EP1881968A2 - Dibenzocycloheptane compounds and pharmaceuticals containing these compounds - Google Patents
Dibenzocycloheptane compounds and pharmaceuticals containing these compoundsInfo
- Publication number
- EP1881968A2 EP1881968A2 EP06742900A EP06742900A EP1881968A2 EP 1881968 A2 EP1881968 A2 EP 1881968A2 EP 06742900 A EP06742900 A EP 06742900A EP 06742900 A EP06742900 A EP 06742900A EP 1881968 A2 EP1881968 A2 EP 1881968A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- oxepin
- dihydrodibenzo
- alkyl
- aryl
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000007654 dibenzocycloheptanes Chemical class 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 title claims description 99
- 239000003814 drug Substances 0.000 title description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 191
- -1 phenyl compound Chemical class 0.000 claims abstract description 17
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims abstract description 13
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 10
- 125000003277 amino group Chemical group 0.000 claims abstract description 8
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 7
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 54
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 9
- BZAIXEGWNRZEFA-UHFFFAOYSA-N 3-fluoro-6h-benzo[c][1]benzoxepin-11-one Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC=C(F)C=C12 BZAIXEGWNRZEFA-UHFFFAOYSA-N 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 7
- AOXYDDZYGQVAAT-UHFFFAOYSA-N 3-(2,4-diaminoanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound NC1=CC(N)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 AOXYDDZYGQVAAT-UHFFFAOYSA-N 0.000 claims description 6
- OGGQAJXJSKXUJD-UHFFFAOYSA-N 3-(2-aminoanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound NC1=CC=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 OGGQAJXJSKXUJD-UHFFFAOYSA-N 0.000 claims description 6
- YZSCRHIOVDJZOG-UHFFFAOYSA-N 3-(2-aminoethylamino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC=C(NCCN)C=C12 YZSCRHIOVDJZOG-UHFFFAOYSA-N 0.000 claims description 6
- SRHHWORGZGVXOP-UHFFFAOYSA-N 3-(3-aminoanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound NC1=CC=CC(NC=2C=C3C(C(C4=CC=CC=C4CO3)=O)=CC=2)=C1 SRHHWORGZGVXOP-UHFFFAOYSA-N 0.000 claims description 6
- HMXKVBLOKBFAIO-UHFFFAOYSA-N 3-(4-amino-2-fluoroanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound FC1=CC(N)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 HMXKVBLOKBFAIO-UHFFFAOYSA-N 0.000 claims description 6
- CYSVAWNOUBFRDJ-UHFFFAOYSA-N 3-(4-aminoanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound C1=CC(N)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 CYSVAWNOUBFRDJ-UHFFFAOYSA-N 0.000 claims description 6
- BHLPETOVIJEDPJ-UHFFFAOYSA-N 3-amino-6h-benzo[c][1]benzoxepin-11-one Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC=C(N)C=C12 BHLPETOVIJEDPJ-UHFFFAOYSA-N 0.000 claims description 6
- YXEDJELOIRQBGT-UHFFFAOYSA-N 8-(2-aminoanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound NC1=CC=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3OCC2=C1 YXEDJELOIRQBGT-UHFFFAOYSA-N 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- JJDAAQSOVDMVIT-UHFFFAOYSA-N 3-(4-fluoro-2-nitroanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound [O-][N+](=O)C1=CC(F)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 JJDAAQSOVDMVIT-UHFFFAOYSA-N 0.000 claims description 5
- VFIXAHOUZWGASM-UHFFFAOYSA-N 3-[(2-aminophenyl)methylamino]-6h-benzo[c][1]benzoxepin-11-one Chemical compound NC1=CC=CC=C1CNC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 VFIXAHOUZWGASM-UHFFFAOYSA-N 0.000 claims description 5
- RADAVDILQLBKBD-UHFFFAOYSA-N 3-[2-(methylamino)anilino]-6h-benzo[c][1]benzoxepin-11-one Chemical compound CNC1=CC=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 RADAVDILQLBKBD-UHFFFAOYSA-N 0.000 claims description 5
- WWFXUOLWUURANF-UHFFFAOYSA-N 3-amino-6h-benzo[c][1]benzothiepin-11-one Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(N)C=C12 WWFXUOLWUURANF-UHFFFAOYSA-N 0.000 claims description 5
