Fatty acid esters as bioactive compounds

• US 6,245,811 B1
• Filed: 08/18/1999
• Issued: 06/12/2001
• Est. Priority Date: 05/01/1995
• Status: Expired due to Fees

• Current Assignee: Scarista Limited (FSD Pharma, Inc.)
• Original Assignee: Scotia Holdings Plc
• Inventors: Redden, Peter, Manku, Mehar, McMordie, Austin, Horrobin, David Frederick, Knowles, Philip, Pitt, Andrea
• Primary Examiner(s): Carr, Deborah D.
• Application Number:
  US09/376,617
• Time in Patent Office: 664 Days
• Field of Search: 554/110, 554/223, 554/224, 554/227, 514/546, 514/547, 514/549, 514/552
• US Class Current: 514/547
• CPC Class Codes: A61K 31/23 of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/26 Psychostimulants, e.g. nicotine, cocaine
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• 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 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: C07C 69/007 : Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
• CPC Class Codes: C07C 69/16 : of dihydroxylic compounds
• CPC Class Codes: C07C 69/587 : Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
• 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
• CPC Class Codes: C07D 209/28 : 1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/66 : having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
• CPC Class Codes: C07D 233/94 : with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
• CPC Class Codes: C07D 279/36 : [b, e]-condensed, at least one with a further condensed benzene ring
• CPC Class Codes: C07D 321/00 : Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
• CPC Class Codes: C07D 339/04 : having the hetero atoms in positions 1 and 2, e.g. lipoic acid
• CPC Class Codes: C07D 499/00 : Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula: , e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• CPC Class Codes: C07F 9/091 : with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/65522 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07J 1/0059 : substituted in position 17 by a keto group
• CPC Class Codes: C07J 5/0053 : not substituted in position 16
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds of structure (I), and when for use in therapy: where R₁ is an acyl group derived from a C_16-30 fatty acid with two or more cis or trans double bonds and particularly an n-6 or n-3 series EFA or conjugated linoleic acid, or columbinic acid, or parinaric acid and R₂ is as R₁ the same or different, or any other nutrient, drug or other bioactive residue released as the active in the body and R₃ is either hydrogen, fully hydrocarbon, or containing heteroatoms, preferably an alkyl group particularly a C₁-C₄ alkyl group.

Claims

1. A compound having the following structure

where R₁ is an acyl group derived from a C_16-30 fatty acid with two or more cis or trans double bonds and R₂ is a nutrient, drug or other bioactive residue as the active in the body and R₃ is either hydrogen of gydrocarbyl, with the proviso that R₂ is not the residue of nicotinic acid.

2. A compound according to claim 1 wherein said fatty acid is an n-6 or n-3 series EFA or conjugated linoleic acid, or columbinic acid, or parinaric acid.

3. A compound according to claim 1 wherein the fatty acid is gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid n-3 or docosahexaenoic acid.

4. A compound according to claim 1, 2 or 3 wherein R₃ is an alkyl group.

5. A compound according to claim 1, 2 or 3 wherein R₃ is a C₁-C₄ alkyl group.

6. A compound according to any of claims 1 to 3 where R₂ is a drug or other active required to cross lipid membranes in the body to exert its action whether in entry to or movement within a cell in which it is to act, or in passing the skin, blood-brain or other barrier.

7. A compound according to any of claims 1 to 3 wherein R₂ is a drug, vitamin, amino acid, anti-oxidant or other active which is required to have an action additive to complementary to or synergistic with R₁.

8. A method of manufacturing a medicament for improving the transport of a drug or other active across lipid membranes in the body or securing an action as set out in claim 7, characterised by use of the active in the form of a compound as in any preceding claim.

9. A method of improving the transport of a drug or other active across lipid membranes in the body, characterised by use of the active in the form of a compound as set out in claim 1.

10. The compound according to claim 1, where R₁ is an acyl moiety corresponding to an acid selected from the group consisting of λ

-linolenic acid (GLA), dihomo-λ

-linolenic acid (DGLA), arachidonic acid (AA), stearidonic acid (SA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and conjugated linoleic acid (cLA) and R₂ is a nutrient, drug, or other bioactive residue selected from the group consisting of amino acids, adenylsuccinate or derivatives thereof, nonsteroidal antiinflammatory drugs, antibiotics, antimalarial or antiprotozoal drugs, antifungal drugs, antiinflammatory steroids, gonadal steroids, adrenal steroids, retinoids, anticancer agents, antipsychotic agents, antidepressive agents, antianxiety agents, immunosuppressive agents, proton pump inhibitors or H2 antagonists, diuretics, calcium antagonists, angiotensin converting enzyme inhibitors or angiotensin antagonists, beta-adrenergic blockers, antiepileptic drugs, hypolipidaemic agents, oral hypoglycaemics or insulin-sensitizing agents, bisphosphonates, radiological contrast agents, peptides or proteins, vitamins, antioxidants, and porphyrin, chlorin, or bacteriochlorin-based drugs.

