Nm to 10 Mm) in combination with 0.1 Nm R1881. After 24 h of treatment, cells were washed with cold PBS and harvested. Protein was extracted using salt-containing lysis buffer with three freeze-thaw cycles.
- the protein concentration was estimated and five microgram of total protein was loaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane.
- the membrane was probed with AR N-20 antibody (SantaCruz Biotechnology, Inc., Dallas, Texas 75220) and actin antibody (Sigma-Aldrich, St. Louis, MO).
- AR The effect of SARD treatment on the AR levels was measured in androgen-refractory 22RV- 1 or D567es prostate cancer cells.
- test compound was incubated with liver microsomes and disappearance of drug was determined using discovery grade LC-MS/MS.
- discovery grade LC-MS/MS To simulate Phase II metabolic pathway (glucuronidation), UDPGA and alamethicin were included in the assay. From %PCR (% Parent Compound Remaining), rate of compound disappearance is determined (slope of concentration vs. time plot) and in vitro CLint (pl/min/mg protein) was calculated.
- results are reported in Table 1 in the column labeled “DMPK (MLM) T1/2 (min) & CLint (uL/min/mg)”.
- the first value is the calculated half-life (T1/2) of the test article in MLM expressed in minutes and the 2 nd value is the intrinsic CL (CLint) of the test article in MLM expressed as Ml/mm/mg protein.
- Mobile phase was consisting of channel A (95% acetonitrile + 5% water + 0,1 % formic acid) and channel C (95% water + 5% acetonitrile + 0.1% formic acid) and was delivered at a flow rate of 0.4 Ml/min.
- the volume ratio of acetonitrile and water was optimized for each of the analytes.
- Multiple reaction monitoring scans were made with curtain gas, collision gas, nebulizer gas, and auxiliary gas optimized for each compound, and source temperature at 55O°C.
- Molecular ions were formed using an ion spray voltage of -4200 V (negative mode). Declustering potential, entrance potential, collision energy, product ion mass, and cell exit potential were optimized for each compound.
- the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like;
- the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps;
- the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ ‘preferred,’ ‘desi
- a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise.
- a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.
Abstract
This disclosure is directed to selective androgen receptor degrader (SARD) compounds, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, spinal (and) bulbar muscular atrophy (SBMA), amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.
Description
SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) O-LINKED LIGANDS
AND METHODS OF USE THEREOF
GOVERNMENT INTEREST STATEMENT
[0001] This invention was made with government support under R01 CA229164, awarded by the National Cancer Institute. The government has certain rights in the invention.
FIELD OF THE DISCLOSURE
[0002] This disclosure is directed to selective androgen receptor degrader (SARD) compounds, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogemc dermal diseases, spinal (and) bulbar muscular atrophy (SBMA), amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.
BACKGROUND OF THE DISCLOSURE
[0003] Prostate cancer (PCa) is one of the most frequently diagnosed noncutaneous cancers among men in the US and is the second most common cause of cancer deaths with more than 200,000 new cases and over 30,000 deaths each year in the United States. PCa therapeutics market is growing at an annual rate of 15-20% globally.
[0004] Androgen-deprivation therapy (ADT) is the standard of treatment for advanced PCa. Patients with advanced prostate cancer undergo ADT, either by luteinizing hormone releasing hormone (LHRH) agonists, LHRH antagonists or by bilateral orchiectomy. Despite initial response to ADT, disease progression is inevitable and the cancer emerges as castration-resistant prostate cancer (CRPC). Up to 30% of patients with prostate cancer that undergo primary treatment by radiation or surgery will develop metastatic disease within 10 years of the primary treatment. Approximately’ 50,000 patients a year will develop metastatic disease, which is termed metastatic CRPC (mCRPC).
[0005] Patients with CRPC have a median survival of 12-18 months. Though castration-resistant, CRPC is still dependent on the androgen receptor (AR) signaling axis for continued growth. The primary reason for CRPC re-emergence is re-activation of AR by alternate mechanisms such as: 1) intracrine androgen synthesis, 2) AR splice variants (AR.-SV), e.g., that lack ligand binding domain (LBD), 3) AR-LBD mutations with potential to resist AR antagonists (z.e., mutants that are not sensitive to inhibition by AR antagonists, and in some cases AR antagonists act as agonists of the AR bearing these LBD mutations), and 4) amplications of the AR gene within the tumor.
[0006] A critical barrier to progress in treating CRPC is that AR signaling inhibitors such as enzalutamide, bicalutamide, and abiraterone, acting through the LBD, fail to inhibit growth driven by the N-terminal domain (NTD)-dependent constitutively active AR-SV. Recent high- impact clinical trials with enzalutamide and abiraterone in CRPC? patients demonstrated that 0% of AR-V7 (the predominant AR-SV) expressing patients responded to either of the treatments, indicating the requirement for next generation AR antagonists that target AR-SVs. In addition, a significant number of CRPC patients are becoming refractory to abiraterone or enzalutamide, emphasizing the need for next generation AR antagonists.
[0007] Current evidences demonstrate that CRPC? growth is dependent on constitutively active AR including AR-SV’ s that lack the LBD such as AR-V7 and therefore cannot be inhibited by conventional antagonists. AR inhibition and degradation through binding to a domain that is distinct from the AR LBD provides alternate strategies to manage CRPC.
[0008] Molecules that degrade the AR prevent any inadvertent AR activation through growth factors or signaling pathways, or promiscuous ligand-dependent activation. In addition, molecules that inhibit the constitutive activation of AR-SVs are extremely important to provide extended benefit to CRPC patients.
[0009] Currently only a few chemotypes are known to degrade AR which include the SARDs ARN-509, AZD-3514, and ASC-J9. However, these molecules degrade AR indirectly at much higher concentrations than their binding coefficient and they fail to degrade the AR-SVs that have become in recent years the primary reason for resurgence of treatment-resistant CRPC.
SUMMARY OF THE DISCLOSURE
[0010] One embodiment encompasses a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:
wherein
T is I L OH. OR, ()( OR OCH2C(=CH2)C(=O)OCH3, ( Hr \HCO( Hr or M R 'OR;
Ri is H, CI-I3, CI-bF, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Z is NO2, CN, COOH. COR, M K'OR. or CONHR;
X is CH or N;
Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
F, Cl, Br, I, or OH; and
A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q1, Q2, Q3, or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, maieimide, NHCOOR, N(R)z, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0011] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IA:
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCHy or NHCOR;
R : is H, ('l l :. CH2F, CHF2, ('!• :. CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Z is NO2, CN, COOH, COR, NHCOR or COM IR;
X is CH or N;
RisH, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH -Cl. CH2CH2CI, aryl,
F, Cl, Br, I, or OH, and
A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q1, Q2, Q3, or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, malemnde, NHCOOR, N(R)2, NHCOR, COM IR. COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0012] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IB:
wherein
T is H, OH, OR, OCOR, OCHjCi—CHzICi—OIOCH?, CH3, NHCOCH3, or NHCOR;
Ri is II, CI -fe, CII2F, CI- IF?, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring,
Y is H, CF3, F, I, Br, Cl, CN, or C(R ) 3;
Z is NO2, CN, COOH, COR, NUCOR, or CONHR;
X is CH orN;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
F, Cl, Br, I, or OH; and
A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q1, Q2, Q3, or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, aiylalkyl, NCS, maleimide, NHCOOR, N(R)?„ NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0013] The disclosure encompasses a SARD compound represented by the structure of formula II:
wherein
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR;
Ri is H, CI <3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri formr a 3-8 carbocyclic or heterocyclic ring;
Y is II, CF3, F, I, Br, Cl, CN, or C(R h ;
Z is NO?„ CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CFFCHiCl, aryl,
F, Cl, Br, I, or OH; and
A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, Qy or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aiyd, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N( R) 2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0014] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IIA:
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR;
Ri is H, CH3, CHZF, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
F, Cl, Br, I, or OH; and
A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, Q3, or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleirnide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0015] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IIB:
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR;
Ri is II, CH3, CH2F , CHF2, CF3, CH2CH3, or CF2CF3; or T and R1 form a 3-8 carbocyclic or heterocyclic ring,
Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3;
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH orN;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
F, Cl, Br, I, or OH; and
A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, Q3, or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, C1, Br, I, CN, NO2., hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, N ICOOR . N(R)2., NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0016] The disclosure encompasses a SARD compound represented by the structure of formula III:
wherein
T is H, OH, OR, OCOR, OCH-O ( C H 2( = 0)0( 1 C. CH3, NHCOCH3, or NI K OR.
Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri formr a 3-8 carbocyclic or heterocyclic ring;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, O'. or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0017] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula III A:
wherein
T is H, OH, OR. OCOR, OCH2C(-CH2)C(-O)OCH3, CH3, NHCOCH3, or NHCOR;
Ri is H, Cl b. CU T. CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is 11, CF3, F. I, Br, Cl, CN, or C( R ) 3;
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
F, Cl, Br, I, or OH; and
A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, Q i or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0018] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IIIB:
wherein
T is H, OH, OR, OCOR, OCHjCi—CHzlCt—OlOCH?, CH3, NHCOCH3, or NHCOR;
Ri is H, CHy CH2F, CHF2, CFy CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring,
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH orN;
Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,
F, Cl, Br, I, or OH; and
A is a pyrrole, pyrroline, pyrrolidine, pyrazoie, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, QJ, or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof,
[0019] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IV:
wherein
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)i;
Ri is H, CI-I3, CH2F, CHF2, CFs, CH.-CH 3, or CF2CF3;
T is H, OH, OR. OCOR, OCI l-C( CH -)('( OjOCI h. Cl b. NFICOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is FI, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CFs, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q’, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Ci, Br, I, CN, NOz, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0020] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVA:
wherein
Z is NO2, CN, COOi L COR, NHCOR, or CONHR;
X is CH or N;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
T is H, OH, OR. ()( OR. OCH.'Ci CH'lCi O)OCH CH 3, NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CFs, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hy drate or any combination thereof.
[0021] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVB:
IVB wherein
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Y is H, ('!• :. F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
T is H, OH, OR. O( OR. OCH2C(=CH2)C(=O)OCH3, CH.. NHCOCH 3 , or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0022] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula V:
V wherein
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Y is H, ('!• :. F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
T is H, OH, OR. O( OR . OCH2C(=CH2)C(=O)OCH3, CH.. NHCOCH 3 , or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR: or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0023] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VA:
wherein
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
R : is H, Ci h. Ci Nd CHF.'. CF3, CH Ci I3, or CF.'CN.
T is i i. OH, OR, OCOR, OCi i <( Ci i ’.)('( =O)OCH 3, CH3, NHCOCHs, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
O', Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)?., NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0024] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VB:
wherein
Z is NOz, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Y is I L CL\ IL I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH2F, CHF2, CF3> CH2CH3, or CF2CF3;
T is H, OH, OR. (X OR . OCH2C(=CH2)C(=O)OCH3, OI L.. NT ICOCH 3 , or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0025] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VI:
wherein
Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
¥ is H, C F3, F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH?F, CHF?, CF3, CH?CH3, or CF?CF3;
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH?C1, aryl, F, Cl, Br, I, or OH; and
Q2, Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0026] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VIA:
wherein
Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
¥ is H, CH. F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH?F, CHF?, CF3, CH?CH3, or CF?CF3;
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH?C1, aryl, F, Cl, Br, I, or OH; and
Q2, Q3, or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0027] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VIB:
wherein
Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
¥ is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH?F, CHF?, CF3, CH?CH3, or CF?CF3;
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH?, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH?C1, aryl, F, Cl, Br, I, or OH; and
Q2, Q\ or Q': are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleinride, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0028] Yet another embodiment encompasses the SARD compound represented by the structure of any one of the following compounds:
CPD. 13
[0029] One embodiment encompasses the SARD compound having at least one of the following properties: binds to the AR through an alternate binding and degradation domain (BDD), e.g, in the NTD, binds to the AR through the AR ligand binding domain (LBD); exhibits AR- splice variant (AR-SV) degradation activity; exhibits AR-full length (AR-FL) degradation activity including pathogenic mutations thereof, exhibits AR-SV inhibitory activity (z.e., is an AR-SV antagonist); exhibits AR-FL inhibitory activity (i.e., is an AR-FL antagonist) including pathogenic mutations thereof, possesses dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions.
[0030] Another embodiment encompasses pharmaceutical compositions comprising a SARD compound according to this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated for topical use. The topical pharmaceutical composition may be a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soaps or bars, emulsion, mousse, aerosol, or shampoo.
[0031] The disclosure encompasses a method of treating prostate cancer (PCa) or increasing survival in a male subject in need of treatment comprising administering to the subject
a therapeutically effective amount of a compound defined by formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPI). 44, CPD. 45, or CPD. 13. The prostate cancer includes, but is not limited to, advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof. Another embodiment encompasses the method further comprising administering androgen deprivation therapy. Alternatively, the method may treat a prostate or other cancer that is resistant to treatment with known androgen receptor antagonist(s) or ADT. In another embodiment, the method may treat enzalutamide resistant prostate cancer. In another embodiment, the method may treat abiraterone resistant prostate cancer. Yet another embodiment encompasses a method of treating prostate or other AR antagonist resistant cancer with a SARD compound of the disclosure wherein the androgen receptor antagonists) is at least one of enzalutamide, bical utamide, abiraterone, ARN-509, ODM-201 , EPI- 001 , AZD-3514, galeterone, ASC-J9, flutamide, hydroxyfl utamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.
[0032] Yet another embodiment encompasses a method of treating prostate or other cancers using a SARD compound of the disclosure wherein the other cancers are selected from breast cancer such as TNBC, testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer. In another embodiment, the breast cancer is triple negative breast cancer (TNBC).
[0033] The disclosure encompasses a method of reducing the levels of AR-sphce variants in a subject comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. The method may comprise further reducing the levels of AR-full length in the subject.
[0034] Another embodiment encompasses a method of treating Spinal (and) Bulbar Muscular Atrophy (SBMA) (also referred to herein as “Kennedy’s disease”) in a subject comprising administering to the subject a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPI). 44, CPD. 45, or CPD. 13 or a compound of another formula of the disclosure.
[0035] Yet another embodiment encompasses a method of: (a) treating acne in a subject; (b) decreasing sebum production in a subject; (c) treating hirsutism in a subject, e.g., female facial hair; (d) treating alopecia in a subject, e.g., androgenic alopecia; (e) treating a hormonal condition in female; (f) treating sexual perversion, hypersexuality', or paraphilias in a subject; (g) treating androgen psychosis in a subject; (h) treating virilization in a subject; (i) treating complete or partial androgen insensitivity7 syndrome in a subject; (j) increasing or modulating ovulation in an animal; (k) treating of cancer in a subject; or any combination thereof, by administering a compound of this disclosure or a pharmaceutical composition thereof.
[0036] One embodiment encompasses methods of reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject comprising administering a compound according to this disclosure. The method may inhibit, degrade, or both the function of the polyglutamine (polyQ) AR polymorphs (polyQ- AR). The polyQ- AR may be a short polyQ polymorph or a long polyQ polymorph. When the polyQ- AR is a short polyQ polymorph, the method further treats dermal disease. When the polyQ- AR is a long polyQ polymorph, the method further treats Kennedy’s disease.
