CA2304879A1 - New tetracycles, process for their production and pharmaceutical preparations containing these compounds - Google Patents
New tetracycles, process for their production and pharmaceutical preparations containing these compounds Download PDFInfo
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- CA2304879A1 CA2304879A1 CA002304879A CA2304879A CA2304879A1 CA 2304879 A1 CA2304879 A1 CA 2304879A1 CA 002304879 A CA002304879 A CA 002304879A CA 2304879 A CA2304879 A CA 2304879A CA 2304879 A1 CA2304879 A1 CA 2304879A1
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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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- C07C211/26—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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- 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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- 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
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- 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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- 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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- 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
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- 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
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- 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
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- 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
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- C07C2603/86—Ring systems containing bridged rings containing four rings
- C07C2603/88—Ethanoanthracenes; Hydrogenated ethanoanthracenes
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Abstract
The invention relates to tetracyclo[6.6.2.02,7.09,14]hexadeca-2(7),3,5,9(14),10,12-hexaene derivatives of general formula (I), wherein R1 and R2 are hydrogen or a halogen atom and are the same or different, X is hydrogen and Y is a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group CH2-NR5, and Z represents a -CH2-group or a C=NH-group.
Description
New tetracycles, process for their production and pharmaceutical preparations containing these compounds The present invention concerns new tetracycles, a process for their production and pharmaceutical preparations containing these compounds.
The invention concerns tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaene derivatives of the general formula I
(I), in which R1 and R2 are the same or different and denote hydrogen or a halogen atom, X denotes hydrogen and Y denotes a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group ~CH2-NR5 and Z represents a~CH2 group or a~C=NH group in which R3 denotes hydrogen, a lower alkyl group and R4 denotes hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or R3 and R4 together with the nitrogen atom to which they are bound, form a heterocyclic ring which can be optionally broken by a further heteroatom and which can be optionally substituted once or several times, R5 represents hydrogen, an amidino group or a heterocyc1e which is optionally broken by one or several heteroatoms, provided that if R1 and R2 simultaneously denote hydrogen (a) R4 does not denote a lower alkyl group or (b) R5 does not denote hydrogen or (c) R3 and R4 together do not form an unsubstituted piperidine ring or morpholine ring as well as physiologically tolerated salts, esters, optically active forms and racemates thereof as well as derivatives which can be metabolized in vivo to form compounds of the general formula I as well as the use of these compounds to produce pharmaceutical preparations.
The compounds of formula I have valuable pharmacological properties and 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 for example rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respiratory diseases, septic shock, allergic shock, serum disease, auto immune diseases, graft-versus-host reactions, host-versus-graft-diseases, ischaemic or thrombotic diseases such as coronary infarction or cerebral infarction.
Some of the compounds of formula I with pharmacological activity have already been made known. The Dutch application 6 412 205 CChem. Abstr. 63, 14787) describes 11-aminomethyl-9,10-dihydro-9,10-ethanoanthracenes with antiemetic and anaesthetic action. Corresponding substances are published in J. Med. Chem. 10, 86 (1967) with anticholinergic, hypotensive, antihistaminic and local anaesthetic action. However, an anti-inflammatory action and in particular an inhibition of phospholipases has not been previously described.
If not stated otherwise, lower alkyl in the residues R3, R4 and as a substituent denotes alone or in combination with aryl or amino, a straight-chained or branched alkyl chain with 1 to 6 carbon atoms.
Preferred residues are a methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, tert.-butyl, n-pentyl or 3-pentyl residue.
Aryl is understood as a phenyl or naphthyl residue which can be optionally substituted by halogen or lower alkyl.
The phenyl residue is preferred.
Halogen is understood as fluorine, chlorine, bromine or iodine, preferably chlorine.
The invention concerns tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaene derivatives of the general formula I
(I), in which R1 and R2 are the same or different and denote hydrogen or a halogen atom, X denotes hydrogen and Y denotes a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group ~CH2-NR5 and Z represents a~CH2 group or a~C=NH group in which R3 denotes hydrogen, a lower alkyl group and R4 denotes hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or R3 and R4 together with the nitrogen atom to which they are bound, form a heterocyclic ring which can be optionally broken by a further heteroatom and which can be optionally substituted once or several times, R5 represents hydrogen, an amidino group or a heterocyc1e which is optionally broken by one or several heteroatoms, provided that if R1 and R2 simultaneously denote hydrogen (a) R4 does not denote a lower alkyl group or (b) R5 does not denote hydrogen or (c) R3 and R4 together do not form an unsubstituted piperidine ring or morpholine ring as well as physiologically tolerated salts, esters, optically active forms and racemates thereof as well as derivatives which can be metabolized in vivo to form compounds of the general formula I as well as the use of these compounds to produce pharmaceutical preparations.
The compounds of formula I have valuable pharmacological properties and 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 for example rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respiratory diseases, septic shock, allergic shock, serum disease, auto immune diseases, graft-versus-host reactions, host-versus-graft-diseases, ischaemic or thrombotic diseases such as coronary infarction or cerebral infarction.
Some of the compounds of formula I with pharmacological activity have already been made known. The Dutch application 6 412 205 CChem. Abstr. 63, 14787) describes 11-aminomethyl-9,10-dihydro-9,10-ethanoanthracenes with antiemetic and anaesthetic action. Corresponding substances are published in J. Med. Chem. 10, 86 (1967) with anticholinergic, hypotensive, antihistaminic and local anaesthetic action. However, an anti-inflammatory action and in particular an inhibition of phospholipases has not been previously described.
If not stated otherwise, lower alkyl in the residues R3, R4 and as a substituent denotes alone or in combination with aryl or amino, a straight-chained or branched alkyl chain with 1 to 6 carbon atoms.
Preferred residues are a methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, tert.-butyl, n-pentyl or 3-pentyl residue.
Aryl is understood as a phenyl or naphthyl residue which can be optionally substituted by halogen or lower alkyl.
The phenyl residue is preferred.
Halogen is understood as fluorine, chlorine, bromine or iodine, preferably chlorine.
The heteroatoms mentioned for the residues R3 and R4 and R5 are understood as N, O, S and preferably N or O.
N-aralkylheteroaryl is understood as an aralkyl residue bound via the N-atom to the heterocyc1e.
The heteroaryl groups specified for R4 are understood as a pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl or piperazinyl residue. A pyridinyl, piperidinyl or imidazolinyl residue is preferred, in particular a 3-pyridinyl or 4-pyridinyl or 3-piperidinyl or 4-piperidinyl or 4,5-dihydro-imidazol-2y1 residue.
The heterocyclic ring systems mentioned for R3 and R4 together with the N-atom to which they are bound are understood as a pyrrolidine, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, piperidine, piperazine or morpholine ring. A
pyrrolidine, morpholine or piperidine residue are preferred.
Substitutents of the heterocyclic ring system which can be formed by R3 and R4 together are, in addition to common substitutents, preferably benzamido, benzylamino, amino, monoalkylamino or dialkylamino. A single substitution in the 4 position is preferred.
Heterocyc1e in the case of the residue R5 denotes pyrimidine, pyridazine, pyrazole, pyrazine, imidazole, indazole or purine. However, the imidazole residue is particularly preferred.
