EP1590355A1 - Neue tricyclische azepinderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten - Google Patents

Neue tricyclische azepinderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten

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Publication number
EP1590355A1
EP1590355A1 EP04707554A EP04707554A EP1590355A1 EP 1590355 A1 EP1590355 A1 EP 1590355A1 EP 04707554 A EP04707554 A EP 04707554A EP 04707554 A EP04707554 A EP 04707554A EP 1590355 A1 EP1590355 A1 EP 1590355A1
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Prior art keywords
branched
linear
group
formula
ethyl
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English (en)
French (fr)
Inventor
Sébastien GALLET
Pascal Berthelot
Nicolas Lebegue
Nathalie Flouquet
Pascal Carato
John Hickman
Alain Pierre
Bruno Pfeiffer
Pierre Renard
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Laboratoires Servier SAS
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems

Definitions

  • the present invention relates to new derivatives of tricyclic azepines, their preparation process, the pharmaceutical compositions containing them as well as their use as anticancer.
  • the compounds of the invention in addition to the fact that they are new, have interesting antitumor properties.
  • the nitrogen atom of the pyrido group occupies any one of positions 2 to 5 of the ring, optionally substituted by one or more identical atoms or groups or different, chosen from halogen atoms and hydroxy groups, linear or branched (-C ⁇ ) alkyl, linear or branched (Ci-C 6 ) alkoxy, linear or branched trihaloalkyl (C ⁇ -C 6 ), amino (optionally substituted on the nitrogen atom by one or two alkyl (Ci-C 6 ) linear or branched), nitro, acyl (CrC 6 ) linear or branched, and alkylenedioxy (Ci-C 2 ),
  • W represents an X-Y or Y-X group with:
  • Y is an oxygen atom or an NR 3 group
  • R represents a hydrogen atom, alkyl (Ci-C 6) linear or branched aryl- (- C ⁇ ) linear or branched, -Alk-ZR, or -Alk-Z-Alk'-Z'-R with Alk and Alk 'each independently of one another representing a linear or branched alkylene group (dC 6 ) , linear or branched (C 2 -C 6 ) alkenylene, Z and Z 'each independently of one another representing an oxygen or sulfur atom or a group -N (R') -, R and R ' , identical or different, representing a linear or branched (-Ce) alkyl group,
  • n zero or an integer such that 1 ⁇ n ⁇ 6,
  • G represents a hydrogen atom, an aryl or heteroaryl group
  • R and R 2 identical or different, represent a hydrogen or halogen atom, or a hydroxy, alkyl (Ci-C 6) linear or branched, alkoxy (C ⁇ .-C 6 ) linear or branched, trihaloalkyl (CrC 6 ) linear or branched, amino (optionally substituted on the nitrogen atom by one or two alkyl (CrC 6 ) linear or branched), nitro, acyl (Ci-C 6 ) linear or branched, or alkylenedioxy (Ci-C 2 ),
  • R 3 represents a hydrogen atom, an alkyl group (C -C 6 ) linear or branched, or arylalkyl (-C 6 ) linear or branched
  • n is different from 1, 2 or 3
  • the compounds of formula (I) are different from 1-benzyl-5,10-dimethyl-1,5-dihydro-6H-pyrido [2,3-au] [1, 4] benzodiazepin-6-one, 1, 2-dimethyl-5-oxo-5,6-dihydro- 1H- pyrido [2,3 -b] [1,5] benzodiazepine-3-carboxylate ethyl, 3-acetyl-1-ethyl- 2- methyl- 1,6-dihydro-5H-pyrido [2,3-3] [1,5] benzodiazepin-5-one, 2-amino-1-methyl-5-oxo-5,6-dihydro- 1H-pyrido [2,3-b] [1,5] benzodiazepine-3-carbonitrile, and 2-amino-1-methyl-5-oxo-5,6-dihydro-1H-pyrido [2,3- / 3] [1,5] ethyl
  • aryl group we mean phenyl, biphenyl, naphthyl, tetrahydronaphthyl, each of these groups being optionally substituted by one, two or three atoms or groups, identical or different, chosen from halogen atoms and alkyl groups (CrC 6 ) linear or branched, hydroxy, alkoxy (Ci-C 6 ) linear or branched, trihaloalkyl (-C 6 ) linear or branched, or amino (optionally substituted on the nitrogen atom, by one or two alkyl groups (-C 6 ) linear or branched), nitro, acyl (-C ⁇ ) linear or branched, alkylcarbonylamino (C ⁇ -C 6 ) linear or branched, alkylenedioxy (Ci-C 2 ), phenyloxy, benzyloxy, aminoalkoxy (Ci-C 6 ) or branched, aIkyl (C ⁇ -C
  • alkylene group means a bivalent radical of a saturated hydrocarbon chain
  • alkenylene group is meant a bivalent radical of a hydrocarbon chain comprising from 1 to 3 double bonds
  • cycloalkyl means the cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane groups, and
  • heterocyclic group monocyclic groups comprising from 5 to 7 links, saturated or unsaturated, containing from one to three heteroatoms chosen from nitrogen, oxygen, or sulfur.
