MXPA06009953A - Bicyclic substituted indole-derivative steroid hormone nuclear receptor modulators - Google Patents
Bicyclic substituted indole-derivative steroid hormone nuclear receptor modulatorsInfo
- Publication number
- MXPA06009953A MXPA06009953A MXPA/A/2006/009953A MXPA06009953A MXPA06009953A MX PA06009953 A MXPA06009953 A MX PA06009953A MX PA06009953 A MXPA06009953 A MX PA06009953A MX PA06009953 A MXPA06009953 A MX PA06009953A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- disease
- disorders
- represents hydrogen
- compound according
- Prior art date
Links
- 230000000051 modifying Effects 0.000 title claims description 53
- 102000006255 nuclear receptors Human genes 0.000 title description 8
- 239000003270 steroid hormone Substances 0.000 title description 6
- 108020004017 nuclear receptors Proteins 0.000 title description 5
- 125000002619 bicyclic group Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 194
- 239000000203 mixture Substances 0.000 claims abstract description 66
- 201000010099 disease Diseases 0.000 claims abstract description 48
- 239000011780 sodium chloride Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 201000006233 congestive heart failure Diseases 0.000 claims abstract description 27
- 206010020772 Hypertension Diseases 0.000 claims abstract description 19
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 12
- 201000001320 atherosclerosis Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000003085 diluting agent Substances 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- -1 chloro, bromo, methyl Chemical group 0.000 claims description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 38
- 210000004027 cells Anatomy 0.000 claims description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 25
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 22
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 206010061218 Inflammation Diseases 0.000 claims description 17
- 230000004054 inflammatory process Effects 0.000 claims description 17
- 230000001154 acute Effects 0.000 claims description 16
- 230000003205 diastolic Effects 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 206010001367 Adrenal insufficiency Diseases 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 230000001684 chronic Effects 0.000 claims description 12
- 201000001421 hyperglycemia Diseases 0.000 claims description 12
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 11
- 201000004304 Addison's disease Diseases 0.000 claims description 11
- 208000004880 Polyuria Diseases 0.000 claims description 11
- 230000002757 inflammatory Effects 0.000 claims description 11
- 201000004044 liver cirrhosis Diseases 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 210000001519 tissues Anatomy 0.000 claims description 11
- 206010003246 Arthritis Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 206010028594 Myocardial fibrosis Diseases 0.000 claims description 8
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 8
- 206010041277 Sodium retention Diseases 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 210000000056 organs Anatomy 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 201000010874 syndrome Diseases 0.000 claims description 8
- 208000005676 Adrenogenital Syndrome Diseases 0.000 claims description 7
- 208000006673 Asthma Diseases 0.000 claims description 7
- 206010057668 Cognitive disease Diseases 0.000 claims description 7
- 208000008448 Congenital Adrenal Hyperplasia Diseases 0.000 claims description 7
- 201000007397 Conn's syndrome Diseases 0.000 claims description 7
- 206010011652 Cushing's syndrome Diseases 0.000 claims description 7
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 7
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 7
- 230000036826 Excretion Effects 0.000 claims description 7
- 208000010125 Myocardial Infarction Diseases 0.000 claims description 7
- 210000003491 Skin Anatomy 0.000 claims description 7
- 201000008937 atopic dermatitis Diseases 0.000 claims description 7
- 230000033228 biological regulation Effects 0.000 claims description 7
- 230000029142 excretion Effects 0.000 claims description 7
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 7
- MGBKJKDRMRAZKC-UHFFFAOYSA-N 3-aminobenzene-1,2-diol Chemical compound NC1=CC=CC(O)=C1O MGBKJKDRMRAZKC-UHFFFAOYSA-N 0.000 claims description 6
- 206010000496 Acne Diseases 0.000 claims description 6
- 206010002425 Angioedemas Diseases 0.000 claims description 6
- 206010057666 Anxiety disease Diseases 0.000 claims description 6
- 206010059512 Apoptosis Diseases 0.000 claims description 6
- 206010003119 Arrhythmia Diseases 0.000 claims description 6
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 6
- 206010004938 Bipolar disease Diseases 0.000 claims description 6
- 206010048962 Brain oedema Diseases 0.000 claims description 6
- 206010006811 Bursitis Diseases 0.000 claims description 6
- 206010007521 Cardiac arrhythmias Diseases 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 6
- 206010011401 Crohn's disease Diseases 0.000 claims description 6
- 229940104302 Cytosine Drugs 0.000 claims description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N Cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 6
- 206010014954 Eosinophilic fasciitis Diseases 0.000 claims description 6
- 206010015218 Erythema multiforme Diseases 0.000 claims description 6
- 206010015226 Erythema nodosum Diseases 0.000 claims description 6
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 6
- 208000006454 Hepatitis Diseases 0.000 claims description 6
- 206010020112 Hirsutism Diseases 0.000 claims description 6
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 6
- 206010020583 Hypercalcaemia Diseases 0.000 claims description 6
- 206010020993 Hypoglycaemia Diseases 0.000 claims description 6
- 208000001953 Hypotension Diseases 0.000 claims description 6
- 206010024229 Leprosy Diseases 0.000 claims description 6
- 206010024324 Leukaemias Diseases 0.000 claims description 6
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 claims description 6
- 208000010428 Muscle Weakness Diseases 0.000 claims description 6
- 206010028372 Muscular weakness Diseases 0.000 claims description 6
- 210000000066 Myeloid Cells Anatomy 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 206010030113 Oedema Diseases 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 6
- 206010033675 Panniculitis Diseases 0.000 claims description 6
- 241000721454 Pemphigus Species 0.000 claims description 6
- 206010034721 Personality disease Diseases 0.000 claims description 6
- 206010062080 Pigmentation disease Diseases 0.000 claims description 6
- 206010065159 Polychondritis Diseases 0.000 claims description 6
- 206010036067 Polydipsia Diseases 0.000 claims description 6
- 206010061920 Psychotic disease Diseases 0.000 claims description 6
- 208000009954 Pyoderma Gangrenosum Diseases 0.000 claims description 6
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 6
- 210000004761 Scalp Anatomy 0.000 claims description 6
- 208000008513 Spinal Cord Injury Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 206010043255 Tendonitis Diseases 0.000 claims description 6
- 206010043554 Thrombocytopenia Diseases 0.000 claims description 6
- 206010044223 Toxic epidermal necrolysis Diseases 0.000 claims description 6
- 231100000087 Toxic epidermal necrolysis Toxicity 0.000 claims description 6
- 206010046736 Urticarias Diseases 0.000 claims description 6
- 206010047115 Vasculitis Diseases 0.000 claims description 6
- 201000010105 allergic rhinitis Diseases 0.000 claims description 6
- 201000004384 alopecia Diseases 0.000 claims description 6
- 231100000360 alopecia Toxicity 0.000 claims description 6
- 230000006907 apoptotic process Effects 0.000 claims description 6
- 201000000522 chronic kidney disease Diseases 0.000 claims description 6
- 235000009508 confectionery Nutrition 0.000 claims description 6
- 201000001981 dermatomyositis Diseases 0.000 claims description 6
- 230000035619 diuresis Effects 0.000 claims description 6
- 231100000283 hepatitis Toxicity 0.000 claims description 6
- 230000000148 hypercalcaemia Effects 0.000 claims description 6
- 230000002218 hypoglycaemic Effects 0.000 claims description 6
- 230000036543 hypotension Effects 0.000 claims description 6
- 201000011486 lichen planus Diseases 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 230000036210 malignancy Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 201000008895 mood disease Diseases 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 201000011152 pemphigus Diseases 0.000 claims description 6
- 201000001976 pemphigus vulgaris Diseases 0.000 claims description 6
- 230000019612 pigmentation Effects 0.000 claims description 6
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 6
- 230000025627 positive regulation of urine volume Effects 0.000 claims description 6
- 230000035755 proliferation Effects 0.000 claims description 6
- 201000004681 psoriasis Diseases 0.000 claims description 6
- 201000003068 rheumatic fever Diseases 0.000 claims description 6
- 201000000306 sarcoidosis Diseases 0.000 claims description 6
- 230000001629 suppression Effects 0.000 claims description 6
- 201000006704 ulcerative colitis Diseases 0.000 claims description 6
- 230000004580 weight loss Effects 0.000 claims description 6
- 206010003445 Ascites Diseases 0.000 claims description 5
- 206010003816 Autoimmune disease Diseases 0.000 claims description 5
- 208000010062 Bartter Syndrome Diseases 0.000 claims description 5
- 201000009396 Bartter disease Diseases 0.000 claims description 5
- 101710020095 COR9 Proteins 0.000 claims description 5
- 208000001969 Capillary Hemangioma Diseases 0.000 claims description 5
- 208000010247 Contact Dermatitis Diseases 0.000 claims description 5
- 208000004921 Cutaneous Lupus Erythematosus Diseases 0.000 claims description 5
- 206010011732 Cyst Diseases 0.000 claims description 5
- 206010012442 Dermatitis contact Diseases 0.000 claims description 5
- 206010012455 Dermatitis exfoliative Diseases 0.000 claims description 5
- 208000007342 Diabetic Nephropathy Diseases 0.000 claims description 5
- 206010061835 Diabetic nephropathy Diseases 0.000 claims description 5
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 claims description 5
- 208000004526 Exfoliative Dermatitis Diseases 0.000 claims description 5
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 5
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 5
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 5
- 206010034636 Peripheral vascular disease Diseases 0.000 claims description 5
- 206010052381 Primary adrenal insufficiency Diseases 0.000 claims description 5
- 206010038444 Renal failure chronic Diseases 0.000 claims description 5
- 208000003385 Rhinitis, Allergic, Seasonal Diseases 0.000 claims description 5
- 206010039807 Secondary adrenocortical insufficiency Diseases 0.000 claims description 5
- 206010056091 Varices oesophageal Diseases 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 201000006854 congenital adrenal insufficiency Diseases 0.000 claims description 5
- 231100000080 dermatitis contact Toxicity 0.000 claims description 5
- 201000010120 esophageal varix Diseases 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 230000000306 recurrent Effects 0.000 claims description 5
- 238000002054 transplantation Methods 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 208000003543 Lymphoma, T-Cell, Cutaneous Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims description 4
- 201000005962 mycosis fungoide Diseases 0.000 claims description 4
- 230000001919 adrenal Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002685 pulmonary Effects 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 201000004624 dermatitis Diseases 0.000 claims description 2
- 231100000406 dermatitis Toxicity 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 208000001652 Memory Disorders Diseases 0.000 claims 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims 1
- 206010037660 Pyrexia Diseases 0.000 claims 1
- 239000000460 chlorine Chemical group 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 230000000414 obstructive Effects 0.000 claims 1
- 231100000331 toxic Toxicity 0.000 claims 1
- 230000002588 toxic Effects 0.000 claims 1
- 239000000969 carrier Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 68
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 46
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 45
- 238000000034 method Methods 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 230000027455 binding Effects 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- 125000004432 carbon atoms Chemical group C* 0.000 description 35
- 102000005962 receptors Human genes 0.000 description 34
- 108020003175 receptors Proteins 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 125000001931 aliphatic group Chemical group 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 150000002431 hydrogen Chemical class 0.000 description 25
- 108091007893 nuclear steroid hormone receptors Proteins 0.000 description 24
- 239000003446 ligand Substances 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 21
- 101700067048 CDC13 Proteins 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 229960002478 aldosterone Drugs 0.000 description 18
- 241000282414 Homo sapiens Species 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 238000009739 binding Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 102000003998 progesterone receptors Human genes 0.000 description 14
- 238000007792 addition Methods 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 108090000468 progesterone receptors Proteins 0.000 description 13
- 238000000159 protein binding assay Methods 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 102100007495 AR Human genes 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000002395 mineralocorticoid Substances 0.000 description 12
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 12
- 108010080146 androgen receptors Proteins 0.000 description 11
- 238000004166 bioassay Methods 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 10
- 102100002376 NR3C2 Human genes 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- DAZXVJBJRMWXJP-UHFFFAOYSA-N N,N-Dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 230000003042 antagnostic Effects 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 150000002475 indoles Chemical class 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- 239000005089 Luciferase Substances 0.000 description 8
- 102000007399 Nuclear hormone receptors Human genes 0.000 description 8
- 108020005497 Nuclear hormone receptors Proteins 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000008079 hexane Substances 0.000 description 8
- 239000005556 hormone Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 230000002829 reduced Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 229920002676 Complementary DNA Polymers 0.000 description 7
- 229940088597 Hormone Drugs 0.000 description 7
- 229940054051 antipsychotic Indole derivatives Drugs 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000003610 charcoal Substances 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000003862 glucocorticoid Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 125000004430 oxygen atoms Chemical group O* 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 230000002194 synthesizing Effects 0.000 description 7
- BVKRDNIULHRLCO-UHFFFAOYSA-N 2-carboxyethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC(=O)O)C1=CC=CC=C1 BVKRDNIULHRLCO-UHFFFAOYSA-N 0.000 description 6
- 108060001084 Luciferase family Proteins 0.000 description 6
- 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 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- WTFWZOSMUGZKNZ-UHFFFAOYSA-N 1H-indol-7-amine Chemical class NC1=CC=CC2=C1NC=C2 WTFWZOSMUGZKNZ-UHFFFAOYSA-N 0.000 description 5
- IPBNNCSENCVMPY-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indol-7-amine Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1N IPBNNCSENCVMPY-UHFFFAOYSA-N 0.000 description 5
- LZJGQIVWUKFTRD-UHFFFAOYSA-N 7-nitro-1H-indole Chemical class [O-][N+](=O)C1=CC=CC2=C1NC=C2 LZJGQIVWUKFTRD-UHFFFAOYSA-N 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 5
- 210000002370 ICC Anatomy 0.000 description 5
- 210000003734 Kidney Anatomy 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- 230000002354 daily Effects 0.000 description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000002609 media Substances 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 5
- 238000003752 polymerase chain reaction Methods 0.000 description 5
- 239000001184 potassium carbonate Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrugs Drugs 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 229960002256 spironolactone Drugs 0.000 description 5
- 102000005969 steroid hormone receptors Human genes 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 4
- MEWQFKSUHJZGCA-UHFFFAOYSA-N N-(1H-indol-7-yl)methanesulfonamide Chemical class CS(=O)(=O)NC1=CC=CC2=C1NC=C2 MEWQFKSUHJZGCA-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 229960000890 hydrocortisone Drugs 0.000 description 4
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical group ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 229940113083 morpholine Drugs 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000001603 reducing Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 108020003113 steroid hormone receptors Proteins 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- LKKUYGGQEIJGDR-UHFFFAOYSA-N 1-iodopropane Chemical group [CH2]CCI LKKUYGGQEIJGDR-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 3
- 210000004556 Brain Anatomy 0.000 description 3
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N Corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 3
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- 229960003957 Dexamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 206010027175 Memory impairment Diseases 0.000 description 3
- CCCIJQPRIXGQOE-XWSJACJDSA-N Metribolone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C=C2 CCCIJQPRIXGQOE-XWSJACJDSA-N 0.000 description 3
- 108009000118 Nuclear Receptors Proteins 0.000 description 3
- 210000004940 Nucleus Anatomy 0.000 description 3
- 229920001785 Response element Polymers 0.000 description 3
- TVXXNOYZHKPKGW-UHFFFAOYSA-N Sodium molybdate Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 3
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960004544 cortisone Drugs 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 102000015694 estrogen receptors Human genes 0.000 description 3
- 108010038795 estrogen receptors Proteins 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000005842 heteroatoms Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 3
- 150000004694 iodide salts Chemical class 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006011 modification reaction Methods 0.000 description 3
- 150000002829 nitrogen Chemical group 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 230000035790 physiological processes and functions Effects 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002633 protecting Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011684 sodium molybdate Substances 0.000 description 3
- 235000015393 sodium molybdate Nutrition 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- DKMPQUMKZCYVKU-DUXPYHPUSA-N (E)-4-(3-fluorophenyl)but-3-enoic acid Chemical compound OC(=O)C\C=C\C1=CC=CC(F)=C1 DKMPQUMKZCYVKU-DUXPYHPUSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 2,3-dihydrochromen-4-one Chemical class C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 2
- PEUTYYUKCAHEOK-UHFFFAOYSA-N 3-(3-fluorophenoxy)propan-1-ol Chemical compound OCCCOC1=CC=CC(F)=C1 PEUTYYUKCAHEOK-UHFFFAOYSA-N 0.000 description 2
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 description 2
- SFUDEIQDDYJRKV-UHFFFAOYSA-N 4-(3-fluorophenyl)butanoic acid Chemical compound OC(=O)CCCC1=CC=CC(F)=C1 SFUDEIQDDYJRKV-UHFFFAOYSA-N 0.000 description 2
- WVPPBVAMKNQXJA-UHFFFAOYSA-N 5-fluoro-2,3-dihydroinden-1-one Chemical compound FC1=CC=C2C(=O)CCC2=C1 WVPPBVAMKNQXJA-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 229940092229 Aldactone Drugs 0.000 description 2
- 229940083712 Aldosterone antagonists Drugs 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N Ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 206010007554 Cardiac failure Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 241000288140 Gruiformes Species 0.000 description 2
- 206010019280 Heart failure Diseases 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 2
- 206010037833 Rales Diseases 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N Tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 230000036462 Unbound Effects 0.000 description 2
- HKNSIVFWRXBWCK-UHFFFAOYSA-N [N].NC1=CC=CC=C1 Chemical group [N].NC1=CC=CC=C1 HKNSIVFWRXBWCK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002170 aldosterone antagonist Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001445 alitretinoin Drugs 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- NHSHQNSOEFPNBH-UHFFFAOYSA-N benzyl N-(1H-indol-7-yl)carbamate Chemical compound C=1C=CC=2C=CNC=2C=1NC(=O)OCC1=CC=CC=C1 NHSHQNSOEFPNBH-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000000271 cardiovascular Effects 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- 235000013985 cinnamic acid Nutrition 0.000 description 2
- 229930016911 cinnamic acid Natural products 0.000 description 2
- 150000001851 cinnamic acid derivatives Chemical class 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 230000002255 enzymatic Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical class C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 2
- 200000000018 inflammatory disease Diseases 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000004789 organ systems Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920003124 powdered cellulose Polymers 0.000 description 2
- 235000019814 powdered cellulose Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 102000003702 retinoic acid receptors Human genes 0.000 description 2
- 108090000064 retinoic acid receptors Proteins 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 239000005495 thyroid hormone Substances 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- GDBQQVLCIARPGH-ULQDDVLXSA-N (2S)-2-acetamido-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-Tetralone Chemical class C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PBMFUBPKVFLXQY-UHFFFAOYSA-N 1H-indol-3-yl propanoate Chemical class C1=CC=C2C(OC(=O)CC)=CNC2=C1 PBMFUBPKVFLXQY-UHFFFAOYSA-N 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M 2,3-dimethylbenzenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-M 2-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-M 0.000 description 1
