Substituted liposaccharides useful in the treatment and prevention of endotoxemia

• US 5,681,824 A
• Filed: 06/05/1995
• Issued: 10/28/1997
• Est. Priority Date: 06/05/1995
• Status: Expired due to Term

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Inventors: Kobayashi, Seiichi, Rossignol, Daniel P., Christ, William J., Kawata, Tsutomu
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US08/461,677
• Time in Patent Office: 876 Days
• Field of Search: 514/53, 536/55.3, 536/53, 536/17.2, 536/18.5
• US Class Current: 514/53
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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: C07H 11/00 Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof halo-sugars C07H5/02; thio-, seleno-, or telluro-sugars C07H5/08
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 15/12 attached to a nitrogen atom of the saccharide radical
• CPC Class Codes: C07H 3/04 Disaccharides

Abstract

Novel substituted liposaccharides useful as in the prophylactic and affirmative treatment of endotoxemia including sepsis, septicemia and various forms of septic shock and methods of using these agents are provided. Also provided are methods of preparing these agents and intermediates useful therein.

Claims

1. A method for decreasing or blocking the deleterious effects of endotoxin in a patient who has or is at risk of having a detrimental exposure to endotoxin, said method comprising administering to said patient a therapeutic amount of a compound of the formula:

##STR21## where R¹ is selected from the group consisting of ##STR22## where each J, K and Q, independently, is straight or branched C1 to C15 alkyl;

L is O, NH or CH₂ ;

M is O or NH; and

G is NH, O, S, SO, or SO₂ ;

R² is straight or branched C5 to C15 alkyl;

R³ is selected from the group consisting of ##STR23## where E is N, O, S, SO, or SO₂ ;

each A, B and D, independently, is straight or branched C1 to C15 alkyl;

R⁴ is selected from the group consisting of straight or branched C4 to C 20 alkyl, and ##STR24## where each U and V, independently, is straight or branched C2 to C15 alkyl and W is hydrogen or straight or branched C1 to C5 alkyl;

R⁵ is selected from the group consisting of hydrogen, J'"'"',--J'"'"'--OH, --J'"'"'--O--K'"'"',--J'"'"'--O--K'"'"'--OH, and --J'"'"'--O--PO(OH)₂, where each J'"'"' and K'"'"', independently, is straight or branched C1 to C5 alkyl;

R⁶ is selected from the group consisting of hydroxy, halogen, C1 to C5 alkoxy and C1 to C5 acyloxy;

A¹ and A², independently, are selected from the group consisting of ##STR25## where Z is straight or branched C1 to C10 alkyl;

or pharmaceutically acceptable salts thereof.

2. The method of claim 1 where said patient has or is at risk of developing systemic inflammatory response syndrome.

3. The method of claim 2 where said patient has a gram-negative infection.

4. The method of claim 2 where said patient has had a translocation of endotoxin from the gut into the bloodstream.

5. The method of claim 2 where said patient has inhaled or is at risk of inhaling endotoxin.

6. The method of claim 5 where said patient has or is at risk of developing adult respiratory distress syndrome.

7. The method of claim 2 where said patient is infected with a viral pathogen.

8. The method of claim 1 where R² is C8 to C15 straight or branched alkyl.

9. The method of claim 1 where A¹ and A², independently, are OH or --O--PO(OH)₂.

10. The method of claim 1 where R⁵ is C1 to C5 straight or branched alkyl.

11. The method of claim 1 where R¹ is selected from the group consisting of ##STR26## where each J, K and Q, independently, is straight or branched C1 to C15 alkyl.

12. The method of claim 1 where R³ is selected from the group consisting of ##STR27## where each A, B and D, independently, is straight or branched C1 to C15 alkyl.

13. The method of claim 1 where R⁴ is selected from the group consisting of straight or branched C4 to C20 alkyl, and ##STR28## where U is straight or branched C2 to C5 alkyl, V is straight or branched C5 to C12 alkyl, and W is hydrogen or straight or branched C1 to C5 alkyl.

14. A method of claim 1 where R⁶ is hydroxy.

15. The method of claim 1 where each A¹ and A², independently, is selected from the group consisting of OH and --O--PO(OH)₂ ;

R¹ is selected from the group consisting of ##STR29## where each J, K and Q, independently, is straight or branched C1 to C15 alkyl;

R² is straight or branched C8 to C15 alkyl;

R³ is selected from the group consisting of ##STR30## where each A, B and D, independently, is straight or branched C1 to C15 alkyl;

R⁴ is ##STR31## where U is straight or branched C2 to C5 alkyl, V is straight or branched C5 to C12 alkyl and W is hydrogen or straight or branched C1 to C5 alkyl;

and R⁵ is straight or branched C1 to C5 alkyl; and

R⁶ is hydroxy.

16. The method of claim 1 where A¹ and A² are --O--PO(OH)₂ ;

R¹ is ##STR32## R² is (CH₂)₉ CH₃ ;

R³ is ##STR33## R⁴ is ##STR34## R⁵ is methyl; and

R⁶ is hydroxy.

17. A method of claim 1, wherein said compound is ##STR35##