  • heteroaryl groups non-limiting mention may be made of thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl groups.
  • heterocyclic groups non-limiting mention may be made of thienyl, pyridyl, pyrannyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrimidyl, piperidinyl, piperazinyl, morpholino groups.
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic acids. , benzenesulfonic, camphoric.
  • aryl assigned to the group G as defined in formula (I) is preferably a substituted phenyl group.
  • An advantageous criterion of the invention relates to the compounds of formula (I) for which G represents an aryl or heteroaryl group and more advantageously an aryl group.
  • a particularly advantageous aspect relates to the compounds of formula (I) for which G represents a phenyl group substituted by one, two or three groups chosen from linear or branched alkoxy (-), benzyloxy and hydroxy. More preferably, the substitution of G groups are alkoxy phenyl group (-C O) -straight or branched, or hydroxy.
  • the preferred compounds of formula (I) are those for which X represents SO SO and Y represents NR 3 or O.
  • R 3 preferably represents an alkyl group (C ⁇ -C 6 ) linear or branched and more particularly a methyl group.
  • R 3 represents a hydrogen atom or aryl (C O) -straight or branched, more particularly hydrogen.
  • the invention relates to compounds of formula (I) which
  • the substituents are preferably located in position 3 or 4 of the and are selected from halogen atoms, alkyl (C i -C 6) -straight or branched especially methyl, alkoxy (Ci-C 6) linear or branched especially methoxy, and trihaloalkyl (-C 6) linear or branched and more particularly trifluoromethyl.
  • R 1 and R 2 which are identical or different, represent a hydrogen atom, a halogen atom, or a linear or branched (C 6 ) alkyl group, alkoxy ( C ⁇ -C 6 ) linear or branched, or trihaloalkyl (-C ô ) linear or branched.
  • R 1 and R 2 which are identical or different, represent a hydrogen atom, a halogen atom, or a linear or branched (C 6 ) alkyl group, alkoxy ( C ⁇ -C 6 ) linear or branched, or trihaloalkyl (-C ô ) linear or branched.
  • the invention also extends to the process for preparing the compounds of formula (I) characterized in that the following are reacted in basic medium:
  • A has the same meaning as in formula (I)
  • T represents an X-Cl or Yi-H group
  • X having the same meaning as in formula (I) and Yi representing an oxygen atom
  • R 4 represents a hydrogen atom, a linear or branched (-C 6 ) alkyl group, or a group protecting the amino function
  • R Î and R have the same meaning as in formula (I)
  • Zi represents a halogen atom
  • V represents either a group Yi-H when T represents a group X-Cl, or a group X-Cl when T represents a group Yi-H
  • A, Ri, R 2 are as defined in formula (I), Zi is as defined above, and W'i represents a group X-Y'i or Y -X with X is as defined in formula (I) and Y 1 ! represents an oxygen atom, an N-R ' 4 group where R' 4 represents a protective group for the amino function,
  • the compounds of the present invention in addition to the fact that they are new, exhibit advantageous pharmacological properties. They have cytotoxic properties which make them useful in the treatment of cancers.
