Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors

• US 20040063647A1
• Filed: 08/28/2003
• Published: 04/01/2004
• Est. Priority Date: 03/17/2000
• Status: Abandoned Application

• Current Assignee: Corixa Corporation (GlaxoSmithKline PLC)
• Original Assignee: Corixa Corporation (GlaxoSmithKline PLC)
• Inventors: Johnson, David A.
• Application Number:
  US10/652,797
• Publication Number:
  US 20040063647A1
• Time in Patent Office: Days
• US Class Current: 514/23
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/40 : Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07C 65/30 : containing —CHO groups
• CPC Class Codes: C07C 69/76 : Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring

Abstract

This invention relates to novel aldehyde containing compounds and their uses as adjuvants and immunoeffectors.

Claims

1. A compound, having the formula:

2. The compound of claim 1 wherein the saccharyl group is a monoor disaccharide.

3. The compound of claim 1 wherein the saccharyl group is a glucuronic acid group.

4. The compound of claim 1 wherein R, R¹, and R² are hydrogens.

5. The compound of claim 1 wherein R is hydrogen;

R¹ is a saccharyl group, wherein the saccharyl group is a glucuronic acid group; and

R² is hydrogen.

6. The compound of claim 5 wherein the glucuronic acid group is a β

-D-glucuronic acid group.

7. The compound of claim 1 wherein R is hydrogen;

R¹ is represented by the formula —

C(O)—

[C(R³)(R⁴)]_n—

COOH wherein R³ and R⁴ are hydrogens and n is 2; and

R² is hydrogen.

8. The compound of claim 1 wherein R is hydrogen;

R¹ is a saccharyl group, wherein the saccharyl group is a glucuronic acid group; and

R² is (CH₂)_mCH(OH)(CH₂)_mOR⁵, wherein m is 1, and R⁵ is a substituted C_2-20 acyl group, or an unsubstituted C_2-20 acyl group.

9. The compound of claim 8 wherein (CH₂)_mCH(OH)(CH₂)_mOR⁵ is a 1-O-acyl-sn-glyceryl group.

10. The compound of claim 9 wherein the acyl group is a member selected from the group consisting of an acetyl group, an octanoyl group, and a tetradecanoyl group.

11. The compound of claim 1 wherein R is hydrogen;

R¹ is a saccharyl group, wherein the saccharyl group is a glucuronic acid group; and

R² is a group represented by the formula

12. The compound of claim 11 wherein R⁷ is a substituted C₁₁ alkyl group, or an unsubstituted C₁₁ alkyl group.

13. The compound of claim 1, wherein R¹ is an alkyl group having the formula —

(CH₂)_xCOOR⁸, wherein R⁸ is hydrogen, a substituted C_1-20 alkyl group, or an unsubstituted C_1-20 alkyl group, wherein X is an integer from 1 to 7.

14. The compound of claim 13, wherein X is an integer from 2 to 4.

15. A liposome vesicle comprising the compound of claim 1.

16. A compound comprising an antigen covalently linked to the compound of claim 1.

17. A vaccine composition comprising the compound of claim 16.

18. A vaccine composition comprising an antigen and the compound of claim 1.

19. The vaccine composition of claim 18 wherein the antigen is a bacterial antigen.

20. The vaccine composition of claim 18 wherein the antigen is a viral antigen.

21. The vaccine composition of claim 18 wherein the antigen is a tumor associated antigen.

22. The vaccine composition of claim 18 wherein the antigen is a self-antigen.

23. An adjuvant composition for potentiating the immunogenicity of an antigen, comprising a suspension of water or an aqueous solution, wherein said suspension or solution comprises the compound of claim 1.

24. The adjuvant composition of claim 23 wherein the suspension is an oil-in-water emulsion.

25. The adjuvant composition of claim 21 wherein the suspension is a water-in-oil emulsion.

26. The adjuvant composition of claim 23 wherein the suspension is a micellar dispersion comprising at least one surfactant.

27. The adjuvant composition of claim 26 wherein the surfactant comprises dipalmitoyl phosphatidylcholine (DPPC).

28. A method for inducing or enhancing immunogenicity of an antigen in a mammal, comprising administering to said mammal a vaccine composition comprising the antigen and a vaccine adjuvant composition comprising an effective immunopotentiatory amount of the compound of claim 1.

29. The method of claim 28 wherein said vaccine composition is administered orally, topically, epicutaneously, intramuscularly, intradermally, subcutaneously, intranasally, intravaginally, sublingually, or via inhalation.

