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KR-102964218-B1 - Treatment of obesity

KR102964218B1KR 102964218 B1KR102964218 B1KR 102964218B1KR-102964218-B1

Abstract

The present invention provides a novel method for treating or preventing obesity or overweight and closely related comorbidities in mammals, including humans.

Inventors

  • 리 치앙 제이.
  • 데어다크 졸탄
  • 스테바노비치 다코
  • 리우 지펭

Assignees

  • 1글로브 바이오메디칼 씨오., 엘티디.
  • 1글로브 헬스 인스티튜트 엘엘씨

Dates

Publication Date
20260513
Application Date
20190918
Priority Date
20180918

Claims (18)

  1. A pharmaceutical composition for treating a pathological condition selected from the group consisting of obesity, overweight, type II diabetes, and metabolic syndrome in mammals including humans, wherein the treatment comprises administering a therapeutically effective amount of the pharmaceutical composition to a mammalian subject requiring such treatment, and wherein the pharmaceutical composition (a) a compound of the following formula VII-e, or its enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate, and (b) Pharmaceutically acceptable excipients, carriers, or diluents A pharmaceutical composition comprising: In the formula, the symbols have the following meanings and are selected independently in each case: Z is carbon or N; Q-2 is thiazole or piperidine; Q-1 is pyrrole or phenyl; R1 , R2 "" , R3 , R4 , R5" , and R7 are hydrogen, respectively; R 5"' and R 6 are each independently absent or hydrogen; R 2" and R 2"' are independently hydrogen or C 1 -C 6 alkyl; R 2' is a substituted 4 to 7-membered monocyclic heterocycle containing at least one heteroatom selected from substituted C 1 -C 6 alkyl, N, O, and S, or C(=O)NR b R c , where R b is hydrogen or a C 1 -C 6 alkyl, and R c is a C 1 -C 6 alkyl substituted with NR bn R cn , where R bn and R cn are C 1 -C 6 alkyls, or R b and R c optionally form a substituted 4 to 7-membered monocyclic heterocycle containing at least one heteroatom selected from N, O, and S together with the N to which they are bonded; R 5' is a 4 to 7-membered monocyclic heterocycle containing at least one heteroatom selected from C 1 -C 6 alkyl, N, O, and S, phenyl, or substituted phenyl; The substituted group is a group substituted with one to three substituents at any possible bonding site, each substituent being selected from hydrogen, halogen, cyano, nitro, CF₃ , OCF₃ , C₆ - C₆alkyl , NR₆b₆R₆ , C(=O) R₆a , and C (=O) NR₆b₆R₆ , wherein R₆a , R₆b₆ , and R₆c among the substituents are independently C₆ - C₆alkyls substituted by hydrogen, C₆ - C₆alkyl , or N( C₆ - C₆alkyl )( C₆ -C₆alkyl ) .
  2. A pharmaceutical composition according to claim 1, wherein the compound of formula VII-e is a compound selected from the group consisting of the following formulas VII-g, VII-f, VII-h, and VII-m: , , , .
  3. A pharmaceutical composition for treating a pathological condition selected from the group consisting of obesity, overweight, type II diabetes, and metabolic syndrome in mammals including humans, wherein the treatment comprises administering a therapeutically effective amount of the pharmaceutical composition to a mammalian subject requiring such treatment, and wherein the pharmaceutical composition (a) a compound of Formula IV below, or its enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate, and (b) Pharmaceutically acceptable excipients, carriers, or diluents A pharmaceutical composition comprising: In the formula, the symbols have the following meanings and are selected independently in each case: R1 , R3 , R4 , R6 , R7 , and R8 are each hydrogen; R5 is a 4 to 7-membered monocyclic heterocycle containing at least one heteroatom selected from C1 - C6 alkyl, N, O, and S, phenyl, or substituted phenyl; R9 and R10 are each independently C1 - C6 alkyl; R14 is hydrogen or a C1 - C6 alkyl, and R15 is a C1 - C6 alkyl substituted with NRb Rc , wherein Rb and Rc are C1 - C6 alkyls, or R14 and R15 optionally form a substituted 4 to 7-membered monocyclic heterocycle containing at least one heteroatom selected from N, O, and S together with the N to which they are bonded; The substituted group is a group substituted with one to three substituents at any possible bonding site, and each substituent is selected from hydrogen, halogen, cyano, nitro, CF3 , OCF3 , C1 - C3 alkyl, NH2 .
  4. In paragraph 3, a pharmaceutical composition wherein the compound of formula IV is a compound of formula V, or its enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate: In the formula, the symbols have the following meanings and are selected independently in each case: R 11 is hydrogen or C 1-4 alkyl; R 12 and R 13 are independently C 1-6 alkyl; n is an integer selected from 2, 3, 4, 5, and 6.
  5. A pharmaceutical composition for treating a pathological condition selected from the group consisting of obesity, overweight, type II diabetes, and metabolic syndrome in mammals including humans, wherein the treatment comprises administering a therapeutically effective amount of the pharmaceutical composition to a mammalian subject requiring such treatment, and wherein the pharmaceutical composition (a) a compound selected from the group consisting of the following chemical formulas, or its enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate, and (b) Pharmaceutically acceptable excipients, carriers, or diluents A pharmaceutical composition comprising: .
  6. A pharmaceutical composition according to any one of claims 1 to 5, further comprising an additional agent selected from the group consisting of insulin sensitizing agents, diabetes agents, metabolic syndrome treatment agents, and weight loss agents.
  7. A pharmaceutical composition according to any one of claims 1 to 5, wherein at least one symptom or sign known to be associated with obesity, overweight, type II diabetes, or metabolic syndrome is reduced, improved, or eliminated, and said symptom or sign is selected from the group consisting of excessive body weight, excessive fat, BMI ≥ 25 kg/ m² , insulin resistance, frequent urination, increased thirst, increased hunger, increased blood pressure, increased fasting plasma glucose, high serum triglycerides, low high-density lipoprotein (HDL) levels, and increased waist circumference.
  8. A pharmaceutical composition according to claim 7, wherein the symptoms or signs are BMI ≥ 30 kg/ m² .
  9. A pharmaceutical composition according to any one of claims 1 to 5, which reduces or improves mortality or morbidity known to be associated with obesity, overweight, type II diabetes, or metabolic syndrome in mammals, including humans.
  10. Compounds selected from the group consisting of compounds of the following chemical formulas and pharmaceutically acceptable salts thereof: .
  11. In paragraph 10, a compound in which at least one of the hydrogens is deuterium.
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Description