Particularly preferred residues for R1 and R2 are hydrogen and chlorine. A particularly preferred residue for R3 is hydrogen or methyl, R4 particularly preferably denotes carbamoyl, amidino, N-benzylaminopyridine, piperidine, pyridine, methyl, hydroxy or imidazolyl. R3 and R4 together particularly preferably denote 4-benzamidinopiperidine, 4-benzyl-aminopiperidine, 4-aminopiperidine, 4-dimethylaminopiperidine, pyrrolidine, piperidine or morpholine. R5 particularly preferably denotes hydrogen, imidazole or amidino.
In addition to the compounds mentioned in the examples, the invention concerns in particular all substances which have any possible combination of the substituents mentioned in the examples.
The compounds of formula I are produced by known methods as described in the literature (e. g. in standard works such as Houben-Weyl, "Methoden der Organischen Chemie, Georg Thime Verlag", Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York) and in the literature references cited in the examples and namely under reaction conditions that are known and suitable for the said reactions. One can also use known variants that are not mentioned here in detail. Furthermore a compound of formula I can be converted by known methods into another compound of formula I.
The process according to the invention for the production of compounds of formula I is characterized in that, in a known manner, a compound of the general formula I in which a) R1, R2, X, Y and Z have~~he stated meaning and R4 or R5 represent hydrogen, is converted by reaction with an activated carbonic acid derivative or with an agent transferring the imidazoline group into a compound of formula I in which R4 or R5 denote carbamoyl, amidino or imidazolinyl, or b) R1 and R2 have the stated meaning, X denotes hydrogen, Y represents hydrogen or a nucleofuge group and Z represents a carbonyl group, is converted by reaction with a primary or secondary amine and subsequent reduction into a compound of formula I in which Z represents a CH2 group and Y represents NR3R4 or c) R1 and R2 have the stated meaning, X denotes hydrogen, Z represents a cyano group and Y is absent, is reacted with hydroxylamine or a derivative thereof to form a compound of formula I in which Z denotes a ;C=NH group and R4 denotes hydroxyl or d) R1 and R2 have the stated meaning and X-Y-Z
represents a group CO-NH-CO, is converted by reduction into a compound of formula I in which X-Y-Z denotes a group CH2-NH-CH2 and subsequently, if desired, a carbonyl group is reduced to a CH2 group, an arylmethyl group is cleaved off or a tertiary nitrogen atom is quarternized by alkylation and optionally a base is converted into a pharmacologically acceptable salt or the free compound is produced from a salt.
., Compounds of formula I can occur as enantiomers and as racemates. The invention concerns the pure enantiomers as well as racemic mixtures.
Inorganic isocyanates and isourea derivatives which carry a nucleofuge group come into consideration as activated carbonic acid derivatives.
The agents transferring an imidazoline group are for example 1H-imidazolines which carry a nucleofuge 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 aluminium hydride are preferably used as reducing agents.
Compounds of the general formula I can contain one or several chiral centres and can then be present in a racemic or in an optically active form. The optical isomers can be resolved into enantiomers by well-known methods. Wherever appropriate the described methods refer to the resolution of final stages and/or precursors. Either diastereomeric salts are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or an optically active amine such as e.g. D- or L-a-phenyl-ehtylamine, ephedrine, qui~idine or cinchonidine which can be separated by crystallization, or the optical isomers are separated by HPLC. Another method of _ g separating optical isomers is an enzymatic separation during the synthesis.
Suitable pharmacologically acceptable salts are in particular salts with non-toxic inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, benzoic acid, salicylic acid, malonic acid, malefic acid, succinic acid or diaminocaproic acid as well as optionally alkaline salts, alkaline earth salts and ammonium salts.
The salts are obtained in the usual manner e.g. by neutralizing the compounds of formula I with the appropriate acids or lyes. They are usually purified by reprecipitation from water/acetone.
In order to produce pharmaceutical preparations the compounds of the general formula I are mixed in a known manner with suitable pharmaceutical carrier substances, aroma substances, flavourings and dyes and for example formed into tablets or dragees or suspended or dissolved in water or oil e.g. olive oil with the addition of appropriate auxiliary substances.
The substances of the general formula I can be administered orally or parenterally in a liquid or solid form. Water is preferably used as an injection medium which contains the usual stabilizers, solubilizers and/or buffers for injection solutions. Such additives are for example tartrate or borate buffer, ethanol, dimethylsulfoxide, complexing agents (such as ethylene diaminetetraacetic acid), high molecular polymers (such as liquid polyethylene oxide) to regulate viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier substances are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular polymers (such as polyethylene glycols).
Suitable preparations for oral application can if desired contain flavourings and sweeteners. For an external application the substances I according to the invention can also be used in the.form of powders and ointments. For this they are for example mixed with physiologically tolerated diluent powders or common ointment bases.
The administered dose 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 desired effect. The daily dose of the active compound is usually 0.1 to 50 mg/kg body weight.
Normally 0.5 to 40 and preferably 1.0 to 20 mg/kg/day in one or several applications are effective in order to obtain the desired results.
In addition to the substances mentioned in the examples, the following compounds are preferred within the sense of the invention:
1-{3,10-Dichloro-tetracyclo[6.6.2.02~~.0~~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-amino-piperidine hydrochloride ., 1-benzyl-4-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09~14J_ hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl-amino}-piperidine hydrochloride 4-~3,10-Dichloro-tetracyclo[6.6.2.02-~.09~14Jhexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl-amino}-piperidine hydrochloride 1' -Tetracyclo [ 6 . 6 . 2 . 02 - 7 . O9-14 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , -10,12-hexaen-15-yl-methyl}-1,4'-bipiperidine 1'-~3,10-Dichloro-tetracyclo[6.6.2.02~~.0g~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-1,4'-bipiperidine The following examples illustrate the invention without, however, limiting it thereto.
Example i N-~Tetracyclo [ 6 . 6 . 2 . OZ- ~ . O9-14 ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-urea 1.21 g (15 mmol) potassium cyanate is added to a solution of 2.85 g (10 mmol) {tetracyclo[6.6.2.02-~.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15 yl-methyl}-amine hydrochloride (J. Org. Chem. 42, 1131 (1977)) in 200 ml hot water and heated to reflux for 1 h. After cooling 2.4 g (86 ~ of theory) of the title compound with a melting point of 182 - 184°C is isolated by filtration.
Example 2 N-{Tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine A mixture of 3.8 g (16.4 mmol) {tetracyclo[6.6.2.02~~.09~14]-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine and 3.1 g (18 mmol) S-methyl-isothiourea hydrobromide in 30 ml n-propanol is heated for 5 h to reflux under nitrogen, cooled, admixed with diethyl ether, extracted with water, the extract is alkalinized, extracted with ethyl acetate and the organic phase is dried, concentrated by evaporation and triturated with diethyl ether. 2.0 g (44 % of theory) of the title compound with a melting point of 128-130°C is isolated.
Example 3 1-{Tetracyclo[6.6.2.02-~.0914]hexadeca-2(7),3,5,9(14),10,12-hexaen-15 yl-methyl}-4-benzamido-piperidine A mixture of 4.8 g (20 mmol) {tetracyclo[6.6.2.02-~.09-14~-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbaldehyde (Bull. Soc. Chim. France 1964, 550), 4.0 g (20 mmol) 4-benzamido-piperidine, 100 ml toluene and 0.2 g p-toluene-sulfonic acid is heated for 2 h under reflux on a water separator. Subsequently it is concentrated, taken up in 100 ml methanol, 0.96 g sodium borohydr.ide is introduced twice and each time it is heated for 1 h to reflux. It is concentrated, the residue is taken up in ethyl acetate, washed with water, the organic phase is dried and chromatographed on silica c~el. 5.8 g (69 % of theory) of the title compound with a melting point of 168 - 170°C is eluted with isohexane/ethyl acetate 3:1.