30. A method for treating or preventing a disease in a mammal comprising administering to said mammal a vaccine composition comprising an antigen and an effective immunopotentiatory amount of the compound of claim 1.

31. The method of claim 30 wherein the mammal is a human being.

32. The method of claim 30 wherein the disease is cancer, an autoimmune disease, an allergy, or an infectious disease.

33. The method of claim 32 wherein the infectious disease is a bacterial or viral infection.

34. The method of claim 30 wherein the effective amount ranges from about 0.0001 to about 1.0 mg/kg of body weight.

35. The method of claim 34 wherein the effective amount ranges from about 0.001 to about 0.1 mg/kg of body weight.

36. The method of claim 30 wherein the compound of claim 1 is administered once weekly to once monthly for a period of up to about 6 months.

37. The method of claim 36 wherein the effective is administered once monthly for a period of about 2-3 months.

38. A method for preparing an adjuvant or immunoeffector, said method comprising:

contacting a first compound with the formula;

wherein R² and R⁸ are independently selected from the group consisting of hydrogen, a substituted C_1-20 alkyl group, an unsubstituted C_1-20 alkyl group, and a group having the formula —

(CH₂)_mCH(OH)(CH₂)_pOR⁵

wherein m and p are independently 1 or 2, and R⁵ is a substituted C_2-20 acyl group, an unsubstituted C_2-20 acyl group, or a group having the formula;

wherein j is an integer from 1 to 5, and R⁶ and R⁷ are independently selected from the group consisting of hydrogen, a substituted C_1-20 alkyl group, and an unsubstituted C_1-20 alkyl group,

with a second compound selected from the group comprising of;

MX_n, wherein M is selected from the group consisting of Al³⁺, As³⁺, B³⁺, Fe²⁺, Fe³⁺, Ga³⁺, Mg²⁺, Sb³⁺, Sb⁵⁺, Sn²⁺, Sn⁴⁺, Ti²⁺, Ti³⁺, Ti⁴⁺, and Zn²⁺, wherein n is an integer from 2 to 5, MgX₂-OEt₂, BX₃.SMe₂, Et₂AlCl, EtAlCl₂, monoalkyl boronhalides, dialkyl boronhalides, and monoaryl boronhalides, diaryl boronhalides, wherein X is selected from the group consisting of;

Cl, I, F, and Br,

under conditions sufficient to form a third compound or a pharmacologically acceptable salt thereof with the formula of;

39. The method of claim 38, wherein said first compound is:

40. The method of claim 38, wherein R² is methyl.

41. The method of claim 38, wherein R² is hydrogen.

42. The method of claim 38, wherein the second compound is selected from the group consisting of:

AlCl₃, AlI₃, AlF₃, AlBr₃, Et₂AlCl, EtAlCl₂, AsCl₃, AsI₃, AsF₃, AsBr₃, BCl₃, BBr₃, BI₃, BF₃, BCl₃.SMe₂, BI₃.SMe₂, BF₃.SMe₂, BBr₃.SMe₂, FeCl₃, FeBr₃, FeI₃, FeF₃, FeCl₂, FeBr₂, FeI₂, FeF₂, GaCl₃, GaI₃, GaF₃, GaBr₃, MgCl₂, MgI₂, MgF₂, MgBr₂, MgCl₂—

OEt₂, MgI₂—

OEt₂ MgF₂—

OEt₂ MgBr₂—

OEt₂, SbCl₃, SbI₃, SbF₃, SbBr₃, SbCl₅, SbI₅, SbF₅, SbBr₅, SnCl₂, SnI₂, SnF₂, SnBr₂, SnCl₄, SnI₄, SnF₄, SnBr₄, TiBr₄, TiCl₂, TiCl₃, TiCl₄, TiF₃, TiF₄, TiI₄, ZnCl₂, ZnI₂, ZnF₂, and ZnBr₂.

43. The method of claim 38 wherein R² is (CH₂)_mCH(OH)(CH₂)_mOR⁵, wherein m is 1, and R⁵ is a substituted C_2-20 acyl group, or an unsubstituted C_2-20 acyl group.

44. The method of claim 43, wherein (CH₂)_mCH(OH)(CH₂)_mOR⁵ is a 1-O-acyl-sn-glyceryl group.

45. The method of claim 44, wherein the acyl group is a member selected from the group consisting of acetyl, octanoyl, and tetradecanoyl groups.

46. The method of claim 38, wherein R² is a group represented by the formula

47. The method of claim 46 wherein R⁷ is a substituted C₁₁ alkyl group, or an unsubstituted C₁₁ alkyl group.