  • the invention also extends to pharmaceutical compositions containing as active principle at least one compound of formula (I) with one or more inert, non-toxic and suitable excipients.
  • pharmaceutical compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.
  • the useful dosage is adaptable according to the nature and severity of the disease, the route of administration as well as the age and weight of the patient and any associated treatments. This dosage varies from 1 to 500 mg per day in one or more doses.
  • the starting materials used are known products or prepared according to known preparatory methods.
  • the product is obtained according to the method described in the publication J. Med. Chem., 1991, 34 (4), 1356-1362, from 2-chloro-3-pyridinesulfochloride and 2-nitroaniline.
  • 2-chloro-N-methyl-N- (2-nitro ⁇ henyl) -3-pyridinesulfonamide is synthesized by N- alkylation of the compound prepared in the preceding stage using methyl iodide in basic medium (process described in publication J. Med. Chem., 1991, 34 (4), 1356-1362).
  • the 2-chloro-N-methyl-N- (2-nitrophenyl) -3-pyridinesulfonamide (0.005 mol) is then dissolved in concentrated acetic acid (20 ml) and iron (0.025 mol) is added. Evaporate under reduced pressure, take up in water and extract with ethyl acetate. Dry over sodium sulfate and then evaporate under reduced pressure.
  • N- (2-chloro-3-pyridinyl) -N-methyl-2-nitrobenzenesulfonamide is synthesized by N- alkylation of the compound prepared in the preceding stage using methyl iodide in basic medium (process described in publication J. Med. Chem., 1991, 34 (4), 1356-1362).
  • LeN- (2-chloro-3-pyridinyl) -N-methyl-2-nitrobenzenesulfonamide (0.001 mol) is then hydrogenated on Raney nickel (0.003 mol) in absolute ethanol (150 ml) at atmospheric pressure and at temperature room. The nickel is removed, the solvent is evaporated off under reduced pressure, then acetic anhydride (20 ml) is added to the crude. The solution is kept for 12 h with stirring. The mixture is then diluted with water, extracted with dichloromethane, dried, and recrystallized. Melting point 116-118 ° C
  • Stage B H ⁇ -PyridotS ⁇ - lIl ⁇ j Slbenzoxathiazépme-S j S-dio yde
  • the expected product is obtained according to the process described in Preparation A, replacing, in Stage B, methyl iodide with methoxyethoxymethyl chloride. Melting point 119-121 ° C
  • the expected product is obtained according to the process described in Preparation D, replacing in stage A 2-aminophenol with 2-aminoaniline.
  • the intermediate product, 6,11-dihydro-5H-pyrido [2,3- ⁇ ] [1,5] benzodiazepin-5-one is N-alkylated using methyl iodide in basic medium ( method described in the publication J. Med. Chem., 1991, 34 (4), 1356-1362).
