Novel heterocyclic NF-kB inhibitors

• US 20060069102A1
• Filed: 07/29/2005
• Published: 03/30/2006
• Est. Priority Date: 09/20/2004
• Status: Active Grant

• Current Assignee: 4SC AG
• Original Assignee: 4SC AG
• Inventors: Leban, Johann, Wuzik, Andreas, Schmitt, Harald, Wolf, Kristina, Pegoraro, Stefano
• Granted Patent: US 7,812,041 B2
• Time in Patent Office: Days
• US Class Current: 514/253.100
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/08 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 27/16 Otologicals
• 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 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 263/48 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds of the general formula (1) and salts and physiologically functional derivatives thereof, wherein

R¹ is independently hydrogen; alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

R² is independently —NR³R⁴,

R³ is independently alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl,

R⁴ is independently alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R⁵ is independently H, COR⁶, CO₂R⁶, SOR⁶, SO₃R⁶, alkyl, cycloalkyl, alkoxy, —NH₂, alkylamine, —NR⁷COR⁶, halogen, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R⁶ is independently H, alkyl, cycloalkyl, —NH₂, alkylamine, aryl or heteroaryl;

R⁷ is independently H, alkyl, cycloalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, aryl, or heteroaryl; p is 0, or 1; q is 0, or 1;

X is CO, or SO₂.

Claims

1. A compound of the general formula (I) and salts and physiologically functional derivatives thereof,

2. The compound according to claim 1 wherein

p=0, q=1, and X═

CO.

3. The compound according to claim 1 wherein

p=0, q=1, and X═

SO₂.

4. The compound according to claim 1 wherein

p=1, q=1, and X═

CO.

5. The compound according to claim 1 wherein

p=1, q=1, and X═

SO₂.

15. A composition containing a compound according to claim 1 or 6 or 7 and a pharmaceutically acceptable carrier or diluent.

16. A method for the treatment or prevention of a disease characterized by hyperproliferation of cells, wherein said method comprises administering a compound according to claim 1 or 6 or 7 to a patient.

17. A method for the treatment or prevention of a disease resulting from ischemia and/or reperfusion injury of organs and/or of parts of the body selected from the group comprising heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with diseases selected from a group comprising infarctions such as myocardial infarction and critical limb ischemia, and/or wherein the endothelial dysfunction is associated with diseases selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs, wherein said method comprises administering a compound according to claim 1 or 6 or 7 to a patient.

18. A method for the treatment or prevention of a neurological diseases or disorders selected from the group comprising Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington'"'"'s Disease, Down'"'"'s Syndrome, nerve deafness, and Meniere'"'"'s disease, wherein said method comprises administering a compound according to claim 1 or 6 or 7 to a patient.

19. A method for the treatment or prevention of diseases that are caused by protozoal infestations in humans and animals, by bacteria, viruses or proteinaceous agents, wherein said method comprises administering a compound according to claim 1 or 6 or 7 to a patient.

20. A method for the treatment or prevention of disease characterized by hyperproliferation of cells, wherein the disease is selected from the group consisting of psoriasis, atopic dermatits, alopecia areata, alopecia totalis, alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia, allergic contact eczema, irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scaring mucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et atrophicatis, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic ekzema, Ekzema, fixed drug exanthema, photoallergic skin reaction, lichen simplex eriorale, dermatitis and “

Graft versus Host-Disease”

, acne, rosacea, scarring, keloids, vitiligo, actinic keratoses, hyperkeratoses like epidermolytic hyperkeratosis, Hyperkeratosis Lentics Perstans, Keratosis pilaris and Ichthyoses, wherein said method comprises administering a compound according to claim 1 or 6 or 7 to a patient.

21. A method for the treatment or prevention of disease characterized by hyperproliferation of cells, wherein the disease is selected from the group consisting of hematological or solid tumors, wherein said method comprises administering a compound according to claim 1 or 6 or 7 to a patient.

6. A compound of the general formula (III) or a salt or a physiologically functional derivative, or a stereoisomer thereof,

8. The compound according to claim 6 wherein R² and R³ is R;

A is CO;

r is 1, and X is O or S.

9. The compound according to claim 6 wherein R⁴ and R³ is H;

A is CO;

A is CO;

r is 1, and X is O or S, Z forms together with R¹ a 6-membered ring and R² is absent; and

if Z is N then X is O or S, or if Z is CR^2′

, X is O.

10. The compound according to claim 6 wherein R² and R³ is H;

A is CO;

A is CO;

r is 1, and X is O or S, Z is N, R¹ is COR⁷;

wherein R⁷ is an optionally substituted phenyl and R⁵ is C(NR⁷)NR^7′

R^8′

wherein R⁸ is a heterocycloalkyl.

11. The compound according to claim 6 wherein Z forms together with R¹ a 6-membered ring and R² is absent;

A is CO;

r is 1, Z is N, R³ is H;

X is O or S, A is CO and R⁵ is C(NR⁷)NR^7′

R⁸ wherein R⁸ is a heterocycloalkyl.

12. The compound according to claim 6 wherein Z forms together with R¹ a 6-membered ring and R² is absent;

A is CO;

A is CO;

r is 1, X is O or S, and if Z is N, X is O or S, if Z is CH, X is O.

7. A compound of the general formula (II) or a salt or a physiologically functional derivative, or a stereoisomer thereof,

13. The compound according to claim 7 wherein A is CO;

X is O or S, A is CO;

r is 1, R³ is H and Y is NR^2′

wherein R^2′

is optionally substituted phenyl.

14. The compound according to claim 7 wherein A is CO;

X is O or S, A is CO;

r is 1. R³ is H and Y is NR^2′

wherein R^2′

is 3-substituted trifluoromethylphenyl.