IP Library › Patent Application 16291335

Patent Application

App. No. 16/291,335

COMPOUNDS, COMPOSITIONS AND METHODS USEFUL FOR CHOLESTEROL MOBILIZATION

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US None
App. No.: 16/291,335

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to classes of pharmaceutically-active heterocyclic compounds and pharmaceutically acceptable salts, and hydrates thereof, and compositions comprising the same. The invention also relates to methods for treating or preventing a disease or disorder, which comprises administering a therapeutically or prophylactically effective amount a compound described herein.

Claims (143)

1 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

(a) a compound of Formula (I):

wherein

each of R 1 , R 2 , and R 3 is independently H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O— heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

R 4 is —H, —OH, —COOH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), -hydrocarbyl, —O-hydrocarbyl, -aryl, —O-aryl, -aralkyl, —O-aralkyl, -heteroaryl, —O-heteroaryl, -heterocyclyl, —O-heterocyclyl, -halo, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), or —OC(O)N(alkyl)(alkyl);

Z 1 is CH 2 , S, O, NH, N-hydrocarbyl, N-aryl, N-heteroaryl, or N-heterocyclyl;

Z 2 is CH or N; and

n is an integer from 1-6;

(b) a compound of Formula (II):

wherein

each R 9 is independently —H, -hydrocarbyl, -aryl, -aralkyl, -heteroaryl, -heterocyclyl, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), or —SO 2 NH 2 ;

each R 10 is independently —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O— alkyl, —O-alkenyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O— heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), NHC(O)(C 2 -C 10 -alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

each of Q 1 , Q 2 , and Q 3 is independently CR 10 or N;

X is CHR 10 , S, O, or NR 9 ; and

each m is independently an integer from 0-3;

wherein

each of R 1 , R 2 , and R 3 is independently H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

R 5 is —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, or —O-heterocyclyl;

Z 1 is CH 2 , S, O, NH, N-hydrocarbyl, N-aryl, N-heteroaryl, or N-heterocyclyl;

Z 2 is CH or N; and

n is an integer from 1-6;

(d) a compound of Formula (IV):

wherein

R 1 is H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

Z 1 is CH 2 , S, O, NH, N-hydrocarbyl, N-aryl, N-heteroaryl, or N-heterocyclyl; and

Z 2 is CH or N;

(e) a compound of Formula (V):

wherein

each of R 1 , R 2 , and R 3 is independently H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

R 4 is —H, —OH, —COOH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), or —OC(O)N(alkyl)(alkyl);

R 6 is —H, —OH, —SH, —S-hydrocarbyl, —COOH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), or —OC(O)N(alkyl)(alkyl);

R 7 is H, hydrocarbyl, aryl, aralkyl, heteroaryl, or heterocyclyl;

Z 2 is CH or N; and

n is an integer from 1-6;

(f) a compound of Formula (VI):

wherein

R 1 , is H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

R 5 is —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, or halo;

R 7 is H, hydrocarbyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and

Z 2 is CH or N;

(g) a compound of Formula (VII):

wherein

each of R 1a , R 1b , and R 1c is independently —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

each X is independently CHR 10 , S, O, or NR 9 ;

each R 9 is independently H, hydrocarbyl, aryl, aralkyl, heteroaryl, heterocyclyl, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), or —SO 2 N H 2 ;

each R 10 is independently —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O— hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O— heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ; and

m is an integer from 0-3;

(h) a compound of Formula (VIII):

wherein

R 1 is —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

R 11 is H, hydrocarbyl, aryl, aralkyl, heteroaryl, heterocyclyl, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), or —SO 2 NH 2 ;

each of Q 1 , Q 2 , Q 3 , and Q 4 is independently CR 10 or N; and

(i) a compound of Formula (IX):

wherein

each of R 11a , R 11b , and R 11c is independently H, hydrocarbyl, aryl, aralkyl, heteroaryl, heterocyclyl, —C(O)(alkyl), —C(O)O(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), or —SO 2 NH 2 ;

each of X 1 and X 2 is independently CHR 10 , S, O, NR 9 , or N-acyl;

each m is independently an integer from 1-3,

(j) a compound of Formula (XII):

wherein

each of Q 1 , Q 2 , and Q 3 is independently CR 10 or N;