  • Example 1 1- (4-Met oxybenzyl) -6-methyl-1,6-dihydropyrido [3,2-c] [2, 5 5] benzotbiadiazepine-5,5-dioxide
  • Example 2 1- [2- (4-Methoxyphenyl) ethyl] -6-methylH, 6-dihydropyrido [3,2-c] [2, 1, 5] benzothiadiazepine-5,5-dio ⁇ yde
  • the expected product is obtained according to the process described in Example 1, by replacing 4-methoxybenzyl chloride with 4-methoxyphenylethyl methanesulfonate. Melting point 105-107 ° C (ethanop
  • Example 3 l-I3- (4-Methoxypl ⁇ ényl) propyll-6-méthyH :> 6-dihydropyrido [3,2-c] [2, l, 5Jbenzothiadiazêpine-5,5-dioxide
  • the expected product is obtained according to the process described in Example 1, replacing 4-methoxybenzyl chloride with 3- (4-methoxyphenyl) propyl methanesulfonate. Melting point 50-55 ° C (isopropanoP
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, stage A, 2-nitroaniline with 4-chloro-2-nitroaniline, and 4-methoxybenzyl chloride is replaced by 4-methoxy-phenylethyl methanesulfonate. Melting point 163 ° C (ethano)
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, Stage A 2-nitroaniline with 5-chloro-2-nitroaniline, and 4-methoxybenzyl chloride is replaced by methanesulfonate of 4-methoxy-phenylethyl. Melting point 100-101 ° C (ethanol
  • Example 8 1- (4-Methoxybenzyl) -6,9-dimethylH, 6-dil ⁇ ydropyrido [3 ? 2-c] [2, l s 5] benz ⁇ thiadiazepme-5,5-dioxide
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, stage A, 2-nitroaniline with 4-methyl-2-nitroaniline. Melting point 90-92 o Cfé ⁇ hanor)
  • Example 10 9-Methoxy-1- (4-methoxybenzyl) -6-methyH, 6-dihydropyrido [3,2-c] [2, 1, 5] benzothiadiazepine-5 s 5-dioxide
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, stage A, 2-nitroaniline with 4-methoxy-2-nitroaniline. Melting point 95-96 ° C (ethano
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, Stage A 2-nitroaniline with 4-methoxy-2-nitroaniline, and 4-methoxybenzyl chloride is replaced by methanesulfonate of 4-methoxy-phenylethyl.
  • the expected product is obtained according to the process described in Example 1, replacing, in Preparation A, stage B, N-alkylation with methyl iodide with 1- chloro-2- (N, N-diethylamino) hydrochloride ) ethane, and 4-methoxybenzyl chloride is replaced by 4-methoxy-phenylethyl methanesulfonate. Melting point 92 ° C decomposition (ethanoD
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, stage B the N-substitution with methyl iodide with 4-methoxybenzyl chloride.
  • the expected product is obtained according to the process described in Example 1, replacing in Preparation A, stage B the N-substitution with methyl iodide by 4-methoxybenzyl chloride, 4-methoxy-benzyl chloride is replaced by 4-methoxyphenylethyl methanesulfonate. Melting point 67 ° C (ethanoD
  • the expected product is obtained according to the process described in Example 1, starting from the product prepared in stage C, Preparation B. Melting point 174-177 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 15, except that the 4-methoxybenzyl chloride is replaced by 4-methoxyphenylethyl methanesulfonate. Melting point 181-183 ° C (ethanol)
  • Example 18 The expected product is obtained according to the process described in Example 15, except that the 4-methoxybenzyl chloride is replaced by 3- (4-methoxyphenyl) propyl methanesulfonate. Melting point 94-96 ° C (ethanol)
  • Example 18 5-Methyl-1- (3 » 4,5-trimethoxybenzyl) -1,5-dihydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6-dioxide
  • the expected product is obtained according to the process described in Example 15, except that the 4-methoxybenzyl chloride is replaced by 3,4,5-trimethoxybenzyl methanesulfonate.
  • the expected product is obtained according to the process described in Example 15, replacing 2-nitrobenzenesulfochloride in Preparation B, stage A with 4-chloro-2-nitrobenzene sulfochloride.
  • the expected product is obtained according to the process described in Example 15, replacing 2-nitrobenzenesulfochloride in Preparation A, stage A with 4-chloro-2-nitrobenzene sulfochloride, and 4-methoxybenzyl chloride is replaced by the 4-methoxy-phenylpropyl methanesulfonate. Melting point 112-113 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 15, replacing 2-nitrobenzenesulfochloride in Preparation A, stage A with 4-chloro-2-nitrobenzene sulfochloride, and 4-methoxybenzyl chloride is replaced by 2- (3,4,5-trimethoxyphenyl) ethyl methanesulfonate. Melting point 203-204 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 15, replacing 2-nitrobenzenesulfochloride in Preparation A, stage A with 4-chloro-2-nitrobenzene sulfochloride, and 4-methoxybenzyl chloride is replaced by 4-benzyloxybenzyl chloride.
