EP1881968A2 - Dibenzocycloheptanverbindungen und pharmazeutische mittel, welche diese verbindungen enthalten - Google Patents

Dibenzocycloheptanverbindungen und pharmazeutische mittel, welche diese verbindungen enthalten

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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Withdrawn
Application number
EP06742900A
Other languages
German (de)
English (en)
French (fr)
Inventor
Stefan Laufer
Wolfgang Albrecht
Cornelia Greim
Hans-Günter Striegel
Karola Tollmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merckle GmbH
Original Assignee
Merckle GmbH
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Application filed by Merckle GmbH filed Critical Merckle GmbH
Publication of EP1881968A2 publication Critical patent/EP1881968A2/de
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    • C07D313/02Seven-membered rings
    • C07D313/06Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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    • C07C225/22Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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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EP06742900A 2005-05-12 2006-05-12 Dibenzocycloheptanverbindungen und pharmazeutische mittel, welche diese verbindungen enthalten Withdrawn EP1881968A2 (de)

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PCT/EP2006/004488 WO2006120010A2 (de) 2005-05-12 2006-05-12 Dibenzocycloheptanverbindungen und pharmazeutische mittel, welche diese verbindungen enthalten

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EP2410843A4 (en) * 2009-03-27 2012-08-08 Presidio Pharmaceuticals Inc FUSIONED CORE INHIBITORS OF HEPATITIS C
US8822520B2 (en) 2010-09-22 2014-09-02 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 (zh) * 2016-10-19 2019-03-08 浙江师范大学 一种二苯并环庚烷衍生物的制备方法
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
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