SMALL MOLECULE MODULATORS OF PCSK9 AND METHODS OF USE THEREOF

• US 20160031935A1
• Filed: 03/14/2014
• Published: 02/04/2016
• Est. Priority Date: 03/15/2013
• Status: Abandoned Application

• Current Assignee: Adaerata Limited Partnership
• Original Assignee: Adaerata Limited Partnership, AmorChem Holdings Inc.
• Inventors: CRANE, SHELDON, TRUONG, VOUY LINH, GUAY, DANIEL, LACHANCE, NICOLAS, CHIASSON, JEAN-FRANCOIS, LACOMBE, PATRICK, SKOREY, KATHRYN, SEIDAH, NABIL G.
• Application Number:
  US14/776,701
• Publication Number:
  US 20160031935A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/081 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N

Abstract

A compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, or racemic mixture or stereoisomer thereof, and methods for preventing or treating an LDL-cholesterol-related disease or disorder using such compound(s), and kits and compositions comprising such compound(s).

Claims

1. Compound of Formula (I):

2. The compound of claim 1, wherein:

(A)

a. R1 is —

B(OR_b)(OR_c), or —

CH(OH)R_a;

b. R2 is H or —

CH₂(CH₂)_mC(O)R_j;

c. R3 is H or C1-6 alkyl substituted or not;

d. R4 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not or cycloalkyl substituted or not;

e. R5 is H;

f. R6 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not;

g. R7 is H;

h. R8 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not; and

/or

i. R9 is RiOC(O)—

, RiC(O)—

, R_mOR_iC(O)—

, R_mC(O)R_iC(O)—

or R_iS(O)_n—

;

or

(B)

a. R1 is —

B(OR_b)(OR_c) or —

CH(OH)R_a;

b. R2 is H or —

CH₂(CH₂)C(O)R_j;

c. R3 is H or C1-6 alkyl substituted or not;

d. R4 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not or cycloalkyl substituted or not;

e. R5 is H;

f. R6 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not;

g. R7 is H;

h. R8 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not; and

i. R9 is RiOC(O)—

, RiC(O)—

, R_mOR_iC(O)—

, R_mC(O)R_iC(O)—

, R_iS(O)_n—

.

4. The compound of claim 1, wherein:

a. R1 is —

B(OR_b)(OR_c) or —

CH(OH)R_a;

b. R2 is H or —

CH₂(CH₂)_mC(O)R_j;

c. R3 is H or C1-6 alkyl substituted or not;

d. R4 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not;

e. R6 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not;

f. R8 is H, C1-6 alkyl substituted or not, C1-6 thioalkyl substituted or not, aryl substituted or not, or cycloalkyl substituted or not; and

/or

g. R9 is RiOC(O)—

, RiC(O)—

, R_mOR_iC(O)—

, R_mC(O)R_iC(O)—

, or R_iS(O)_n—

.

5. The compound of claim 4, wherein:

a. R1 is;

i. —

B(OR_b)(OR_c) and Rb and Rc are H, or Rb and Rc are connected to form a cyclic 5 membered ring structure or fused with an aliphatic ring system;

or

ii. —

CH(OH)R_a and Ra is C1-2 fluoroalkyl, or Ra is C1-3 alkyl;

b. R2 is —

CH₂(CH₂)_mC(O)R_j and Rj is OR_d or NH₂;

c. R3 is unsubstituted C1-6 alkyl;

d. R4 is unsubstituted C1-6 alkyl, substituted C1-6 alkyl, CH₃S(CH₂)₂—

, or phenyl;

e. R6 is substituted C1-6 alkyl, unsubstituted C1-6 alkyl, CH₃S(CH₂)₂—

, phenyl, or benzocyclopentyl;

f. R8 is unsubstituted C1-6 alkyl, substituted C1-6 alkyl, CH₃S(CH₂)₂—

, unsubstituted aryl, or unsubstituted cycloalkyl; and

/or

g. R9 is;

i. RiOC(O)— and

Ri is C1-10 alkyl, substituted or not;

ii. RiC(O)— and

Ri is aryl substituted or not or heteroaryl substituted or not;

or C1-10 alkyl, substituted or not;

iii. R_mOR_iC(O)— and

R_i is substituted or unsubstituted C1-10 alkyl;

iv. R_mC(O)R_iC(O)— and

R_i is aryl;

or

v. R_iS(O)_n— and

R;

is substituted or unsubstituted aryl.

