HK1088328A - Benzo[b]pyrano[3,2-h]acridin-7-one cinnamate compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents
Benzo[b]pyrano[3,2-h]acridin-7-one cinnamate compounds, a process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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Description
Technical Field
The present invention relates to novel benzo [ b ] pyrano [3, 2-h ] acridin-7-one cinnamate compounds, processes for their preparation and pharmaceutical compositions containing them.
Technical Field
The compounds of the invention are derivatives of oleanoline, an alkaloid with anti-tumor properties that have been demonstrated in experimental models (pharm. sci., 1966,55(8),758-768). However, despite its rather broad spectrum of activity, elaucin is low in potency and moderate in activity. Furthermore, the dissolution of the compoundLow, which limits its bioavailability and its use in pharmaceutical compositions administered by intravenous route.
Various modifications have been made to this molecule, for example j.med.chem., 1996,394762-4766, EP 1042326, EP 1061081 or EP 1297835, so that the efficacy, antitumor efficacy and solubility of the product are significantly improved. However, the need for anticancer treatments constantly requires the development of new antitumor substances, aimed at obtaining drugs with both higher activity and better tolerability. More particularly, solid tumors constitute a major problem in anticancer chemotherapy due to their inherent and/or acquired resistance to existing compounds. It is therefore of utmost importance to obtain as many compounds as possible with potent cytotoxic activity so that the most effective treatment of all tumour disorders can be obtained.
Disclosure of Invention
In addition to the fact that the compounds of the invention are novel compounds, they also have surprising cytotoxic activity in vitro and in vivo, which is greater than that observed hitherto. The compounds discovered by the applicant therefore have anti-tumour properties, which make them particularly useful for the treatment of cancer. Among the various types of cancer that can be treated by the compounds of the invention, mention may be made of adenocarcinomas and carcinomas, sarcomas, gliomas and leukemias, without being limited thereto.
More specifically, the present invention relates to compounds of formula (I):
wherein:
x and Y, which may be identical or different, represent, independently of one another, a group selected from:
-a hydrogen and a halogen atom,
-hydroxy, linear or branched (C)1-C6) Alkoxy, nitro, cyano, straight or branched chain (C)1-C6) Alkyl (optionally substituted with one or more groups selected from hydroxyl and halogen) and straight or branched chain (C)2-C6) Alkenyl and
-formula-NRaRbWherein:
Raand RbMay be the same or different and independently represent a hydrogen atom and a linear or branched chain (C)1-C6) The radical of an alkyl group,
or RaAnd RbTogether with the nitrogen atom to which they are attached form a monocyclic 5-to 7-membered heterocyclic ring optionally containing a second heteroatom selected from oxygen and nitrogen in the ring system,
it is to be understood that the substituents X and Y may be present independently of each other on either of two adjacent phenyl rings,
z represents an oxygen atom or NRcWherein R iscRepresents a group selected from: hydrogen atom, straight or branched chain (C)1-C6) Alkyl, aryl and aryl- (C)1-C6) Alkyl, wherein the alkyl portion is linear or branched,
ar represents an aryl or heteroaryl group,
·R1represents a hydrogen atom or a linear or branched chain (C)1-C6) An alkyl group, a carboxyl group,
·R2represents a group selected from: hydrogen atom, straight or branched chain (C)1-C6) Alkyl, -ORaAnd
-NRaRbwherein R isaAnd RbAs defined above, in the above-mentioned manner,
·R3and R4May be the same or different and independently represent a hydrogen atom or a linear or branched chain (C)1-C6) An alkyl group, a carboxyl group,
·R5represents a group selected from:
1) a hydrogen atom, and a nitrogen atom,
2)ORcand NRcRdA group wherein:
Rcas defined above and RdAs to RcAs is defined in the above-mentioned publication,
3)W1-C(W2) -U-V, wherein:
α)W1represents an oxygen atom or NRc(wherein R iscAs defined above),
β)W2represents an oxygen atom, and represents an oxygen atom,
γ) U represents a single bond or a linear or branched (C)1-C8) Alkylene chains or straight or branched (C)2-C8) An alkenylene chain in which the alkylene group is bonded to,
6) v represents a group selected from:
-a hydrogen atom,
-an aryl group and a heteroaryl group,
-ORc、CO2Rc、CORc、CONR′aR′b、NR′aR′b、N(Rc)-CO2R′cand N (R)c)-COR′cGroup, wherein RcR 'as defined above'cAs to RcAnd R 'is as defined'aAnd R'bMay be the same or different and independently represent a group selected from: hydrogen atom, straight or branched chain (C)1-C6) Alkyl, aryl and aryl- (C)1-C6) Alkyl, wherein the alkyl moiety is linear or branched, or R'aAnd R'bTogether with the nitrogen atom to which they are attached form a monocyclic 5-to 7-membered heterocyclic ring optionally containing a second heteroatom selected from oxygen and nitrogen in the ring systemIn the case of a hybrid vehicle,
4)W1-C(W2)-W3-T1wherein:
α)W1and W2As defined above, in the above-mentioned manner,
β)W3represents an oxygen atom or NRcWherein R iscAs defined above, in the above-mentioned manner,
γ)T1represents a group selected from:
-a hydrogen atom,
-linear or branched (C)1-C6) An alkyl group, a carboxyl group,
-linear or branched (C)2-C6) An alkenyl group which is a radical of an alkylene group,
aryl, aryl- (C)1-C6) Alkyl, wherein the alkyl portion is linear or branched,
-linear or branched (C)1-C6) Alkylene chains and straight or branched (C)2-C6) Alkenylene chains, each of which is substituted by RcOR as defined abovecOr is of R'aAnd R'bNR 'as defined above'aR′bThe substitution is carried out by the following steps,
5) Z-CO-CH ═ CHAR, where Z and Ar are as defined above,
with reference to their enantiomers and diastereomers (when they exist), and to their addition salts with pharmaceutically acceptable acids or bases, as well as to their hydrates and solvates thereof, it is understood that:
aryl means phenyl or naphthyl, which optionally contains one or more identical or different substituents selected from: straight or branched chain (C)1-C6) Alkyl (optionally substituted with one or more hydroxyl or halogen groups), hydroxyl, halogen, carboxyl, nitro, amino, linear or branched mono (C)1-C6) Alkylamino, wherein each alkyl moiety may be straightChain or branched di (C)1-C6) Alkylamino, straight-chain or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) Acyl and straight or branched chain (C)1-C6) An alkyl-carbonyloxy group, which is,
heteroaryl means a 5-to 12-membered group which is monocyclic and aromatic or is a bicyclic group of which at least one ring has aromatic character, containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, it being understood that the heteroaryl group may optionally be substituted by one or more identical or different atoms or groups selected from halogen atoms and linear or branched (C)1-C6) Alkyl (optionally substituted with one or more hydroxyl or halogen groups), hydroxyl, straight or branched (C)1-C6) Alkoxy and amino (optionally substituted by one or two straight or branched chains (C)1-C6) Alkyl substituted).
Among heteroaryl groups, mention may be made of thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl and pyrimidinyl groups, but they are not limited thereto.
Among monocyclic 5-to 7-membered heterocycles optionally containing a second heteroatom selected from oxygen and nitrogen in the ring system, mention may be made of pyrrolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, oxazacyclohexylyl (oxazinanyl), morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, azepanyl, oxazepanyl and diazepanyl, without being limited thereto.
Among the pharmaceutically acceptable acids, mention may be made of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, camphoric acid, lysine and the like, without being limited thereto.
Among the pharmaceutically acceptable bases, there may be mentioned, but not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.
According to the invention, the substituents X and Y are preferably hydrogen atoms.
According to the invention, the substituent R1、R3And R4Preferably straight or branched (C)1-C6) An alkyl group.
According to the invention, the substituent R2Preferably a group-ORaWherein R isaAs defined in formula (I).
According to the invention, the substituent R5Preferably a group-ORcWherein R iscAs defined in formula (I); group W1-C(W2) -U-V, wherein W1、W2U and V are as defined for formula (I).
According to the invention, the substituent R5Even more preferably a group-ORcWherein R iscRepresents a hydrogen atom; group W1-C(W2) -U-V, wherein W1And W2Each represents an oxygen atom, U represents a linear or branched chain (C)1-C8) An alkylene chain and V represents a hydrogen atom.
According to the invention, the substituent Z is preferably an oxygen atom.
According to the invention, the substituent Ar is preferably optionally substituted phenyl.
Particularly advantageously, preferred compounds of the invention are:
(±) -cis-2-cinnamoyloxy-1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cisFormula-1-acetoxy-2-cinnamoyloxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (4-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (4-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (2-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (2-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (3-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (2, 4-dichlorocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3,14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (2, 4-dichlorocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (3, 4-dichlorocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (3, 4-dichlorocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (4-bromocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (4-bromocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-hydroxy-6-methoxy-2- (4-methoxy cinnamoyloxy) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-hydroxy-6-methoxy-2- (4-nitro cinnamoyloxy) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-6-methoxy-2- (4-nitrocinnamoyloxy) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]]Acridin-7-one.