- AFENDNXGAFYKQO-UHFFFAOYSA-M 2-hydroxybutyrate Chemical compound CCC(O)C([O-])=O AFENDNXGAFYKQO-UHFFFAOYSA-M 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GHOFWSMGTDAKCE-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1-methyl-7-nitroindole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CN(C)C2=C1[N+]([O-])=O GHOFWSMGTDAKCE-UHFFFAOYSA-N 0.000 description 1
- WNKKAVKVBMPNBB-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1-methylindol-7-amine Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CN(C)C2=C1N WNKKAVKVBMPNBB-UHFFFAOYSA-N 0.000 description 1
- NBNYIBBDLWFGBL-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1 NBNYIBBDLWFGBL-UHFFFAOYSA-N 0.000 description 1
- ZCMHSHSGVKBEAL-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-7-fluoro-1H-indole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1F ZCMHSHSGVKBEAL-UHFFFAOYSA-N 0.000 description 1
- JLKBESFXROPUIX-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-7-methoxy-1H-indole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1OC JLKBESFXROPUIX-UHFFFAOYSA-N 0.000 description 1
- DKGVNILGIIDVIF-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-7-nitro-1H-indole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1[N+]([O-])=O DKGVNILGIIDVIF-UHFFFAOYSA-N 0.000 description 1
- XQOMHIZHGVPQSF-UHFFFAOYSA-N 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-N,N-dimethyl-1H-indole-7-sulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1S(=O)(=O)N(C)C XQOMHIZHGVPQSF-UHFFFAOYSA-N 0.000 description 1
- SAAKANGUQMVTHQ-UHFFFAOYSA-N 3-(3,5-difluorophenyl)propanoic acid Chemical compound OC(=O)CCC1=CC(F)=CC(F)=C1 SAAKANGUQMVTHQ-UHFFFAOYSA-N 0.000 description 1
- TWGIQPNNPXKPLC-UHFFFAOYSA-N 3-(3-fluorophenoxy)propanoic acid Chemical compound OC(=O)CCOC1=CC=CC(F)=C1 TWGIQPNNPXKPLC-UHFFFAOYSA-N 0.000 description 1
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 description 1
- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 108091005482 5-HT6 receptors Proteins 0.000 description 1
- JBRVVXZFLROXOL-UHFFFAOYSA-N 5-fluoro-7-nitro-1H-indole Chemical compound [O-][N+](=O)C1=CC(F)=CC2=C1NC=C2 JBRVVXZFLROXOL-UHFFFAOYSA-N 0.000 description 1
- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical compound FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 1
- NJYZZEHPEKDFEK-UHFFFAOYSA-N 6-fluoro-3,4-dihydro-2H-naphthalen-1-one Chemical compound O=C1CCCC2=CC(F)=CC=C21 NJYZZEHPEKDFEK-UHFFFAOYSA-N 0.000 description 1
- LQFISYBDTLTLRE-UHFFFAOYSA-N 7-bromo-3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1Br LQFISYBDTLTLRE-UHFFFAOYSA-N 0.000 description 1
- XOMFQRPHXMTJSG-UHFFFAOYSA-N 7-bromo-5-fluoro-1H-indole Chemical compound FC1=CC(Br)=C2NC=CC2=C1 XOMFQRPHXMTJSG-UHFFFAOYSA-N 0.000 description 1
- WMYQAKANKREQLM-UHFFFAOYSA-N 7-chloro-1H-indole Chemical compound ClC1=CC=CC2=C1NC=C2 WMYQAKANKREQLM-UHFFFAOYSA-N 0.000 description 1
- IVDUSYPYGUXWTF-UHFFFAOYSA-N 7-chloro-3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indole Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1Cl IVDUSYPYGUXWTF-UHFFFAOYSA-N 0.000 description 1
- PIIZLMYXLGYWTN-UHFFFAOYSA-N 7-ethyl-1H-indole Chemical compound CCC1=CC=CC2=C1NC=C2 PIIZLMYXLGYWTN-UHFFFAOYSA-N 0.000 description 1
- LFUAHJRKQMAPLF-UHFFFAOYSA-N 7-ethyl-3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indole Chemical compound C1CC2=CC(F)=CC=C2C1(CC)C1=CNC2=C1C=CC=C2CC LFUAHJRKQMAPLF-UHFFFAOYSA-N 0.000 description 1
- XONKJZDHGCMRRF-UHFFFAOYSA-N 7-fluoro-1H-indole Chemical compound FC1=CC=CC2=C1NC=C2 XONKJZDHGCMRRF-UHFFFAOYSA-N 0.000 description 1
- HRPULQFHSZKTNA-UHFFFAOYSA-N 7-fluoro-2,3-dihydrochromen-4-one Chemical compound O=C1CCOC2=CC(F)=CC=C21 HRPULQFHSZKTNA-UHFFFAOYSA-N 0.000 description 1
- FSOPPXYMWZOKRM-UHFFFAOYSA-N 7-methoxy-1H-indole Chemical compound COC1=CC=CC2=C1NC=C2 FSOPPXYMWZOKRM-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 229940030486 ANDROGENS Drugs 0.000 description 1
- 101000169408 AR Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 206010003885 Azotaemia Diseases 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 229910014585 C2-Ce Inorganic materials 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 210000001736 Capillaries Anatomy 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007541 Cardiac disease Diseases 0.000 description 1
- 208000005846 Cardiomyopathy Diseases 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- 210000000805 Cytoplasm Anatomy 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 1
- 229940030606 DIURETICS Drugs 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N Digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 230000036947 Dissociation constant Effects 0.000 description 1
- 229940052760 Dopamine agonists Drugs 0.000 description 1
- 240000006775 Enicostema verticillatum Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- JUKPWJGBANNWMW-VWBFHTRKSA-N Eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000272184 Falconiformes Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010017788 Gastric haemorrhage Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 208000002907 Heart Valve Disease Diseases 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000002682 Hyperkalemia Diseases 0.000 description 1
- 206010020679 Hypernatraemia Diseases 0.000 description 1
- 229960001438 IMMUNOSTIMULANTS Drugs 0.000 description 1
- 229940060367 Inert Ingredients Drugs 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N Iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 206010024119 Left ventricular failure Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010025135 Lupus erythematosus Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027339 Menstruation irregular Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010027626 Milia Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor family Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor family Proteins 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N N,N-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N N-Propyl iodide Chemical class CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- DFFOUKGEAKZASN-UHFFFAOYSA-N N-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1CCC2=CC=CC=C2C1C1=CNC2=C1C=CC=C2NS(=O)(=O)C DFFOUKGEAKZASN-UHFFFAOYSA-N 0.000 description 1
- XDFLQPYWAMEDCN-UHFFFAOYSA-N N-[3-(1-ethyl-3,4-dihydro-2H-naphthalen-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=CC=C4CCC3)CC)=CNC2=C1NS(C)(=O)=O XDFLQPYWAMEDCN-UHFFFAOYSA-N 0.000 description 1
- MZTMZDVNPDIASM-UHFFFAOYSA-N N-[3-(1-ethyl-5,7-difluoro-2,3-dihydroinden-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=C(F)C=C(F)C=C4CC3)CC)=CNC2=C1NS(C)(=O)=O MZTMZDVNPDIASM-UHFFFAOYSA-N 0.000 description 1
- FGPPUDPSWDTJCE-UHFFFAOYSA-N N-[3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1-methylindol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CN(C)C2=C1NS(C)(=O)=O FGPPUDPSWDTJCE-UHFFFAOYSA-N 0.000 description 1
- TZQDYZNBUAUAGX-UHFFFAOYSA-N N-[3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indol-7-yl]acetamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1NC(C)=O TZQDYZNBUAUAGX-UHFFFAOYSA-N 0.000 description 1
- UPZAWBIVUQACCR-UHFFFAOYSA-N N-[3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indol-7-yl]ethanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1NS(=O)(=O)CC UPZAWBIVUQACCR-UHFFFAOYSA-N 0.000 description 1
- CLMPDJFEJHZWAE-UHFFFAOYSA-N N-[3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1NS(C)(=O)=O CLMPDJFEJHZWAE-UHFFFAOYSA-N 0.000 description 1
- FJTDPQYTBPZTNF-UHFFFAOYSA-N N-[3-(1-ethyl-6-fluoro-3,4-dihydro-2H-naphthalen-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CCC3)CC)=CNC2=C1NS(C)(=O)=O FJTDPQYTBPZTNF-UHFFFAOYSA-N 0.000 description 1
- NGALNQRGFPNXIE-UHFFFAOYSA-N N-[3-(1-methyl-2,3-dihydroinden-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=CC=C4CC3)C)=CNC2=C1NS(C)(=O)=O NGALNQRGFPNXIE-UHFFFAOYSA-N 0.000 description 1
- OQGAFDCOEDZWIX-UHFFFAOYSA-N N-[3-(4-ethyl-5,7-difluoro-2,3-dihydrochromen-4-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=C(F)C=C(F)C=C4OCC3)CC)=CNC2=C1NS(C)(=O)=O OQGAFDCOEDZWIX-UHFFFAOYSA-N 0.000 description 1
- CBEGOFASQXKPPQ-UHFFFAOYSA-N N-[3-(4-ethyl-7-fluoro-2,3-dihydrochromen-4-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4OCC3)CC)=CNC2=C1NS(C)(=O)=O CBEGOFASQXKPPQ-UHFFFAOYSA-N 0.000 description 1
- FCJQSWKTRFMANI-UHFFFAOYSA-N N-[3-(4-methyl-2,3-dihydrochromen-4-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=CC=C4OCC3)C)=CNC2=C1NS(C)(=O)=O FCJQSWKTRFMANI-UHFFFAOYSA-N 0.000 description 1
- IDRHGOFQVRNTAU-UHFFFAOYSA-N N-[3-(4-methyl-2,3-dihydrothiochromen-4-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=CC=C4SCC3)C)=CNC2=C1NS(C)(=O)=O IDRHGOFQVRNTAU-UHFFFAOYSA-N 0.000 description 1
- VEKZMALNRAQOJO-UHFFFAOYSA-N N-[3-(5,7-difluoro-1-methyl-2,3-dihydroinden-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=C(F)C=C(F)C=C4CC3)C)=CNC2=C1NS(C)(=O)=O VEKZMALNRAQOJO-UHFFFAOYSA-N 0.000 description 1
- QTJVIZIRRNIIIW-UHFFFAOYSA-N N-[3-(5-fluoro-1-methyl-2,3-dihydroinden-1-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)C)=CNC2=C1NS(C)(=O)=O QTJVIZIRRNIIIW-UHFFFAOYSA-N 0.000 description 1
- LYAIAEDTXJLUQJ-UHFFFAOYSA-N N-[3-(6-fluoro-4-methyl-2,3-dihydrochromen-4-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC(F)=CC=C4OCC3)C)=CNC2=C1NS(C)(=O)=O LYAIAEDTXJLUQJ-UHFFFAOYSA-N 0.000 description 1
- AZSBKRNIVPDJAO-UHFFFAOYSA-N N-[3-(7-fluoro-4-methyl-2,3-dihydrochromen-4-yl)-1H-indol-7-yl]methanesulfonamide Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4OCC3)C)=CNC2=C1NS(C)(=O)=O AZSBKRNIVPDJAO-UHFFFAOYSA-N 0.000 description 1
- WHVGXADXWUPBPR-UHFFFAOYSA-N N-[3-[5-fluoro-1-(3-iodopropyl)-2,3-dihydroinden-1-yl]-1H-indol-7-yl]methanesulfonamide Chemical compound C1CC2=CC(F)=CC=C2C1(CCCI)C1=CNC2=C1C=CC=C2NS(=O)(=O)C WHVGXADXWUPBPR-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- 101710027499 Os03g0268000 Proteins 0.000 description 1
- 206010025310 Other lymphomas Diseases 0.000 description 1
- 229940100467 POLYVINYL ACETATE PHTHALATE Drugs 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 210000001774 Pressoreceptors Anatomy 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 229940048084 Pyrophosphate Drugs 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000009169 Relapsing Polychondritis Diseases 0.000 description 1
- 108009000466 Renin Angiotensin Aldosterone System (RAAS) Proteins 0.000 description 1
- 229940076279 Serotonin Drugs 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010085012 Steroid Receptors Proteins 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 206010071436 Systolic dysfunction Diseases 0.000 description 1
- 210000001744 T-Lymphocytes Anatomy 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J Tetrasodium pyrophosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 description 1
- 229960001727 Tretinoin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N Triphenylphosphine oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- 229940046008 Vitamin D Drugs 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- DXGTUUQHTDOFFQ-UHFFFAOYSA-N [N].C1=CC=C2NC=CC2=C1 Chemical group [N].C1=CC=C2NC=CC2=C1 DXGTUUQHTDOFFQ-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000003281 allosteric Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229920002892 amber Polymers 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000011162 ammonium carbonates Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000003288 anthiarrhythmic Effects 0.000 description 1
- 230000001772 anti-angiogenic Effects 0.000 description 1
- 230000001396 anti-anti-diuretic Effects 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000002519 antifouling agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 108091008020 baroreceptors Proteins 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- YNKBWASXNYFOTQ-UHFFFAOYSA-N benzyl N-[3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indol-7-yl]carbamate Chemical compound C1CC2=CC(F)=CC=C2C1(CC)C(C1=CC=C2)=CNC1=C2NC(=O)OCC1=CC=CC=C1 YNKBWASXNYFOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000002051 biphasic Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M caprate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 201000008031 cardiomyopathy Diseases 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001149 cognitive Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 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
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000008286 diarrhea Diseases 0.000 description 1
- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- 230000003467 diminishing Effects 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- XGZRAKBCYZIBKP-UHFFFAOYSA-L disodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[Na+] XGZRAKBCYZIBKP-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000008391 electroluminescent agent Substances 0.000 description 1
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 108091007046 endothelial receptors Proteins 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 210000002919 epithelial cells Anatomy 0.000 description 1
- 229960001208 eplerenone Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003850 glucocorticoid receptor antagonist Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003054 hormonal Effects 0.000 description 1
- 102000034729 human AR protein Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000004179 hypothalamic–pituitary–adrenal axis Effects 0.000 description 1
- 230000003344 immunostimulant Effects 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000297 inotrophic Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 102000027634 intracellular receptors Human genes 0.000 description 1
- 108091007905 intracellular receptors Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- RAGALTIACFNKSO-UHFFFAOYSA-N methyl 3-(1-ethyl-5-fluoro-2,3-dihydroinden-1-yl)-1H-indole-7-carboxylate Chemical compound C1=CC=C2C(C3(C4=CC=C(F)C=C4CC3)CC)=CNC2=C1C(=O)OC RAGALTIACFNKSO-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical compound C[Cl-]OC=O UAVOCTDYPKOULU-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
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000269 nucleophilic Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-M oxolane-2-carboxylate Chemical compound [O-]C(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-M 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 229960004723 phenylbutyrate Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000003428 phospholipase inhibitor Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 108010042121 probasin Proteins 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical compound CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N propyl 3,4,5-trihydroxybenzoate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 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
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-M pyridine;chloride Chemical compound [Cl-].C1=CC=NC=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-M 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 201000010384 renal tubular acidosis Diseases 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 230000001718 repressive Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 230000035916 transactivation Effects 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
- 108090000464 transcription factors Proteins 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004961 triphenylmethanes Chemical class 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 230000000261 vasodilator Effects 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 102000009310 vitamin D receptors Human genes 0.000 description 1
- 108050000156 vitamin D receptors Proteins 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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
Abstract
The present invention provides a compound of the formula:Formula (I);or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising an effective amount of a compound of Formula I in combination with a suitable carrier, diluent, or excipient, and methods for treating physiological disorders, particularly congestive heart disease, hypertension, and atherosclerosis, comprising administering to a patient in thereof an effective amount of a compound of Formula I. X-16125
Description
MODULATORS OF THE NUCLEAR RECEIVER OF THE HORMONE STEROID DERIVATIVES OF INDOL BICÍCLICO SUBSTITUTES
BACKGROUND OF THE INVENTION Nuclear hormone receptors are an evolutionarily conserved class of intracellular receptor proteins, which have been called "ligand-dependent transcription factors". Evans et al. , SCIENCE, 240: 889 (1988). The superfamily of the nuclear hormone receptor gene encodes structural receptor proteins related to glucocorticoids (eg, cortisol, corticosterone, cortisone), androgens, mineral corticosteroids (eg, aldosterone), progestins, estrogen, and thyroid hormone. Also included within this superfamily of nuclear receptors are receptor proteins for vitamin D, retinoic acid, 9-cis retinoic acid, as well as those receptors for which no cognate ligands ("orphan receptors") have been identified, Ribeiro et al. . , Annual Rev. Med., 46: 443-453 (1995). The steroid hormone receptors represent a subset of the nuclear hormone receptor superfamily. So called in accordance with the cognate ligand which forms complexes with the receptor in its native state, the nuclear steroid hormone receptors include the glucocorticoid receptor (GR), the androgen receptor (AR), the ineralcorticoid receptor (MR), the Estrogen receptor (ER), and the progesterone receptor (PR). Tenbaum et al. , Int. J. Biochem. Cell. Biol., 29 (12): 1325-1341 (1997). Contrary to membrane-bound receptors, the nuclear hormone receptors find their respective ligands after the entry of the ligand into the cell, once ligand binding occurs, the ligand-receptor complex modulates the transcription of target genes inside the nucleus of the cell. For example, most ligand-free nuclear receptors are bound in a complex with heat shock proteins (PCT) in the cytoplasm. After the entry of the circulating hormone into the cell, the binding stimulates a conformational change in the receptor, dissociating the receptor from the pct. The receptors bound to the ligand are translocated to the nucleus, where as monomers, as well as hetero and homodimers they bind to particular hormone response elements (ERH) in the promoter regions of target genes. The ERH-receptor complex then, on the other hand, regulates the transcription of locally located genes, (see Ribeiro et al., Supra.). On the other hand, the thyroid hormone (RT) receptors and other non-steroidal receptors such as the vitamin D receptor (RVD) and retinoic acid receptors (RAR) are bound to their respective ERH in the absence of PCTs and / or cognate ligands. Hormones released from the circulation enter the cell, binding in the nucleus to these receptors which, in turn, hetero-dimerize other nuclear receptors such as 9-cis retinoic acid (RXR). As with nuclear steroid hormone receptors, after binding to the ligand, the receptor complex bound to the ligand again regulates the transcription of nearby genes. The ineralcorticoids and glucocorticoids exert profound influences on a multitude of physiological functions by virtue of their various functions in the growth, development and maintenance of homeostasis. The actions are mediated by the MC and GR, which carry approximately 94% homology in their respective DNA binding regions, and approximately 57% homology in their respective ligand binding domains. Kino et al. , J. of Endocrinology, 169, 437-445 (2001). In visceral tissues, such as the kidney and intestine, MR regulates sodium retention, potassium excretion and water balance, in response to aldosterone. In addition, the expression of MR in the brain, seems to play a role in the control of neuronal excitability, in the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, in the cognitive aspects of behavior performance. Castren et al. , J. of Neuroendocrinology, 3, 461-466 (1993). The GR, which is ubiquitously expressed in almost all tissue and organ systems, is crucial for the integrity of central nervous system function and the maintenance of cardiovascular, metabolic and immune homeostasis. Kino et al. , J. of Endocrinology, 169, 437-445 (2001). Elevations in aldosterone levels, or stimulation in excess of mineralcorticoid receptors, are linked to various physiological disorders or pathological disease states including, Conn syndrome, primary hyperaldosteronism and secondary hyperaldosteronism, increased sodium retention, increased excretion of magnesium and potassium (diuresis), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bertter syndrome and disorders associated with catecholamine excess levels. Hadley, M.E., ENDOCRINOLOGY, 2nd. Ed., Pp. 366-381, (1988); and Brilla et al. , Journal of Molecular and Cellular Cardiology, 25 (5), pp. 563-575 (1993). Additionally, elevated aldosterone levels have been increasingly implicated with congestive heart failure (CHF). In CHF, heart failure activates hormonal mechanisms in other organs, in response to reductions in attention to blood flow and blood pressure seen in CHF. In particular, the kidney activates the renin-angiotensin-aldosterone system (RAAS), causing an increase in the production of aldosterone by the adrenals which, in turn, promote water and sodium retention, potassium loss and additional edema. Although aldosterone was historically thought to have participated in the etiology of CHF only as a result of its salt retention effects, several recent studies have implicated elevated levels of aldosterone with events in extra-adrenal tissues and organs, such as myocardial fibrosis and vascular, direct vascular damage and baroreceptor dysfunction. Pitt et al. , New Eng. J. Med., 341: 709-717 (1999). These findings are particularly significant, since inhibitors of the angiotensin-converting enzyme (ACE), which were once indicated to completely abolish aldosterone production, are now believed to only temporarily suppress aldosterone production, which has been shown to occur in extra-adrenal tissues, which include the heart and vasculature. Eber, New Eng. J. Med., 341: 753-755 (1999); Fardella and Miller, Annu. Rev. Nutr., 16: 443-470 (1996). The involvement of aldosterone acting via MR in ICC was confirmed in the recently completed RALES study (Aldactone Randomized Evaluation Study). Pitt et al. , New. Eng. J. Med., 341: 709-717 (1999). The RALES study demonstrates that the use of Aldactone ™ (spironolactone), a well-known competitive MR antagonist, in combination with standard ICC therapy, reduces the cardiac-related mortality by 30% and the frequency of hospitalization by 35% in patients who suffer of advanced ICC. However, spironolactone therapy has also been associated with side effects of attention, such as gastric bleeding, diarrhea, azotemia, hyperchloremic metabolic acidosis, renal tubular acidosis type 4, nausea, gynecomastia, erectile dysfunction, hyperkalemia, and