Euample 4 1-{Tetracyclo[6.6.2.02~~.0914]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-benzylamino-piperidine hydrochloride A solution of 5.4 g (12.8 mmol) of the compound of example 3 in 50 ml tetrahydrofuran is added dropwise to a suspension of 1.5 g lithium aluminium hydride in 100 ml tetrahydrofuran, it is subsequently heated for 3 h to reflux, admixed with sodium chloride solution, filtered and the filtrate is dried and concentrated. After adding excess ethereal hydrogen chloride solution to the methanolic solution, 5.1 g (98 % of theory) of the title compound is isolated as a crude product.
Example 5 1-{Tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . 09- la ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl-methyl}-4-amino-piperidine hydrochloride 5.0 g (12.3 mmol) of the compound of example 4 is hydrogenated in 50 ml methanol over 1 g l0 % palladium carbon at 50°C and 1 bar hydrogen pressure. It is filtered, concentrated and chromatographed on silica gel. 2.9 g of the target compound is eluted with ethyl acetate/methanol 1:1. After trituration with acetone, 2.3 g (60 % of theory) of the title compound with a melting point of 225 - 230°C
remains.
EBample 6 1-Benzyl-4-{tetracyclo[6.6.2.02-x.09.14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-piperidine hydrochloride The title compound is obtained as a crude product in 80 %
yield in an analogous manner to example 3 from { tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . 09.14 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12 hexaen-15-yl}-carbaldehyde and 4-amino-1-benzyl-piperidine.
Example 7 4-{Tetracyclo[6.6.2.02~~.09~1q]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-piperidine hydrochloride The title compound with a melting point of 226 - 228°C is obtained in an 89 % yield in an analogous manner to that described example 5.
Euample 8 1-{Tetracyclo[6.6.2.02-~.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-dimethylamino-piperidine hydrochloride The title compound is obtained in a 65 % yield as an amorphous solid in an analogous manner to that described in example 3 from {tetracyclo[6.6.2.02-7.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbaldehyde and 4-dimethylamino-piperidine.
Example 9 4-{Tetracyclo[6.6.2.0z~~.O9-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino]-pyridine The title compound is obtained in an analogous manner to that described in example 4 in a yield of 71 % of theory with a melting point of 164 - 166°C by reduction of 4-{tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-carbonylamino}-pyridine and subsequent trituration with diethyl ether.
The starting material used above can be obtained as follows:
A mixture of 5.4 g (20 mmol) {tetracyclo[6.6.2.02-7.09'14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride) (J. Am. Chem. Soc. 94, 1193 (1972)) and 4.7 g (50 mmol) 4-aminopyridine in 50 ml tetrahydrofuran is stirred for 1 h at room temperature and 2 h under reflux, it is subsequently filtered and the filtrate is chromatographed on silica gel. After elution with ethyl acetate, one obtains 2.5 g {tetracyclo-[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-carbonylamino}-pyridine (38 % of theory) with a melting point of 217-219°C.
Example 10 4-{3,10-Dichloro-tetracyclo[6.6.2.02-7.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-pyridine The title compound with a melting point of 322 - 325°C is obtained in a 61 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound that can be obtained from {3,10-dichloro-tetracyc lo- [ 6 . 6 . 2 . 02 ~ ~ . 09 ~ 1 ~ ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12 -hexaen-15-yl}-carbonyl chloride (Tetrahedron 28, 1435 (1972)) and 4-amino-pyridine.
Example 11 {3,10-Dichloro-tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-dimethylamine The title compound with a melting point of 88 - 90°C is obtained in a 64 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound that can be obtained from {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . O9-1q ] -hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl}-carbonyl chloride and dimethylamine.
Example 12 N-{3,10-Dichloro-tetracyclo[6.6.2.02-~.O9~lq]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-piperidine The title compound is obtained as an amorphous solid in a 40 % yield in an analogous manner to that described in example 9 by reducing a carbonylamino compound obtainable from {3,10-dichloro-tetracyclo[6.6.2.02-x.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride and piperidine.
Example 13 N-{6,13-Dichloro-tetracyclo[6.6.2.02-~.09~19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-piperidine The title compound is eluted as an amorphous by-product in a 15 % yield during the chromatographic purification of the previous compound.
Example 14 N-{6,13-Dichloro-tetracyclo[6.6.2.02-7.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-pyrrolidine The title compound is obtained as an oil in a 28 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from {3,10, dichloro-tetracyclo [ 6. 6. 2 . 02-~ . 09~ 19 ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride and pyrrolidine.
Example 15 N-~3,10-Dichloro-tetracyclo[6.6.2.02-7.09-i4]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-morpholine The title compound with a melting point of 175 - 177°C is obtained in a 41 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . O9~ 14 ] ~exadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl}-carbonyl chloride and morpholine.
Example 15 N-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-morpholine The title compound with a melting point 175 -177°C is obtained in a 41 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from X3,10-dichloro-tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride and morpholine.
Example 16 1-{3,10-Dichloro-tetracyclo[6.6.2.0z-~.09~19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-dimethyl-amino-piperidine hydrochloride The title compound with a melting point of 295°C (decomp.) is obtained in a 70 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from X3,10-dichloro-tetracyclo-6 . 6 . 2 . 02 ~ ~ . O9- 14 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12 -hexaen-15-yl}-carbonyl chloride and 4-dimethylamino-piperidine and subsequent precipitation of the hydrochloride.
Example 17 ~ 3 ,10-Dichloro-tetracyclo [ 6 . 6 . 2 . 02- ~ . O9~ 1 ~ ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-trimethylammonium iodide , A mixture of 0.5 g (1.5 mmol) of the compound of example 11, 10 ml acetone and 0.47 ml {7.5 mmol) methyl iodide is stirred for 8 h at room temperature and the precipitate is subsequently removed by filtration. 0.5 g (70 % of theory) of the title compound with a melting point of 172 - 175°c remains.
Euample 18 N-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-N-methyl-piperidinium iodide The title compound with a melting point of 254 - 256°C is obtained in a 43 % yield in an analogous manner to that described in example 17 from the compound of example 12 and methyl iodide.
Euample 19 N-Hydroxy-{3,10-dichloro-tetracyclo[6.6.2.02~~.09~14]-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carboximidamide A mixture of 8.25 g (25 mmol) {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 - ~ . O9-19 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl}-carbonitrile (Tetrahedron 28, 1435 (1972)), 5.3 g sodium carbonate, 7.0 g hydroxylamine hydrochloride, 100 ml ethanol and 25 ml water is refluxed for 20 h. It is filtered and the precipitate is chromatographed on silica gel. 0.75 g (9 % of theory) of the title compound with a melting point of 203 - 205°C is isolated with ethyl acetate.
The isomeric N-hydroxy-{6,13-dichloro-tetracyclo-[6.6.2.02-~.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carboximidamide can be detected as a by-product.