The invention also relates to a process for the preparation of a compound of formula (I), characterized in that a compound of formula (II):
x, Y, R therein3And R4R represents a hydrogen atom, a hydroxyl group or a linear or branched (C) group as defined above1-C6) Alkyl, the nitrogen atom of the compound of formula (II) being substituted or unsubstituted, reacting the compound of formula (II) with an alkyl halide or dialkyl sulfate in the presence of a deprotonating agent, in an aprotic polar solvent or under phase transfer conditions to give a compound of formula (III):
x, Y, R, R therein3And R4R 'as defined above'1Represents a straight chain or branched chain (C)1-C6) Alkyl, reacting the compound of formula (III) with an alkylating agent under conventional conditions of organic synthesis to give a compound of formula (IV):
wherein X, Y, R'1、R3And R4R 'as defined above'2Is selected from OR'aWherein R'aRepresents a straight chain or branched chain (C)1-C6) An alkyl group, a carboxyl group,
in which R'2In the case of alkoxy, reacting a compound of formula (IV) with a compound of formula (V):
HNRaRb (V)，
wherein R isaAnd RbAs defined in formula (I),
to give a compound of formula (VI):
wherein X, Y, R'1、R3、R4、RaAnd RbAs defined above, in the above-mentioned manner,
the sum of the compounds of formulae (II), (III), (IV) and (VI) forms the compound of formula (VII):
x, Y, R therein1、R2、R3And R4As defined in formula (I),
reacting a compound of formula (VII):
a) with osmium tetroxide in a polar medium and in the presence of 4-methylmorpholine N-oxide to give compounds of the formula (VIII/a):
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
b) or with potassium permanganate in a polar medium and then NaBH4Treatment under reducing conditions in the presence of a reducing agent to give a compound of formula (VIII/b):
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
the sum of the compounds of formulae (VIII/a) and (VIII/b) forms a compound of formula (VIII), wherein the 2 alcohol groups may be in cis or trans configuration with respect to each other:
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
reacting a compound of formula (VIII) with 1 or 2 equivalents of an anhydride of formula (IX) or an acid chloride of formula (X):
[Ar-CH＝CH-C(O)12O(IX) Ar-HC＝CH-C(O)-Cl(X)，
wherein Ar is as defined for formula (I),
to obtain the formula (I/a)1) Or (I/a)2) Compounds which are particular examples of compounds of formula (I):
x, Y, R therein1、R2、R3、R4And Ar is as defined above，
c) Or with NaN3Reaction in the presence of hydrogen peroxide, followed by a reduction step, to give a compound of formula (XI):
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
reacting a compound of formula (XI) with a compound of formula (IX) or (X) as hereinbefore defined under the same conditions as the reaction of a compound of formula (VIII) with a compound of formula (IX) or (X) to give a compound of formula (I/b)1) Or (I/b)2) Compounds which are particular examples of compounds of formula (I):
x, Y, R therein1、R2、R3、R4And Ar is as defined above, and wherein,
let formula (I/b)1) Or (I/b)2) Optionally reacting the compound with a compound of formula (XII):
R′c-Hal(XII)，
wherein Hal represents halogen, R'cRepresents a group selected from: straight or branched chain (C)1-C6) Alkyl, aryl and aryl- (C)1-C6) Alkyl, wherein the alkyl portion is linear or branched,
to obtain the formula (I/c)1) Or (I/c)2) A compound:
x, Y therein,R1、R2、R3、R4、R′cAnd Ar is as defined above, and wherein,
formula (I/a)1)、(I/b1) And (I/c)1) Compounds and formula (I/a)2)、(I/b2) And (I/c)2) The sum of the compounds each form the formula (I/d)1) And (I/d)2) A compound:
x, Y, R therein1、R2、R3、R4Y and Ar are as defined in formula (I), R5aRepresents a hydroxyl group or NH2Or NHR'cWherein R' c is as defined above,
let formula (I/d)1) The compound is optionally:
a) with an alkylating agent to give a compound of formula (I/e), a particular case of compounds of formula (I):
x, Y, R therein1、R2、R3、R4Y and Ar are as defined above, R5bRepresents a group ORcOr NRcRdWherein R iscAnd RdAs defined in formula (I),
b) with an acid anhydride of formula (XIII) or an acid chloride of formula (XIV):
(R10)2O (XIII) R10-Cl (XIV)，
wherein R is10Is represented by formula C (W)2) -U-V or C (W)2)-W3-T1Wherein W is2、W3U, V and T1As defined in formula (I) to obtainTo compounds of formula (I/f), which are particular examples of compounds of formula (I):
x, Y, R therein1、R2、R3、R4Y, Ar and R10As defined above, W1As defined in formula (I),
the compounds (I/a) to (I/f) constitute the sum of the compounds of the invention, which are, if necessary, purified according to conventional purification techniques, if desired separated into their different isomers according to conventional separation techniques, and, if desired, converted into their addition salts with pharmaceutically acceptable acids or bases.
The compounds of the formulae (II), (V), (IX), (X), (XII), (XIII) and (XIV) are either commercially available products or are obtained according to conventional methods of organic synthesis, which are well known to the person skilled in the art.
The compounds of formula (I) have particularly valuable antitumor properties. They have excellent in vitro cytotoxicity against murine and human tumor-derived cell lines by specifically blocking the cell cycle and have in vivo activity in mice against transplantable murine and human tumors. The characteristic properties of these compounds make them useful in therapy as antitumor agents.
The invention also relates to pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I), an enantiomer or diastereomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions of the present invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transdermal, intravaginal, rectal, nasal, lingual, buccal, ocular or respiratory administration.
The pharmaceutical compositions for parenteral injection according to the invention include in particular aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions, and also sterile powders for the reconstitution of injectable solutions or dispersions.
The pharmaceutical compositions of the invention for solid oral administration include especially tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, and for liquid oral, nasal, buccal or ocular administration include especially emulsions, solutions, suspensions, drops, syrups and aerosols.
Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and pharmaceutical compositions for transdermal or transdermal administration include, inter alia, powders, aerosols, creams, ointments, gels and patches.
The pharmaceutical compositions mentioned above illustrate the invention but do not limit it in any way.
