Deuterated benzylbenzene derivatives and methods of use

• US 9,061,060 B2
• Filed: 07/15/2009
• Issued: 06/23/2015
• Est. Priority Date: 07/15/2008
• Status: Active Grant

• Current Assignee: Theracos Inc
• Original Assignee: Theracos Inc
• Inventors: Seed, Brian, Lv, Binhua, Roberge, Jacques Y., Chen, Yuanwei, Peng, Kun, Dong, Jiajia, Xu, Baihua, Du, Jiyan, Zhang, Lili, Tang, Xinxing, Xu, Ge, Feng, Yan, Xu, Min
• Primary Examiner(s): Pihonak, Sarah
• Application Number:
  US12/503,384
• Publication Number:
  US 20100063141A1
• Time in Patent Office: 2,169 Days
• Field of Search: 514/460, 549/417
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric 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 3/10 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 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: C07D 309/10 Oxygen atoms

Abstract

Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by SGLT inhibition.

Claims

1. A composition comprising a compound having the structure:

2. The composition of claim 1, wherein one of R¹, R², R³, R⁴ and R⁵ is group Q;

one of the remaining groups R¹, R², R³, R⁴ and R⁵ represents hydrogen, deuterium, halo, cyano, nitro, amino, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ cycloalkenyl, C₁-C₆ alkoxy, C₃-C₁₀ cycloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, C₅-C₇ cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C₂-C₄ alkenyl)C₁-C₃ alkoxy, (C₂-C₄ alkynyl)C₁-C₃ alkoxy, (aryl)C₁-C₃ alkoxy, (heteroaryl)C₁-C₃ alkoxy, (C₃-C₁₀ cycloalkyl)C₁-C₃ alkyl, (C₃-C₁₀ cycloalkyl)C₁-C₃ alkoxy, (C₅-C₁₀ cycloalkenyl)C₁-C₃ alkyl, (C₅-C₁₀ cycloalkenyl)C₁-C₃ alkoxy, (C₁-C₄ alkoxy)C₁-C₃ alkyl, (C₃-C₇ cycloalkoxy)C₁-C₃ alkyl, (C₃-C₇ cycloalkoxy)C₂-C₄ alkenyl, (C₃-C₇ cycloalkoxy)C₂-C₄ alkynyl, (C₃-C₇ cycloalkoxy)C₁-C₃ alkoxy, (C₁-C₄ alkylamino)C₁-C₃ alkyl, di-(C₁-C₃ alkylamino)C₁-C₃ alkyl, tri-(C₁-C₄ alkyl)silyl-C₁-C₆ alkyl, tri-(C₁-C₄ alkyl)silyl-C₂-C₆ alkenyl, tri-(C₁-C₄ alkyl)silyl-C₂-C₆ alkynyl, tri-(C₁-C₄ alkyl)silyl-C₁-C₆ alkoxy, (C₃-C₇ cycloalkyl)C₂-C₅ alkenyl, (C₃-C₇ cycloalkyl)C₃-C₅ alkenyloxy, (C₃-C₇ cycloalkyl)C₃-C₅ alkynyloxy, (C₅-C₈ cycloalkenyl)C₃-C₅ alkenyloxy, (C₅-C₈ cycloalkenyl)C₃-C₅ alkynyloxy, C₃-C₆ cycloalkylidenmethyl, (C₁-C₄ alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl, di-(C₁-C₃ alkyl)aminocarbonyl, hydroxycarbonyl, (C₁-C₄ alkoxy)carbonyl, C₁-C₄ alkylamino, di-(C₁-C₃ alkyl)amino, (C₁-C₄ alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C₁-C₄ alkylsulfonylamino, arylsulfonylamino, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₃-C₁₀ cycloalkylthio, C₃-C₁₀ cycloalkylsulfinyl, C₃-C₁₀ cycloalkylsulfonyl, C₅-C₁₀ cycloalkenylthio, C₅-C₁₀ cycloalkenylsulfinyl, C₅-C₁₀ cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl;

two of the remaining groups R¹, R², R³, R⁴ and R⁵ each independently represent hydrogen, deuterium, halo, cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₃ alkoxy or C₃-C₁₀ cycloalkoxy; and

one of the remaining groups R¹, R², R³, R⁴ and R⁵ represents hydrogen or deuterium;