irregular menstruation. Thus, the mineralcorticoid receptor represents a viable target for ICC therapy either alone or in combination with conventional ICC therapies such as, vasodilators (ACE inhibitors), inotropics (digoxin), diuretics or beta-blockers. Molecules, preferably non-steroids, which bind to the mineralcorticoid receptor and modulate receptor activity without the attendant side effects of current therapies, could be particularly desirable. Recently, aldosterone blockers, selective in the treatment of atherosclerosis, have been implicated. S. Keider, et al., Cardiovascular Pharmacology 41 (6), 955-963 (2003). Finally, the published international PCT application WO 02/17895, discloses that aldosterone antagonists are useful in the treatment of subjects suffering from one or more cognitive dysfunctions including, but not limited to, psychoses, cognitive disorders (such as memory disturbances), mood disorders (such as depression and bipolar disorders), anxiety disorders and personality disorders. Glucocorticoids (eg, cortisol, corticosterone and cortisone), and the glucocorticoid receptor, have also been implicated in the etiology of a variety of physiological disorders or disease states of disease. For example, cortisol hyposecretion is implicated in the pathogenesis of Addison's Disease and may result in muscle weakness, increased skin melanin pigmentation, weight loss, hypotension, and hypoglycemia. On the other hand, excessive or prolonged glucocorticoid secretion has been correlated with Cushing's syndrome and may also result in obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria and polydipsia. Hadley, M.E., ENDOCRINOLOGY, 2nd. Ed., Pp. 366-381 (1988). In addition, US Patent No. 6,166,013, published on December 26, 2000, discloses that GR-selective agents could modulate GR activity and thus be useful in the treatment of inflammation, tissue rejection, self-immunity , malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, proliferation / immune apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little. U.S. Patent No. 6,166,013 also discloses that GR modulators are especially useful in disease states involving systemic inflammation, such as inflammatory bowel disease, systemic lupus erythematosus, polyarthritis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis. , orteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis and cirrhosis; and compounds that modulate GR have been used as immunostimulants, repressors and as wound healers and tissue repair agents. In addition, US Patent No. 6,166,013 also discloses that GR modulators have also found use in a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cystis, atopic dermatitis, pyoderma gangrenosum , pemphigus vulgaris, pemphigus bulosus, systemic lupus erythematosus, dermatomyositis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type I, and capillary angiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme and cutaneous lymphoid-T cells. Thus, it is clear that a ligand which has the affinity for nuclear steroid hormone receptors, and particularly for MR and / or GR, could be used to modulate (that is, suppress, antagonize, agonize , partially antagonizing, partially agonizing) the activity of the receptor and directing the expression of the gene, thereby, influencing a multitude of physiological functions related to alterations in steroid hormone levels and / or steroid hormone receptor activity. In this regard, such ligands could be used to treat a wide range of physiological disorders susceptible to modulation of the nuclear steroid hormone receptor. Published literature references describe indole-derived molecules useful in a wide range of indications from electroluminescent agents to anti-fouling agents. In addition, indole-derived compounds have also been described as having pharmacological utility as, inter alia, serotonin 5HT-6 receptor modulators, anticoagulant, antiangiogenic, antiparasitic agents, integrin inhibitors, phospholipase inhibitors, endothelial receptor antagonists, antiarrhythmics and dopamine antagonists. Surprisingly, however, and in accordance with the present invention, applicants have discovered a series of non-steroidal indole derivatives, particularly bicyclic substituted indole derivatives, with affinity for the nuclear steroid hormone receptors, and particularly, for MR and GR. Such compounds can modulate the activity of the nuclear receptor and, therefore, have utility in treating physiological disorders related to alterations in the level of the steroid hormone and / or alterations in the activity of the nuclear receptor of the steroid hormone. Furthermore, such compounds could indicate a broad sense and need for continuation of safe and effective pharmaceutical interventions without the side effects of attention to steroidal agents. The treatment of disorders related to the steroid hormone is thereby encouraged. The following references describe examples of the state of the art as it relates to the present invention. The International PCT application published WO
96/19458 and U.S. Patent Nos. 5,696,130; 5,994,544; 6,017,924, and 6,121,450, describe quinoline-derived analogs as modulators of the steroid hormone receptor. The International Published PCT application WO
00/06137 and U.S. Patent No. 6,166,013 describe triphenylmethane compounds as glucocorticoid receptor modulators. U.S. Patent No. 6,147,066 discloses ani-mineralcorticoid receptor compounds for use in the treatment of drug abstinence syndrome. U.S. Patent Nos. 6,008,210 and
No. 6,093,708, discloses spirolactone compounds, such as spironolactone and epoxymexrenone, with affinity for the mineralcorticoid receptor for use in the treatment of myocardial fibrosis. The International Published PCT Application WO
02/17895, discloses that aldosterone antagonists are useful in the treatment of subjects suffering from one or more cognitive functions. The International Published PCT Application WO 02/09683, discloses aldosterone blockers useful for treating inflammatory disorders. The Published International PCT Application WO 02/051832 describes heterocyclalkylindoles as 5HT-6 ligands. The International Published PCT Application WO
02/016348, discloses indole-derived molecules as anti-angiogenic agents. The International Published PCT Application WO 02/012227 discloses nine- and ten-element bicyclic heteroaryl molecules as inhibitors of angiogenesis. The International Published PCT Application WO 01/058893 discloses indole-3-yl propionates as integrin inhibitors. The published International PCT Application WO 99/43672 describes indole derivatives as inhibitors of the enzyme phospholipase. The published International PCT Application WO 98/42696 and related family elements describe inhibitors of nitric oxide synthase. The International Published PCT Application WO
97/43260 and related family elements describe indole derivatives useful as endothelin receptor antagonists. The published International PCT Application WO 96/03377 and related family elements describe heterocyclic compounds useful as allosteric effectors of muscarinic receptors. US Patent EP683166 discloses l- (3-indolyalkyl) -4- (3-indolyl) piperidines as dopamine agonists or antagonists. Japanese Patent JP 05339565 and JP 3229654 describe indole derivatives for electroluminescent devices. U.S. Patent No. 5,342,547 discloses indole derivatives for controlling underwater incrustations. Whitehead and Whitesitt, Journal of Medicinal Chemistry (1974), 17 (12), 1298-304 describes the effects of lipophilic substituents on the biological properties of Inners. The Co-pending International Patent Application
PCT / US04 / 0017 describes indole derivatives as modulators of the mineralcorticoid and glucocorticoid receptor.
BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to the discovery that certain indole derivative compounds, as defined below, are modulators of the nuclear steroid hormone receptors and, therefore, may have utility as pharmaceutical agents. Accordingly, the present invention provides a compound of the formula:
Formula I wherein, X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, -CH2S-, or -CH2NR10-; R1 represents hydrogen, (C1-C4) alkyl, (C3-C) cycloalkyl, (C1-C4) hydroxyalkyl, haloalkyl
(C1-C4), (C1-C4) alkyl -heterocycle, (C1-C4) alkyl-NH-alkylamino (C1-C4), or (C1-C4) alkyl-N, N-dialkylamine
(C1-C4); R 2 represents hydrogen, halo, (C 1 -C 4) alkyl, heterocycle, or substituted heterocycle; R3 represents hydrogen, halo, (C1-C4) alkyl, heterocycle, or substituted heterocycle; R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, NHS02R7, NHCOR8, or COR9; R5 represents hydrogen or halo; R6 represents hydrogen or (C1-C4) alkyl; R7 represents alkyl (Cj.-C4), aryl, NHalkylamine (C1-C4), or N, N-dialkylamine (C1-C4); R8 represents (C? -C4) alkyl, (C1-C4) alkoxy or (C1-C4) arylalkoxy; and R9 represents alkyl (C? -C4) or alkoxy (Cj-C); R10 represents hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl- (C3-C7) cycloalkyl; or a pharmaceutically acceptable salt thereof. As another aspect, the present invention provides a method for treating a physiological disorder susceptible to modulation of the nuclear steroid hormone receptor comprising, administering to a patient in need thereof, an effective amount of a compound of Formula I as described in this document and previously. Examples of such disorders include Conn syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness , increased pigmentation of melanin in the skin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, rejection of associated tissue with the organ transplant, malignancies such as leukemia and lympholas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of cytosine balance Thl / Th2, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little syndrome, systemic inflammation, inflammatory disease of the intestine, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, dermatitis is exfoliative, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum , pemphigus vulgaris, pemphigus bullosa, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, lymphoma cutaneous T cells, psychosis, cognitive disorders (such as memory disturbances), mood disorders (such as depression and bipolar disorder), anxiety disorders and personality disorders. As a further aspect, the present invention provides a method for treating a physiological disorder susceptible to modulation of the mineralocorticoid or glucocorticoid receptor, which comprises administering to a patient in need thereof, an effective amount of a compound of Formula I as described herein. document and previously. As a particular aspect, the present invention provides a method for treating a physiological disorder susceptible to antagonism of the mineralocorticoid or glucocorticoid receptor., comprising administering to a patient in need thereof, an effective amount of a compound of Formula I. As an even more particular aspect, the present invention provides a method for treating hypertension (isolated systolic and systolic / combined diastolic), heart failure congestive systolic and / or diastolic, atherosclerosis, arthritis or rheumatoid inflammation comprising administering to a patient in need thereof, an effective amount of a compound of Formula I as described herein and above. As a separate aspect, the present invention also provides a method for modulating a nuclear steroid hormone receptor, comprising contacting said receptor with an effective amount of a compound of Formula I. More particularly, the present invention provides a method for modulating the mineralocorticoid or glucocorticoid receptor comprising contacting said receptor with an effective amount of a compound of Formula I. More particularly, the present invention provides a method for antagonizing the mineralocorticoid or glucocorticoid receptor comprising contacting said receptor with a effective amount of a compound of Formula I, as described herein and above. In addition, the present invention provides pharmaceutical compositions of compounds of Formula I, which include any of the pharmaceutically acceptable salts and hydrates thereof, which comprise a compound of Formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of Formula I. The present invention also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a physiological disorder susceptible to modulation of the nuclear steroid hormone receptor. More particularly, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating hypertension, congestive heart failure, atherosclerosis, arthritis or rheumatoid inflammation. Still further, the present invention also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a physiological disorder susceptible to modulation of the nuclear steroid hormone receptor. More particularly, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating hypertension, congestive heart failure, atherosclerosis, arthritis or rheumatoid inflammation.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula I with affinity for nuclear steroid hormone receptors, particularly MR and / or GR, which can be used to modulate (i.e., repress, antagonize, agonize, partially antagonize, partially agonizing) the activity of the nuclear receptor and expression of the target gene, thereby influencing physiological functions related to steroid hormone levels and / or steroid hormone receptor activity. In this regard, the compounds of Formula I are believed to be useful in the treatment or prevention of a multitude of physiological disorders susceptible to modulation of the nuclear steroid hormone receptor. Thus, methods for the treatment or prevention of physiological disorders susceptible to modulation of the nuclear steroid hormone receptor constitute another important embodiment of the present invention. As a particular aspect, the present invention provides compounds useful as modulators of the mineralocorticoid or glucocorticoid receptor. As a more particular aspect, the present invention provides compounds useful as mineralocorticoid or glucocorticoid receptor antagonists. As will be understood by the person skilled in the art, some of the compounds useful for the methods of the present invention may be available for formulation of the prodrug. As used herein, the term "prodrug" refers to a compound of Formula I which has been structurally modified such that the prodrug in vivo is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage. , in the original molecule ("drug") as given by Formula I. Such prodrugs may be, for example, derivatives of the metabolically labile ester of the parent compound, wherein said original molecule carries a carboxylic acid group. Conventional procedures for the selection and preparation of suitable prodrugs are well known to one of ordinary skill in the art. It is understood that many modulators of the nuclear steroid hormone receptor of the present invention can exist as pharmaceutically acceptable salts and, as such, the pharmaceutically acceptable salts are therefore included within the scope of the present invention. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of Formula I, which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or a pharmaceutically acceptable organic or inorganic base. Such salts are known as base addition salts and acid addition. It will further be understood by the skilled reader, that the salt forms of pharmaceutical compounds are commonly used because they are often more easily crystallized, or more easily purified, than what the free bases are. In all cases, the use of pharmaceutical compounds of the present invention as salts is contemplated in the description herein. Therefore, it is understood that wherein the compounds of Formula I are capable of forming salts, the pharmaceutically acceptable salts and isoforms thereof are encompassed in the names provided herein. Acids commonly employed to form acid addition salts are inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, acid p-bromophenylsulfonic, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dehydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, iodide, dihydrodite, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate , succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexin-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylene sulfonate, phenylacetate, phenyl propionate, phenylbutyrate, citrate , lactate, α-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Base addition salts include those derived from inorganic bases, such as alkali metal, alkaline earth or ammonium hydroxides, carbonates, bicarbonates and the like. Such bases useful in the preparation of salts of this invention thus include, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and Similar. As used herein, the term "stereoisomer" refers to a compound made from the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are reflected images not on one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomer" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration in only one chiral center, are referred to herein as "epimers". The terms "racemate", "racemic mixtures" or "racemic modification", refer to a mixture of equal parts of enantiomers. The term "enantiomeric enrichment" as used herein, refers to the increase in the amount of one enantiomer compared to another. A convenient method achieved to express enantiomeric enrichment is the concept of enantiomeric excess, or "ee", which is found using the following equation:
ee = E1 - E2 X 100 E1 + E2
where E1 is the amount of the first enantiomer and
E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, as such it is present in a racemic mixture, and sufficient enantiomeric enrichment is achieved to produce a final ratio of 50:30, ee with respect to the first enantiomer It is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee greater than 90% is preferred, an ee greater than 95% is more preferred, and ee greater than 99% is more especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high-performance liquid chromatography with a chiral column. The selection of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair, is also within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of the compounds of Formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions. ", John Wiley and Sons, Inc., 1981. The compounds of the present invention may have one or more chiral centers and may, therefore, exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention can originate as racemates, mixtures of enantiomers, and as individual enantiomers, as well as diastereomers and mixtures of distereomers. All racemates, enantiomers and distereomers are within the scope of the present invention. Enantiomers of the compounds provided by the present invention can be resolved, for example, by one of ordinary skill in the art using standard techniques such as those described by J. Jacques, et al. , "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. The terms "R" and "S" are used in this document as is commonly used in organic chemistry to denote the specific configuration of a chiral center . The term "R" (right) refers to such a configuration of a chiral center with a clockwise relation of group priorities (highest to the lowest second), when viewed along the link of the chiral carbon towards the lowest priority group. The term "S" (left) refers to that configuration of a chiral center with a counterclockwise relation of group priorities (highest to the lowest second), when viewed along the link of the chiral carbon towards the lowest priority group. The priority of the group is based on its atomic number (to decrease the atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice" (Nomenclature of Organic Compounds: Principles and Practice), (JH Fletcher, et al., Eds., 1974) in the pages 103-120. Specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art using well-known techniques and processes, such as those described by Eliel and Wilen, "Stereochemistry of Organic Compounds" (Stereochemistry of Organic Compounds), John Wiley & Sons, Inc., 1994, Chapter 7; Separation of Stereoisomers, Resolution, Racemization (Separation of stereoisomers, resolution, racemization); and by Collect and Wilen, "Enantiomers, Racemates and Resolutions" (Enantiomers, racemates and resolutions), John Wiley & Sons, Inc., 1981. For example, specific stereoisomers and enantiomers can be prepared by stereospecific synthesis using enantiomeric and geometrically pure starting materials., or enantiomerically or geometrically enriched. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for such purposes. In addition, as will be appreciated by one of ordinary skill in the art, the compounds of the present invention that contain a carbon-carbon double bond can exist as geometric isomers. Two methods are commonly used to designate specific isomers, the "cis-trans" method and the "E" and "Z" methods, these methods designate a particular isomer based on whether the groups attached to each of the ethylene carbons are the same or different. A discussion of geometric isomerism and the appointment of specific isomers is found in March, "Advanced Organic Chemistry", John Wiley & amp; amp;; Sons, 1992, Chapter 4. All geometric isomers, as well as mixtures of individual isomers, are contemplated and provided by the present invention. As appreciated by one of ordinary skill in the art, suitable oxygen or nitrogen protecting groups are used as needed. Suitable oxygen or nitrogen protecting groups, as used herein, refer to those groups proposed to protect or block the oxygen or nitrogen group against undesirable reactions during synthetic procedures. The suitability of the oxygen or nitrogen protecting group used will depend on the conditions that will be employed in subsequent reaction stages where protection is required, and is also within the knowledge of one of ordinary skill in the art. Commonly used protective groups suitable for practicing the present invention are described in "Protective Groups in Organic Synthesis, 3rd Edition" by Theodara Greene, Peter G.M. Wutus, John Wiley & Sons, New York (1999). As used herein, the term "(C? -C4) alkyl" refers to an aliphatic, saturated, monovalent, linear or branched chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl and the like. As used herein, the term "(C? -C6) alkyl" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and the like. It is understood that the term "(C 1 -C 4) alkyl" is included within the definition of "(C 1 -C 6) alkyl". As used herein, the term "(C? -C?) Alkyl" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl , octyl, 4-methyl-3-heptyl and the like. It is understood that the terms "(C 1 -C 4) alkyl" and "(C 1 -C 6) alkyl" are included within the definition of "alkyl (C 1 -C 6)". As used herein, the terms "Me", "Et", "Pr", "I-Pr", "Bu" and "t-Bu" refer to methyl, ethyl, propyl, isopropyl, butyl and ter. -butyl, respectively.
