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  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
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  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C255/47—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of rings being part of condensed ring systems
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
  • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
  • C07C259/16—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of rings other than six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
  • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
  • C07C275/22—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/44—Nitrogen atoms not forming part of a nitro radical
  • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
  • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/86—Ring systems containing bridged rings containing four rings
  • C07C2603/88—Ethanoanthracenes; Hydrogenated ethanoanthracenes

Definitions

• the present invention relates to new tetracycles, processes for their preparation and medicaments which contain these compounds.
• the invention relates to tetracyclo [6.6.2.0 2 ' 7 .0 9 ' 14 ] hexadeca-2 (7), 3.5.9 (14), 10,12-hexaene derivatives of the general formula I.
• Rl and R2 are identical or different hydrogen or a halogen atom
• X is hydrogen and
• R3 is hydrogen, a lower alkyl group
• R4 is hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or
• R3 and R4 together with the nitrogen atom to which they are attached form a heterocyclic ring which may be replaced by another
• Hetero atom can be interrupted and can optionally be substituted one or more times
• R5 represents hydrogen, an amidino group or a heterocycle optionally interrupted by one or more heteroatoms
• R4 does not represent a lower alkyl group
• R5 is not hydrogen or (c) R3 and R4 together do not represent an unsubstituted piperidine ring or
• the compounds of the formula I have valuable pharmacological properties, in particular they can inhibit the activity of phospholipases. They are therefore suitable for the treatment of acute and chronic, allergic, non-allergic and traumatic inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respiratory diseases, septic shock, allergic shock, serum disease, autoimmune diseases, graft-versus-host reactions, host-versus-graft diseases, ischemic or thrombotic diseases, for example coronary infarction or cerebral infarction.
• acute and chronic, allergic, non-allergic and traumatic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respiratory diseases, septic shock, allergic shock, serum disease, autoimmune diseases, graft-versus-host reactions, host-versus-graft diseases, ischemic or thrombotic diseases, for example
• radicals R3, R4 and as a substituent means, unless otherwise stated, by itself or in combination with aryl or amino a straight-chain or branched alkyl chain with 1 to 6 carbon atoms.
• Preferred radicals are the methyl, ethyl, propyl, isopropyl, «-butyl, isobutyl, tert-butyl, w-pentyl or 3-pentyl radical.
• Aryl is understood to mean the phenyl or naphthyl radical, which can optionally be substituted by halogen or lower alkyl.
• the phenyl radical is preferred.
• Halogen means fluorine, chlorine, bromine or iodine, preferably chlorine.
• heteroatoms mentioned for the radicals R3 and R4 and R5 are taken to mean N, O, S, preferably N or O.
• N-aralkyl heteroaryl is understood to mean an aralkyl radical bonded to the heterocycle via the N atom.
• the heteroaryl groups listed under R4 are understood to mean the pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl or thepiperazinyl radical.
• the pyridinyl, piperidinyl or imidazolinyl radical in particular the 3- or 4-pyridinyl or the 3- or 4-piperidinyl or the 4,5-dihydro-imidazol-2yl radical, is preferred.
• heterocyclic ring systems listed for R3 and R4 together with the N atom to which they are attached are understood to mean pyrrolidine, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, piperidine, piperazine or the morpholine ring.
• the pyrrolidine, morpholine and piperidine residues are preferred.
• Substituents of the heterocyclic ring system which can be formed together by R3 and R4 are, in addition to generally customary substituents, preferably benzamido, benzylamino, amino, monoalkylammo or dialkylamino. The simple substitution in the 4-position is preferred.
• Heterocycle in the radical R5 means pyrimidine, pyridazine, pyrazole, pyrazine, imidazole, indazole or purine.
• the imidazole radical is particularly preferred.
• Particularly preferred radicals for R1 and R2 are hydrogen and chlorine.
• a particularly preferred radical for R3 is hydrogen or methyl
• R4 particularly preferably denotes carbamoyl, amidino, N-benzylaminopyridine, piperidine, pyridine, methyl, hydroxy or imidazolyl.
• R3 and R4 together are particularly preferably 4-benzamidinopiperidine, 4-benzylaminopiperidine, 4-aminopiperidine, 4-dimethylaminopiperidine, pyrrolidine, piperidine or morpholine.
• R5 particularly preferably denotes hydrogen, imidazole or amidino.
• the invention relates in particular to all substances which have any possible combination of the substituents mentioned in the examples.
• the compounds of the formula I are prepared by methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thime Verlag, Stuttgaart; Organic Reactions, John Wiley & Sons, Inc., New York) and in the references cited in the examples, under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
• a compound of the formula I can be converted into another compound of the formula I by methods known per se.
• R1, R2, X, Y and Z have the meaning given and R4 or R5 are hydrogen, by reaction with an activated carbonic acid derivative or an agent which transfers the imidazoline group, to give a compound of the formula I in which R4 or R5 is carbamoyl, Amidino or Imidazolinyl means, or
• Rl and R2 have the meaning given, X is hydrogen, Y is hydrogen or a nucleofugic group and Z is a carbonyl group, by reaction with a primary or secondary amine and subsequent reduction to a compound of formula I, in which Z represents a CH 2 group and Y represents NR3R4, or
• R4 is hydroxyl, or d) Rl and R2 have the meaning given and XYZ for a group
• CO-NH-CO is converted by reduction to a compound of the formula I in which XYZ is a group CH 2 -NH-CH 2 ,
• the compounds of formula I can exist as enantiomers and as racemates.
• the invention relates to both the pure enantiomers and the racemic mixtures.
