CA2096719A1 - Pyridobenzoindole derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

2096719 9209602 PCTABS00130 New pyridobenzoindole derivatives of general formula (I), in which R is H or alkyl (1 or 2 C), alk is alkylene (2 to 4 C) straight or branched, R1 represents a hydrogen atom or a alkyl radical (1 or 2 C) and R2 represents a hydroxy or methoxy radical and their addition salts with acids, useful as anti-tumor agents.

Description

- ~ 92/0960 ~ 1 PCT / FR91 / 00926 PYRIDOBENZOINDELE DERIVATIVES, THEIR PREPARATION AND COMPOSITIONS
PHARMACEUTI ~ UES ~ UI CONTAIN THEM
~ present ~ lnventlon conoer ~ e of ~ open - deactivated ux of pysidoben ~ oindo ~ e de for ~ ule g-nér-le R2 ~ ~ ~ llt - N

Rl the es ~ ch ~ ant their hy r-tes, l-uss ~ els of add ~ tlon ~ vee e ~ des, leus prepar ~ tlon and co ~ positions pb-s ~ 30eutiques qui le`s contain D-ns l- de ~ nde d- ~ r- ~ -t europ ~ en 239 476 were déerit ~
of ~ -cr ~ olln- de for ~ ule q ~ n ~ r-le NRS) n ~ t:
~ 4 Ri ~ N

d ns l ~ u ~ R1 t Rs have ontr uts-s nton s of hy ~ so9-n-, R2 ; ~ -ut s-pr ~ s nt-r ~ n tone C'hy ~ rog ~ n, un s ~ dlc ~ l hydroxy ou looy-loxy, ~ 3 t ~ ont ~ ot- ~ oont do ~ rd ~ e ~ ux ~ leoyl- t ~ 2 ~, Cul ~ r ~ -ontont un- otlvlt ~ nntl-tunor le.
~ -s Ill-urx, l-- d ~ slv ~ s du Fysldolndol- ~ on u ~ tltu ~ s : n lpo ~ ltl ~ n - ~ Jo ~ td ~ osltx dbn ~ 1 ~ lltt s tur IJ. N ~. Cb- ~., 31, ~ 9 ~ ~ 193B ~ co ~ o- d ~ oospox ~ ~ n ~ ctl ~.
Lo ~ ~ u ~ ~ ux ~ sl ~ du Fysldob-nsol ~ ol- de lor ~ ule g & n ~ I) d-ns l-qu ~ ll-:
sp ~ nte a ~ hydsog tose; ne or Yn r ~ c ~ l ~ lcoyl ~ cont nant 1 o ~ 2 ~ ton ~ dc sbone, REPLACEMENT SHEET ~ T

WO 92/0960 ~ 2 Q ~ ~ 7 ~ 3 2 PCT / FR91 / 00926. ~

alk represents a straight or branched alkylene radical containing 2 to 4 carbon atoms, R1 represents a hydrogen atom or a radical lcoyl containing 1 or 2 carbon atoms and R2 represents a hydroxy or methoxy radical, have particularly interesting anti-tumor properties-health.
According to the invention, the products of general formula (I) can be obtained from the chlorinated derivative of general formula:

H3C0 ~ Cl D l I
~ N (II) in which R1, is defined as above by the action of a a ~ ine of general formula:

H2N - alk - N ~ R) 2 (III) in which alk and R are defined as previously, su $ v $ e the if necessary, the transformat $ on of the methoxylated product t $ a $ ns $
general formula H3CO ~ alk - N (R) 2 . ~ ~ ~ a) ,.

, ~.

