HK1070360B

HK1070360B - Benzo[a]pyrano[3,2-h]acridin-7-one compounds, a process for their preparation and pharmaceutical compositions thereof

Info

Publication number: HK1070360B
Application number: HK05103023.0A
Authority: HK
Inventors: Michel Koch; Francois Tillequin; Sylvie Michel; John Hickman; Alain Pierre; Stephane Leonce; Bruno Pfeiffer; Pierre Renard
Original assignee: Les Laboratoires Servier
Priority date: 2003-06-25
Filing date: 2005-04-11
Publication date: 2007-05-04

Description

Benzo [ a ] pyrano [3, 2-h ] acridin-7-one compounds, process for their preparation and pharmaceutical compositions containing them

Technical Field

The present invention relates to novel benzo [ a ] pyrano [3, 2-h ] acridin-7-one compounds, to a process for their preparation and to pharmaceutical compositions containing them.

Background

The compounds of the invention are derivatives of acronycine, an alkaloid that has been demonstrated to have anti-cancer properties in experimental models (j.pharm.sci., 1966,55(8),758-768). However, despite its very broad spectrum of activity, elaeagrinine is low in potency and moderate in activity. Furthermore, the low solubility of this compound limits its bioavailability and its use in pharmaceutical compositions administered by the intravenous route.

Various modifications to this molecule have been made, such as those described in j.med.chem., 1996, 39, 4762-. However, the requirement for anticancer therapy requires continuous development of new anticancer agents in order to obtain drugs having both higher activity and better tolerance. More specifically, solid tumors are a major problem in anticancer chemotherapy because of their intrinsic and/or acquired resistance to existing compounds. Therefore, it is of primary importance to obtain compounds with powerful cytotoxic activity, with the widest possible range, in order to obtain the most effective treatment of all neoplastic diseases.

Disclosure of Invention

In addition to the fact that the compounds of the invention are novel, they also have surprising cytotoxic activity in vitro and in vivo, which is higher than that observed hitherto. The compounds found by the applicant thus have anti-cancer properties, which make them particularly useful for the treatment of cancer. Among the types of cancer that can be treated with the compounds of the present invention, mention may be made, without limitation, of adenocarcinomas and carcinomas, sarcomas, gliomas and leukemias.

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, straight or branched chain (C)₂-C₆) Alkenyl and straight-chain or branched (C)₁-C₆) Polyhaloalkyl, and

-formula-NR_aR_bA group wherein:

R_aand R_bWhich may be identical or different, independently of one another represent a group selected from: hydrogen atom, -C (O) -CF₃-、-C(O)-NH₂And optionally by a group NR'_aR′_bSubstituted straight or branched chain (C)₁-C₆) An alkyl group, wherein:

R′_aand R'_bWhich may be identical or different, independently of one another represent a group selected from: hydrogen atom, straight or branched chain (C)₁-C₆) Alkyl, aryl and aryl in which the alkyl moiety is linear or branched- (C)₁-C₆) Alkyl, or R'_aAnd R'_bTogether with the nitrogen atom which carries them, form a monocyclic 5-to 7-membered heterocyclic ring which optionally contains a further heteroatom selected from oxygen and nitrogen in the ring system,

or R_aAnd R_bTogether with the nitrogen atom which carries them, form a monocyclic 5-to 7-membered heterocyclic ring which optionally contains a further heteroatom selected from oxygen and nitrogen in the ring system,

with the following conditions: the substituents X and Y may be present on either of two adjacent phenyl rings,

●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 and straight or branched chain (C)₁-C₆) Alkyl, -OR ″)_a、-NR′_aR′_b、-O-T_a-OR″_a、-NR″_a-T_a-NR′_aR′_b、-NR″_a-C(O)-T_aH、-O-C(O)-T_aH、-O-T_a-NR′_aR′_b、-NR″_a-Ta-OR″_a、-NR″_a-T_a-CO₂R″_aand-NR_a-C(O)-T_a-NR′_aR′_bA group wherein:

*T_arepresents a straight chain or branched chain (C)₁-C₆) An alkylene chain, which is a linear chain of alkylene,

*R′_aand R'_bAs defined above, the above-mentioned materials,

*R″_arepresents a hydrogen atom and a linear or branched chain (C)₁-C₆) The radical of an alkyl group,

●R₃and R₄May be the same or different and independently represent a hydrogen atom or a linear or branched chain (C)₁-C₆) Alkyl, or R₃And R₄Together with the carbon atom bearing them form a monocyclic 3-to 6-membered ring group,

● A represents a group of the formula:

a)-CH(R₅)-CH(R₆) -, wherein:

R₅and R₆Which may be identical or different, independently of one another represent a group selected from:

1) a hydrogen atom, and a nitrogen atom,

2)OR_c、NR_cR_dand SR_cA group wherein:

-R_cand R_dWhich may be identical or different, independently of one another represent a group selected from: hydrogen atom, straight or branched chain (C)₁-C₆) Alkyl, aryl and aryl in which the alkyl moiety is linear or branched- (C)₁-C₆) Alkyl, and C (O) -R_eGroup, wherein R_eRepresents a group selected from a hydrogen atom, an aryl group and NR *_aR*_bGroup of radicals in which R *_aAnd R *_bMay be the same or different and each represents a hydrogen atom or a linear or branched chain (C)₁-C₆) Alkyl, or R *_aAnd R *_bTogether with the nitrogen atom which carries them, form a monocyclic 5-to 7-membered heterocyclic ring which optionally contains a further heteroatom selected from oxygen and nitrogen in the ring system,

3)W₁-C(W₂) -U-V, wherein:

α)W₁represents an oxygen atom, a sulfur atom or NR_cWherein R is_cAs defined above, the above-mentioned materials,

β)W₂represents an oxygen atom or a sulfur atom,

γ) U represents a linear or branched chain (C)₁-C₈) Alkylene chains or straight or branched chains (C)₂-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,

-OR_c、CO₂R_c、COR_c、CONR′_aR′_b、NR′_aR′_b、N(R_c)-CO₂R′_cand N (R)_c)-COR′_cGroup, wherein R'_a、R′_bAnd R_cR 'as hereinbefore defined'_cRepresents a group selected from: hydrogen atom, straight or branched chain (C)₁-C₆) Alkyl, aryl and aryl in which the alkyl moiety is linear or branched- (C)₁-C₆) An alkyl group, a carboxyl group,

ε) when W₂When not representing an oxygen atom and at the same time V does not represent a group selected from the group consisting of:

-a hydrogen atom,

-an aryl group,

-NH₂，

4)W₁-C(W₂)-W₃-T₁wherein:

α)W₁and W₂As defined above, the above-mentioned materials,

β)W₃represents an oxygen atom, a sulfur atom or NR_cWherein R is_cAs defined above, the above-mentioned materials,

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 in which the alkyl moiety is linear or branched- (C)₁-C₆) An alkyl group, a carboxyl group,

-linear or branched (C)₁-C₆) Alkylene chains and straight or branched (C)₂-C₆) Alkenylene chains, each of which is OR_cIs substituted by radicals in which R_cAs previously defined, or by NR'_aR′_bSubstituted, wherein R'_aAnd R'_bAs defined above, the above-mentioned materials,

5)W₁-S(O)_n-W₃-T₁wherein:

α)W₁、W₃and T₁As defined above, the above-mentioned materials,

beta) n represents an integer selected from 1 and 2,

6)W₁-S(O)_n-U '-V', wherein:

alpha) U' represents a linear or branched chain (C)₁-C₈) Alkylene chains or straight or branched chains (C)₂-C₈) An alkenylene chain in which the alkylene group is bonded to,

β) V' represents a group selected from:

-a hydrogen atom,

-an aryl group,

-OR_c、CO₂R_c、COR_c、CONR′_aR′_b、NR′_aR′_b、N(R_c)-CO₂R′_cand N (R)_c)-COR′_cGroup, wherein R'_a、R′_b、R_cAnd R'_cAs defined above, and, as such,

γ)W₁and n is as defined above, and n is,

7)C(W₂)-T₁wherein W is₂And T₁As defined above, the above-mentioned materials,

or R₅And R₆Together form:

1) radical (I)Or

Wherein Z represents an oxygen atom or a sulfur atom,

2) group-O- (CH)₂)_m-O-, wherein m represents an integer from 1 to 4, inclusive,

3) radical (I)Or

Wherein B represents a single bond, a straight chain or a branched chain (C)₁-C₆) Alkylene chains or straight or branched chains (C)₂-C₆) An alkenylene chain in which the alkylene group is bonded to,

or R₅And R₆Together with the carbon atom bearing them forming an oxirane group or optionally, by a straight or branched chain on the nitrogen atom (C)₁-C₆) An alkyl-substituted aziridine group, or a pharmaceutically acceptable salt thereof,

b)-CH＝C(R₇) -or-C (R)₇) CH-where R₇Represents a group selected from:

-a hydrogen atom,

-OR″_a、W₁-C(W₂)-U-V、W₁-C(W₂)-W₃-T₁、W₁-S(O)_n-W₃-T₁、W₁-S(O)_n-U '-V' and C (W)₂)-T₁Group, wherein R ″)_a、W₁、W₂、W₃、U、V、U′、V′、T₁And n is as previously defined, or

c)-C(O)-CH(R₈) -or-CH (R)₈) -C (O) -, wherein R₈Represents a group selected from:

-a hydrogen atom,

-linear or branched (C)₁-C₆) Alkyl-carbonyloxy and OR_aGroup, wherein R ″)_aAs defined above, the above-mentioned materials,

their enantiomers, diastereomers and N-oxides and their addition salts with a pharmaceutically acceptable acid or base,

aryl is understood to mean phenyl or naphthyl, which optionally contains one or more identical or different substituents selected from the group consisting of: hydroxy, halogen, carboxy, nitro, amino, straight or branched chain (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,

for monocyclic 5-to 7-membered heterocyclic rings optionally containing a further heteroatom selected from oxygen and nitrogen in the ring system, non-limiting examples which may be mentioned are the following groups: pyrrolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, imidazolyl, piperidinyl, oxazinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidyl, piperazinyl, azepanyl, oxazepanyl, diazepanyl,

for monocyclic 3-to 6-membered ring groups, the following may be mentioned as non-limiting examples: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Among the pharmaceutically acceptable acids, mention may be made, without being limited thereto, 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.

Among the pharmaceutically acceptable bases, mention may be made, without being limited thereto, of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.

According to an advantageous embodiment of the invention, preferred compounds are compounds of formula (LA):

x, Y therein,R₁、R₂、R₃、R₄、R₅And R₆As defined for formula (I).

Preferred compounds of the formula (IA) are those in which R is₅And R₆May be the same OR different and each represents the formula-OR_c、W₁-C(W₂)-U-V、W₁-C(W₂)-W₃-T₁、C(W₂)-T₁A group, or R₅And R₆Together form a radicalWherein R is_c、W₁、W₂、W₃、U、V、T₁And Z is as defined for formula (I).

In a particularly interesting aspect, preferred compounds of formula (IA) are those wherein R is₅And R₆Are identical and each represents the formula-OR_cGroup, wherein R_cRepresents a hydrogen atom.

In another aspect of particular interest, preferred compounds of formula (IA) are those wherein R is₅And R₆May be the same or different and each represents the formula W₁-C(W₂) A group of-U-V wherein W₁And W₂Each represents an oxygen atom, U is as defined for formula (I) and V represents a hydrogen atom, or U represents a linear or branched chain (C)₁-C₈) Alkylene chain and V represents a group NR'_aR′_bWherein R'_aAnd R'_bMay be the same or different and each represents a hydrogen atom or a linear or branched chain (C)₁-C₆) An alkyl group.

In an even more interesting aspect, preferred compounds of formula (IA) are those wherein R is₅Is represented by the formula-OR_cGroup, wherein R_cRepresents a hydrogen atom, and R₆Representative formula W₁-C(W₂) A group of-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.

In another even more interesting aspect, preferred compounds of formula (IA) are those wherein R is₅Is represented by the formula-OR_cOr W₁-C(W₂) -U-V group, wherein R_cRepresents a hydrogen atom, 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, and R₆Representative formula W₁-C(W₂) A group of-U-V wherein W₁And W₂Each represents an oxygen atom, U represents a linear or branched chain (C)₂-C₈) An alkenylene chain and V represents a hydrogen atom or an aryl group.

In one aspect of interest, preferred compounds of formula (IA) are those wherein R is₅And R₆May be the same or different and each represents the formula W₁-C(W₂)-W₃-T₁Group wherein W₁And W₂Each represents an oxygen atom, W₃Represents the group-NR_cWherein R is_cRepresents a straight chain or branched chain (C)₁-C₆) Alkyl radical, and T₁Represents a straight chain or branched chain (C)₁-C₆) An alkyl group.

In another very interesting aspect, preferred compounds of formula (IA) are those wherein R is₅And R₆Together form a radicalWherein Z represents an oxygen atom.

According to a further advantageous embodiment of the invention, preferred compounds are compounds of formula (IB):

x, Y, R therein₁、R₂、R₃And R₄As defined for formula (I).

Preferred substituents R according to the invention₃And R₄Is straight chain orBranched chain (C)₁-C₆) An alkyl group.

Even more preferred are the substituents R preferred according to the invention₃And R₄Is methyl.

Preferred substituents R according to the invention₂Is a group-OR_aand-NR_a-T_a-NR′_aR′_bWherein R'_a、R′_b、R″_aAnd Ta is as defined for formula (I).

Even more preferred are the substituents R preferred according to the invention₂Is a group-OR_aWherein R ″)_aAs defined for formula (I), and a group-NR ″)_a-T_a-NR′_aR′_bWherein R ″)_aRepresents a hydrogen atom, T_aAs defined for formula (I), and R'_aAnd R'_bMay be the same or different and each represents a straight chain or a branched chain (C)₁-C₆) An alkyl group.

Preferred substituents X and Y according to the invention are hydrogen atoms.

In a particularly advantageous aspect, preferred compounds of the invention are:

- (+ -) -cis-1, 2-dihydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one,

- (+ -) -cis-1, 2-diacetoxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one,

- (±) -cis-7-methoxy-4, 4, 15-trimethyl-15, 15 c-dihydro-4H-benzo [ a ] [1, 3] dioxolo [4 ', 5': 4, 5] pyrano [3, 2-h ] acridine-2, 8(3aH) -dione,

-6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one,

-6-hydroxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one,

-6-hydroxy-3, 3-dimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one.

The enantiomers, diastereomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base of the above preferred compounds form an integral part of the invention.

The invention also relates to a process for the preparation of a compound of formula (I), which process is characterized in that:

a compound of formula (II) is used as starting material:

wherein X and Y are as defined for formula (I),

treating the compound of formula (II) with dimethyl sulfate in an alkaline medium to obtain a compound of formula (III):

wherein X and Y are as previously defined,

treating the compound of formula (III) with claisen's base solution (a solution of potassium hydroxide in a water-methanol mixture) followed by a hydrochloric acid solution to give the compound of formula (IV):

wherein X and Y are as previously defined,

treating the compound of formula (IV) with thionyl chloride and then with a compound of formula (V) in anhydrous medium:

wherein R represents a hydrogen atom, a hydroxyl group, a linear or branched chain (C)₁-C₆) Alkyl or straight or branched chain (C)₁-C₆) An alkoxy group,

to give a compound of formula (VI):

wherein X, Y and R are as previously defined,

treating the compound of formula (VI) with a suspension of sodium hydride in an anhydrous aprotic solvent to give a compound of formula (VII):

wherein X, Y and R are as previously defined,

treating the compound of formula (VII) with aqueous hydrobromic acid in acetic acid to give a compound of formula (VIII):

wherein X, Y and R are as previously defined,

the compound of formula (VIII) is then treated with an alkyne of formula (IX) in an anhydrous aprotic solvent under basic conditions:

wherein Hal represents a halogen atom, and R₃And R₄As defined for formula (I),

to give compounds of formula (I/a), a special case of compounds of formula (I):

x, Y, R, R therein₃And R₄As defined above, the above-mentioned materials,

the nitrogen atom of the compound of formula (I/a) is optionally substituted by reaction with an alkyl halide or dialkyl sulfate in a polar aprotic solvent in the presence of a deprotonating agent to give a compound of formula (I/b), which is a special case of the compounds of formula (I):

wherein R'₁Represents a straight chain or branched chain (C)₁-C₆) Alkyl radical, and X, Y, R, R₃And R₄(ii) as defined hereinbefore, optionally reacting the compound of formula (I/b) wherein R represents hydroxy with an alkylating or acylating agent to give a compound of formula (I/c), a special case of compounds of formula (I):

wherein R'₂Represents selected from-OR_a、-O-T_a-OR″_a、-O-C(O)-T_aH and-O-T_a-NR′_aR′_bWherein R ″)_a、R′_a、R′_bAnd T_aAs defined for formula (I), and X, Y, R'₁、R₃And R₄As defined above, the above-mentioned materials,

optionally R'₂Represents a straight chain or branched chain (C)₁-C₆) The alkoxy compound of formula (I/c) is treated with a compound of formula (X):

