DIBENZOCYCLOHEPTATONE DERIVATIVES AND PHARMACEUTICAL AGENTS CONTAINING SAID COMPOUNDS

• US 20120115862A1
• Filed: 10/09/2009
• Published: 05/10/2012
• Est. Priority Date: 10/09/2008
• Status: Active Grant

• Current Assignee: C-A-I-R Biosciences GmbH
• Original Assignee: C-A-I-R Biosciences GmbH
• Inventors: Laufer, Stefan, Albrecht, Wolfgang
• Granted Patent: US 8,633,312 B2
• Time in Patent Office: Days
• US Class Current: 514/232.8
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 205/45 the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• CPC Class Codes: C07C 205/58 the carbon skeleton being further substituted by halogen atoms
• CPC Class Codes: C07C 205/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 225/22 having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 229/12 to carbon atoms of acyclic carbon skeletons
• CPC Class Codes: C07C 229/34 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2603/32 Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
• CPC Class Codes: C07C 271/54 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 49/747 containing six-membered aromatic rings
• CPC Class Codes: C07C 49/755 a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 309/12 : only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 313/12 : [b,e]-condensed
• CPC Class Codes: C07D 317/22 : etherified
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to compounds of the formula I

wherein R1, R2, R3, R4, X and Y have the meanings given in the description. The compounds have an action which is immunomodulating and inhibits or regulates the release of IL-1β and/or TNF-α. They can therefore be used for treatment of diseases connected with a disturbance in the immune system.

Claims

1. A compound of the formula I

2. The compound according to claim 1 of the formula Ia

3. The compound according to claim 1 of the formula Ib

4. The compound according to claim 1 of the formula Ic

5. The compound according claim 1, wherein R1 is chosen from C₁-C₆-alkyl which is substituted by 1, 2 or 3 hydroxyl groups, a saturated non-aromatic heterocyclic radical having 5 or 6 ring atoms, which contains 1 or 2 hetero atoms which are chosen independently of each other from O and N, and which can optionally contain 1 or 2 C₁-C₆-alkyl substituents, C₁-C₆-alkoxy, hydroxyl and NR6R7.

6. The compound according to claim 1, wherein R3 is chosen from

7. The compound according to claim 6, wherein R9 and R10 independently of each other are chosen from H, NH₂, mono-C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, halogen, CF₃, C₁-C₆-alkyl and C₁-C₆-alkoxy and R11 represents H or halogen.

8. The compound according to claim 6, wherein R3 represents a radical of the formula

9. The compound according to claim 1, wherein R4 represents H.

10. The compound according to claim 1, wherein R6 and R7 represent H.

11. The compound according to claim 1 of the formula

12. The compound according to claim 2 of the formula Iaa

13. The compound according to claim 4 of the formula Ica:

14. The compound according to claim 1:

(1) 2-(2-aminoanilino)-7-methoxydibenzosuberone

(2) 2-(2-amino-4-fluoroanilino)-7-methoxydibenzosuberone

(3) 2-(2,4-difluoroanilino)-7-methoxydibenzosuberone

(4) 2-(2-chloro-4-fluoroanilino)-7-methoxydibenzosuberone

(5) 2-(2,4,5-trifluoroanilino)-7-methoxydibenzosuberone

(6) 2-(2-trifluoromethylanilino)-7-methoxydibenzosuberone

(7) 2-(anilino)-7-methoxydibenzosuberone

(8) 2-(2-methoxyanilino)-7-methoxydibenzosuberone

(9) 2-(3-methyl-4-fluoroanilino)-7-methoxydibenzosuberone

(10) 2-(2-amino-4-trifluoromethylanilino)-7-methoxydibenzosuberone

(11) 2-(phenyl)-7-methoxydibenzosuberone

(12) 2-(2,4-difluoroanilino)-7-methoxydibenzosuberenone

(13) 2-(2,4-difluoroanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(14) 2-(2,4-difluoroanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(15) 2-(2-aminoanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(16) 2-(2-aminoanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(17) 2-(2,4-difluoroanilino)-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(18) 2-(2,4-difluoroanilino)-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(19) 2-(2-aminoanilino-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(20) 2-(2-aminoanilino-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(21) 2-(2,4-difluoroanilino)-7-(2-hydroxy-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(22) 2-(2,4-difluoroanilino)-7-(3-hydroxy-propoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(23) 2-(2,4-difluoroanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(24) 2-(2-aminoanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(25) 2-(2,4-difluoroanilino)-7-(2-tetrahydropyran-4-yl-oxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(26) (S)-2-(2,4-difluorophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(27) (R)-2-(2,4-difluorophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(28) (S)-2-(2-aminophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(29) (R)-2-(2-aminophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(30) 2-(2,4-difluorophenylamino)-8-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(31) 8-(2,4-difluorophenylamino)-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(32) 8-(2,4-difluorophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(33) 8-(2-aminophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(34) (S)-8-(2,4-difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(35) (R)-8-(2,4-difluorophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclohepten-5-one

(36) (S)-8-(2-aminophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a, d]cyclohepten-5-one

(37) (R)-8-(2-aminophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclo-hepten-5-one

(38) 8-(2,4-difluorophenylamino)-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one

(39) 8-(2,4-difluorophenylamino)-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo-[a,d]cyclo-hepten-5-one

(40) 3-(2,4-difluorophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one

(41) 3-(2-aminophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one

(42) 8-amino-3-(2-methoxyphenylamino)-6H-dibenzo□

b,e□

oxepin-11-one

(43) 8-amino-3-(4-fluoro-2-methoxyphenylamino)-6H-dibenzo□

b,e□

-oxepin-11-one

(44) 8-amino-3-(2-amino-4-trifluoromethylphenylamino)-6H-dibenzo[b,e]oxepin-11-one

(45) 8-amino-3-(tetrazol-1-yl)-6H-dibenzo[b,e]oxepin-11-one

(46) 3-(2,4-difluorophenylamino)-8-tetrazol-1-yl-6H-dibenzo[b,e]oxepin-11-one

(47) 2-(2-methyl-4-Fluoroanilino)-7-methoxydibenzosuberone

(48) 2-(2-chloroanilino)-7-methoxydibenzosuberone

(49) 2-(2-amino-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(50) 2-(2,4-difluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(51) 2-(2-chloro-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(52) 2-(2-chloroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(53) 2-(anilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(54) 2-(2,4-difluoroanilino)-7-hydroxy-dibenzo[a,d]-cyclohepten-5-one

(55) 2-(2,4-difluoroanilino)-7-[3-(4-Hydroxypiperidin-4-yl-propoxy)]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one

(56) 3-(2-amino-4-fluorophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one

(57) morpholine-4-carboxylic acid [3-(2,4-difluorophenylamino)-1-oxo-6,11-dihydrodibenzo[b,e]oxepin-8-yl]amide.

15. A pharmaceutical composition containing at least one compound of the formula I according to claim 1, optionally together with physiologically acceptable excipients.

16. The compound of the formula I according to claim 1 for use in a method for immunomodulation and/or for inhibition of the release of IL-1β

and/or TNF-α

.

17. A method for immunomodulation and/or for inhibition of the release of IL-1β

and/or TNF-α

in a patient, wherein an active amount of a compound of the formula I according to claim 1 is administered to the patient.