Aryl-substituted n-alkyl indoles and their use as pharmacologically active agents
Disclosed herein are novel aryl-substituted N-alkyl indoles useful as pharmacologically active agents, the novel compounds having the structure of formula wherein m, p, q, L 1 through L 3 , R 1 through R 5 , and Ar are defined herein. Also provided are pharmaceutical formulations comprising at least one aryl-substituted N-alkyl indole of the invention, at least one pharmaceutically acceptable excipient, and, optionally, an additional beneficial agent, along with methods for treating a subject affected by a condition, disorder, or disease responsive to administration of the aryl-substituted N-alkyl indole. Exemplary methods of use include treatment of pain, treatment of inflammation, treatment of endometriosis, and a method for inducing weight loss.
1 . An aryl-substituted N-alkyl indole having the structure of formula
wherein:
m, p, and q are independently selected from zero and 1;
L 1 is selected from C 1 -C 3 alkylene and C 2 -C 3 alkenylene, and is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, or halo;
L 2 is selected from —(CO)— and —(SO 2 )—;
L 3 is selected from C 2 -C 3 alkylene and C 2 -C 3 alkenylene, and is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, or halo;
R 1 is H or C 1 -C 3 alkyl;
R 2 is selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, halogenated C 1 -C 3 alkyl, halogenated C 2 -C 3 alkenyl, hydroxyl, hydroxyl-substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy, cyano, amino, mono-C 1 -C 3 alkyl-substituted amino, di-C 1 -C 3 alkyl-substituted amino, and morpholinyl;
R 3 is selected from hydroxyl, C 1 -C 3 alkoxy, and amino;
R 4 and R 5 are independently selected from H and C 1 -C 3 alkyl or are linked to form an aliphatic N-heterocycle optionally substituted with one or two non-hydrogen substituents selected from C 1 -C 3 alkyl, hydroxyl, and C 1 -C 3 alkoxy, or wherein two non-hydrogen substituents on the aliphatic N-heterocycle are linked to form a bridged bicyclic moiety comprising a 1-, 2-, or 3-carbon atom bridge; and
Ar is bicyclic N-heteroaryl bound to L 3 through a ring carbon atom and is optionally substituted with at least one substituent selected from hydroxyl, amido, mono-(C 1 -C 3 alkyl)amido, di-(C 1 -C 3 alkyl)amido, and C 2 -C 3 acylamino.
2 . The aryl-substituted N-alkyl indole of claim 1 , wherein p and q are zero.
3 . The aryl-substituted N-alkyl indole of claim 2 , wherein:
m is 1;
L 1 is C 1 -C 3 alkylene;
L 3 is —CH 2 CH 2 —;
R 1 is C 1 -C 3 alkyl;
R 2 is cyano;
R 4 and R 5 are linked to form a morpholinyl group optionally substituted with one or two C 1 -C 3 alkyl groups or with two substituents that together form a bridged bicyclic moiety having a 2-carbon atom bridge; and
Ar is selected from quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl, and is optionally substituted with a hydroxyl, amido, methylamido, dimethylamido, or acetylamino group.
4 . The aryl-substituted N-alkyl indole of claim 3 , wherein L 1 is —CH 2 —, R 1 is methyl, R 4 and R 5 are linked to form an unsubstituted morpholinyl group, and Ar is isoquinolinyl optionally substituted with a hydroxyl, methylamido, or acetylamino group.
5 . The aryl-substituted N-alkyl indole of claim 4 , wherein Ar is unsubstituted isoquinolinyl.
6 . The aryl-substituted N-alkyl indole of claim 1 , wherein:
m is zero or 1;
p is 1;
q is zero;
L 1 is C 1 -C 3 alkylene;
L 3 is —CH 2 CH 2 —;
R 1 is C 1 -C 3 alkyl;
R 2 is selected from hydroxyl, amino, and C 1 -C 3 alkoxy;
R 4 and R 5 are linked to form a morpholinyl group optionally substituted with one or two C 1 -C 3 alkyl groups or with two substituents that together form a bridged bicyclic moiety having a 2-carbon atom bridge; and
Ar is selected from quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl, and is optionally substituted with a hydroxyl, amido, methylamido, dimethylamido, or acetylamino group.