Among the inert, non-toxic, pharmaceutically acceptable excipients or carriers, mention may be made, by way of non-limiting example, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, extenders, disintegrants, retarding agents, lubricants, absorbents, suspending agents, colorants, fragrances and the like.
Useful dosages will vary depending upon the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and the administration of any relevant treatment. The dosage ranges from 0.1mg to 1000mg per day, administered one or more times.
Detailed Description
The following examples illustrate the invention but do not limit it in any way.
The starting materials used are products which are known or prepared according to known operating methods. Each preparation gives synthetic intermediates useful in the preparation of the compounds of the invention.
The structures of the compounds described in the examples and preparations were determined according to the usual spectroscopic techniques (infrared, nuclear magnetic resonance, mass spectrometry).
Melting points were determined with a Kofler hot plate or a hot plate under a microscope. When a compound is in the form of a salt, the melting point given refers to the melting point of the salt form of the compound.
Preparation example 1: 4-chlorocinnamyl chloride
7ml of thionyl chloride are added dropwise, with stirring, to a suspension of 1.75g of 4-chlorocinnamic acid in 40ml of anhydrous dichloromethane at 43 ℃. After 3 hours of reaction, the unreacted excess acid remained undissolved and was removed by decantation. The filtrate was evaporated to dryness to give 4-chlorocinnamoyl chloride.
Preparation example 2: 2-chlorocinnamyl chloride
The product was obtained by following the procedure of preparation example 1, using 2-chlorocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 3: 3-chlorocinnamyl chloride
The product was obtained by following the procedure of preparation example 1, using 3-chlorocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 4: 2, 4-dichloro-cinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 2, 4-dichlorocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 5: 3, 4-dichloro-cinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 3, 4-dichlorocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 6: 4-Bromocinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 4-bromocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 7: 4-methoxy cinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 4-methoxycinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 8: 4-Nitrocinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 4-nitrocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 9: 4-Fluorocinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 4-fluorocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 10: 3, 4-dimethoxy cinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 3, 4-dimethoxycinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 11: 3-trifluoromethyl cinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 3-trifluoromethylcinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 12: 3-bromolauroyl chloride
The product was obtained by following the procedure of preparation example 1, using 3-bromocinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 13: 4-trifluoromethyl cinnamoyl chloride
The product was obtained by following the procedure of preparation example 1, using 4-trifluoromethylcinnamic acid instead of 4-chlorocinnamic acid.
Preparation example 14: 3- (1-naphthyl) acryloyl chloride
This product was obtained by following the procedure of preparation example 1, using 3- (1-naphthyl) acrylic acid instead of 4-chlorocinnamic acid.
Preparation example 15: 3- (2-naphthyl) acryloyl chloride
This product was obtained by following the procedure of preparation example 1, using 3- (2-naphthyl) acrylic acid instead of 4-chlorocinnamic acid.
Example 1: (±) -cis-2-cinnamoyloxy-1-hydroxy-6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
619mg of cinnamoyl chloride was added to a solution of 520mg of (. + -.) cis-1, 2-dihydroxy-6-methoxy-3, 3, 14-trimethyl-2, 3, 7, 14-tetrahydro-1H-benzo [ b ] pyrano [3, 2-H ] acridin-6-one (EP 1042326) in 15ml of anhydrous pyridine. After stirring at 20 ℃ for 48 hours, the solvent was evaporated to dryness under reduced pressure at a temperature not exceeding 20 ℃. Chromatography on silica gel (dichloromethane followed by a gradient from 0.2 to 1% methanol) followed by precipitation from ethanol isolated to yield 233mg of the desired product.
Mass spectrometry(DIC/NH3)：m/z＝536[MH]+
Example 2: (±) -cis-1-acetoxy-2-cinnamoyloxy-6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
3ml of acetic anhydride and 7mg of 4-dimethylaminopyridine are added to a solution of 170mg of the compound from example 1 in 5ml of anhydrous pyridine. The reaction mixture was stirred at ambient temperature for 5 hours and then poured into 20ml of ice-cooled water. The resulting precipitate was filtered off, washed with water, dried over phosphorus pentoxide under vacuum and isolated to yield 130mg of the desired product.
Mass spectrometry(ES+)：m/z＝578[MH]+
Example 3: (±) -cis-2- (4-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 1 instead of cinnamoyl chloride.
Mass spectrometry(ES+): m/z 569 and 571 MH]+
Example 4: (±) -cis-1-acetoxy-2- (4-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 3.
Mass spectrometry(ES+): 612 and 614[ MH ] m/z]+
Example 5: (±) -cis-2- (2-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 2 instead of cinnamoyl chloride.
Mass spectrometry(ES+): 570 and 572 MH]+
Example 6: (±) -cis-1-acetoxy-2- (2-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 5.
Mass spectrometry(ES+): 612 and 614[ MH ] m/z]+
Example 7: (±) -cis-2- (3-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 3 instead of cinnamoyl chloride.
Mass spectrometry(ES+): 570 and 572 MH]+
Example 8: (+) -cis-1-acetoxy-2- (3-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 7.