2 0 9 ~
- ~) 92/0960 ~ 3 PCT / FR91 / 0092fi in which R, R1 and alk are defined as above, in a derivative 9-hydroxy pyrido ~, 3-b] benzole] lndole The reaction of the amine of general formula (SII) on the chlorinated derivative of general formula (II) is carried out in the presence of a excess of the amine, preferably under nitrogen, e ~ entirely in a inert organic solvent, or ~ 601 before, at a temperature between the reflux temperature of the reaction mixture, and 250C (autoclave) Demethylation 6 'performs by any known method which does not alter the rest of 1 ~ molecule The chlorinated derivative of general formula (II) for leguel R1, is a hydrogen atom can be prepared from pyridone corresponding, of formula ~ (IV ~

per action of an ehloration agent We generally operate on the nucleus of an ehloration gent selected by ~ i pho oxychloride ~ phor- or 1- ~ d ~ r ~ vé6 halogenés du phosphorus in the presence of a base t tia ~ re ~ di-thylaniline, dimethyl-laniline for example ~ ple) dbns an organic solvent such as nitrile ~ ac ~ tonitsile for example), at Uno toop ~ raturo co ~ priz- ntre ~ 5 ot 90 C (r-flux tacporature of ~ ng ~ r ~ aug ~ oM ~ l) Do pr ~ f ~ r ~ nco, la r ~ ctlon ~ i-otu ~ ~ OUJ nitrogen ; Lo prsduit de ior ~ ule g ~ n ~ ralé (~) for l ~ qual ~ 1 e ~ t un alkyl radical can be obtained by alkylation of the product to leguel ~ t a hydrogen atom by x ~ mple per act ~ on d; rivé
halog ~ né con ~ en ~ blo, en pr ~ sen ~ od carbonat- de potasslum . . . . .

2 a ~
:
WO 92/09602 PCT / FR91 / 0092h ~ -The product for ~ ule ~ IV) can be prepared from hydrazone for ~ ule H3C0 ~ 0 H

by thermal Fisher reaction, by analogy with the ~ method described by CH NGUYEN and E. BISAGN ~, ~ etrahedron, 42 ~ 8), 2203 (19B6) The hydrazone of for ~ ule (V) is prepared by condensation hydrazino-4-1H-pyridone-2 with 6-hydroxy-tetralone-2 La reaction is generally carried out in an organic solvent such as alcohol ~ ethanol for example), at te ~ reflux temperature of ~ momentum ~ e r ~ action The nethoxy-6 tétralon can be obtained according to the ~ method described in JA ~ Chem Soc, 82, 2573 (1960) Hydrazino-4-1H-pyridone-2 can be prepared according to the ~ method described- by CH NGUY ~ N t ~ BSS ~ CNT, Setrahedron, 42 (B), 2203 (19B6) Pyrldob derivatives ~ nzo ~ ndol- of general formula ~ I) can be purified by cry ~ tallization or by chro ~ atographle The nou ~ to derivative6 of pyr ~ doben20indole ~ -lon l'ln ~ n-tlon can; be tr ~ nJfor éa n c-ls d'-dd ~ t ~ on ~ c l- ~ c ~ d ~ s, by actlon of a c ~ of dan- a rolv nt org n ~ qu- L- ol pr ~ olplte, ~ vantu ll-mont pr ~ con ¢ ntr-tlon d- ~ a ~ olut ~ on, ll ~ t ~ by ~ by ; flltratlon or cantatlon Com ~ e els pharnac-utlquan nt ccep Wbl- ~, on p ut c ~ ter 1-8 ~ el6 d'-ddltlon av-c 1-6 c ~ dos ln ~ raux tl ~ qu- hydrochloride-s, hydrobromides, ~ ulfat-6, nltrate ~, pho ~ phat-s, or orgaD ~ qu-s such that c ~ tate, proplonates, ~ uccinates, al ~ ate ~, fu ~ arates, ~ éthanesul-fonates, p toluenesulfonate ~, ~ sethlonates or derivatives of '.

