IP Library › Granted Patent US 7,145,020
Granted Patent B2
US 7,145,020 · App. 10/822,129 · Granted Dec 5, 2006

Materials and methods for treating coagulation disorders

View Patent ↗
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 7,145,020
App. No.
10/822,129
Granted
Dec 5, 2006
Kind
B2
Abstract

This invention is drawn to compounds which are more easily metabolized by the metabolic drug detoxification systems. Particularly, warfarin analogs which have been designed to include esters within the structure of the compounds are taught. The invention teaches methods of reducing the toxicity of drugs comprising the introduction of ester groups into drugs during the synthesis of the drug. This invention is also drawn to methods of treating coagulation disorders comprising the administration of compounds which have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the ester containing warfarin, analogs are also taught.

Claims (145)

1. A compound or pharmaceutically acceptable salt thereof, that is

3-(1-Hydroxy-3-oxo-3,4-dihydro-naphthalen-2-yl)-3H -isobenzofuran-1-one;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid;

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid;

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid methyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid ethyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n -propyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid 2-propyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n -butyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid methyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl) butyric acid ethyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid isopropyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-butyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -propyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -butyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -butyl ester;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl) benzoic acid;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester;

3-(4-Hydroxy-2-oxo-2H-chromen3-ylmethyl)-benzoic acid ethyl ester;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -propyl ester;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -butyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-butyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid methyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid ethyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n -propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n -butyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl) (4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid methyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid ethyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-propyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-butyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]benzoic acid;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid methyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid ethyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-propyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-butyl ester;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid methyl ester;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid ethyl ester;

2[(4Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; or

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-butyl ester.

2. A compound or salt according to claim 1 that is

3-(1-Hydroxy-3-oxo-3,4-dihydro-naphthalen-2-yl) 3H -isobenzofuran-1-one.

3. A compound or salt according to claim 1 that is

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; or

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid.

4. A compound or salt according to claim 1 that is

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; or

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester.

5. A compound or salt according to claim 1 that is

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid methyl ester; or

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid ethyl ester.

6. A compound or salt according to claim 1 that is

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n -propyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid 2-propyl ester;

(4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n -butyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid methyl ester; or 2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid ethyl ester.

7. A compound or salt according to claim 1 that is

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid isopropyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-butyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; or

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester.

8. A compound or salt according to claim 1 that is

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid isopropyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-butyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; or

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester.

9. A compound or salt according to claim 1 that is

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -propyl ester;

4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -butyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -butyl ester;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; or

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester.

10. A compound or salt according to claim 1 that is

3-(4Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -propyl ester;

3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n -butyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester;

2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-butyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid; or

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid methyl ester.

11. A compound or salt according to claim 1 that is

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid ethyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n -propyl ester;

2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n -butyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid methyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid ethyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-propyl ester;

4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-butyl ester; or

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid.

12. A compound or salt according to claim 1 that is

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid methyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid ethyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-propyl ester;

3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-butyl ester;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid methyl ester;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid ethyl ester;

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; or

2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H -isochromen-3-yl)-methyl]-benzoic acid n-butyl ester.

Assignments (7)
RELEASE OF SECURITY INTEREST Recorded Oct 4, 2022
From: HORIZON TECHNOLOGY FINANCE CORPORATION
To: ESPERO BIOPHARMA, INC.
Reel/Frame 061299/0927 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2022
From: HESP LLC
To: CADRENAL THERAPEUTICS
Reel/Frame 059811/0221 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2020
From: ESPERO BIOPHARMA, INC.
To: HESP LLC
Reel/Frame 054150/0011 →
CHANGE OF NAME Recorded Jul 23, 2020
From: ARMETHEON, INC.
To: ESPERO BIOPHARMA, INC.
Reel/Frame 053293/0930 →
SECURITY INTEREST Recorded Apr 16, 2019
From: ESPERO BIOPHARMA, INC.
To: HORIZON TECHNOLOGY FINANCE CORPORATION
Reel/Frame 048918/0544 →
RELEASE OF SECURITY INTEREST Recorded Feb 6, 2013
From: AYER CAPITAL PARTNERS MASTER FUND, L.P.; MPM BIOVENTURES III, L.P.; MPM BIOVENTURES III-QP, L.P.; MPM BIOVENTURES III GMBH & CO. BETEILIGUNGS KG; MPM BIOVENTURES III PARALLEL FUND, L.P.; AYER CAPITAL PARTNERS KESTREL FUND, L.P.; MPM ASSET MANAGEMENT INVESTORS 2002 BVIII LLC
To: ARYX THERAPEUTICS, INC.
Reel/Frame 029767/0524 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2012
From: DRUZGALA, PASCAL; ZHANG, XIAOMING; PFISTER, JURG
To: ARYX THERAPEUTICS
Reel/Frame 028411/0068 →