CN1278789A - 9,10-Dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors - Google Patents

9,10-Dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors Download PDF

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CN1278789A
CN1278789A CN98811160A CN98811160A CN1278789A CN 1278789 A CN1278789 A CN 1278789A CN 98811160 A CN98811160 A CN 98811160A CN 98811160 A CN98811160 A CN 98811160A CN 1278789 A CN1278789 A CN 1278789A
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compound
ring
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hydrogen
hexane
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W·G·弗里贝
U·蒂贝斯
W·朔伊尔
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Roche Diagnostics GmbH
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    • 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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    • 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
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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
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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
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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

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

As 9 of inhibitor of phospholipase enzymes, 10-dihydro-9,10-ethano-anthracene derivant
The present invention relates to new tetracyclic compound, its preparation method and contain the pharmaceutical preparation of these compounds.
The present invention relates to the Fourth Ring [6.6.2.0 of formula I 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10, the 12-hexame derivatives, and physiology salt, ester, optical activity form and the racemic modification that can tolerate and the derivative that can be metabolized to generalformula in vivo, the invention still further relates to the purposes that these compounds are used for useful in preparing drug formulations. Wherein
R1 is identical or different with R2, the expression hydrogen or halogen atom,
X represent hydrogen and
Y represents-NR3R4 or-N +CH 3R3R4, or
X and Y form CH together 2-NR5 and
Z represents CH 2Or C=NH-, wherein
R3 represent hydrogen or low alkyl group and
R4 represents hydroxyl, formamyl, and amidino groups, heteroaryl, N-aralkyl heteroaryl or low alkyl group, or
R3 and R4 form to choose wantonly with the nitrogen-atoms that they were connected and are interrupted by other heteroatoms and can choose the heterocycle that is substituted one or many wantonly,
R5 represents hydrogen, amidino groups or the optional heterocycle that is interrupted by one or more heteroatomss,
Condition is, if R1 and R2 represent hydrogen simultaneously, then
A) R4 does not represent low alkyl group, or
B) R5 does not represent hydrogen, or
C) R3 and R4 form unsubstituted piperidine ring or morpholine ring not together.
Formula I compound has important pharmacological action, and particularly, they can suppress the activity of Phospholipid hydrolase.Therefore they are suitable for treating acute, chronic, supersensitivity, nonallergic and damaging inflammation, rheumatic arthritis for example, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, struvite and allergic respiratory, toxic shock, anaphylactic shock, serum sickness, autoimmune disease, grafting-virus-host response, host-virus-grafting disease, local asphyxia or thrombus disease be coronary artery infraction or cerebral infarction for example.
Some formula I compound with pharmacologically active is synthesized.The 11-amino methyl-9 with antiemetic and anesthetic action has been described, 10-dihydro-9,10-ethano-anthracene in application 6 412 205 (Chem.Abstr.63,14787) by Holland.Have anticholinergic effect, bring high blood pressure down, the respective substance of antihistamine and local anesthetic action is published in J.Med.Chem.10, in 86 (1967).But the restraining effect of antiinflammation, particularly Phospholipid hydrolase did not have report in the past.
If explanation in addition, among R3 and the R4 and represent independent or with aryl or straight or branched alkyl amino, a 1-6 carbon atom as substituent low alkyl group.Preferably methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or 3-amyl group.
Aryl can be understood as the phenyl or naphthyl that can choose wantonly by halogen or low alkyl group replacement.Preferred phenyl.
Halogen can be understood as fluorine, chlorine, bromine or iodine, preferred chlorine.
Heteroatoms among R3, R4 and the R5 can be regarded as N, O, S, preferred N or O.
N-aralkyl heteroaryl can be regarded as the aralkyl that links to each other with heterocycle by nitrogen-atoms.
Heteroaryl among the R4 can be regarded as pyridyl, piperidyl, pyridazinyl, pyrimidyl, pyrazinyl or piperazinyl.Preferred pyridyl, piperidyl or imidazolinyl, particularly 3-pyridyl or 4-pyridyl or 3-piperidyl or 4-piperidyl or 4,5-dihydro-imidazol--2-base.
R3 be can be regarded as tetramethyleneimine with R4 with the described heterocyclic system of N-atom that is connected, pyrroles, pyrazoles, imidazoles, pyridine, pyridazine, pyrimidine, pyrazine, pyrans, piperidines, piperazine or morpholine ring.Preferred tetramethyleneimine, morpholine or piperidines.