11. The compound according to claim 10, wherein R₂ is the residue of an amino acid selected from the group consisting of tryptophan, phenylalanine, arginine, carnitine or derivatives thereof, and aminolevulinic acid.

12. The compound according to claim 10, wherein R₂ is the residue of adenylosuccinate or derivative thereof.

13. The compound according to claim 10, wherein R₂ is the residue of a nonsteroidal antiinflammatory drug selected from the group consisting of aspirin, salicylic acid, indomethacin, and ibuprofen.

14. The compound according to claim 10, wherein R₂ is the residue of an antibiotic selected from the group consisting of tetracycline, clindamycin, minocycline, chlortetracycline, and erythromycin.

15. The compound according to claim 10, wherein R₂ is the residue of an antimalarial or antiprotozoal drug selected from the group consisting of chloroquine, mepacrine, quinacrine and mefloquine.

16. The compound according to claim 10, wherein R₂ is the residue of an antifungal drug selected from the group consisting of metronidazole, antifungal imidazoles and nitroimidazoles, and amphotericin.

17. The compound according to claim 10, wherein R₂ is the residue of an antiinflammatory steroid selected from the group consisting of hydrocortisone, betamethasone, beclomethasone, and budesonide.

18. The compound according to claim 10, wherein R₂ is the residue of a gonadal steroid selected from the group consisting of oestrogens, progestogens, and androgens.

19. The compound according to claim 10, wherein R₂ is the residue of an adrenal steroid.

20. The compound according to claim 19, wherein the adrenal steroid is dehydroepiandrosterone.

21. The compound according to claim 10, wherein R₂ is the residue of a retinoid selected from the group consisting of tretinoin and isotretinoin.

22. The compound according to claim 10, wherein R₂ is the residue of an immunosuppressive agent selected from the group consisting of cyclosporin and tacrolimus.

23. The compound according to claim 10, wherein R₂ is the residue of an antiepileptic drug selected from the group consisting of phenytoin, carbamazepine, valproate, ethosuximide, vigabatrin, and lamotrigine.

24. The compound according to claim 10, wherein R₂ is the residue of a hypolipidaemic agent selected from the group consisting of fibrates and statins.

25. The compound according to claim 10, wherein R₂ is the residue of a radiological contrast agent selected from the group consisting of diatrizoate compounds, iodipamide, ioglycamates, iopanoates, iophendylate, iothalamate, ioxaglate, metrizamide, and derivatives thereof.

26. The compound according to claim 10, wherein R₂ is the residue of a peptide or protein selected from the group consisting of insulin, calcitonin, and erythropoietin.

27. The compound according to claim 10, wherein R₂ is the residue of a porphyrin, chlorin, or bacteriochlorin-based drug or tetrakis(hydroxyphenyl) derivatives thereof.

28. A method for treating a disorder selected from the group consisting of complications of diabetes;

cancer;

osteoarthritis;

rheumatoid arthritis;

inflammatory and auto-immune diseases other than arthritis;

respiratory diseases;

neurological disorders;

renal and urinary tract disorders;

cardiovascular disorders;

degenerative diseases of the eye;

psychiatric disorders;

prostatic hypertrophy and prostatitis;

impotence and male infertility;

mastalgia;

male pattern baldness;

osteoporosis;

dermatological disorders;

dyslexia and other learning disabilities; and

cancer cachexia;

comprising administering to a patient in need thereof an effective amount of the compound of claim 10.

29. The method according to claim 28, wherein said disorder is a complication of diabetes selected from the group consisting of neuropathy, retinopathy, and insufficient response to insulin.

30. The method according to claim 28, wherein said disorder is an inflammatory and autoimmune disease other than arthritis selected from the group consisting of Sjogren'"'"'s syndrome, systemic lupus, ulcerative colitis, Crohn'"'"'s disease, and uveitis.

31. The method according to claim 28, wherein said disorder is asthma.

32. The method according to claim 28, wherein said disorder is a neurological disorder selected from the group consisting of multiple sclerosis, Parkinson'"'"'s disease, and Huntington'"'"'s chorea.

33. The method according to claim 28, wherein said disorder is a degenerative disease of the eye selected from the group consisting of retinitis pigmentosa and senile macular degeneration.

34. The method according to claim 28, wherein said disorder is a psychiatric disorder selected from the group consisting of schizophrenia, Alzheimer'"'"'s disease, attention deficit disorder, alcoholism, and depression.

35. The method according to claim 28, wherein said disorder is a dermatological disorder selected from the group consisting of atopic eczema, hand eczema, psoriasis, urticaria, and allergic disorders.

