Antagonists of the glucagon receptor

• US 10,807,946 B2
• Filed: 03/25/2019
• Issued: 10/20/2020
• Est. Priority Date: 02/09/2007
• Status: Active Grant

• Current Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Gomez-Galeno, Jorge E., Reddy, Raja K., Van Poelje, Paul D., Lemus, Robert Huerta, Nguyen, Thanh Huu, Grote, Matthew P., Dang, Qun, Hecker, Scott J., Mali, Venkat Reddy, Chen, Mingwei, Sun, Zhili, Boyer, Serge Henri, Li, Haiqing, Craigo, William
• Primary Examiner(s): Chen, Po-Chih
• Application Number:
  US16/363,825
• Publication Number:
  US 20190218176A1
• Time in Patent Office: 575 Days
• Field of Search: None
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 307/02 : Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
• CPC Class Codes: C07C 309/11 : with the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 309/15 : the nitrogen atom of at least one of the amino groups being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/62 : having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07D 209/20 : substituted additionally by nitrogen atoms, e.g. tryptophane
• CPC Class Codes: C07D 213/53 : Nitrogen atoms
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 235/30 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 261/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/56 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/81 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/66 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems

Abstract

The present invention provides for novel compounds of Formula (I) and pharmaceutically acceptable salts and co-crystals thereof which have glucagon receptor antagonist or inverse agonist activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia. The present invention also provides for processes of making the compounds of Formula I, including salts and co-crystals thereof and pharmaceutical compositions comprising the same.

Claims

1. A method for treating, delaying the time to onset or reducing the risk for the development or progression of diabetes, the method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I)

2. The method according to claim 1, wherein

D is a substituted group selected from phenyl or heteroaryl, wherein said group is substituted with L and, optionally, one or more additional substituents independently selected from C_1-6-alkyl, halogen, —

CF₃, or C_1-6-haloalkyl;

wherein said heteroaryl contains one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The method according to claim 1, wherein

Z is —

C(O)N(R²)—

;

wherein said R² is hydrogen or C_1-3-alkyl;

Y is a group selected from —

O—

or —

CHR²⁷—

;

wherein R²⁷ is hydrogen or C_1-3-alkyl; and

R¹ is a group selected from hydrogen, —

F, or —

CH₃.

4. The method according to claim 1, wherein

E is a group selected from phenyl, C_3-8-cycloalkyl-substituted phenyl, C_4-8-cycloalkenyl-substituted phenyl, phenyl-substituted phenyl, benzyl, C_3-8-cycloalkyl-substituted benzyl, C_4-8-cycloalkenyl-substituted benzyl, or phenyl-benzyl;

wherein each group is optionally substituted with one to three groups independently selected from halogen, —

CN, —

C_1-6-alkyl, halogen, —

CF₃, —

OCF₃, or —

OCH₂CF₃.

5. The method according to claim 1, wherein the compound is a pharmaceutically acceptable salt of a compound with the following chemical structure:

6. The method according to claim 1, wherein the diabetes is characterized by one or more of the following:

hyperglycemia, glycosuria, ketoacidosis, neuropathy or nephropathy, increased hepatic glucose production, insulin resistance in various tissues, insufficient insulin secretion or enhanced or poorly controlled glucagon secretion from the pancreas.

7. The method according to claim 6, wherein the diabetes is characterized by ketoacidosis.

8. The method according to claim 1, wherein the diabetes is Type II diabetes.

9. The method according to claim 8, wherein the Type II diabetes manifests as one or more of the following:

impaired glucose tolerance, fasting hyperglycemia, glycosuria, decreased levels of insulin, increased levels of glucagon, increased hepatic glucose output, reduced hepatic glucose uptake and glycogen storage, reduced whole body glucose uptake and utilization, dyslipidemia, fatty liver, ketoacidosis, microvascular diseases, or macrovascular diseases.

10. The method according to claim 9, wherein the Type II diabetes manifests as ketoacidosis.