7 . The aryl-substituted N-alkyl indole of claim 6 , wherein m is 1, L 1 is —CH 2 —, R 1 is methyl, R 4 and R 5 are linked to form an unsubstituted morpholinyl group, and Ar is isoquinolinyl optionally substituted with a hydroxyl, methylamido, or acetylamino group.
8 . A pharmaceutical formulation comprising a therapeutically effective amount of the aryl-substituted N-alkyl indole of claim 1 and a pharmaceutically acceptable excipient.
9 . The pharmaceutical formulation of claim 8 , wherein the therapeutically effective amount is a unit dosage.
10 . The pharmaceutical formulation of claim 8 , comprising an oral dosage form.
11 . The pharmaceutical formulation of claim 10 , comprising a gummy.
12 . The pharmaceutical formulation of claim 8 , comprising a suppository.
13 . A method for treating a subject affected by a condition responsive to administration of an aryl-substituted N-alkyl indole, comprising administering to the subject, optionally within the context of an ongoing dosage regimen, an effective amount of the compound of claim 1 , wherein the condition comprises pain, endometriosis, primary dysmenorrhea, secondary premenstrual syndrome, uterine fibroid pain, menopausal symptoms, adenomyosis, polycystic ovary syndrome, alcoholism, anxiety, autism spectrum disorder, inflammatory bowel disease, celiac disease, systemic lupus erythematosus, Addison's disease, celiac disease, Graves' disease, Hashimoto thyroiditis, myasthenia gravis, psoriasis, Sjogren's disease, pernicious anemia, vasculitis, autoimmune hepatitis, and type 1 diabetes, burns, cardiac disorders, peripheral artery disease, cognitive pain, mild cognitive impairment, non-neurodegenerative dementia, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barre Syndrome, gingivitis, periodontitis, type 2 diabetes, glucose regulation, drug withdrawal, fibroses, acne, contact dermatitis, eczema, infectious skin ulcers, cellulitis, immunodeficiency, inflammation, ischemia, infertility, fatty liver disease, cirrhosis, hepatitis, Metabolic Syndrome and any condition associated therewith, headaches, nausea, neurological disorders, neurodegenerative disorders, obesity, overweight, conditions caused by or associated with excess weight or obesity, osteoporosis, osteopenia, pelvic pain, attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), psychosis, schizophrenia, respiratory disorders, seizure disorders, sleep apnea, insomnia, restless leg syndrome, REM sleep dysfunction, or stress.
14 . The method of claim 13 , wherein the condition comprises pain, inflammation, or both pain and inflammation.
15 . The method of claim 14 , wherein the condition is pain.
16 . The method of claim 15 , wherein the pain is neuropathic, nociceptive, or both neuropathic and nociceptive.
17 . The method of claim 15 , wherein the pain is incident to an injury, chemotherapy, surgery, inflammation, or a disease.
18 . The method of claim 13 , wherein the subject is female and the condition is endometriosis, dysmenorrhea, premenstrual syndrome, uterine fibroid pain, adenomyosis, polycystic ovary syndrome, menopause, or infertility.
19 . The method of claim 18 , wherein the condition is endometriosis.
20 . The method of claim 1 , wherein the aryl-substituted N-alkyl indole is administered vaginally.
21 . The method of claim 13 , further comprising co-administering at least one additional pharmacologically active agent to the subject.
22 . The method of claim 21 , wherein the at least one additional pharmacologically active agent is administered to treat the condition.
23 . A method of opioid sparing in a subject in need of pain management, comprising co-administering to the subject an effective opioid-sparing dose of the aryl-substituted N-alkyl indole of claim 1 and an opioid analgesic.
24 . A method for inducing weight loss in a subject, comprising co-administering to the subject the aryl-substituted N-alkyl indole of claim 1 and a glucagon-like peptide 1 receptor agonist (GLP-1 RA).