  • the expected product is obtained according to the process described in Example 15, replacing in Preparation B, Stage A 2-nitrobenzenesulfochloride with 4-chloro-2-nitrobenzene-sulfochloride, 4-methoxybenzyl methanesulfonate is replaced by 2- (4-benzyloxyphenyl) ethyl chloride. Melting point 121-122 ° C (ethanol)
  • Example 25 9-Chloro-1,5-bis (4-methoxybenzyl) -1,5-dihydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6-dioxide
  • the expected product is obtained according to the process described in Example 15, replacing in Preparation B, stage A 2-nitrobenzenesulfochloride with 4-chloro-2-nitrobenzene sulfochloride, the N-substitution of the compound by iodide methyl is replaced by 4-methoxybenzyl chloride. Melting point 70-71 ° C f ethanol)
  • the expected product is obtained according to the process described in Example 15 by replacing, in Preparation B, stage A, 2-nitrobenzenesulfochloride with 4-chloro-2-nitrobenzene sulfochloride, the N-substitution of the compound by iodide of methyl is replaced by 4-methoxybenzyl methanesulfonate, and 4-methoxybenzyl chloride is replaced by 2- (4-benzyloxyphenyl) ethyl chloride. Melting point 168-169 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 19, starting from 5-chloro-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzenesulfochloride, in Preparation B. Melting point 162-163 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 19, starting from 5-chloro-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzenesulfochloride, in Preparation B, and 2- (4-methanesulfonate) -methoxyphenyl) ethyl in place of 4-methoxybenzyl chloride. Melting point 186-188 ° C (ethanoD
  • the expected product is obtained according to the process described in Example 21, starting from 5-chloro-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzenesulfochloride, in Preparation B. Melting point 62-65 ° C (isopropanol)
  • the expected product is obtained according to the process described in Example 19, starting from the
  • the expected product is obtained according to the process described in Example 20, starting from 4-methyl-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzenesulfochloride, in Preparation B. Melting point 128 ° C (ethanol )
  • the expected product is obtained according to the process described in Example 21, starting from 4-methyl-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzenesulfochloride, in Preparation B. Melting point 130-131 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 19, starting with 4-methoxy-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzene sulfochloride, in Preparation B. Melting point 179 -180 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 20, starting from 4-methoxy-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzene-sulfochloride, in Preparation B. Melting point 65 -68 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 21, starting from the
  • Example 36 1- (4-Methoxybenzyl) -5-methyl-9- (trifluoromethyl) -1,5-dil ⁇ ydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6-dioxide
  • the expected product is obtained according to the process described in Example 19, starting from 4-trifluoromethyl-2-nitrobenzenesulfochloride in place of 4-chloro-2-nitrobenzene-sulfochloride, in Preparation B. Melting point 142-143 ° C (ethanol)
  • Example 37 1- [2- (4-Methoxyphenyl) ethyl] -5-methyl-9- (trifluoromethyl) -1,5-hydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6 -dioxide
  • the expected product is obtained according to the process described in Example 20, starting from the
  • Example 38 1- [3- (4-Methoxyphenyl) propyl] -5-methyl-9- (triflnoromethyl) -1,5-dihydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6 -dioxide
  • the expected product is obtained according to the process described in Example 21, starting from the
  • Example p 39 1- ⁇ 2- [4- (Benzyloxy) phenyl] ethyl ⁇ -5-methyl-1,5-dihydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6- dioxide
  • the expected product is obtained according to the method described in Example 24, starting from 2-nitrobenzenesulfochloride instead of 4-chloro-2-nitrobenzenesulfochloride, in Preparation B. Melting point 133-134 ° C (ethanol )
  • Example 40 1- [2- (4-phenol) ethyl] -5 "methyH, 5-dihydropyrido [3,2-c] [1,2,5] benzothiadiazepine-6,6-dioxide
  • the expected product is obtained according to the process described in Example 1, starting from the compound prepared in stage B of Preparation C.
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by the methanesulfonate of
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by 3- (4-methoxyphenyl) propyl methanesulfonate. Melting point 99-100 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by 2- (3,4,5-trimethoxyphenyl) ethyl methanesulfonate.
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by [2- (1-naphthyethyl) methanesulfonate.