Mass spectrometry(ES+): 612 and 614[ MH ] m/z]+
Example 9: (±) -cis-2- (2, 4-dichlorocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 4 instead of cinnamoyl chloride.
Mass spectrometry(ES+): 604, 606 and 608[ MH ] m/z]+
Example 10: (±) -cis-1-acetoxy-2- (2, 4-dichlorocinnamoyloxy) -6-methoxy
-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 9.
Mass spectrometry(ES+): m/z 646, 648 and 650[ MH ]]+
Example 11: (±) -cis-2- (3, 4-dichlorocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 5 instead of cinnamoyl chloride.
Mass spectrometry(ES+): 604, 606 and 608[ MH ] m/z]+
Example 12: (±) -cis-1-acetoxy-2- (3, 4-dichlorocinnamoyloxy) -6-methoxy
-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 11.
Mass spectrometry(ES+): m/z 646, 648 and 650[ MH ]]+
Example 13: (±) -cis-2- (4-bromocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl
1, 2, 3, 14-tetrahydro-1H-benzo [ b ] yl]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 6 instead of cinnamoyl chloride.
Mass spectrometry(ES+): 614 and 616[ MH ] m/z]+
Example 14: (±) -cis-1-acetoxy-2- (4-bromocinnamoyloxy) -6-methoxy-3, 3, 14-
Trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 13.
Mass spectrometry(ES+): 656 and 658[ MH ] m/z]+
Example 15: (±) -cis-1-hydroxy-6-methoxy-2- (4-methoxy cinnamoyloxy) -3, 3, 14-
Trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 7 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝566[MH]+
Example 16: (±) -cis-1-acetoxy-6-methoxy-2- (4-methoxy cinnamoyloxy) methoxy
Yl) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 15.
Mass spectrometry(ES+)：m/z＝608[MH]+
Example 17: (±) -cis-6-methoxy-1, 2-di- (4-methoxy cinnamoyloxy) -3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
This product was obtained during the procedure described in example 15.
Mass spectrometry(ES+)：m/z＝726[MH]+
Example 18: (±) -cis-1-hydroxy-6-methoxy-2- (4-nitro cinnamoyloxy) -3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 8 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝581[MH]+
Example 19: (±) -cis-1-acetoxy-6-methoxy-2- (4-nitrocinnamoyloxy) methoxy
Yl) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 18.
Mass spectrometry(ES+)：m/z＝623[MH]+
Example 20: (±) -cis-1, 2-bis- (4-fluorocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 9 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝703[MH]+
Example 21: (±) -cis-2- (3, 4-dimethoxy cinnamoyloxy) -1-hydroxy-6-methoxy
-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 10 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝596[MH]+
Example 22: (+/-) -Cis-1-acetoxy-2- (3, 4-dimethoxy cinnamoyloxy) -6-methoxy
-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 21.
Mass spectrometry(ES+)：m/z＝638[MH]+
Example 23: (±) -cis-1-hydroxy-6-methoxy-2- (3-trifluoromethyl cinnamoyloxy) -3, 3, 14-
Trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained according to the procedure of example 1, using the compound of preparation 11 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝604，605[MH]+
Example 24: (+ -) -cis-1-acetoxyl-6-methoxy-2- (3-trifluoromethyl cinnamoyloxy) propanoic acid
3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained by following the procedure of example 2 using the compound of example 23.
Mass spectrometry(ES+)：m/z＝646，647[MH]+
Example 25: (±) -cis-2- (3-bromocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl
-1, 2, 3, 14-tetrahydro-7H-benzo [ b ]]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained according to the procedure of example 1, using the compound of preparation 12 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝614，616[MH]+；636，638[MNa]+
Example 26: (±) -cis-1-acetoxy-2- (3-bromocinnamoyloxy) -6-methoxy-3, 3, 14-tris
Methyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-ones
The product was obtained by following the procedure of example 2 using the compound of example 25.
Mass spectrometry(ES+)：m/z＝656，658[MH]+
Example 27: (±) -cis-1-hydroxy-6-methoxy-2- (4-trifluoromethyl cinnamoyloxy) -3, 3, 14-
Trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained according to the procedure of example 1, using the compound of preparation 13 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝604，605[MH]+
Example 28: (+ -) -cis-1-acetoxyl-6-methoxy-2- (4-trifluoromethyl cinnamoyloxy) propanoic acid
3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained by following the procedure of example 2 using the compound of example 27.
Mass spectrometry(ES+)：m/z＝646，647[MH]+
Example 29: (±) -cis-1-hydroxy-6-methoxy-2- (3- (1-naphthyl) -acryloyloxy) -3, 3, 14-
Trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained according to the procedure of example 1, using the compound of preparation 14 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝586[MH]+
Example 30: (±) -cis-1-acetoxy-6-methoxy-2- (3-1-naphthyl acryloyloxy)
Yl) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained by following the procedure of example 2 using the compound of example 29.
Mass spectrometry(ES+)：m/z＝628[MH]+
Example 31: (±) -cis-1-hydroxy-6-methoxy-2- (3- (2-naphthyl) acryloyloxy) -3, 3, 14-
Trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ b]Pyrano [3, 2-h ]]-acridin-7-one
The product was obtained according to the procedure of example 1, using the compound of preparation 15 instead of cinnamoyl chloride.