,. , U ~ J ~ J

~ ubstitution of these compounds The pyridobenzoindole derivatives according to the invention and their salts may exist in the form of hydrates, it is understood that these hydrated forms also come within the scope of this invention In addition when the symbol alk is an alkylene radical branched, pyridobenzoindole derivatives have forms isomers It is understood that these isomeric forms also enter into the scope of the invention The derivatives of general formula (I) ~ have particularly interesting as anti-tumor agents Their anti-tumor properties have notably been highlighted in vitro evidence at a concentration close to 15 to 1.5 ~ g / disgue in the differential cytotoxicity test, according to the technique described by TH Corbett et al, Investigational new druy, 4, 207-220 (19B6), and in vivo ~ grafted mouse tumors, more particularly on leukemia P38 ~, the product studied was shown active at a dose of 20 mg / kg intraperitoneally Their toxicity in mice6 expressed by their dose maximum tolerated is ~ higher than 20 and 40 mg / kg intraper-ritoneal Of particular interest for their act ~ lives ~ ant ~ -tumorale 60nt mainly the ~ Fyridobenzolndole derivatives of formula general (I), for the ~ quel6 R is a methyl radical, alk is a straight alkyl radical or branched containing 2 to 4 carbon atoms, R1 is an atom `~ hydrogen or a methyl radical, t R2 is a hydroxy radical, as well as their 6 salts and l- cas ~ ch ~ nt their hydr ~ tos In particular l- l (dln ~ thyl-olno-3) pr ~ pyll ~ ino-1 hydroxy-9-SH- ~ yrldo ~ 4,3- ~] bsnzoll-] lndolo, lnsl qu- o ~ t ~ efi lormos hydrates, The examples shown 6 given to be non-limiting Illustrating the present invention 'J 1 ~
WO 92/0960 '6 PCT / FR91 / 00926 i-L (3-dimethylamino) psopyl] amino-1 methoxy-9 5H-pyrido t4,3-bl benzo tel indole (free base) is released by ammonia in exoès from 1.8 g of the corresponding bimaleate then extracted and dried The product thus obtained is placed in a reaction allon of 250 cm3 with an argon agltator, with 66 cm3 of hydrobromic acid (d ~ 1.47; 47%) This mixture, which has become homogeneous at boiling, is ; heated at reflux for 6 hours and concentrated at ~ ec ~ or pressure reduced The solid residue is dissolved in water (200 cm3) alkali-nized by ammonia at 28% (20 cm3) which is added ~ out to drop, to form a gummy precipitate To the resulting mixture, we have ~ 200 cm3 of ethyl acetate and agitates the whole for one hour The organic phase is decanted and the mother liquors saturated with ~ odium chloride are extracted two faith6 with 100 cm3 of ethyl acetate The phase organic is ~ filtered on sodium sulfate, filtered, treated with S
g of animal charcoal to discolor it, then filtered and concentrated to ~ ec The residue ~ olide is repri ~ in 40 c ~ 3 ethanol, and treated with 2.5 g of ac ~ maleic in ~ solution in 20 cm3 of ethanol at boiling point The bi random of lldimethylamino-3) propyll amino-1 hydroxy-9 5H-pyrido [4,3-b] b nzo ~ -] ~ hydrated ndole with 0.25 H20 ~ 1.25 g, yield ~ 70%) is thus obtained, or form ~ lcrocrystals;
F ~ 195-200C ~ decompositlon) [(Dimethylamino-3) propyl] bimaleate ~ mino-1 methoxy-9 5H-pyrido 14.3-bl benzo lel lndole can be obtained from next way Chloro-l n6thoxy-9 5H-pysldo t ~, 3-bl b nzo le ~ lndole ~ 1.8 9) 9t placed ~ in a 250 c balloon ~ 3 containing 50 cm3 ~ large xcès) dlnéthylamlno-3 propyla ~ lne t chauff ~ à reflux ~ 150 C), under nitrogen and rour gltatlon, during ~ B hours-s ~ d ~ aparitlon total chlorine-fired, controlled ~ aur clquce plate) The excess of the dlamln is ~ vaporized with baln-marle 80US
presslon reduces and the residue e ~ t reprl ~ in the - to pul ~ alkalized by the ~ onla ~ ue The ~ olide formed is filtered, washed with water, taken up ~ 671 ~
92/0960 ~ PCT / FR91 / 00926 in methylene chloride and washed with ~ ec 150 cm3 of water and 10 cm3 of am ~ oniac After chromatography on alumina and ~ allfication by ~ random acid under usual conditions, 2.56 g are obtained (R ~ 69%) bimaleate of ~ (dimethylamino-3) propyllamino-1 metho-xy-9 5H-pyrido [4,3-bl benzo lel indole expected, melting at 204-206C
with decomposition Chloro-1 methoxy-9 5H-pyrido ~ 4,3-b ~ benzo [e] indole can be obtained in the ~ u ~ way In a 1 liter flask fitted with a magnetic stirrer, an addition funnel, a refrigerant and maintained ~ or nitrogen, we introduce 4 g of methoxy-9-2H, SH-pyrido ~ 4,3-bl benzo le] indol-one-1 taken up in boiling ethanol and ~ carefully dried, 14.1 9 (4 equivalents) of benzyl triethylammonium chloride, 3.6 g (4 15 equivalents) of acetamide, 40 cm3 of acetonitrile and 9.12 g (4 equivalents) of freshly rectified diethylaniline Through the bulb, 70 cm3 of oxy-rectified phosphorus chloride, and observes an exotherm reaction ~ i-the mixture is heated to reflux for 20 hours, while that after being p ~ es6 by a homogeneous phae, a precipitate appears Concentrate to dryness, in a bain-marie heated to 70 ~ C and ~ under pressure reduced (15 mm Hg) To the residue obtained, we have ~ 300 cc of ice water and the mixture, well stirred for 2 hours, ~ 6t heated to 70 C for 20 ninut- ~ We complete to 600 cm3 with au-au, boil $ tion for 5 m ~ nutes and laic ~ er cool to room temperature 60us stirring 4 very cool, we get a preclpit ~ ~ yardstick, that we filter cold and lv- nault ~ trold- C pr ~ clplt ~ Jt r-pri ~ dan ~ S00 cm3 d'-au di ~ tlll ~ - t l- n ~ lan p ~ t lcalln ~
cold, by the ~ ~ monlaque L'-n ~ ble st l-laa ~! ow gltatlon p-ndant 1 nu ~ tt le pr ~ clp ~ t ~ st flltr ~ and washed at-it is rocri6tall ~ é in l-alcohol n giving 2.6 g of igullle ~ ~ -unes of chloro ~ thoxy-9 5H-pyrido 14.3-bl benzo [-1 lndol-; F) 260C;
R nd nent 60 ~
La ~ ethoxy-9-2H, SH-pyrido [4,3-b ~ benzo lel lndolone-1 can be obtained from the following In a 1 liter three-necked flask, the N- (1H-pyridone-2) is mixed 2 0 ~
WO 92 / 096Q ~ PCT / FR91 / 00926 ~ `