- PCIKLINTBUEMBG-UHFFFAOYSA-N n-[2-[(11-oxo-6h-benzo[c][1]benzoxepin-3-yl)amino]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 PCIKLINTBUEMBG-UHFFFAOYSA-N 0.000 claims description 5
- 239000008177 pharmaceutical agent Substances 0.000 claims description 5
- GXFIQHWKGLBSLN-UHFFFAOYSA-N 2-benzoxepine Chemical compound O1C=CC=C2C=CC=CC2=C1 GXFIQHWKGLBSLN-UHFFFAOYSA-N 0.000 claims description 4
- HKOINQDOCFZCDK-UHFFFAOYSA-N 3-(2,4-dibromoanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound BrC1=CC(Br)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 HKOINQDOCFZCDK-UHFFFAOYSA-N 0.000 claims description 4
- NKFLZOCCIOWWMB-UHFFFAOYSA-N 3-(2,4-dichloroanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound ClC1=CC(Cl)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 NKFLZOCCIOWWMB-UHFFFAOYSA-N 0.000 claims description 4
- JELAHDQPMBHMAI-UHFFFAOYSA-N 3-(2,4-difluoroanilino)-6h-benzo[c][1]benzoxepin-11-one Chemical compound FC1=CC(F)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 JELAHDQPMBHMAI-UHFFFAOYSA-N 0.000 claims description 4
- CGAAKTKBAFAOFR-QZTJIDSGSA-N 3-[[(1r,2r)-2-aminocyclohexyl]amino]-6h-benzo[c][1]benzoxepin-11-one Chemical compound N[C@@H]1CCCC[C@H]1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 CGAAKTKBAFAOFR-QZTJIDSGSA-N 0.000 claims description 4
- CGAAKTKBAFAOFR-ZWKOTPCHSA-N 3-[[(1r,2s)-2-aminocyclohexyl]amino]-6h-benzo[c][1]benzoxepin-11-one Chemical compound N[C@H]1CCCC[C@H]1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 CGAAKTKBAFAOFR-ZWKOTPCHSA-N 0.000 claims description 4
- CGAAKTKBAFAOFR-ROUUACIJSA-N 3-[[(1s,2s)-2-aminocyclohexyl]amino]-6h-benzo[c][1]benzoxepin-11-one Chemical compound N[C@H]1CCCC[C@@H]1NC1=CC=C2C(=O)C3=CC=CC=C3COC2=C1 CGAAKTKBAFAOFR-ROUUACIJSA-N 0.000 claims description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 230000002519 immonomodulatory effect Effects 0.000 claims description 4
- UVDGWJRJTOCJTR-UHFFFAOYSA-N indol-7-one Chemical compound O=C1C=CC=C2C=CN=C12 UVDGWJRJTOCJTR-UHFFFAOYSA-N 0.000 claims description 4
- ZNLXUEAUVPNLQF-UHFFFAOYSA-N n-(11-oxo-6h-benzo[c][1]benzothiepin-3-yl)acetamide Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(NC(=O)C)C=C12 ZNLXUEAUVPNLQF-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- IOOZCOQPRDZWOX-UHFFFAOYSA-N 3-(2-methoxyanilino)-5,6-dihydrodibenzo[2,1-b:3',1'-f][7]annulen-11-one Chemical compound COC1=CC=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3CCC2=C1 IOOZCOQPRDZWOX-UHFFFAOYSA-N 0.000 claims description 2
- 208000030507 AIDS Diseases 0.000 claims description 2
- 201000004384 Alopecia Diseases 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010006895 Cachexia Diseases 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010012289 Dementia Diseases 0.000 claims description 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 2
- 208000031886 HIV Infections Diseases 0.000 claims description 2
- 208000037357 HIV infectious disease Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010023126 Jaundice Diseases 0.000 claims description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 206010033647 Pancreatitis acute Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 201000003229 acute pancreatitis Diseases 0.000 claims description 2
- 230000000172 allergic effect Effects 0.000 claims description 2
- 231100000360 alopecia Toxicity 0.000 claims description 2
- 208000010668 atopic eczema Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 208000004296 neuralgia Diseases 0.000 claims description 2
- 208000021722 neuropathic pain Diseases 0.000 claims description 2
- 208000028169 periodontal disease Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 206010047470 viral myocarditis Diseases 0.000 claims description 2
- WHYPHFTVWTTWOY-UHFFFAOYSA-N 3-(4-aminoanilino)dibenzo[1,2-a:1',2'-e][7]annulen-11-one Chemical compound C1=CC(N)=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3C=CC2=C1 WHYPHFTVWTTWOY-UHFFFAOYSA-N 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000001105 regulatory effect Effects 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 206010003210 Arteriosclerosis Diseases 0.000 claims 1
