Compositions and methods for treating amyloidosis

• US 20090099100A1
• Filed: 07/07/2008
• Published: 04/16/2009
• Est. Priority Date: 04/28/1999
• Status: Abandoned Application

• Current Assignee: Bellus Health (Interational) Limited
• Original Assignee: Bellus Health (Interational) Limited
• Inventors: Kong, Xianqi, Szarek, Walter, Weaver, Donald, Gordon, Heather
• Application Number:
  US12/217,580
• Publication Number:
  US 20090099100A1
• Time in Patent Office: Days
• US Class Current: 514/23
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4152 having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/47 : Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 : Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/472 : Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/4725 : containing further heterocyclic rings
• CPC Class Codes: A61K 31/473 : ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/4741 : condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/675 : having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/706 : containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61P 17/04 : Antipruritics
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• 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 27/16 : Otologicals
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Therapeutic compounds and methods for modulating amyloid aggregation in a subject, whatever its clinical setting, are described. Amyloid aggregation is modulated by the administration to a subject of an effective amount of a therapeutic compound of the formula

or a pharmaceutically acceptable salt or ester, such that modulation of amyloid aggregation occurs. R¹ and R² are each independently a hydrogen atom or a substituted or unsubstituted aliphatic or aryl group. Z and Q are each independently a carbonyl (C═O), thiocarbonyl (C═S), sulfonyl (SO₂), or sulfoxide (S═O) group. “k” and “m” are 0 or 1, provided when k is 1, R¹ is not a hydrogen atom, and when m is 1, R² is not a hydrogen atom. In an embodiment, at least one of k or m must equal 1. “p” and “s” are each independently positive integers selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound. T is a linking group and Y is a group of the formula -A X wherein A is an anionic group at physiological pH, and X is a cationic group.

Claims

1. A method for treating or preventing an amyloid-related disease or disorder comprising administering an effective amount of a therapeutic compound to a subject in need thereof, where said therapeutic compound has the formula:

wherein

R¹ is an aliphatic group selected from a branched or unbranched, hydroxyl-substituted lower alkyl or an unsubstituted straight-chain C₁-C₂₂alkyl;

R² is a hydrogen atom;

Z and Q are absent;

k and m are 0;

p and s are one;

T is an alkylene group;

Y is SO₃X, and X is a cationic group;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein R¹ is an unsubstituted straight-chain C₅-C₁₈ alkyl.

3. The method of claim 2, wherein R¹ is an unsubstituted straight-chain C₅-C₉ alkyl.

4. The method of claim 1, wherein R¹ is a branched or unbranched C₂-C₆ alkyl group substituted with a hydroxyl group.

5. The method of claim 4, wherein R¹ is a branched C₂-C₆ alkyl group substituted with a hydroxyl group.

6. The method of claim 4, wherein R¹ is an unbranched C₂-C₆ alkyl group substituted with a hydroxyl group.

7. The method of claim 1, wherein said therapeutic compound is selected from the group consisting of 3-amylamino-1-propanesulfonic acid, 3-hexylamino-1-propanesulfonic acid, 3-heptylamino-1-propanesulfonic acid, 3-octylamino-1-propanesulfonic acid, 3-nonylamino-1-propanesulfonic acid, 3-decylamino-1-propanesulfonic acid, 3-undecylamino-1-propanesulfonic acid, 3-dodecylamino-1-propanesulfonic acid, 3-tridecylamino-1-propanesulfonic acid, 3-tetradecylamino-1-propanesulfonic acid, 3-hexadecylamino-1-propanesulfonic acid, and 3-octadecylamino-1-propanesulfonic acid;

and pharmaceutically acceptable salts thereof.

8. The method of claim 1, wherein said therapeutic compound is selected from the group consisting of 2-deoxy-2-(3-sulfopropyl)amino-D-glucose;

3-(2-hydroxyethyl)amino-1-propanesulfonic acid;

3-(3-hydroxy-1-propyl)amino-1-propanesulfonic acid;

(−

)-(3)-[(R)-2-hydroxy-1-propyl]amino-1-propanesulfonic acid;

(3)-[(d,l)-1-hydroxy-2-propyl]amino-1-propanesulfonic acid;

3-(4-hydroxy-1-butyl)amino-1-propanesulfonic acid;

3-(5-hydroxy-1-pentyl)amino-1-propanesulfonic acid;

3-(6-hydroxy-1-hexyl)amino-1-propanesulfonic acid;

(+)-3-[(S)-2-hydroxy-1-propyl]amino-1-propanesulfonic acid;

(+)-3-[(S)-1-hydroxy-2-propyl]amino-1-propanesulfonic acid;

(−

)-3-[(R)-1-hydroxy-2-propyl]amino-1-propanesulfonic acid;

(+)-3-[(S)-1-hydroxy-2-butyl]amino-1-propanesulfonic acid;

(−

)-3-[(R)-1-hydroxy-2-butyl]amino-1-propanesulfonic acid;

3-[(dl)-5-hydroxy-2-pentyl]amino-1-propanesulfonic acid;

3-[(dl)-6-hydroxy-2-hexyl]amino-1-propanesulfonic acid;

3-(1-hydroxymethyl-1-cyclopentyl)amino-1-propanesulfonic acid, and pharmaceutically acceptable salts thereof.

9. The method of claim 1, wherein said amyloid-related disease or disorder is a disease associated with Amyloid-β

, Amyloid A or IAPP.

10. The method of claim 9, wherein the disease or disorder is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome, or hereditary cerebral hemorrhage.

11. The method of claim 10, wherein the disease or disorder is Alzheimer'"'"'s disease.

12. The method of claim 9, wherein the disease or disorder is adult onset diabetes.

13. The method of claim 7, wherein said amyloid-related disease or disorder is a disease associated with Amyloid-β

, Amyloid A or LAPP.

14. The method of claim 13, wherein the disease or disorder is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome, or hereditary cerebral hemorrhage.

15. The method of claim 14, wherein the disease or disorder is Alzheimer'"'"'s disease.

16. The method of claim 13, wherein the disease or disorder is adult onset diabetes.

17. The method of claim 8, wherein said amyloid-related disease or disorder is a disease associated with Amyloid-β

, Amyloid A or IAPP.

18. The method of claim 17, wherein the disease or disorder is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome, or hereditary cerebral hemorrhage.

19. The method of claim 18, wherein the disease or disorder is Alzheimer'"'"'s disease.

20. The method of claim 17, wherein the disease or disorder is adult onset diabetes.