Chroman derivatives

• US 20050065150A1
• Filed: 09/15/2004
• Published: 03/24/2005
• Est. Priority Date: 09/19/2003
• Status: Active Grant

• Current Assignee: PTC Therapeutics, Inc.
• Original Assignee: Edison Pharmaceuticals, Inc.
• Inventors: Wang, Bing, Chen, Jian, Walkinshaw, Gail, Zhang, Wei, Elizarov, Arkadij M., Song, Jiangao, James, Donald R., Boddupalli, Sekhar, Jin, Xianming, Li, Xianfeng
• Granted Patent: US 7,514,461 B2
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• 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 11/06 Antiasthmatics
• 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• 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 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 25/16 : Anti-Parkinson drugs
• 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 27/02 : Ophthalmic agents
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 311/70 : with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
• CPC Class Codes: C07D 311/74 : Benzo[b]pyrans, hydrogenated in the carbocyclic ring
• CPC Class Codes: C07D 311/94 : condensed with rings other than six-membered or with ring systems containing such rings
• CPC Class Codes: C07D 319/08 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to novel chroman derivatives, stereoisomers and pharmaceutically acceptable salts of Formula I wherein the substituents are as defined in the specification. They are useful in the treatment of disorders mediated by lipoxygenase, such as immune diseases, respiratory diseases and cardiovascular diseases, as well as in the treatment of neurodegenerative disorders and/or mitochondrial disorders. They are also useful in the manufacture of pharmaceutical formulations for the treatment of such conditions.

Claims

1. A compound represented by Formula I selected from the groups i), ii), and iii)

2. The compound of claim 1 is selected from Formula I group (i), and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

3. The compound of claim 2, wherein R⁵ and R⁶ are C_1-4 alkyl and R⁴ is hydrogen.

4. The compound of claim 3, wherein R¹, R², R⁵ and R⁶ are methyl and R⁴ is hydrogen.

5. The compound of claim 2, wherein R³ is aryl or saturated, partially saturated or unsaturated heterocyclyl both optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —

SO₂NR₂, and —

C(O)OR.

6. The compound of claim 5, selected from:

5-(4-Methoxy-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

2,2,7,8-Tetramethyl-5-phenyl-chroman-6-ol;

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzoic acid methyl ester;

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzoic acid;

2,2,7,8-Tetramethyl-5-pyridin-4-yl-chroman-6-ol;

2,2,7,8-Tetramethyl-5-pyridin-3-yl-chroman-6-ol;

5-(4-Methanesulfonyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

5-(4-Dimethylamino-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

5-(4-Chloro-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzenesulfonamide;

2,2,7,8-Tetramethyl-5-(3-nitro-phenyl)-chroman-6-ol;

2,2,7,8-Tetramethyl-5-(4-trifluoromethyl-phenyl)-chroman-6-ol;

5-(4-tert-Butyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

2,2,7,8-Tetramethyl-5-(3,4,5-trimethoxy-phenyl)-chroman-6-ol;

5-(2,5-Dimethoxy-3,4-dimethyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzonitrile;

5-(2,5-Dimethoxy-3,4-dimethyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

5-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzene-1,2,3-triol;

5-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-2,3-dimethyl-benzene-1,4-diol;

5-(2-Chloro-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;

5-Furan-2-yl-2,2,7,8-tetramethyl-chroman-6-ol;

and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

7. The compound of claim 2, wherein R³ is —

CR=Het and Het is an unsaturated heterocycyl optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —

SO₂NR₂, and —

C(O)OR.

8. The compound of claim 7 selected from:

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one;

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylene)-3-phenyl-4H-isoxazol-5-one;

4-[4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylene)-3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl]-benzoic acid;

4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylene)-2-methyl-5-propyl-2,4-dihydro-pyrazol-3-one;

5-Hydroxy-3-(6-hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylene)-3H-benzofuran-2-one; and

single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

9. The compound of claim 1 selected from Formula I group (ii), and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

10. The compound of claim 9, wherein n=0 and R² is -Het selected from furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, thiazolidine, pyrazolyl, and thiadiazol-2-yl, optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, amino, nitro, —

SO₂NR₂, and —

C(O)OR.

11. The compound of claim 10 selected from:

2,5,7,8-Tetramethyl-2-thiophen-2-yl-chroman-6-ol;

2-(2,5-Dimethyl-thiophen-3-yl)-2,5,7,8-tetramethyl-chroman-6-ol;

2-(2,5-Dimethyl-thiophen-3-yl)-2,7,8-trimethyl-chroman-6-ol

8-Chloro-2-(2,5-dimethyl-thiophen-3-yl)-2,5,7-trimethyl-chroman-6-ol;

5-Chloro-2,7,8-trimethyl-2-thiophen-2-yl-chroman-6-ol;

2-(3-Chloro-propyl)-5,7-dimethyl-2-thiophen-2-yl-chroman-6-ol;

5-Chloro-2-(2,5-dimethyl-thiophen-3-yl)-2,7,8-trimethyl-chroman-6-ol;

and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

12. The compound of claim 9, wherein R is —

CH-(Het)₂ or —

CH=Het, where Het is saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —

SO₂NR₂, and —

C(O)OR.

13. The compound of claim 12, wherein R² is 2,4-dioxo thiazolidin-5-methylene;

2,4-dioxo-thiazolidin-5-methyl;

3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-methyl;

or di-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-methyl.