X is CHR 10 , S, O, or NR 9 ; and

each m is independently an integer from 0-3; or

(k) a compound of Formula (XIII):

wherein

R 1 is is independently —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O— hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O— heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;

each of Q 1 , Q 2 , Q 3 , and Q 4 is independently CR 10 or N;

n is an integer from 1-4 and

2 - 6 . (canceled)

7 . A composition comprising an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable vehicle or carrier.

8 - 10 . (canceled)

11 . A method for treating or preventing a disorder of lipoprotein metabolism, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

12 . (canceled)

13 . A method of treating a disorder of glucose metabolism, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

14 . (canceled)

15 . A method of treating a cardiovascular disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

16 - 18 . (canceled)

19 . A method of treating inflammation, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

20 . A method of treating ischemic necrosis, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

21 . A method of treating colon cancer, lung cancer, breast cancer, or skin cancer, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

22 . A method of treating a thrombotic disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

23 . A method of treating Alzheimer's Disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

24 . A method of treating Parkinson's Disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

25 . A method of treating pancreatitis, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

26 . A method of treating pancreatitius, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

27 . A method of treating abnormal bile production, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .

28 . A method of monitoring the progress of therapy for a cardiovascular disorder in a subject, the method comprising:

a. determining the level of free cholesterol in the high-density lipoprotein in the blood of the subject;

b. administering to the subject a compound of claim 1 ;

c. monitoring the level of free cholesterol in the blood of the subject for a period of time after administration of the compound; and

d. evaluating the level of improvement in the subject based on a comparison of the results of steps a. and c.

29 . (canceled)

30 . A method of determining the level of P2Y13 activity in a subject, the method comprising:

a. determining the level of free cholesterol in the high-density lipoprotein in the blood of the subject;

b. administering to the subject a compound of claim 1 ;

c. monitoring the level of free cholesterol in the blood of the subject for a period of time after administration of the compound; and

d. evaluating the level of P2Y13 activity in the subject based on a comparison of the results of steps a. and c.

31 - 91 . (canceled)

92 . A method for treating or preventing a disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of:

Formula X:

wherein

each of Q 1 , Q 2 , and Q 3 is independently CR 10 or N;

X is CHR 10 , S, O, or NR 9 ; and

each m is independently an integer from 0-3; or

Formula XI:

wherein

each of X 1 and X 2 is independently CHR 10 , S, O, NR 9 , or N-acyl;

each m is independently an integer from 0-3,

wherein the disorder is a disorder of lipoprotein metabolism, a disorder of glucose metabolism, a cardiovascular disorder, inflammation, ischemic necrosis, colon cancer, lung cancer, breast cancer, skin cancer, a thrombotic disorder, Alzheimer's Disease, Parkinson's Disease, pancreatitis, pancreatitius, or abnormal bile production.

93 - 97 . (canceled)

98 . A method of monitoring the progress of therapy for a cardiovascular disorder in a subject, the method comprising:

a. determining the level of free cholesterol in the high-density lipoprotein in the blood of the subject;

b. administering to the subject a compound or a pharmaceutically acceptable salt of a compound of either Formula X or Formula XI;

c. monitoring the level of free cholesterol in the blood of the subject for a period of time after administration of the compound; and

d. evaluating the level of improvement in the subject based on a comparison of the results of steps a. and c.,

wherein Formula X is:

wherein

each of Q 1 , Q 2 , and Q 3 is independently CR 10 or N;

X is CHR 10 , S, O, or NR 9 ; and

each m is independently an integer from 0-3; and

Formula XI is:

wherein

each of X 1 and X 2 is independently CHR 10 , S, O, NR 9 , or N-acyl;

each m is independently an integer from 0-3.

99 - 100 . (canceled)