- 208000011775 arteriosclerosis disease Diseases 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 125000003282 alkyl amino group Chemical group 0.000 abstract description 5
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 5
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 230000002456 anti-arthritic effect Effects 0.000 abstract 1
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- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract 1
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- 230000000387 litholytic effect Effects 0.000 abstract 1
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- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 abstract 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 abstract 1
- 239000012873 virucide Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
- 238000002844 melting Methods 0.000 description 44
- 230000008018 melting Effects 0.000 description 44
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 238000007429 general method Methods 0.000 description 40
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- 229910000104 sodium hydride Inorganic materials 0.000 description 21
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- OKQMZXDGFJIXER-UHFFFAOYSA-N 3-(2-aminoanilino)dibenzo[1,2-a:1',2'-e][7]annulen-11-one Chemical compound NC1=CC=CC=C1NC1=CC=C2C(=O)C3=CC=CC=C3C=CC2=C1 OKQMZXDGFJIXER-UHFFFAOYSA-N 0.000 description 5
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
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Definitions
- Dibenzocycloheptane compounds and pharmaceutical agents containing these compounds Dibenzocycloheptane compounds and pharmaceutical agents containing these compounds.
- the present invention relates to dibenzocycloheptane compounds of the formula I.
- X, Y and R 1 to R 4 have the meanings given below, and also pharmaceutical agents which contain the compounds of the formula I.
- the compounds are interleukin-1 ⁇ (IL-1 ⁇ ) and tumor necrosis factor ⁇ (TNF- ⁇ ) inhibitors which are useful for the treatment of inflammatory diseases.
- IL-1 ⁇ interleukin-1 ⁇
- TNF- ⁇ tumor necrosis factor ⁇
- IL-1 ⁇ and TNF- ⁇ protect the body from infectious agents, tumors or tissue damage.
- autoimmune diseases there is an increased production of IL-1ß and TNF- ⁇ , which may for example result in bone and cartilage degradation.
- Drugs which regulate the release of IL-1 ⁇ and TNF- ⁇ are therefore useful for the treatment of inflammatory diseases.
- inflammatory bowel disease inflammatory bowel disease
- proliferative and inflammatory skin diseases such as psoriasis and atopic dermatitis.
- the present invention is therefore based on the object of providing anti-inflammatory compounds which have improved activity.
- the invention thus relates to dibenzocycloheptane compounds of the formula I.
- R3 is selected under:
- R 4 is H, halogen or C 1 -C 6 -alkyl or R 3 and R 4 are bonded to adjacent C atoms of the phenyl ring and together with these C atoms form a 5- or 6-membered aromatic or non-aromatic heterocycle having a nitrogen heteroatom, wherein the heterocycle may be substituted with one or two C r C 6 alkyl groups or may be fused with a cyclohexyl group;
- R5 is H or C 1 -C 6 alkyl
- R 6 is H or C 1 -C 6 alkyl
- R7 is selected under:
- R8 is H, NH 2, mono-d-C ⁇ -alkylamino, di-Ci-C 6 -alkylamino, C 1 -C 6 -alkoxy or halogen;
- R9 is H or NH 2 ;
- alkyl (also in combination with other groups such as haloalkyl, etc.) includes straight and branched chain alkyl groups preferably having 1 to 6 and 1 to 4 carbon atoms, respectively, such as methyl, ethyl, n-propyl and n-propyl, n-, i and t-butyl, sec-butyl, n-pentyl and n-hexyl.
- halogen represents a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.
- R1 and R2 are preferably H.
- R3 is selected according to one embodiment from the above-mentioned formulas (b) to (e) and in particular (b) and (c). More preferably, R3 is selected under
- R7 and R8 have the meanings given above.
- R4, R5 and R6 are preferably H.