Mass spectrometry(ES+)：m/z＝586[MH]+
Example 32: (±) -cis-1-acetoxy-2- (3, 4-dichlorocinnamoyloxy) -6-methoxy
-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-one (enantiomer a)
The alpha enantiomer of the compound of example 12 was obtained by chiral column chiralcel oc separation.
Example 33: (±) -cis-1-acetoxy-2- (3, 4-dichlorocinnamoyloxy) -6-methoxy
-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]]Acridin-7-one (enantiomer beta)
The beta enantiomer of the compound of example 12 was obtained by chiral column chiralcel oc separation.
Pharmacological study of the Compounds of the invention
Example A: in vitro cytotoxicity
2 cell lines were used:
-1 murine leukemia cell line: l1210
-1 human epidermoid carcinoma cell line: KB-3-1
Cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 2mM glutamine, 50 units/ml penicillin, 50 μ g/ml streptomycin, and 10mM Hepes at pH 7.4. Cells were distributed on microplates and exposed to cytotoxic compounds. Cells were then incubated for 2 days (L1210) or 4 days (KB-3-1). And then analyzed by colorimetric analysis, i.e. microculture tetrazolium salt analysis (Cancer res.1987,47939-942) for quantification of viable cell number.
IC for result50(the concentration of cytotoxic agent that inhibits the proliferation of treated cells by 50%). For example, IC of the Compound of example 2 on L121050IC at 0.59. mu.M for KB-3-150It was 0.151. mu.M.
Example B: in vivo Activity
Antitumor activity against C38 colon adenocarcinoma
Tumor fragments weighing approximately 30mg of C38 colon adenocarcinoma were implanted under the skin of B6D2F1 mice (Iffa Credo, france) on day 0. After tumor growth, mice were divided into control group (18 animals) and treatment group (6 or 7 animals), which were similar in tumor size. Each product was administered by intravenous route at its Maximum Tolerated Dose (MTD), MTD/2 and MTD/4, once weekly for 3 weeks (on days 10, 17 and 24).
Tumors were measured twice a week and tumor volume was calculated according to the following formula: volume (mm)3) Long (mm) functionWidth (mm)2)/2。
The antitumor activity was expressed as% T/C:
v0 and Vt are the initial volume of the tumor and the volume at the measurement time t, respectively.
The optimal dose is the dose that gives the lowest T/C value without toxicity (early death or weight loss over 20%).
For example, the compound of example 33 showed 50% of the antitumor activity at the optimal dose of 4mg/kg, whereas the oleanoline showed 27% of the antitumor activity at the optimal dose of 100mg/kg, thus demonstrating their strong therapeutic potential.
Example C: pharmaceutical composition
1000 tablets of a formulation containing 10mg of active ingredient per tablet were prepared:
the
The
A
The
.
The.
Claims (12)
1. A compound of formula (I):
wherein:
x and Y, which may be identical or different, represent, independently of one another, a group selected from:
-a hydrogen and a halogen atom,
-hydroxy, linear or branched (C)1-C6) Alkoxy, nitro, cyano, straight or branched chain (C)1-C6) Alkyl (optionally substituted with one or more groups selected from hydroxyl and halogen) and straight or branched chain (C)2-C6) Alkenyl and
-formula-NRaRbWherein:
Raand RbMay be the same or different and independently represent a hydrogen atom and a linear or branched chain (C)1-C6) The radical of an alkyl group,
or RaAnd RbTogether with the nitrogen atom to which they are attached form a monocyclic 5-to 7-membered heterocyclic ring optionally containing a second heteroatom selected from oxygen and nitrogen in the ring system,
it is to be understood that the substituents X and Y may be present independently of each other on either of two adjacent phenyl rings,
z represents an oxygen atom or NRcWherein R iscRepresents a group selected from: hydrogen atom, straight or branched chain (C)1-C6) Alkyl, aryl and aryl- (C)1-C6) Alkyl, wherein the alkyl portion is linear or branched,
ar represents an aryl or heteroaryl group,
·R1represents a hydrogen atom or a linear or branched chain (C)1-C6) An alkyl group, a carboxyl group,
·R2represents a group selected from: hydrogen atom, straight or branched chain (C)1-C6) Alkyl, -ORaand-NRaRbWherein R isaAnd RbAs defined above, in the above-mentioned manner,
·R3and R4May be the same or different and independently represent a hydrogen atom or a linear or branched chain (C)1-C6) An alkyl group, a carboxyl group,
·R5represents a group selected from:
1) a hydrogen atom, and a nitrogen atom,
2)ORcand NRcRdA group wherein:
Rcas defined above and RdAs to RcAs is defined in the above-mentioned publication,
3)W1-C(W2) -U-V, wherein:
α)W1represents an oxygen atom or NRc(wherein R iscAs defined above),
β)W2represents an oxygen atom, and represents an oxygen atom,
γ) U represents a single bond or a linear or branched (C)1-C8) Alkylene chains or straight or branched chains
(C2-C8) An alkenylene chain in which the alkylene group is bonded to,
δ) V represents a group selected from:
-a hydrogen atom,
-an aryl group and a heteroaryl group,
-ORc、CO2Rc、CORc、CONR′aR′b、NR′aR′b、N(Rc)-CO2R′cand N (R)c)-COR′cGroup, wherein RcR 'as defined above'cAs to RcAnd R 'is as defined'aAnd R'bMay be the same or different and independently represent a group selected from: hydrogen atom, straight or branched chain (C)1-C6) Alkyl, aryl and aryl- (C)1-C6) Alkyl, wherein the alkyl moiety is linear or branched, or R'aAnd R'bTogether with the nitrogen atom to which they are attached form a monocyclic 5-to 7-membered heterocyclic ring optionally containing a second heteroatom selected from oxygen and nitrogen in the ring system,
