IP Library › Granted Patent US 9,108,934

Granted Patent B2

US 9,108,934 · App. 13/911,819 · Granted Aug 18, 2015

Neprilysin inhibitors

Inventors: Adam D. Hughes (Belmont, CA); Melissa Fleury (San Francisco, CA)

Assignee: Theravance Biopharma R&D IP, LLC

C07D249/18 A61K31/41 A61K31/415 A61K31/4155 A61K31/4192 A61K31/4196 A61K31/42 A61K31/4439 A61K31/675 A61K45/06 C07D231/14 C07D231/18 C07D231/20 C07D249/04 C07D249/12 C07D253/08 C07D257/04 C07D261/18 C07D401/04 C07D405/12 C07D405/14 C07F9/65031

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Quick Facts

Patent No.: US 9,108,934
App. No.: 13/911,819
Granted: Aug 18, 2015
Kind: B2

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Abstract

In one aspect, the invention relates to compounds having the formula XII: where R a , R b , R 2 , R 7 , and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds described herein are prodrugs of compounds having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

Claims (87)

1. A compound of formula XII:

where:

(i) R a is H; R b is Cl; X is

and

R 2 is H, R 4 is —OH, and R 7 is selected from —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, and

or R 2 is H, R 4 is selected from —O-benzyl, —OCHR c OC(O)—C 1-4 alkyl, —OCH 2 OC(O)CHR d —NH 2 , and —OCH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, and R 7 is selected from H and —CH 2 OC(O)CH 3 ; or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 4 is —OH, and R 7 is H; or

(ii) R a is H; R b is Cl; X is

and

R 2 is H, R 3 is —OH and R 7 is selected from —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, and

or R 3 is selected from —OC(O)CH 2 CH 3 , —OC(O)CH 2 CH(CH 3 ) 2 , —OC(O)-phenyl, —OCH 2 OC(O)CHR d —NH 2 , and —OCH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, and R 7 is H; or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 3 is —OH, and R 7 is H; or

(iii) R a is H; R b is Cl; X is

and

R 2 is H, R 3 is —OH and R 7 is selected from —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, and

or R 2 is H, R 3 is selected from —OC(O)CH 2 CH 3 , —OC(O)CH 2 CH(CH 3 ) 2 , —OC(O)-phenyl, —OCH 2 OC(O)CHR d —NH 2 , and —OCH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, and R 7 is H; or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 3 is —OH, and R 7 is H; or

(iv) R a is F; R b is Cl; X is

and

R 2 is H and R 7 is selected from H, —CH 2 CH 3 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, and

or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , and R 7 is H; or

(v) R a is H; R b is Cl; X is

and

or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , and R 7 is H; or

(vi) R a is H; R b is Cl; X is

and

or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , and R 7 is H; or

(vii) R a is H; R b is Cl; X is

R is H or —CH 3 ; and

R 2 is H and R 7 is selected from —CH 2 CH 3 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, and

or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , and R 7 is H; or

(viii) R a is F; R b is Cl; X is

and

or R 2 is H, R 4 is selected from —O-benzyl, —OCHR c OC(O)—C 1-4 alkyl, —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 and

and R 7 is H; or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 4 is —OH, and R 7 is H; or

(ix) R a is H; R b is Cl; X is

and

or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , and R 7 is H; or

(x) R a is H; R b is H; X is

and

R 2 and R 4 are H, and R 7 is selected from —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, and benzyl; or R 2 is H, R 4 is selected from —CH 2 OC(O)CH[CH(CH 3 ) 2 ]-NHC(O)OCH 3 and —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and R 7 is H; or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 4 is H, and R 7 is H; or R 2 is H, R 4 is —CH 2 OP(O)(OR e ) 2 or —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and R 7 is —CH 2 CH 3 ; or R 2 is —C(O)CH[CH(CH 3 ) 2 ]NH 2 , R 4 is H, and R 7 is —CH 2 CH 3 ; or

(xi) R a is H; R b is Cl; X is

and

R 2 and R 4 are H, and R 7 is selected from H, —CH 2 CH 3 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, and benzyl; or R 2 is H, R 4 is selected from —CH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 and —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and R 7 is H; or R 2 is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 4 is H, and R 7 is H; or R 2 is H, R 4 is —CH 2 OP(O)(OR e ) 2 or —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and R 7 is —CH 2 CH 3 ; or R 2 is —C(O)CH[CH(CH 3 ) 2 ]NH 2 , R 4 is H, and R 7 is —CH 2 CH 3 ;

where each R e is independently H or —C 1-3 alkyl; each R d is independently H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl; and each R e is independently H, —C 1-6 alkyl, or phenyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , of the formula IV:

3. The compound of claim 2 , where R 2 is H and R 7 is selected from H and —CH 2 CH 3 .

4. The compound of claim 1 , of formula V:

5. The compound of claim 4 , where R 2 is H and R 7 is selected from H and —CH 2 CH 3 .

6. The compound of claim 1 , of the formula I:

7. The compound of claim 6 , where R 2 is H, R 4 is —OH and R 7 is selected from —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CF 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 , benzyl, and

or R 2 is H, R 4 is —OCH 2 OC(O)CH 3 and R 7 is selected from H and —CH 2 OC(O)CH 3 ; or R 2 is H, R 4 is selected from —OCH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 , and R 7 is H; or R 2 is H, R 4 is —O-benzyl and R 7 is H.