Euample 20 2-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-4,5-dihydro-1H-imidazole A mixture of 4.55 g (15 mmol) {3,10-dichloro-tetracyclo[6.6.2.02-7.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine, which is prepared from the nitrile used in example 19 by reduction with lithium aluminium hydride, and 3.36 g (17 mmol) 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrobromide is heated at 15 mbar for 30 min to 160°C and for 10 min to 180°C. After cooling, acetone is added, it is filtered and the precipitate is recrystallized from ethanol. 5.0 g (73 % of theory) of the title compound with a melting point of 194 - 195°C is isolated.
Example 21 2-{Tetracyclo [ 6 . 6 . 2 . OZ ~ ~ . O9~ 14 ] hexadeca-2 ( 7 ) , 3 , 5, 9 ( 14 ) , 10, 12-hexaen-15-yl-methylamino}-4,5-dihydro-1H-imidazole The title compound with a melting point of 160 - 162°C is obtained (57 % of theory) in an analogous manner to that described in example 20 from {tetracyclo[6.6.2.02~~.09-14]-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine.
Example 22 N-{3,10-Dichloro-tetracyclo[6.6.2.02-x.09-14]hexadeca 2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine The title compound with a melting point of 211 - 213°C
is obtained in a 58 % yield in an analogous manner to that described in example 2 from {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 - ~ . 09 ~ i4 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , -10,12-hexaen-15-yl-methyl}-amine.
Example 23 2-{6,10-Dichloro-tetracyclo[6.6.2.02~~.0~~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-4,5-dihydro-1H-imidazole hydrobromide The title compound with a melting point of 155 - 158°C
(decomp.) is obtained in a yield of 28 % of theory in an analogous manner to that described in example 20 from {6,10-dichloro-tetracyclo[6.6.2.02~~.09-1~]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine that is obtainable by reduction of the corresponding nitrile.
Example 24 N-{6,10-Dichloro-tetracyclo[6.6.2.02-~.0~~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine hydrobromide The title compound with a melting point of 93 - 95°C
(decomp.) is obtained in a yield of 24 % of theory in an analogous manner to that described in example 2 from {6,10-dichloro-tetracyclo[6.6.2.02-~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine.
Example 25 N-{ 6-Chloro-tetracyclo [ 6 . 6 . 2 . 02- ~ . O9~ 14 ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine hydrobromide The title compound with a melting point of 151 - 153°C
(decomp.) is obtained in a yield of 32 % of theory in an analogous manner to that described in example 22 from {6-chloro-tetracyclo[6.6.2.02~~.09-19]hexadeca-2(7),3,5,9(14),-10,12-hexaene-15-yl-methyl}-amine.
EBample 26 5,10-Dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindole A solution of 23.0 g (67 mmol) 5, I0-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-Benz[f]isoindole-1,3-divne in 290 ml tetrahydrofuran is added dropwise to a suspension of 5.1 g (134 mmol) lithium aluminium hydride in 45 ml diethyl ether, it is subsequently refluxed for 8 h, admixed with sodium chloride solution, the organic phase is concentrated and the residue is purified by conversion into hydrochloride and subsequent release of the base. 11.0 g (52 % of theory) of the title compound with a melting point of 126 - 130°C is isolated.
The 5,10-dichloro-3a,4,9,9a=tetrahydro-4,9-o-benzeno-benz-[f]isoindole-1,3-dione used as a starting substance can be obtained as follows:
83 g (0.24 mol) 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isobenzofuran-1,3-dione (Bull. Soc.
Chim. France 1973, 190) is introduced into a mixture of 370 ml chloroform and 370 ml liquefied ammonia, it is stirred for a further 3 h, filtered, the precipitate is taken up in a large amount of water, heated to boiling point, filtered and the filtrate is acidified. 77 g (88 % of theory) 3,10-dichloro-tetracyclo[6.6.2.02-x.09~19]_ hexadeca-2(7),3,5,9(14),10,12-hexaen-15,16-dicarboxylic acid monoamide with a melting point of 274 - 276°C
precipitates.
27.5 g of the previously described amide in 400 ml xylene is refluxed for 30 min on a water separator. The precipitate that forms on cooling is removed by filtration and washed with diethyl ether. 23.5 g (90 %
of theory) 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-0-benzeno-benz[f]isoindole-1,3-dione with a melting point of 279 - 281°C is obtained.
Example 27 5,10-Dichloro-2-(4,5-dihydro-1H-imidazol-2-yl)-3a,4,9,9a-tetrahydro-4,9-o-benzeno-Benz[f] isoindole The title compound with a melting point of 325 - 326°C
is obtained in a 41 % yield in an analogous manner to that described in example 20 from 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindole and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrobromide.
, Example 28 5,10-Dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindol-2-yl-carboximidamide The title compound in with a melting point of 236 -238°C is obtained a 27 % yield in an analogous manner to that described in example 2 from 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindole and S-methyl-isothiourea hydrobromide.
Example 29 Enzyme Assay and Pharmakological Tests As a representative compound of this application, the compound of Example 28 was tested in the PLA2-enzyme assay and in the animal experiment.
1. In the PLA,-enzyme assay, the compound of Example 28 showed an inhibition of the cytosolical PLAz-enzyme activity, but no inhibition of the secretorial PLA~-activity.
2. In the animal experiment (rats), the compound of Example 28, administered i.p., showed an inhibition of the acute inflammatory carrageenin edema (EDso -16 mg/kg) as well as an inhibition of the generalized adjuvans arthritis.
N-aralkylheteroaryl is understood as an aralkyl residue bound via the N-atom to the heterocyc1e.
The heteroaryl groups specified for R4 are understood as a pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl or piperazinyl residue. A pyridinyl, piperidinyl or imidazolinyl residue is preferred, in particular a 3-pyridinyl or 4-pyridinyl or 3-piperidinyl or 4-piperidinyl or 4,5-dihydro-imidazol-2y1 residue.
The heterocyclic ring systems mentioned for R3 and R4 together with the N-atom to which they are bound are understood as a pyrrolidine, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, piperidine, piperazine or morpholine ring. A
pyrrolidine, morpholine or piperidine residue are preferred.
Substitutents of the heterocyclic ring system which can be formed by R3 and R4 together are, in addition to common substitutents, preferably benzamido, benzylamino, amino, monoalkylamino or dialkylamino. A single substitution in the 4 position is preferred.
Heterocyc1e in the case of the residue R5 denotes pyrimidine, pyridazine, pyrazole, pyrazine, imidazole, indazole or purine. However, the imidazole residue is particularly preferred.
Particularly preferred residues for R1 and R2 are hydrogen and chlorine. A particularly preferred residue for R3 is hydrogen or methyl, R4 particularly preferably denotes carbamoyl, amidino, N-benzylaminopyridine, piperidine, pyridine, methyl, hydroxy or imidazolyl. R3 and R4 together particularly preferably denote 4-benzamidinopiperidine, 4-benzyl-aminopiperidine, 4-aminopiperidine, 4-dimethylaminopiperidine, pyrrolidine, piperidine or morpholine. R5 particularly preferably denotes hydrogen, imidazole or amidino.
In addition to the compounds mentioned in the examples, the invention concerns in particular all substances which have any possible combination of the substituents mentioned in the examples.