[0037] Another embodiment encompasses methods of treating amyotrophic lateral sclerosis (ALS) in a subject by administering a therapeutically effective amount of the compound of the disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
[0038] Another embodiment encompasses methods of treating abdominal aortic aneurysm (AAA) in a subject by administering a therapeutically effective amount of the compound of the disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
[0039] Yet another embodiment encompasses methods of treating uterine fibroids in a subject by administering a therapeutically effective amount of the compound of this disclosure, or
its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
DETAILED DESCRIPTION
[0040] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present disclosure.
[0041] Androgens act in cells by binding to the AR, a member of the steroid receptor superfamily of transcription factors. As the growth and maintenance of prostate cancer (PCa) is largely controlled by circulating androgens, treatment of PCa heavily relies on therapies that target AR Treatment with AR antagonists such as enzalutamide, bicalutamide or hydroxyfl utamide to disrupt receptor activation has been successfully used in the past to reduce PCa growth. All currently available AR antagonists competitively bind AR and recruit corepressors such as NCoR and SMRT to repress transcription of target genes. However, altered intracellular signaling, AR mutations, and increased expression of coactivators lead to functional impairment of antagonists or even transformation of antagonists into agonists. Studies have demonstrated that mutation of W741 and T877 within AR converts bicalutamide and hydroxyflutamide, respectively , to agonists. Similarly, increased intracellular cytokines recruit coactivators instead of corepressors to AR- responsive promoters subsequently converting bicalutamide to an agonist. Similarly, mutations that have been linked to enzalutamide resistance include F876, H874, T877, and di-mutants T877/S888, T877ZD890, F876/T877 (z.e., MR49 cells), and H874/T877 (Genome Biol. (2006) 17:10 (doi: 10.1186/sl3059-015-0864-l)). Abiraterone resistance mutations include L702H mutations which results in activation of the AR by glucocorticoids such as prednisone, causing resistance to abiraterone because abiraterone is usually prescribed in combination with prednisone. If resistance develops to enzalutamide then often the patient is refractory to abiraterone also and vice versa; or the duration of response is very’ short. This situation highlights the need for a definitive androgen ablation therapy’ to prevent AR reactivation in advanced prostate cancers.
[0042] Despite initial response to androgen deprivation therapy (ADT), PCa disease progression is inevitable and the cancer emerges as castration-resistant prostate cancer (CRPC). The primary reason for castration resistant prostate cancer (CRPC) re-emergence is re-activation of androgen receptor (AR) by alternate mechanisms such as:
(a) intracrine androgen synthesis;
(b) expression of AR splice variants (AR-SV), e.g, that lack ligand binding domain (LBD);
(c) AR-L.BD mutations with potential to resist antagonists;
(d) hyper-sensitization of AR to low androgen levels, e.g., due to AR gene amplification or AR mutation;
(e) amplication of the AR gene within the tumor; and
(f) over expression of coactivators.
[0043] This disclosure describes novel AR antagonists with unique pharmacology that strongly (high potency and efficacy) and selectively bind AR (better than known antagonists in some cases; bind to LBD and/or NTD), antagonize AR, and degrade AR full length (AR-FL) and AR-SV. Selective androgen receptor degrader (SARD) compounds possess dual degradation and AR-SV inhibitory functions and hence are distinct from any available CRPC therapeutics. These novel selective androgen receptor degrader (SARD) compounds inhibit the growth of PCa cells and tumors that are dependent on AR-FL and AR-SV for proliferation.
[0044] SARDs have the potential to evolve as new therapeutics to treat CRPCs that are unbeatable with any other antagonists. This unique property of degrading AR-SV has extremely important health consequences for prostate cancer. Till date only one synthetic molecule (EPI-001) and some marine natural products such as the sinkotamides and glycerol ether Naphetenone B, are reported to bind to AR-NTD and inhibit AR function and PCa cell growth, albeit at lower affinity and inability to degrade the receptor. The SARDs reported herein also bind to AR-NTD and inhibit NTD-driven (e.g., ligand independent) AR activity.
[0045] The positive correlation between AR and PCa and the lack of a fail-safe AR antagonist, emphasizes the need for molecules that inhibit AR function through novel or alternate mechanisms and/or binding sites, and that can elicit antagonistic activities within an altered cellular environment.
[0046] Although traditional antiandrogens such as enzalutamide, bicalutamide and flutamide and androgen deprivation therapies (ADT) were approved for use in prostate cancer, there is significant evidence that antiandrogens could also be used in a variety of other hormone dependent and hormone independent cancers. For example, antiandrogens have been tested in breast cancer (enzalutamide; Breast Cancer Res. (2014) 16(1): R7), non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity syndrome (PAIS) associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J. Gastroenterology 20(29):9229), cancer of the ovary', fallopian tubes, or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT was tested in AR-expressing recurrent metastatic salivary gland cancers and was confirmed to have benefit on progression free survival and overall survival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876); Int J. Endocrinol (2015), Article ID 384860), pancreatic cancer, lymphoma (including mantle cell), and hepatocellular carcinoma. Use of a more potent antiandrogen such as a SARD in these cancers may more efficaciously treat the progression of these and other cancers. Other cancers may also benefi t from SARD treatment such as breast cancer (e.g., triple negative breast cancer (TNBC)), testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer. Triple negative breast cancer (TNBC) is a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase. As such, TNBC lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers. Correspondingly, chemotherapy is often the initial pharmacotherapy for TNBC. Interestingly, AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy. In ER-positive breast cancer, AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors. However, in the absence of ER, it is possible that AR actually' supports the growth of breast cancer tumors. Though the role of AR is not fully understood in TNBC, we have evidence that certain
TNBC’s may be supported by androgen independent activation of AR-SVs lacking the LBD or androgen-dependent activation of AR full length. As such, enzalutamide and other LBD-directed traditional AR antagonists would not be able to antagonize AR-SVs in these TNBC’s. However, SARDs which are capable of destroying AR-SVs through a binding site in the NTD of AR would be able to antagonize AR in these TNBC’s and provide an anti-tumor effect.
[0047] Traditional antiandrogens such as bicalutamide and flutamide were approved for use in prostate cancer. Subsequent studies have demonstrated the utility of antiandrogens (e.g., flutamide, spironolactone, cyproterone acetate, finasteride and chlormadmone acetate) in androgen-dependent dermatological conditions such as androgenic alopecia (male pattern baldness), acne vulgaris, and hirsutism (e.g, in female facial hair). Prepubertal castration prevents sebum production and androgenic alopecia but this can be reversed by use of testosterone, suggesting its androgen-dependence.
[0048] The AR gene has a polymorphism of glutamine repeats (polyQ) within exon 1 which when shortened may augment AR transactivation (/.<?., hyperandrogenism). It has been found that shortened polyQ polymorphisms are more common in people with alopecia, hirsutism, and acne. Classic antiandrogens are undesirable for these purposes because they are ineffective through dermal dosing and their long-term systemic use raises the risks of untoward sexual effects such as gynecomastia and impotence. Further, similar to CPRC discussed above, inhibition of ligand- dependent AR activity alone may not be sufficient as AR can be activated by various cellular factors other than the endogeneous androgens testosterone (T) and dihydrotestosterone (DHT), such as growth factors, kinases, co-activator overexpression and/or promiscuous activation by other hormones (e.g., estrogens or glucocorticoids). Consequently, blocking the binding of T and DHT to AR with a classical antiandrogen may not be sufficient to have the desired efficacy.
[0049] An emerging concept is the topical application of a SARD to destroy the AR locally to the affected areas of the skin or other tissue without exerting any systemic antiandrogemsm. For this use, a SARD that does not penetrate the skin or is rapidly metabolized would be preferrable.
[0050] Supporting this approach is the observation that cutaneous wound healing has been demonstrated to be suppressed by androgens. Castration of mice accelerates cutaneous wound healing while attenuating the inflammation in the wounds. The negative correlation between
androgen levels and cutaneous healing and inflammation, in part, explains another mechanism by which high levels of endogenous androgens exacerbate hyperandrogenic dermatological conditions. Further, it provides a rationale for the treatment of wounds such as diabetic ulcers or even trauma, or skin disorders with an inflammatory component such as acne or psoriasis, with a topical SARD.
[0051] Androgenic alopecia occurs in -50% of Caucasian males by midlife and up to 90% by 80 years old. Minoxidil (a topical vasodilator) and finasteride (a systemic 5alpha reductase type II inhibitor) are FDA approved for alopecia but require 4-12 months of treatment to produce a therapeutic effect and only arrest hair loss in most with mild to moderate hair regrowth in 30- 60%, Since currently available treatments have slow and limited efficacy that varies widely between individuals, and produce unwanted sexual side effects, it is important to find a novel approach to treat androgenic alopecia and other hyperandrogenic dermatologic diseases.
[0052] Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis (The anabolic/androgenic steroid nandrolone exacerbates gene expression modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis. Galbiati M, Onesto E, Zito A, Crippa V, Rusmmi P, Mariotti R, Bentivoglio M, Bendotti C, Poletti A. Pharmacol. Res. 2012, 65(2), 221-230), but the mechanism through which androgens modify the ALS phenotype is unknown. A transgenic animal model of ALS demonstrated improved survival upon surgical castration (i.e., androgen ablation). Treatment of these castrated animals with the androgen agonist nandrolone decanoate worsened disease manifestations. Castration reduces the AR level, which may be the reason for extended survival. The survival benefit is reversed by androgen agonist (Androgens affect muscle, motor neuron, and survival in a mouse model of SOD 1 -related amyotrophic lateral sclerosis. Aggarwal T, Polanco MJ, Scaramuzzino C, Rocchi A, Milioto C, Emionite L, Ognio E, Sambataro F, Galbiati M, Poleti A, Pennuto M. Neurobiol. Aging. 2014 35(8), 1929-1938). Notably, stimulation with nandrolone decanoate promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, these results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of
androgen receptor homeostasis. Antiandrogens should block the effects of nandrolone undecanoate or endogeneous androgens and reverse the toxicides due to AR aggegregation. Further, an antiandrogen that can block both action of LBD-dependent AR agonists and lower AR protein levels, such as the SARDs of this disclosure, would be therapeutic in ALS. Riluzole is an available drug for ALS treatment, however, it only provides short-term effects. There is an urgent need for drugs that extend the survival of ALS patients.
[0053] Androgen receptor action promotes uterine proliferation. Hyperandrogenicity of the short polyQ AR has been associated with increased leiomyoma or uterine fibroids. (Hsieh YY, Chang CC, Tsai FJ, Lin CC, Yeh LS, Peng CT. J. Assist. Reprod. Genet. 2004, 21 (12), 453-457). A separate study of Brazilian women found that shorter and longer [CAG](n) repeat alleles of AR were exclusive to the leiomyoma group in their study (Rosa FE, Canevari Rde A, Ambrosio EP, Ramos Cirilo PD, Pontes A, Rainho CA, Rogato SR. Clin. Chem. Lab. Med. 200S, 46(6), 814- 823). Similarly, in Asian Indian women long polyQ AR was associated with endometriosis and leiomyoma and can be regarded as high-risk markers. SARDs could be used in women with uterine fibroids, especially those expressing shorter and longer [CAG](n) repeat alleles, to treat existing uterine fibroids, prevent worsening of fibroids and/or ameliorate carcinogenicity associated with fibroids.
[0054] An abdominal aortic aneurysm (AAA) is an enlarged area m the lower part of the aorta, the major blood vessel that supplies blood to the body. The aorta, about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the aorta is the body’s mam supplier of blood, a ruptured abdominal aortic aneurysm can cause life- threatening bleeding. Depending on the size and the rate at which your abdominal aortic aneurysm is growing, treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery can be planned if it's necessary. Emergency surgery for a ruptured abdominal aortic aneury sm can be risky. AR blockade (pharmacologic or genetic) reduces AAA. Davis et al. (Davis JP, Salmon Al, Pope NH, Lu G, Su G, Meher A, Ailawadi G, Upchurch GR Jr. J Vase Sure (2016) 63(6): 1602-1612) showed that flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated porcine pancreatic elastase (0.35 U/mL) induced AAA by 84.2% and 91.5% compared to vehicle (121%). Further AR -/- mice showed attenuated AAA growth (64.4%) compared to wildtype (both treated with elastase).
Correspondingly, administration of a SARD to a patient suffering from an AAA may help reverse, treat or delay progression of AAA to the point where surgery is needed.
[0055] X-linked spinal-bulbar muscular atrophy (SBMA-also known as Kennedy’s disease) is a muscular atrophy that arises from a defect in the androgen receptor gene on the X chromosome. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases. The mutation results in a protracted polyglutamine tract added to the N-terminal domain of the androgen receptor (polyQ AR). Binding and activation of this lengthened polyQ AR by endogeneous androgens (testosterone and DHT) results in unfolding and nuclear translocation of the mutant androgen receptor. The androgen-induced toxicity and androgen-dependent nuclear accumulation of polyQ AR protein seems to be central to the pathogenesis. Therefore, the inhibition of the androgen-activated polyQ AR might be a therapeutic option (A. Baniahmad. Inhibition of the androgen receptor by antiandrogens in spmobulbar muscle atrophy. J. Mol. Neurosci. 2016 58(3), 343-347). These steps are required for pathogenesis and result in partial loss of transactivation function (i.e., an androgen insensitivity) and a poorly understood neuromuscular degeneration. Support of use antiandrogen comes in a report in which the antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy (Renier KJ, Troxell-Smith SM, Johansen J A, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim II, Lieberman AP, Breedlove SM, Jordan CL. Endocrinology 2014, 155(7), 2624-2634). Currently there are no disease-modifying treatments but rather only symptom directed treatments. Efforts to target the polyQ AR of Kennedy’s disease as the proximal mediator of toxicity by harnessing cellular machinery to promote its degradation, i.e., through the use of a SARD, hold promise for therapeutic intervention. Selective androgen receptor degraders such as those reported herein bind to and degrade all androgen receptors tested (full length, splice variant, antiandrogen resistance mutants, etc.) so degradation of polyQ AR polymorphism is also expected, indicating that they are promising leads for treatment of SBMA.
[0056] Here we describe pyrrole, pyrazole, triazole, imidazole, and morpholine based selective androgen receptor degrader (SARD) compounds that may bind to the LBD and/or an alternate binding and degradation domain (BDD) located in the NTD, antagonize AR, and degrade AR thereby blocking ligand-dependent and ligand-independent AR activities. This novel
mechanism produces improved efficacy when dosed systemically
for prostate cancer) or topically (<?.g, dermatological diseases).
[0057] The disclosure encompasses novel selective androgen receptor degrader (SARD) compounds encompassed by Formula I, which inhibit the growth of prostate cancer (PCa) cells and tumors that are dependent on AR full length (AR-FL) including pathogenic and resistance mutations and wildtype, and/or AR splice variants (AR-SV) for proliferation.