As used herein, the term "(C 1 -C 4) alkoxy" refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to a is limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like. As used herein, the term "(Ci-Cβ) alkoxy" refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, n-hexoxy and the like. It is understood that the term "(C3-C4) alkoxy" is included within the definition of "(Ci-Cß) alkoxy". As used herein, the term "(C 1 -C 4) hydroxyalkyl" refers to a saturated, monovalent, straight or branched aliphatic chain of 1 to 4 carbon atoms carrying a hydroxyl group attached to one of the carbon atoms. As used herein, the term "hydroxyalkyl (Ci-Cß)" refers to an aliphatic, saturated, monovalent, linear or branched chain of 1 to 6 carbon atoms carrying a hydroxyl group attached to one of the carbon atoms. It is understood that the term "(C 1 -C 4) hydroxyalkyl" is included within the definition of "hydroxyalkyl (Ci-Cß)". As used herein, the term "(C 1 -C 4) hydroxyalkoxy" refers to to an oxygen atom carrying a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, furthermore carrying a hydroxyl group attached to one of the carbon atoms As used herein, the term "hydroxyalkoxy" (C? -Ce) "refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms, in addition to carrying a hydroxyl group attached to one of the carbon atoms. It is understood that the term "hydroxyalkoxy (C? -C4)" is included within the definition of "hydroxyalkoxy (C? -C6)". As used in this document, the terms "halo",
"halide" or "hal" of "Hal" refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein. As used herein, the term "(C 1 -C 4) haloalkyl" refers to a saturated, monovalent, straight or branched aliphatic chain of 1 to 4 carbon atoms carrying one or more halo groups attached to one or more of the carbon atoms. As used herein, the term "haloalkyl (C? -C6)" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms carrying one or more halo groups attached to one or more of the carbon atoms. It is understood that the term "haloalkyl (C? -C4)" is included within the definition of "haloalkyl (C? -C6)". As used herein, the term "(C 1 -C 4) haloalkoxy" refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, in addition to carrying one or more halo groups attached to one or more of the carbon atoms. As used herein, the term "haloalkoxy (C-C6)" refers to an oxygen atom carrying a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms, in addition carrying one or more groups Halo bonded to one or more of the carbon atoms It is understood that the term "(C1-C4) haloalkoxy" is included within the definition of "haloalkoxy (C? -C6)." As used herein, the The term "(C2-C6) alkenyl" refers to an unsaturated, monovalent, linear or branched aliphatic chain having from two to six carbon atoms and having a double bond Typical (C2-C6) alkenyl groups include ethenyl (also known as vinyl), 1-methylenetetenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and the like As used herein, the term "(C2-Ce) alkynyl" refers to an unsaturated aliphatic chain, monovalent, linear or branched having two to six carbon atoms and having a triple bond. Typical (C2-C6) alkynyl groups include propynyl, ethynyl and the like. As used herein, the term "acyl" refers to a hydrogen to an alkyl group (Ci-Cß) attached to a carbonyl group. Typical acyl groups include formyl, acetyl, propionyl, butyryl, valeryl and caproyl. As used herein, the term "aryl" refers to a monovalent carbocyclic group that contains one or more unbound phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1 , 2,3,4-tetrahydronaphthyl and the like. The term "substituted aryl" refers to an aryl group optionally substituted with one to three portions, preferably one or two, selected from the group consisting of halo, amino, cyano, alkyl (C? -C4), alkoxy (C? -C4), -S-alkyl (C? -C4). As used herein, the term "arylalkoxy (C? -C6)" (or "alkoxy-aryl (C? -C6)"), refers to an oxygen atom that carries a saturated, monovalent, linear aliphatic chain or branched from 1 to 6 carbon atoms, wherein said aliphatic chain, on the other hand, carries an aryl group. Examples of "arylalkoxy (Cx-Cß)" include benzyloxy, phenylethoxy and the like. As used in this document, the term
"(C3-C10) cycloalkyl" refers to a saturated hydrocarbon ring structure composed of one or more fused or unfused rings containing from three to ten carbon atoms. Typical (C3-C? 0) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like. "(C3-C7) cycloalkyl" refers to a saturated hydrocarbon ring structure composed of one or more fused or unfused rings containing three to seven carbon atoms It is understood that the definition of "(C3-C7) cycloalkyl" is included within the definition of "cycloalkyl (C3-C? 0)". "(C3-C7) substituted cycloalkyl", refers to a (C3-C7) cycloalkyl group optionally substituted with one or more portions selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, alkyl (C? -C6) ), alkoxy (C? -Ce), alkyl (C? -C4) -cycloalkyl (C3-C? 0), alkyl-aryl (C? -C4), alkoxycarbonyl (C? -C6), N, N-dialkylamine (C) C6), NH-alkylaminamine (C? -C6), alkyl (C? -C) -N, N-dialkylamine C? -C6, difluoromethyl, difluoromethoxy, trifluoromethyl and trifluoromethoxy. In this document, the term "(C? -C4) alkyl- (C3-C7) cycloalkyl", refers to a saturated, monovalent, linear or branched aliphatic chain, of 1 to 4 carbon atoms, which has a cycloalkyl (C3) -C7) attached to the aliphatic chain. Included within the term "alkyl (C? -C4) -cycloalkyl (C3-C7)", are the following:
and similar. As used herein, the term "substituted (C? -C4) alkyl- (C3-C7) cycloalkyl", refers to a saturated, monovalent, linear or branched aliphatic chain, of 1 to 4 carbon atoms, which carries an optionally substituted cycloalkyl (C3-C7) group attached to the aliphatic chain. As used herein, the term "heterocycle" refers to a ring of five or six elements, saturated or unsaturated, which contains one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. It is understood that the remaining atoms are carbon and that the heterocycle may be attached at any point which provides a stable structure. Examples of heterocyclic groups include, thiophenyl, furanyl, tetrahydrofuryl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridinyl, pyrimidyl, pyrazinyl, pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl, tetrahydropyrimidyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrimidinyl, imidazolidimyl, morpholinyl, pyranyl, thiomorpholinyl, and the like. The term "substituted heterocycle", represents a heterocycle optionally substituted with one or two portions, selected from the group consisting of halo, amino, cyano, alkyl (C? -C4), alkoxy (C? -C4), -S- alkyl (C? -C). As used herein, the term "(C? -C4) alkyl -heterocycle" refers to a saturated, monovalent, linear or branched aliphatic chain, of 1 to 4 carbon atoms, which has a linked heterocycle group to the aliphatic chain. Examples of "alkyl heterocycle (C? -C4)" include:
Q. ~ 'O
and similar. The term "(C 1 -C 4) substituted heterocycle" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms carrying an optionally substituted heterocycle group attached to the aliphatic chain. As used herein, the term "NH-alkylamine (C? -C4)" refers to a nitrogen atom substituted with saturated, monovalent, linear or branched aliphatic chains of 1 to 4 carbon atoms. Included within the term "NH-alkylamine (C? -C4) are -NH (CH3), -NH (CH2CH3), -NH (CH2CH2CH3), -NH (CH2CH2CH2CH3), and the like. "N, N-dialkylamine (C? -C4)" refers to a nitrogen atom substituted with two saturated, monovalent, linear or branched aliphatic chains of 1 to 4 carbon atoms, included within the term "N, N- dialkyl amine (C1-C4) "are -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, N (CH2CH2CH2CH3) 2, -N, N (CH3) (CH2CH3), -N, N (CH2CH3) (CH2CH3) and the like As used herein, the term "alkyl"
(C? -C4) -N, N-dialkylamine (C? -C4) ", refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, which has an N, N-dialkylamine (C? -C4) attached to the aliphatic chain Included within the term "(C? -C4) alkyl-N, N-dialkylamine (C? -C4)", are the following:
and similar. As used herein, the term "(C? -C4) alkyl-N-Hyalkylamine (CX-C4)", refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, which has an NH-alkylamine (C? -C4) attached to the aliphatic chain. Included within the term "alkyl (C? -C4) -NH-alkylamine (C1-C4) are the following:
The designation "- ** ß-l" refers to a link that protrudes forward of the plane of the page. The designation "" HMII "refers to a link projecting back from the plane of the page As used herein, the term" nuclear steroid hormone receptor modulator "refers to those ligands of the steroid receptor. Nuclear hormone which bind to any of GR, MR, AR, ER, or PR, of the largest class of nuclear hormone receptors, and either agonize, antagonize, partially agonize or partially antagonize receptor activity. As used herein, the term "mineralocorticoid receptor" or "MR" refers to the mineralocorticoid receptor subtype, the largest class of nuclear hormone receptors, which bind to the aldosterone of the mineralocorticoid hormone, as its cognate ligand The term "mineralocorticoid receptor modulator" or "mineralocorticoid modulator" or "MR modulator" as used herein, refers to those ligands of the hormone receptor. These receptors bind to the mineralocorticoid receptor subtype and modulate (ie, agonize, antagonize, partially agonize, or partially antagonize) receptor activity. As a particular embodiment, the present invention provides antagonists of MR activity. As used herein, the term "glucocorticoid receptor" or "GR" refers to the subtype of the glucocorticoid receptor, the largest class of nuclear hormone receptors, which bind to cortisol, corticosterone or cortisone of the glucocorticoid hormones as their cognate ligand. The term "glucocorticoid receptor modulator" or "glucocorticoid modulator" or "GR modulator," as used herein, refers to those ligands of the nuclear hormone receptor which bind to the glucocorticoid receptor subtype and modulate say, agonize, antagonize, partially agonize or partially antagonize) the activity of the receptor. As used herein, the term "disorder susceptible to modulation of the nuclear steroid hormone receptor" refers to any physiological disorder, of any origin, known or believed to be responsible for the administration of a modulator (i.e. , agonist, antagonist, partially agonist or partially antagonist) of a nuclear steroid hormone receptor. Such disorders include Conn syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and / or combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, atherosclerosis, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, rejection of tissue associated with organ transplantation, malignancies such as leukemia and lympholas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, adrenal insufficiency chronic primary, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid erythematosus lupus, polyartitis nodosa, Wegener's granulomatosis, arthritis giant cell itis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bullosa, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, cutaneous T-cell lymphoma, psychosis, cognitive disorders
(such as memory disturbances), mood disorders
(such as depression and bipolar disorder), anxiety disorders and personality disorders. As used in this document, the term
"Congestive heart failure" (CHF) or "congestive heart disease" refers to a disease state of the cardiovascular system whereby the heart is unable to efficiently pump an adequate volume of blood to meet the requirements of tissues and organ systems of the body. Typically, CFH is characterized by left ventricular failure (systolic dysfunction) and fluid accumulation in the lungs, with the underlying cause being attributed to one or more states of cardiac or cardiovascular disease including coronary artery disease, myocardial infarction, hypertension , diabetes, valvular heart disease, and cardiomyopathy. The term "diastolic congestive heart failure" refers to a state of CHF characterized by impairment in the ability of the heart to properly relax and fill with blood. Reciprocally, the term "systolic congestive heart failure" refers to a state of CFH characterized by impairment in the ability of the heart to properly contract and expel blood. As will be appreciated by one skilled in the art, physiological disorders may present as a "chronic" condition, or an "acute" episode. The term "chronic", as used herein, means a condition of slow progress and long duration. As such, a chronic condition is treated when it is diagnosed and treatment continues throughout the course of the disease. Reciprocally, the term "acute" means an exacerbated event or attack, of short course, followed by a period of remission. Thus, the treatment of physiological disorders includes both acute events and chronic conditions. In an acute event, the compound is administered at the beginning of the symptoms and is interrupted when the symptoms disappear. As described above, a chronic condition is treated throughout the course of the disease. As used in this document, the term
"patient" refers to a mammal, such as a mouse, gerbil, guinea pig, rat, dog or human. It is understood, however, that the preferred patient is a human. As used herein, the terms "treated," "treatment," or "to treat," each means alleviating symptoms, eliminating the cause of the resulting symptoms on either a temporary or permanent basis, and preventing, diminishing appearance. , or reverse the progress or severity of the symptoms resulting from the named disorder. As such, the methods of this invention encompass both therapeutic and prophylactic administration. As used herein, the term "effective amount" refers to the amount or dose of the compound, after administration of single or multiple doses to the patient, which provides the desired effect on the patient under diagnosis or treatment. An effective amount can be readily determined by the attending physician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the amount or effective dose of the compound administered, a number of factors are considered by the attending physician, including, but not limited to: the mammalian species; its size, age and general health; the degree of complication or the severity of the disease involved; the patient's individual response; the particular compound administered; the form of administration; the bioavailability characteristics of the preparation administered; the selected dose regimen; the use of concomitant medication; and other relevant circumstances. A typical daily dose will contain from about 0.01 mg / kg to about 100 mg / kg of each compound used in the present treatment method. Preferably, daily doses will be from about 0.05 mg / kg to about 50 mg / kg, more preferably from about 0.1 mg / kg to about 25 mg / kg. Oral administration is a preferred route of administration of the compounds employed in the present invention if administered alone, or as a combination of compounds capable of acting as a modulator of the nuclear steroid hormone receptor. Oral administration, however, is not the only route, not even the only preferred route. Other preferred routes of administration include transdermal, percutaneous, pulmonary, intravenous, intramuscular, intranasal, buccal, sublingual or intrarectal routes. Where the nuclear steroid hormone receptor modulator is administered as a combination of compounds, one of the compounds can be administered by one route, such as orally, and the other can be administered by transdermal, percutaneous, pulmonary, intravenous routes, intramuscular, intranasal, buccal, sublingual, or intrarecal, as the particular circumstances require. The route of administration can be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the care giver. The compounds employed in the present invention can be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating compounds of Formula I are important embodiments of the present invention. Such compositions can take any physical form that is pharmaceutically acceptable, but orally administered pharmaceutical compositions are particularly preferred. Such pharmaceutical compositions contain, as an active ingredient, an effective amount of a compound of Formula I, as described herein and above, which includes the pharmaceutically acceptable salts and hydrates thereof, in which the effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a given compound, or may contain a fraction of the daily dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit depends on the identity of the particular compound chosen for the therapy, and other factors such as the indication for which it is given. The pharmaceutical compositions of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, employing well known procedures. The following discussion provides typical procedures for preparing pharmaceutical compositions incorporating the compounds of the present invention. However, the following is not in any way proposed to limit the scope of the pharmaceutical compositions provided by the present invention. The compositions are preferably formulated in a unit dosage form, each dosage contains from about 1 to about 500 mg of each compound individually or in a unit dosage form, more preferably about 5 to about 300 mg (eg, 25 mg). The term "unit dosage form" refers to a physically discrete unit suitable as unit dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutical carrier, diluent or excipient. suitable. The inert ingredients and the manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science can be used in this document. All usual types of compositions can be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches and suspensions. In general, the compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used. The amount of the compound, however, is better defined as the "effective amount", that is, the amount of each compound which provides the desired dose to the patient in need of such treatment. The activity of the compounds employed in the present invention does not depend on the nature of the composition, therefore, the compositions are chosen and formulated solely for convenience and economy. The capsules are prepared by mixing the compound with a suitable diluent and filling the appropriate amount of the mixture in the capsules. Customary diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain meal and similar edible powders. The tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators, as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellose and waxes can also serve as binders. The tablets are often coated with sugar as a flavor and sealer. The compounds can also be formulated as chewable tablets, using large amounts of pleasant tasting substances such as mannitol in the formulation, as is now well established in practice. Formulations such as tablets that dissolve instantly are also now frequently used to ensure that the patient consumes the dosage form and to avoid difficulties in the expansion of solid objects that bother some patients. A lubricant is often necessary in a tablet formulation, to prevent the tablet and perforations from adhering to the die. The lubricant is chosen from such slippery solids as talcum, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances which expand when wetted to break the tablet and release the compound. They include starches, clays, celluloses, alginas and gums. More particularly, potato and corn starch, methylcellulose, agar, bentonite, wood cellulose, natural powder sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, can be used. sodium lauryl sulfate. Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer, which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. When it is desired to administer the compound as a suppository, the usual bases can be used. Cocoa butter is a traditional suppository base, which can be modified by the addition of waxes to raise its melting point slightly. Suppository bases miscible in water, particularly polyethylene glycols of various molecular weights, are in wide use as well. Transdermal patches have become popular recently. Typically, they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which are maintained in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other more complicated patch compositions are also in use, particularly those having a perforated membrane with innumerable pores through which the drugs are pumped by osmotic action. It is understood by one of ordinary skill in the art, that the methods as described above, can be readily applied to a method for treating physiological disorders susceptible to modulation of the nuclear steroid hormone receptor, and particularly, congestive heart failure.
Particular Aspects of the Compounds and Methods of the Invention The following list sets forth several groupings of particular substituents for compounds of formula I. It will be understood that compounds of Formula I having such particular substituents, and methods employing such compounds, represent particular aspects of the present invention. It will further be understood that each of these groupings of particular substituents can be combined with other provided groupings to create still further particular aspects of the compounds of the present invention.
