Hydroxy-substituted amino and ammonium derivatives and their medical use
The present invention relates to hydroxy-substituted amino and ammonium derivatives, in particular the compounds of formula (1) or (2), and their medical use, including their use in the treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder, or a proliferative, neoplastic or dysplastic disease or disorder.
1. A method of inhibiting inflammation that comprises at least one of Akt kinase activation or mast cell degranulation,
the method comprising administering to a subject in need of such inhibiting, an effective amount of a compound of the following formula 1
wherein:
R 1 is a C 10-20 hydrocarbon group;
R 2 is a C 1-4 alkyl group, and R 3 is —H, a C 1-4 alkyl group or R 3 is absent; or
R 2 and R 3 are mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with the nitrogen atom X to which they are attached, wherein said pyrrolidine ring, said piperidine ring or said azepane ring is optionally substituted with one or more groups independently selected from —OH, —O(C 1-3 alkyl), —O—C(O)—(C 1-3 alkyl), C 1-3 alkyl, —NH 2 , —NH(C 1-3 alkyl) or —N(C 1-3 alkyl)(C 1-3 alkyl);
R 4 is —H or a C 1-4 alkyl group;
R 5 is a C 2-8 alkyl group, wherein one or more hydrogen atoms of said C 2-8 alkyl group are replaced by —OH, or R 5 is a C 5-7 cycloalkyl group, wherein one ring carbon atom of said C 5-7 cycloalkyl group is optionally replaced by an oxygen atom and wherein one or more hydrogen atoms of said C 5-7 cycloalkyl group are independently replaced by —OH or —CH 2 OH;
X is N + or, if R 3 is absent, X is N; and
p is 1, 2 or 3;
or a pharmaceutically acceptable salt or solvate thereof.
2. The method of claim 1 , wherein R 5 is a C 2-8 alkyl group, wherein one or more hydrogen atoms of said C 2-8 alkyl group are replaced by —OH.
3. The method of claim 1 , wherein R 5 is —CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH, —CH 2 CH(OH)CH(OH)CH 2 OH, —CH 2 CH(OH)CH(OH)CH(OH)CH 2 OH, —CH 2 CH(OH)CH(OH)CH(OH)CH(OH)CH 2 OH, or —CH(CH 2 OH)CH(OH)CH(OH)CH(OH)CH 2 OH.
4. The method of claim 1 , wherein R 4 is methyl.
5. The method of claim 1 , wherein R 1 is a linear C 10-20 alkyl group, a linear C 10-20 alkenyl group, or a linear C 10-20 alkynyl group.
6. The method of claim 1 , wherein R 1 is —(CH 2 ) 11 —CH 3 , —(CH 2 ) 13 —CH 3 , or —(CH 2 ) 15 —CH 3 .
7. The method of claim 1 , wherein R 2 is methyl, and R 3 is —H, methyl or R 3 is absent.
8. The method of claim 1 , wherein R 2 and R 3 are mutually linked to form a piperidine ring together with the nitrogen atom X to which they are attached, wherein the piperidine ring is optionally substituted with —OH.
9. The method of claim 1 , wherein p is 1.
10. The method of claim 1 , wherein the compound is a compound of the following formula 2
wherein;
R 1 is a C 10-20 hydrocarbon group;
R 4 is —H or a C 1-4 alkyl group;
R 5 is a C 2-8 alkyl group, wherein one or more hydrogen atoms of said C 2-8 alkyl group are replaced by —OH, or R 5 is a C 5-7 cycloalkyl group, wherein one ring carbon atom of said C 5-7 cycloalkyl group is optionally replaced by an oxygen atom and wherein one or more hydrogen atoms of said C 5-7 cycloalkyl group are independently replaced by —OH or —CH 20 H;
each R 6 is independently selected from —OH, —O(C 1-3 alkyl), —O—C(O)—(C 1-3 alkyl), C 1-3 alkyl, —NH 2 , —NH(C 1-3 alkyl) or —N(C 1-3 alkyl)(C 1-3 alkyl);
p is 1, 2 or 3;
n is 1, 2, or 3; and
m is an integer from 0 to 4; or
a pharmaceutically acceptable salt or solvate thereof.
11. The method of claim 1 , wherein the compound is a compound of the formula 1a, 1b, 1c, or 1d
or a pharmaceutically acceptable salt or solvate thereof.
12. The method of claim 1 , wherein said inflammation is part of a disorder selected from psoriasis, atopic dermatitis (atopic eczema), contact dermatitis, xerotic eczema, seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis, Duhring's Disease, autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis, food allergy, or allergic reactions to venomous stings.
13. The method of claim 1 , wherein said inflammation is part of a disorder selected from acute urticarias, chronic urticarias, physical urticarias including aquagenic urticaria, cholinergic urticaria, cold urticaria (chronic cold urticaria), delayed pressure urticaria, dermatographic urticaria, heat urticaria, solar urticaria, vibration urticaria, adrenergic urticaria, or urticaria angioedema.
14. The method of claim 1 , wherein said inflammation is part of a disorder selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, diversion colitis (diverticulitis), Behçet's syndrome, indeterminate colitis, celiac disease, irritable bowel syndrome, postoperative ileus, eosinophilic gastroenteropathy, or gastritis.
15. The method of claim 1 , wherein said selected from chronic allergic rhinitis, seasonal allergic rhinitis (hay-fever), allergic conjunctivitis, chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angle glaucoma, dry eye disease, or diabetic macular edema.
16. The method of claim 1 , wherein said inflammation is part of a disorder selected from chronic obstructive pulmonary disease (COPD), allergic asthma, allergic bronchopulmonary aspergillosis hypersensitivity pneumonitis, or lung fibrosis.
17. The method of claim 1 , wherein said inflammation is part of a disorder selected from rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, osteoarthritis, reactive arthritis, or polymyalgia rheumatica.
18. The method of claim 1 , wherein said inflammation is part of a disorder selected from multiple sclerosis, Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave's disease, temporal arteritis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, alopecia areata, or autoimmune lymphoproliferative syndrome (ALPS).
19. The method of claim 1 , wherein said inflammation is part of a disorder selected from a graft-versus-host disease, a host-versus-graft disease or a transplant rejection.
20. The method of claim 1 , wherein said inflammation is part of a disorder an inflammatory contribution to Alzheimer's disease or Parkinson's disease.
21. The method of claim 1 , wherein said compound is administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route.
22. The method of claim 1 , further comprising administering one or more immunomodulatory drugs and/or one or more anti-inflammatory drugs.
23. The method of claim 1 , wherein said subject is a human.
24. The method of claim 1 , wherein said subject is a nonhuman mammal.
25. The method of claim 1 , wherein the subject has a disease selected from the group consisting of: rheumatoid arthritis (RA), diabetes mellitus, lupus, multiple sclerosis, COPD, bullous pemphigoid, mastocytosis, allergic reaction, asthma, eczema, itch, rhinitis, conjunctivitis and urticarial, delayed-type hypersensitivity, allergic contact dermatitis inflammatory response, collagen type II-induced arthritis, wherein the disease comprises the inflammation.
26. The method of claim 1 , wherein the subject has autoimmune hepatitis that comprises the inflammation.