[0058] As used herein, unless otherwise defined, a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of inhibiting the growth of PCa cells and tumors that are dependent on AR-full length (AR-FL) and/or AR splice variants (AR-SV) for proliferation. The SARD compound may not bind to ligand binding domain (LBD). Alternatively, a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of causing degradation of a variety of pathogenic mutant variant AR’s and wildtype AR and hence are capable of exerting anti-androgenism is a wide variety of pathogenic altered cellular environments found in the disease states embodied in this disclosure. In one embodiment, the SARD is orally active. In another embodiment, the SARD is applied topically to the site of action.
[0059] The SARD compound may bind to the N-terminal domain (NTD) of the AR; to an alternate binding and degradation domain (BDD) of the AR, to both the AR ligand binding domain (LBD) and to an alternate binding and degradation domain (BDD); or to both the N- terminal domain (NTD) and to the ligand binding domain (LBD) of the AR. In one embodiment, the BDD may be located in the NTD. In one embodiment, the BDD is located in the AF-1 region of the NTD. Alternatively, the SARD compound may be capable of: inhibiting growth driven by the N-tenninal domain (NTD)-dependent constitutively active AR-SV; or inhibiting the AR through binding to a domain that is distinct from the AR LBD. Also, the SARD compound may be a strong (i.e., highly potent and highly efficacious) selective androgen receptor antagonist, which antagonizes the AR stronger than other known AR antagonists (e.g., enzalutamide, bicalutamide and abiraterone).
[0060] The SARD compound may be a selective androgen receptor antagonist, which targets AR-SVs, which cannot be inhibited by conventional antagonists. The SARD compound may exhibit one of several activities including, but not limited to: AR-SV degradation activity'; AR-
FL degradation activity; AR-SV inhibitory’ activity (i.e., is an AR-SV antagonist); AR-FL inhibitory activity' (i.e., is an AR-FL antagonist); inhibition of the constitutive activation of AR- SVs; or inhibition of the constitutive activation of AR-FLs. Alternatively, the SARD compound may possess dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions; or alternatively possess all four of these activities.
[0061] The SARD compound may also degrade AR-FL and AR-SV. The SARD compound may degrade the AR through binding to a domain that is distinct from the AR LBD. The SARD compound may possess dual degradation and AR-SV inhibitory functions that are distinct from any available CRPC therapeutics. The SARD compound may inhibit the re-activation of the AR by alternate mechanisms such as: intracrine androgen synthesis, expression of AR-SV that lack ligand binding domain (LBD) and AR-LBD mutations with potential to resist antagonists, or inhibit re-activated androgen receptors present in pathogenic altered cellular environments.
[0062] Examples of AR-splice variants include, but are not limited to, AR-V7 and ARv567es (a.k.a. AR-V12; S. Sun, etal. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. (2010) 120(8), 2715- 2730). Nonlimiting examples of AR mutations conferring antiandrogen resistance are: W741L, T877A, and F876L (J. D. Joseph et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. (2013) 3(9), 1020-1029) mutations. Many other LBD resistance conferring mutations are known in the art and will continue to be discovered. AR-V7 is a splice variant of AR that lacks the LBD (A. H. Bryce & E. S. Antonarakis. Androgen receptor splice variant 7 in castration-resistant prostate cancer: Clinical considerations. Int J Urol. (2016 Jun 3). doi: 10.1111/iju.13134. [Epub ahead of print]). It is constitutively active and has been demonstrated to be responsible for aggressive PCa and resistance to endocrine therapy .
[0063] The disclosure encompasses novel selective androgen receptor degrader (SARD) compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any’ of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 which bind to the AR through an alternate binding and degradation domain (BDD). The SARDs may’ further bind the AR ligand binding domain (LBD).
[0064] The SARD compounds may be used in treating CRPC that cannot be treated with any other antagonist. The SARD compounds may treat CRPC by degrading AR-SVs. The SARD compounds may maintain their antagonistic activity in AR mutants that normally convert AR antagonists to agonists. For instance, the SARD compounds maintain their antagonistic activity to AR mutants W741L, T877A, and F876L (J. D. Joseph el al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN- 509. Cancer Discov. (2013) 3(9): 1020-1029). Alternatively, the SARD compounds elicit antagonistic activity within an altered cellular environment in which LBD-targeted agents are not effective or in which NTD-dependent AR activity is constitutively active.
[0065] In one embodiment, A of formula I, IA, IB, II, IIA, TIB, III, TITA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom. In another embodiment, A is a substituted or unsubstituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, morpholine, or other heterocyclic ring. In another embodiment, A is a five or six-membered heterocyclic ring.
[0066] In a particular embodiment of formulas I, I A, IB, II, ILA, IIB, III, III A, IIIB, IV,
IVA, IVB, V, VA, VB, VI, ATA, or VIB, Q1 is hydrogen. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, ATA, or VIB, Q1 is CN. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q! is F. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is NCS. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is maleimide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA,
IVB, V, VA, VB, VI, VIA, or VIB, Ql is NHCOOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, Q1 is N(R)?„ In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q{ is CONHR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Qj is NHCOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Qf is Cl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB,
V, VA, VB, VI, VIA, or VIB, Q{ is Br. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q{ is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Ql is NO?.. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, I VB,
V, VA, VB, VI, VIA, or VIB, Q1 is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI. VIA, or VIB, Q'1 is 4-fluorophenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB,
VI, VIA, or MB, Q1 is CF?. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV7, IVA, IVB, V7, VA, VB, V7!, VIA, or VIB, Q! is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, Q1 is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, Q1 is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is substituted or unsubstituted aryl. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is alkoxy. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q! is OR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q! is arylalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q] is amine. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is amide. In a particular embodiment of formulas I --- VI, IA, IB, IIA, and IIB, Qf is COOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q1 is COR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Qf is keto.
[0067] In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, I V, I VA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is CN. In a particular embodiment of formulas I, IA,
IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is hydrogen. In a particular embodiment of fomiuias I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is keto. In a particular embodiment of fomiuias I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is NCS. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is maleimide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is NHCOOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB. V, VA, VB. V. VIA, or VIB, Q 2 is N(R)2. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is CONHR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2, is NHCOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is F. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is Cl. In a particular embodiment of formulas I, LA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is Br. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB,Q2 is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IILA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is NO2. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is 4-fluorophenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is CFs. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is substituted or unsubstituted aryl. In
a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB,
III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is alkoxy. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is OR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB,
V, VA, VB, VI, VIA, or VIB, Q2 is arylalkyl. In a particular embodiment of formulas I, IA, IB, II,
IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB, Q2 is amine. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is amide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB,
IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB, Q2 is COOR. In a particular embodiment of formulas
I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is COR.
[0068] In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV,
IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q' is CN. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is F. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is NCS. In a particular embodiment of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB,
IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is maleimide. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is NHCOOR. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA,
IVB, V, VA, VB, VI, VIA, or VIB, Q3 is N(R)?.. In a particular embodiment of formulas I, LA, IB,
II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is CONFER.. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB,
VI, VIA, or VIB, Q\ is NHCOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is hydrogen. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is keto. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB,
V, VA, VB, VI, VIA, or VIB, Q3 is Cl. In a particular embodiment of formulas I, IA, IB, II, IIA,
IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is Br. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,
VA, VB, VI, VIA, or VIB, Q3 is NCh. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q 3 is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q' is 4-fluorophenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q' is CF3. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB,Q3 is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB,Q3 is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, O' is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. Q- is substituted or unsubstituted aryl. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VLA,
VB, VI, VIA, or VIB, Q3 is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB,
III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is alkoxy. In a particular embodiment of formulas I, LA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is OR. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is arylalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is amine. In a particular embodiment of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q" is amide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB,
IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is COOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is COR.
[0069] In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, I VA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is CN. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is F. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is NCS. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is maleimide. In a particular embodiment of
formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIE, Q4 is NHCOOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is N(R)2. In a particular embodiment of formulas I, IA, IB,
II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is CONHR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4, is NHCOR. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is hydrogen. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is keto. In a particular embodiment of formulas I, IA, IB, II, II A, IIB, III, IIIA, IIIB, IV, IVA, IVB,
V, VA, VB, V7!, VIA, or VIB, Q4 is Cl. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB, V7, VA, VB, VI, VIA, or VIB, Q4 is Br. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VI A, or VIB, Q4 is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, TUB, IV, IVA, IVB, V,
VA, VB, VI, VIA, or VIB, Q4 is NO2. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is 4-fluorophenyl. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV7 A, IVB, V, VA, VB, VI, VIA, or VIB, Q4is CF3. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB,
III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB,
VI, VIA, or VIB, Q4 is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV7, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is substituted or unsubstituted aryl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, I VA, IVB, V, V A,
VB, VI, VIA, or VIB, Q4 is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V7, VA, VB, VI, VIA, or VIB, Q4 is alkoxy. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4
is OR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is arylalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is amine. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, I VB, V, VA, VB, VI, VIA, or VIB, Q7 is amide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB, Q4 is COOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is COR.
[0070] In a particular embodiment of formula IV7, IVA, IVB, V7, VA, VB, VI, VIA, or VIB, Q1 is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CHs)3.
[0071] In a particular embodiment of formula IV7, IVA, IVB, V7, VA, VB, VI, VIA, or In a particular embodiment of formulalV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q2 is H, CN, CFi, phenyl, 4-fluorophenyl, F, Br, or NHCOOCfCFhh.
[0072] In a particular embodiment of formula IV, IV7 A, IVB, V, VA, VB, VI, VIA, or VIB, Q3 is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CH3)3.
[0073] In a particular embodiment of formula IV, IV7 A, IVB, V, VA, VB, VI, VIA, or VIB, Q4 is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CH3)3.
[0074] In a particular embodiment of formula IV, IV7 A, IVB, V, VA, VB, VI, VIA, or VIB, X is CH.
[0075] As used herein, the term “heterocycle” or “heterocyclic ring” group refers to a ring structure comprising in addition to carbon atoms, at least one atom of sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. The heterocycle may be a 3-12 membered ring; 4- 8 membered ring; a 5-7 membered ring; or a 6 membered ring. Preferably, the heterocycle is a 5 to 6 membered ring. Typical examples of heterocycles include, but are not limited to, piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazole, pyrazine, piperazine or pyrimidine. Examples of Cs-Cs heterocyclic rings include pyran, dihydropyran, tetrahydropyran, dihydropyrrole, tetrahydropyrrole, pyrazine, dihydropyrazine, tetrahydropyrazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidone, pyrazole, dihydropyrazole, tetrahydropyrazole, triazole, tetrazole, piperidine, piperazine, pyridine, dihydropyridine, tetrahydropyridine, morpholine, thiomorpholine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, thiazole, imidazole, isoxazole, and the like. The heterocycle ring may be fused
to another saturated or unsaturated cycloalkyl or a saturated or unsaturated heterocyclic ring. When the heterocycle ring is substituted, the substituents include at least one of halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylaniido, dialkylamido, cyano, nitro, CO2H, amino, alkylaniino, dialkylamino, carboxyl, thiol, or thioalkyl.
[0076] The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms. A cycloalkyl group can have one or more carbon-carbon double bonds in the ring so long as the ring is not rendered aromatic by their presence. Examples of cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C3-C7) cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes. Examples of Cb-Cs carbocyclic include cyclopentane, cyclopentene, cyclohexane, and cyclohexene rings. A cycloalkyl group can be unsubstituted or substituted by at least one substituent. Preferably, the cycloalkyl group is a monocyclic ring or bicyclic ring.
[0077] The term “alkyl” refers to a saturated aliphatic hydrocarbon, including straight- chained and branched-chained. Typically, the alkyl group has 1-12 carbons, 1 -7 carbons, 1-6 carbons, or 1-4 carbon atoms. A branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. The branched alkyl may have an alkyl substituted by a C1-C5 haloalkyl. Additionally, the alkyl group may be substituted by at least one of halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, ammo, alkylaniino, dialkydamino, carboxyl, thio or thioalkyl.
[0078] An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined herein. An example of an ary lalkyl group is a benzyl group.
[0079] An “alkenyl” group refers to an unsaturated hydrocarbon, including straight chain and branched chain having one or more double bonds. The alkenyl group may have 2-12 carbons, preferably the alkenyl group has 2-6 carbons or 2-4 carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, cyclohexenyl, etc. The alkenyl group may be substituted by at least one halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio, or thioalkyl.
[0080] As used herein ther term “aryl” group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted. When present, substituents include, but are not limited to, at least one halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio or thioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridmyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. The aryl group may be a 4-12 membered ring, preferably the aryl group is a 4-8 membered ring. Also the aryl group may be a 6 or 5 membered ring.
[0081] As used herein, the term “haloalkyl” group refers to an alkyl group that is substituted by one or more halogen atoms, e.g., by F, Cl, Br or I.
[0082] A “hydroxyl” group refers to an OH group. It is understood by a person skilled in the art that when T, Q1, Qz, Q3, or Q4, in the compounds of the present disclosure is OR, then R is not OH.
[0083] The term “halogen” or “halo” refers to a halogen, F, Cl, Br or I.
[0084] In one embodiment, the compounds and/or its use and/or, its derivative, optical isomer, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal or combinations thereof are provided.
[0085] In one embodiment, the methods make use of “pharmaceutically acceptable salts” of the compounds, which may be produced, by reaction of a compound of this disclosure with an acid or base.
[0086] The compounds may be converted into pharmaceutically acceptable salts. A pharmaceutically acceptable salt may be produced by reaction of a compound with an acid or base.
[0087] Suitable pharmaceutically acceptable salts of amines may be prepared from an inorganic acid or from an organic acid. Examples of inorganic salts of amines include, but are not limited to, bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates, or thiocyanates.
[0088] Examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, arahphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, carboxylates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates, gluconates, glutamates, glycolates, glucorates, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamates, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxy benzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, nitrates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates, 7V-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilates, subacetates, tartarates, theophyllineacetates, p- toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates. Examples of inorganic salts of carboxylic acids or phenols may be selected from ammonium, alkali metals, and alkaline earth metals. Alkali metals include, but are not limited to, lithium, sodium, potassium, or cesium. Alkaline earth metals include, but are not limited to, calcium, magnesium, aluminium; zinc, barium, cholines, or quaternary ammoniums. Examples of organic salts of carboxylic acids or phenols may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, r-butylamines, benethamines (A;~benzylphenethylaniine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglammes, JV-methyl-D-glucamines, N,N ’-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolines, piperazines, procaine,
tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.
[0089] Salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.
[0090] The methods of the disclosure may use an uncharged compound or a pharmaceutically acceptable salt of the compound. In particular, the methods use pharmaceutically acceptable salts of compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,
VA, VB, VI, VIA, or VIB. The pharmaceutically acceptable salt may be an amine salt or a salt of a phenol of the compounds of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, ALA,
VB, VI, VIA, or VTB.
[0091] In one embodiment, the methods make use of a free base, free acid, non charged or non-complexed compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,
VA, VB, VI, VIA, or VIB, and/or its isomer, pharmaceutical product, hydrate, polymorph, or combinations thereof.