- R 7 is preferably NH 2 , C 1 -C 6 -alkyl-CONH, C 1 -C 6 -alkyl-NHCONH- or C 1 -C 6 -alkyl-O-CO-NH; R 8 is preferably H, NH 2 or halogen.
- the invention also encompasses the physiologically tolerated salts of the compounds of the formula I.
- these are in particular the acid addition salts.
- inorganic acids such as hydrochloric acid, Sulfuric acid or phosphoric acid
- organic acids such as tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, mandelic acid, ascorbic acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid and the like.
- the invention also provides the solvates of the compounds of the formula I or the salts thereof, in particular the hydrates.
- the compound (3a) can be converted into the compound (4a) with ring closure, for example with polyphosphoric acid in a polar organic solvent such as sulfolane. Acid or alkaline hydrolysis gives the compound (5a).
- oxepine derivatives ie compounds of formula I wherein X is CH 2 and Y is O, can be prepared in an analogous manner starting from 3-aminophenol.
- Scheme II illustrates the introduction of the radical R3 using the example of the preparation of the compound (7a).
- the compound (5a) is reacted with 2-nitrofluorobenzene in a nucleophilic aromatic substitution in a polar solvent to give the compound (6a).
- the nitro group in the compound (6a) is reduced in a customary manner, for example with Sn / HCl, to the amino group to give the compound (7a).
- the first step is to introduce the residue R3 into a nucleophilic aromatic substitution by reacting the compound (5c) with 3-nitroaniline.
- the obtained compound (6e) is then converted into the compound (7e).
- the reactions are carried out as described above in connection with Scheme II.
- the introduction of other radicals R3 can be carried out in an analogous manner, as well as the preparation of corresponding thiepine compounds.
- the reaction of the compound (5) with the corresponding amine is advantageously carried out without solvent at elevated temperature.
- the reaction is carried out at a temperature in the range of about 80 to 150 ° C.
- the amine is generally used in excess, in particular in a 5- to 25-fold excess.
- R7 C j -C 8 alkylamino or di-C, -C 6 alkylamino
- R 7 C 1 -C 6 -alkyl-CONH
- R 7 C 1 -C 6 -alkyl-NH-CO-NH-
- R 7 C r C 6 -alkyl-O-CO-NH-
- the reaction takes place in a polar organic solvent, for example an alkanol, such as methanol, ethanol or isopropanol and at elevated temperature.
- a polar organic solvent for example an alkanol, such as methanol, ethanol or isopropanol and at elevated temperature.
- the reaction temperature is generally in the range of the boiling point of the reaction mixture.
- Scheme VII illustrates the preparation of the starting compound using the example of compounds (25) and (35).
- (25) or (35) is prepared starting from methyl 2-methylbenzoate (20) in a customary manner by first brominating (20), for example with N-bromosuccinimide (NBS) in an inert solvent such as methylene chloride or chloroform, in the presence of a radical initiator, such as azoisobutyronitrile.
- NBS N-bromosuccinimide
- a radical initiator such as azoisobutyronitrile
- triphenylphosphine to give the compound (22).
- This is converted in a Wittig reaction with the 3-nitrobenzaldehyde or 3-fluorobenzaldehyde into the compound (24) or (34). Ester hydrolysis gives the compound (25) or (35).
- Scheme VIII illustrates the preparation of the dibenzocycloheptanone compounds exemplified by compounds (30) and (32), respectively.
- the nitro group is first reduced, for example with hydrogen / noble metal catalysts or tin / hydrochloric acid, to give the compound (26).
- the amino group in (26) is acylated in a conventional manner, for example with acetic anhydride.
- ring closure to (28) is carried out using polyphosphoric acid (PPA) in an inert, polar solvent such as sulfolane at a temperature in the range of 100 to 200 ° C.
- PPA polyphosphoric acid
- the compounds according to the invention exhibit in vitro and in vivo immunomodulatory activity and the inhibition of the release of TNF- ⁇ and IL-1 ⁇ .