7. The compound of claim 5, wherein:

a. R1 is 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2,6]decan-4-yl, or —

CH(OH)R_a wherein Ra is —

CF₃, —

CH₂F, or —

CH₃;

b. Rd is CH₃;

c. R3 is CH₃;

d. R4 is —

CH₃, CH₃CH₂—

, —

CH₂CH(CH₃)₂, aryl substituted C1-6 alkyl, or —

(CH₂)₂C(O)NH₂;

e. R6 is aryl substituted C1-6 alkyl, CH₃, or —

CH(CH₃)₂;

f. R8 is —

CH(CH₃)₂, —

CH₃, aryl substituted C1-6 alkyl, phenyl, cyclopentyl, or cyclopropyl; and

/or

g. R9 is;

i. RiOC(O)— and

Ri is unsubstituted C1-10 alkyl-, or substituted C1-10 alkyl-;

ii. RiC(O)— and

Ri is aryl substituted or not, heteroaryl substituted or not, substituted C1-10 alkyl-, or unsubstituted C1-10 alkyl-;

iii. R_mOR_iC(O)— and

R_i is —

CH₂—

;

iv. R_mC(O)R_iC(O)— and

R_i is phenyl;

or

v. R_iS(O)_n— and

R_i is substituted aryl.

31. The compound of claim 7, wherein:

a. R4 is phenyl-CH₂—

;

b. R6 is -alkyl-phenyl, or —

CH₂-indole,

c. R8 is —

CH₂-phenyl; and

/or

d. R9 is;

i. RiOC(O)— and

Ri is CH₃—

, or phenyl-CH₂—

;

ii. RiC(O)— and

Ri is substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, aryl-C1-10 alkyl-, or CH₃(CH₂)₈—

;

or

iii. R_iS(O)_n— and

R_i is substituted phenyl.

43. The compound of claim 31, wherein:

a. R6 is —

CH₂-phenyl, or —

(CH₂)₂-phenyl; and

/or

b. R9 is;

i. RiC(O)— and

Ri is aryl-phenyl-, heterocyclyl-phenyl-, alkyl-phenyl-, fluorophenyl, phenyl, aryl-heteroaryl-, heteroaryl-heteroaryl-, pyridine, pyrazine, indole, or phenyl-C1-10 alkyl-;

or

ii. R_iS(O)_n— and

R_i is phenyl-phenyl.

148. The compound of claim 1, which is:

149. A pharmaceutical composition comprising at least one of the compounds as defined in claim 1.

150. The pharmaceutical composition of claim 149, further comprising (a) at least one other compound as defined in claim 1;

and/or (b) at least one other active ingredient which improves a patient'"'"'s lipid profile.

152. The pharmaceutical composition of claim 149, further comprising a pharmaceutically acceptable carrier or excipient.

157. A method for preventing or treating an low density lipid (LDL)-cholesterol-related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound as defined in claim 1, or of a pharmaceutical composition comprising said compound, with the proviso that the compound is not:

158. The method of claim 157, wherein the LDL-cholesterol-related disease or disorder is hypercholesterolemia.

163. A kit for preventing or treating a low density lipid (LDL)-cholesterol-related disease or disorder in a subject comprising

(i) at least one of the compounds as defined in claim 1 or of a pharmaceutical composition comprising said compound, and

(i) (a) at least one other active ingredient which improve a patient'"'"'s lipid profile;

(b) at least one other compound as defined in claim 1 or a pharmaceutical composition comprising said compound;

(c) a container for the compound and/or active ingredients; and

/or

(d) instructions to use the compound for preventing or treating the LDL-cholesterol-related disease or disorder in the subject, with the proviso that the compound is not;

3. (canceled)

6. (canceled)

8-30. -30. (canceled)

32-42. -42. (canceled)

45-86. -86. (canceled)

89-121. -121. (canceled)

123-131. -131. (canceled)

134-147. -147. (canceled)

151. (canceled)

153-156. -156. (canceled)

159-162. -162. (canceled)

164. (canceled)