# US 10,441,567 B2 · Methods and compositions for modulating hormone levels

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- Number: US 10,441,567 B2
- Document ID: US10441567B2
- Status: Granted
- Kind: B2
- Application number: 15/111,741
- Filed: 2015-01-14
- Published: 2016-11-24
- Granted: 2019-10-15
- Earliest claimed: 2014-01-17
- Assignees: Ligand Pharmaceuticals Incorporated
- Applicants: Ligand Pharmaceuticals Incorporated
- Inventors: Lin Zhi
- Web page: https://patentgrep.com/patent/US10441567B2

## CPC

- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/402: 1-aryl substituted, e.g. piretanide
- A61K 31/4535: containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/567: substituted in position 17 alpha, e.g. mestranol, norethandrolone
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 5/24: of the sex hormones
- A61K 31/47: Quinolines; Isoquinolines
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compositions and methods for the treatment of androgen and estrogen receptors mediated conditions. Specifically, a composition that includes an effective amount of a selective estrogen receptor modulator (SERM) and an effective amount of a 5a-reductase inhibitor, or a pharmaceutically acceptable salt, ester or prodrug of the foregoing is provided. Also provided are methods for the treatment of aging related conditions and diseases.

## Claims

### Claim 1

A method of treating a disease, disorder or condition by administering an effective amount of a selective androgen receptor modulator compound and an effective amount of an estrogen receptor modulator, or a pharmaceutically acceptable salt, ester or prodrug of the foregoing; and wherein the selective androgen receptor modulator is 4-(2(R)-(1(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile, or a pharmaceutically acceptable salt, ester or prodrug thereof;
wherein the estrogen receptor modulator is lasofoxifene; and
where the disease, disorder, or condition is selected from the group consisting of aging skin; Alzheimer's disease; an anemia; anorexia; arthritis; gout; arteriosclerosis; atherosclerosis; bone disease; bone damage; bone fracture; distraction osteogenesis; reduced bone mass, reduced bone density; reduced bone growth; bone weakening induced by glucocorticoid administration; musculoskeletal impairment (e.g., in the elderly); cachexia; breast cancer and osteosarcoma; cardiac dysfunction; myocardial infarction; cardiac hypertrophy; congestive heart failure; cardiomyopathy; catabolic side effects of glucocorticoids; Crohn's disease; growth retardation in connection with Crohn's disease; short bowel syndrome; irritable bowel syndrome; inflammatory bowel disease; ulcerative colitis; cognitive decline; cognitive impairment; dementia; short term memory loss; COPD; chronic bronchitis; decreased pulmonary function; emphysema; decreased libido in men; decreased libido in women; depression; nervousness, irritability and/or stress; reduced mental energy and low self-esteem (e.g., motivation/assertiveness); dyslipidemia; erectile dysfunction; frailty; age-related functional decline (“ARFD”) in the elderly; growth hormone deficiency; hematopoietic disorders; sex hormone deficiency (male and female); hyper-cholesterolemia; hyperinsulinemia; hyperlipidemia; hypertension; hyperandrogenemia; hypogonadism (including primary and secondary); hypothermia (including hypothermia following anesthesia); impotence; insulin resistance; type 2 diabetes; lipodystrophy; male menopause; metabolic syndrome (syndrome X); loss of muscle strength; loss of muscle strength function; muscular dystrophies; muscle loss following surgery; muscular atrophy; neurodegenerative diseases; neuromuscular disease; decreased platelet count; platelet aggregation disorders; obesity; osteoporosis; osteopenia; glucocorticoid-induced osteoporosis; osteochondrodysplasias; periodontal disease; premenstrual syndrome; postmenopausal symptoms in women; Reaven's syndrome; rheumatological disease; sarcopenia; male sexual dysfunction; female sexual dysfunction; erectile dysfunction; decreased sex drive; decreased libido; physiological short stature, including growth hormone deficient children and short stature associated with chronic illness and growth retardation associated with obesity; tooth damage; thrombocytopenia; vaginal dryness; atrophic vaginitis; ventricular dysfunction; and wasting.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease, disorder or condition is selected from among muscular atrophy; osteoporosis; male sexual dysfunction; female sexual dysfunction; hypogonadism; frailty; cancer cachexia; and decreased libido.

### Claim 3 (depends on 1)

The method of claim 1, wherein the treatment produces an effect selected from group consisting of improved bone strength, improved muscle strength; improved muscle tone; reduced subcutaneous fat in a subject; increased athletic performance; attenuation or reversal of protein catabolic responses following trauma; improved sleep quality; correction of the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency; modification of lipid profile; correction of female androgen deficiency; and correction of male androgen decline.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disease, disorder or condition is selected from the group consisting of acanthosis nigricans; acne; adrenal hyperandrogenism; androgenetic alopecia (male-pattern baldness); BPH; breast cancer; bladder cancer; brain cancer; endometrium cancer; kidney cancer; lung (non-small cell lung) cancer; ovarian cancer; pancreatic cancer; skin cancer; lymphatic cancer; bulimia nervosa; chronic fatigue syndrome (CFS); chronic myalgia; acute fatigue syndrome; counteracting preeclampsia, eclampsia of pregnancy and preterm labor; delayed wound healing; erythrocytosis; gestational diabetes; hirsutism; hyper-insulinemia; nesidioblastosis; hyperandrogenism; hypercortisolism; Cushing's syndrome; hyperpilosity; menstrual irregularity; ovarian hyperandrogenism; polycystic ovarian syndrome; seborrhea; sleep disorders; sleep apnea; and visceral adiposity.