HNR₁₀R₁₁ (X)，

wherein R is₁₀Represents R 'as defined for formula (I)'_aAnd R ″)_aAnd R is₁₁Represents selected from R'_b、-T_a-NR′_aR′_b、-C(O)-T_aH、-T_a-OR″_aand-T_a-CO₂R″_aIn which T is_a、R′_a、R′_bAnd R ″)_aAs defined above, the above-mentioned materials,

to give compounds of formula (I/d), a special case of compounds of formula (I):

wherein X, Y, R'₁、R₃、R₄、R₁₀And R₁₁As defined above, the above-mentioned materials,

all compounds of formulae (I/a) to (I/d) constitute compounds of formula (I/e):

x, Y, R therein₁、R₂、R₃And R₄As defined for formula (I),

the compounds of formula (I/e) can be subjected to the following actions:

a) with a reducing agent to give a compound of formula (I/f), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃And R₄As defined above, the above-mentioned materials,

b) or with osmium tetroxide in the presence of 4-methylmorpholine N-oxide in a polar medium to give the formula (I/g)₁) And (I/g)₂) A compound which is a particular case of a compound of formula (I):

all of formula (I/g)₁) And (I/g)₂) The compounds constitute cis-diol compounds of formula (cis-I/g):

(cis-I/g)

optionally reacting a cis-diol compound of formula (cis-I/g) with a compound of formula (XI):

wherein Z is as defined for formula (I),

to give a compound of formula (cis-I/h), a special case of compounds of formula (I):

(cis-I/h)

c) or with potassium permanganate in a polar medium to give compounds of the formula (I/I), which are particular examples of compounds of the formula (I):

the compounds of formula (I/I) may be subjected to the following actions:

α) with an alkylating or acylating agent to give a compound of the formula (I/j), a special case of compounds of the formula (I):

x, Y, R therein₁、R₂、R₃And R₄As previously defined, and R₂₀Represents a linear or branched chain selected from (C)₁-C₆) Alkyl and straight or branched chain (C)₁-C₆) The radical of an alkylcarbonyl group,

beta) or in NaBH₄Exposure to reducing conditions in the presence of a reducing agent to give a compound of formula (I/k), a special case of compounds of formula (I):

all compounds of formula (cis-I/g) and (I/k) constitute compounds of formula (I/l):

gamma) or with tosyl chloride and then with NaN in the presence of hydrogen peroxide₃Acting, followed by a reduction step, to give the compound of formula (I/m), a particular case of the compound of formula (I):

subjecting a compound of formula (I/m) to the following actions:

1) with carbon dioxide in the presence of diphenyl phosphite to give compounds of formula (I/n), a special case of compounds of formula (I):

2) or with a compound of formula (XII),

Hal-G′₁ (XII)

wherein Hal is as previously defined, and G'₁Represents a group selected from-R_c、C(W₂)-U-V、C(W₂)-W₃-T₁、S(O)_n-W₃-T₁And S (O)_nA group of-U '-V' -wherein R_c、W₂、W₃、U、V、U′、V′、T₁And n is as defined for formula (I),

to obtain the formula (I/o)₁)、(I/o₂) And (I/o)₃) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄And G'₁As defined above, the above-mentioned materials,

will be represented by the formula (I/o)₂) And (I/o)₃) The primary amine function of the compound is protected with a protecting group for the primary amine group to give compounds of formula (XIII/a) and (XIII/b),

x, Y, R therein₁、R₂、R₃、R₄And G'₁As defined above and P₁A protecting group representing a primary amine group,

optionally having the formula (I/O)₁) The compounds (XIII/a) and (XIII/b) are reacted with a compound of formula (XIV):

R_c1-Hal (XIV)，

wherein Hal represents halogen, and R_c1Represents a group selected from: straight or branched chain (C)₁-C₆) Alkyl, aryl and aryl in which the alkyl moiety is linear or branched- (C)₁-C₆) Alkyl, for the compounds of formulae (XIII/a) and (XIII/b), exposure to conditions which deprotect the primary amine function, gives compounds of formula (I/p)₁) (I/p2) and (I/p₃) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、G′₁And R_c1As defined above, the above-mentioned materials,

optionally, the formula (I/p)₂) And (I/p)₃) The compound is reacted sequentially with a compound of formula (XIV) as defined above, and then with a compound of formula (XV):

R_d′1-Hal (XV)，

wherein Hal is as previously defined, and R_d′1May have a group with R_c1The same meaning is given to the same person,

to obtain the formula (I/q)₂) And (I/q)₃) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、G′₁、R_c1And R_d′1As defined above, the above-mentioned materials,

the compounds of formula (I/l) can be subjected to the following actions:

α) with a compound of formula (XII) as defined above to give a compound of formula (I/r)₁)、(I/r₂) And (I/r)₃) A compound which is a particular case of a compound of formula (I):

let formula (I/r)₁) The compound performs the following actions:

1) when G'₁Represents a group C (W)₂) when-U-V is substituted with a compound of formula R₃₀Alcohol action of-OH, wherein R₃₀Represents a straight chain or branched chain (C)₁-C₆) Alkyl radical, to obtainTo (I/s)₁) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、G′₁And R₃₀As defined above, the above-mentioned materials,

2) or when G'₁Represents a group C (W)₂) U-V with a thiol of the formula (XVI),

G₁S-H (XVI)，

wherein G is₁Represents a group selected from R_c、C(W₂) -U-V and C (W)₂)-W₃-T₁Wherein R is_c、W₂、W₃U, V and T₁As defined for formula (I),

to obtain the formula (I/t)₁) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、G₁And G'₁As defined above, the above-mentioned materials,

optionally, the formula (I/t)₁) The compound is treated by a reducing agent and then subjected to a reaction for removing hydroxyl functional groups,

to obtain the formula (I/u)₁) A compound which is a particular case of a compound of formula (I):

let formula (I/r)₂) And (I/r)₃) The compound performs the following actions:

1) with an acid anhydride of the formula (XVII) or an acid chloride of the formula (XVIII),

[V-U-C(W₂)]₂O (XVII)，Cl-C(W₂)-U-V (XVIII)，

wherein W₂U and V are as defined for formula (I),

to obtain the formula (I/v)₂) And (I/v)₃) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、G′₁、W₂U and V are as defined above,

2) or exposure to dehydration conditions in an acid medium to give the formula (I/w)₂) And (I/w)₃) A compound which is a particular case of a compound of formula (I):

beta) or with a compound of formula (XIX) or (XX),

wherein B is as defined for formula (I) and W represents a halogen atom or a hydroxyl group,

to give compounds of formula (I/x), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃、R₄And B is as defined above, and B is,

γ) or with straight chains (C)₁-C₆) Reaction of the alkyl dihalide to give the compound of formula (I/y), which is a particular case of the compound of formula (I):

x, Y, R therein₁、R₂、R₃And R₄As defined hereinbefore, and m is as defined for formula (I),

delta) or with one equivalent of a compound of formula (XVII) or (XVIII) to give a compound of formula (I/z),

it is a particular case of the compounds of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、W₂U and V are as defined above,

the compound of formula (I/z) may be exposed to an excess of the anhydride of formula (XVII ') or the acid chloride of (XVIII'),

[V₁-U₁-C(W₂)]₂O (XVII′)，Cl-C(W₂)-U₁-V₁ (XVIII′)，

wherein U is₁And V₁May have a and aV has the same meaning, and W₂As defined above, the above-mentioned materials,

to give a compound of formula (I/aa), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、W₂、U、V、U₁And V₁As defined above, the above-mentioned materials,

ε) or exposure to dehydration conditions in an acid medium, to give compounds of formula (I/ab), a special case of compounds of formula (I):

optionally, the compound of formula (I/ab) is placed in NaBH₄Reduction in the presence of a reducing agent to give a compound of formula (I/ac), a particular case of compounds of formula (I):

d) or with a peracid or a dimethyldioxirane (dioxirane) to give a compound of formula (I/ad), a particular case of compounds of formula (I):

if desired, treating the compound of formula (I/ad) with ammonia or a primary or secondary amine to give the compound of formula (I/ae)₁) And (I/ae)₂) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃And R₄As previously defined, R_cAs defined for formula (I), and R_d1Represents a group selected from R_d、-C(W₂)-U-V、-C(W₂)-W₃-T₁、-S(O)_n-W₃-T₁and-S (O)_nA group of-U '-V' -wherein R_d、W₂、W₃、U、V、T₁U ', V' and n are as defined above,

can be made into the formula (I/ae)₁) And (I/ae)₂) The compound performs the following actions:

α) when R_cAnd R_d1Each represents a hydrogen atom, with a compound of formula (XI) as defined above,

to give the formula (I/af)₁) And (I/af)₂) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄And Z is as defined above, and Z is,

beta) or with a compound of formula (XIX) or (XX) as defined above, to give a compound of formula (I/ag)₁) And (I/ag)₂) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄And B is as defined above, and B is,

γ) or with a compound of formula (XII) as defined above, to give a compound of formula (I/ah)₁) And (I/ah)₂) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、R_c、R_d1And G'₁As defined above, the above-mentioned materials,

δ) or with triphenylphosphine dibromide in the presence of triethylamine to give compounds of formula (I/ai), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃、R₄And R_d1As defined above, the above-mentioned materials,

epsilon) or under dehydration conditions in an acid medium to give the formula (I/aj)₂) And (I/aj)₃) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、R_cAnd R_d1As defined above, the above-mentioned materials,

e) or with a compound of formula (XXI):

Hal-C(W₂)-T₁ (XXI)，

wherein Hal represents a halogen atom, and W₂And T₁As defined for formula (I),

to give a compound of formula (I/aj), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃、R₄、W₂And T₁As defined above, the above-mentioned materials,

the compounds (I/a) to (I/aj) are integral parts of the compounds of the invention, and these compounds are purified, if necessary, according to conventional purification techniques, separated, if necessary, according to conventional separation techniques into their different isomers, and converted, if necessary, into their N-oxides and, if necessary, their addition salts with pharmaceutically acceptable acids or bases.

The compounds of formulae (II), (IV), (IX) to (XII), (XIV) to (XXI), (XVII ') and (XVIII') are commercially available compounds or can be obtained according to conventional organic synthesis methods well known to the person skilled in the art.

A compound of formula (I) wherein A represents a compound of formula-CH (R)₅)-CH(R₆) Group, wherein R₅And R₆May be the same OR different and independently represent a hydrogen atom, OR_cGroup and W₁-C(W₂) A radical of the group-U-V, in which R_cAs defined for formula (I), 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, or R₅And R₆Together form a radicalWherein Z is as defined for formula (I),

can advantageously be obtained as follows:

the compound of formula (I/e) is used as starting material:

the compound of formula (I/e) is reacted in a polar medium with osmium tetroxide or with potassium permanganate in the presence of 4-methylmorpholine N-oxide, followed by reduction with sodium borohydride to give, depending on the process, cis-or trans-diol compounds of formula (I/ak), which are particular examples of compounds of formula (I):

optionally, the cis-diol compound of formula (cis-I/ak) is subjected to the following actions:

● or with N, N '-carbonyldiimidazole or N, N' -thiocarbonyldiimidazole in the presence of 2-butanone to give compounds of the formula (cis-I/al), a special case of compounds of the formula (I):

(cis-I/al)

X, Y, R therein₁、R₂、R₃And R₄As previously defined, and Z is as defined for formula (I),

● with either a compound of formula (XXII) or a compound of formula (XXIII):

Hal-G₂(XXII), or G₂-O-G₂ (XXIII)，

Wherein Hal represents a halogen atom, and G₂Represents a group selected from-C (W)₂)-U-V、-C(W₂)-W₃-T₁、-S(O)_n-W₃-T₁and-S (O)_nA group of-U '-V' -wherein W₂、W₃、U、V、U′、V′、T₁And n is as defined for formula (I),

to give compounds of formula (I/am), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃、R₄And G₂As defined above, the above-mentioned materials,

the compounds of formula (I/am) are integral parts of the compounds of the invention, and these compounds are purified, if necessary, according to conventional purification techniques, separated, if desired, into their different isomers according to conventional separation techniques, and converted, if desired, into their N-oxides and, if desired, into their addition salts with pharmaceutically acceptable acids or bases.

The compounds of formula (XXII) and (XXIII) are commercially available compounds or can be obtained according to conventional organic synthesis methods well known to those skilled in the art.

The compounds of formula (I) have particularly important anti-cancer properties. They have excellent in vitro cytotoxic activity against cell lines derived from murine and human tumors by specifically blocking the cell cycle, and in vivo activity in mice against transplantable murine and human tumors. The characteristic properties of these compounds make them therapeutically useful 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 N-oxide 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 according to the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transcutaneous, intravaginal, rectal, nasal, lingual, buccal, ocular or respiratory administration.

Pharmaceutical compositions of the invention for parenteral injection include, inter alia, aqueous or non-aqueous sterile solutions, dispersions, suspensions or emulsions, and also sterile powders for reconstitution of the injectable solutions or dispersions.

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 described hereinbefore illustrate the invention but do not limit it in any way.

Among 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, dispersants, binders, swelling agents, disintegrants, retarding agents, lubricants, absorbents, suspending agents, colorants, fragrances and the like.

Useful dosages will vary with the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the disease, and the administration of any relevant treatment. The dosage range is 0.1mg to 1000mg per day, administered in one or more divided doses.

The following examples illustrate the invention but do not limit it in any way.

Examples

The starting materials used are products which are known or prepared according to known operating procedures. Various preparations give synthetic intermediates which can be used to prepare the compounds of the invention.

The structures of the compounds described in the examples and preparations were determined according to conventional spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).

Melting points were determined using either Kofler hot plate or hot plate under microscope. When the compound is in the form of a salt, the melting point is given as the melting point of the salt form of the compound.

Preparation 1: n- (3, 5-dimethoxyphenyl) acetamide

A solution of 15.3g of 3, 5-dimethoxyaniline and 57.5ml of acetic anhydride in 40ml of anhydrous pyridine is heated under reflux for 1 hour. The reaction mixture was then cooled and poured into 350ml of water. The precipitate formed was suspended in 20% Na₂CO₃The aqueous solution was then filtered off using a Buchner funnel, washed with water and dried under vacuum over phosphorus pentoxide. 14.5g of the expected product are obtained in the form of a white amorphous solid.

Mass spectrometry (DIC/NH)₃)：m/z＝196(M+H)⁺

Preparation 2: 9, 11-dihydroxybenzo [ a ] acridin-12 (7H) -one

Step A: 2-methoxy-1-naphthoic acid methyl ester

54ml of dimethyl sulfate were added to a solution of 26.32g of 2-hydroxy-1-naphthoic acid in 70ml of 4.5N aqueous NaOH solution. The reaction mixture was then kept at room temperature, stirred for 4 hours, diluted with 250ml of water and extracted with dichloromethane (4X 100 ml). The combined organic phases were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Chromatography on silica gel (cyclohexane followed by a gradient of 1-10% acetone/cyclohexane) gave 21.5g of the expected product.

Mass spectrometry (DIC/NH)₃)：m/z＝217(M+H)⁺

And B: 2-methoxy-1-naphthoic acid

A solution of 21.6g of the compound of step A above in 48ml of a claisen's base solution (21g KOH in 15ml water, made up to 60ml with methanol) was heated under reflux for 4 hours. The reaction mixture is then diluted with 50ml of water and poured, with stirring, into 75ml of 15.5% hydrochloric acid solution cooled to 0 ℃. The white precipitate formed was then filtered off via a Buchner funnel, washed with water and dried under vacuum over phosphorus pentoxide. The resulting dry residue was dissolved in a boiling solution of ethanol and water (80: 20, v/v). After cooling to 0 ℃ 13.7g of the expected product are obtained.

Melting point: 56-57 deg.C

Mass spectrometry (DIC/NH)₃)：m/z＝203(M+H)⁺

And C: n- [3, 5-dimethoxy-2- (2-methoxy-1-naphthoyl) phenyl ] acetamide

30ml of SOCl were added over 30 minutes₂15.15g of the above compound of step B were added dropwise to a flask equipped with a condenser and connected to a gas collector. The reaction mixture was then heated at 60 ℃ for 3 hours and evaporated to dryness under reduced pressure. The 2-methoxy-1-naphthoyl chloride thus obtained was dissolved in 50ml of anhydrous dichloroethane and added dropwise to 12.5g of AlCl₃With 12.7g of the compound of preparation 1 in 100ml of anhydrous dichloroethane previously cooled to 0 ℃. The reaction mixture was kept at 0 ℃ for 3 hours and then at 20 ℃ for 3 hours. The reaction mixture was then poured, with stirring, into 250ml of 15% hydrochloric acid solution cooled beforehand in an ice bath and extracted with dichloromethane (3X 40 ml). The combined organic phases are washed with NaHCO₃The solution was then washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Warp beamSilica gel chromatography (dichloromethane followed by a gradient of 0.2-4% methanol in dichloromethane) can isolate 7.74g of the desired product.