Therefore, a particular aspect of the present invention is one wherein the compound of Formula I is one wherein: (a) X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, or -CH2S -; (b) X represents -CH2-, -CH2CH2-, or -CH20-; (c) X represents -CH2-; (d) X represents -CH2CH2-; (e) X represents -CH20-; or (f) X represents -CH2NR10-. (g) R1 represents hydrogen, (C? -C4) alkyl, (C3-C7) cycloalkyl, (C? -C4) hydroxyalkyl, (C? -C4) haloalkyl, (C? -C4) alkyl, -heterocycle, alkyl ( C-C4) -N-Alkylamine (C? -C4), or alkyl (C? -C) -N, N-dialkylamine (C? -C4); (h) R1 represents hydrogen, methyl, ethyl, propyl, isopropyl, (C3-C7) cycloalkyl, hydroxyalkyl (C? -C4), haloalkyl (C? -C4), (C? -C4) alkyl-heterocycle, alkyl ( C? -C4) -NHalkylamine (C? -C4), or alkyl (C? -C4) -N, N-dialkylamine (C? -C4); (i) R1 represents hydrogen, methyl, ethyl, propyl, or isopropyl; (j) R1 represents hydrogen, methyl or ethyl; (k) R1 represents methyl or ethyl; (1) R1 represents hydrogen or (C3-C7) cycloalkyl;
(m) R1 represents (C3-C7) cycloalkyl; (n) R1 represents cyclopropyl; (o) R1 represents hydrogen or hydroxyalkyl (C? -C4); (p) R1 represents hydroxyalkyl (C? -C4); (q) R1 represents 3-hydroxypropyl; (r) R1 represents hydrogen or (C? -C4) alkyl-heterocycle; (s) R1 represents alkyl (C? -C4) -heterocycle; (t) R1 represents 3-morpholino-4-ylpropyl (u) R1 represents hydrogen or haloalkyl (C? -C4); (v) R1 represents haloalkyl (C? -C4); (w) R1 represents 3-iodopropyl; (x) R1 represents hydrogen or (C? -C4) alkyl-NHalkylamine (C? -C4); (y) R1 represents alkyl (C? -C4) -NHalkylamine (C? -C); (z) R 1 represents 3-methylamino propyl (aa) R 1 represents hydrogen or (C 1 -C 4) alkyl-N, N-dialkylamine (C 1 -C 4); (bb) R1 represents alkyl (C? -C4) -N, N-dialkylamine (C1-C4); or (ce) R 1 represents 3-dimethylamino propyl. (dd) R 2 represents hydrogen, halo, methyl, ethyl, propyl, isopropyl, heterocycle, or substituted heterocycle; (ee) R2 represents hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or heterocycle;
(ff) R 2 represents hydrogen, fluoro, chloro, or bromo;
(gg) R2 represents hydrogen or fluoro; (hh) R2 represents fluoro; (ii) R2 represents hydrogen, methyl, ethyl, propyl, or isopropyl; (jj) R 2 represents hydrogen or heterocycle; (kk) R2 represents pyrazolyl; or (11) R2 represents hydrogen; (mm) R3 represents hydrogen, fluoro, chloro, or bromine;
(nn) R3 represents hydrogen, fluoro, or chloro; (oo) R3 represents hydrogen or fluoro; (pp) R3 represents fluoro; or (qq) R3 represents hydrogen; (rr) R4 represents hydrogen, halo, amino, nitro, (C? -C4) alkyl, (C? -C4) alkoxy, NHS02R7, NHCOR8 wherein R8 represents alkyl (C? ~ C4) or (C1-C4) alkoxy , or COR9 wherein R9 represents alkyl (C? -C4) or (C3-C4) alkoxy; (ss) R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, NHS02R7, NHCOR8 wherein R8 represents methyl, ethyl, methoxy, or ethoxy, or COR9 wherein R9 represents methyl , ethyl, methoxy, or ethoxy; (tt) R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C3-C4) alkoxy, NHS02R7, NHCOR8 wherein R8 represents methyl or methoxy, or COR9 wherein R9 represents methyl or methoxy; (uu) R4 represents hydrogen, halo, amino, nitro, (C? -C4) alkyl, (C1-C4) alkoxy, or NHS02R7; (vv) R4 represents hydrogen, fluoro, chloro, bromo, amino, nitro, methyl, ethyl, methoxy, ethoxy or NH S02R7; (ww) R 4 represents hydrogen, fluoro, chloro, bromo, amino, or nitro; (xx) R4 represents fluoro, chloro, bromo, amino, or nitro; (yy) R4 represents fluoro, chloro, or bromo; (zz) R 4 represents amino or nitro; (aaa) R 4 represents hydrogen, methyl, ethyl, methoxy, or ethoxy; (bbb) R 4 represents methyl, ethyl, methoxy, or ethoxy; (ccc) R 4 represents methyl or ethyl; (ddd) R 4 represents methoxy or ethoxy; (eee) R4 represents hydrogen or NHS02R7; (fff) R4 represents hydrogen or NHS02R7 wherein R7 represents (C? -C4) alkyl, aryl, or N, N-dialkylamine (C1-C4); (ggg) R4 represents hydrogen, NHS02CH3, NHS02CH2CH3, NHS02 (C6H5), or NHS02N (CH3) 2; (hhh) R4 represents NHS02CH3, or NHS02CH2CH3; (iii) R represents NHS02CH3; or (jjj) R 4 represents hydrogen. (kkk) R5 represents hydrogen, fluoro, or chloro; (111) R5 represents hydrogen. (mmm) R6 represents hydrogen, methyl, or ethyl;
Furthermore, even as another particular embodiment of the present invention, the compounds of Formula I have the following configuration
Formula I
Furthermore, it will be understood that where X represents -CH20-, -CH2S-, or -CH2NR10, either a heteroatom or the carbon of such groups, they may be directly attached to the fused phenyl ring. The compounds of Formula I can be chemically prepared, for example, by following the synthetic routes set forth in the Reaction Schemes below. However, the following discussion is not proposed to limit the scope of the present invention in any way. For example, the specific synthetic steps for the routes described herein can be combined in different ways, or with different reaction scheme stages, to prepare additional compounds of Formula I. Furthermore, it must be recognized that the sequence in which Synthetic reactions take place, it is not involved and can be done in any way to achieve the desired final product. All substituents, unless otherwise indicated, are as previously defined. Reagents and starting materials are readily available to one of ordinary skill in the art. Reagents and starting materials are readily available to one of ordinary skill in the art. Other necessary reagents and starting materials can be made by methods which are selected from standard techniques of organic and heterocyclic chemistry, techniques which are analogous to the synthesis of known structurally similar compounds, and the methods described in the Preparations and Examples below, which include any of the new procedures. In addition, one of ordinary skill in the art will readily appreciate that many of the necessary reagents and starting materials are readily obtained from commercial suppliers.
The compounds of Formula I can be synthesized by coupling the appropriately substituted or unsubstituted indole with the appropriately substituted or unsubstituted carbinol, in accordance with the procedures as generally described in Reaction Scheme I, below. Any of the subsequent modifications that appear necessary to produce the final product of Formula I, which include but are not limited to deprotection reactions, can be readily performed by one of ordinary skill in the art. The appropriately substituted or unsubstituted carbinols used in the following processes can either be purchased from commercial suppliers or can be prepared from appropriately substituted or unsubstituted ketones, as depicted in Reaction Scheme I, using methods known in the art. . Ketones for use in the following procedures are either purchased from commercial suppliers or synthesized as described in Schemes II through VIII below. The characters for use in the following procedures are also either purchased from commercial suppliers, or synthesized in the manner as described in Reaction Schemes IX and X.
REACTION SCHEME 1
R, gBr
or toluene (1) or tetrahydrofuran (2) (3) trifluoroacetic acid dichloromethane
Formula I
In Reaction Scheme 1, an appropriately substituted or unsubstituted ketone of the general structure (I) is dissolved in a suitable solvent such as diethyl ether or toluene or tetrahydrofuran. An alkylmagnesium or alkyllithium halide reagent is then added under nitrogen at room temperature or lower temperatures and the reaction mixture is allowed to proceed for ten minutes to several days. The reaction is then quenched using a suitable reagent such as aqueous ammonium chloride, and the carbinol of the general structure (2) is isolated using techniques common in the art. Electrophilic aromatic substitution occurs by methods known in the art. For example, the appropriately substituted or unsubstituted indole (3), and the appropriately substituted or unsubstituted carbinol (2), are first dissolved in a suitable solvent such as dichloromethane or acetic acid or methanol, then treated with a suitable Lewis or protic acid such as acid trifluoroacetic, boron trifluoride etherate, hydrogen chloride or aluminum chloride. The reaction proceeds in any way from ten minutes to several days, depending on the stability of the starting materials. The product of Formula I can then be isolated by normal phase chromatographic methods or recrystallization techniques commonly employed in the art. The substituted or unsubstituted indanones of the general structure (6), wherein R 2 and R 3 independently can be, for example, hydrogen, alkyl, aryl, halo, or heterocycle, can be synthesized in accordance with Reaction Scheme II, using techniques common in art.
REACTION SCHEME II
In Reaction Scheme II, an appropriately substituted or unsubstituted cinnamic acid of the general structure (4) is reduced using methods known in the art. Hydrogenation can occur in a suitable solvent such as tetrahydrofuran or acetic acid, employing but not limited to, an appropriate catalyst such as palladium on carbon or palladium hydroxide or platinum oxide. The reaction takes place under a hydrogen atmosphere at various pressures and temperatures. The addition of acid such as concentrated sulfuric acid can facilitate the reaction. The substituted or unsubstituted 3-arylpropionic acid of the general structure (5) can then be cycled using common methods in the art such as heating the substituted substituted or unsubstituted cinnamic acid with polyphosphoric acid at various temperatures with or without a suitable solvent (Reaction Scheme II), to form substituted or unsubstituted indanones of the general structure (6). Alternatively, (5) can be activated by conversion to the corresponding acid halide or anhydride using a suitable reagent, such as thionyl chloride or trifluoroacetic anhydride, and then subjecting it to cycles in the presence of a suitable Lewis acid such as aluminum trichloride or Boron trifluoride etherate in a suitable solvent using techniques and methods common in the art. The substituted or unsubstituted tetralones of the general structure (12), wherein R2 and R3 independently, can be for example, hydrogen, alkyl, aryl, halo or heterocycle, can be synthesized according to Reaction Scheme III using common techniques in the art.
REACTION SCHEME III
O Br O Ph3P Br CH3CN, OH OH Ph3P heat (6)
PPA, heat
In Reaction Scheme III, triphenylphosphine can be reacted with 4-bromobutanoic acid in a suitable solvent such as acetonitrile at various temperatures, to obtain the Wittig reagent (2-carboxy-ethyl) -triphenyl-phosphonium bromide (8). As in Reaction Scheme III, (2-carboxy-ethyl) -triphenyl-phosphonium bromide can be used, with an appropriately substituted or unsubstituted aldehyde in the general structure (9), in the presence of a suitable base such as t -sodium butoxide or sodium hydride and a suitable solvent such as dichloromethane or tetrahydrofuran at various temperatures, to obtain the corresponding substituted or unsubstituted beta-gamma-butenoic acid (10), using techniques common in the art. The isolated beta-gamma-butenoic acid (10) can be a mixture of cis / trans isomers, depending on the substitution of the aryl ring, the base, the solvent and other reaction conditions, such as temperature and reagent concentration. The substituted or unsubstituted beta-gamma-butenoic acid can be used in the next step as a cis / trans mixture or after the chromatographic separation. The substituted or unsubstituted beta-gamma-butenoic acid can then be hydrogenated to a 4-aryl butenoic acid of general structure (11) and cycled using the same or similar method and conditions known in the art, which were described in Reaction Scheme II, to obtain the substituted or unsubstituted tetralone of the general structure (12). The substituted or unsubstituted 4-chromanones of the general structure (16), wherein R 2 and R 3 independently can be, for example, hydrogen, alkyl, aryl, halo or heterocyclic, can be synthesized in accordance with Reaction Scheme IV, using common techniques in art.
REACTION SCHEME IV
In Reaction Scheme IV, an appropriately substituted or unsubstituted phenol is alkylated with 3-chloro-1-propanol, using a suitable base such as sodium hydride in a suitable solvent such as dimethylformamide. The alcohol resulting from the general structure (14) can be isolated using standard methods known in the art. The alcohol portion of (14) can be oxidized using standard oxidation procedures, common in the art, such as chromium trioxide in aqueous sulfuric acid / acetone. The acid resulting from the general structure (15) can be converted to the corresponding acid halide using methods known in the art such as oxalyl chloride in dichloromethane with a catalytic amount of dimethylformamide. The intramolecular acylation of the aryl ring in (15), can be achieved using a suitable Lewis acid such as aluminum trichloride to obtain the corresponding chromanone of the general structure (16). Compounds of Formula I, wherein R4 represents amino or an amino-derived substituent such as NHS02R7 or NHCOR8 (as represented by structures (18) and (19) below), may be prepared in accordance with Reaction Scheme V , using methods known in the art.
REACTION SCHEME V
1. R6-l or R6-Br or R6-CI NaOM e / D F 2. 5% P / C, H2, EtOH
As depicted in Reaction Scheme V, a 7-nitroindole derivative can be fused to a carbinol of the general structure (2), using conditions known in the art that were described in Reaction Scheme I above. The alkylation / acylation / sulfonation of the indole nitrogen atom can take place in the presence of an appropriate alkylation / acylation / sulfonation agent, respectively, such as methyl iodide, acetyl chloride or methanesulfonyl chloride. A suitable base, such as sodium methoxide or sodium hydroxide and solvent, such as dimethylformamide, should also be used. The alkylated / acylated / sulfonated product can be isolated using standard techniques common in the art, such as aqueous lifting and chromatographic purification. The reduction of the nitro group can be achieved using methods known in the art. The nitro compound can be dissolved in an appropriate solvent such as ethyl acetate, methanol, ethanol, tetrahydrofuran or acetic acid, then an appropriate catalyst such as palladium on carbon, or Pearlman catalyst or platinum oxide, and the mixture is added. The resultant is hydrogenated for 10 minutes to 6 hours. The products of the general structure (18), can be isolated using common techniques. The aniline nitrogen atom can then be alkylated / acylated / sulphonated using an appropriate alkylation / acylation / sulfonation agent, and a suitable solvent / base, such as pyridine. Co-solvents such as tetrahydrofuran, dimethyl sulfoxide or dimethylformamide can also be added. Additional procedures for the synthesis of compounds of Formula I, wherein R 4 represents amino or an amino derivative, are provided by Reaction Scheme VI.
REACTION SCHEME VI
% Pd (OHyC, H2, BOH
In Reaction Scheme VI, a Cbz-protected 7-aminoindole derivative (made according to the procedures as described in Reaction Scheme X, below), can be condensed with a carbinol of the general structure (2), using conditions known in the art which are described in Reaction Scheme 1 above. The removal of the Cbz protecting group in structure (20) can be achieved using methods known in the art. The compound (20) can be dissolved in an appropriate solvent such as ethyl acetate, methanol, ethanol, tetrahydrofuran, or acetic acid, then, an appropriate catalyst such as palladium on carbon, or Pearlman catalyst, or platinum oxide, is added, and the resulting mixture is hydrogenated using conditions known in the art. The products of the general structure (21) can be isolated using common techniques. The aniline nitrogen atom can then be alkylated / acylated / sulphonated using an appropriate alkylation / acylation / sulfonation agent, such as methanesulfonyl chloride or acetyl chloride and a suitable base / solvent such as pyridine. Co-solvents such as tetrahydrofuran, dimethyl sulfoxide or dimethylformamide can also be added. Ketones of the general structure (24) can be prepared according to Reaction Scheme VII using methods known in the art. In Reaction Scheme VII, Rx and R? they can be independently, for example, hydrogen, alkyl or acyl groups or part of a heterocyclic ring such as imidazole, pyrazole, pyrrole, or morpholine, and the like.
REACTION SCHEME VII
In Reaction Scheme VII, a structure ketone (24) can be prepared by reacting a compound of structure (23) in an appropriate solvent such as dimethyl sulfoxide in the presence of a base such as potassium carbonate and a nucleophilic amine or nitrogen that contains heterocycle. The reaction takes place at temperatures of 100 degrees Celsius to 300 degrees Celsius, depending on the nucleophilicity of the nitrogen atom. The compounds of Formula I wherein R 1 is, for example, an alkyl-alkylamine derivative (as represented by structure (29) below), can be prepared according to the reaction sequence in Reaction Scheme VIII. In Reaction Scheme VIII, Rx and R? they can be independently, for example, hydrogen, alkyl or acyl group or part of a heterocyclic ring such as imidazole, pyrazole, pyrrole or morpholine and the like.
REACTION SCHEME VII
In Reaction Scheme VIII, the cyclopropylcarbinol of structure (2a) is condensed with an N- (lH-indol-7-yl) -methanesulfonamide derivative (prepared according to procedures as described in Reaction Scheme IX , below), under standard conditions that were previously described (Reaction Scheme 1). A mixture of the propyl ester of trifluoroacetate (25) and product (26) results. Compounds (25) and (26) can be separated using standard techniques such as reverse or normal phase chromatography, or taken directly to the next step as a mixture. The hydrolysis of the TFA ester can take place in a suitable solvent such as methanol, using an appropriate base such as aqueous lithium hydroxide. The isolation and separation of (27) from (26), can be achieved using standard techniques common in the art. The propyl alcohol (27) can be converted to the corresponding propyl halide (28), using standard Mitsunobu-type conditions. For example, a suitable halogen such as iodine or bromine can be added to a mixture of triphenylphosphine and imidazole in tetrahydrofuran under nitrogen to prepare the Mitsunobu reagent. For example, a paropylated halogen such as iodine or bromine can be added to a mixture of triphenylphosphine and imidazole in tetrahydrofuran under nitrogen to prepare the Mitsunobu reagent. The alcohol (27) is then added as a solid or in solution in tetrahydrofuran and the reaction mixture is stirred to completion. The propyl iodide derivative can be isolated and purified using standard techniques such as aqueous lifting and normal phase chromatography. The iodide derivative (28) can then be converted to a secondary or tertiary amine by reacting it with an excess of amine such as morpholine or dimethylamine. The reaction can then be run either using the amine as the solvent or using an appropriate co-solvent such as tetrahydrofuran. The amines of the general structure (29) can then be isolated using common methods in the art. Reaction Scheme IX represents the preparation of N- (lH-indol-7-yl) -methanesulfonamide derivatives using methods common in the art.
REACTION SCHEME IX
In Reaction Scheme IX, Step A or B, nitro reduction occurs by methods commonly employed in the art. For example, a 7-nitroindole derivative (Step A), is dissolved in a suitable solvent such as ethanol, and is reduced by hydrogenation conditions, such as Pd / C and a source of hydrogen such as hydrogen gas or ammonium formate. The reaction can occur at ambient temperature at reflux conditions and the product can be isolated by standard techniques such as filtration or standard aqueous lifting. Alternatively, (Step B), the 7-nitroindole derivative is treated with a reducing agent, such as tin chloride dihydrate at elevated temperatures. The reaction may proceed for approximately 1-24 hours. The product can be isolated by methods known in the art, such as a standard aqueous lift, and purified by chromatography. In Reaction Scheme IX, Step C, the 7-aminoindole derivative is dissolved in dichloromethane and pyridine and methanesulfonyl chloride is added. The reaction is stirred at room temperature for a minimum of six hours. The structure product (30) can be isolated by methods known in the art, such as standard aqueous lifting, and can be purified via standard chromatography techniques. In Reaction Scheme X, a 7-aminoindole derivative is protected with a Cbz group using conditions common in the art. For example, 7-aminoindole is dissolved in dichloromethane, aqueous sodium hydroxide is added, followed by Cbz chloride. After completion of the reaction, the Cbz-protected product (30) is isolated using techniques known in the art.
X REACTION SCHEME
Determination of Biological Activity: To demonstrate that the compounds of the present invention have affinity for nuclear steroid hormone receptors, and thus, have the ability to modulate nuclear steroid hormone receptors, MR binding assays were performed and Soluble GR. All ligands, radioligands, solvents and reagents used in binding assays are readily available from commercial sources, or can be easily synthesized by experts of ordinary skill.