[0092] In one embodiment, the methods make use of an optical isomer of a compound of formulas I, IA, IB, II, IIA, IIB, 111, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. In one embodiment, the methods make use of an isomer of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. In one embodiment, the methods make use of a pharmaceutical product of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB. In one embodiment, the methods make use of a hydrate of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA,
VB, VI, VIA, or VIB. In one embodiment, the methods make use of a polymorph of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VTB. In one embodiment, the methods make use of a metabolite of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VTB. In another embodiment, the methods make use of a composition comprising a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, as described herein, or, in another
embodiment, a combination of isomer, metabolite, pharmaceutical product, hydrate, polymorph of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
[0093] As used herein, the term “isomer” includes, but is not limited to, optical isomers, structural isomers, or conformational isomers,
[0094] The term “isomer” is meant to encompass optical isomers of the SARD compound. It will be appreciated by those skilled in the art that the SARDs of the present disclosure contain at least one chiral center. Accordingly, the compounds may exist as optically-active (such as an (/?) isomer or (S) isomer) or racemic forms. Optically active compounds may exist as enantiomer! cal ly enriched mixtures. Some compounds may also exhibit polymorphism. It is to be understood that the present disclosure encompasses any racemic, optically active, polymorphic, or stereroisomeric form, or mixtures thereof Thus, the disclosure may encompass SARD compounds as pure (A’)-isomers or as pure (A)-isomers. It is known in the art how to prepare optically active forms. For example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary' phase.
[0095] Compounds may be hydrates of the compounds. As used herein, the term “hydrate” includes, but is not limited to, hemihydrate, monohydrate, dihydrate, or trihydrate. The disclosure also includes use of A'-oxides of the ammo substituents of the compounds described herein.
[0096] This disclosure provides, in other embodiments, use of metabolites of the compounds as herein described. In one embodiment, “metabolite” means any substance produced from another substance by metabolism or a metabolic process.
[0097] In one embodiment, the compounds of this disclosure are prepared according to Example 1.
Biological Activity of Selective Androgen Receptor Degraders
[0098] A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically
effective amount of a compound or its pharmaceutically acceptable salt, represented by a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
[0099] A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, or isomer, represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
[0100] The prostate cancer may be advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (rnCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
[0101] The prostate cancer may depend on AR-FL and/or AR-SV for proliferation. The prostate or other cancer may be resistant to treatment with an androgen receptor antagonist. The prostate or other cancer may be resistant to treatment with enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. The method may also reduce the levels of AR, AR-FL, AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-SV, gene-amplified AR, or any combination thereof.
[0102] In one embodiment, this disclosure provides a method of treating enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0103] In one embodiment, this disclosure provides a method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0104] In one embodiment, this disclosure provides a method of treating triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
[0105] The method may further comprise a second therapy such as androgen deprivation therapy (ADT) or LHRH agonist or antagonist. LHRH agonists include, but are not limited to, leuprolide acetate.
[0106] The disclosure encompasses a method of treating or inhibiting the progression of prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is at least one of compounds of formula I, I A. IB, II, ll A. IIB, III, Hl A. IIIB, IV, IVA, IVB. V, VA, VB. AT, ATA, or ATB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0107] The disclosure encompasses a method of treating or inhibiting the progression of refractory prostate cancer (PCa) or increasing the survival of a male subject suffering from refractory prostate cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, Ill, IIIA, IIIB, IV, IArA, IVB, Ar, AA, VB, AT, VIA, or ATB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0108] The disclosure encompasses a method of treating or increasing the survival of a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering to the subject a therapeutically effective amount of a SARD wherein the compound is represented by a compound of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, ATA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0109] The method may further comprise administering androgen deprivation therapy to the subject.
[0110] The disclosure encompasses a method of treating or inhibiting the progression of enzalutamide resistant prostate cancer (PCa) or increasing the survival of a male subject suffering from enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a SARI) compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0111] The method may further comprise administering androgen deprivation therapy to the subject.
[0112] The disclosure encompasses a method of treating or inhibiting the progression of tripie negative breast cancer (TNBC) or increasing the survival of a female subject suffering from triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, XT, ATA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0113] As used herein, the term “increase the survival” refers to a lengthening of time when describing the survival of a male subject. Thus in this context, the compounds may be used to increase the survival of men with advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC) or high-risk nmCRPC.
[0114] Alternatively, as used herein, the terms “increase”, increasing” and “increased” may be used interchangeably and refer to an entity becoming progressively greater (as in size, amount, number, or intensity), wherein for example the entity is sex hormone-binding globulin (SHBG) or prostate-specific antigen (PSA).
[0115] The compounds and compositions of the disclosure may be used for increasing metastasis-free survival (MFS) in a subject suffering from non-metastatic prostate cancer. The non- metastatic prostate cancer may be non-metastatic advanced prostate cancer, non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.
[0116] The SARD compounds described herein may be used to provide a dual action. For example, the SARD compounds may treat prostate cancer and prevent metastasis. The prostate cancer may be refractory prostate cancer: advanced prostate cancer; castration resistant prostate cancer (CRPC); metastatic CRPC (mCRPC); non-metastatic CRPC (nmCRPC); or high-risk nmCRPC.
[0117] The SARD compounds described herein may be used to provide a dual action. For example, the SARD compounds may treat TNBC and prevent metastasis.
[0118] Men with advanced prostate cancer who are at high risk for progression to castration resistant prostate cancer (CRPC) are men on ADT with serum total testosterone
concentrations greater than 20 ng/dL or men with advanced prostate cancer who at the time of starting ADT had either (1) confirmed Gleason pattern 4 or 5 prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time <3 months, (4) a PSA >20 ng/mL, or (5) a PSA relapse in < 3 years after definitive local therapy (radical prostatectomy or radiation therapy).
[0119] Normal levels of prostate specific antigen (PSA) are dependent on several factors, such as age and the size of a male subject's prostate, among others. PSA levels in the range between 2,5-10 ng/mL are considered “borderline high” while levels above 10 ng/mL are considered “high,” A rate change or “PSA velocity” greater than 0.75/year is considered high. PSA levels may increase despite ongoing ADT or a history of ADT, surgical castration or despite treatment with antiandrogens and/or LHRH agonist.
[0120] Men with high risk non-metastatic castration resistant prostate cancer (high-risk nmCRPC) may include those with rapid PSA doubling times, having an expected progression-free survival of approximately 18 months or less (Miller K, Moul JW, Gleave M, et al. 2013. “Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer,” Prostate Cane Prost Dis. Feb; 16: 187-192). This relatively rapid progression of their disease underscores the importance of novel therapies for these individuals.
[0121] The methods of the disclosure may treat subjects with PSA levels greater than 8 ng/mL where the subject suffers from high-risk nmCRPC. The patient population includes subjects suffering from nmCRPC where PSA doubles in less than 8 months or less than 10 months. The method may also treat patient populations where the total serum testosterone levels are greater than 20 ng/mL in a subject suffering from high-risk nmCRPC. In one case, the serum free testosterone levels are greater than those observed in an orchiechtomized male in a subject suffering from high- risk nmCRPC.
[0122] The pharmaceutical compositions of the disclosure may further comprise at least one LHRH agonist or antagonist, antiandrogen, anti-programmed death receptor 1 (anti-PD-1) drugs or anti-PD-Ll drugs. LHRH agonist includes, but is not limited to, leuprolide acetate (Lupron®) (US 5,480,656; US 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (US 7,118,552; 7,220,247; 7,500,964 hereby incorporated by reference). LHRH antagonists include, but are not limited to,
degarelix or abarelix. Antiandrogens include, but are not limited to, bicalutaniide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, abiraterone, or any combination thereof. Anti-PD-1 drugs include, but are not limited to, AMP-224, nivolumab, pembrolizumab, pidihzumab, and AMP-554. Anti-PD-Ll drugs include, but are not limited to, BMS-936559, atezolizumab, durvalumab, avelumab, and MPDL3280A. Anti-CTLA-4 drugs include, but are not limited to, ipilimumab and tremelimumab.
[0123] Treatment of prostate cancer, advanced prostate cancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningful improvement in prostate cancer related symptoms, function and/or survival. Clinically meaningful improvement can be determined by an increase in radiographic progression free survival (rPFS) if cancer is metastatic, or an increase metastasis-free survival (MFS) if cancer is non-metastatic, among others,
[0124] The disclosure encompasses methods of lowering serum prostate specific antigen (PSA) levels in a male subject suffering from prostate cancer, advanced prostate cancer, metastatic prostate cancer or castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount, of a SARD compound, wherein the compound is represented by the structure of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, AT, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0125] The disclosure encompasses a method of secondary hormonal therapy that reduces serum PSA in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, that reduces serum PSA in a male subject suffering from castration resistant prostate cancer.
[0126] The disclosure encompasses a method of reducing levels of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), and/or amplications of the AR gene within the tumor in the subject in need thereof comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, I V, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, to reduce the level of AR, AR-full length (AR-FL), AR-FL with
antiandrogen resistance-conferring AR-LBD mutations, AR-spiice variant (AR- SV), and/or amplications of the AR gene within the tumor.
[0127] The method may increase radiographic progression free survival (rPFS) or metastasis-free survival (MFS).
[0128] Subjects may have non-metastatic cancer; failed androgen deprivation therapy (ADT), undergone orchidectomy, or have high or increasing prostate specific antigen (PSA) levels; subjects may be a patient with prostate cancer, advanced prostate cancer, refractory prostate cancer, CRPC patient, metastatic castration resistant prostate cancer (mCRPC) patient, or non-metastatic castration resistant prostate cancer (nmCRPC) patient. In these subjects, the refractory may be enzalutamide resistant prostate cancer. In these subjects, the nmCRPC may be high-risk nmCRPC. Further the subject may be on androgen deprivation therapy (ADT) with or without castrate levels of total T.
[0129] As used herein, the phrase “a subject suffering from castration resistant prostate cancer” refers to a subject with at least one of the following characteristics: has been previously treated with androgen deprivation therapy (ADT); has responded to the ADT and currently has a serum PSA > 2 ng/mL or >2 ng/rnL and representing a 25% increase above the nadir achieved on the ADT; a subject which despite being maintained on androgen deprivation therapy is diagnosed to have serum PSA progression, a castrate level of serum total testosterone (<50 ng/dL) or a castrate level of serum total testosterone (<20 ng/dL). The subject may have rising serum PSA on two successive assessments at least 2 weeks apart; been effectively treated with ADT; or has a history of serum PSA response after initiation of ADT.
[0130] As used herein, the term “serum PSA progression” refers to a 25% or greater increase in serum PSA and an absolute increase of 2 ng/ml or more from the nadir; or to serum PSA >2 ng/mL, or >2 ng/mL and a 25% increase above the nadir after the initiation of androgen deprivation therapy (ADT). The term “nadir” refers to the lowest PSA level while a patient is undergoing ADT.
[0131] The term “serum PSA response” refers to at least one of the following: at least 90% reduction in serum PSA value prior to the initiation of ADT; to <10 ng/mL undetectable level of serum PSA (<0.2 ng/mL) at any time; at least 50% decline from baseline in serum PSA; at least
90% decline from baseline in serum PSA; at least 30% decline from baseline in serum PSA; or at least 10% decline from baseline in serum PSA.
[0132] The methods comprise administering a combination of forms of ADT and a compound of this disclosure. Forms of ADT include a LHRH agonist. LHRH agonist includes, but is not limited to, leuprolide acetate (Lupron®)(US 5,480,656; US 5,575,987; 5,631 ,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (US 7,1 18,552; 7,220,247; 7,500,964 hereby incorporated by reference). Forms of ADT include, but are not limited to LHRH antagonists, reversible antiandrogens, or bilateral orchidectomy. LHRH antagonists include, but are not limited to, degarelix and abarelix. Antiandrogens include, but are not limited to, bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, ARN-509, ODM-201, nilutamide, chlormadinone, abiraterone, or any combination thereof.
[0133] The methods of the disclosure encompass administering at least one compound of the disclosure and a lyase inhibitor (e.g., abiraterone).
[0134] The term “advanced prostate cancer” refers to metastatic cancer having originated in the prostate, and having widely metastasized to beyond the prostate such as the surrounding tissues to include the seminal vesicles the pelvic lymph nodes or bone, or to other parts of the body. Prostate cancer pathologies are graded with a Gleason grading from 1 to 5 in order of increasing malignancy. Patients with significant risk of progressive disease and/or death from prostate cancer should be included in the definition and any patient with cancer outside the prostate capsule with disease stages as low as IIB clearly has “advanced” disease. “Advanced prostate cancer” can refer to locally advanced prostate cancer. Similarly, “advanced breast cancer” refers to metastatic cancer having originated in the breast, and having widely metastasized to beyond the breast to surrounding tissues or other parts of the body such as the liver, brain, lungs, or bone.
[0135] The term “refractory” may refer to cancers that do not respond to treatment. E.g. , prostate or breast cancer may be resistant at the beginning of treatment or it may become resistant during treatment. “Refractory cancer” may also be referred to herein as “resistant cancer”.
[0136] The term “castration resistant prostate cancer” (CRPC) refers to advanced prostate cancer that is worsening or progressing while the patient remains on ADT or other therapies to reduce testosterone, or prostate cancer which is considered hormone refractory’, hormone naive, androgen independent or chemical or surgical castration resistant. CRPC may be
the result of AR activation by intracrine androgen synthesis: expression of AR splice variants ( AR- SV) that lack ligand binding domain (LBD); or expression of AR-LBD mutations with potential to resist antagonists. Castration resistant prostate cancer (CRPC) is an advanced prostate cancer which developed despite ongoing ADT and/or surgical castration. Castration resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the health of the patient despite prior surgical castration, continued treatment with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitimb (Iressa®), cabozantimb (Cometriq™, also known as XI/184)) or other prostate cancer therapies (e.g, vaccines (sipuleucel- T (Provenge®), GV AX, etc.), herbal (PC-SPES) and lyase inhibitor (abiraterone)) as evidenced by increasing or higher serum levels of prostate specific antigen (PSA), metastasis, bone metastasis, pain, lymph node involvement, increasing size or serum markers for tumor growth, worsening diagnostic markers of prognosis, or patient condition.
[0137] Castration resistant prostate cancer may be defined as hormone naive prostate cancer. In men with castration resistant prostate cancer, the tumor cells may have the ability to grow' in the absence of androgens (hormones that promote the development and maintenance of male sex characteristics).
[0138] Many early prostate cancers require androgens for growth, but advanced prostate cancers are androgen-independent, or hormone naive.