one of the groups R⁶, R⁷, R⁸, R⁹ and R¹⁰ represents hydrogen, deuterium, halo, cyano, nitro, amino, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, C₁-C₆ alkoxy, C₃-C₁₀ cycloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, (C₁-C₃ alkoxy)C₃-C₇ cycloalkoxy, C₅-C₇ cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C₂-C₄ alkenyl)C₁-C₃ alkoxy, (C₂-C₄ alkynyl)C₁-C₃ alkoxy, (aryl)C₁-C₃ alkoxy, (heteroaryl)C₁-C₃ alkoxy, (C₃-C₁₀ cycloalkyl)C₁-C₃ alkyl, (C₃-C₁₀ cycloalkyl)C₁-C₃ alkoxy, (C₅-C₁₀ cycloalkenyl)C₁-C₃ alkyl, (C₅-C₁₀ cycloalkenyl)C₁-C₃ alkoxy, (C₁-C₄ alkoxy)C₁-C₃ alkyl, (C₃-C₇ cycloalkoxy)C₁-C₃ alkyl, (C₃-C₇ cycloalkoxy)C₂-C₄ alkenyl, (C₃-C₇ cycloalkoxy)C₂-C₄ alkynyl, (C₃-C₇ cycloalkoxy)C₁-C₃ alkoxy, (C₁-C₄ alkylamino)C₁-C₃ alkyl, di-(C₁-C₃ alkylamino)C₁-C₃ alkyl, tri-(C₁-C₄ alkyl)silyl-C₁-C₆ alkyl, tri-(C₁-C₄ alkyl)silyl-C₂-C₆ alkenyl, tri-(C₁-C₄ alkyl)silyl-C₂-C₆ alkynyl, tri-(C₁-C₄ alkyl)silyl-C₁-C₆ alkoxy, (C₃-C₇ cycloalkyl)C₂-C₅ alkenyl, (C₃-C₇ cycloalkyl)C₃-C₅ alkenyloxy, (C₃-C₇ cycloalkyl)C₃-C₅ alkynyloxy, (C₅-C₈ cycloalkenyl)C₃-C₅ alkenyloxy, (C₅-C₈ cycloalkenyl)C₃-C₅ alkynyloxy, C₃-C₆ cycloalkylidenmethyl, (C₁-C₄ alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl, di-(C₁-C₃ alkyl)aminocarbonyl, hydroxycarbonyl, (C₁-C₄ alkoxy)carbonyl, C₁-C₄ alkylamino, di-(C₁-C₃ alkyl)amino, (C₁-C₄ alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C₁-C₄ alkylsulfonylamino, arylsulfonylamino, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₃-C₁₀ cycloalkylthio, C₃-C₁₀ cycloalkylsulfinyl, C₃-C₁₀ cycloalkylsulfonyl, C₅-C₁₀ cycloalkenylthio, C₅-C₁₀ cycloalkenylsulfinyl, C₅-C₁₀ cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl;

two of the remaining groups R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently represent hydrogen, deuterium, halo, cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₃ alkoxy or C₃-C₁₀ cycloalkoxy; and

two of the remaining groups R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently represent hydrogen or deuterium;

R¹⁴, R¹⁵ and R¹⁶ each independently represent hydrogen, (C₁-C₁₈ alkyl)carbonyl, (C₁-C₁₈ alkyl)oxycarbonyl, arylcarbonyl, aryl-(C₁-C₃ alkyl)carbonyl, (C₃-C₁₀ cycloalkyl)carbonyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₅-C₇ cycloalkenyl)C₁-C₃ alkyl, (aryl)C₁-C₃ alkyl, (heteroaryl)C₁-C₃ alkyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, aryl, heteroaryl, (C₃-C₇ cycloalkyl)C₁-C₃ alkyl, (C₅-C₇ cycloalkenyl)C₁-C₃ alkyl, (aryl)C₁-C₃ alkyl, (heteroaryl)C₁-C₃ alkyl, C₁-C₄ alkylsulfonyl, arylsulfonyl, (aryl)C₁-C₃ alkylsulfonyl, trimethylsilyl or t-butyldimethylsilyl;

R¹⁹ represents hydroxy, (C₁-C₁₈ alkyl)carbonyloxy, (C₁-C₁₈ alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C₁-C₃ alkyl)carbonyloxy, (C₃-C₁₀ cycloalkyl)carbonyloxy, hydrogen, deuterium, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₃-C₁₀ cycloalkyl)C₁-C₃ alkyl, (C₅-C₇ cycloalkenyl)C₁-C₃ alkyl, (aryl)C₁-C₃ alkyl, (heteroaryl)C₁-C₃ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₃-C₇ cycloalkoxy, C₅-C₇ cycloalkenyloxy, aryloxy, heteroaryloxy, (C₃-C₇ cycloalkyl)C₁-C₃ alkoxy, (C₅-C₇ cycloalkenyl)C₁-C₃ alkoxy, (aryl)C₁-C₃ alkoxy, (heteroaryl)C₁-C₃ alkoxy, aminocarbonyl, hydroxycarbonyl, (C₁-C₄ alkyl)aminocarbonyl, di-(C₁-C₃ alkyl)aminocarbonyl, (C₁-C₄ alkoxy)carbonyl, (aminocarbonyl)C₁-C₃ alkyl, (C₁-C₄ alkyl)aminocarbonyl-(C₁-C₃)alkyl, di-(C₁-C₃ alkyl)aminocarbonyl-(C₁-C₃)alkyl, (hydroxycarbonyl)C₁-C₃ alkyl, (C₁-C₄ alkoxy)carbonyl-(C₁-C₃)alkyl, (C₃-C₇ cycloalkoxy)C₁-C₃ alkyl, (C₅-C₇ cycloalkenyloxy)C₁-C₃ alkyl, (aryloxy)C₁-C₃ alkyl, (heteroaryloxy)C₁-C₃ alkyl, C₁-C₄ alkylsulfonyloxy, arylsulfonyloxy, (aryl)C₁-C₃ alkylsulfonyloxy, trimethylsilyloxy, t-butyldimethylsilyloxy, or cyano,

wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions optionally may be partly or completely substituted with fluorine or deuterium and may be mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C₁-C₃ alkoxy and C₁-C₃ alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NR^a, O, S, CO, SO or SO₂;

R^a independently represents hydrogen, C₁-C₄ alkyl or (C₁-C₄ alkyl)carbonyl, wherein alkyl groups or portions optionally may be partly or completely substituted with fluorine or deuterium.

3. The composition of claim 1, wherein said composition further comprises an amino acid.

4. The composition of claim 1, wherein R¹¹ and R¹² are both -D.

5. The composition of claim 1, wherein R¹³ is -D.

6. The composition of claim 1, wherein one of R¹, R², R³, or R⁵ is halogen.

7. The composition of claim 6, wherein R³ is —

Cl.

8. The composition of claim 1, wherein R⁴ is Q.

9. The composition of claim 1, wherein

each R¹, R², R³, R⁴ and R⁵ is, independently, —

H, -D, group Q, halogen, or an optionally deuterated substituent selected from hydroxyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcycloalkyl;

each R⁶, R⁷, R⁸, R⁹, R¹⁰ is, independently, —

H, -D, halogen, or an optionally deuterated substituent selected from hydroxyl, optionally substituted carbamoyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcycloalkyl; and

each R¹⁴, R¹⁵, and R¹⁶ is, independently, —

H, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkcycloalkyl, —

C(O)R^A, —

C(O)OR^A, or —

C(O)NR^AR^B, wherein each R^A and R^B is, independently, hydrogen, deuterium, or an optionally deuterated substituent selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted aryl.

10. The composition of claim 9, wherein R⁴ is Q and R⁸ is -D, halogen, or an optionally deuterated substituent selected from hydroxyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcycloalkyl.

11. The composition of claim 10, wherein R² is H;

R³ is halogen;

R⁵, R⁶, R⁷, R⁹, and R¹⁰ are H; and

R¹⁴, R¹⁵, and R¹⁶ are, independently, selected from H, —

C(O)R^A, —

C(O)OR^A, or —

C(O)NR^AR^B.

12. The composition of claim 11, wherein R³ is —

Cl.

13. The composition of claim 11, wherein R¹¹ and R¹² are both -D.

14. The composition of claim 11, wherein R¹³ is -D.

15. The composition of claim 11, wherein R⁸ is a deuterated substituent.

22. The composition of claim 1, wherein said isotopic enrichment factor for deuterium is at least 500, 1000, or 3000 for said compound.

23. The composition of claim 1, wherein said composition further comprises a pharmaceutically acceptable carrier, and wherein said compound of Formula (I) is present in an effective amount.

24. The composition of claim 8, wherein R¹⁴, R¹⁵, and R¹⁶ are H;

and wherein R¹⁹ is hydroxy.

25. The composition of claim 24, wherein R¹¹ and R¹² are both -D.

26. The composition of claim 24, wherein R¹³ is -D.

27. The composition of claim 24, wherein R¹ is a deuterated substituent.

28. The composition of claim 24, wherein R⁸ is a deuterated substituent.

29. A method of treating a disease affected by inhibition of the sodium-dependent glucose transporter (SGLT), comprising administering the composition of claim 1.

30. The method of claim 29, wherein said disease affected by inhibition of the SGLT is:

type 1 diabetes mellitus, type 2 diabetes mellitus, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome (Syndrome X), hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, or atherosclerosis.

31. The method of claim 29, wherein said method further comprises administering a second therapeutic agent.

32. The method of claim 31, wherein said therapeutic agent is:

an antidiabetic agent, a lipid-lowering/lipid-modulating agent, an agent for treating diabetic complications, an anti-obesity agent, an antihypertensive agent, an antihyperuricemic agent, an agent for treating chronic heart failure, or an agent for treating atherosclerosis.

33. The method of claim 29, wherein said disease is type 1 diabetes mellitus or type 2 diabetes mellitus.

16. A composition comprising a compound selected from the group consisting of:

17. The composition of claim 16, wherein said compound is selected from:

18. The composition of claim 16, wherein said compound is selected from:

19. The composition of claim 16, wherein said compound is selected from:

20. The composition of claim 16, wherein said compound is selected from:

21. The composition of claim 16, wherein said compound is