yl) - ~ N '- (~ 6-ethoxy-1,2,3,4-tetrahydro-naphthalenylidene) -2 hydrazine (18 g) and the diphenyl ether (700 cm3) pUi6 heats at reflux for 30 minutes, maintaining the ~ SOU5 emble good agitation and ~ ou nitrogen ~ e mixture becomes homogeneous and discolours Heating is interrupted to allow it to cool to 200C and check that the starting compound is completely transformed silica plate Merck, eluent methylene chloride-ethanol 8/2 by volume, ~ rf hydrazone ~ 0, S, rf compound lnter ~ ediary - 0.8) Continuing to shake, the 10% palladium darbon (4g) suspended in the di-phenyl ether (20 cm3) is added gradually, carefully (foams and release of hydrogen), and the new mixture is heated at reflux for 30 minutes (appearance of the compound inter-medium) (rf = 0.35 silica-pure ethyl acetate; expected product rf = 0.5B) The mixture is then taken up in 600 cm3 of 2-ethoxy boiling ethanol, filtered to remove palladium on carbon and concentrated to ~ ec The solid obtained is added with 70 cm3 of ethanol absolute, stirred for 18 hours, filtered and dried to give 11 g (R
68%) of yellowish microcrystals (F> 260C) corresponding to the ~ ethoxy-9-2H, 5H-pyrido [4,3-b ~ benzo ~ e] lndolone-1 N- ~ 1H-pyridone-2 yl) -4 N '- (6-methoxy-1,2,3,4 tetrahydro naphthalenylidene) -2 hydrazine can be obtained from the ~ aniere next The mixture of hydrazino-4-1H-pyridone-2 (9.8 g) in absolute ethanol (lS0 c ~ 3) is heated ~ at reflux In solution, of homogeneous ~ enue to boiling, we ~ 6-methoxy-2-tetralone (16.6 g) ot the mixture, which has become rapidly heterogeneous, is heated to reflux for 2 hours (di ~ paritlon of hydrazine controlled by TLC on Merck silica plate, ~ glow chloride d- n ~ thyl ~ n-- ~ thanol 1/1 volu ~ es) Te ~ r ~ clplte for ~ st ~ lltr ~, reprls d ~ nE
l ~ thanol dr ~ l ~ qu-l hydrazone ~ t pu pu pu ~ s flltr ~ à
~ rold to donate (19.3 g (63%)) dd crocrl-ux ~ -unes from N- (1H-pyrldone-2 yl) -4 N '~ thoxy-6 t ~ trahydro-1,2,3,4-naphth-l nylldene) -2 hydr zine, F 220 - 225-C, vc déco ~ posltlon Hydrazlno-4-1H-pyridon -2 can be ~ btenue depending on the ~ method declt- by ~ Bi ~ agni ot CH Nguyen, ~ etrahedron, 42, 2303 (1sa6).