- the compounds according to the invention are therefore suitable for the treatment of diseases which are associated with a disorder of the immune system. They are suitable for treatment, for example autoimmune diseases, cancer, rheumatoid arthritis, gout, septic shock,
- Osteoporosis neuropathic pain, HIV spread, HIV dementia, viral myocarditis, insulin-dependent diabetes, periodontal disease, restenosis, alopecia, T-cell depletion in HIV infection or AIDS, psoriasis, acute pancreatitis, allogeneic graft rejection, allergic pneumonia , Atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, jaundice, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome, systemic Lupus erythematosus, adult respiratory distress syndrome (ARDS) and respiratory distress syndrome.
- IBD inflammatory bowel disease
- the compounds of the invention can be administered either as individual therapeutic agents or as mixtures with other therapeutic agents.
- the compounds may be administered alone, but in general they are dosed and administered in the form of pharmaceutical agents, i. as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents.
- the compounds or agents may be administered orally or parenterally, preferably given in oral dosage forms.
- Oral agents may, for example, be present as tablets or capsules and may contain conventional excipients such as binders (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine), lubricants (eg magnesium stearate, talc, polyethylene glycol or silica), disintegrating agent (eg starch) or wetting agent (eg sodium lauryl sulfate).
- binders eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
- fillers eg lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine
- lubricants eg magnesium stearate, talc, polyethylene glycol or silica
- disintegrating agent
- Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays, and the like. They may also be in the form of dry powder, which is prepared for reconstitution with water or other suitable carrier. Such liquid preparations may contain conventional additives, for example suspending agents, flavorings, diluents or emulsifiers. For parenteral administration, solutions or suspensions may be employed with conventional pharmaceutical carriers.
- the compounds or agents of the invention may be administered to mammals (human or animal) at a dose of from about 0.5 mg to 100 mg per kg of body weight per day. They can be given in a single dose or in multiple doses.
- the spectrum of activity of the compounds as inhibitors of TNF- ⁇ and IL-1 ⁇ release was determined by the following test systems as described by Donat C. and Laufer S. in Arch. Pharm. Pharm. Med. Chem. 333, Suppl. 1, 1-40 , 2000, examined. In vitro test method with human whole blood
- Samples of human potassium EDTA whole blood are mixed with the test substance and preincubated for 15 minutes at 37 ° C. in a CO 2 incubator (5% CO 2, 95% moisture-saturated air). Thereafter, the samples 4 hours with 1 ug / ml LPS (E.coli 026: B6) stimulated at 37 0 C in a CO 2 -lnkubator (5% CO 2, 95% moisture-saturated air). The reaction is stopped by placing the samples on ice, mixed with DPBS buffer and then centrifuged at 1000 g for 15 min. " Subsequently, the amount of IL-1 ß and TNF ⁇ is determined in the plasma supernatant by ELISA.
- PBMCs Human mononuclear cells
- Human potassium-EDTA whole blood diluted 1: 3 by means of density gradient centrifugation (Histopaque®-1, 077). These are washed 2 times with DPBS buffer, resuspended-SFM medium in macrophages and 10 6 cells / adjusted to a cell count of 1 * ml.
- PBMCs suspension (ä 390 ul samples) is incubated with the test substance for 15 min at 37 ° C in a CO 2 incubator (5% CO 2, 95% moisture-saturated air). Thereafter, the samples are incubated for 4 hours with 1 ⁇ g / ml LPS (E. coli
- Microtitre plates were coated with 50 ul ATF2 solution (20 ug / ml) for one hour at 37 0 C. After washing three times with water, 50 ⁇ l of kinase mixture
- the alkaline phosphatase substrate solution (3 mM 4-NPP, 50 mM NaHCO 3, 50 mM MgCl 2, 100 ul / well) 1, 5 hours at 37 0 C. added.
- the formation of 4-nitrophenolate was measured at 405 nm using a microtiter plate reader. The IC 50 values are calculated.
- the reactant to be deprotonated is added in small portions. After the end of gas evolution, the second reactant is added and refluxed at about 16O 0 C.
- Reaction mixture is added after cooling with ice water and acidified with hydrochloric acid (20%).
- the resulting precipitate is filtered off, washed with hydrochloric acid (10%) and dried over calcium chloride.
- the compound to be reduced is dissolved in isopropanol by heating to reflux. When all starting material is dissolved, slowly add concentrated hydrochloric acid. Subsequently, tin is added in portions. After completion of the addition of tin, the mixture is refluxed for about 1, 5 - 2 h. After cooling, it is alkalized with sodium hydroxide solution (20%) and shaken out with ethyl acetate (EtOAc). The combined ethyl acetate extracts are evaporated in a rotary evaporator and purified by column chromatography.