Mineralcorticoid Receptor Linkage Assay (Method 1): The full length human MR gene is cloned from human kidney or human brain cDNA library. Briefly, using synthetic oligonucleotide primers (Eli Lilly and Company, Indianapolis), targeting nucleotides 20-54 and 3700-3666 of the human MR, polymerase chain reaction (PCR) was performed under standard conditions using a human cDNA library . The PCR reaction was performed in a final volume of 50 μl containing approximately 1 μl of a 50X base solution of polymerase; about 1 μl of a 50X base solution of dNTP; approximately 5 μl of an appropriate CPR buffer; about 1 μl of each primer; about 5 μl of a human brain or human kidney cDNA library; and approximately 36 μl of water. The reaction was allowed to denature for about 30 seconds at 95 ° C, strengthened for about 30 seconds at 55 ° C, and extended for about 5 minutes at 72 ° C, the sequence is repeated for a total of about 35 cycles. The desired PCR product (3.68 Kb) was confirmed by gel electrophoresis and subsequently cut from the gel and stored at about -20 ° C until extraction. To extract the cDNA product from the agarose gel, the QIAEX II Gel Extraction protocol (QIAGEN, Inc.) was used, in accordance with the manufacturer's instructions. After extraction, the MR cDNA was cloned into an appropriate cloning vector (Zero Blunt TOPO PCR Cloning Kit (Invitrogen, Inc.), and a pAcHLT-baculovirus (BD / Pharminogen) transfer vector, then expressed in SF9 insect cells, essentially in accordance with the manufacturer's instructions.Sf9 cells are grown on a scale where cell pellets are obtained in gram quantities for subsequent use in the MR binding assay. they are subjected to lysis by repeated freeze-thaw cycles (approximately 4) in a suitable lysis buffer, then centrifuged at approximately 1 x 103G (with the supernatant being stored for future tests). MR binding assays were performed at a total volume final of approximately 250 μl containing approximately 20-25 μg of protein and 0.5nM of [3H] -aldosterone plus varying concentrations of the compound or vehicle The test buffer consists of 30 mM sodium molybdate, 30 mM TRIS-HCl, 5 mM sodium phosphate, 5 mM sodium pyrophosphate, and approximately 10% glycerol, pH = 7.5 . Briefly, TA assays were prepared in 96-well Falcon 3072 plates, each well containing 210 μl of binding buffer, 10 μl of [3 H] -aldosterone, 10 μl of compound / test vehicle, and 20 μl of protein extract of the resuspended receiver. Incubations were carried out at 4 ° C with shaking for approximately 16 hours. 200 μl aliquots of each incubation were filtered on Millipore HA 0.45 micron filter 96-well plates pre-moistened with 30 mM cold TRIS-HC1. The filter plates are suctioned dry with vacuum and immediately washed 3X with 30 mM cold TRIS-HCL. The plates are then perforated and the amount of the receptor-ligand complex was determined by liquid scintillation counting using 4 ml of Ready Protein Plus ™ liquid scintillation cocktail. IC50 values (defined as the concentration of the test compound required to decrease the binding of
[3 H] -aldosterone by 50%), are then determined. The Ki values for each respective test compound can then be calculated by applying the Cheng-Prusoff equation as described in Cheng et al. , Relationship Between The Inhibition Constant (Ki) and The Concentration of Inhibitor Which Causes 50% Inhibition (IC50) of an Enzymatic Reaction (Relationship between the inhibition constant (Ki) and the concentration of inhibitor that causes 50% inhibition (IC50 ) of an enzymatic reaction), Biochem. Pharmacol., 22: 3099-31088; (1973).
Glucocorticoid Receptor Binding Assay (Method 1): To demonstrate the GR modulation potency of compounds of the present invention, the following source of the glucocorticoid receptor was employed. Human lung epithelial cells A549 (ATCC) are grown on a scale where cell pellets of gram quantity are obtained. Harvested cell pellets were washed twice in cold phosphate buffered saline, centrifuged, and resuspended in cold binding assay buffer. The binding assay buffer consists of 10% glycerol, 50 mM Tris-HC1 (pH 7.2), 75 mM sodium chloride, 1.5 mM magnesium chloride, 1.5 mM EDTA, and 10 mM sodium molybdate. . The cell suspensions were lysed via sonication, centrifuged and the "extract" supernatant is frozen under pressure and stored at -80 ° C until needed. GR-binding assays were performed in a final volume of 140 ul containing 50-200 ug of cell extract A549 and 1.86 nM of [3H] -dexametasone (Amersham) plus varying concentrations of the test compound or vehicle. Briefly, TA assays were prepared in Fisher 3356 96-well plates, each containing 100 ul of A549 cell extract, 20 ul of [3 H] -dexametasone and 20 ul of the test compound / vehicle. Incubations were carried out at 4 ° C for 16 hours. After incubation, 70 ul of charcoal solution coated with 3X dextran was added to each reaction, mixed and incubated for 8 minutes at RT. The 3X dextran-coated charcoal solution consists of 250 ml of binding assay buffer, 3.75 g of Norit A charcoal (Sigma), and 1.25 g of dextran T-70 (Amersham). Charcoal / unbound radioligand complexes were removed by centrifugation of the plate and 140 ul of supernatant was transferred from each cavity to another 96-well Optiplate (Packard Instruments). 200 ul of Microscint-20 scintillant (Packard Instruments) was added to each well and the amount of bound radioligand receptor was determined using a Packard Instruments TopCount instrument. The IC5o values, defined as the concentration of the test compound, required to decrease the binding of [3 H] -dexametasone by 50%, are then determined. The Ki values for each respective test compound can then be calculated by applying the Cheng-Prusoff equation as described in Cheng et al. , Relationship Between The Inhibition Constant (Ki) and The Concentration of Inhibitor Which Causes 50% Inhibition (IC50) of an Enzymatic Reaction, Biochem. Pharmacol., 22: 3099-31088; (1973).
Alternative Linkage Assay Protocol for MR, GR, AR and PR (Method 2): Cell lysates of 293 cells overexpressing the GR (glucocorticoid receptor), AR (androgen receptor), MR (mineralcorticoid receptor) or PR (progesterone receptor) ) human, are used for competition binding assays to determine Ki values for test compounds. Briefly, competition binding assays are run in a buffer containing 20 mM Hepes, pH 7.6, 0.2 mM EDTA, 75 mM NaCl, 1.5 mM MgC12, 20% glycerol, 20 mM sodium molybdate, 0.2 mM DTT, 20 ug / ml aprotinin and 20 ug / ml leupeptin, using either 0.3 mM of 3H-dexamethasone for GR binding, 0.36 nM of 3H-methyltrienolone for AR binding, 0.25 nM of 3H-aldosterone for linkage MR, or 0.29 nM of 3H-methyltrienolone for PR binding, and either 20 ug of Used 293-GR, 22 ug of Used 293-AR, 20 ug of Used 293-MR or 40 ug of used 293-PR per well. The competition compounds are added at several concentrations in increments of half logarithm. The nonspecific binding is determined in the presence of 500 nM dexamethasone for GR binding, 500 nM aldosterone for MR binding, or 500 nM methyltrienolone for AR and PR binding. The binding reaction (140 μl) is incubated overnight at 4 ° C, then 70 μl of cold charcoal-dextran buffer (containing 50 ml of assay buffer, 0.75 g of carbon) is added to each reaction. vegetable and 0.25 g dextran). The plates are mixed 8 minutes in an orbital shaker at 4 ° C. The plates are then centrifuged at 3,000 rpm at 4 ° C for 10 minutes. An aliquot of 120 μl of the mixture is transferred to another 96-well plate and 175 μl of "Hisafe 3" scintillation fluid from Wallac Optiphase is added to each well. The plates are sealed and shaken vigorously in an orbital shaker. After a 2 hour incubation, the plates are read in a Wallac Microbeta counter. The data is used to calculate an IC50 and% inhibition at 10 μM. The Kd for 3H-dexamethasone for GR bond, 3H-methyltrienolone for AR bond, 3H-aldosterone for MR bond, or 3H-methyltrienolone for PR bond, is determined by saturation bond. The IC50 values for the compounds are converted to Ki using the Cheng-Prusoff equation and the Kd is determined by saturation binding assay. The binding assay protocols for nuclear steroid hormone receptors, similar to those described above, can be easily designated by the ordinarily skilled artisan. U.S. Patent No. 6,166,013 provides examples of such protocols. Representative compounds of the present invention have a Ki in the MR or GR binding assay of <; 50 μM. Table I (see below) provides MR and GR link data for a representative sample of the exemplified compounds of the present invention. To demonstrate the ability of the compounds of the present invention to modulate the activity of a nuclear steroid hormone receptor (i.e., either agonize, antagonize, partially agonize or partially antagonize), bioassays were performed which detected the modulation of the expression of the target gene in cells temporarily transfected with a nuclear receptor protein and a reporter gene-hormone response element construct. The solvents, reagents and ligands employed in the functional assays are readily available from commercial sources, or can be synthesized by one of ordinary skill in the art.
Functional Modulation Assay of the Mineralcorticoid Receptor (Method 1): For the MR transfection assay, COS-7 cells were transfected with full-length human MR and a 2XGRE-luciferase gene construct. After transfection, the ability of the test compounds to modulate the expression of the luciferase reporter gene product is monitored. Briefly, at day one, COS cells are harvested from cell culture plates using standard procedures such as trypsin-EDTA (GIBCO BRL) treatment. The culture medium is then added to the cells and the mixture of the cell medium is placed in plates, in 96 cavity plates coated with poly- (d) -lysine (approximately 3 x 104 cells / well). Cells are grown for approximately 4 hours, then transfected with Fugene-6 reagent with plasmids containing human MR, previously cloned into the expression vector pe.DNA 3.1, and the reporter gene construct 2XGRE (GRE-luciferase), previously cloned in the vector pTAL-luc. Transfection was carried out in DMEM with 5% fetal bovine serum, treated with charcoal. 24 hours later, the cells are exposed to various concentrations of aldosterone in the presence and absence of the test compound and incubated for an additional 24 hours. The reaction was terminated by the addition of lysis buffer, followed by luciferin (luciferase substrate). Luciferase expression, as an indicator of MR-induced transactivation by ligand, is monitored by chemiluminescence measured using a microtiter plate luminometer (MLX). The kinetic inhibition constant (Kb or Kp) can be determined by analysis of dose response curves for aldosterone, in the presence and absence of the test compound, using standard techniques.
Alternative Functional Assay for MR, GR, PR and AR Activity (Method 2): Human embryonic kidney hEK293 cells were co-transfected using Fugene. Briefly, the reporter plasmid containing two copies of GRE (glucocorticoid response element 5'TGTACAGGATGTTCT3) and TK promoter upstream of the luciferase reporter cDNA, was transfected with a plasmid that constitutively expresses either the human glucocorticoid receptor (GR) receptor human mineralcorticoid (MR), or human progesterone receptor (PR), using a viral CMV promoter. The reporter plasmid containing two copies of ARE probasin (element of "androgen response 5'GGTTCTTGGAGTACT3 ') and TK promoter upstream of the luciferase reporter cDNA, was transfected with a plasmid that constitutively expresses the human androgen receptor (AR) using CMV promoter The cells are transfected in T150 cm2 flasks in DMEM medium with Fetal Bovine Serum from 5% charcoal (FBS) After an overnight incubation, the transfected cells are trypsinized, plated on 96-well dishes. cavities in DMEM medium containing FBS released from 5% charcoal, incubated for 4 hours and then exposed to various concentrations of the test compounds in increments of logarithm medium In the antagonist assays, low concentrations of agonist were added for each receptor relative to the medium (0.25 nM dexamethasone for GR, 0.3 nM of methyltrienolone for RA, 0.05 nM of progesterone for PR and 0.05 nM aldosterone). After 24 hours of incubations with the compounds, the cells are lysed and the luciferase activity is determined. The data are adjusted to a logistics of parameter adjustment, to determine the EC50 values. The% of efficacy is determined against the maximum stimulation obtained with 100 nM of methyltrienolone for the AR assay, with 30 nM of progesterone for PR assay, with 30 nM of aldosterone for MR assay and with 100 nM of dexamethasone for GR assay.
Table 1 Glucocorticoid and Mineralocorticoid Receptor Binding Assay Values (values are for racemic mixtures unless otherwise indicated)
Continuation of table 1
Continuation of table 1
continuation of table 1
Legend: "+" represents a value of < 10,000 nM "++" represents a value of < 1,000 nM "+++" represents a value of < 500 nM "-" indicates that the value was not determined
The following Preparations and Examples further illustrate the invention and represent the typical synthesis of the compounds of Formula I, which include any of the novel compounds, as generally described in the above Reaction Schemes. Reagents and starting materials are readily available from commercial suppliers or can be easily synthesized by one of ordinary skill in the art, following the general procedures as described herein. Where the synthesis of the compound is not explicitly stated, a reference is given to a previous Example or representative Reaction Scheme which describes procedures for the synthesis of the compounds. It should be understood that the Preparations and Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art. As used in this document, the following terms have the indicated meanings: "i.v." refers to intravenously; "p.o" refers to orally; "i.p" refers to intraperitoneally; "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "μL" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles ";" psi "refers to pounds per square inch;" mm Hg "refers to millimeters of mercury;" min "refers to minutes;" h "or" hr "refers to hours "C" refers to degrees Celsius; "CCD" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography "; "Rf" refers to retention factor; "Rt" refers to retention time; "d" refers to low fields of parts per million tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N, N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "ac." refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to methyl tertiary butyl ether; "PPh3" refers to triphenylphosphine; "DEAD" refers to diethyl azodicarboxylate; "TA" refers to room temperature; "Pd-C" refers to palladium on carbon; "SAX" refers to strong anion exchange; "SCX" refers to strong cation exchange; NaBH (Oac) 3 refers to sodium triacetoxyborohydride; "Bn" refers to benzyl; "BnNH2" refers to benzylamine; m-CPBA refers to meta-chloroperoxybenzoic acid; H2 refers to hydrogen; "Ki" refers to the dissociation constant of an enzyme antagonist complex and serves as a ligand binding index; e "ID50" and "ID10o", refers to doses of a therapeutic agent administered which produces, respectively, a reduction of 50% and 100% in a physiological response.
Instrumental Analysis: Unless otherwise stated, the? H NMR spectrum is recorded in either a 300 MHz or 400 MHz Varian Mercury nuclear magnetic resonance spectrometer at room temperature. The data are reported as follows: chemical change (D) in ppm from standard tetramethylsilane, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, and m = multiplet), and integration. Liquid chromatography-mass spectrometry (LC-MS) data were obtained in an Agilent 1100 Series CL / EMD instrument.
PREPARATION 1 l-Ethyl-5-fluoro-indan-1-ol and HOpsF Ethyl magnesium bromide (1.3 ml, 3.90 mmol, 1.30 equivalents, 3.0 M in tetrahydrofuran) was added dropwise to a solution of 5-fluoroindanone (450 mg , 3.00 mmol) in anhydrous ether (5 ml) under nitrogen at room temperature and stirred overnight. The reaction was quenched by dropwise addition of 10% aqueous ammonium chloride, diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (502). mg, 93%). NMR (400 MHz, CDC13) d 0.94 (t, 3H), 1.79 (m, 1H), 1.92 (m, 1H), 2.12 (m, 1H), 2.31 (, 1H), 2.81 (m, 1H), 2.98 (m, 1H), 6.91 (m, 2H), 7.24 (m, 1H).
PREPARATION 2 Bromide (2-carboxy-ethyl) -triphenyl-phosphonium + Br "
A solution of triphenylphosphine (91.3 g, 348 mmol, 1.05 equivalents) and 3-bromopropionic acid (50.7 g, 331 mmol) in acetonitrile (250 mL) was allowed to reflux for three hours, allowed to stir at room temperature overnight. Ether (400 ml) was added and cooled in the freezer for two hours. The solids were filtered, rinsed with ether and the solids were dried under high vacuum to obtain the title compound (94.1 g, 68%). NMR (400 MHz, CDC13): d 3.15 (m, 2H), 3.73 (m, 2H), 7.69-7.83 (m, 15H).
PREPARATION 3 4- (3-Fluoro-phenyl) -but-3-enoic acid
To a suspension of 3-fluoroaldehyde (13.4 mL, 126 mmol) and (2-carboxy-ethyl) -triphenyl-phosphonium bromide (62.85 g, 151 mmol, 1.20 equivalents) in anhydrous dichloromethane (150 mL) at 0 ° C under nitrogen, portions of t-butoxide (315 mmol, 2.50 equivalents) were added over two hours and stirred at room temperature overnight. It was diluted with water, washed with dichloromethane (2x), the aqueous layer was acidified with 1N hydrochloric acid to pH 1, diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (24.28 g, ~ 99%, containing approximately 1.6 g of triphenylphosphine oxide). NMR (400 MHz, CDC13): d 3.26 (d, 2H), 6.32 (m, 1H), 6.48 (d, 1H), 6.95 (t, 1H), 7.08 (d, 1H), 7.14 (d, 1H) , 7.27 (m, 1H). The product is an EZ 95: 5 mixture.
PREPARATION 4 4- (3-Fluoro-phenyl) -butyric acid
A mixture of 4- (3-fluoro-phenyl) -but-3-enoic acid (22 g, 122 mmol), concentrated sulfuric acid (24 mL), and 5% palladium on carbon (3.58 g) in tetrahydrofuran was hydrogenated. (470 ml) at 60 psi at room temperature overnight. After the catalyst filtration, more tetrahydrofuran was removed by rotary evaporation, the residue was diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound ( 22.50 g, 100%). NMR (400 MHz, CDC13): d 1.98 (m, 2H), 2.38 (t, 2H), 2.65 (t, 2H), 6.88 (m, 2H), 6. 96 (d, 1H), 7. 23 (m, 1H)
PREPARATION 5 6-Fluoro-3, 4-dihydro-2H-naphthalen-1-one
A mixture of 4- (3-fluoro-phenyl) -butyric acid (1.92 g, 10.5 mmol) and phosphoric acid (2 g) was heated at 110 ° C under nitrogen for two hours. After cooling to room temperature, quenched with water, diluted with ether, washed with saturated aqueous sodium bicarbonate (2x), dried over anhydrous sodium sulfate and concentrated to obtain the title compound (1.5 g, 87%). %). NMR (400 MHz, CDC13): d 2.16 (m, 2H), 2.64 (t, 2H), 2.97 (t, 2H), 6.92 (dd, 1H), 6.99 (dt, 1H), 8.04 (dd, 1H) .
PREPARATION 6 5-Pyrazol-l-il-indan-l-one
-Fluoro-indan-l-one (1.02 g, 6.79 mmol), pyrazole (0.46 g, 6.79 mmol) and potassium carbonate were combined.
(1.03 g, 7.47 mmol, 1.10 equivalents) in dimethyl sulfoxide (5 ml) in a sealed tube and heated at 100 ° C for 48 hours. It was cooled to room temperature, diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a brown solid (0.98 g, 73%). LC-MS m / z 199.1 (M ++ 1).
PREPARATION 7 3- (3,5-Difluoro-phenyl) -propionic acid
A mixture of 3,5-difluoroacetic acid (10.0 g, 54.3 mmol), 5% palladium on carbon (1.5 g) and concentrated sulfuric acid (10 ml) in tetrahydrofuran (195 ml) at 60 psi at room temperature was hydrogenated. the night. After filtering the catalyst, it was diluted with ether, washed with water twice, dried over anhydrous sodium sulfate and concentrated to obtain the title compound as clear colorless crystals (9.32 g, 92%). NMR (400 MHz, CDC13): d 2.67 (t, 2H), 2.94 (t, 2H), 6.65 (t, 1H), 6.74 (d, 2H).
PREPARATION 8 l-Cyclopropyl-5-fluoro-indan-l-ol
To a solution of 5-fluoroindanone (0.95 g, 6.33 mmol) in anhydrous ether (30 mL) under nitrogen at room temperature, cyclopropyl magnesium bromide (9.1 ml, 7.28 mmol, 1.15 equivalents, 0.80 M tetrahydrofuran) was added by dripping while keeping at gentle reflux. After stirring overnight, the reaction was quenched at room temperature via dropwise addition of 10% aqueous ammonium chloride. The reaction was diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.30 g, -100%). NMR (CDC13, 400 MHz): d 0.26 (m, 1H), 0.36-0.51 (m, 3H), 1.21 (m, 1H), 2.13 (m, 1H), 2.28 (m, 1H), 2.80 (m, 1H), 2.95 (m, 1H), 6.88 (m, 2H), 7.29 (m, 1H).