Treatment of obesity Cross-reference regarding related applications This application claims priority and benefit of concurrently pending U.S. provisional application serial number 62/732,650 filed on September 18, 2018, the entirety of which is incorporated herein by reference. Technology field The present invention generally relates to a method for treating obesity and obesity-related pathological conditions and disorders in subjects, and to a related composition thereof. Globally, obesity is becoming a major threat to public health, placing a massive financial burden on many families and nations. It is estimated that there are approximately 600 million obese adults worldwide with a Body Mass Index (BMI) ≥ 30 kg/ m² . Childhood obesity is of particular concern as it is a often overlooked condition that can lead to long-term health problems. In the United States alone, adult obesity rates have increased significantly over the past few decades. Obesity is a well-established risk factor for related diseases, including type II diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, polycystic ovary syndrome (PCOS), obstructive sleep apnea, osteoarthritis, and various forms of cancer (endometrial, esophageal, gastric, liver, kidney, multiple myeloma, meningioma, colorectal, gallbladder, breast, etc.). In a society where stereotypes about obesity are prevalent, overweight people also face numerous psychological and social challenges and often suffer from low self-esteem, prejudice, and discrimination. Clinically significant weight loss (> 5%) can reduce risk factors for cardiovascular disease (CVD), delay or prevent the onset of various cancers and type II diabetes, and ultimately improve quality of life. However, most patients cannot achieve sustained and clinically significant weight loss with current treatments. Currently, bariatric surgery is the most effective treatment for obesity, despite having significant limitations including the irreversibility of the procedure, surgical risks such as hemorrhage, anastomosis leakage, infection, internal hernia, nutritional deficiencies, postprandial hypoglycemia, death, and high financial costs. There is an ongoing unmet need for effective treatment and/or prevention of obesity and closely related conditions/disorders. Summary of the Invention The present invention is intended to address these needs. The present invention provides a novel method of using the compound of the present invention (an embodiment described in detail below). In one aspect, the present invention provides a method for treating or preventing obesity or overweight in mammals, including humans, comprising administering to a mammal in need a therapeutically effective amount of a pharmaceutical composition comprising the compound of the present invention, or its enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester, or prodrug, and a pharmaceutically acceptable excipient, carrier, or diluent, which is effective for treating or preventing obesity or overweight in mammals, including humans. In another aspect, the present invention provides a method for treating or preventing type II diabetes mellitus in mammals, including humans, comprising administering to a mammal in need a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present invention, or a mirror image isomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, which is effective for treating or preventing type II diabetes mellitus in mammals, including humans. In another aspect, the present invention provides a method for treating or preventing metabolic syndrome in mammals, including humans, comprising administering to a mammal in need a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present invention, or a mirror image isomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, which is effective for treating or preventing metabolic syndrome in mammals, including humans. In one aspect, the present invention provides a method for reducing, improving, or eliminating morbidity or mortality, which includes at least symptoms or signs known to be associated with obesity or overweight, such as excessive body weight, excessive fat, or an elevated BMI ≥ 30 kg/ m² or 25 kg/ m² . In one aspect, the present invention provides a method for reducing, improving, or eliminating morbidity or mortality, including at least symptoms or signs known to be associated with type II diabetes mellitus, such as insulin resistance, frequent urination, increased thirst, and increased hunger. In one aspect, the present invention provides a method for reducing, improving, or elimin