  • Example 46 1- (2- [1'-Bipbenyl] -4-ylétI ⁇ yl) -li ⁇ -pyrido [3,2-c] [1,2,5] benzoxathiazepine-5,5-dioxide
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by [2- (4-biphenypethyl) methanesulfonate. Melting point 163-165 ° C. (ethanol )
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by 2- (4-benzyloxyphenypethyl methanesulfonate. Melting point 142 ° C (ethanol)
  • Example 49 9-Methyl-1- [2- (4-methoxyphenyl) ethyl] -1 J H-pyrido [3,2-c] [1,2,5] benzoxathiazepine-5,5-dioxide
  • the expected product is obtained according to the process described in Example 41, replacing in stage A of Preparation C 2-aminophenol with 2-amino-4-methylphenol, and 4-methoxybenzyl chloride is replaced by methanesulfonate of 4-methoxyphenylethyl. Melting point 114-115 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 41, replacing in stage A of Preparation C 2-aminophenol with 2-amino-4-methoxyphenol, and 4-methoxybenzyl chloride is replaced by methanesulfonate of 4-methoxyphenylethyl. Melting point 115-116 ° C (ethanol)
  • the expected product is obtained according to the process described in Example 15, except that the 4-methoxybenzyl chloride is replaced by 2- (3,4,5-tri-methoxyphenyl) ethyl methanesulfonate.
  • Example 54 6 - [(2-Methyloxyethoxy) methyl] -1- [2- (4-methoxyplenyl) ethyl] -1,6-dihydropyrido [3,2-c] [2, 1, 5] benzothiadiazepine-5, 5-dioxide
  • the expected product is obtained according to the process described in Example 2, replacing the azepine of preparation A with that of preparation E.
  • Example 55 1- [2- (4-Methoxyphenyl) ethyl] -1,6-dil ⁇ ydropyrido [3,2-c] [2,1,5] benzothiadiazepme-5,5-dioxide
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by 2- (2-methoxyphenyl) methyl methanesulfonate. Melting point 138-140 ° C (isopropanol /water)
  • the expected product is obtained according to the process described in Example 41, except that the 4-methoxybenzyl chloride is replaced by 2- [3- (benzyloxy) - 4-methoxyphenyl] ethyl methanesulfonate.
  • Example 59 5- [2- (5,5-Dioxido-li ⁇ -pyrido [3,2-c] [1,2,5] benzoxathiazepin-l-yl) ethyl] - 2-methoxyphenol
  • the expected product is obtained according to the process described in Example 56, replacing the compound of Example 47 with that of Example 58 as the starting reagent. Melting point 158-160 ° C (isopropanol / water)
  • Example 60 1- [2- (4-Methoxyphenyl) ethyl] pyrido [3,2-c] [1,5] benzoxazepin-5 (li?) - one
  • the expected product is obtained according to the process described in Example 42, starting from the compound prepared in stage B of Preparation D.
  • Example 61 1- [2- (3-Hydroxy-4-methoxyphenyl) ethyl] pyrido [3,2-c] [1,5] benzoxazepin-5 (lff) -one
  • the expected product is obtained according to the process described in Example 59, starting from the compound prepared in stage B of Preparation D.
  • Example 62 1- [2- (4-Methoxyphenyl) ethyl] -6-methylH, 6-dihydro-5 ⁇ -pyrido [2,3-ô] [1,5] benzodiazepin-5-one
  • the expected product is obtained according to the process described in Example 42, starting from the compound prepared in stage B of Preparation F.
  • the expected product is obtained according to the process described in Example 59, starting from the compound prepared in stage B of Preparation F.
  • EXAMPLE A In Vitro Cytotoxicity Five cell lines were used: - 1 murine leukemia, L1210,
  • the cells are distributed in microplates and exposed to cytotoxic compounds. The cells are then incubated for 2 days (L1210) or
  • IC 50 a concentration of cytotoxic agent which inhibits the proliferation of the treated cells by 50%.
  • the compound of Example 42 has the IC 50 mentioned in the table below:
  • the compound of Example 42 is therefore powerfully cytotoxic for these tumor lines.