PREPARATION 9 lH-indol-7-ilamine
7-Nitroindole was dissolved in ethanol and ammonium formate (10 equivalents) and a catalytic amount of 10% palladium on carbon were added. The mixture was refluxed for 1 hour before cooling, filtered through celite and evaporated to give the product as a purple solid (99%).
PREPARATION 10 N- (lH-Indol-7-yl) -methanesulfonamide
LH-indol-7-ylamine was stirred with pyridine (1 equivalent) and methanesulfonyl chloride (1 equivalent) in dichloromethane for 12 hours. The reaction was washed with 1 N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue was recrystallized from isopropanol to obtain the title product as a purple solid (94%). MS (ES +) 210 (M), MS (ES ") 209 (M-1) LC / MS showed 95% impurity.
PREPARATION 11 3- (3-Fluorophenoxy) -propan-1-ol
To a pre-dried round bottom flask, equipped with a magnetic stirrer, sodium hydride (60% dispersion in mineral oil, 4.80 g, 0.120 mol) was added under a nitrogen atmosphere. The sodium hydride was washed with hexanes (3 x 100 mL) to remove the mineral oil, then dimethylformamide (165 mL) was added. The resulting suspension was cooled to 0 ° C and a solution of 3-fluorophenol (11.20 g, 0.100 mol) in dimethylformamide (35 ml) was added dropwise resulting in gas evolution and a color change from green to blue-green. After the reaction mixture was stirred at room temperature for approximately 30 minutes, the reaction was cooled to 0 ° C and a solution of 3-chloro-1-propanol (9.46 g, 0.100 mol) in dimethylformamide (35 ml) was added dropwise. ). The resulting reaction mixture was heated at 60 ° C for 2.5 hours. The solution was cooled, the dimethylformamide was removed under reduced pressure and the resulting reaction mixture was diluted with water (250 ml) and extracted with diethyl ether (3 x 150 ml). The organic extracts were washed with water (200 ml), 2M aqueous sodium hydroxide (200 ml), water (200 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate, dried and concentrated to give the title compound slightly impure
(13.32 g, 78%) as an amber oil which was used directly in the next reaction without purification: Rf
0. 40 (19: 1 CH2Cl2 / MeOH); XH NMR (300 MHz, CDC13) d 1.68 (t, J
= 5.1 Hz, 1H), 2.04 (quintuplet, J = 6.0 Hz, 2H), 3.83-3.89 (, 2H), 4.10 (t, J = 6.0 Hz, 2H), 6.59-6.70 (, 3H), 7.17-7.25 (m, 1H); 19 F NMR (282 MHz, CDC13) d 112.13; APCI MS m / z 153 [C9HuF02 + H - H20] +.
PREPARATION 12 3- (3-fluorophenoxy) -propionic acid
Acetone (600 ml) was cooled using a saturated ice / water bath, then chromium trioxide was added
(14.45 g, 145 mmol), followed by water (32 ml) and concentrated sulfuric acid (16 ml). The mixture was allowed to stir for several minutes, then a solution of 3- (3-fluorophenoxy) -propan-1-ol (6.15 g, 36.1 mmol) in acetone was slowly added.
(300 mi) via an addition funnel for ~ 1 hour. The reaction was stirred at 0 ° C for 5 hours, and then 2-propanol (70 ml) was added. The reaction was filtered over diatomaceous earth, rinsed with acetone (~100 mL), and the filtrate was evaporated under reduced pressure, reconstituted in diethyl ether (500 mL), and washed with brine (2 x 500 mL). The organic layer was then dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound (6.00 g, 90%) as an off-white solid which was used without further purification: Rf 0.34
(95: 5: 0.5 dichloromethane / methanol / ammonium hydroxide); 1H NMR
(300 MHz, CDC13) d 2.85 (t, J = 6.2 Hz, 2H), 4.23 (t, J = 6.2
Hz, 2H), 6.59-6.70 (m, 3H), 7.18-7.24 (m, 1H), 7.30-9.60 (br s, 1H); 19 F NMR (282 MHz, CDCl 3) d-112. 01; APCI MS (negative form) m / z 183 [C9H9FO3-H] ".
PREPARATION 13 7-Fluoro-chroman-4-one
To a solution of 3- (3-fluorophenoxy) -propionic acid (4.94 g, 26.8 mmol) in dichloromethane (135 ml) were added several drops of anhydrous dimethylformamide., followed by oxalyl chloride (4.68 ml, 53.6 mmol). The reaction was stirred at room temperature until evolution ceased (~ 30 minutes), then it was evaporated under reduced pressure and reconstituted in dichloromethane (135 ml). After the addition of aluminum trichloride (4.28 g, 32.1 mmol), the reaction was stirred for 1 hour, then 2M aqueous hydrochloric acid (100 mL) and dichloromethane (100 mL) were added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude residue was recrystallized twice from 2-propanol to give the slightly impure title compound (1.79 g, 40%), and the mother liquor was subjected to flash chromatography (silica gel, 3: 1 pentane / Et20) provide the pure title compound (1.15 g, 26%): Rf 0.45 (1: 1 ethyl acetate / hexanes); mp 53-56 ° C; E NMR (300 MHz, CDC13) d 2.75 (t, J = 6.4 Hz, 2H), 4.51 (t, J = 6.4 Hz, 2H), 6.61 (dd, J = 2.3, 9.9 Hz, 1H), 6.65-6.72 (m, 1H), 7.87 (dd, J = 6.7, 8.8 Hz, 1H); 19 F NMR (282 MHz, CDC13) d-101.06; APCI EM m / z 167
[C9H7F02 + H] +,
PREPARATION 14 lH-Indol-7-ilamine
An autoclave of 11.3562 1 (3 gal) was charged with 7-nitroindole (250 g, 1542 moles), ethyl 2B-3 alcohol (5.0 1) and 10% Pd / C (50.0 g). Stirred at 50 psi H2 for 2 hours at < 27 ° C. When the reaction was considered complete, the contents of the reactor were filtered through celite, followed by concentration of the filtrate to dryness to yield 197.0 g (96.7%) of the title compound as a purple solid, ""? -RMN (CD3OD , 300MHz) d 7.16 (d, 1H), 7.00 (dd, 1H), 6.81 (t, 1H), 6.50 (dd, 1H), 6.37 (d, 1H).
PREPARATION 15 (lH-indol-7-yl) -carbamic acid benzyl ester
A 12 1 reaction flask was equipped with a cooling bath, air conducting agitation apparatus, addition funnel and thermometer probe. The flask was completely purged with nitrogen, charged with 7-aminoindole (352 g, 2663 moles), CH2C12 (5.30 1, 15 volumes) and 2N NaOH (1.76 1, 3.515 moles). After cooling of the biphasic solution to less than 10 ° C, benzyl chloroformate (500 g, 2,929 moles) was added dropwise at such rate to maintain the temperature at less than 10 ° C for one hour. The reaction was stirred vigorously for 1 hour until complete by CCD. The layers were separated and the aqueous layer was extracted with CH2C12 (1.7 1). The combined organic layers were washed with 2N NaOH (2 x 21) and dried over Na 2 SO 4. After filtering the dried agent, the filtrate was concentrated in vacuo to a volume of ~ 1.5 1 resulting in a thin dark mixture. The solvent gradually changed using heptane (~4 1) to form a slurry as coarse sand and increase the bath temperature to 50-60 ° C. It was concentrated to a volume of ~ 1.5 1, filtered while heating (50-60 ° C), washed with hot heptane (45 ° C) (11) and heptane at room temperature (11), and dried to yield 683.5 g (96.7%) of the title compound as a light purple solid. 1H-RM (DMSO-d6, 300MHz) d 10.79 (br s, 1H), 9.42 (br s, 1H), 7.20-7.56 (m, 8H), 6.92 (t, 1H), 6.41 (dd, 1H), 5.18 (s, 1H).
EXAMPLE 1 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide
L-ethyl-5-fluoro-indan-1-ol (502 mg, 2.79 mmol, 1.30 equivalents), N- (1 H -indol-7-yl) -methanesulfonamide (450 mg, 2.14 mmol, 1.00 equivalents) were combined, and trifluoroacetic acid (0.25 ml, 3.21 mmol, 1.50 equivalents) in dichloromethane (5 ml) and stirred at room temperature under nitrogen overnight. The solution was loaded onto silica and purified by levigating with 0 to 100% ethyl acetate / hexanes for 25 minutes to obtain the title compound (672 mg, 84%), LC-MS m / z 373.0 (M ++ l ). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column with methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 230 nm) to provide the individual enantiomers, Examples 1A and IB, in 96.3% ee and 97.4% ee, respectively.
EXAMPLE 2 3- (1-Ethyl-5-fluoro-indan-1-yl) -7-nitro-1H-indole
Using l-ethyl-5-fluoro-indan-1-ol and 7-nitroindole, the title compound was prepared as in Example 1. 0.37 g (42%). NMR (400 MHz, CDC13): d 0.85 (t, 3H), 2.18 (m, 2H), 2.35 (m, 1H), 2.53 (m, 1H), 3.00 (m, 2H), 6.83 (t, 1H) , 6.92 (t, 1H), 7.01 (m, 2H), 7.08 (s, 1H), 7.44 (d, 1H), 8.09 (d, 1H), 9.76 (s, 1H, NH).
EXAMPLE 3 3- (1-Ethyl-5-fluoro-indan-1-yl) -l-methyl-7-nitro-1H-indole
3- (1-ethyl-5-fluoro-indan-1-yl) -7-nitro-1H-indole (0.33 g, 1.02 mmol), sodium methoxide (110 mg, 2.04 mmol) and iodomethane (0.10 ml) were combined. , 1.53 mmol) in dimethylformamide
(5 ml) and stirred at room temperature under nitrogen overnight. It was diluted with ether, washed with water (2x), dried over sodium sulfate, filtered and concentrated to obtain the title compound as a yellow amorphous solid (0.33 g, 94%). LC-MS m / z 339.1 (M ++ 1).
EXAMPLE 4 3- (1-Ethyl-5-fluoro-indan-1-yl) -l-methyl-1H-indol-7-ylamine
A mixture of 3- (1-ethyl-5-fluoro-indan-1-yl) -l-methyl-7-nitro-1H-indole (0.26 g, 0.77 mmol) and 5% palladium on carbon was hydrogenated (26 mg) in ethanol (50 ml) at 60 psi at room temperature overnight. The catalyst was filtered and concentrated under high vacuum to obtain the title compound as oil (0.17 g, 71%). NMR (400 MHz, CDC13): d 0.83 (t, 3H), 2.05 (m, 1H), 2.25 (, 2H), 2.60 (, 1H), 2.96 (, 2H), 3.72 (broad s, 2H, NH2) , 4.02 (s, 3H), 6.43 (m, 2H), 6.76 (d, 2H), 6.83 (t, 1H), 6.97 (d, 1H), 7.02 (m, 1H).
EXAMPLE 5 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -l-methyl-1H-indol-7-yl] methanesulfonamide
3- (1-ethyl-5-fluoro-indol-1-yl) -1-methyl-1H-indole-7-ylamine (0.18 g, 0.58 mmol) was dissolved in pyridine (3 mL). Methanesulfonyl chloride (0.05 ml, 0.70 mmol, 1.20 equivalents) was added and stirred at room temperature under nitrogen overnight. It was diluted with ether, washed with 1N aqueous hydrochloric acid (2x), dried over anhydrous sodium sulfate, filtered and the solution concentrated in vacuo.
The residue was purified on silica by levigating with 0 to 100% ethyl acetate / hexanes for 25 minutes to give the title compound as a white solid.
(0.19 g, 86%). LC-MS m / z 387.1 (M ++ l).
EXAMPLE 6 3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indole
Using l-ethyl-5-fluoro-indan-1-ol and indole, the title compound was prepared as in Example 1. 89 mg (54%). LC-MS 280.0 (M ++ l).
EXAMPLE 7 3- (1-Ethyl-5-fluoro-indan-1-yl) -7-fluoro-1H-indole
Using l-ethyl-5-fluoro-indan-1-ol and 7-fluoroindole, the title compound was prepared as in Example 1. 217 mg (92%). NMR (400 MHz, CDC13): d 0.85 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.31 (m, 1H), 2.58 (m, 1H), 2.97 (m, 2H) , 6.83 (m, 4H), 6.98 (m, 3H), 8.06 (s, 1H, NH).
EXAMPLE 8 7-Bromo-3- (l-ethyl-5-fluoro-indan-l-yl) -lH-indole
Using l-ethyl-5-fluoro-indan-1-ol and 7-bromoindole, the title compound was prepared as in Example 1. 51 mg (16%). NMR (400 MHz, CDC13): d 0.82 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.30 (m, 1H), 2.59 (m, 1H), 2.97
(m, 2H), 6.82 (m, 2H), 6.90 (s, 1H), 6.99 (m, 2H), 7.12 (d,
1H), 7.28 (d, 1H), 8.08 (s, 1H, NH).
EXAMPLE 9 7-Chloro-3- (l-ethyl-5-fluoro-indan-1-yl) -IH-indole
Using l-ethyl-5-fluoro-indan-1-ol and 7-chloroindole, the title compound was prepared as in Example 1. 90 mg (60%). NMR (400 MHz, CDC13): d 0.85 (t, 3H), 2.15 (m, 1H), 2.22 (m, 1H), 2.34 (m, 1H), 2.59 (m, 1H), 2.98 (m, 2H) , 6.82 (t, 1H), 6.87 (m, 2H), 7.00 (m, 2H), 7.11 (d, 1H), 7.16 (d, 1H), 8.12 (s, 1H, NH).
EXAMPLE 10 7-Ethyl-3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indole
Using l-ethyl-5-fluoro-indan-1-ol and 7-ethylindole, the title compound was prepared as in Example 1. 104 mg (58%). LC-MS m / z 308.1 (M ++ 1).
EXAMPLE 11 3- (1-Ethyl-5-fluoro-indan-1-yl) -1H-indole-7-carboxylic acid methyl ester
Using l-ethyl-5-fluoro-indan-1-ol and lH-indole-7-carboxylic acid methyl ester, the title compound was prepared as in Example 1. 103 mg (75%). LC-MS m / z 338.1 (M ++ 1).
EXAMPLE 12 3- (1-Ethyl-5-fluoro-indan-1-yl) -7-methoxy-1H-indole
Using l-ethyl-5-fluoro-indan-1-ol and 7-methoxyindole, the title compound was prepared as in Example 1. 123 mg (59%). LC-MS m / z 310.2 (M ++ l).
EXAMPLE 13 [3- (L-Ethyl-5-fluoro-indan-1-yl) -1H-indol-7-yl] -carbamic acid benzyl ester
Using l-ethyl-5-fluoro-indan-1-ol and (lH-indol-7-yl) -carbamic acid benzyl ester, the title compound was prepared as in Example 1. 7.78 g (100%). LC-MS m / z 249.1 (M ++ 1).
EXAMPLE 14 3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-7-ylamine
A mixture of [3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -carbamic acid benzyl ester (7.78 g, 18.2 mmol) and palladium hydroxide on carbon at 20% (1.6 g) in ethanol was hydrogenated at 50 ° C at 60 psi for 18 hours. After filtration of the catalyst, the solution was concentrated in vacuo to give the title compound as a black solid (5.04 g, 94%). LC-MS m / z 295.1 (M ++ 1).
EXAMPLE 15 [3- (L-Ethyl-5-fluoro-indan-1-yl) -1H-indol-7-yl] -carbamic acid methyl ester
3- (1-ethyl-5-fluoro-indan-1-yl) -1H-indol-7-ylamine (0.35 g, 1.19 mmol) was dissolved in pyridine (3 mL). Methyl chloroformate (0.10 ml, 1.31 mmol, 1.1 equivalents) was added and stirred at room temperature under nitrogen overnight. It was diluted with ether, washed with 1N aqueous hydrochloric acid (2x), dried over anhydrous sodium sulfate, filtered and the solution concentrated in vacuo. The residue was purified on silica by levigating with 0 to 75% ethyl acetate / hexanes for 30 minutes to give the title compound as a white solid (0.15 g, 36%). LC-MS m / z 353.1 (M ++ l).
EXAMPLE 16 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -acetamide
Using 3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indol-7-ylamine and acetic anhydride, the title compound was prepared as in Example 15. 0.16 g (46%). LC-MS m / z 337.1 (M ++ 1).
EXAMPLE 17 7-Dimethylsulfamoyl-3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indole
Using 3- (1-ethyl-5-fluoro-indan-1-yl) -iH-indol-1-ylamine and dimethyl sulfamoyl chloride, the title compound was prepared as in Example 15. 0.16 g (29%) . LC-MS m / z 402.1 (M ++ l).
EXAMPLE 18 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-1-yl] -benzenesulfonamide
Using 3- (1-ethyl-5-fluoro-indan-1-yl) -IH-indol-7-ylamine and benzenesulfonyl chloride, the title compound was prepared as in Example 15. 0.21 g (33%). LC-MS m / z 295.1 (M ++ 1).
EXAMPLE 19 Ethanesulfonic acid [3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -amide
Using 3- (1-ethyl-5-fluoro-indan-1-yl) -iH-indol-7-ylamine and ethanesulfonyl chloride, the title compound was prepared as in Example 15. 0.18 g (35%). LC-MS m / z 387.1 (M ++ l). Carbinoles used in Examples 20-39 of the appropriate ketone were prepared as in Preparation 1.
EXAMPLE 20 N- [3- (1-Methyl-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 634 mg (74%). LC-MS m / z 341.1 (M ++ 1).
EXAMPLE 21 N- [3- (5-Fluoro-l-methyl-indan-l-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-Indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 737 mg (83%). LC-MS m / z 359.1 (M ++ 1). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column by levigating with 15/85 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 400 ml / min, UV detection at 275 nm) to give the individual enantiomers, Examples 21A and 21B, in greater than 99.9% ee and 97.4% ee, respectively.
EXAMPLE 22 N- [3- (5,7-Difluoro-1-methyl-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-11) -metanesulfonamide, the title compound was prepared as in Example 1. 1.25 g (71%). LC-MS m / z 377.1 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column by levigating with 20/20/60 of 3A alcohol / methanol / heptane with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 300 nm) to provide the individual enantiomers, Examples 22A and 22B, in 99.3% ee and 99.6% ee, respectively.
EXAMPLE 23 N- [3- (1-Ethyl-5,7-difluoro-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 0.41 g (69%). LC-MS m / z 391.0 (M ++ l). The racemic mixture was separated on a Chiralcel OD 8 x 34 cm column by levigating with 30/10/60 isopropanol / methanol / heptane with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 300 nm) to give the enantiomers Individuals, Examples 23A and 23B, in 97.2% ee and 98.5% ee, respectively.
EXAMPLE 24 N- [3- (l-Methyl-5-pyrazol-l-yl-indan-l-yl) -lH-indol-7-yl] • methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 0.43 g (32%). LC-MS m / z 407.1 (M ++ l).