Melting point: 149 ℃ C. and 150 ℃ C

Mass spectrometry (DIC/NH)₃)：m/z＝379(M+H)⁺

Step D: 9, 11-Dimethoxybenzo [ a ] acridin-12 (7H) -one

A solution of 3.79g of the compound of step C above in 60ml of anhydrous dimethylformamide is added dropwise to a suspension of 1.2g of NaH in 50ml of anhydrous dimethylformamide, previously cooled to 0 ℃. The reaction mixture was kept at 0 ℃ for 15 minutes and then at 20 ℃ for 4 hours and 30 minutes under stirring and an inert atmosphere. The reaction mixture was then poured into 200ml of water and extracted with ethyl acetate (3X 50 ml). The combined organic phases were washed successively with NaOH solution and then with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane followed by a gradient of 0.5-5% methanol/dichloromethane) can be used to isolate 2.05g of the expected product.

Melting point: 258 ℃ 259 DEG C

Mass spectrometry (DIC/NH)₃)：m/z＝305(M+H)⁺

Step E: 9, 11-dihydroxybenzo [ a ] acridin-12 (7H) -one

80ml of 48% aqueous HBr are added to a solution of 1.89g of the above compound of step D in 90ml of acetic acid and then heated under reflux for 4 days. After the reaction mixture was cooled, it was poured into 1000ml of ice-cold water. The brown precipitate formed was filtered off via a Buchner funnel, washed with water and dried under vacuum over phosphorus pentoxide. Chromatography on silica gel (dichloromethane followed by a gradient of 1-10% methanol in dichloromethane) can yield 1.55mg of the expected product.

Melting point: 311 deg.C, 312 deg.C

Mass spectrometry (DIC/NH)₃)：m/z＝278(M+H)⁺

Preparation 3: n- (3-methoxyphenyl) acetamide

This compound was obtained according to the procedure of preparation 1, but using 3-methoxyaniline instead of 3, 5-dimethoxyaniline.

Preparation 4: 9-hydroxybenzo [ a ] acridin-12 (7H) -one

Step A: n- [ 5-methoxy-2- (2-methoxy-1-naphthoyl) phenyl ] acetamide

This compound was obtained according to the procedure of preparation 2, step C, but using the compound of preparation 3 instead of the compound of preparation 1.

And B: 9-methoxybenzo [ a ] acridin-12 (7H) -one

This compound was obtained according to the procedure of preparation 2 step D, but using the compound of step a above.

And C: 9-hydroxybenzo [ a ] acridin-12 (7H) -one

This compound was obtained according to the procedure of preparation 2 step E, but using the compound of step B above.

Preparation 5: 3-bromo-9, 11-dihydroxybenzo [ a ] acridin-12 (7H) -one

This compound was obtained according to the procedure of preparation 2 step a-step E, but using 6-bromo-2-hydroxy-1-naphthoic acid instead of 2-hydroxy-1-naphthoic acid.

Mass spectrometry (ESI)⁺)：m/z＝354(M+H)⁺

Example 1: 6-hydroxy-3, 3-dimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

732mg of the compound of preparation 2 was dissolved in 20ml of anhydrous dimethylformamide, and then 732mg of anhydrous potassium carbonate was added. The mixture thus obtained was stirred under argon at 65 ℃ for 15 minutes, then 876.5mg of anhydrous potassium iodide and 2.47g of 3-chloro-3-methyl-1-butyne were added. At the end of 5 hours, the reaction mixture was heated at 130 ℃ for 2 hours to allow rearrangement of the propargyl ether. The reaction mixture was then diluted with 50ml of water and extracted with dichloromethane (3X 40 ml). The combined organic phases were washed with water and then with 1M potassium hydroxide solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (cyclohexane followed by a gradient of 1-5% acetone/cyclohexane) gave 326mg of the expected product.

Mass spectrometry (DIC/NH)₃)：m/z＝345(M+H)⁺

Example 2: 6-hydroxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

1.324g of sodium carbonate are added to 411.6mg of the compound of example 1 dissolved in 50ml of anhydrous acetone. The mixture was kept under argon atmosphere at 0 ℃ for 15 minutes with stirring, and then after addition of 852mg of methyl iodide, the reaction mixture was heated under reflux for 2 hours. After cooling, the excess methyl iodide was destroyed by adding 40ml methanol and 50ml water. The methanol was distilled off and the aqueous phase was extracted with dichloromethane (3X 30 ml). The combined organic phases were washed with 10% aqueous NaOH and then with water, dried over anhydrous sodium sulfate, then filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (cyclohexane followed by a gradient of 0.5-5% acetone/cyclohexane) gave 374.2mg of the expected product.

Mass spectrometry (DIC/NH)₃)：m/z＝358(M+H)⁺

Example 3: 6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

A solution of 604.3mg of the compound according to example 2 in 40ml of anhydrous acetone is gradually added to a suspension of 61mg of sodium hydride in 10ml of acetone, which is kept under an argon atmosphere and at 0 ℃. The mixture thus obtained was kept at 0 ℃ for 30 minutes, and then 1.2g of methyl iodide was added. The reaction mixture was heated to reflux for 6 hours. After cooling, the excess methyl iodide was destroyed by adding 40ml methanol and 50ml water. The methanol was distilled off and the aqueous phase was extracted with dichloromethane (3X 30 ml). The combined organic phases were washed with 10% aqueous NaOH and then with water, dried over anhydrous sodium sulfate, then filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (cyclohexane followed by a gradient of 1-10% acetone/cyclohexane) gave 469.5mg of the expected product.

Mass spectrometry (DIC/NH)₃)：m/z＝372(M+H)⁺

Example 4: (±) -cis-1, 2-dihydroxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

A mixture of 0.4859g of the compound from example 3, osmium tetroxide (2.5%) dissolved in 1.05ml of 2-methyl-2-propanol and 96.7mg of 4-methylmorpholine N-oxide monohydrate was dissolved in 40ml of tert-BuOH THF H₂O (10: 3: 1) mixture. The reaction mixture was kept at room temperature for 4 days with stirring, and then saturated NaHSO was added₃Solution (30 ml). After stirring for 1 hour, the reaction mixture was extracted with dichloromethane (4X 25 ml). The combined organic phases were dried over anhydrous sodium sulfate, then filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (cyclohexane followed by a gradient of 1-15% acetone/cyclohexane) gave 452.7mg of the expected product.

Mass spectrometry (DIC/NH)₃)：m/z＝406(M+H)⁺

Example 5: (±) -cis-1, 2-diacetoxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

61mg of the compound from example 4 and 1mg of DMAP were added (in an ice bath) to a previously cooled mixture of anhydrous pyridine (4ml) and acetic anhydride (0.4 ml). The reaction mixture was kept at room temperature for 3 days under stirring, protected from light. The reaction mixture was then poured into 10ml ice-cold H₂In O, the precipitate formed is filtered off and washed with H₂O (2X 5ml) was washed and then dried under vacuum over phosphorus pentoxide. 62.4mg of the expected product crystallized from a mixture of dichloromethane: ethyl acetate (9: 1, v/v) as fine white prisms.

Melting point: 161-162 ℃.

Mass spectrometry (DIC/NH)₃)：m/z＝477(M+H)⁺

Example 6: (±) -cis-7-methoxy-4, 4, 15-trimethyl-15, 15 c-dihydro-4H-benzo [ a ] [1, 3] dioxolo [4 ', 5': 4, 5] pyrano [3, 2-h ] acridine-2, 8(3aH) -dione

230.5mg of N, N' -carbonyldiimidazole are added to a solution of 109.4mg of the compound from example 4 in 5ml of 2-butanone. The reaction mixture was kept at reflux for 3 hours and then after cooling with 5% Na₂CO₃The aqueous solution (7ml) was diluted and extracted with ethyl acetate (3X 10 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane followed by a gradient of 1-7% acetone/dichloromethane) can yield 65.7mg of the expected product.