- ketones (28) and (36) For the synthesis of the ketones (28) and (36) the indicated amount of carboxylic acid is dissolved in a dry 500 ml three-necked flask under an argon atmosphere in sulfolane and heating, then polyphosphoric acid is added and refluxed at 110 0 C. After hydrolyzing with ice-water, the mixture is stirred at RT, the precipitated crude product is purified after filtration by washing with H 2 O.
- IR (ATR) (cm -1 ): 1699, 1580, 1542, 1420, 1397, 1292, 1247, 1230, 778, 720.
- IR (ATR) (cm -1 ): 1650, 1597, 1583, 1558, 1537, 1276, 1240, 931, 735, 685
- IR (ATR) (cm -1 ): 2922, 2852, 1642, 1622, 1598, 1542, 1459, 1301, 1252, 1151, 1124, 755,
- IR (ATR) Cm- 1 ): 1690, 1613, 1595, 1581, 1490, 1311, 1287, 1273, 1165, 1139, 1042, 999, 957, 755, 735, 679, 671.
- IR (ATR) (cr ⁇ T 1 ): 1643, 1611, 1596, 1576, 1296, 1242, 1208, 1138, 1115, 1104, 1023, 851, 753, 695
- Powder can be purified by column chromatography to an orange powder.
- IR (ATR) (cm '1 ): 1590, 1578, 1498, 1441, 1347, 1251, 1233, 1167, 1146, 732.
- IR (ATR) (cm 1 ): 1588, 1577, 1504, 1330, 1296, 1257, 1214, 1150, 1124, 735, 713.
- IR (ATR) (cm -1 ): 1587, 1559, 1498, 1459, 1297, 1276, 1253, 1229, 1154, 1118, 746.
- IR (ATR) (cm '1 ): 1588, 1575, 1528, 1505, 1489, 1320, 1290, 1271, 1251, 1 188, 1154, 1122,
- IR (ATR) (cm -1 ): 2923, 2854, 1587, 1528, 1479, 1458, 1350, 1325, 1292, 1250, 1119, 1100, 712.
- IR (ATR) (cm -1 ): 1585, 1569, 1490, 1459, 1297, 1276, 1254, 1230, 1156, 1121, 759, 701
- IR (ATR) (cm-1): 1622, 1590, 1563, 1514, 1468, 1384, 1300, 1276, 1255, 1235, 1155,
- IR (ATR) (cm -1 ): 1626, 1591, 1564, 1495, 1458, 1302, 1262, 1233, 1156, 1121, 750, 703
- IR (ATR) (cm -1 ): 2924, 1628, 1591, 1564, 1524, 1452, 1299, 1274, 1250, 1157, 1115, 756,
- IR (ATR) (cm -1 ): 2924, 1628, 1592, 1569, 1525, 1452, 1299, 1275, 1248, 1157, 1137, 1116,
- IR (ATR) (cm -1 ): 1667, 1629, 1588, 1575, 1552, 1523, 1500, 1479, 1457, 1436, 1376, 1360, 1348, 1329, 1307, 1288, 1261, 1231, 1219, 1181, 1157, 1142, 1121, 1097, 1062, 1028, 965, 926, 849, 827, 761, 720, 711, 704
- Dimethylformamide used. The batch is refluxed for about 8 h. The workup is carried out with about 30 ml of ice water without acidification. Purification of the filtered precipitate by means of MPLC on a RP18 silica gel column using acetonitrile as eluant gives the yellowish product. Yield: 80 mg (8.0%); Melting point 157.2 - 159.2 0 C.
- IR (ATR) (cm -1 ): 1634, 1602, 1586, 1561, 1463, 1329, 1301, 1276, 1252, 1121, 1049,
- IR (ATR) (cm -1 ): 1607, 1588, 1509, 1461, 1421, 1310, 1298, 1261, 1244, 1229, 1212, 1187, 1154, 1122, 1060, 1025, 933, 924, 821, 758, 697th
- stage e The residue obtained in stage e) is admixed with 25 ml of acetic anhydride and stirred at RT for 15 h. 200 ml of ice-water are added to the mixture, which is shaken out repeatedly with 200 ml of EtOAc. The combined organic phases are concentrated to about 50 ml and re-extracted with 2 times 50 ml of water, then freed from the solvent in vacuo.