[0139] The term “androgen deprivation therapy” (ADT) may include orchiectomy; administering luteinizing hormone-releasing hormone (LHRH) analogs; administering luteinizing hormone-releasing hormone (LHRH) antagonists; administering 5a.-reductase inhibitors; administering antiandrogens, administering inhibitors of testosterone biosynthesis, administering estrogens; or administering l7a-hydroxylase/C17,20 lyase (CYP17A1) inhibitors. LHRH drugs lower the amount of testosterone made by the testicles. Examples of LHRH analogs available in the United States include leuprolide (Lupron®, Viadur®, Eligard®), goserehn (Zoladex®), triptorelm (Trelstar®), and histrelin (Vantas®). Antiandrogens block the body's ability to use any androgens. Examples of antiandrogens drugs include enzalutamide (Xtandi®), flutamide
(Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®). Luteinizing hormone- releasing hormone (LHRH) antagonists include abarelix (Plenaxis®) or degarelix (Firmagon®) (approved for use by the FD A in 2008 to treat advanced prostate cancer). 5a-Reductase inhibitors block the body’s ability to convert testosterone to the more active androgen, 5a- dihydrotestosterone (DHT) and include drugs such as finasteride (Proscar®) and dutasteride (Avodart®). Inhibitors of testosterone biosynthesis include drugs such as ketoconazole (Nizoral®). Estrogens include diethylstilbestrol or 17P-estradiol. 17a-Hydroxylase/C17,20 lyase (CYP17A1) inhibitors include abiraterone (Zytiga®).
[0140] The disclosure encompasses a method of treating antiandrogen-resi stant prostate cancer. The antiandrogen may include, but is not limited to, bicalutamide, hydroxyflutamide, flutamide, enzalutamide or abiraterone.
Treatment of Triple Negative Breast Cancer (TNBC)
[0141] Triple negative breast cancer (TNBC) is a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase. As such, TNBC lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers. Correspondingly, chemotherapy is often the initial pharmacotherapy for TNBC. Interestingly, AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy. In ER-positive breast cancer, AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors. However, in the absence of ER, it is possible that AR actually supports the growth of breast cancer tumors. Though the role of AR is not fully understood in TNBC, we have evidence that certain TNBC’s may be supported by androgen independent activation of AR-SVs lacking the LBD or androgen-dependent activation of AR full length. As such, enzalutamide and other LBD-directed traditional AR antagonists would not be able to antagonize AR-SVs in these TNBC’s. However, SARDs of this disclosure which are capable of destroying AR-SVs through a binding site in the NTD of AR would be able to antagonize AR in these TNBC’s and provide an anti-tumor effect.
Treatment of Kennedy’s Disease
[0142] Muscle atrophy (MA) is characterized by wasting away or diminution of muscle and a decrease in muscle mass. For example, post-polio MA is muscle wasting that occurs as part of the post-polio syndrome (PPS). The atrophy includes weakness, muscle fatigue, and pain. Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA - also known as Kennedy’s Disease), This disease arises from a defect in the androgen receptor gene on the X chromosome, affects only males, and its onset is in late adolescence to adulthood. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases. The mutation results in an extended polyglutamine tract at the N-terminal domain of the androgen receptor (polyQ AR).
[0143] Binding and activation of the polyQ AR by endogeneous androgens (testosterone and DHT) results in unfolding and nuclear translocation of the mutant androgen receptor. The androgen-induced toxicity and androgen-dependent nuclear accumulation of polyQ AR protein seems to be central to the pathogenesis. Therefore, the inhibition of the androgen- activated polyQ AR might be a therapeutic option (A. Baniahmad. Inhibition of the androgen receptor by antiandrogens in spinobulbar muscle atrophy. J. Mol. Neurosci. 2016 58(3), 343- 347). These steps are required for pathogenesis and result in partial loss of transactivation function (/.<?., an androgen insensitivity) and a poorly understood neuromuscular degeneration. Peripheral polyQ AR anti-sense therapy rescues disease in mouse models of SBMA (Cell Reports 7 , 774-784, May 8, 2014). Further support of use antiandrogen comes in a report in which the antiandrogen flutamide protects male mice from androgen-dependent toxicity' in three models of spinal bulbar muscular atrophy (Renier KJ, Troxell-Smith SM, Johansen JA, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim H, Lieberman AP, Breedlove SM, Jordan CL. Endocrinology 2014, 155(7), 2624-2634). These steps are required for pathogenesis and result in partial loss of transactivation function (i.e., an androgen insensitivity) and a poorly understood neuromuscular degeneration. Currently there are no disease-modifying treatments but rather only symptom directed treatments. Efforts to target the polyQ AR as the proximal mediator of toxicity by harnessing cellular machinery to promote its degradation hold promise for therapeutic intervention.
[0144] Selective androgen receptor degraders such as those reported herein bind to, inhibit transactivation, and degrade all androgen receptors tested to date (full length, splice variant,
antiandrogen resistance mutants, etc.), indicating that they are promising leads for treatment diseases whose pathogenesis is androgen-dependent such as SBMA.
[0145] The disclosure encompasses methods of treating Kennedy’s disease comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI. MA, or MB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0146] As used herein, the term “androgen receptor associated conditions” or “androgen sensitive diseases or disorders” or “androgen-dependent diseases or disorders” are conditions, diseases, or disorders that are modulated by or whose pathogenesis is dependent upon the activity of the androgen receptor. The androgen receptor is expressed in most tissues of the body however it is overexpressed in, inter alia, the prostate and skin. ADT has been the mainstay of prostate cancer treatment for many years, and SARDs may also be useful in treating various prostate cancers, benign prostatic hypertrophy, prostamegaly, and other maladies of the prostate.
[0147] The disclosure encompasses methods of treating benign prostatic hypertrophy comprising administering a therapeutically effective amount of at least, one compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, MA, or MB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0148] The disclosure encompasses methods of treating prostamegaly comprising administering a therapeutically effective amount of at least one compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.
[0149] The disclosure encompasses methods of treating hyperproliferative prostatic disorders and diseases comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0150] The effect of the AR on the skin is apparent in the gender dimorphism and puberty related dermatological problems common to teens and early adults. The hyperandrogenism of puberty stimulates terminal hair growth, sebum production, and predisposes male teens to acne, acne vulgaris, seborrhea, excess sebum, hidradenitis suppurativa, hirsutism, hypertrichosis, hyperpilosity, androgenic alopecia, male pattern baldness, and other dermatological maladies. Although antiandrogens theoretically should prevent the hyperandrogenic dermatological diseases
discussed, they are limited by toxicities, sexual side effects, and lack of efficacy when topically applied. The SARDs of this disclosure potently inhibit ligand-dependent and ligand-independent AR activation, and (in some cases) have short biological half-lives in the serum, suggesting that topically formulated SARDs of this disclosure could be applied to the areas affected by acne, seborrheic dermatitis, and/or hirsutism without risk of systemic side effects.
[0151] The disclosure encompasses methods of treating acne, acne vulgaris, seborrhea, seborrheic dermatitis, hidradenitis supporativa, hirsutism, hypertrichosis, hyperpilosity, or alopecia comprising administering a therapeutically effective amount of a compound of formulas I, TA, IB, II, II A, IIB, III, IIIA, IIIB, IV, IV.A, IVB, \r, V A, VB, VI, VIA, or VI B, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0152] The compounds and/or compositions described herein may be used for treating hair loss, alopecia, androgenic alopecia, alopecia areata, alopecia secondary to chemotherapy, alopecia secondary to radiation therapy, alopecia induced by scarring or alopecia induced by stress. Generally “hair loss” or “alopecia” refers to baldness as in the very common type of male-pattern baldness. Baldness typically begins with patch hair loss on the scalp and sometimes progresses to complete baldness and even loss of body hair. Hair loss affects both males and females.
[0153] The disclosure encompasses methods of treating androgenic alopecia comprising administering a therapeutically effective amount of a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0154] SARDs of this disclosure may also be useful in the treatment of hormonal conditions in females which can have hyperandrogenic pathogenesis such as precocious puberty, early puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, and/or vaginal dryness.
[0155] The disclosure encompasses methods of treating precocious puberty or early puberty, dysmenorrhea or amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, hyper-androgenic diseases (such as polycystic ovary syndrome (PCOS)), fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary’
syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, or vaginal dryness comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0156] SARDs of this disclosure may also find utility in treatment of sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization, androgen insensitivity syndromes (AIS) (such as complete AIS (CAIS) and partial AIS (PAIS)), and improving ovulation in an animal.
[0157] The disclosure encompasses methods of treating sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization androgen, insensitivity syndromes, increasing or modulating or improving ovulation comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, TUB, IV, IVA, IVB, V, VA, VB, VI, VI A, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.
[0158] SARDs of this disclosure may also be useful for treating hormone-dependent cancers such as prostate cancer, breast cancer, testicular cancer, ovarian cancer, hepatocellular carcinoma, urogenital cancer, etc. In another embodiment, the breast cancer is triple negative breast cancer. Further, local or systemic SARD administration may be useful for treatment of precursors of hormone-dependent cancers such as prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP).
[0159] The disclosure encompasses methods of treating breast cancer, testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, precursors of prostate cancer, or AR related or AR expressing solid tumors, comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. A precursor of prostate cancers may be prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP). The tumor may be hepatocellular carcinoma (HCC) or bladder cancer. Serum testosterone may be positively linked to the development of HCC. Based on epidemiologic, experimental observations, and notably the fact that men have a substantially higher risk of bladder cancer than women, androgens and/or the AR may also play a role in bladder cancer initiation.
[0160] Although traditional antiandrogens such as enzalutamide, bicalutamide and flutamide and androgen deprivation therapies (ADT) such as leuprolide were approved for use in prostate cancer, there is significant evidence that antiandrogens could also be used in a variety of other hormone-dependent and hormone-independent cancers. For example, antiandrogens have been successfully tested in breast cancer (enzalutamide; Breast Cancer Res (2014) 16(1): R7), non- small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J Gastroenterology 20(29): 9229), cancer of the ovary, fallopian tubes, or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT was tested in AR-expressing recurrent metastatic salivary gland cancers and was confirmed to have benefit on progression free survival and overall survival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876); Int J Endocrinol (2015), Article ID 384860 ), pancreatic cancer, lymphoma (including mantle cell), and hepatocellular carcinoma. Use of a more potent antiandrogen such as a SARD in these cancers may treat the progression of these and other cancers. Other cancers may also benefit from SARD treatment such as testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, breast cancer, brain cancer, skin cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, perianal adenoma, or central nervous system cancer.
[0161] SARDs of this disclosure may also be useful for treating other cancers containing AR such as breast, brain, skin, ovarian, bladder, lymphoma, liver, kidney, pancreas, endometrium, lung (e.g, NSCLC), colon, perianal adenoma, osteosarcoma, CNS, melanoma, hypercalcemia of malignancy and metastatic bone disease, etc.
[0162] Thus, the disclosure encompasses methods of treating hypercalcemia of malignancy, metastatic bone disease, brain cancer, skin cancer, bladder cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, central nervous system cancer, gastric cancer, colon cancer, melanoma, amyotrophic lateral sclerosis (ALS), and/or uterine fibroids comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. The lung cancer may be non-small cell lung cancer (NSCLC).
[0163] SARDs of this disclosure may also be useful for the treating of non-hormone- dependent cancers. Non-hormone-dependent cancers include liver, salivary’ duct, etc.
[0164] In another embodiment, the SARDs of this disclosure are used for treating gastric cancer. In another embodiment, the SARDs of this disclosure are used for treating salivary duct carcinoma. In another embodiment, the SARDs of this disclosure are used for treating bladder cancer. In another embodiment, the SARDs of this disclosure are used for treating esophageal cancer. In another embodiment, the SARDs of this disclosure are used for treating pancreatic cancer. In another embodiment, the SARDs of this disclosure are used for treating colon cancer. In another embodiment, the SARDs of this disclosure are used for treating non-small cell lung cancer. In another embodiment, the S ARDs of this disclosure are used for treating renal cell carcinoma.
[0165] AR plays a role in cancer initiation in hepatocellular carcinoma (HCC). Therefore, targeting AR may be an appropriate treatment for patients with early stage HCC. In late- stage HCC disease, there is evidence that metastasis is suppressed by androgens. In another embodiment, the SARDs of this disclosure are used for treating hepatocellular carcinoma (HCC).
[0166] Locati et al. in Head & Neck, 2016, 724-731 demonstrated the use of androgen deprivation therapy (ADT) in AR-expressing recurrent/metastatic salivary gland cancers and confirmed improved progression free survival and overall survival endpoints with ADT. In another embodiment, the SARDs of this disclosure are used for treating salivary gland cancer.
[0167] Kawahara et al. in Oncotarget, 2015, Vol 6 (30), 29860-29876 demonstrated that ELK 1 inhibition, together with AR inactivation, has the potential of being a therapeutic approach for bladder cancer. McBeth et al. Int J Endocrinology, 2015, Vol 2015, Article ID 384860 suggested that the combination of antiandrogen therapy pl us glucocorticoids as treatment of bladder cancer as this cancer is believed to have an inflammatory etiology. In another embodiment, the SARDs of this disclosure are used for treating bladder cancer, optionally in combination with glucocorticoids.
Abdominal Aortic Aneurysm (AAA)
[0168] An abdominal aortic aneurysm (AAA) is an enlarged area in the lower part of the aorta, the major blood vessel that supplies blood to the body. The aorta, about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the
aorta is the body's main supplier of blood, a ruptured abdominal aortic aneurysm can cause life- threatening bleeding. Depending on the size and the rate at which your abdominal aortic aneurysm is growing, treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery’ can be planned if it's necessary. Emergency surgery’ for a ruptured abdominal aortic aneurysm can be risky. AR blockade (pharmacologic or genetic) reduces AAA. Davis et al. (Davis JP, Salmon M, Pope NH, Lu G, Su G, Meher A, Ailawadi G, Upchurch GR Jr. J Vase Surg (2016) 63(6): 1602-1612) showed that flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated AAA induced by porcine pancreatic elastase (0.35 U/mL) by 84.2% and 91.5% compared to vehicle (121 %). Further AR -/- mice showed attenuated AAA growth (64.4%) compared to wildtype (both treated with elastase). Correspondingly, administration of a SARD to a patient suffering from an AAA may help reverse, treat or delay progression of AAA to the point where surgery/ is needed.
Treatment, of Wounds
[0169] Wounds and/or ulcers are normally found protruding from the skin or on a mucosal surface or as a result of an Infarction in an organ. A wound may be a result of a soft tissue defect or a lesion or of an underlying condition. The term “wound” denotes a bodily injury with disruption of the normal integrity of tissue structures, sore, lesion, necrosis, and/or ulcer. The term “sore” refers to any lesion of the skin or mucous membranes and the term “ulcer” refers to a local defect, or excavation, of the surface of an organ or tissue, which is produced by the sloughing of necrotic tissue. “Lesion” generally includes any tissue defect. “Necrosis” refers to dead tissue resulting from infection, injury, inflammation, or infarctions. All of these are encompassed by the term “wound,” which denotes any wound at any particular stage in the healing process including the stage before any healing has initiated or even before a specific wound like a surgical incision is made (prophylactic treatment).