14. The compound of claim 13 selected from:

5-[3-(6-Methoxymethoxy-2,7,8-trimethyl-chroman-2-y)-propylidene]-thiazolidine-2,4-dione;

5-[3-(6-Hydroxy-2,7,8-tri methyl-chroma n-2-yl)-propylidene]-thiazolidine-2,4-dione; and

single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

15. The compound of claim 9, wherein n=0 and R² is dihalovinyl.

16. The compound of claim 15, selected from:

2-(2,2-Dibromo-vinyl)-2,5,7,8-tetramethyl-chroman-6-ol;

2-(2,2-Dichloro-vinyl)-2,5,7,8-tetramethyl-chroman-6-ol;

and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

17. The compound of claim 1 is selected from Formula I group (iii), and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

18. The compound of claim 17, wherein n is 0;

R¹ is methyl and R² is C₁₆alkyl or C₁₆ alkenyl; and

R³ is —

(CR₂)_mSR^a

19. The compound of claim 18 selected from:

3-[6-Hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-5-ylmethylsulfanyl]-2-methyl-propionic acid;

2,7,8-Trimethyl-5-(5-methyl-1H-benzoimidazol-2-ylsulfanylmethyl)-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol;

2-[6-Hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-5-ylmethylsulfanyl]-ethanesulfonic acid;

5-(4,6-Dimethyl-pyrimidin-2-ylsulfanylmethyl)-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol;

4-[2-(4,8-Dimethyl-tridecyl)-6-hydroxy-2,7,8-trimethyl-chroman-5-ylmethylsufanyl]-benzoic acid;

1-{3-[6-Hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-5-ylmethylsulfanyl]-2-methyl-propionyl}-pyrrolidine-2-carboxylic acid;

and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

20. The compound of claim 17, wherein n is 0;

R¹ and R² are independently of each other C_1-4 alkyl; and

R³ is —

(CR₂)_mSR^a.

21. The compound of claim 20, wherein the compound is selected from:

5-Allylsulfanylmethyl-2,2,8-trimethyl-7-(3-methyl-butyl)-chroman-6-ol;

5-Cyclopentylsulfanylmethyl-2,2,7,8-tetramethyl-chroman-6-ol;

5-Hexylsulfanylmethyl-2,2,7,8-tetramethyl-chroman-6-ol

5-Allylsulfanylmethyl-2,2,7,8-tetramethyl-chroman-6-ol;

5-(4,6-Dimethyl-pyrimidin-2-ylsulfanylmethyl)-2,2,7,8-tetramethyl-chroman-6-ol,

1-[3-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylsulfanyl)-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid;

and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising a compound of claim 1 admixed with a pharmaceutically acceptable excipient.

23. A method of treating a subject suffering from neurodegenerative disorders, oxidative stress disorders or mitochondrial disorders comprising administering to said subject a therapeutically effective amount of a compound of claim 1 or steroisomers, mixture of stereoisomers or pharmaceutically acceptable salts thereof.

24. The method of claim 23, wherein the subject is suffering from a neurodegenerative disorder selected from stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunctions, peripheral neuropathy/neuropathic pain, spinal cord injury, head injury, and surgical trauma.

25. The method of claim 23, wherein the subject is suffering from a mitochondrial disorder selected from epilepsy, Parkinsonism or Parkinson'"'"'s disease, Alzheimer'"'"'s disease amyotrophic lateral sclerosis (ALS), motor neuron diseases, macular degeneration, mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), Myoclonic epilepsy with ragged red fibers (MERFF), Friedreich'"'"'s ataxia and cerebellar ataxias.

26. The method of claim 23, wherein the subject is suffering from an oxidative stress disorder with inflammatory or autoimmune components selected from diabetes, renal disease, premenstrual syndrome, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, osteoarthritis, muscle fatigue, irritable bowel syndrome, inflammatory bowel disease (IBD), premenstrual syndrome (PMS), and intermittent claudication

27. The method of claim 23, wherein the subject is suffering from dermatological conditions characterized by oxidative stress, selected from age-related skin damage, damage resulting to the skin from insults such as harmful ultraviolet (UV) radiation, pollution, stress and fatigue, contact dermatitis, skin irritation, skin pigmentation, psoriasis and acne.

28. A method of inhibiting a lipoxygenase enzyme in a subject in need of such inhibition which comprises administering to said subject a therapeutically effective amount of a compound of claim 1 or steroisomers, mixture of stereoisomers or pharmaceutically acceptable salts thereof.

29. A method of treating a subject with a lipoxygenase mediated condition comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

30. The method of claim 29, wherein the subject is a mammal suffering from diseases involving apoptosis in cancer cells including prostatic cancer, gastric cancer, colorectal or esophageal cancer and airways carcinoma;

diseases involving hypoxia, or anoxia including atherosclerosis, myocardial infarction, cardiovascular disease, heart failure (including chronic and congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, post surgical cognitive dysfunction and other ischemias;

diseases involving inflammation, including diabetes, arterial inflammation, inflammatory bowel disease, renal disease, pre-menstrual syndrome, asthma, allergic rhinitis, gout;

cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue, disorders of the skin, including acne, dermatitis and psoriasis;

disorders of the airways including asthma, chronic bronchitis, human airway carcinomas, mucus hypersecretion, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome;

diseases involving neurodegeneration and neuroinflammation including Alzheimer'"'"'s, dementia and Parkinson'"'"'s disease;

peripheral neuropathy including spinal chord injury, head injury and surgical trauma, and allograft tissue and organ transplant rejection;

diseases involving the autoimmune system including psoriasis, eczema, rheumatoid arthritis, and diabetes; and

disorders involving bone loss or bone formation.

31. The method of claim 29, wherein the subject is a mammal suffering from diabetes, arthritis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, or atherosclerosis.