8. The compound of claim 1 , of the formula II:

9. The compound of claim 8 , where R 2 is H, R 3 is —OH and R 7 is selected from —CH 2 CH 3 , —CH 2 CF 2 CF 3 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , benzyl, and

10. The compound of claim 1 , of the formula III:

11. The compound of claim 10 , where R 2 is H, R 3 is —OH and R 7 is selected from —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, and

where R d is —CH(CH 3 ) 2 ; or R 2 is H, R 3 is —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and R 7 is H; or R 2 is —C(O)CH[CH(CH 3 ) 2 ]NH 2 , R 3 is —OH, and R 7 is H.

12. The compound of claim 1 , of the formula VI:

13. The compound of claim 12 , where R 2 is H and R 7 is selected from H, —CH 2 OC(O)CH 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , and —C(O)CH[CH(CH 3 ) 2 ]-NHC(O)OCH 3 .

14. The compound of claim 1 , of the formula VII:

15. The compound of claim 14 , where R is —CH 3 , R 2 is H, and R 7 is selected from —CH 2 OC(O)CH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH 2 OC(O)OCH 2 CH 3 , and —CH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 .

16. The compound of claim 1 , of the formula VIIIa or VIIIb:

17. The compound of claim 16 , where R 2 is H, R 4 is —OH and R 7 is selected from —CH 2 CF 2 CF 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH(CH 3 )OC(O)O-cyclohexyl, —CH 2 OC(O)CH[CH(CH 3 ) 2 ]-NHC(O)OCH 3 , and

or R 2 is H, R 4 is selected from —OCH 2 OC(O)(CH 2 ) 2 CH 3 , —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 , and

and R 7 is H.

18. The compound of claim 1 , of the formula IX:

19. The compound of claim 18 , where R 2 is H and R 7 is selected from —CH 2 OC(O)OCH 2 CH 3 and —CH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 .

20. The compound of claim 1 , of the formula Xa or Xb:

21. The compound of claim 20 , where R 2 is H, R 4 is —CH 2 OP(O)(OH) 2 or —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and R 7 is —CH 2 CH 3 ; or R 2 is —C(O)CH[CH(CH 3 ) 2 ]NH 2 , R 4 is H, and R 7 is —CH 2 CH 3 .

22. The compound of claim 1 , of the formula XIa or XIb:

23. The compound of claim 22 , where R 2 , R 4 , and R 7 are H; or R 2 and R 4 are H, and R 7 is —CH 2 OC(O)OCH 2 CH 3 .

24. A process for preparing the compound of claim 1 , comprising the step of:

(a) reacting a compound of formula

with a compound of formula HO—R 7 in a transesterification reaction; or

(b) reacting a compound of formula

with a compound of formula L-R 7 in a nucleophilic substitution reaction, where L is a leaving group; or

with a compound of formula L-R 2 in a nucleophilic substitution reaction, where L is a leaving group; or

(d) reacting a compound of formula

with a compound of formula HOOC—X in a coupling reaction, where P is H or an amino-protecting group;

to produce a compound of formula XII.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .

26. The pharmaceutical composition of claim 25 , further comprising a therapeutic agent selected from adenosine receptor antagonists, α-adrenergic receptor antagonists, β 1 -adrenergic receptor antagonists, β 2 -adrenergic receptor agonists, dual-acting β-adrenergic receptor antagonist/α 1 -receptor antagonists, advanced glycation end product breakers, aldosterone antagonists, aldosterone synthase inhibitors, aminopeptidase N inhibitors, androgens, angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzyme/neprilysin inhibitors, angiotensin-converting enzyme 2 activators and stimulators, angiotensin-II vaccines, anticoagulants, anti-diabetic agents, antidiarrheal agents, anti-glaucoma agents, anti-lipid agents, antinociceptive agents, anti-thrombotic agents, AT 1 receptor antagonists and dual-acting AT 1 receptor antagonist/neprilysin inhibitors and multifunctional angiotensin receptor blockers, bradykinin receptor antagonists, calcium channel blockers, chymase inhibitors, digoxin, diuretics, dopamine agonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, HMG-CoA reductase inhibitors, estrogens, estrogen receptor agonists and/or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and their analogs, natriuretic peptide clearance receptor antagonists, neprilysin inhibitors, nitric oxide donors, non-steroidal anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterase inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blocker, soluble guanylate cyclase stimulators and activators, tricyclic antidepressants, vasopressin receptor antagonists, and combinations thereof.

27. The pharmaceutical composition of claim 26 , wherein the therapeutic agent is an AT 1 receptor antagonist.

28. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of claim 1 .

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 28, 2026

From: THERAVANCE BIOPHARMA R&D IP, LLC

To: EONHF, INC.

Reel/Frame 075494/0756 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 5, 2014

From: THERAVANCE, INC.

To: THERAVANCE BIOPHARMA R&D IP, LLC

Reel/Frame 033124/0456 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 6, 2013

From: HUGHES, ADAM D.; FLEURY, MELISSA

To: THERAVANCE, INC.

Reel/Frame 030562/0398 →

Continuity (3)

Provisional Application 61773969 · Mar 7, 2013

Provisional Application 61657229 · Jun 8, 2012

Related Publication 20130330366A1 · Dec 12, 2013