[0170] Examples of wounds which can be treated in accordance with the present disclosure are aseptic wounds, contused wounds, incised wounds, lacerated wounds, non- penetrating wounds (?.<?. wounds in which there is no disruption of the skin but there is injury to underlying structures), open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, subcutaneous wounds, etc. Examples of sores include, but are not limited to, bed
sores, canker sores, chrome sores, cold sores, pressure sores, etc. Examples of ulcers include, but are not limited to, peptic ulcer, duodenal ulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer, submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, veneral ulcer, e.g., caused by gonorrhoea (including urethritis, endocervicitis and proctitis). Conditions related to wounds or sores which may be successfully treated according to the disclosure include, but are not limited to, burns, anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae, folliculitis, impetigo contagiosa, impetigo bullosa, etc. It is understood, that there may be an overlap between the use of the terms “wound” and “ulcer,” or “wound” and “sore” and, furthermore, the terms are often used at random.
[0171] The kinds of wounds to be treated according to the disclosure include also: i) general wounds such as, e.g., surgical, traumatic, infectious, ischemic, thermal, chemical and bullous wounds, li) wounds specific for the oral cavity such as, e.g., post-extraction wounds, endodontic wounds especially in connection with treatment of cysts and abscesses, ulcers and lesions of bacterial, viral or autoimmunological origin, mechanical, chemical, thermal, infectious and lichenoid wounds; herpes ulcers, stomatitis aphthosa, acute necrotising ulcerative gingivitis and burning mouth syndrome are specific examples; and iii) wounds on the skin such as, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial, viral, autoimmunological), bites and surgical incisions. Another way of classifying wounds is by tissue loss, where: i) small tissue loss (due to surgical incisions, minor abrasions, and minor bites) or ii) significant tissue loss. The later group includes ischemic ulcers, pressure sores, fistulae, lacerations, severe bites, thermal burns and donor site wounds (in soft and hard tissues) and infarctions. Other wounds include ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns, or donor site wounds.
[0172] Ischemic ulcers and pressure sores are wounds, which normally only heal very slowly and especially in such cases an improved and more rapid healing is of great importance to the patient. Furthermore, the costs involved in the treatment of patients suffering from such wounds are markedly reduced when the healing is improved and takes place more rapidly.
[0173] Donor site wounds are wounds which e.g., occur in connection with removal of hard tissue from one part of the body to another part of the body e.g., in connection with transplantation. The wounds resulting from such operations are very painful and an improved healing is therefore most valuable.
[0174] In one case, the wound to be treated is selected from the group consisting of aseptic wounds, infarctions, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, and subcutaneous wounds.
[0175] The disclosure encompasses methods of treating a subject suffering from a wound comprising administering to the subject a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, TITA, IIIB, IV, IVA, IVB, V, VA, VB, AT, ATA, or ATB, or any of compounds CPD, 9, CPD. 44, CPD. 45, or CPD. 13, pharmaceutically acceptable salt thereof, or a pharmaceutical compostion thereof.
[0176] The disclosure encompasses methods of treating a subject suffering from a burn comprising administering to the subject a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, AT, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
[0177] The term “skin” is used in a very broad sense embracing the epidermal layer of the skin and in those cases where the skin surface is more or less injured also the dermal layer of the skin. Apart from the stratum corneum, the epidermal layer of the skin is the outer (epithelial) layer and the deeper connective tissue layer of the skin is called the dermis.
[0178] Since the skin is the most exposed part of the body, it is particularly susceptible to various kinds of injuries such as, e.g., ruptures, cuts, abrasions, burns and frostbites or inj uries arising from various diseases. Furthermore, much skin is often destroyed in accidents. However, due to the important barrier and physiologic function of the skin, the integrity of the skin is important to the well-being of the individual, and any breach or rupture represents a threat that must be met by the body in order to protect its continued existence.
[0179] Apart from injuries on the skin, injuries may also be present in all kinds of tissues (i.e., soft and hard tissues). Injuries on soft tissues including mucosal membranes and/or skin are especially relevant in connection with the present disclosure.
[0180] Healing of a wound on the skin or on a mucosal membrane undergoes a series of stages that results either in repair or regeneration of the skin or mucosal membrane. In recent years, regeneration and repair have been distinguished as the two types of healing that may occur.
Regeneration may be defined as a biological process whereby the architecture and function of lost tissue are completely renewed. Repair, on the other hand, is a biological process whereby continuity of disrupted tissue is restored by new tissues which do not replicate the structure and function of the lost ones.
[0X81] The majority of wounds heal through repair, meaning that the new tissue formed is structurally and chemically unlike the original tissue (scar tissue). In the early stage of the tissue repair, one process which is almost always involved is the formation of a transient connective tissue in the area of tissue injury. This process starts by formation of a new extracellular collagen matrix by fibroblasts. This new extracellular collagen matrix is then the support for a connective tissue during the final healing process. The final healing is, in most tissues, a scar formation containing connective tissue. In tissues which have regenerative properties, such as, e.g., skin and bone, the final healing includes regeneration of the original tissue. This regenerated tissue has frequently also some scar characteristics, e.g., a thickening of a healed bone fracture.
[0182] Under normal circumstances, the body provides mechanisms for healing inj ured skm or mucosa in order to restore the integrity of the skin barrier or the mucosa. The repair process for even minor ruptures or wounds may take a period of time extending from hours and days to weeks. However, in ulceration, the healing can be very slow and the wound may persist for an extended period of time, i.e., months or even years.
[0183] Burns are associated with reduced testosterone levels, and hypogonadism is associated with delayed wound healing. The disclosure encompasses methods for treating a subject suffering from a wound or a burn by administering at least one SARD compound according to this disclosure. The SARD may promote resolving of the burn or wound, participates in the healing process of a burn or a wound, or, treats a secondary complication of a burn or wound.
[0184] The treatment of burns or wounds may further use at least one growth factor such as epidermal growth factor (EGF), transforming growth factor-a (TGF-a), platelet derived growth factor (PDGF), fibroblast growth factors (FGFs) including acidic fibroblast growth factor (a-FGF) and basic fibroblast growth factor (P-FGF), transforming growth factor-P (TGF-3) and insulin like growth factors (IGF-1 and IGF-2), or any combination thereof, which promote wound healing.
[0185] Wound healing may be measured by many procedures known in the art, including, but not limited to, wound tensile strength, hydroxyproline or collagen content, procollagen expression, or re-epithelialization. As an example, a SARD as described herein may be administered orally or topically at a dosage of about 0.1-10 mg per day. Therapeutic effectiveness is measured as effectiveness in enhancing wound healing as compared to the absence of the SARD compound. Enhanced wound healing may be measured by known techniques such as decrease in healing time, increase in collagen density', increase in hydroxyproline, reduction in complications, increase in tensile strength, and increased cellulanty of scar tissue.
[0186] The term “reducing the pathogenesis” is to be understood to encompass reducing tissue damage, or organ damage associated with a particular disease, disorder or condition. The term may include reducing the incidence or severity of an associated disease, disorder or condition, with that in question or reducing the number of associated diseases, disorders or conditions with the indicated, or symptoms associated thereto.
Pharmaceutical Compositions
[0187] The compounds may be used in pharmaceutical compositions. As used herein, “pharmaceutical composition” means either the compound or pharmaceutically acceptable salt of the active ingredient with a pharmaceutically acceptable carrier or diluent. A “therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.
[0188] As used herein, the term “administering” refers to bringing a subject in contact with a compound of the present disclosure. As used herein, administration can be accomplished in vitro, i.e., in a test tube, or in vivo, i.e., in cells or tissues of living organisms, for example humans. The subjects may be a male or female subject or both.
[0189] Numerous standard references are available that describe procedures for preparing various compositions or formulations suitable for administration of the compounds. Examples of methods of making formulations and preparations can be found in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).
[0190] The mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.
[0191] The pharmaceutical compositions of the disclosure can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, mtraventricularly, intracranially, intra vaginal ly, by inhalation, rectally, or intratum orally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces. Another method of administration is via aspiration or aerosol formulation. The pharmaceutical compositions may be administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administrations, the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
[0192] Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for sy stemic delivery of active ingredients. Depending on the indication, formulations suitable for oral or topical administration are preferred.
Topical Administration
[0193] The compounds of formulasl, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 may be administered topically. As used herein, “topical administration” refers to application of the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 (and optional carrier) directly to the skin and/or hair. The topical composition can be in the form of solutions, lotions, salves,
creams, ointments, liposomes, sprays, gels, foams, roller sticks, and any other formulation routinely used in dermatology.
[0194] Topical administration is used for incidations found on the skin, such as hirsutism, alopecia, acne, and excess sebum. The dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable carrier in an amount of from about 0.01 to 50 w/w %, and more typically from about 0.1 to 10 w/w %. Typically, the dermatological preparation will be applied to the affected area from 1 to 4 times daily. “Dermatologically acceptable” refers to a carrier which may be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically “site of action”, it refers to a site where inhibition of androgen receptor or degradation of the androgen receptor is desired.
[0195] The compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, maybe used topically to relieve alopecia, especially androgenic alopecia. Androgens have a profound effect on both hair growth and hair loss. In most body sites, such as the beard and pubic skin, androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing follicle size. Hair growth on the scalp does not require androgens but, paradoxically, androgens are necessary' for the balding on the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decline in the duration of anagen and in hair follicle size. Androgenic alopecia is also common in women where it usually presents as a diffuse hair loss rather than showing the paterning seen in men.
[0196] While the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 will most typically be used to alleviate androgenic alopecia, the compounds may be used to alleviate any type of alopecia. Examples of non-androgenic alopecia include, but are not limited to, alopecia areata, alopecia due to radiotherapy or chemotherapy , scarring alopecia, or stress related alopecia.
[0197] The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can be applied topically to the scalp and hair to prevent, or treat balding. Further, the compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any
of compounds CPD. 9, CPD. 44, CPD 45, or CPD. 13 can be applied topically in order to induce or promote the growth or regrowth of hair on the scalp.
[0198] The disclosure also encompasses topically administering a compound of formula I, I A. IB, II, II A, I IB, III, I II A, I IIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to treat or prevent the growth of hair in areas where such hair growth in not desired. One such use will be to alleviate hirsutism. Hirsutism is excessive hair growth in areas that typically do not have hair (e.g., a female face). Such inappropriate hair growth occurs most commonly in women and is frequently seen at menopause. The topical administration of the compounds of formulas I, IA, IB, II, IIA, IIB, III, TITA, IIIB, IV, IV A, IVB, V, V A, VB, VI, VTA, or VIB, or any of compounds CPD, 9, CPD. 44, CPD. 45, or CPD. 13 will alleviate this condition leading to a reduction, or elimination of this inappropriate, or undesired, hair growth.
[0199] The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 may also be used topically to decrease sebum production. Sebum is composed of triglycerides, wax esters, fatty acids, sterol esters and squalene. Sebum is produced in the acinar cells of the sebaceous glands and accumulates as these cells age. At maturation, the acinar cells lyse, releasing sebum into the luminal duct so that it may be deposited on the surface of the skin.
[0200] In some individuals, an excessive quantity of sebum is secreted onto the skin. This can have a number of adverse consequences. It can exacerbate acne, since sebum is the primary food source for Propionbacterium acnes, the causative agent of acne. It can cause the skin to have a greasy appearance, typically considered cosmetically unappealing.
[0201] Formation of sebum is regulated by growth factors and a variety of hormones including androgens. The cellular and molecular mechanism by which androgens exert their influence on the sebaceous gland has not been fully elucidated. However, clinical experience documents the impact androgens have on sebum production. Sebum production is significantly increased during puberty, when androgen levels are their highest. The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 inhibit the secretion of sebum and thus reduce the amount of sebum on the surface of the skin. The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA,
111 B, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can be used to treat a variety of dermal diseases such as acne or seborrheic dermatitis.
[0202] In addition to treating diseases associated with excess sebum production, the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, TUB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can also be used to achieve a cosmetic effect. Some consumers believe that they are afflicted with overactive sebaceous glands. They feel that their skin is oily and thus unattractive. These indiviuals may use the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, XT, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to decrease the amount of sebum on their skin. Decreasing the secretion of sebum will alleviate oily skin in mdvi duals afflicted with such conditions.
[0203] To treat these topical indications, the disclosure encompasses cosmetic or pharmaceutical compositions (such as dermatological compositions), comprising at least one of the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. Such dermatological compositions will contain from 0.001% to 10% w/w% of the cornpound(s) in admixture with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 w/w % of the compounds. Such compositions will typically be applied from 1 to 4 times daily. The reader’s attention is directed to Remington’s Pharmaceutical Science, Edition 17, Mark Publishing Co., Easton, PA for a discussion of how to prepare such formulations.
[0204] The compositions of the disclosure may also include solid preparations such as cleansing soaps or bars. These compositions are prepared according to methods known in the art.
[0205] Formulations such as aqueous, alcoholic, or aqueous-alcoholic solutions, or creams, gels, emulsions or mousses, or aerosol compositions with a propellant may be used to treat indications that arise where hair is present. Thus, the composition can also be a hair care composition. Such hair care compositions include, but are not limited to, shampoo, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition, or a lotion or gel for preventing hair loss. The amounts of the various constituents in the dermatological compositions are those conventionally used in the fields considered.
[0206] Medicinal and cosmetics containing the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 will typically be packaged for retail distribution (i.e., an article of manufacture). Such articles will be labeled and packaged in a manner to instruct the patient how to use the product. Such instructions will include the condition to be treated, duration of treatment, dosing schedule, etc,
[0207] Antiandrogens, such as finasteride or flutamide, have been shown to decrease androgen levels or block androgen action in the skin to some extent but suffer from undesirable systemic effects. An alternative approach is to topically apply a selective androgen receptor degrader (SARD) compound to the affected areas. Such SARD compound would exhibit potent but local inhibition of AR activity, local degradation of AR activity, would not penetrate to the systemic circulation of the subject, or would be rapidly metabolized upon entry into the blood, limiting systemic exposure.
[0208] To prepare such pharmaceutical dosage forms, the active ingredient may be mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.
[0209] ,As used herein “pharmaceutically acceptable carriers or diluents” are well known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid formuations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
[0210] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g, corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcry stalline cellulose), an acrylate (e.g, polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
Oral and Parenteral Administration
[0211] In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For solid oral preparations such as, powders, capsules, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating
agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.
[0212] For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
[0213] In some applications, it may be advantageous to utilize the active agent in a “vectorized” form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
[0214] Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
[0215] A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
[0216] A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredients) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
[0217] Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents
and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.
[0218] Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, mtra -abdominal (e.g, intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired admini strati on modal ity .
[0219] Nasal and other mucosal spray formulations (e.g., inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
[0220] Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
[0221] Transdennal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
[0222] In addition to the aforementioned ingredients, formulations of this disclosure may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
[0223] The formulations may be of immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
[0224] For administration to mammals, and particularly humans, it is expected that the physician wall determine the actual dosage and duration of treatment. For administration to mammals, and particularly humans, it is expected that the physician will determine the actual
dosage and duration of treatment, which wiil be most suitable for an individual and can vary with the age, weight, genetics and/or response of the particular individual.