The compounds of formula I are produced by known methods as described in the literature (e. g. in standard works such as Houben-Weyl, "Methoden der Organischen Chemie, Georg Thime Verlag", Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York) and in the literature references cited in the examples and namely under reaction conditions that are known and suitable for the said reactions. One can also use known variants that are not mentioned here in detail. Furthermore a compound of formula I can be converted by known methods into another compound of formula I.
The process according to the invention for the production of compounds of formula I is characterized in that, in a known manner, a compound of the general formula I in which a) R1, R2, X, Y and Z have~~he stated meaning and R4 or R5 represent hydrogen, is converted by reaction with an activated carbonic acid derivative or with an agent transferring the imidazoline group into a compound of formula I in which R4 or R5 denote carbamoyl, amidino or imidazolinyl, or b) R1 and R2 have the stated meaning, X denotes hydrogen, Y represents hydrogen or a nucleofuge group and Z represents a carbonyl group, is converted by reaction with a primary or secondary amine and subsequent reduction into a compound of formula I in which Z represents a CH2 group and Y represents NR3R4 or c) R1 and R2 have the stated meaning, X denotes hydrogen, Z represents a cyano group and Y is absent, is reacted with hydroxylamine or a derivative thereof to form a compound of formula I in which Z denotes a ;C=NH group and R4 denotes hydroxyl or d) R1 and R2 have the stated meaning and X-Y-Z
represents a group CO-NH-CO, is converted by reduction into a compound of formula I in which X-Y-Z denotes a group CH2-NH-CH2 and subsequently, if desired, a carbonyl group is reduced to a CH2 group, an arylmethyl group is cleaved off or a tertiary nitrogen atom is quarternized by alkylation and optionally a base is converted into a pharmacologically acceptable salt or the free compound is produced from a salt.
., Compounds of formula I can occur as enantiomers and as racemates. The invention concerns the pure enantiomers as well as racemic mixtures.
Inorganic isocyanates and isourea derivatives which carry a nucleofuge group come into consideration as activated carbonic acid derivatives.
The agents transferring an imidazoline group are for example 1H-imidazolines which carry a nucleofuge 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 aluminium hydride are preferably used as reducing agents.
Compounds of the general formula I can contain one or several chiral centres and can then be present in a racemic or in an optically active form. The optical isomers can be resolved into enantiomers by well-known methods. Wherever appropriate the described methods refer to the resolution of final stages and/or precursors. Either diastereomeric salts are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or an optically active amine such as e.g. D- or L-a-phenyl-ehtylamine, ephedrine, qui~idine or cinchonidine which can be separated by crystallization, or the optical isomers are separated by HPLC. Another method of _ g separating optical isomers is an enzymatic separation during the synthesis.
Suitable pharmacologically acceptable salts are in particular salts with non-toxic inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, benzoic acid, salicylic acid, malonic acid, malefic acid, succinic acid or diaminocaproic acid as well as optionally alkaline salts, alkaline earth salts and ammonium salts.
The salts are obtained in the usual manner e.g. by neutralizing the compounds of formula I with the appropriate acids or lyes. They are usually purified by reprecipitation from water/acetone.
In order to produce pharmaceutical preparations the compounds of the general formula I are mixed in a known manner with suitable pharmaceutical carrier substances, aroma substances, flavourings and dyes and for example formed into tablets or dragees or suspended or dissolved in water or oil e.g. olive oil with the addition of appropriate auxiliary substances.
The substances of the general formula I can be administered orally or parenterally in a liquid or solid form. Water is preferably used as an injection medium which contains the usual stabilizers, solubilizers and/or buffers for injection solutions. Such additives are for example tartrate or borate buffer, ethanol, dimethylsulfoxide, complexing agents (such as ethylene diaminetetraacetic acid), high molecular polymers (such as liquid polyethylene oxide) to regulate viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier substances are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular polymers (such as polyethylene glycols).
Suitable preparations for oral application can if desired contain flavourings and sweeteners. For an external application the substances I according to the invention can also be used in the.form of powders and ointments. For this they are for example mixed with physiologically tolerated diluent powders or common ointment bases.
The administered dose 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 desired effect. The daily dose of the active compound is usually 0.1 to 50 mg/kg body weight.
Normally 0.5 to 40 and preferably 1.0 to 20 mg/kg/day in one or several applications are effective in order to obtain the desired results.
In addition to the substances mentioned in the examples, the following compounds are preferred within the sense of the invention:
1-{3,10-Dichloro-tetracyclo[6.6.2.02~~.0~~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-amino-piperidine hydrochloride ., 1-benzyl-4-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09~14J_ hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl-amino}-piperidine hydrochloride 4-~3,10-Dichloro-tetracyclo[6.6.2.02-~.09~14Jhexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl-amino}-piperidine hydrochloride 1' -Tetracyclo [ 6 . 6 . 2 . 02 - 7 . O9-14 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , -10,12-hexaen-15-yl-methyl}-1,4'-bipiperidine 1'-~3,10-Dichloro-tetracyclo[6.6.2.02~~.0g~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-1,4'-bipiperidine The following examples illustrate the invention without, however, limiting it thereto.
Example i N-~Tetracyclo [ 6 . 6 . 2 . OZ- ~ . O9-14 ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-urea 1.21 g (15 mmol) potassium cyanate is added to a solution of 2.85 g (10 mmol) {tetracyclo[6.6.2.02-~.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15 yl-methyl}-amine hydrochloride (J. Org. Chem. 42, 1131 (1977)) in 200 ml hot water and heated to reflux for 1 h. After cooling 2.4 g (86 ~ of theory) of the title compound with a melting point of 182 - 184°C is isolated by filtration.
Example 2 N-{Tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine A mixture of 3.8 g (16.4 mmol) {tetracyclo[6.6.2.02~~.09~14]-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine and 3.1 g (18 mmol) S-methyl-isothiourea hydrobromide in 30 ml n-propanol is heated for 5 h to reflux under nitrogen, cooled, admixed with diethyl ether, extracted with water, the extract is alkalinized, extracted with ethyl acetate and the organic phase is dried, concentrated by evaporation and triturated with diethyl ether. 2.0 g (44 % of theory) of the title compound with a melting point of 128-130°C is isolated.
Example 3 1-{Tetracyclo[6.6.2.02-~.0914]hexadeca-2(7),3,5,9(14),10,12-hexaen-15 yl-methyl}-4-benzamido-piperidine A mixture of 4.8 g (20 mmol) {tetracyclo[6.6.2.02-~.09-14~-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbaldehyde (Bull. Soc. Chim. France 1964, 550), 4.0 g (20 mmol) 4-benzamido-piperidine, 100 ml toluene and 0.2 g p-toluene-sulfonic acid is heated for 2 h under reflux on a water separator. Subsequently it is concentrated, taken up in 100 ml methanol, 0.96 g sodium borohydr.ide is introduced twice and each time it is heated for 1 h to reflux. It is concentrated, the residue is taken up in ethyl acetate, washed with water, the organic phase is dried and chromatographed on silica c~el. 5.8 g (69 % of theory) of the title compound with a melting point of 168 - 170°C is eluted with isohexane/ethyl acetate 3:1.