  • the resistant line KB-A1 is as sensitive as the sensitive line KB-3-1, which demonstrates that 42 is not recognized by the glycoprotein P, responsible for multiple resistance to cytotoxic drugs.
  • the compounds of the invention are therefore, moreover, of interest in the treatment of human tumors resistant to chemotherapy.
  • L1210 cells are incubated for 21 hours at 37 ° C in the presence of different concentrations of products tested. The cells are then fixed with 70% ethanol (V / V), washed twice in PBS and incubated for 30 minutes at 20 ° C. in PBS containing 100 ⁇ g / ml of RNAse and 50 ⁇ g / ml of iodide of propidium. The results are expressed as a percentage of the cells accumulated in the G2 + M phases after 21 hours compared to the control.
  • the compounds of the invention are powerful cytotoxic agents having a selective action on the cell cycle.
  • the compound of Example 42 induces an 80-90% accumulation of cells in G2 + M phases after 21 hours at a concentration of 25 nM (untreated cells: 20% in G2 + M phases) .

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP04707554A 2003-02-03 2004-02-03 Neue tricyclische azepinderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten Withdrawn EP1590355A1 (de)

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FR0301181 2003-02-03
FR0301181A FR2850654A1 (fr) 2003-02-03 2003-02-03 Nouveaux derives d'azepines tricycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
PCT/FR2004/000234 WO2004069843A1 (fr) 2003-02-03 2004-02-03 Derives d'azepines tricycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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CN (1) CN1745087A (de)
AR (1) AR043691A1 (de)
AU (1) AU2004208890A1 (de)
BR (1) BRPI0407215A (de)
CA (1) CA2513059A1 (de)
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FR (1) FR2850654A1 (de)
MA (1) MA27576A1 (de)
MX (1) MXPA05007977A (de)
MY (1) MY138865A (de)
NO (1) NO20054092L (de)
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EP2049493B1 (de) * 2006-07-31 2012-03-21 Cadila Healthcare Limited Als modulatoren von hdl einsetzbare verbindungen
AU2010210646B2 (en) 2009-02-05 2015-10-29 Immunogen, Inc. Novel benzodiazepine derivatives
SI2675479T1 (sl) 2011-02-15 2016-04-29 Immunogen, Inc. Citotoksični derivati benzodiazepina
EP2887965A1 (de) 2012-08-22 2015-07-01 ImmunoGen, Inc. Zytotoxische benzodiazepin-derivate
US9381256B2 (en) 2014-09-03 2016-07-05 Immunogen, Inc. Cytotoxic benzodiazepine derivatives
CN116514903A (zh) 2014-09-03 2023-08-01 伊缪诺金公司 细胞毒性苯并二氮杂䓬衍生物
US20180346488A1 (en) 2017-04-20 2018-12-06 Immunogen, Inc. Cytotoxic benzodiazepine derivatives and conjugates thereof
EP3732178A1 (de) 2017-12-28 2020-11-04 ImmunoGen, Inc. Benzodiazepinderivate
JP2022529583A (ja) 2019-03-29 2022-06-23 イミュノジェン・インコーポレーテッド 異常細胞増殖を阻害するまたは増殖性疾患を治療するための細胞毒性ビス－ベンゾジアゼピン誘導体及び細胞結合剤とのその複合体

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US20060079677A1 (en) 2006-04-13
FR2850654A1 (fr) 2004-08-06
JP2006515350A (ja) 2006-05-25
MXPA05007977A (es) 2005-09-20
AU2004208890A1 (en) 2004-08-19
MA27576A1 (fr) 2005-10-03
CN1745087A (zh) 2006-03-08
ZA200505430B (en) 2006-09-27
NO20054092L (no) 2005-09-02
EA200501232A1 (ru) 2006-02-24
KR20050096970A (ko) 2005-10-06
MY138865A (en) 2009-08-28
CA2513059A1 (fr) 2004-08-19
BRPI0407215A (pt) 2006-01-24
PL376621A1 (pl) 2006-01-09
AR043691A1 (es) 2005-08-10
WO2004069843A1 (fr) 2004-08-19

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