[0225] The methods of the disclosure comprise administration of a compound at a therapeutically effective amount. The theraperutically effective amount may include various dosages.
[0226] In one embodiment, a compound of this disclosure is administered at a dosage of 1-3000 mg per day. In additional embodiments, a compound of this disclosure is administered at a dose of 1 -10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 15-60 mg per day, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 25 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 40 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 50 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 67.5 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 75 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 80 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 100 mg per day.
In one embodiment, a compound of this disclosure is administered at a dosage of 125 mg per day.
In one embodiment, a compound of this disclosure is administered at a dosage of 250 mg per day.
In one embodiment, a compound of this disclosure is administered at a dosage of 300 mg per day.
In one embodiment, a compound of this disclosure is administered at a dosage of 500 mg per day.
In one embodiment, a compound of this disclosure is administered at a dosage of 600 mg per day.
In one embodiment, a compound of this disclosure is administered at a dosage of 1000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 1500 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 2000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 2500 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 3000 mg per day.
[0227] The methods may comprise administering a compound at various dosages. For example, the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.
[0228] Alternatively, the compound may be administered at a dosage of 0.1 mg/kg/day. The compound may administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.
[0229] The pharmaceutical composition may be a solid dosage form, a solution, or a transdermal patch. Solid dosage forms include, but are not limited to, tablets and capsules.
[0230] The following examples are presented in order to more fully illustrate the preferred embodiments of the disclosure. They should in no way, however, be construed as limiting the broad scope of the disclosure.
EXAMPLES
EXAMPLE 1
Synthesis of SARDs
Synthetic Scheme for l-(3-(4-Cvano-3-(trifluoromethyr)phenoxy)-2-hvdroxy-2-methylpropyl)-lH- pyrazole-4-carbonitrile - CPD. 9
[0231] To a solution of 4-hydroxy-2-(trifluoromethyl)benzonitrile (0.55g, 0.0029393mol) and K2CO3 (1.22g, 0.0088179mol) in lOmL of dry 2-butanone was added 3- bromo-2-methylprop-l-ene (0.60g, 0.00409mol). The resulting mixture was stirred for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using DCM as eluent to afford 0.685g (96.6%) of the titled compound as colorless oil.
[0232] 1HNMR (400MHz, DMSO-d6) 5 8.10(d, J=8.4Hz, 1H, ArH), 7.52(d, J=2.4Hz, 1H, ArH), 7.44(dd, J=8.4Hz, J=2.4Hz, 1H, ArH), 5.07(s, 1H, CH=C), 5.00(s, 1H, CH=C), 4.69(s, 2H, CH2), 1.706(s, 3H, CH3).
[0233] Mass (ESI, Positive): [M+H]+.
[0234] Mass (ESI, Positive): [M+H]+.
[0235] HRMS [C12H11F3N2O+]: calcd 242.0793 found 242.0793 [M+H]+. Purity: 98.29% (HPLC).
[0236] HRMS [C 12H9F3N2O-]: calcd 240.0636 found 240.0624 [M H ]- Purity: 98.29% (HPLC).
[0237] To a solution of 4-((2-methylallyl)oxy)-2-(trifluoromethyl)benzonitrile (0.65g, 0.0026974mol) in lOmL of dry DCM was added 3-chlorobenzoperoxoic acid (mCPBA, 0.93g, 0.0053895moi). The resulting mixture was stirred for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using DCM as eluent to afford 0.68g (98.5%) of the titled compound as white solid.
: HNMR (400MHZ, DMSO-de) 5 8.11 (d, J=8.8Hz, 1H, ArH), 7.54(d, J=2.4Hz, 1H, ArH), 7.46(dd, J=8.8Hz, J=2.4Hz, 1H, ArH), 4.43(d, J 9. H E. 1 H, CH Cg 4.10(d, J 9.1 Hz. 1H, CH=C), 2.83(d, J=4.8Hz, 1H, CH), 2.50(d, J=4.8Hz, 1H, CH), 1 ,38(s, 3H, CH3).
[0239] Mass (ESI, Positive): [ M H ]
[0240] HRMS [CI2HIIF3NO2 +]: calcd 258.0742 found 258.0742 [M+H]+. Purity: 90.73% (HPLC).
[0241] HRMS [C 12H9F3NO2 "]: calcd 256.0585 found 256.0585 [M+H]“. Purity: 90.73% (HPLC). l-(3-(4-cyano-3-(trifluoromethyl)phenoxy)-2-hydroxy-2-methylpropyl)-lH-pyrazo1e-4- carbonitrile (C16H13F3N4O2) - CPD. 9
[0242] To a solution of 1 H-pyrazole-4-carbonitrile (0.136g, 0.0014578mol) in anhydrous THF (lOmL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil, 0.078g, 0.0019438mol). After addition, the resulting mixture was stirred for three hours. 4-((2-methyloxiran-2-yl)methoxy)-2- (trifluoromethyl) benzonitrile (0.25g, 0.0009719mol) was added to above solution, and the resulting reaction mixture was stirred overnight at room temperature under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using hexanes and ethyl acetate (1:1) as eluent to afford 0.224g (65.9%) of the titled compound as off-white oil.
[0243] !HNMR (400MHZ, DMSO-de) 6 8.48(s, 1H, Pyrazole-H), 8. 12(d, J=8.2Hz, 1H, ArH), 8.05(s, 1H, Pyrazole-H), 7.51(d, J=2.4Hz, 1H, ArH), 7.44(dd, J=8.4Hz, J=2.4Hz, ArH), 5.40(s, 1H, OH), 4.35(s, 2H, CH2), 3.99-3.94(m, 2H, ('l l.’).. 1.16(s, 3H, ( f l -)
[0244] Mass (ESI, Positive): I X I 11 ] .
[0245] HRMS [C16H15F3N5O +]: calcd 351.1069 found [M+H]+. Purity: 98.30% (HPLC).
[0246] HRMS [CieHnFsNsO’]: calcd 349.0912 found 349.0912 [M+H]“. Purity: 98.30% (HPLC).
Synthetic Scheme for 4-(3-(4-cyanophenoxy)-2-hydroxy-2-methylpropoxy)-2- (trifluoromethyl)benzonitrile (C19H15F3N2O3) - CPD. 44
4-(3-(4-cvanophenoxy)-2-hvdroxy-2-methylpropoxy)-2-(trifluoromethyl)benzonitrile
[0247] A solution of 4-((2-methyloxiran-2-yl)methoxy)-2-
(trifluoromethyl)benzonitrile (0.20g, 0.0007776mol), 4-cyanophenol (0.111g, 0.000933 Imoi), and potassium carbonate (0.215g, 0.0015552mol) in 10ml of 2-butanone was heated at reflux for 12 hours under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (19: 1) as eluent to afford 0.23g (79.3%) of the titled compound as yellowish solid.
[0248] T INMR (400MHz, DMSO-ds) 3 8.09(d, J=8.4Hz, 1H, ArH), 7.76-7.73(m, 2H,
Ari l). 7.51(d, J=2.4Hz, I I I. ArH), 7.46(dd, J=8.4Hz, J=2.4Hz, 1H, ArH), 7.14-7.1 l(m, 2H, ArH), 5.32(s, 1H, OH), 4.19-4.12(m, 2H, CH:j. 4.09(d, .1 9.611:.-. 1H, CH), 4.02(d, ,1 9.6Hz. 1H, CH), 1.32(s, 3H, CM ).
[0249] Mass (ESI, Positive): [ M H ] ,
[0250] HRMS [CwHuFsNzOid]: calcd 377.1113, found 377.1105 [M+H]+ Purity: 97.19% (HPLC).
Synthetic scheme for Methyl 2-(((l-(4-cyano-lH-pyrazol-l-yl)-3-(4-cvano-3-
(trifluoromethyl)phenoxy)-2-methylpropan-2-yl)oxy)methyl)acrylate (C21H19F3N4O4) - CPD.
Methyl 2-(((l-(4-cvano-lH-pyrazol-1-vl)-3-(4-cyano-3-(trifluoromethyl)phenoxv)-2- methylpropan-2-yl)oxY)methyl)acrylate (C21H19F3N4O4) - CPD. 45
[0251] To a solution of 4-(3-(4~cyanophenoxy)-2-hydroxy-2-methylpropoxy)-2- (tnfluoromethyl)benzomtrile (0.20g, 0.000571 mol) in anhydrous THF (5mL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil,
0.046g, 0.0011418moi). After addition, the resulting mixture was stirred for three hours. Methyl 2- (bromomethyl)acrylate (0.307g, 0.0017128niol) was added to above solution, and the resulting reaction mixture was stirred overnight at room temperature under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (19: 1 to 9: 1) as eluent to afford 30mg (11.7%) of the titled compound as off-white oil.
[0252] ’HNMR (400MHz, DMSO-de) 8 8.47(s, 1H, Pyrazole-H), 8. 13(d, J=8.4Hz, 1H, ArH), 8.06(s, 1H, Pyrazole-H), 7.55(d, J=2.4Hz, 1H, ArH), 7.45(dd, J=8.4Hz, J=2.4Hz, 1H), 6.13(d, J=1.2Hz, 1H, CH=C), 5.80(d, J=2.0Hz, 1H, CH=C), 4.49(s, 2H, CH2), 4.26-4.23(m, 1H, CH), 4.15-4. 12(m„ 1H, CH), 3.74-3.71 (m, 2H, CH2), 3.68(s, 3H,OCH3), 1.26(s, 3H, CH3).
[0253] Mass (ESI, Positive): i A I • 11 ] .
[0254] HRMS [CEiIhoFsN-iO-C]: calcd 449.1437, found 449.1440 [M+Hf. Purity; 91.39% (HPLC).
Synthetic scheme for l-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methy1propyl)- lH-pyrazole-4-carbonitrile (C16H14F3N5O) - CPD. 13
[0255] To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (0.50g, 0.0026862mol) and K2CO3 (1.12g, 0.0080586mol) in lOmL of dry acetonitrile was added 3- bromo-2-methylprop-l-ene (0.54g, 0.0040293mol). The resulting mixture was heated at reflux for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The
organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using hexanes and ethyl acetate (3:1) as eluent to afford 0.44g (68.2%) of the titled compound as oil.
[0256] iI iN.MR (400MHz. DMSO-de) 8 7.71 (d, ,1 8.2Hz. 1H, ArH), 7.53(t, J=6.4Hz, 1H, NH), 7.01(d, J=1.6Hz, 1H, ArH), 6.80(d, J 8.2Hz, H I. ArH), 4.84(d. .1 =1.2Hz, 2H, CH2=C), 3.75(d, J 6.0Hz. 2H, C1 H. 1.70(s, 3H, CH A
[0257] Mass (ESI, Positive): [ M H ]
[0258] HRMS [ C 12H i 0F3N 2" ] : calcd 239.0796 found 239.0795 [ M-H ]". Purity
4-(((2-methyloxiran-2-yl)methyl)amino)-2-(trifluoromethyl)benzonitrile (C12H11F3N2O)
[0259] To a solution of 4-((2-methylallyl)ammo)-2-(trifluoromethyl)benzonitrile (0.44g, 0.0018316moi) in lOmL of dry DCM was added 3-chlorobenzoperoxoic acid (mCPBA, 0.63g, 0.0036632mol). The resulting mixture was stirred for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (98:2) as eluent to afford 0.29g (61.7%) of the titled compound as colorless oil.
[0260] !HNMR (400MHz. DMSO-de) 8 7.72(d, .1 8.2Hz. 1H, ArH), 7.53(t, J=6.4Hz, 1H, NH), 7.1 l(d, J 2.0Hz. 1H, ArH), 6.93(dd, J =8.2Hz, J=2.0Hz, ArH), 3.51-3.46(m, 1H, CH), 3.27-3.22(m, 1H, CH), 2.66(d, J 6.0Hz. 1H, CH), 2.61 (d, J=6.0Hz, 1H, CH), 1.28(s, 3H, CH3).
[0261] Mass (ESI, Positive): i M H |
[0262] HRMS [C12H13F3N2O +]: calcd 257.0902 found [M+H]+. Purity: % (HPLC).
[0263] HRMS [C12H11F3N2O "]: calcd 255.0745 found 255.0748 [M-H]’. Purity: 97.67
% (HPEC),
1 -(3-((4-c\,ano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methylpropYl)-1H- pyrazole-4 -carbonitrile (C16H14F3N5O) - CPD. 13
[0264] To a solution of lH-pyrazole-4-carbonitrile (0.093g, 0.0009757mol) in anhydrous THF (lOmL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil, 0.117g, 0.003 mol). After addition, the resulting mixture was stirred for three hours. 4-(((2-methyloxiran-2-yl)methyl)amino)-2- (trifluoromethyl)benzonitrile (0.25g, 0.0009757mol) was added to above solution, and the resulting reaction mixture was stirred overnight at room temperature under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and methanol (19:1 to 9:1) as eluent to afford 0.22g (6-4.7%) of the titled compound as off-white oil.
[0265] T-INMR (400MHz, DMSO-de) 5 8.45(s, 1H, Pyrazole-H), 8.07(s, 1H, Pyrazole- 1 1). 7.71 (d, J 8.21 iz. HI, ArH), 7.53(8. J 641 Iz. H i. XI I) 7.20-7.18(m, 2H, M l ArH), 6.95(dd, J 8.41 lz. .1 2.0Hz. ArH), 5.16(s, 1H, OH), 4.27-4.23(m, 2H, CTb), 3.20-3.16(m, 2H, CH2), 1.05(s, 3H, CIL).
[0266] Mass (ESI, Positive): [M+H]+.
[0267] HRMS i CM I rl+X T) j: calcd 350.1129 found [M+Hf. Purity: % (HPLC).
[0268] HRMS [CMHisFiNsO’]: calcd 348.1072 found 348.1089[M+H]'. Purity: 87.63% (HPLC).
EXAMPLE 2
Octanol-Water Partition Coefficient (Log P)
[0269] Log P is the log of the octanol-water partition coefficient, commonly used early in drug discovery efforts as a rough estimate of whether a particular molecule is likely to cross biological membranes. Log P was calculated using ChemDraw Ultra version is 12.0.2.1016 (Perkin-Elmer, Waltham, Massachusetts 02-451). Calculated Log P values are reported in Table 1 in the column labeled ‘Log P (-0.-4 to +5.6)’, Lipinski’s rule of five is a set of criteria intended to
predict oral bioavailability. One of these criteria for oral bioavailability is that the Log P is between the values shown in the column heading (“0.4 (relatively hydrophilic) to +5.6 (relatively lipophilic) range), or more generally stated <5. The compounds tested exhibit acceptable water solubility.