Substituting group on the heterocyclic system that R3 and R4 form together except common substituting group, preferred benzamido, benzyl amino, amino, alkyl monosubstituted amino or dialkyl amido.Go up single the replacement for preferred 4.
Heterocycle among the R5 is represented pyrimidine, pyridazine, pyrazoles, pyrazine, imidazoles, indazole or purine.But preferred especially imidazolyl.
Particularly preferred R1 and R2 are hydrogen and chlorine.Particularly preferred R3 is hydrogen or methyl, and particularly preferred R4 represents formamyl, amidino groups, N-benzyl aminopyridine, piperidines, pyridine, methyl, hydroxyl or imidazolyl.R3 and R4 together particularly preferably be 4-benzamidine phenylpiperidines, 4-benzylamino piperidines, 4-amino piperidine, 4-dimethylamino piperidine, tetramethyleneimine, piperidines or morpholine.Particularly preferred R5 represents hydrogen, imidazoles or amidino groups.
Except the compound among the embodiment, the present invention also is particularly related to the substituent possible combination of mentioning among the embodiment and all substances that form.
Formula I compound with currently known methods described in document preparation (ordinary method for example, as Houben-Weyl, " Methoden der Organischen Chemie, Georg ThimeVerlag ", Stuttgart; Organic Reactions, John Wiley﹠amp; Sons, Inc., New York) and embodiment in the reference quoted, promptly known and be applicable under the condition of described reaction.Also can use the known distortion of these reactions that this paper do not describe in detail.And available currently known methods is transformed into another kind of formula I compound with a kind of formula I compound.
The preparation method of formula I compound of the present invention is characterised in that, in a known way
A) incite somebody to action wherein R1, R2, X; Y and Z have described meaning, formula I compound that R4 and R5 represent hydrogen and active carbonic acid derivatives reaction, or represent formamyl to generate wherein R4 or R5 with the reagent react that shifts imidazolinyl; the formula I compound of amidino groups or imidazolinyl, or
B) wherein R1 and R2 have described meaning, and X represents hydrogen, and Y represents hydrogen or leavings group, and Z represents formula I compound and the primary amine or the secondary amine reaction of carbonyl, is reduced into Z subsequently and represents CH 2, Y is the formula I compound of NR3R4, or
C) will be wherein R1 and R2 have described meaning, X represent hydrogen, Z represents cyano group, does not contain the formula I compound of Y and azanol or hydroxylamine derivative and reacts, and generates wherein that Z is the formula I compound that C=NH-and R4 represent hydroxyl, or
D) wherein R1 and R2 have described meaning, and X-Y-Z represents to be reduced into wherein by the formula I compound of CO-NH-CO, and X-Y-Z represents CH 2-NH-CH 2Formula I compound,
And, if necessary, subsequently carbonyl reduction is become CH 2, interrupt arylmethyl, or tertiary N atom be alkylated into quaternary nitrogen atoms,
Randomly alkali is transformed into pharmaceutically useful salt or makes free cpds from salt.
Formula I compound can enantiomer and the existence of racemic modification form.The present invention relates to pure enantiomer and racemic mixture.
The inorganic isocyanic ester or the isourea derivatives that for example have leavings group are considered to active carbonic acid derivatives.
The reagent that shifts imidazolinyl is for for example having the 1H-tetrahydroglyoxaline of leavings group on 2.
Leavings group is for example halogen atom, azido-, alkoxyl group, aryloxy, alkylthio and arylthio.
The metal hydride title complex, for example sodium borohydride and lithium aluminium hydride are preferred reductive agents.
Formula I compound has one or more chiral centres, thereby has racemize or optical activity form.Available currently known methods splits into enantiomer with optical isomer.As long as suitable, described method just refers to the fractionation of final stage and/or precursor.The reaction of racemic mixture and following optically active acid or amine generates two kinds of enantiomer salt: for example D-or L-tartrate, amygdalic acid, oxysuccinic acid, lactic acid or camphorsulfonic acid; D-or L-α-Ben Yian, ephedrine, quinidine or quinine are fixed.These salt can pass through Crystallization Separation, or with HPLC separating optical isomeric body.The method of another kind of separating optical isomeric body is to carry out enzymatic to separate in synthetic.