4)W1-C(W2)-W3-T1wherein:
α)W1and W2As defined above, in the above-mentioned manner,
β)W3represents an oxygen atom or NRcWherein R iscAs defined above, in the above-mentioned manner,
γ)T1represents a group selected from:
-a hydrogen atom,
-linear or branched (C)1-C6) An alkyl group, a carboxyl group,
-linear or branched (C)2-C6) An alkenyl group which is a radical of an alkylene group,
aryl, aryl- (C)1-C6) Alkyl, wherein the alkyl portion is linear or branched,
-linear or branched (C)1-C6) Alkylene chains and straight or branched (C)2-C6) Alkenylene chains, each of them being represented by RcOR as defined abovecOr is of R'aAnd R'bNR 'as defined above'aR′bThe substitution is carried out by the following steps,
5) Z-CO-CH ═ CHAR, where Z and Ar are as defined above,
their enantiomers and diastereomers, when present, and their addition salts with a pharmaceutically acceptable acid or base, as well as hydrates and solvates thereof,
it should be understood that:
aryl means phenyl or naphthyl, which optionally contains one or more identical or different substituents selected from: straight or branched chain (C)1-C6) Alkyl (optionally substituted with one or more hydroxyl or halogen groups), hydroxyl, halogen, carboxyl, nitro, amino, linear or branched mono (C)1-C6) Alkylamino, di (C) wherein each alkyl moiety may be straight or branched chain1-C6) Alkylamino, straight-chain or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) Acyl and straight or branched chain (C)1-C6) An alkyl-carbonyloxy group, which is,
heteroaryl means a 5-to 12-membered group which is monocyclic and aromatic or is a bicyclic group of which at least one ring has aromatic character, containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, it being understood that the heteroaryl group may optionally be substituted by one or more identical or different atoms or groups selected from halogen atoms and linear or branched (C)1-C6) Alkyl (optionally substituted with one or more hydroxyl or halogen groups), hydroxyl, straight or branched (C)1-C6) Alkoxy and amino (optionally substituted by one or two straight or branched chains (C)1-C6) Alkyl substituted).
2. Compounds of formula (I) according to claim 1, characterized in that X and Y represent a hydrogen atom, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.
3. A compound of formula (I) according to claim 1 or claim 2, characterised in that R is1、R3And R4Represents a straight chain or branched chain (C)1-C6) Alkyl, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
4. A compound of formula (I) according to any one of claims 1 to 3, characterized in that R2Represents a group-ORaWherein R isaAs defined in formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
5. A compound of formula (I) according to any one of claims 1 to 4, characterized in that R5Represents a group-ORcOr W1-C(W2) -U-V, wherein Rc、W1、W2U and V are as defined in formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
6. A compound of formula (I) according to any one of claims 1 to 5, characterized in that R5Represents a group-ORcWherein R iscRepresents a hydrogen atom, or R5Represents a group W1-C(W2) -U-V, wherein W1And W2Each represents an oxygen atom, U represents a linear or branched chain (C)1-C8) Alkylene chain, V represents a hydrogen atom, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
7. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that Z represents an oxygen atom, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that Ar represents an optionally substituted phenyl group, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
9. A compound of formula (I) according to claim 1, which is:
(±) -cis-2-cinnamoyloxy-1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2-cinnamoyloxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (4-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (4-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (2-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3,14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (2-chlorocinnamyl oxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (3-chlorocinnamyl oxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (2, 4-dichlorocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (2, 4-dichlorocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (3, 4-dichlorocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (3, 4-dichlorocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-2- (4-bromocinnamoyloxy) -1-hydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-2- (4-bromocinnamoyloxy) -6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-hydroxy-6-methoxy-2- (4-methoxy cinnamoyloxy) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-hydroxy-6-methoxy-2- (4-nitro cinnamoyloxy) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b]Pyrano [3, 2-h ]](ii) an acridin-7-one,
(±) -cis-1-acetoxy-6-methoxy-2- (4-nitrocinnamoyloxy) -3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-1H-benzo [ b ]]Pyrano [3, 2-h ]](ii) an acridin-7-one,
their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
10. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that compounds of formula (II) are used as starting materials:
x, Y, R therein3And R4R represents a hydrogen atom, a hydroxyl group or a linear or branched (C) group as defined above1-C6) Alkyl, the nitrogen atom of the compound of formula (II) being substituted or unsubstituted, reacting the compound of formula (II) with an alkyl halide or dialkyl sulfate in the presence of a deprotonating agent, in an aprotic polar solvent or under phase transfer conditions to give a compound of formula (III):
x, Y, R, R therein3And R4R 'as defined above'1Represents a straight chain or branched chain (C)1-C6) Alkyl, reacting the compound of formula (III) with an alkylating agent under conventional conditions of organic synthesis to give a compound of formula (IV):
wherein X, Y, R'1、R3And R4R 'as defined above'2Is selected from OR'aWherein R'aRepresents a straight chain or branched chain (C)1-C6) An alkyl group, a carboxyl group,
in which R'2In the case of alkoxy, reacting a compound of formula (IV) with a compound of formula (V):
HNRaRb (V)，
wherein R isaAnd RbAs defined in formula (I),
to give a compound of formula (VI):
wherein X, Y, R'1、R3、R4、RaAnd RbAs defined above, in the above-mentioned manner,
the sum of the compounds of formulae (II), (III), (IV) and (VI) forms the compound of formula (VII):
x, Y, R therein1、R2、R3And R4As defined in formula (I),
reacting a compound of formula (VII):
a) with osmium tetroxide in a polar medium and in the presence of 4-methylmorpholine N-oxide to give compounds of the formula (VIII/a):
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
b) or with potassium permanganate in a polar medium and then NaBH4Treatment under reducing conditions in the presence of a reducing agent to give a compound of formula (VIII/b):
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
the sum of the compounds of formulae (VIII/a) and (VIII/b) forms a compound of formula (VIII), wherein the 2 alcohol groups may be in cis or trans configuration with respect to each other:
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
reacting a compound of formula (VIII) with 1 or 2 equivalents of an anhydride of formula (IX) or an acid chloride of formula (X):
[Ar-CH＝CH-C(O)]2O(IX) Ar-HC＝CH-C(O)-Cl(X)，
wherein Ar is as defined for formula (I),
to obtain the formula (I/a)1) Or (I/a)2) Compounds which are particular examples of compounds of formula (I):
x, Y, R therein1、R2、R3、R4And Ar is as defined above, and wherein,
c) or with NaN3Reaction in the presence of hydrogen peroxide, followed by a reduction step, to give a compound of formula (XI):
x, Y, R therein1、R2、R3And R4As defined above, in the above-mentioned manner,
reacting a compound of formula (XI) with a compound of formula (IX) or (X) as hereinbefore defined under the same conditions as the reaction of a compound of formula (VIII) with a compound of formula (IX) or (X) to give a compound of formula (I/b)1) Or (I/b)2) Compounds which are particular examples of compounds of formula (I):
x, Y, R therein1、R2、R3、R4And Ar is as defined above, and wherein,
let formula (I/b)1) Or (I/b)2) Optionally reacting the compound with a compound of formula (XII):
R′c-Hal(XII)，
wherein Hal represents halogen, R'cRepresents a group selected from: straight or branched chain (C)1-C6) Alkyl, aryl and aryl- (C)1-C6) Alkyl, wherein the alkyl portion is linear or branched,
to obtain the formula (I/c)1) Or (I/c)2) A compound:
x, Y, R therein1、R2、R3、R4、R′cAnd Ar is as defined above, and wherein,
formula (I/a)1)、(I/b1) And (I/c)1) Compounds and formula (I/a)2)、(I/b2) And (I/c)2) The sum of the compounds each form the formula (I/d)1) And (I/d)2) A compound:
x, Y, R therein1、R2、R3、R4Y and Ar are as defined in formula (I), R5aRepresents a hydroxyl group or NH2Or NHR'cWherein R'cAs defined above, in the above-mentioned manner,
let formula (I/d)1) The compound is optionally:
a) with an alkylating agent to give a compound of formula (I/e), a particular case of compounds of formula (I):
x, Y, R therein1、R2、R3、R4Y and Ar are as defined above, R5bRepresents a group ORcOr NRcRdWherein R iscAnd RdAs defined in formula (I),
b) with an acid anhydride of formula (XIII) or an acid chloride of formula (XIV):
(R10)2O (XIII) R10-Cl (XIV)，
wherein R is10Is represented by formula C (W)2) -U-V or C (W)2)-W3-T1Wherein W is2、W3U, V and T1As defined in formula (I), to give compounds of formula (I/f), which are particular examples of compounds of formula (I):
x, Y, R therein1、R2、R3、R4Y, Ar and R10As defined above, W1As defined in formula (I),
the compounds (I/a) to (I/f) constitute the sum of the compounds of the invention, which are, if necessary, purified according to conventional purification techniques, if desired separated into their different isomers according to conventional separation techniques, and, if desired, converted into their addition salts with pharmaceutically acceptable acids or bases.
11. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 9 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
12. The pharmaceutical composition according to claim 11, comprising at least one active ingredient according to any one of claims 1 to 9, which is a pharmaceutical composition for use as a medicament in the treatment of cancer.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0413682 | 2004-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1088328A true HK1088328A (en) | 2006-11-03 |
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