Mass spectrometry (DIC/NH)₃)：m/z＝432(M+H)⁺

Example 7: (±) -cis-1- { [ (dimethylamino) carbonyl ] oxy } -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl dimethylcarbamate

A solution of 0.123mmol of the compound from example 4 in 4ml of anhydrous tetrahydrofuran was added to 0.698mmol of potassium hydride washed with hexane at-10 ℃. 0.327mmol of N, N-dimethylcarbamoyl chloride was added dropwise at-10 ℃ and stirred at room temperature for 3 hours and 30 minutes. 50ml of ethyl acetate and 10ml of saturated NaHCO were added₃After the solution, the organic phase was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give the desired product.

Example 8: (±) -cis-6-methoxy-3, 3, 14-trimethyl-2- { [ (4-methylphenyl) sulfonyl ] -oxy } -7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-1-yl 4-methylbenzenesulfonate

This compound was obtained according to the procedure of example 7, but using tosyl chloride instead of N, N-dimethylcarbamoyl chloride.

Example 9: (±) -cis- { [1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ] oxy } -4-oxobutanoic acid

To a solution of 0.5mmol of the compound of example 4 in 3ml of anhydrous pyridine was added 1.1 equivalents of succinic anhydride and 1mg of dimethylaminopyridine. After stirring in the dark at room temperature for 2 days, 25ml of acetic anhydride were added at-15 ℃ and stirred for 1.5 hours, after which it was concentrated under reduced pressure. The desired product can be isolated by chromatography on silica gel (dichloromethane/acetic acid: 99/1).

Example 10: (±) -cis-5- { [1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ] oxy } -5-oxopentanoic acid

This compound was obtained according to the procedure of example 9, but using glutaric anhydride instead of succinic anhydride.

Example 11: [ tert-Butoxycarbonyl) amino ] acetic acid (. + -.) -cis-1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

0.6mmol of dicyclohexylcarbodiimide was slowly added to a solution of 0.5mmol of the compound of example 4 and 0.5mmol of 2- [ (tert-butoxycarbonyl) amino ] acetic acid in 10ml of dimethylformamide at 0 ℃. The reaction mixture was kept at 0 ℃ for 5 hours and then at room temperature for 16 hours. After filtration and evaporation under reduced pressure, the residue was dissolved in 2ml of anhydrous pyridine; 2ml of acetic anhydride were added and the mixture was stirred at room temperature in the dark for 48 hours. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel chromatography (dichloromethane), and the desired product was isolated.

Example 12: (±) -cis-1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl aminoacetate

Mu.l of iodotrimethylsilane was added to a solution of 0.1mmol of the compound from example 11 in 1ml of chloroform at room temperature. The reaction mixture was stirred at room temperature for 5 minutes and then evaporated to dryness under reduced pressure. The desired product can be isolated by chromatography on silica gel (dichloromethane/methanol: 85/15).

Example 13: 2-butyryl-6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-2-one

0.81mmol of butyryl chloride and 0.673mmol of AlCl₃The mixture in 2ml of anhydrous dichloromethane was added in small portions to 0.135mmol of the product of example 3 in 2ml of dichloromethane at 0 ℃. The reaction mixture was stirred at room temperature for 4 hours and then poured into 10% HCl solution. After the organic phase has been worked up conventionally and evaporated under reduced pressure, the residue is chromatographed on silica gel (dichloromethane/methanol) to give the desired product.

Example 14: (±) -cis-1-hydroxy-6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl butyrate

2 equivalents of butyryl chloride were added to a solution of 0.74mmol of the compound of example 4 in 7ml of anhydrous pyridine in the presence of 4-dimethylaminopyridine. Stirring for 72 hours at room temperature, then adding 5 equivalents of butyryl chloride, and continuing stirring for 72 hours; then evaporated to dryness. The desired product can be isolated by silica gel chromatography.

Example 15: butyric acid 6-methoxy-3, 3, 14-trimethyl-7-oxo-7, 14-dihydro-3H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

4 drops of 10% HCl solution are added to a solution of 0.29mmol of the compound from example 14 in 6ml of dichloromethane. The reaction mixture was stirred at room temperature for 3 days, then dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (dichloromethane/methanol) to give the desired product.

Example 16: 2-hydroxy-6-methoxy-3, 3, 14-trimethyl-2, 3-dihydro-1H-benzo [ a ] pyrano [3, 2-H ] acridine-1, 7(14H) -dione

1.28g KMnO in 30 min₄A suspension in 15ml of water is added dropwise to a solution of 0.5g of the product of example 3 dissolved in 25ml of acetone. The reaction mixture was stirred at room temperature for 8 hours, then after extraction and conventional work-up. The residue is chromatographed on silica gel (dichloromethane/methanol: 98: 2) to give the desired product.

Example 17: acetic acid 6-methoxy-3, 3, 14-trimethyl-1, 7-dioxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 14, but starting from the compound of example 16 and using acetic anhydride instead of butyryl chloride.

Example 18: 3, 3-dimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

This compound was obtained according to the procedure of example 1, but using the compound of preparation 4 instead of the compound of preparation 2.

Example 19: 3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

This compound was obtained according to the procedure of example 2, but using the compound of example 18 instead of the compound of example 2.

Example 20: (±) -cis-1, 2-dihydroxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

This compound was obtained according to the procedure of example 4, but using the compound of example 19 instead of the compound of example 3.

Example 21: acetic acid (±) -cis-1- (acetoxy) -3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 5, but using the compound of example 20 instead of the compound of example 4.

Example 22: acetic acid 1-hydroxy-6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

2.2mmol of acetic anhydride are added to a solution of 2mmol of the compound from example 4 in 5ml of anhydrous pyridine, cooled to 0 ℃. After the reaction mixture was stirred at room temperature for 3 hours, it was concentrated under reduced pressure. The desired product can be isolated by chromatography on silica gel (dichloromethane followed by diaminomethane/methanol: 99/1).

Example 23: benzoic acid 1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 9, but using benzoic anhydride instead of succinic anhydride.

Example 24: propionic acid 1-hydroxy-6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 22, but using propionic anhydride instead of acetic anhydride.

Example 25: propionic acid 6-methoxy-3, 3, 14-trimethyl-7-oxo-1- (propionyloxy) -2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 5, but using propionic anhydride instead of acetic anhydride.

Example 26: 4-pentenoic acid 1-hydroxy-6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 14, but using pentenoic anhydride instead of butyryl chloride.

Example 27: 4-pentenoic acid 6-methoxy-3, 3, 14-trimethyl-7-oxo-1- (4-pentenoyloxy) -2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 14, but using pentenoic anhydride instead of butyryl chloride. The desired product can be isolated by chromatography on silica gel (dichloromethane followed by dichloromethane/methanol: 99/1 to 98/2).

Example 28: 4-pentenoic acid 1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 9, but using pentenoic anhydride instead of succinic anhydride.

Example 29: 3-Methylbutanoic acid 6-methoxy-3, 3, 14-trimethyl-1- [ (3-methylbutyryl) oxy ] -7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 5, but using isovaleryl chloride instead of acetic anhydride.

Example 30: 4- { [1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ] oxy } -4-oxobutanoic acid

This compound was obtained according to the procedure of example 9, but using an excess of succinic anhydride. The desired product can be isolated by chromatography on silica gel (dichloromethane followed by dichloromethane/methanol: 99/1).

Example 31: 5- ({ [1- [ (4-carboxybutanoyl) oxy ] -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ] oxy } -5-oxopentanoic acid

This compound was obtained according to the procedure of example 9, but using an excess of glutaric anhydride instead of succinic anhydride.

Example 32: diethylcarbamic acid 1- { [ (diethylamino) carbonyl ] oxy } -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

This compound was obtained according to the procedure of example 7, but using N, N-diethylcarbamoyl chloride instead of N, N-dimethylcarbamoyl chloride.

Example 33: 6- { [2- (dimethylamino) ethyl ] amino } -3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

4ml of N, N-dimethylethylenediamine were added to 0.15g of the product of example 3. After allowing the reaction mixture to react at 70 ℃ under an inert atmosphere for 5 days, it was evaporated under reduced pressure. The resulting residue was subjected to silica gel chromatography (cyclohexane/ethyl acetate: 80/20) to isolate the desired product.

Melting point: and (3) oil.

Example 34: 6- { [3- (diethylamino) propyl ] amino } -3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

The procedure was carried out as described in example 33, but using N, N-diethylpropanediamine as reagent.

Melting point: and (3) oil.

Example 35: (2E) -3-phenyl-2-propenoic acid 1-hydroxy-6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

1.33mmol of cinnamoyl chloride was added to a pre-cooled solution of 0.30mmol of the compound of example 4 in 4ml of pyridine. After stirring the reaction mixture at 0 ℃ for 90 minutes, it was evaporated under reduced pressure. The desired product can be isolated by chromatography on silica gel (cyclohexane followed by cyclohexane/acetone: 94/6 to 90/10).