EXAMPLE 3
Transactivation Assay
[0270] Methods: HEK-293 cells were transfected with the indicated receptors and GRE-LUC and CMV-renilla luc. Cells were treated 24 hours after transfection and luciferase assay performed 48 hours after transfection. The SARD compounds did not inhibit transactivation of receptors other than AR until 10 pM. The experimental method is described below,
[0271] Human AR was cloned into a CMV vector backbone and was used for the transactivation study. HEK-293 cells were plated at 120,000 cells per well of a 24 well plate in DME + 5% csFBS. The cells were transfected using Lipofectamine (Invitrogen, Carlsbad, CA) with 0.25 pg GRE-LUC, 0.01 pg CMV-LUC (renilla luciferase) and 25 ng of the AR The cells were treated 24 h after transfection and the luciferase assay performed 48 h after transfection. Transactivation results were based on measured luciferase light emissions and reported as relative light unit intensity' (RLU). The assay was run in antagonist mode (ICso) using known agonist R1881 at its ECso concentration of 0. 1 Nm and increasing concentrations of SARDs of this disclosure. Antagonist data are represented as ICso (Nm) obtained from four parameter logistics curve and are reported in Table 1 in the column labeled ‘ICso’.
[0272] Results'. In vivo pharmacodynamics demonstrate potent and highly efficacious antagonism of androgen dependent tissues.
EXAMPLE 4
Human Androgen Receptor (Har) Ligand Binding Domain (LBD) Affinity Assay
[0273] Methods: Har-LBD (633-919) was cloned into pGex4t.1. Large scale GST- tagged AR-LBD was prepared and purified using a GST column. Recombinant AR-LBD was combined with [3H]mibolerone (PerkmElmer, Waltham, MA) in buffer A (10 Mm Tris, Ph 7.4, 1.5 Mm disodium EDTA, 0.25
sucrose, 10 Mm sodium molybdate, 1 Mm PMSF) to determine the equilibrium dissociation constant (Ka) of [’H]mibolerone. Protein was incubated with increasing concentrations of [3H]mibolerone with and without a high concentration of unlabeled mibolerone at 4°C for 18 h in order to determine total and non-specific binding. Non-specific binding was then
subtracted from total binding to determine specific binding and non-linear regression for the ligand binding curve with one site saturation was used to determine the Kd of mibolerone.
[0274] Increasing concentrations of SARDs or DHT (range: 10'!2 to 10’4 M) were incubated with [JH]mibolerone and AR-LBD using the conditions described above. Following incubation, the ligand bound AR-LBD complex was isolated using BiogelHT hydroxyapatite, washed and counted in a scintillation counter after adding scintillation cocktail.
[0275] Results: The results of this assay are reported as Ki values (Nm) inTable 1.
EXAMPLE 5
In Vitro Assays to Determine SARD Activity
[0276] LNCaP or ADI androgen receptor degradation (fill! length AR): The compounds were tested for their effect on full length AR protein expression.
[0277] Methods: LNCaP or ADI cells expressing full length AR were plated at 750,000-1 ,000,000 cells/well of a 6 well plate in growth medium (RPMI + 10% FBS). Twenty four hours after plating, the medium was changed to RPMI + 1% csFBS without phenol red and maintained in this medium for 2 days. The medium again was changed to RPMI + 1% csFBS without phenol red and cells were treated with SARDs (1 Nm to 10 Mm) in combination with 0.1 Nm R1881. After 24 h of treatment, cells were washed with cold PBS and harvested. Protein was extracted using salt-containing lysis buffer with three freeze-thaw cycles. The protein concentration was estimated and five microgram of total protein was loaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane. The membrane was probed with AR N-20 antibody (SantaCruz Biotechnology, Inc., Dallas, Texas 75220) and actin antibody (Sigma-Aldrich, St. Louis, MO).
[0278] Results: Degradation in LNCaP or ADI cells are reported in Table 1 in the column labeled ‘Full Length % Inhibition at 1, 10 uM’.
[0279] 22RV1 or I)567es androgen receptor degradation (splice variant (S.V.)
AR): The effect of SARD treatment on the AR levels was measured in androgen-refractory 22RV- 1 or D567es prostate cancer cells.
[0280] Methods: 22RV1 or D567es cells expressing AR splice variants were plated at 750,000-1,000,000 cells/well of a 6 well plate in growth medium (RPMI + 10% FBS). Twenty four hours after plating, medium was changed and treated. After 24-30 h of treatment, cells were washed
with cold PBS and harvested. Protein was extracted using salt-containing lysis buffer with three freeze-thaw cycles. Protein concentration was estimated and five microgram of total protein was loaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane. The membrane was probed with AR N-20 antibody (Santa Cruz Biotechnology, Inc., Dallas, Texas 75220) and actin antibody (Sigma -Aid rich, St. Louis, MO).
[0281] Results’. Degradation in 22RV1 or D567es cells are reported in Table 1 in the column labeled “S.V. % inhibition at 10 μM.”
EXAMPLE 6
Metabolism Studies with Mouse Liver Microsomes (DMPK (MLM)) -
Metabolic stability in Phase I & Phase II pathways
[0282] In this assay, the test compound was incubated with liver microsomes and disappearance of drug was determined using discovery grade LC-MS/MS. To simulate Phase II metabolic pathway (glucuronidation), UDPGA and alamethicin were included in the assay. From %PCR (% Parent Compound Remaining), rate of compound disappearance is determined (slope of concentration vs. time plot) and in vitro CLint (pl/min/mg protein) was calculated.
[0283] Results’. The results of this assay utilizing mouse liver microsomes (MLM) are reported in Table 1 in the column labeled “DMPK (MLM) T1/2 (min) & CLint (uL/min/mg)”. The first value is the calculated half-life (T1/2) of the test article in MLM expressed in minutes and the 2nd value is the intrinsic CL (CLint) of the test article in MLM expressed as Ml/mm/mg protein.
LC-MS/MS analysis
[0284] The analysis of the compounds tinder investigation was performed using LC- MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000 Q-Trap™ mass spectrometer. The separation was achieved using a Cis analytical column (Alltima™, 2.1 X 100 mm, 3 pm) protected by a Cis guard cartridge system (SecuntyGuard™ ULTRA Cartridges UHPL.C for 4.6 mm ID columns, Phenomenex). Mobile phase was consisting of channel A (95% acetonitrile + 5% water + 0,1 % formic acid) and channel C (95% water + 5% acetonitrile + 0.1% formic acid) and was delivered at a flow rate of 0.4 Ml/min. The volume ratio of acetonitrile and water was optimized for each of the analytes. Multiple reaction monitoring scans were made with
curtain gas, collision gas, nebulizer gas, and auxiliary gas optimized for each compound, and source temperature at 55O°C. Molecular ions were formed using an ion spray voltage of -4200 V (negative mode). Declustering potential, entrance potential, collision energy, product ion mass, and cell exit potential were optimized for each compound.
[0285] While the disclosure has been illustrated and described in detail in the foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure and the appended claims.
[0286] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
[0287] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated. Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead
should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the disclosure, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the disclosure. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.
[0288] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Roman numerals and Arabic numerals can be used interchangeably.
[0289] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
[0290] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory’ phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should typically
be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc,” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc. ). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”
[0291] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term ‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
[0292] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description
and examples should not be construed as limiting the scope of the disclosure to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.
Claims
1. A selective androgen receptor degrader (SARD) compound represented by the structure of formula I: wherein
T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR;
Ri is H, CH 3, CH2F, CHF2, CF3, CFI2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is FI, CF3, F, I, Br. Cl, CN, or C(R) 3,
Z is NO?, CN, COOFI, COR, NHCOR, or CONHR;
X is CH or N;
R is FI, alkyl, alkenyl, haloalkyl, alcohol, CH2CFI2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q1, Q2, Q3 or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, benzyl, NCS, maleiniide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
4. A selective androgen receptor degrader (SARD) compound represented by the structure of formula II:
wherein
T is H, OH, OR, OCOR, CI I3 , -NHCOCH3, or NHCOR;
Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3;
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
A is a pyrrole, pyrrolidine, pyrazole, pyrazolidme, triazole, imidazole, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, Q3 or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
7. A selective androgen receptor degrader (SARD) compound represented by the structure of formula III:
T is H, OH. OR, OCOR, CH 3, -NHCOCH3, or NHCOR;
Ri is H, CH.3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
Y is H, CF3, F, I, Br, Cl, CN, or C( R } w
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aiyl, F, Cl, Br, I, or OH; and
A is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole, imidazole, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q1, Q2, O' or Q4, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
10. A selective androgen receptor degrader (SARD) compound represented by the structure of formula IV:
Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
X is CH or N;
Y is I L (T\ IL I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH2F, CHF2, CF3> CH2CH3, or CF2CF3;
T is H, OH, OR, OCOR CH3, -NHCOCHy or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aiyl, F, Cl, Br, I, or OH; and
Q2, Q3 or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR: or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
IVA or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof
12. The SARD compound of claim 10, represented by the structure of formula IVB:
13. A selective androgen receptor degrader (SARD) compound represented by the structure of formula V: wherein
Z is NO2, CN, COOH, COR, NHCOR, or CONOR
X is CH or N;
Y is H, CF3, F, I, Br, Cl, CN, or C(R)3;
Ri is H, CH3, CH2F, CHF2, CFj, CH2CH 3, or CF2CF3;
T is H. OH, OR. (X OR. CH3, -NHCOCH3, or NHCOR, or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q3 or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryL substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NOz, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
16. A selective androgen receptor degrader (SARD) compound represented by the structure of formula VI:
Z is NO2, CN, ( 10011, COR, NHCOR, or CONHR;
X is CH or N;
Y is H, CF\ F, I, Br, Cl, CN, or C(R)3;
Ri is H, CHb, CHzF, CHF2, CF3, CH2CH3, or CF2CF3;
T is H, OH, OR, OCOR, Ci T. -NHCOCHy or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
Q2, Q' or Q4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
19. The SARD compound of any one of claims 1-18, wherein Q1, Q2, Q3 or Q4 is hydrogen, CN, CF3, F, Br, NHCOOR, or substituted or unsubstituted phenyl.
20. A selective androgen receptor degrader (SARD) compound represented by the structure of any one of the following compounds:
21. The compound according to any one of claims 1-20, wherein the compound exhibits at least one of AR-splice variant (AR-SV) degradation activity, full length (AR-FL) degradation activity, AR-SV inhibitory, or AR-FL inhibitory activity.
22. A pharmaceutical composition comprising a SARD compound according to any one of claims 1-21, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition according to claim 22, wherein the composition is formulated for topical use.
24. The pharmaceutical composition according to claim 22, wherein the composition is in the form of a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soaps or bars, emulsion, mousse, aerosol, or shampoo.
25. A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-21, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
26. The method according to claim 25, wherein the prostate cancer is at least one of advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.
27. The method according to claim 25 or 26 further comprising administering androgen deprivation therapy (ADT).
28. The method according to any one of claims 25-27, wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist(s).
29. The method according to claim 28, wherein the androgen receptor antagonist is at least one of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.
30. A method of treating enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1- 21, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
31. A method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-21, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
32. A method of treating triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 -21 , or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
33. A method of reducing the levels of AR-splice variants in a subject comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-21, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
34. A method of treating Kennedy’s disease in a subject comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-21, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
35. A method of treating acne in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22,
36. A method of decreasing sebum production in a subject comprising administering to the subject a therapeutically effecti ve amount of the pharmaceutical composition of claim 22.
37. A method of treating hirsutism or alopecia in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
38. A method of treating a hormonal condition in a female comprising administering to the female a therapeutically effective amount of the pharmaceutical composition of claim 22.
39. The method according to claim 38, wherein the hormonal condition is at least one of precocious puberty, early puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, or vaginal dryness.
40. A method of treating sexual perversion, hypersexuality, or paraphilias in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
41. A method of treating androgen psychosis in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
42. A method of treating virilization in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
43. A method of treating androgen insensitivity syndrome in a subject comprising administering to the subject a therapeutically effective amount of pharmaceutical composition of claim 22.
44. A method of increasing or modulating ovulation in an animal comprising administering to the animal a therapeutically effective amount of the pharmaceutical composition of claim 22.
45. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
46. The method according to claim 45, wherein the cancer is at least one of breast cancer, testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer.
47. A method of reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
48. A method of treating amyotrophic lateral sclerosis (ALS) in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22.
49. A method of treating uterine fibroids in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 22,
50. A method of treating abdominal aortic aneurysm (AAA) in a subject comprising administering a therapeutically effecti ve amount of the pharmaceutical composition of claim 22.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263359126P | 2022-07-07 | 2022-07-07 | |
US63/359,126 | 2022-07-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2024010817A2 true WO2024010817A2 (en) | 2024-01-11 |
WO2024010817A3 WO2024010817A3 (en) | 2024-02-29 |
Family
ID=89454044
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/026942 WO2024010817A2 (en) | 2022-07-07 | 2023-07-05 | Selective androgen receptor degrader (sard) o-linked ligands and methods of use thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024010817A2 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1740533A1 (en) * | 2004-04-22 | 2007-01-10 | Warner-Lambert Company LLC | Androgen modulators |
US7834063B2 (en) * | 2004-10-13 | 2010-11-16 | Glaxosmithkline Llc | Benzonitryl and nitrobenzyl derivatives that modulate androgen receptors |
AU2005307003B2 (en) * | 2004-11-16 | 2011-10-13 | Janssen Pharmaceutica N.V. | Novel heterocycle derivatives useful as selective androgen receptor modulators (SARMs) |
US10314797B2 (en) * | 2016-06-10 | 2019-06-11 | University Of Tennessee Research Foundation | Selective androgen receptor degrader (SARD) ligands and methods of use thereof |
-
2023
- 2023-07-05 WO PCT/US2023/026942 patent/WO2024010817A2/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2024010817A3 (en) | 2024-02-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10314797B2 (en) | Selective androgen receptor degrader (SARD) ligands and methods of use thereof | |
US20230002326A1 (en) | Selective androgen receptor degrader (sard) ligands and methods of use thereof | |
US9815776B2 (en) | Selective androgen receptor degrader (SARD) ligands and methods of use thereof | |
US20210196678A1 (en) | Selective androgen receptor degrader (sard) ligands and methods of use thereof | |
US10806719B2 (en) | Selective androgen receptor degrader (SARD) ligands and methods of use thereof | |
WO2016172358A1 (en) | Selective androgen receptor degrader (sard) ligands and methods of use thereof | |
US11591290B2 (en) | Selective androgen receptor degrader (SARD) ligands and methods of use thereof | |
US9834507B2 (en) | Selective androgen receptor degrader (SARD) ligands and methods of use thereof | |
US20230146829A1 (en) | Selective androgen receptor degrader (sard) ligands and methods of use thereof | |
US20230303496A1 (en) | SELECTIVE ANDROGEN RECEPTOR COVALENT ANTAGONISTS (SARCAs) AND METHODS OF USE THEREOF | |
WO2020051344A1 (en) | Selective androgen receptor degrader (sard) ligands and methods of use thereof | |
WO2024010817A2 (en) | Selective androgen receptor degrader (sard) o-linked ligands and methods of use thereof | |
WO2024010818A2 (en) | Proteolysis targeting chimera (protac) of selective androgen receptor degrader (sard) compounds and methods of use thereof | |
WO2020073017A1 (en) | Selective androgen receptor degrader (sard) ligands and methods of use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23836061 Country of ref document: EP Kind code of ref document: A2 |