Suitable pharmaceutically useful salt is and following nontoxic mineral acid or organic acid hydrochloric acid for example, sulfuric acid, phosphoric acid, Hydrogen bromide, acetic acid, lactic acid, citric acid, oxysuccinic acid, phenylformic acid, Whitfield's ointment, propanedioic acid, toxilic acid, the salt that succsinic acid or diaminocaproic acid generate, and randomly alkali-, alkaline earth-and ammonium salt.
Obtain salt by ordinary method, for example through type I compound and suitable acid or alkali lye neutralization.Usually be purified by redeposition from water/acetone.
For useful in preparing drug formulations, with currently known methods with formula I compound and suitable pharmaceutically useful carrier substance, aromatoising substance, flavouring agent and dyestuff mix, and for example make tablet or coated tablet or suspension or are dissolved in water or oil for example in the sweet oil, add suitable adjuvant.
Formula I compound can be with the liquid or solid form oral or parenterai administration.Water is preferred injectable media, contains common stablizer in the injection liquid, solubilizing agent and/or buffer reagent.This class additive is for example tartrate or borate buffer solution, ethanol, and dimethyl sulfoxide (DMSO), Synergist S-421 95 (for example ethylenediamine tetraacetic acid (EDTA)) is used for regulating the high molecular polymer (for example liquid polyethylene oxide) of viscosity or the polythene derivative of sorboside.
The solid carrier material is for example starch, lactose, N.F,USP MANNITOL, methylcellulose gum, talcum, high dispersive silicic acid, high molecular polymer (for example polyoxyethylene glycol).
If necessary, Shi Yi oral preparations can contain seasonings and sweeting agent.For external application, chemical compounds I of the present invention also can be used as powder and ointment.For this reason, they can be for example mix with the thinner or the common ointment base that can tolerate on the physiology.
Taking dose depends on receptor's age, healthy state and body weight, disease degree, other treatment type of carrying out simultaneously, the type of treatment frequency and required effect.The per daily dose of active compound is generally the 0.1-50mg/kg body weight.Usually 0.5-40, preferred 1.0-20mg/kg/ days, once or divide and take several times to obtain desired result.
Except the material of mentioning among the embodiment, following compound is the preferred compound on the meaning of the present invention:
1-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-4-amino-piperadine hydrochloride
1-benzyl-4-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl-amino }-piperidine hydrochlorate
4-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl-amino }-piperidine hydrochlorate
1 '-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-1,4 '-two piperidines
1 '-3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-1,4 '-two piperidines
The following example is used to illustrate the present invention but does not limit the present invention.
Embodiment 1
N-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-urea
1.21g (15 mmol) potassium cyanate is added to 2.85g (10 mmol) { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-amine hydrochlorate (J.Org.Chem.42,1131 (1977)) is dissolved in the solution of 200ml hot water and was heated to back flow reaction 1 hour.After the cooling, filtering to isolate 2.4g (theoretical yield 86%) fusing point is 182-184 ℃ title compound.
Embodiment 2
N-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-guanidine
Under the nitrogen protection, with 3.8g (16.4 mmol) { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-mixture heating up that amine and 3.1g (18mmol) S-methyl-isothiourea hydrobromate are dissolved in the 30ml n-propyl alcohol refluxed 5 hours, cooling, mix with ether, use water extraction, extracting solution is alkalized, use ethyl acetate extraction, dry organic layer, evaporation concentration is ground with ether.Isolating 2.0g (theoretical yield 44%) fusing point is 128-130 ℃ title compound.
Embodiment 3
1-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-4-benzamido-piperidines
On water trap with 4.8g (20 mmol) { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-(Bull.Soc.Chim.France 1964 for formaldehyde, 550), 4.0g (20mmol) 4-benzamido-piperidines, the mixture heating up of 100ml toluene and 0.2g tosic acid refluxed 2 hours.Concentrate then, handle, add the 0.96g sodium borohydride at twice, each reflux 1 hour with 100ml methyl alcohol.Concentrate, resistates is handled with ethyl acetate, washes with water, dry organic layer, chromatography on silica gel.With 3: 1 wash-outs of isohexane/ethyl acetate, obtaining 5.8g (theoretical yield 69%) fusing point is 168-170 ℃ title compound.