Example 36: (2E) -3-phenyl-2-propenoic acid 1- (acetoxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3, 7, 14-tetrahydro-1H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl ester

31mmol of acetic anhydride are added to a previously cooled solution of 0.18mmol of the compound from example 35 in 3ml of pyridine. After the reaction mixture was stirred at room temperature for 3 days, it was evaporated under reduced pressure. The desired product can be isolated by chromatography on silica gel (cyclohexane/acetone: 94/6).

Example 37: 6-methoxy-3, 3-dimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

A solution of 300mg of the compound according to example 1 in 15ml of anhydrous dimethylformamide is added dropwise to a suspension of 125mg of sodium hydride in 10ml of anhydrous dimethylformamide, previously cooled to 0 ℃. The reaction mixture was kept at 0 ℃ for 15 minutes and at room temperature for 30 minutes, after which 0.57ml of dimethyl sulfate was added. After 17 hours, the reaction mixture was poured into 150ml ice-cold water and extracted with dichloromethane (3 × 50 ml). The combined organic phases were dried over anhydrous sodium sulfate, then filtered and evaporated to dryness under reduced pressure. The desired product can be isolated by silica gel chromatography (cyclohexane followed by a gradient of 5-20% acetone/cyclohexane).

Mass spectrum (ESI): 358(M + H) M/z⁺

Example 38: (±) -cis-1-hydroxy-6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-2-yl dimethylcarbamate

A solution of 0.124mmol of the compound from example 4 in 8ml of anhydrous tetrahydrofuran is added to 1.24mmol of potassium hydride washed with hexane at-10 ℃. 0.49mmol of N, N-dimethylcarbamoyl chloride was added dropwise at-10 ℃ and stirred at room temperature for 20 hours. 25ml of ethyl acetate and 10ml of saturated NaHCO were added₃After the solution, the organic phase is washed with water, dried over sodium sulfate and then evaporated under reduced pressure. The desired product can be isolated by chromatography on silica gel (dichloromethane/acetone: 80/20).

Mass spectrum (ESI): m/z＝477(M+H)⁺

Example 39: 10-bromo-6-hydroxy-3, 3-dimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

This compound was obtained according to the procedure of example 1, but using the compound of preparation 5 instead of the compound of preparation 2.

Mass spectrometry (ESI)⁺)：m/z＝422(M+H)⁺

Example 40: 10-bromo-6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

This compound was obtained according to the procedure of example 3, but using the compound of example 39 instead of the compound of example 2.

Mass spectrometry (ESI)⁺)：m/z＝450(M+H)⁺

Example 41: 10-bromo-6-hydroxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one

This compound was obtained according to the procedure of example 2, but using the compound of example 39 instead of the compound of example 1.

Pharmacological study of the compositions of the invention

Example 42: in vitro cytotoxic Activity

The following four cell lines were used:

murine leukemia: the total weight of the L1210,

-human epidermoid carcinoma: the molecular weight of the KB-3-1,

-human colon cancer: the components of the light-emitting diode (HT 29),

-human prostate cancer: LNCap.

The cells were completely cultured in RPMI 1640 pH7.4 containing 10% fetal bovine serum, 2mM glutamine, 50 units/ml penicillin, 50. mu.g/ml streptomycin and 10mM HepesCulturing in the medium. Cells are distributed on microplates and exposed to cytotoxic compounds. The cells were then cultured for 2 days (L1210) or 4 days (human cell line). The samples were then analyzed by a colorimetric method, i.e., Microculture tetrazolium detection (Cancer res.1987,47939-942) quantitate the number of surviving cells.

Result in IC₅₀(concentration of cytotoxic agent that inhibited proliferation of treated cells by 50%). For example, IC of the Compounds of examples 5 and 6 on L1210₅₀0.73. mu.M and 0.06. mu.M, respectively, for IC of KB-3-1₅₀0.14. mu.M and 0.015. mu.M, respectively. IC of the Compound of example 5 on HT29₅₀IC at 1.18 μ M for LNCap₅₀It was 0.57. mu.M.

Example 43: in vivo Activity

Anticancer Activity against C38 Colon adenocarcinoma

Tumor fragments weighing approximately 30mg of C38 colon adenocarcinoma were implanted subcutaneously in 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 uniform in tumor size. Animals were given the product of the invention twice by intravenous route on days 12 and 22 at the Maximum Tolerated Dose (MTD), MTD/2 and MTD/4.

Tumors were measured twice a week and tumor volume was calculated according to the following formula: volume (mm)³) Length (mm) × width (mm)²)/2。

Antitumor activity is expressed as% T/C:

v0 and Vt are the initial volume of the tumor and the volume at the time t measured, respectively.

The optimal dose is the dose that gives the lowest T/C value, no cytotoxic activity (early death or weight loss greater than 20%).

For example, the compound of example 5 showed 95% inhibition of tumor growth at an optimal dose of 4mg/kg (T/C ═ 5%), whereas acronycine showed 27% T/C at an optimal dose of 100mg/kg, thus demonstrating its strong therapeutic potential.

Example 44: the pharmaceutical composition comprises: injection solution

Compound … … … … … … … … … … … … … … … … … … 10mg of example 6

… … … … … … … … … … … … … … … … 25mg of distilled water for injection preparation

Claims

1. A compound of formula (I):

wherein:

● x and YWhich may be identical or different, independently of one another represent a group selected from:

hydrogen and a halogen atom,

with the following conditions: the substituents X and Y may be present in either of two adjacent phenyl rings,

● R₁represents a hydrogen atom or a linear or branched C₁-C₆An alkyl group;

● R₂represents a group selected from: a hydrogen atom and-OR_a、-NR″_a-T_a-NR′_aR′_bWherein:

^*T_arepresents a straight or branched chain C₁-C₆An alkylene chain, which is a linear chain of alkylene,

^*R′_aand R'_bMay be the same or different and independently represent a hydrogen atom, a linear or branched chain

C₁-C₆The radical of an alkyl group,

^*R″_arepresents a hydrogen atom and a linear or branched C₁-C₆A group of alkyl groups;

● R₃and R₄May be the same or different and independently represent a hydrogen atom or a linear or branched C₁-C₆An alkyl group;

● Arepresents a group of formula:

a)-CH(R₅)-CH(R₆) -, wherein:

1) a hydrogen atom, and a nitrogen atom,

2)OR_c、NR_cR_dand SR_cA group wherein:

-R_cand R_dWhich may be identical or different, independently of one another represent a group selected from: hydrogen atom, straight or branched C₁-C₆Alkyl, and C (O) -R_eGroup, wherein R_eRepresents a hydrogen atom or NR *_aR*_bGroup of radicals in which R *_aAnd R *_bCan be the same as orDifferent from each other, each represents a hydrogen atom or a linear or branched C₁-C₆An alkyl group;

3)W₁-C(W₂) -U-V, wherein:

α)W₁represents an oxygen atom, and is represented by,

β)W₂represents an oxygen atom, and is represented by,

γ) U represents a linear or branched C₁-C₈An alkylene chain, which is a linear chain of alkylene,

δ) V represents a group selected from:

-a hydrogen atom,

or R₅And R₆Together form:

radical (I)

Wherein Z represents an oxygen atom, and wherein,

or b) -CH ═ CH-,

or their addition salts with pharmaceutically acceptable acids or bases.

2. A compound of formula (I) according to claim 1, characterized in that: they are compounds of formula (IA):

x, Y, R therein₁、R₂、R₃、R₄、R₅And R₆As defined for formula (I) in claim 1, or their addition salts with a pharmaceutically acceptable acid or base.

3. A compound of formula (I) according to claim 1, characterized in that: they are compounds of formula (IA) wherein R₅And R₆May be the same OR different and each represents the formula-OR_c、W₁-C(W₂) -U-V, or R₅And R₆Together form a radicalWherein R is_c、W₁、W₂U, V and Z are as defined for formula (I) in claim 1 or their addition salts with a pharmaceutically acceptable acid or base.

4. A compound of formula (I) according to claim 1, characterized in that: they are compounds of formula (IA) wherein R₅And R₆Are identical and each represents the formula-OR_cGroup, wherein R_cRepresents a hydrogen atom or an addition salt thereof with a pharmaceutically acceptable acid or base.