36. The method according to claim 28, wherein said disorder is selected from the group consisting of complications of diabetes;

neurological disorders;

cardiovascular disorders;

degenerative diseases of the eye;

psychiatric disorders;

dermatological disorders; and

dyslexia and other learning disabilities; and

wherein R¹ is arachidonic acid (AA) and R² is selected from the group consisting of λ

-linolenic acid (GLA), dihomo-λ

-linolenic acid (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

37. The method according to claim 28, wherein said disorder is selected from the group consisting of cancer;

osteoarthritis;

rheumatoid arthritis;

inflammatory and auto-immune diseases other than arthritis;

respiratory diseases;

neurological disorders;

renal and urinary tract disorders;

cardiovascular disorders;

degenerative diseases of the eye;

psychiatric disorders;

osteoporosis;

dermatological disorders;

dyslexia and other learning disabilities; and

cancer cachexia; and

wherein R¹ is eicosapentaenoic acid (EPA) and R₂ is selected from the group consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

38. The method according to claim 28, wherein said administering comprises oral, topical, enteral or parenteral administration.

39. A method of treating or preventing a nutritional deficiency, comprising administering to a patient in need thereof an effective amount of a compound according to claim 10.

40. The method according to claim 39, wherein administering comprises oral administration of a composition comprising said compound and a food, nutritional supplement, or food additive.

41. The method according to claim 39, said administering comprises enteral or parenteral administration.

42. A cosmetic composition comprising a compound according to claim 10 in combination with a carrier suitable for application to the hair or skin.

43. A method for treating skin disorders comprising applying to the skin or hair of a patient in need thereof the composition of claim 39.

44. A method for treating psychiatric, neurological, behavioral, steep, or pain disorders comprising administering to a patient in need thereof an effective amount of the compound of claim 11, wherein said amino acid is tryptophan.

45. The method according to claim 44, wherein said disorders comprise depression or migraine.

46. A method for treating depression, multiple sclerosis, or chronic fatigue syndrome comprising administering to a patient in need thereof an effective amount of the compound of claim 11, wherein said amino acid is phenylalanine.

47. A method for treating diseases associated with defective nitric oxide production, comprising administering to a patient in need thereof an effective amount of the compound of claim 11, wherein said amino acid is arginine.

48. A method for treating muscle weakness, cardiac failure, chronic fatigue syndrome, Alzheimer'"'"'s disease, or peripheral neuropathies, comprising administering to a patient in need thereof an effective amount of the compound of claim 11, wherein said amino acid is carnitine or a carnitine derivative.

49. A method for treating cancer comprising administering to a patient in need thereof an effective amount of the compound of claim 11, wherein said amino acid is aminolevulinic acid.

50. A method for treating muscular dystrophy, cardiac failure, chronic fatigue syndrome, or Alzheimer'"'"'s disease, comprising administering to a patient in need thereof an effective amount of the compound of claim 12.

51. A method for treating inflammatory disorders of pain, Alzheimer'"'"'s disease, or for inhibiting platelet aggregation, comprising administering to a patient in need thereof an effective amount of the compound of claim 13.

52. A method of treating or preventing a bacterial infection, comprising administering to a patient in need thereof an effective amount of the compound of claim 14.

53. The method according to claim 52, wherein said bacterial infection comprises acne.

54. The method of treating malaria, protozoal disorders, inflammatory disorders, or schizophrenia, comprising administering to a patient in need thereof an effective amount of the compound of claim 15.

55. A method for treating fungal infections, comprising administering to a patient in need thereof an effective amount of the compound of claim 16.

56. A method for treating skin disorders or asthma, comprising administering to a patient in need thereof an effective amount of the compound of claim 17.

57. A method for treating ovarian deficiency, osteoporosis or testicular deficiency, comprising administering to a patient in need thereof an effective amount of the compound of claim 18.

58. A method of treating disorders associated with aging comprising administering to a patient in need thereof an effective amount of the compound of claim 19.

59. A method for treating dermatological disorders, comprising administering to a patient in need thereof an effective amount of the compound of claim 21.

60. A method for treating autoimmune and inflammatory disorders comprising administering to a patient in need thereof an effective amount of the compound of claim 22.

61. The method according to claim 60, wherein said autoimmune or inflammatory disorders are selected from the group consisting of psoriasis, eczema, asthma, rheumatoid arthritis, and inflammatory bowel disease.

62. A method for treating epilepsy, comprising administering to a patient in need thereof an effective amount of the compound of claim 23.

63. A method of lowering cholesterol level, comprising administering to a patient in need thereof an effective amount of the compound of claim 24.

64. A method for treating cancer cachexia, comprising administering to a patient in need thereof an effective amount of the compound of claim 10.