US2020199079A1PendingUtilityA1
Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
Est. expiryDec 30, 2035(~9.4 yrs left)· nominal 20-yr term from priority
C07D 239/47A61K 31/506A61P 35/00A61P 9/10C07D 401/04A61P 3/10A61P 29/00A61K 31/505C07D 233/28A61P 43/00A61P 17/00A61P 35/02C07D 239/14A61P 17/02C07D 401/12A61P 25/00C07D 239/16C07D 239/02A61P 19/10A61P 1/16A61P 27/02A61P 3/14A61P 31/00A61P 13/12A61P 37/02A61K 31/495A61P 17/06A61P 19/02A61P 9/00A61P 1/02A61P 11/00A61P 1/18
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Claims
Abstract
wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such pharmaceutical agents. Methods of using the pharmaceutical agents for the treatment of a variety of diseases and disorders are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of making a compound of Formula (I-a), comprising the step of coupling the carboxylic acid group of the compound of Formula (A):
with a compound of Formula (B) or a salt thereof:
to form a compound of Formula (I-a):
wherein:
A is C—OH or N;
R′ is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
X and Y are each independently cyano, halo, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , with the proviso that X and Y are not both cyano or alkyl (C1-2) ,
or a pharmaceutically acceptable salt or tautomer of the above formula.
2 . The method of claim 1 , wherein X is —F, —Cl, or —Br.
3 . The method of claim 2 , wherein X is —Cl or —Br.
4 . The method of claim 1 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
5 . The method of claim 3 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
6 . The method of claim 1 further comprises converting the ester of Formula (I-a) to a carboxylic acid using an inorganic base to form compound of Formula (I):
7 . The method of claim 6 , wherein the inorganic base is a metal hydroxide selected from the group consisting of hydroxides of sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum.
8 . The method of claim 7 , wherein the inorganic base is lithium hydroxide.
9 . The method of claim 1 wherein the compound of Formula (B) is synthesized by coupling compound of Formula (D)
with 2,5-dioxopyrrolidin-1-yl-(tert-butoxycarbonyl)glycinate followed by hydrolysis with mineral acid to yield compound of Formula (B).
10 . The method of claim 9 , wherein the mineral acid is selected from the group consisting of HCl, HNO 3 , H 3 PO 4 , H 2 SO 4 , HBr, and HClO 4 .
11 . A method of making a compound of Formula (I), comprising the step of coupling the carboxylic acid group of the compound of Formula (C):
with a compound of Formula (D) or a salt thereof:
to form a compound of Formula (I-a):
wherein:
A is C—OH or N;
R′ is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
X and Y are each independently cyano, halo, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , with the proviso that X and Y are not both cyano or alkyl (C1-2) ,
or a pharmaceutically acceptable salt or tautomer of the above formula.
12 . The method of claim 11 , wherein X is —F, —Cl, or —Br.
13 . The method of claim 12 , wherein X is —Cl or —Br.
14 . The method of claim 11 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
15 . The method of claim 13 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
16 . The method of claim 11 further comprises converting the ester of Formula (I-a) to a carboxylic acid using an inorganic base to form compound of Formula (I):
17 . The method of claim 16 , wherein the inorganic base is a metal hydroxide selected from the group consisting of hydroxides of sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum.
18 . The method of claim 17 , wherein the inorganic base is lithium hydroxide.
19 . The method of claim 11 , wherein the compound of Formula (D) is synthesized by a method comprising treatment of compound of Formula (D-2)
with HCl gas in ethanol under reflux conditions.
20 . The method of claim 19 , wherein the compound of Formula (D-2) is synthesized by a method comprising treatment of compound of Formula (D-1)
with malonic acid and ammonium acetate under reflux conditions in isopropanol.
21 . A compound of Formula (B):
wherein:
X is selected from the group consisting of cyano, halo, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , and
Y is selected from the group consisting of cyano, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , and
with the proviso that X and Y are not both cyano or alkyl (C1-2) ,
or a pharmaceutically acceptable salt or tautomer of the above formula.
22 . The compound of claim 21 , wherein X is —F, —Cl, or —Br.
23 . The compound of claim 22 , wherein X is —Cl or —Br.
24 . The compound of claim 21 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
25 . The compound of claim 23 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
26 . A method of making the compound of Formula (B) of claim 21 , wherein the compound is synthesized by coupling compound of Formula (D)
with 2,5-dioxopyrrolidin-1-yl-(tert-butoxycarbonyl)glycinate followed by hydrolysis with mineral acid to yield compound of Formula (B).
27 . The method of claim 26 , wherein X is —F, —Cl, or —Br.
28 . The method of claim 27 , wherein X is —Cl or —Br.
29 . The method of claim 26 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
30 . The method of claim 28 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
31 . A compound of Formula (D-2):
wherein:
X is selected from the group consisting of cyano, halo, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , and
Y is selected from the group consisting of cyano, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , and
with the proviso that X and Y are not both cyano or alkyl (C1-2) ,
or a pharmaceutically acceptable salt or tautomer of the above formula.
32 . The compound of claim 31 , wherein X is —F, —Cl, or —Br.
33 . The compound of claim 32 , wherein X is —Cl or —Br.
34 . The compound of claim 31 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
35 . The compound of claim 33 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
36 . A method of making the compound of Formula (D-2) of claim 31 , wherein the compound is synthesized by treatment of compound of Formula (D-1)
with malonic acid and ammonium acetate under reflux conditions in isopropanol.
37 . The method of claim 36 , wherein X is —F, —Cl, or —Br.
38 . The method of claim 37 , wherein X is —Cl or —Br.
39 . The method of claim 36 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
40 . The method of claim 38 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
41 . A compound of Formula (D):
wherein:
X is selected from the group consisting of cyano, halo, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , and
Y is selected from the group consisting of cyano, fluoroalkoxy (C1-2) , alkyl (C1-2) , or fluoroalkyl (C1-2) , and
with the proviso that X and Y are not both cyano or alkyl (C1-2) ,
or a pharmaceutically acceptable salt or tautomer of the above formula.
42 . The compound of claim 41 , wherein X is —F, —Cl, or —Br.
43 . The compound of claim 42 , wherein X is —Cl or —Br.
44 . The compound of claim 41 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
45 . The compound of claim 43 , wherein Y is —OCF 3 , —CHF 2 or —CF 3 .
46 . A method of making the compound of Formula (D) of claim 41 wherein the compound is synthesized by treatment of compound of Formula (D-2)
with HCl gas in ethanol under reflux conditions.
47 . The method of claim 46 , wherein X is —F, —Cl, or —Br.
48 . The method of claim 47 , wherein X is —Cl or —Br.
49 . The method of claim 46 , wherein Y is —OCF 3 , —CHF 2 , —CF 3 , or —CH 3 .
50 . The method of claim 48 wherein Y is —OCF 3 , —CHF 2 or —CF 3 .Join the waitlist — get patent alerts
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