Embodiment 4
1-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-4-benzyl amino-piperadine hydrochloride
The drips of solution that the compound of 5.4g (12.8 mmol) embodiment 3 is dissolved in the 50ml tetrahydrofuran (THF) is added to the 1.5g lithium aluminium hydride and is dissolved in the solution of 100ml tetrahydrofuran (THF), and reflux is 3 hours then, mixes with sodium chloride solution, filters, and the filtrate drying concentrates.After in methanol solution, adding excessive ether solution of hydrogen chloride, separate obtaining 5.1g (theoretical yield 98%) title compound crude product.
Embodiment 5
1-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-4-amino-piperadine hydrochloride
Under the hydrogen-pressure of 50 ℃ and 1 crust, the compound of 5.0g (12.3 mmol) embodiment 4 is dissolved in the 50ml methyl alcohol, with 1g 10% palladium hydrocarbonize.Filter, concentrate silica gel column chromatography.Go out the 2.9g target compound with 1: 1 wash-out of ethyl acetate/methanol.After grinding with acetone, obtaining 2.3g (theoretical yield 60%) fusing point is 225-230 ℃ title compound.
Embodiment 6
1-benzyl-4-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-piperidine hydrochlorate
With the method that is similar to embodiment 3, from { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-to obtain yield be 80% title compound crude product for formaldehyde and 4-amino-1-benzyl piepridine.
Embodiment 7
4-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-piperidine hydrochlorate
With the method that is similar to embodiment 5, obtain fusing point and be 226-228 ℃ title compound, yield is 89%.
Embodiment 8
1-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-4-dimethylamino-piperidine hydrochlorate
With the method that is similar to embodiment 3, from { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-to obtain yield be 65% title compound for formaldehyde and 4-dimethylamino-piperidines, is amorphous solid.
Embodiment 9
4-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-pyridine
With method similar to Example 4, by reduction 4-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-carbonylamino }-pyridine, grind with ether subsequently, obtain fusing point and be 164-166 ℃ title compound, yield is 71% of a theoretical yield.
Above-mentioned starting raw material can obtain with laxative remedy:
Under the room temperature, with 5.4g (20 mmol) { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-carbonyl chloride (J.Am.Chem.Soc.94,1193 (1972)) and 4.7g (50 mmol) the 4-aminopyridine mixture that is dissolved in the 50ml tetrahydrofuran (THF) stirred 1 hour, back flow reaction 2 hours is filtered then, and filtrate is used silica gel column chromatography.Behind eluent ethyl acetate, obtain the 2.5g fusing point and be 217-219 ℃ { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-carbonylamino }-pyridine (theoretical yield 38%).
Embodiment 10
4-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-pyridine
With the method that is similar to embodiment 9, will from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-(Tetrahedron 28 for carbonyl chloride, 1435 (1972)) and the carbonylamino compound that obtains of 4-amino-pyridine reduce, obtain fusing point and be 322-325 ℃ title compound, yield 61%.
Embodiment 11
3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-dimethylamine
With the method that is similar to embodiment 9, will from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-carbonylamino compound that carbonyl chloride and dimethylamine obtain reduces, and obtains fusing point and be 88-90 ℃ title compound, yield 64%.
Embodiment 12
N-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-piperidines
With the method that is similar to embodiment 9, will from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-carbonylamino compound that carbonyl chloride and piperidines make reduces and obtains title compound, is amorphous solid, yield 40%.
Embodiment 13
N-{6,13-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-piperidines
In last compound chromatography purge process, title compound is come out by wash-out as by product, is amorphous solid, yield 15%.
Embodiment 14
N-{6,13-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-tetramethyleneimine
With the method that is similar to embodiment 9, will from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-carbonylamino compound that carbonyl chloride and tetramethyleneimine are made reduces, and obtains title compound, is oil, yield 28%.
Embodiment 15
N-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-morpholine
With the method that is similar to embodiment 9, will from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-carbonylamino compound that carbonyl chloride and morpholine obtain reduces, and obtains fusing point and be 175-177 ℃ title compound, and yield is 41%.
Embodiment 16
1-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-4-dimethylamino-piperidine hydrochlorate
With the method that is similar to embodiment 9, will from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-carbonylamino compound that carbonyl chloride and 4-dimethylamino-piperidines are made reduces, and uses the salt Acid precipitation then, obtains the title compound that fusing point is 295 ℃ (decomposition), yield 70%.