5. A compound of formula (I) according to claim 1, characterized in that: they are compounds of formula (IA) wherein R₅And R₆Are the same or different and each represents the formula W₁-C(W₂) A group of-U-V wherein W₁And W₂Each represents an oxygen atom, U is as defined for formula (I) in claim 1 and V represents a hydrogen atom, or their addition salts with pharmaceutically acceptable acids or bases.

6. A compound of formula (I) according to claim 1, characterized in that: they are compounds of formula (IA) wherein R₅Is represented by the formula-OR_cGroup, wherein R_cRepresents a hydrogen atom, and R₆Representative formula W₁-C(W₂) A group of-U-V wherein W₁And W₂Each represents an oxygen atom, U represents a linear or branched C₁-C₈An alkylene chain and V represents a hydrogen atom, or their addition salts with a pharmaceutically acceptable acid or base.

7. A compound of formula (I) according to claim 1, characterized in that: they are compounds of the formula (IA),

wherein R is₅And R₆Together form a group which is,

wherein Z represents an oxygen atom, or an addition salt thereof with a pharmaceutically acceptable acid or base.

8. A compound of formula (I) according to claim 1, characterized in that: they are compounds of formula (IB):

x, Y, R therein₁、R₂、R₃And R₄As defined for formula (I) in claim 1, or their addition salts with a pharmaceutically acceptable acid or base.

9. A compound of formula (I) according to claim 1, characterized in that: r₃And R₄Each represents a straight chain or branched C₁-C₆Alkyl, or their addition salts with pharmaceutically acceptable acids or bases.

10. A compound of formula (I) according to claim 9, characterized in that: r₃And R₄Each represents a methyl group, or an addition salt thereof with a pharmaceutically acceptable acid or base.

11. A compound of formula (I) according to claim 1, characterized in that: r₂Represents the group-OR_aor-NR_a-T_a-NR′_aR′_bWherein R'_a、R′_b、R″_aAnd T_aAs defined for formula (I) in claim 1, or their addition salts with a pharmaceutically acceptable acid or base.

12. A compound of formula (I) according to claim 11, characterized in that: r₂Represents the group-OR_aWherein R ″)_aAs defined for formula (I) in claim 1, or represents the group-NR_a-T_a-NR′_aR′_bWherein R ″)_aRepresents a hydrogen atom, T_aR 'as defined for formula (I) in claim 1 and'_aAnd R'_bMay be the same or different and each represents a straight or branched chain C₁-C₆Alkyl, or their addition salts with pharmaceutically acceptable acids or bases.

13. Compounds of formula (I) according to any one of claims 1 to 12, characterized in that: x and Y each represent a hydrogen atom, or an addition salt thereof with a pharmaceutically acceptable acid or base.

14. Compounds of formula (I) according to claim 1, which are:

-6-hydroxy-3, 3-dimethyl-3, 14-dihydro-7H-benzo [ a ] pyrano [3, 2-H ] acridin-7-one,

or their addition salts with pharmaceutically acceptable acids or bases.

15. A process for the preparation of a compound of formula (I) according to claim 1, or of an addition salt thereof with a pharmaceutically acceptable acid or base, wherein the compound of formula (I) is selected from the group consisting of compounds (I/a), (I/b), (I/c), (I/d), (I/e), (I/f), (I/g) as defined in the claims₁)、(I/g₂) (cis-I/g), (cis-I/h), (I/k) and (I/I),

the method is characterized in that:

a compound of formula (II) is used as starting material:

wherein X and Y are as defined for formula (I) in claim 1,

wherein X and Y are as previously defined in the claims,

treating the compound of formula (III) with a claisen's base solution of potassium hydroxide in a water-methanol mixture, followed by a hydrochloric acid solution to give a compound of formula (IV):

wherein X and Y are as previously defined in the claims,

wherein R represents a hydrogen atom, a hydroxyl group or a linear or branched C₁-C₆An alkoxy group,

to give a compound of formula (VI):

wherein X, Y and R are as previously defined in the claims,

the compound of formula (VIII) is then treated with an alkyne of formula (IX) under basic conditions in an anhydrous aprotic solvent:

wherein Hal represents a halogen atom, and R₃And R₄As defined for formula (I) in claim 1, to give compounds of formula (I/a), which are particular cases of compounds of formula (I):

x, Y, R, R therein₃And R₄As previously defined in the claims,

optionally substituting the nitrogen atom of the compound of formula (I/a) by reaction with an alkyl halide or dialkyl sulfate in a polar aprotic solvent in the presence of a deprotonating agent to give a compound of formula (I/b), which is a particular case of compounds of formula (I):

wherein R'₁Represents a straight or branched chain C₁-C₆Alkyl radical, and X, Y, R, R₃And R₄As previously defined in the claims,

(ii) optionally reacting the compound of formula (I/b) wherein R represents hydroxy with an alkylating agent to give a compound of formula (I/c), a particular case of compounds of formula (I):

wherein R'₂represents-OR_aWherein R ″)_aRepresents a straight or branched chain C₁-C₆Alkyl, and X, Y, R'₁、R₃And R₄As previously defined in the claims,

optionally R'₂Represents a straight or branched chain C₁-C₆The compound of formula (I/c) at alkoxy is treated with a compound of formula (X):

wherein R is₁₀Represents R' as defined for formula (I) in claim 1_aAnd R is₁₁represents-T_a-NR′_aR′_bWherein T is_a、R′_a、R′_bAs defined for formula (I) in claim 1, to give compounds of formula (I/d), which are particular cases of compounds of formula (I):

wherein X, Y, R'₁、R₃、R₄、R₁₀And R₁₁As previously defined in the claims, all compounds of formulae (I/a) to (I/d) constitute compounds of formula (I/e):

x, Y, R therein₁、R₂、R₃And R₄The compounds of formula (I/e) can be subjected to the following actions, as defined in the corresponding parts of formulae (I/a) to (I/d) above, respectively:

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims,

b) orWhich is reacted with osmium tetroxide in the presence of 4-methylmorpholine N-oxide in a polar medium to give the formula (I/g)₁) And (I/g)₂) A compound which is a particular case of a compound of formula (I):

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims,

wherein Z is as defined for formula (I) in claim 1,

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims,

c) or with potassium permanganate in a polar medium to give a compound of the formula (XII):

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims,

the compounds of formula (XII) may be subjected to the following actions:

beta) in NaBH₄Exposure to reducing conditions in the presence of a reducing agent to give a compound of formula (I/k), a special case of compounds of formula (I):

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims,

compounds (I/a), (I/b), (I/c), (I/d), (I/e), (I/f), (I/g)₁)、(I/g₂) (cis-I/g), (cis-I/h), (I/k) and (I/l) are integral parts of the totality of the compounds of the invention, these compounds being optionally purified according to conventional purification techniques or being optionally converted into their addition salts with a pharmaceutically acceptable acid or base.

16. A process for the preparation of a compound of formula (I) according to claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds (I/ak), (cis-I/al) and (I/am) as defined in the claims, wherein a represents the formula-CH (R) or a salt thereof with a pharmaceutically acceptable acid or base₅)-CH(R₆) A group in which R₅And R₆May be the same OR different and independently represent a hydrogen atom, OR_cGroup and W₁-C(W₂) A radical of the group-U-V, in which R_cAs defined for formula (I) in claim 1, W₁And W₂Each represents an oxygen atom, U represents a linear or branched C₁-C₈Alkylene oxideA radical chain and V represents a hydrogen atom, or R₅And R₆Together form a radical

Wherein Z is as defined for formula (I) in claim 1,

the method is characterized in that:

the compound of formula (I/e) is used as starting material,

x, Y, R therein₁、R₂、R₃And R₄As defined for (I/e) in claim 15,

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims,

optionally subjecting the cis-diol compound of formula (cis-I/ak) to the following:

x, Y, R therein₁、R₂、R₃And R₄As previously defined in the claims and Z is as defined for formula (I) in claim 1,

● orAnd formula(XXII) or a compound of formula (XXIII):

Hal-G₂(XXII), or G₂-O-G₂ (XXIII)，

Wherein Hal represents a halogen atom, and G₂represents-C (W)₂) -U-V, wherein W₂U, V is as defined for formula (I) in claim 1,

x, Y, R therein₁、R₂、R₃、R₄And G₂As previously defined in the claims,

the compounds of formula (I/am) are integral parts of the compounds of the invention, and these compounds are optionally purified according to conventional purification techniques, or are optionally converted into their addition salts with pharmaceutically acceptable acids or bases.

17. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 14 together with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.

18. Use of a pharmaceutical composition according to claim 17 comprising at least one active ingredient according to any one of claims 1 to 14 for the preparation of a medicament for the treatment of cancer.