Euample 4 1-{Tetracyclo[6.6.2.02~~.0914]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-benzylamino-piperidine hydrochloride A solution of 5.4 g (12.8 mmol) of the compound of example 3 in 50 ml tetrahydrofuran is added dropwise to a suspension of 1.5 g lithium aluminium hydride in 100 ml tetrahydrofuran, it is subsequently heated for 3 h to reflux, admixed with sodium chloride solution, filtered and the filtrate is dried and concentrated. After adding excess ethereal hydrogen chloride solution to the methanolic solution, 5.1 g (98 % of theory) of the title compound is isolated as a crude product.
Example 5 1-{Tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . 09- la ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl-methyl}-4-amino-piperidine hydrochloride 5.0 g (12.3 mmol) of the compound of example 4 is hydrogenated in 50 ml methanol over 1 g l0 % palladium carbon at 50°C and 1 bar hydrogen pressure. It is filtered, concentrated and chromatographed on silica gel. 2.9 g of the target compound is eluted with ethyl acetate/methanol 1:1. After trituration with acetone, 2.3 g (60 % of theory) of the title compound with a melting point of 225 - 230°C
remains.
EBample 6 1-Benzyl-4-{tetracyclo[6.6.2.02-x.09.14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-piperidine hydrochloride The title compound is obtained as a crude product in 80 %
yield in an analogous manner to example 3 from { tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . 09.14 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12 hexaen-15-yl}-carbaldehyde and 4-amino-1-benzyl-piperidine.
Example 7 4-{Tetracyclo[6.6.2.02~~.09~1q]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-piperidine hydrochloride The title compound with a melting point of 226 - 228°C is obtained in an 89 % yield in an analogous manner to that described example 5.
Euample 8 1-{Tetracyclo[6.6.2.02-~.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-dimethylamino-piperidine hydrochloride The title compound is obtained in a 65 % yield as an amorphous solid in an analogous manner to that described in example 3 from {tetracyclo[6.6.2.02-7.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbaldehyde and 4-dimethylamino-piperidine.
Example 9 4-{Tetracyclo[6.6.2.0z~~.O9-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino]-pyridine The title compound is obtained in an analogous manner to that described in example 4 in a yield of 71 % of theory with a melting point of 164 - 166°C by reduction of 4-{tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-carbonylamino}-pyridine and subsequent trituration with diethyl ether.
The starting material used above can be obtained as follows:
A mixture of 5.4 g (20 mmol) {tetracyclo[6.6.2.02-7.09'14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride) (J. Am. Chem. Soc. 94, 1193 (1972)) and 4.7 g (50 mmol) 4-aminopyridine in 50 ml tetrahydrofuran is stirred for 1 h at room temperature and 2 h under reflux, it is subsequently filtered and the filtrate is chromatographed on silica gel. After elution with ethyl acetate, one obtains 2.5 g {tetracyclo-[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-carbonylamino}-pyridine (38 % of theory) with a melting point of 217-219°C.
Example 10 4-{3,10-Dichloro-tetracyclo[6.6.2.02-7.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-pyridine The title compound with a melting point of 322 - 325°C is obtained in a 61 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound that can be obtained from {3,10-dichloro-tetracyc lo- [ 6 . 6 . 2 . 02 ~ ~ . 09 ~ 1 ~ ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12 -hexaen-15-yl}-carbonyl chloride (Tetrahedron 28, 1435 (1972)) and 4-amino-pyridine.
Example 11 {3,10-Dichloro-tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-dimethylamine The title compound with a melting point of 88 - 90°C is obtained in a 64 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound that can be obtained from {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . O9-1q ] -hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl}-carbonyl chloride and dimethylamine.
Example 12 N-{3,10-Dichloro-tetracyclo[6.6.2.02-~.O9~lq]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-piperidine The title compound is obtained as an amorphous solid in a 40 % yield in an analogous manner to that described in example 9 by reducing a carbonylamino compound obtainable from {3,10-dichloro-tetracyclo[6.6.2.02-x.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride and piperidine.
Example 13 N-{6,13-Dichloro-tetracyclo[6.6.2.02-~.09~19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-piperidine The title compound is eluted as an amorphous by-product in a 15 % yield during the chromatographic purification of the previous compound.
Example 14 N-{6,13-Dichloro-tetracyclo[6.6.2.02-7.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-pyrrolidine The title compound is obtained as an oil in a 28 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from {3,10, dichloro-tetracyclo [ 6. 6. 2 . 02-~ . 09~ 19 ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride and pyrrolidine.
Example 15 N-~3,10-Dichloro-tetracyclo[6.6.2.02-7.09-i4]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-morpholine The title compound with a melting point of 175 - 177°C is obtained in a 41 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 ~ ~ . O9~ 14 ] ~exadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl}-carbonyl chloride and morpholine.
Example 15 N-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-morpholine The title compound with a melting point 175 -177°C is obtained in a 41 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from X3,10-dichloro-tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carbonyl chloride and morpholine.
Example 16 1-{3,10-Dichloro-tetracyclo[6.6.2.0z-~.09~19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-4-dimethyl-amino-piperidine hydrochloride The title compound with a melting point of 295°C (decomp.) is obtained in a 70 % yield in an analogous manner to that described in example 9 by reducing the carbonylamino compound obtainable from X3,10-dichloro-tetracyclo-6 . 6 . 2 . 02 ~ ~ . O9- 14 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12 -hexaen-15-yl}-carbonyl chloride and 4-dimethylamino-piperidine and subsequent precipitation of the hydrochloride.
Example 17 ~ 3 ,10-Dichloro-tetracyclo [ 6 . 6 . 2 . 02- ~ . O9~ 1 ~ ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-trimethylammonium iodide , A mixture of 0.5 g (1.5 mmol) of the compound of example 11, 10 ml acetone and 0.47 ml {7.5 mmol) methyl iodide is stirred for 8 h at room temperature and the precipitate is subsequently removed by filtration. 0.5 g (70 % of theory) of the title compound with a melting point of 172 - 175°c remains.
Euample 18 N-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-N-methyl-piperidinium iodide The title compound with a melting point of 254 - 256°C is obtained in a 43 % yield in an analogous manner to that described in example 17 from the compound of example 12 and methyl iodide.
Euample 19 N-Hydroxy-{3,10-dichloro-tetracyclo[6.6.2.02~~.09~14]-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carboximidamide A mixture of 8.25 g (25 mmol) {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 - ~ . O9-19 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , 10 , 12-hexaen-15-yl}-carbonitrile (Tetrahedron 28, 1435 (1972)), 5.3 g sodium carbonate, 7.0 g hydroxylamine hydrochloride, 100 ml ethanol and 25 ml water is refluxed for 20 h. It is filtered and the precipitate is chromatographed on silica gel. 0.75 g (9 % of theory) of the title compound with a melting point of 203 - 205°C is isolated with ethyl acetate.
The isomeric N-hydroxy-{6,13-dichloro-tetracyclo-[6.6.2.02-~.09-14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl}-carboximidamide can be detected as a by-product.
Euample 20 2-{3,10-Dichloro-tetracyclo[6.6.2.02~~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-4,5-dihydro-1H-imidazole A mixture of 4.55 g (15 mmol) {3,10-dichloro-tetracyclo[6.6.2.02-7.09-19]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine, which is prepared from the nitrile used in example 19 by reduction with lithium aluminium hydride, and 3.36 g (17 mmol) 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrobromide is heated at 15 mbar for 30 min to 160°C and for 10 min to 180°C. After cooling, acetone is added, it is filtered and the precipitate is recrystallized from ethanol. 5.0 g (73 % of theory) of the title compound with a melting point of 194 - 195°C is isolated.