Embodiment 17
3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-the trimethyl ammonium iodide
Under the room temperature, with the compound of 0.5g (1.5mmol) embodiment 11, the mixture of 10ml acetone and 0.47ml (7.5mmol) methyl iodide stirred 8 hours, removed by filter precipitation then.Obtain the 0.5g fusing point and be 172-175 ℃ title compound (theoretical yield 70%).
Embodiment 18
N-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-N-methyl-piperidines iodide
With the method that is similar to embodiment 17, obtaining fusing point from the compound of embodiment 12 and methyl iodide is 254-256 ℃ title compound, yield 43%.
Embodiment 19
The N-hydroxyl-and 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-azomethine acid acid amides (carboximidamide)
With 8.25g (25mmol) 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-nitrile (Tetrahedron28,1435 (1972)), 5.3g yellow soda ash, the 7.0g oxammonium hydrochloride, the mixture of 100ml ethanol and 25ml water refluxed 20 hours.Filter, will precipitate and use silica gel column chromatography.Isolating 0.75g (theoretical yield 9%) fusing point with ethyl acetate is 203-205 ℃ title compound.
Can detect the isomer N-hydroxyl that generates as by product-6,13-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-yl }-azomethine acid acid amides.
Embodiment 20
2-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-4,5-dihydro-1H-imidazoles
The 4.55g that obtains with the lithium aluminium hydride nitrile reducing among the embodiment 19 (15 mmol) 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-amine and 3.36g (17mmol) 2-methyl sulfanyl-4, the mixture of 5-dihydro-1H-imidazoles hydrobromate is heated to 160 ℃ of reactions 30 minutes under 15mbar, and 180 ℃ were reacted 10 minutes, after the cooling, add acetone, filter, will precipitate recrystallization with ethanol.Isolating 5.0g (theoretical yield 73%) fusing point is 194-195 ℃ title compound.
Embodiment 21
2-{ Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-4,5-dihydro-1H-imidazoles
With the method that is similar to embodiment 20, from { Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-to obtain fusing point be 160-162 ℃ title compound (theoretical yield 57%) to amine.
Embodiment 22
N-{3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-guanidine
With the method that is similar to embodiment 2, from 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-to obtain fusing point be 211-213 ℃ title compound to amine, yield is 58%.
Embodiment 23
2-{6,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methylamino-}-4,5-dihydro-1H-imidazoles-hydrobromate
With the method that is similar to embodiment 20, from by reduce that corresponding nitrile obtains 6,10-chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-amine obtains the title compound that fusing point is 155-158 ℃ (decomposition), and yield is 28% of a theoretical yield.
Embodiment 24
N-{6,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-the guanidine hydrobromate
With the method that is similar to embodiment 2, from 6,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-amine obtains the title compound that fusing point is 93-95 ℃ (decomposition), and yield is 24% of a theoretical yield.
Embodiment 25
N-{6-chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-the guanidine hydrobromate
With the method that is similar to embodiment 22, from { 6-chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15-base-methyl }-amine obtains the title compound that fusing point is 151-153 ℃ (decomposition), and yield is 32% of a theoretical yield.
Embodiment 26
5,10-two chloro-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isoindole
With 23.0g (67 mmol) 5,10-two chloro-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isoindole-1, the drips of solution that the 3-diketone is dissolved in the 290ml tetrahydrofuran (THF) is added to 5.1g (134 mmol) lithium aluminium hydride and is dissolved in the suspension of 45ml ether, refluxes then 8 hours, mixes with sodium chloride solution, organic layer is concentrated, by resistates being transformed into hydrochloride and then the alkali that dissociates carries out purifying.Isolating 11.0g (theoretical yield 52%) fusing point is 126-130 ℃ title compound.
As 5 of initial substance, 10-two chloro-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo-[f] isoindole-1, the 3-diketone can obtain with laxative remedy:
With 83g (0.24 mol) 5,10-two chloro-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isobenzofuran-1, (Bull.Soc.Chim.France 1973 for the 3-diketone, 190) be added in the mixture of 370ml chloroform and 370ml liquefied ammonia, further stirred 3 hours, filter, use a large amount of water treatment depositions, be heated to boiling point, filter the filtrate acidifying.Precipitation separate out 77g (theoretical yield 88%) fusing point be 274-276 ℃ 3,10-two chloro-Fourth Ring [6.6.2.0 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10,12-hexane-15,16-dicarboxylic acid monoamide.