- IR (ATR): 1690 (C O) 1 1664 (amide), 1593 (amide II), 1558, 1489, 1305, 1278, 782, 747, 699 cm -1 .
- IR (ATR): 1599 (C O), 1581, 1566, 1499, 1290, 1279, 1258, 1111, 750, 694 cm -1 .
- Fluornitrobenzol added dropwise and the mixture is refluxed for 17 h at about 150 0 C. It is followed by hydrolysis with 75 ml of ice-water and filtering off the resulting precipitate, which contains the
- This nitro compound (filtration residue about 0.2 g) is carried out according to the general method G using 10 ml of i-PrOH, 5 ml of conc. HCl and 200 mg of tin powder. For shaking after alkalization 2 times 50 ml EtOAc are used.
- Esters 70 ml of MeOH and 60 ml of 20% sodium hydroxide solution. Refluxing time 6 h, extraction with 2 x 75 ml CH 2 Cl 2 . The crude product precipitates with concentrated HCl in the form of a yellowish oil, which gradually solidifies with stirring to a precipitate which is filtered off. Purification is carried out by leaching with Et 2 O and concentration of the filtrate to dryness.
- this nitro compound (filtration residue about 0.4 g) is carried out according to the general method G using 20 ml of i-PrOH, 10 ml of conc. HCl and 400 mg of tin powder. For shaking after alkalization 2 times 75 ml EtOAc are used. Purification is carried out by column chromatography on SiO 2 with CH 2 Cl 2 / EtOH (95 + 5) and subsequent recrystallization from MeOH / H 2 O.
- IR (ATR) (cm -1 ): 1691, 1600, 1586, 1497, 1344, 1242, 1274, 1046, 811, 750
- the mixture is mixed with ice water and alkalized with sodium hydroxide solution.
- IR (ATR) (cm -1 ): 1602, 1579, 1550, 1303, 1276, 1023, 757, 692.
- IR (ATR) Cm- 1 ): 1591, 1577, 1546, 1301, 1245, 1208, 767, 736.
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US67996705P | 2005-05-12 | 2005-05-12 | |
DE102005022020A DE102005022020A1 (en) | 2005-05-12 | 2005-05-12 | New dibenzocycloheptane compounds are tumor necrosis factor-alpha inhibitors useful to treat e.g. cancer, rheumatic arthritis, gout, septic shock, osteoporosis, naturopathic pain, HIV-propagation and periodontal diseases |
PCT/EP2006/004488 WO2006120010A2 (en) | 2005-05-12 | 2006-05-12 | Dibenzocycloheptane compounds and pharmaceuticals containing these compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1881968A2 true EP1881968A2 (en) | 2008-01-30 |
Family
ID=37310919
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06742900A Withdrawn EP1881968A2 (en) | 2005-05-12 | 2006-05-12 | Dibenzocycloheptane compounds and pharmaceuticals containing these compounds |
Country Status (7)
Country | Link |
---|---|
US (1) | US20090105327A1 (en) |
EP (1) | EP1881968A2 (en) |
JP (1) | JP2008544952A (en) |
CN (1) | CN101223153A (en) |
CA (1) | CA2608889A1 (en) |
DE (1) | DE102005022020A1 (en) |
WO (1) | WO2006120010A2 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2206534A1 (en) | 2008-10-09 | 2010-07-14 | c-a-i-r biosciences GmbH | Dibenzocycloheptanone derivatives und pharmaceutical agents containing these compounds |
BRPI1012282A2 (en) * | 2009-03-27 | 2015-09-22 | Presidio Pharmaceuticals Inc | fused hepatitis ring inhibitors c. |
WO2012040389A2 (en) | 2010-09-22 | 2012-03-29 | Presidio Pharmaceuticals, Inc. | Substituted bicyclic hcv inhibitors |
US8999967B2 (en) | 2010-09-29 | 2015-04-07 | Presidio Pharmaceuticals, Inc. | Tricyclic fused ring inhibitors of hepatitis C |