Example 21 2-{Tetracyclo [ 6 . 6 . 2 . OZ ~ ~ . O9~ 14 ] hexadeca-2 ( 7 ) , 3 , 5, 9 ( 14 ) , 10, 12-hexaen-15-yl-methylamino}-4,5-dihydro-1H-imidazole The title compound with a melting point of 160 - 162°C is obtained (57 % of theory) in an analogous manner to that described in example 20 from {tetracyclo[6.6.2.02~~.09-14]-hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine.
Example 22 N-{3,10-Dichloro-tetracyclo[6.6.2.02-x.09-14]hexadeca 2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine The title compound with a melting point of 211 - 213°C
is obtained in a 58 % yield in an analogous manner to that described in example 2 from {3,10-dichloro-tetracyclo [ 6 . 6 . 2 . 02 - ~ . 09 ~ i4 ] hexadeca-2 ( 7 ) , 3 , 5 , 9 ( 14 ) , -10,12-hexaen-15-yl-methyl}-amine.
Example 23 2-{6,10-Dichloro-tetracyclo[6.6.2.02~~.0~~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methylamino}-4,5-dihydro-1H-imidazole hydrobromide The title compound with a melting point of 155 - 158°C
(decomp.) is obtained in a yield of 28 % of theory in an analogous manner to that described in example 20 from {6,10-dichloro-tetracyclo[6.6.2.02~~.09-1~]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine that is obtainable by reduction of the corresponding nitrile.
Example 24 N-{6,10-Dichloro-tetracyclo[6.6.2.02-~.0~~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine hydrobromide The title compound with a melting point of 93 - 95°C
(decomp.) is obtained in a yield of 24 % of theory in an analogous manner to that described in example 2 from {6,10-dichloro-tetracyclo[6.6.2.02-~.09~14]hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-amine.
Example 25 N-{ 6-Chloro-tetracyclo [ 6 . 6 . 2 . 02- ~ . O9~ 14 ] hexadeca-2(7),3,5,9(14),10,12-hexaen-15-yl-methyl}-guanidine hydrobromide The title compound with a melting point of 151 - 153°C
(decomp.) is obtained in a yield of 32 % of theory in an analogous manner to that described in example 22 from {6-chloro-tetracyclo[6.6.2.02~~.09-19]hexadeca-2(7),3,5,9(14),-10,12-hexaene-15-yl-methyl}-amine.
EBample 26 5,10-Dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindole A solution of 23.0 g (67 mmol) 5, I0-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-Benz[f]isoindole-1,3-divne in 290 ml tetrahydrofuran is added dropwise to a suspension of 5.1 g (134 mmol) lithium aluminium hydride in 45 ml diethyl ether, it is subsequently refluxed for 8 h, admixed with sodium chloride solution, the organic phase is concentrated and the residue is purified by conversion into hydrochloride and subsequent release of the base. 11.0 g (52 % of theory) of the title compound with a melting point of 126 - 130°C is isolated.
The 5,10-dichloro-3a,4,9,9a=tetrahydro-4,9-o-benzeno-benz-[f]isoindole-1,3-dione used as a starting substance can be obtained as follows:
83 g (0.24 mol) 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isobenzofuran-1,3-dione (Bull. Soc.
Chim. France 1973, 190) is introduced into a mixture of 370 ml chloroform and 370 ml liquefied ammonia, it is stirred for a further 3 h, filtered, the precipitate is taken up in a large amount of water, heated to boiling point, filtered and the filtrate is acidified. 77 g (88 % of theory) 3,10-dichloro-tetracyclo[6.6.2.02-x.09~19]_ hexadeca-2(7),3,5,9(14),10,12-hexaen-15,16-dicarboxylic acid monoamide with a melting point of 274 - 276°C
precipitates.
27.5 g of the previously described amide in 400 ml xylene is refluxed for 30 min on a water separator. The precipitate that forms on cooling is removed by filtration and washed with diethyl ether. 23.5 g (90 %
of theory) 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-0-benzeno-benz[f]isoindole-1,3-dione with a melting point of 279 - 281°C is obtained.
Example 27 5,10-Dichloro-2-(4,5-dihydro-1H-imidazol-2-yl)-3a,4,9,9a-tetrahydro-4,9-o-benzeno-Benz[f] isoindole The title compound with a melting point of 325 - 326°C
is obtained in a 41 % yield in an analogous manner to that described in example 20 from 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindole and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrobromide.
, Example 28 5,10-Dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindol-2-yl-carboximidamide The title compound in with a melting point of 236 -238°C is obtained a 27 % yield in an analogous manner to that described in example 2 from 5,10-dichloro-3a,4,9,9a-tetrahydro-4,9-o-benzeno-benz[f]isoindole and S-methyl-isothiourea hydrobromide.
Example 29 Enzyme Assay and Pharmakological Tests As a representative compound of this application, the compound of Example 28 was tested in the PLA2-enzyme assay and in the animal experiment.
1. In the PLA,-enzyme assay, the compound of Example 28 showed an inhibition of the cytosolical PLAz-enzyme activity, but no inhibition of the secretorial PLA~-activity.
2. In the animal experiment (rats), the compound of Example 28, administered i.p., showed an inhibition of the acute inflammatory carrageenin edema (EDso -16 mg/kg) as well as an inhibition of the generalized adjuvans arthritis.
Claims (4)
1. Use of tetracyclo [6.6.2.02,7.09,14]
hexadeca-2(7),3,5,9(14),10,12-hexaene derivatives of the general formula I
in which R1 and R2 are the same or different and denote hydrogen or a halogen atom, X denotes hydrogen and Y denotes a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group ~CH2-NR5 and Z represents a ~CH2 group or a~C==H group in which R3 denotes hydrogen, a lower alkyl group and R4 denotes hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or R3 and R4 together with the nitrogen atom to which they are bound form a heterocyclic ring which can be optionally broken by a further heteroatom and which can be optionally substituted once or several times, R5 represents hydrogen, an amidino group or a heterocycle which is optionally broken by one or several other heteroatoms, for the production of pharmaceutical preparations with phospholipase-inhibiting action as well as physiologically tolerated salts, esters, optically active forms and racemates thereof as well as derivatives which can be metabolized in vivo to form compounds of the general formula I.
hexadeca-2(7),3,5,9(14),10,12-hexaene derivatives of the general formula I
in which R1 and R2 are the same or different and denote hydrogen or a halogen atom, X denotes hydrogen and Y denotes a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group ~CH2-NR5 and Z represents a ~CH2 group or a~C==H group in which R3 denotes hydrogen, a lower alkyl group and R4 denotes hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or R3 and R4 together with the nitrogen atom to which they are bound form a heterocyclic ring which can be optionally broken by a further heteroatom and which can be optionally substituted once or several times, R5 represents hydrogen, an amidino group or a heterocycle which is optionally broken by one or several other heteroatoms, for the production of pharmaceutical preparations with phospholipase-inhibiting action as well as physiologically tolerated salts, esters, optically active forms and racemates thereof as well as derivatives which can be metabolized in vivo to form compounds of the general formula I.