EXAMPLE 25 N- [3- (1, 2, 3, 4-Tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-Indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 197 mg (40%). LC-MS m / z 341.1 (M ++ 1).
EXAMPLE 26 N- [3- (1-Methyl-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 541 mg (78%). LC-MS m / z 355.0 (M ++ l).
EXAMPLE 27 N- [3- (1-Ethyl-1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 140 mg (54%). LC-MS m / z 369.1 (M ++ l).
EXAMPLE 28 N- [3- (6-Fluoro-l-methyl-1,2,3-tetrahydro-naphthalen-1-yl) -1H-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 0.81 g (76%). LC-MS m / z 373.2 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column with 20/80 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 316 nm) to provide the individual enantiomers, Examples 28A and 28B, greater than 99.9% ee and greater than 99.9% ee, respectively.
EXAMPLE 29 N- [3- (1-Ethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -1H-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 2.23 g (74%). NMR (400 MHz, CDC13): d 0.89
(t, 3H), 1.62-1.86 (m, 2H), 2.05 (m, 1H), 2.16-2.42 (m, 4H), 2.84 (t, 2H), 3.01 (s, 3H), 6.42 (s, 1H) ), 6.70 (s, 1H), 6.75
(t, 1H), 6.82-6.93 (m, 3H), 7.05 (m, 1H), 7.21 (d, 1H), 8.91
(broad s, 1H, NH). The racemic mixture was separated on a Chiralpak AD 8 x 30 cm column, levigating with alcohol 3A with 0.2% dimethylethylamine (flow: 300 ml / min, UV detection at 270 nm) to provide the individual enantiomers,
Examples 29A and 29B, in 99.5% ee and 99.6% ee, respectively.
EXAMPLE 30 N- [3- (6, 8-Difluoro-l-methyl-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-Indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 3.12 g (68%). LC-MS m / z 391.0 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column, by levigating with 5/95 acetonitrile / methanol (flow: 375 ml / min, UV detection at 225 nm) to give the individual enantiomers, Examples 31A and 31B, greater than 99.9% ee and 99.3% ee, respectively.
EXAMPLE 31 N- [3- (1-Ethyl-6,8-difluoro-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 380 mg (40%). NMR (400 MHz, CDC13): d 0.82 (t, 3H), 1.58-1.78 (, 2H), 2.08 (m, 1H), 2.17 (m, 1H), 2.40 (m, 1H), 2.55 (m, 1H) ), 2.82 (m, 2H), 3.01 (s, 3H), 6.47 (s, 1H), 6.57 (t, 1H), 6.67 (s, 1H), 6.74 (d, 1H), 6.87 (d, 1H) , 6.94 (t, 1H), 7.31 (d, 1H), 8.94 (broad s, 1H, NH). The racemic mixture was separated on a Chiralcel OJ 8 x 33 xm column, levigated with 5/95 acetonitrile / methanol (flow: 375 ml / min, UN detection at 230 nm) to give the individual enantiomers, Examples 31A and 31B, greater than 99.9% ee and 99.5% ee, respectively.
EXAMPLE 32 N- [3- (4-Methyl-chroman-4-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 226 mg (99%). LC-MS m / z 357.0 (M ++ l).
EXAMPLE 33 N- [3- (6-Fluoro-4-methyl-chroman-4-yl) -lH-indol-7-yl] methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 270 mg (99%). LC-MS m / z 375.0 (M ++ l).
EXAMPLE 34 N- [3- (7-Fluoro-4-methyl-chroman-4-yl) -lH-indol-7-yl] methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 3.6 g (100%). LC-MS m / z 375.0 (M ++ l). The racemic mixture was separated on a Chiralpak AD 8 x 30 cm column, levigating with 100% 3A alcohol (flow: 375 ml / min, UV detection at 230 nm) to give the individual enantiomers, Examples 34A and 34B, in 98.9% ee and 99.1% ee, respectively.
EXAMPLE 35 N- [3- (4-Ethyl-7-fluoro-chroman-4-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 3.85 g (99%). LC-MS m / z 389.1 (M ++ l). The racemic mixture was separated on a Chiralcel OJ column 8 x 33 cm, levigated with 10/90 acetonitrile / methanol (flow: 375 ml / min, UV detection at 230 nm) to give the individual enantiomers, Examples 35A and 35B, 96.5% ee and 98.2% ee, respectively.
EXAMPLE 36 N- [3- (4-Ethyl-5,7-difluoro-chroman-4-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 4.13 g (94%). LC-MS m / z 407.0 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column, levigating with 20/80 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 280 nm) to give the individual enantiomers, Examples 36A and 36B, greater than 99.9% ee and 99.9% ee, respectively.
EXAMPLE 37 N- [3- (4-Methyl-thiochroman-4-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-11) -metanesulfonamide, the title compound was prepared as in Example 1. 195 mg (74%). LC-MS m / z 390.1 (M ++ H20).
EXAMPLE 38 N- [3- (5-Methyl-6,7,8,8-tetrahydro-5H-benzocyclohepten-5-yl) -lH-indol-7-yl] -methanesulfonamide
Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 213 mg (66%). NMR (400 MHz, CDC13): d 1.47 (m, 1H), 1.75 (m, 1H), 1.78 (s, 3H), 1.87 (m, 3H), 2.60 (m, 1H), 2.67 (, 1H), 2.79 (m, 1H), 6.43 (s, 1H), 6.67 (s, 1H), 6.87 (d, 1H), 6.93 (t, 1H), 7.11 (, 1H), 7.16-7.21 (m, 3H), 7.41 (, 1H), 8.91 (broad s, 1H, NH).
EXAMPLE 39 N- [3- (l-Cyclopropyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] • methanesulfonamide
N- (lH-indol-7-yl) -metanesulfonamide (0.95 g, 4.51 mmol), l-cyclopropyl-5-fluoro-indan-1-ol (1.30 g, 6.76 mmol, 1.50 equivalents) and trifluoroacetic acid ( 0.70 ml, 9.02 mmol, 2.00 equivalents) in dichloromethane (20 ml) and stirred at room temperature under nitrogen overnight. The solution was preloaded on silica and purified on 40 g of silica, levigating with 0 to 50 ethyl acetate / hexanes for 30 minutes. The product was isolated as a white crystalline solid (1.42 g). NMR analysis indicated one to one of the mixtures of the title compound and propyl trifluoroacetate ester. The product was dissolved in methanol (20 mL) and 2M aqueous lithium hydroxide (20 mL) and stirred at room temperature overnight. It was diluted with ether, washed with 1N hydrochloric acid (2x), dried over sodium sulfate, filtered and concentrated. It was purified on 40 g of silica by levigating with 0 to 100 ethyl acetate / hexanes for 30 minutes to obtain the title compound as a white solid (0.39 g). The title compound is the less polar component. NMR (400 MHz, CDC13): d 1.47 (m, 1H), -0.15 (m, 1H), 0.11 (m, 1H), 0.49 (m, 2H), 1.45 (m, 1H), 2.21 (m, 1H) ), 2.67 (, 1H), 2.94 (m, 1H), 3.01 (s, 3H), 3.05 (m, 1H), 6.55 (s, 1H), 6.72 (m, 2H), 6.83 (m, 3H), 6.97 (d, 1H), 7.33 (s, 1H), 9.02 (broad s, 1H, NH). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column, levigating with 60/40 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 275 nm) to give the individual enantiomers, Examples 39A and 39B, greater than 99.9% ee and 99.6% ee, respectively.
EXAMPLE 40 N-. { 3- [5-Fluoro-l- (3-hydroxy-propyl) -indan-1-yl] -lH-indol-7-yl} -methanesulfonamide
The title compound is the most polar component of the final chromatography described in Example 39. NMR (400 MHz, CDCl 3): d 1.47-1.60 (m, 2H), 2.08-2.29 (, 3H), 2.58 (m, 1H ), 2.97 (m, 2H), 2.99 (s, 3H), 2.61 (m, 2H), 6.77 (t, 1H), 6.85-6.98 (m, 6H), 7.05 (d, 1H), 9.01 (broad) , 1H, NH). The racemic mixture was separated on a Chiralpak AD 8 x 30 cm column, levigating with 40/10/50 isopropanol / methanol / heptane with 0.2% dimethylethylamine (flow: 350 ml / min, UV detection at 232 nm) to give the individual enantiomers, Examples 40A and 40B, in 98.2% ee and 96.8% ee, respectively.
EXAMPLE 41 N-. { 3- [5-Fluoro-l- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} - methanesulfonamide
To a solution of triphenylphosphine (422 mg, 1.61 mmol, 1.30 equivalents) and imidazole (219 mg, 3.22 mmol, 2.60 equivalents) in anhydrous tetrahydrofuran (10 mL), iodide (410 mg, 1.61 mmol, 1.30 equivalents) was added. After stirring for 20 minutes at room temperature under nitrogen, N- was added. { 3- [5-Fluoro-l- (3-hydroxy-prspil) -indan-1-yl] -lH-indol-7-yl} -methansulfonamide (500 mg, 1.24 mmol) and stirred for 48 hours. It was diluted with ether, washed with water (2x), washed with 1N aqueous hydrochloric acid (2x), dried over anhydrous sodium sulfate, filtered and the solution was concentrated. The residue was purified on silica by levigating with 50 to 100% ethyl acetate / hexanes for 25 minutes to obtain the title compound as a white solid (254 mg, 40%). LC-MS m / z 385.0 (M + -l).
EXAMPLE 42 N-. { 3- [5-Fluoro-l- (3-methylamino-propyl) -indan-1-yl] -IH-indol-7-yl} -methanesulfonamide
N- stirred. { 3- [5-fluoro-1- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} -metanesulfonamide (88 mg, 0.17 mmol) and methylamine (40% in water, 2 ml) in tetrahydrofuran (1 ml) at room temperature under nitrogen for 30 minutes. It was diluted with dichloromethane and 10% aqueous potassium carbonate. The white solids that were compressed were filtered and dried under high vacuum to obtain the title compound (35 mg, 49%). LC-MS m / z 416.1 (M ++ l).
EXAMPLE 43 N-. { 3- [1- (3-Dimethylamino-propyl) -5-fluoro-indan-1-yl] -1H-indol-7-yl} -methanesulfonamide
N- stirred. { 3- [5-fluoro-l- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} -metanesulfonamide (65 mg, 0.13 mmol) and dimethylamine (5.0 ml, 2. OM in tetrahydrofiran) at room temperature under nitrogen overnight. The volatiles were removed under high vacuum, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica by levigating with 10% methanol in dichloromethane to obtain the title compound as a white solid (34 mg, 65%). LC-MS m / z 430.2 (M ++ l).
EXAMPLE 44 N-. { 3- [5-Fluoro-l- (3-morpholin-4-yl-propyl) -indan-1-yl] -1H-indol-7-yl} -methanesulfonamide
N- was combined. { 3- [5-fluoro-l- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} methansulfonamide (65 mg, 0.13 mmol) and morpholine (2 mL) in anhydrous tetrahydrofuran (2.5 mL) and stirred at room temperature under nitrogen overnight. The volatiles were removed under high vacuum, the residue was dissolved in dichloromethane, solid potassium carbonate was added, stirred for ten minutes, filtered and concentrated in vacuo. The residue was purified on silica by levigating with 5 to 10% methanol in dichloromethane over 15 minutes to obtain the title compound as a white solid (50 mg, 83%). LC-MS m / z 472.2 (M ++ l).
Claims (25)
1. A compound of the formula: Formula I characterized in that X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, -CH2S-, or -CH2NR10-; R1 represents hydrogen, (C? -C4) alkyl, (C3-C7) cycloalkyl, (C? -C4) hydroxyalkyl, (Cj-C4) haloalkyl, (C? -C4) alkyl -heterocycle, (C? -C) alkyl ) -N-Alkylamine (C? -C4), or alkyl (C? -C4) -N, N-dialkylamine (C? -C); R 2 represents hydrogen, halo, (C 1 -C 4) alkyl, heterocycle, or substituted heterocycle; R3 represents hydrogen, halo, alkyl (Cj.-C), heterocycle, or substituted heterocycle; R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (Cj-C4) alkoxy, NHS02R7, NHCOR8, or COR9; R5 represents hydrogen or halo; R6 represents hydrogen or alkyl (C? -C4); R7 represents (C1-C4) alkyl, aryl, NHalkylamine (C1-C4), or N, N-dialkylamine (C1-C4); R8 represents (C1-C4) alkyl, (C1-C4) alkoxy or (C1-C4) arylalkoxy; and R9 represents (C1-C4) alkyl or (C1-C4) alkoxy; R10 represents hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl- (C3-C7) cycloalkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, characterized in that X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, or -CH2S-.
3. The compound according to claim 2, characterized in that X represents -CH2-, -CH2CH2-, or -CH20-.
4. The compound according to claim 3, characterized in that X represents -CH2- or -CH2CH2- •
5. The compound according to claim 3, characterized in that X represents -CH20-.
6. The compound according to any of claims 1-5, characterized in that R1 represents hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) hydroxyalkyl, (C1-C4) haloalkyl, alkyl -heterocycle (C3.-C4), alkyl (C? -C4) -NHalkylamine (C? ~ C4), or (C1-C4) alkyl-N, N-dialkylamine (Cj.-C4).
7. The compound according to claim 6, characterized in that R1 represents hydrogen, methyl, ethyl, propyl, isopropyl, (C3-C7) cycloalkyl, (C1-C4) hydroxyalkyl, (C1-C4) haloalkyl, (C1-C4) alkyl -heterocycle, (C 1 -C 4) alkyl-N-Hyalkylamine (C 1 -C 4), or (C 1 -C 4) alkyl-N, N-dialkylamine (C 3 -C 4).
The compound according to claim 7, characterized in that R1 represents methyl, ethyl, propyl, isopropyl, (C3-C7) cycloalkyl, (C1-C4) hydroxyalkyl, (C1-C4) haloalkyl, (C1-C4) alkyl -heterocycle, (C3-C4) -NH-alkylamino (C1-C4) alkyl, or (C1-C4) -N, N-dialkylamine (C1-C4) alkyl.
9. The compound according to any of claims 1-8, characterized in that R2 represents hydrogen, halo, methyl, ethyl, propyl, isopropyl, heterocycle or substituted heterocycle.
10. The compound according to claim 9, characterized in that R2 represents hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl and isopropyl.
11. The compound according to any of claims 1-10, characterized in that R3 represents hydrogen, fluoro, chloro or bromo.
12. The compound according to claim 11, characterized in that R3 represents hydrogen or fluoro.
13. The compound according to any of claims 1-12, characterized in that R4 represents hydrogen, halo, amino, nitro, alkyl (C? -C4), alkoxy (C1-C4), NHS02R7, NHCOR8, wherein R8 represents alkyl (Cj-Ca) or (C 1 -C 4) alkoxy or COR 9, wherein R 9 represents (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy.
14. The compound according to claim 13, characterized in that R4 represents hydrogen, halo, amino, nitro, (C? -C4) alkyl, (C1-C4) alkoxy or NHS02R7.
15. The compound according to claim 14, characterized in that R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C? -C4) alkoxy or NHS02R7, wherein R7 represents alkyl (C? ~ C4) ), aryl or N, N-dialkylamine (C? -C4).
16. The compound according to any of claims 1-15, characterized in that R5 represents hydrogen, chlorine or fluoro.
17. The compound according to claim 16, characterized in that R5 represents hydrogen.
18. The compound according to any of claims 1-17, characterized in that R6 represents hydrogen, methyl or ethyl.
19. A pharmaceutical composition, characterized in that it comprises the compound according to any of claims 1-18 in combination with a pharmaceutically acceptable carrier, diluent or excipient.
20. A method for treating a disorder selected from the group consisting of Conn Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and systolic / combined diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, rejection of tissue associated with organ transplantation, malignancies such as leukemia and lympholas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and syndrome of Little, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, dermatitis of contact, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis , inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bullosa, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, epidermal necrolysis toxic, erythema multiforme, cutaneous T-cell lymphoma, psychosis, cognitive disorders, memory disorders, mood disorders, depression, bipolar disorder, anxiety disorders and personality disorders, which includes administering a patient in need of it, a compound as claimed in accordance with which of Claims 1-18, or a pharmaceutically acceptable salt.
The method according to claim 20, characterized in that the disorder is selected from the group consisting of diastolic or systolic congestive heart failure, inflammation, rheumatoid arthritis, hypertension, asthma or chronic obstructive pulmonary disease.
22. The method according to claim 21, characterized in that the disorder is diastolic or systolic congestive heart failure, inflammation, hypertension or rheumatoid arthritis.
23. The method according to claim 20, characterized in that the disorder is atherosclerosis.
24. The use of a compound according to any of claims 1-18, or a pharmaceutically acceptable salt thereof, as an agent for the treatment of Conn Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome , disorders associated with excess levels of catecholamine, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin , weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, tissue rejection associated with organ transplantation, malignancies as leukemia and lymphomas, insuficie Acute adrenal syndrome, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic renal disease, apoplexy and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, disease chronic obstructive pulmonary age, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bullosum, dermatomyositis , eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, cutaneous T-cell lymphoma, psychosis, disorders cognitive disorders, memory disorders, mood disorders, depression, bipolar disorder, anxiety disorders or personality disorders.
25. The use of a compound according to any of claims 1-18, for the manufacture of a medicament for the treatment of Conn Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased excretion of magnesium and potassium (diuresis ), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF) , peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, intolerance to glucose, hyperglycemia, diabetes mellitus, osteoporosis, poliur ia, polydipsia, inflammation, autoimmune disorders, rejection of tissue associated with organ transplantation, malignancies such as leukemia and lymphomas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, insufficiency secondary adrenal, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, fever hay, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, alopecia nflamatoria of the scalp, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bulosus, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, cutaneous T-cell lymphoma, psychosis, cognitive disorders, memory disorders, mood disorders, depression, bipolar disorder, anxiety disorders or personality disorders.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/549,754 | 2004-03-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06009953A true MXPA06009953A (en) | 2007-04-20 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7728150B2 (en) | Bicyclic substituted indole-derivative steroid hormone nuclear receptor modulators | |
ES2325861T3 (en) | TRICYCLE MODULATORS OF NUCLEAR RECEPTORS OF STEROID HORMOSAS. | |
US7250442B2 (en) | Dihydroindol-2-one derivatives as steroid hormone nuclear receptor modulators | |
EP2565191B1 (en) | 4-(Indol-7-ylcarbonylaminomethyl)cyclohexanecarboxylic acid derivatives as EP4 receptor antagonists useful for the treatment of chronic renal failure or diabetic nephropathy | |
JP2007500253A (en) | Indole derivative modulators of steroid hormone nuclear receptors | |
US5618833A (en) | 1-benzyl-1,3-dihydroindol-2-one derivatives, their preparation and the pharmaceutical compositions in which they are present | |
US6593322B1 (en) | Compounds and methods for modulation of estrogen receptors | |
ZA200604889B (en) | Tricyclic steroid hormone nuclear receptor modulators | |
US7482344B2 (en) | Tricyclic steroid hormone nuclear receptor modulators | |
AU3895693A (en) | Imidazole, triazole and tetrazole derivatives | |
MXPA06009953A (en) | Bicyclic substituted indole-derivative steroid hormone nuclear receptor modulators |