Arginase inhibitors as therapeutics

Patent metadata

Field	Value
Publication number	US-9233985-B2
Application number	US-201113276806-A
Country	US
Kind code	B2
Filing date	Oct 19, 2011
Priority date	Oct 26, 2010
Publication date	Jan 12, 2016
Grant date	Jan 12, 2016

Abstract

Compounds according to Formula I are potent inhibitors of Arginase I and II activity:

where R 1 , R 2 , R 3 , R 4 , D, W, X, Y, and Z are defined in the specification. The invention also provides pharmaceutical compositions of the compounds and methods of their use in treating or preventing a disease or a condition associated with arginase activity.

First claim

We claim:

1. A compound according to Formula I,

wherein
R 1 is selected from the group consisting of —OH, OR a , and NR b R c ;
R a is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-;
R b and R c are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl—SO 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-;

R 2 is selected from H, straight or branched (C 1 -C 6 ) alkyl, and (C 1 -C 6 )alkyl-C(O)—;
W, X, Y, and Z are each independently selected from —C(R′)(R′″)—, —C(R′″) 2 —, —NR′″—,—O—,—C(O)—, and —S—; at least one of W, X, Y, or Z is selected from —NR′″—, —O—, and —S—; and no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, or —NR′″—;
l, m, n and p are each independently 0 or 1 or 2, wherein the sum of 1+m+n+p is 3 or 4;
R 3 and R 4 are each independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, and C(O)—R′,
or R 3 and R 4 together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated, or partially saturated;
D is selected from straight or branched (C 3 -C 5 )alkylene,
wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″;
provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ;

R′, R″ and R′″ are each independently selected from H, OH, S(O)R d , S(O) 2 R d , (C 1 -C 8 )alkyl, (C 3 -C 6 )aryl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —C(O) NR d R e , —C(O)(C 1 -C 6 )alkyl, —C(O)(C 3 -C 14 )aryl, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(C 3 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 14 )heterocycloalkyl, —C(O)(C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, —C(O)(C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, —C(O)(C 3 -C 14 )aryl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heterocycle -(C 1 -C 6 )alkylene-; and
wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkoxy, (C 3 -C 14 )aryl, (C 1 -C 6 )haloalkyl and (C 3 -C 14 )aryloxy;
wherein R d , R e , R g , and R h are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, NR′R″C(O)—, and (C 3 -C 6 )aryl-(C 3 -C 14 )-cycloalkylene-,

or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

2. The compound according to claim 1 , wherein in Formula I

R 1 is selected from —OH, OR a , and NR b R c ;
R a is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-;
R b and R c are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl-SO 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-;

R 2 is selected from H, straight or branched (C 1 -C 6 )-alkyl, and (C 1 -C 6 )alkyl-C(O)—;
W, X, Y, and Z are each independently selected from a —C(R′″) 2 —, —NR′″—, —O—, —C(O)—, and —S—, wherein
at least one of W, X, Y, or Z is selected from —NR′″—, —O—, and —S—; and no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, or —NR′″—;

l, m, n and p are each independently 0 or 1 or 2, wherein the sum of l+m+n+p is 3 or 4;
R 3 and R 4 are each independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, and C(O)—R′,
or R 3 and R 4 together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated, or partially saturated;
D is selected from straight or branched (C 3 -C 5 )alkylene,
wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″;
provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ;

R′, R″ and R′″ are each independently selected from H, OH, (C 1 -C 8 )alkyl, (C 3 -C 6 )aryl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —C(O)(C 1 -C 6 )alkyl, —C(O)(C 3 -C 14 )aryl, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(C 3 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heterocycle-(C 1 -C 6 )alkylene-; and
wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkoxy, and (C 3 -C 14 )aryloxy;
wherein R d , R e , R g , and R h are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, NR′R″C(O)—, and (C 3 -C 6 )aryl-(C 3 -C 14 )-cycloalkylene-,
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

3. The compound according to claim 1 , wherein D is selected from:
-L 1 -L 2 -CH 2 —CH 2 —,
—CH 2 -L 1 -L 2 -CH 2 —,
—CH 2 —CH 2 -L 1 -L 2 -,
-L 1 -CH 2 —CH 2 -L 2 -,
-L 1 -CH 2 -L 2 -CH 2 —,
—CH 2 -L 1 -CH 2 -L 2 -,
-L 1 -CH 2 —CH 2 —,
—CH 2 -L 1 -CH 2 —,
—CH 2 —CH 2 -L 1 -,
-L 2 -CH 2 —CH 2 —,
—CH 2 -L 2 -CH 2 —, and
—CH 2 —CH 2 -L 2 -,
wherein L 1 and L 2 are independently selected from O, NR′, S, SO, SO 2 , and CR′R″, wherein R′ and R″ are as defined in claim 1 ; and
when L 1 and L 2 are adjacent to each other, then L 1 and L 2 are not simultaneously O, NR′, S, SO, or SO 2 .

4. The compound according to claim 1 , wherein D is straight or branched (C 3 -C 5 )alkylene.

5. The compound according to claim 4 , wherein D is propylene.

6. The compound according to claim 5 , wherein R 1 is —OH.

7. The compound according to claim 6 , wherein each of R 2 , R 3 and R 4 is hydrogen.

8. The compound according to claim 7 , wherein any one of W, X, Y and Z is —NR′″— and each instance of the remaining three is —C(R′″) 2 —.

9. The compound according to claim 8 , wherein R′″ is H.

10. The compound according to claim 8 , wherein

Assignees

• Van Zandt Michael
• Jagdmann Jr Gunnar Erik
• Mars Inc

Inventors

• Van Zandt Michael
• Jagdmann Jr Gunnar Erik

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title