2. Compounds of the general formula I
in which R1 and R2 are the same or different and denote hydrogen or a halogen atom, X denotes hydrogen and Y denotes a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group ~CH2-NR5 and Z represents a~CH2 group or a ~C=NH group in which R3 denotes hydrogen, a lower alkyl group and R4 denotes hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or R3 and R4 together with the nitrogen atom to which they are bound form a heterocyclic ring which can be optionally broken by a further heteroatom and which can be optionally substituted once or several times, R5 represents hydrogen, an amidino group or a heterocycle which is optionally broken by one or several other heteroatoms, provided that if R1 and R2 simultaneously denote hydrogen (a) R4 does not denote a lower alkyl group or (b) R5 does not denote hydrogen or (c) R3 and R4 together do not form an unsubstituted piperidine ring or morpholine ring as well as physiologically tolerated salts, esters, optically active forms and racemates thereof as well as derivatives which can be metabolized in vivo to form compounds of the general formula I.
in which R1 and R2 are the same or different and denote hydrogen or a halogen atom, X denotes hydrogen and Y denotes a group -NR3R4 or a group -N+CH3R3R4 or X and Y together form a group ~CH2-NR5 and Z represents a~CH2 group or a ~C=NH group in which R3 denotes hydrogen, a lower alkyl group and R4 denotes hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or a lower alkyl group or R3 and R4 together with the nitrogen atom to which they are bound form a heterocyclic ring which can be optionally broken by a further heteroatom and which can be optionally substituted once or several times, R5 represents hydrogen, an amidino group or a heterocycle which is optionally broken by one or several other heteroatoms, provided that if R1 and R2 simultaneously denote hydrogen (a) R4 does not denote a lower alkyl group or (b) R5 does not denote hydrogen or (c) R3 and R4 together do not form an unsubstituted piperidine ring or morpholine ring as well as physiologically tolerated salts, esters, optically active forms and racemates thereof as well as derivatives which can be metabolized in vivo to form compounds of the general formula I.
3. Pharmaceutical preparation containing at least one compound of formula I as claimed in claim 2 in addition to common carrier and auxiliary substances.
4. Use of compounds of formula I as claimed in claim 2 for the production of pharmaceutical preparations with phospholipase-inhibiting action.
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| PCT/EP1998/006096 WO1999015493A1 (en) | 1997-09-24 | 1998-09-24 | 9,10-dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors |
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| AUPS282602A0 (en) | 2002-06-07 | 2002-06-27 | Garvan Institute Of Medical Research | Method of inhibiting cell proliferation |
| AU2003251970A1 (en) | 2002-07-18 | 2004-02-09 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor and method |
| US7625921B2 (en) | 2004-01-16 | 2009-12-01 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7326728B2 (en) | 2004-01-16 | 2008-02-05 | Bristol-Myers Squibb Company | Modulators of glucocorticoid receptor, AP-1, and/or NF-κβ activity and use thereof |
| US7569689B2 (en) * | 2004-01-16 | 2009-08-04 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7605264B2 (en) | 2004-01-16 | 2009-10-20 | Bristol-Myers Squibb Company | Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7253283B2 (en) * | 2004-01-16 | 2007-08-07 | Bristol-Myers Squibb Company | Tricyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7273881B2 (en) | 2004-01-16 | 2007-09-25 | Bristol-Myers Squibb Company | Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7317024B2 (en) | 2005-01-13 | 2008-01-08 | Bristol-Myers Squibb Co. | Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7411071B2 (en) | 2005-01-13 | 2008-08-12 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7361654B2 (en) | 2005-01-13 | 2008-04-22 | Bristol-Myers Squibb Co. | Substituted heteroaryl amide modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
| US7642273B2 (en) | 2005-01-13 | 2010-01-05 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
Family Cites Families (11)
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| US3123618A (en) * | 1964-03-03 | Io-dihydroanthkacene-z | ||
| NL123295C (en) * | 1963-10-21 | |||
| CH429711A (en) * | 1963-10-21 | 1967-02-15 | Geigy Ag J R | Process for the production of new ethanoanthracene derivatives |
| CH426789A (en) * | 1963-10-21 | 1966-12-31 | Geigy Ag J R | Process for the production of new ethanoanthracene derivatives |
| US3422104A (en) * | 1964-10-20 | 1969-01-14 | Geigy Chem Corp | 9,10-dihydro-11-amino-alkylene-9,10-ethanoanthracenes |
| FR1459843A (en) * | 1965-07-27 | 1966-06-17 | Soc Ind Fab Antibiotiques Sifa | New quaternary ammonium salts derived from 9-ethano-9,10-dihydro-anthracene and method of preparation |
| CH482642A (en) * | 1967-10-17 | 1969-12-15 | Geigy Ag J R | Process for the preparation of 11-aminoalkyl-9,10-dihydro-9,10-ethano-anthracenes |
| US5039706A (en) * | 1987-11-30 | 1991-08-13 | Du Pont Merck Pharmaceutical Company | Antiinflammatory PLA2 inhibitors |
| US5055468A (en) * | 1989-10-30 | 1991-10-08 | G. D. Searle & Co. | Use of bridged tricyclic amine derivatives as anti-ischemic agents |
| US5409932A (en) * | 1993-12-09 | 1995-04-25 | Bayer Ag | Piperazine-substituted pyrroloanthracenes |
| WO1995033715A1 (en) * | 1994-06-02 | 1995-12-14 | Smithkline Beecham Corporation | Anti-inflammatory compounds |
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1997
- 1997-09-24 DE DE19742014A patent/DE19742014A1/en not_active Withdrawn
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1998
- 1998-09-23 ZA ZA9808711A patent/ZA988711B/en unknown
- 1998-09-23 AR ARP980104764A patent/AR019256A1/en unknown
- 1998-09-24 CA CA002304879A patent/CA2304879A1/en not_active Abandoned
- 1998-09-24 KR KR1020007003134A patent/KR20010024258A/en not_active Withdrawn
- 1998-09-24 AU AU97466/98A patent/AU9746698A/en not_active Abandoned
- 1998-09-24 WO PCT/EP1998/006096 patent/WO1999015493A1/en not_active Ceased
- 1998-09-24 BR BR9813217-2A patent/BR9813217A/en not_active IP Right Cessation
- 1998-09-24 EP EP98951464A patent/EP1034162A1/en not_active Withdrawn
- 1998-09-24 JP JP2000512804A patent/JP2002505999A/en active Pending
- 1998-09-24 TR TR2000/01222T patent/TR200001222T2/en unknown
- 1998-09-24 CN CN98811160A patent/CN1278789A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9498460B1 (en) | 2016-04-06 | 2016-11-22 | King Saud University | Halogenated tetracyclic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002505999A (en) | 2002-02-26 |
| WO1999015493A8 (en) | 1999-05-06 |
| WO1999015493A1 (en) | 1999-04-01 |
| CN1278789A (en) | 2001-01-03 |
| EP1034162A1 (en) | 2000-09-13 |
| DE19742014A1 (en) | 1999-03-25 |
| TR200001222T2 (en) | 2000-09-21 |
| AR019256A1 (en) | 2002-02-13 |
| ZA988711B (en) | 2000-03-23 |
| AU9746698A (en) | 1999-04-12 |
| BR9813217A (en) | 2000-08-29 |
| KR20010024258A (en) | 2001-03-26 |
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