Methods for preventing progressive tissue necrosis, reperfusion injury, bacterial translocation and adult respiratory distress syndrome

• US 6,187,767 B1
• Filed: 05/14/1999
• Issued: 02/13/2001
• Est. Priority Date: 03/09/1993
• Status: Expired due to Fees

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: Pharmadigm, Inc., University of Utah Research Foundation (State of Utah)
• Inventors: Araneo, Barbara A., Orlinska, Urszula, Farrukh, Imad S., Daynes, Raymond A.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US09/311,306
• Time in Patent Office: 641 Days
• Field of Search: 514/178
• US Class Current: 514/178
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/569 substituted in position 17 alpha, e.g. ethisterone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

The present invention is related to a method for preventing or reducing the effects of ischemia. The ischemia may be associated with injury or reperfusion injury, such as occurs as a result of infarctions, thermal injury (burns), surgical trauma, accidental trauma, hemorrhagic shock and the like. The invention is also related to methods for preventing or reducing bacterial translocation, adult respiratory distress syndrome, adherence of blood cells and platelets to endothelial cells and pulmonary hypertension. In accordance with the present invention, these conditions are prevented or reduced by administering a dehydroepiandrosterone (DHEA) derivative as defined herein.

Claims

1. A method for preventing or reducing adult respiratory distress syndrome (ARDS) in a patient at risk of ARDS which comprises administering to said patient an effective amount of a dehydroepiandrosterone (DHEA) derivative having the general formulas I and II and their pharmaceutically acceptable salts

wherein

R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁹ are independently H, —

OH, halogen, C_1-10 alkyl or C_1-10 alkoxy;

R⁵ is H, —

OH, halogen, C_1-10 alkyl, C_1-10 alkoxy or OSO₂R²⁰;

R¹⁵ is

(1) H, halogen, C_1-10 alkyl or C_1-10 alkoxy when R¹⁶ is —

C(O)OR²¹ or

(2) H, halogen, OH or C_1-10 alkyl when R¹⁶ is H, halogen, OH or C_1-10 alkyl or

(3) H, halogen, C_1-10 alkyl, C_1-10 alkenyl, C_1-10 alkynyl, formyl, C_1-10 alkanoyl or epoxy when R¹⁶ is OH;

or

R¹⁵ and R¹⁶ taken together are ═

O;

R¹⁷ and R¹⁸ are independently

(1) H, —

OH, halogen, C_1-10 alkyl or C_1-10 alkoxy when R¹⁶ is H, OH, halogen, C_1-10 alkyl or —

C(O)OR²¹ or

(2) H, (C_1-10 alkyl)_namino, (C_1-10 alkyl)_namino-C_1-10 alkyl, C_1-10 alkoxy, hydroxy-C_1-10 alkyl, C_1-10 alkoxy-C_1-10 alkyl, (halogen)_m-C1-10 alkyl, C_1-10 alkanoyl, formyl, C_1-10 carbalkoxy or C_1-10 alkanoyloxy when R¹⁵ and R¹⁶ taken together are ═

O;

or

R¹⁷ and R¹⁸ taken together are ═

O or taken together with the carbon to which they are attached form a 3-6 member ring containing 0 or 1 oxygen atoms;

or

R¹⁵ and R¹⁷ taken together with the carbons to which they are attached form an epoxide ring;

R²⁰ is OH, pharmaceutically acceptable ester or pharmaceutically acceptable ether;

R²¹ is H, (halogen)_m-C_1-10 alkyl or C_1-10 alkyl;

n is 0, 1 or 2; and

m is 1,2 or 3,

with the provisos that

(a) R³ is not H, OH or halogen when R¹, R², R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁷ and R¹⁹ are H and R⁵ is OH or C_1-10 alkoxy and R⁸ is H, OH or halogen and R¹¹ is H or OH and R¹⁸ is H, halogen or methyl and R¹⁵ is H and R¹⁶ is OH;

(b) R³ is not H, OH or halogen when R¹, R², R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹², R¹³, R¹⁴ and R¹⁹ are H and R⁵ is OH or C_1-10 alkoxy and R⁸ is H, OH or halogen and R¹¹ is H or OH and R¹⁸ is H, halogen or methyl and R¹⁵ and R¹⁶ taken together are ═

O;

(c) R⁵ is not H, halogen, C_1-10 alkoxy or OSO₂R²⁰ when R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴ and R¹⁷ are H and R¹¹ is H, halogen, OH or C_1-10 alkoxy and R¹⁸ is H or halogen and R¹⁵ and R¹⁶ taken together are ═

O; and

(d) R⁵ is not H, halogen, C_1-10 alkoxy or OSO₂R²⁰ when R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴ and R¹⁷ are H and R¹¹ is H, halogen, OH or C_1-10 alkoxy and R¹⁸ is H or halogen and R¹⁵ is H and R¹⁶ is H, OH or halogen.

2. The method of claim 1, wherein R¹⁵ is H, halogen, C_1-10 alkyl or C_1-10 alkoxy and R¹⁶ is —

C(O)OR²¹.

3. The method of claim 1, wherein R¹⁵ is H, halogen, OH or C_1-10 alkyl and R¹⁶ is H, halogen, OH or C_1-10 alkyl.

4. The method of claim 1, wherein R¹⁵ is H, halogen, C_1-10 alkyl, C_1-10 alkenyl, C_1-10 alkynyl, formyl, C_1-10 alkanoyl or epoxy and R¹⁶ is OH.

5. The method of claim 1, wherein R¹⁵ and R¹⁶ taken together are ═

O.

6. The method of claim 1, wherein said compound is to be administered prior to onset of clinical symptoms of ARDS.

7. The method of claim 1, wherein the compound is administered intavenously.

8. The method of claim 1, wherein the compound is administered orally.

9. The method of claim 1, wherein the compound is administered in the amount of 1-1000 mg/kg.

10. The method of claim 1, wherein the compound is administered in the amount of 2-200 mg/kg.