Above-mentioned acid amides 27.5g is dissolved in 400ml dimethylbenzene, and backflow 30 minutes on water trap, the precipitation that generates when removing by filter cooling are washed with ether.Obtain 23.5g (theoretical yield 90%) fusing point and be 279-281 ℃ 5,10-two chloro-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isoindole-1,3-diketone.
Embodiment 27
5,10-two chloro-2-(4,5-dihydro-1H-imidazoles-2-yl)-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isoindole
With the method that is similar to embodiment 20, from 5,10-two chloro-3a, 4,9,9a-tetrahydrochysene-4, it is 325-326 ℃ title compound that 9-o-benzeno-benzo [f] isoindole and 2-methyl sulfanyl-4,5-dihydro-1H-imidazoles hydrobromate obtain fusing point, and yield is 41%.
Embodiment 28
5,10-two chloro-3a, 4,9,9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isoindole-2-base-azomethine acid acid amides
With the method that is similar to embodiment 2, from 5,10-two chloro-3a, 4,9, it is 236-238 ℃ title compound that 9a-tetrahydrochysene-4,9-o-benzeno-benzo [f] isoindole and S-methyl-isothiourea hydrobromate obtain fusing point, yield is 27%.
Embodiment 29
Enzyme test and pharmacological testing
As the application's representative compounds, use experimentation on animals, PLA 2-enzyme assay has been measured the compound of embodiment 28.
1.PLA 2In-the enzyme assay, the compound exhibits of embodiment 28 goes out cytosolicalPLA 2The restraining effect of-enzyme, but to secretorial PLA 2-active unrestraint.
2. in animal (mouse) experiment, the compound intraperitoneal administration of embodiment 28 demonstrates and suppresses acute inflammatory carrageenin oedema (ED 50=16mg/kg) and auxiliary (adjuvans) sacroiliitis of generalization.

Claims (4)

1. Fourth Ring [the 6.6.2.0 of formula I 2,7.0 9,14] 16-2 (7), 3,5,9 (14), 10, the salt that can tolerate on 12-hexame derivatives and the physiology, ester, optical activity form and racemic modification thereof and in vivo the derivative of energy metabolism accepted way of doing sth I compound be used to prepare purposes with the inhibiting medicine of Phospholipid hydrolase:
Figure 9881116000021
In the formula
R1 is identical or different with R2, the expression hydrogen or halogen atom,
X represent hydrogen and
Y represents-NR3R4 or-N +CH 3R3R4, or
X and Y form CH together 2-NR5 and
Z represents CH 2Or C=NH, wherein
R3 represent hydrogen or low alkyl group and
R4 represents hydroxyl, formamyl, and amidino groups, heteroaryl, N-aralkyl heteroaryl or low alkyl group, or
R3 and R4 form to choose wantonly with the nitrogen-atoms that they were connected and are interrupted by other heteroatoms and can choose the heterocycle that is substituted one or many wantonly,
R5 represents hydrogen, amidino groups or the optional heterocycle that is interrupted by one or more heteroatomss.
2. the salt that can tolerate on the compound of formula I and the physiology thereof, ester, optical activity form, racemic modification, and the derivative of energy metabolism accepted way of doing sth I compound in vivo: In the formula
R1 is identical or different with R2, the expression hydrogen or halogen atom,
X represent hydrogen and
Y represents-NR3R4 or-N +CH 3R3R4, or
X and Y form CH together 2-NR5 and
Z represents CH 2Or C=NH, wherein
R3 represents hydrogen, low alkyl group and
R4 represents hydroxyl, formamyl, and amidino groups, heteroaryl, N-aralkyl heteroaryl or low alkyl group, or
R3 and R4 form to choose wantonly with the nitrogen-atoms that they were connected and are interrupted by other heteroatoms and can choose the heterocycle that is substituted one or many wantonly,
R5 represents hydrogen, amidino groups or the optional heterocycle that is interrupted by one or more heteroatomss,
Condition is, if R1 and R2 represent hydrogen simultaneously, then
(a) R4 does not represent low alkyl group, or
(b) R5 does not represent hydrogen, or
(c) R3 and R4 represent unsubstituted piperidine ring or morpholine ring not together.
3. the medicine that except common carrier and auxiliary substance, also contains the formula I compound of at least a claim 2.
4. the formula I compound of claim 2 is used to prepare the purposes with the inhibiting medicine of Phospholipid hydrolase.
CN98811160A 1997-09-24 1998-09-24 9,10-Dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors Pending CN1278789A (en)

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