• Activated carbonic acid derivatives are, for example, inorganic isocyanates and isourea derivatives which carry a nucleofugic group.
• Agents which transfer the imidazoline group are, for example, IH imidazolines which carry a nucleofugic group in the 2-position.
• Nucleofuge groups are, for example, halogen atoms, the azido group, alkoxy groups, aryloxy groups, alkylthio groups and arylthio groups.
• Complex metal hydrides such as sodium borohydride and lithium aluminum hydride are preferably used as reducing agents.
• Compounds of the general formula I can contain one or more chiral centers and can then be present in racemic or in optically active form.
• the optical isomers can be separated into the enantiomers by methods known per se. The methods described relate, wherever appropriate, to the separation of final stages and / or preliminary stages. Either from the racemic mixtures by reaction with an optically active acid such as. B. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or an optically active amine such as. B.
• D- or L- ⁇ -phenylethylamine, ephedrine, quinidine or cinchonidine diastereomeric salts are formed, which can be separated by crystallization, or the optical isomers are separated by HPLC. Another possibility of separating optical isomers is by enzymatic separation during synthesis.
• salts with non-toxic inorganic or organic acids such as e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, benzoic acid, sahcylic acid, malonic acid, maleic acid, succinic acid or diaminocaproic acid as well as optionally alkali, alkaline earth and ammonium salts.
• non-toxic inorganic or organic acids such as e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, benzoic acid, sahcylic acid, malonic acid, maleic acid, succinic acid or diaminocaproic acid as well as optionally alkali, alkaline earth and ammonium salts.
• the salts are obtained in the usual way e.g. by neutralizing the compounds of formula I with the corresponding acids or alkalis. They are usually cleaned by falling over from water / acetone.
• the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as e.g. Olive oil, suspended or dissolved.
• the substances of the general formula I can be administered orally or parenterally in liquid or solid form.
• Water is preferably used as the injection medium, which contains the stabilizing agents customary for injection solutions, Contains solubilizers and / or buffers.
• Such additives are, for example, tartrate or borate buffers, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
• Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular weight polymers (such as polyethylene glycols).
• Preparations suitable for oral administration can, if desired
• the substances I according to the invention can also be used in the form of powders and ointments. You will e.g. mixed with powdery, physiologically compatible diluents or common ointment bases.
• the dose administered depends on the age, health and weight of the recipient, the extent of the disease, the type of additional treatments that may be carried out at the same time, the frequency of the treatments and the type of effect desired.
• the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Typically 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications to achieve the desired results.
• Example 5 A solution of 5.4 g (12.8 mmol) of the compound of Example 3 in 50 ml of tetrahydrofuran is added dropwise to a suspension of 1.5 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, and the mixture is then heated under reflux for 3 h, mixed with sodium chloride solution, filtered, the filtrate is dried and concentrated on. After the methanolic solution has been treated with excess ethereal hydrogen chloride solution, 5.1 g (98% of theory) of the title compound are isolated as a crude product.
• Example 5 A solution of 5.4 g (12.8 mmol) of the compound of Example 3 in 50 ml of tetrahydrofuran is added dropwise to a suspension of 1.5 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, and the mixture is then heated under reflux for 3 h, mixed with sodium chloride solution, filtered, the filtrate is dried and concentrated on. After the methanolic solution has been treated
• Example 8 In an analogous manner to that described in Example 5, the title compound of melting point 226-228 ° C. is obtained from the compound of Example 6 in 89% yield.
• Example 8 In an analogous manner to that described in Example 5, the title compound of melting point 226-228 ° C. is obtained from the compound of Example 6 in 89% yield.
• the starting material used above can be obtained as follows:
• the title compound of mp 322-325 ° C. is obtained in 61% yield by reducing the from ⁇ 3,10-dichlorotetracyclo [6.6.2.0 2 ' 7 .0 9 ' 14 ] hexadeca -2 (7), 3,5,9 (14), 10,12-hexaen-15-yl ⁇ carbonyl chloride (Tetrahedron 28, 1435 (1972)) and 4-aminopyridine available carbonylamino compound.
• Example 13 In an analogous manner to that described in Example 9, the title compound is obtained as an amorphous solid in 40% yield by reducing the from ⁇ 3,10-dichlorotetracyclo [6.6.2.0 2 ' 7 .0 9.14 ] hexadeca-2 (7) , 3,5,9 (14), 10,12-hexaen-15-yl ⁇ carbonyl chloride and piperidine available carbonylamino compound.
• Example 13
• the title compound is obtained as an oil in 28% yield by reducing the from ⁇ 3,10-dichlorotetracyclo [6.6.2.0 2 ' 7 .0 9 14 ] - hexadeca-2 (7), 3, 5, 9 (14), 10, 12-hexaen-15-yl ⁇ carbonyl chloride and pyrrolidine available carbonylamino compound.
• Example 19 In an analogous manner to that described in Example 17, the title compound of mp 254-256 ° C. is obtained from the compound of Example 12 and methyl iodide in 43% yield.
• Example 19 In an analogous manner to that described in Example 17, the title compound of mp 254-256 ° C. is obtained from the compound of Example 12 and methyl iodide in 43% yield.
• Example 20 In an analogous manner as described in Example 20 is obtained from ⁇ tetracyclo [6.6.2.0 2 '7 .0 9-14] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15 -yl-methyl ⁇ amine with 57% of theory the title compound of mp. 160 - 162 ° C.
• Example 28 As a representative compound of the present application, the compound of Example 28 was tested in the PLA 2 enzyme assay and in animal experiments.
• the compound of Example 28 showed in the PLA 2 enzyme assay an inhibition of the cytosolic PLA 2 enzyme activity, but no inhibition of the secretory PLA 2 activity.

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