CN106631793B (en) * | 2016-10-19 | 2019-03-08 | 浙江师范大学 | A kind of preparation method of dibenzocycloheptane derivative |
US20230017312A1 (en) * | 2019-08-27 | 2023-01-19 | Synovo Gmbh | Centrally active p38alpha inhibiting compounds |
WO2023186881A1 (en) | 2022-03-29 | 2023-10-05 | Baden-Württemberg Stiftung Ggmbh | P38 map kinase inhibitors for use in the treatment of colorectal cancer |
WO2023221981A1 (en) * | 2022-05-16 | 2023-11-23 | Bp Apollo Limited | Taxamairin analogs and methods of use thereof |
CN115385887B (en) * | 2022-06-08 | 2024-01-23 | 北京联本医药化学技术有限公司 | Method for preparing isoxadifen by catalyzing cyclization reaction through ammonium salt ionic liquid |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2138257B1 (en) * | 1971-05-21 | 1974-08-23 | Roussel Uclaf | |
IL57077A0 (en) * | 1978-04-21 | 1979-07-25 | Syntex Inc | 6,11-dihydrodibenzo-thiepin-11-one s-oxides their preparation and pharmaceutical compositions containing them |
JPS55108868A (en) * | 1979-02-14 | 1980-08-21 | Dai Ichi Seiyaku Co Ltd | Dibenzoxepin derivative |
JPS55124777A (en) * | 1979-03-20 | 1980-09-26 | Toa Eiyou Kagaku Kogyo Kk | Novel dibenzoxepin derivative and its preparation |
AU2258683A (en) * | 1983-01-03 | 1984-07-05 | American Home Products Corporation | Dibenzocycloheptenylidenes and derivatives theof |
JPH03181443A (en) * | 1989-12-08 | 1991-08-07 | Hisamitsu Pharmaceut Co Inc | Novel dibenzo(a,d)cycloheptene derivative |
JPH0478774A (en) * | 1990-07-19 | 1992-03-12 | Mazda Motor Corp | Front body structure of automobile |
ES2159047T3 (en) * | 1995-10-16 | 2001-09-16 | Kyowa Hakko Kogyo Kk | TRICYCLE COMPOUNDS. |
ZA978792B (en) * | 1996-10-04 | 1998-04-06 | Novo Nordisk As | N-substituted azaheterocyclic compounds. |
GB9701453D0 (en) * | 1997-01-24 | 1997-03-12 | Leo Pharm Prod Ltd | Aminobenzophenones |
CZ20033519A3 (en) * | 2001-06-27 | 2004-06-16 | Ube Industries, Ltd. | Dibenzocycloheptene compound |
CA2458611C (en) * | 2001-08-28 | 2012-05-29 | Leo Pharma A/S | Aminobenzophenones as interleukin 1-beta and tumour necrosis factor-alpha inhibitors |
TW200400816A (en) * | 2002-06-26 | 2004-01-16 | Lilly Co Eli | Tricyclic steroid hormone nuclear receptor modulators |
US7803814B2 (en) * | 2003-12-19 | 2010-09-28 | Eli Lilly And Company | Tricyclic steroid hormone nuclear receptor modulators |
-
2005
- 2005-05-12 DE DE102005022020A patent/DE102005022020A1/en not_active Withdrawn
-
2006
- 2006-05-12 CA CA002608889A patent/CA2608889A1/en not_active Abandoned
- 2006-05-12 US US11/914,078 patent/US20090105327A1/en not_active Abandoned
- 2006-05-12 CN CNA2006800229705A patent/CN101223153A/en active Pending
- 2006-05-12 EP EP06742900A patent/EP1881968A2/en not_active Withdrawn
- 2006-05-12 JP JP2008510505A patent/JP2008544952A/en active Pending
- 2006-05-12 WO PCT/EP2006/004488 patent/WO2006120010A2/en active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2006120010A2 * |
Also Published As
Publication number | Publication date |
---|---|
US20090105327A1 (en) | 2009-04-23 |
CN101223153A (en) | 2008-07-16 |
JP2008544952A (en) | 2008-12-11 |
WO2006120010A2 (en) | 2006-11-16 |
WO2006120010A3 (en) | 2007-01-18 |
CA2608889A1 (en) | 2006-11-16 |
DE102005022020A1 (en) | 2006-11-23 |
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