2 ~ 5 ~
~ 92/0960 'PCT / FR91 / 00926 The present invention also relates to the compositions pharmaceuticals that contain corme product act ~ f at mo ~ ns a product of general formula (I) in a pure state (80US for ~ e free or in salt form) or in combination with one or more additives pharmaceutically acceptable These compositions can be used parenterally Compositions for parenteral administration, few be 601utionc 6terile ~ aqueous ~ or non-aqueous, pen ~ ions or emul6ions Like ~ ol ~ ant or vehicle, we can e ~ bend propylene glycol, polyethylene glycol, oils vegetable, in particular olive oil and organic esters injectables, for example ethyl oleate These compositions can equal ~ ent contain adju ~ ants, in particular wet agents lants, emulsifiers or dispersants ~ sterilization can do 6th of several ways, for example ~ ple using a bacterio- filter logic, by incorporating i the co ~ positlon of agents ~ teril $ s ~ nts, by irradiation or by heating They little ~ ent equal ~ ent be prepared ~ or form 601ide ~ terile conposltions which will di- ~ out-fi u nom de l 'mploi danc do l'-au térlle or any other mili-u ctérile in ~ ectsble In human therapeutics, 1-6 eds of celon 1A pr ~ en-you in ~ ention ~ have particull ~ rly utlles in the tralt ~ ment of cancer dig ~ tives, cancer ~ puL ~ onalr-s, cancerfi testl-cule ~ ou o ~ alresi qu- dan ~ 1-8 tralt ment ~ canc-rs de head and neck Generally speaking, 1- ed cin will determine the po ~ ology that he / she estimates the most appropriate according to the age, the weight and tow le6 others ~ actor ~ own ~ at u ~ -t ~ traltor - Lo ~ ode d'-d ~ inl ~ tratlon ~ r ~ r ~ ~ t la vol- lntra-v ln-w e A t ~ tr- lndlc ~ tl ~ J ~ dlca ~ -nt- olon l'lnv-ntlon Fu ~ ent; tr- d ~ lnl ~ tr ~ J ch z l'hom ~ - i ral ~ on d- 30 i 200 ng / n2 par tr lte ~ ent, by vol- lntra- ~ ~ n use .

2 ~ 9 ~ '. J19 WO 92/09602 10 PCT / FR91 / 00926 ' L'-xe ~ ple cui ~ tant, given without limitation, illustrates a composition according to the present in ~ ention:

EXAMPLE:
A colution containing 8.54 g of bimaleate of the I (dimethylamino-3) propyll amino-1 hydroxy-9 5H-pyrido 14,3-bl benzo lel indole hydrated (0.5 N20), by dissolving this product in sufficient pyrogen-free physiological properties to obtain 100 cm3.
The colution obtained is r-part ~ e aseptically in am-hens, at a rate of 2 cm3 per bulb. The bulbs were sealed and each contain 100 mg of l (3-dimethylamino) propyll amino-1 bydro ~ y-9 SN-pyrldo t-, 3- ~ 1 be ~ zo 1-1 1ndole.

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Claims (5)

?? 92/09602 PCT/FR91/00926 1 - A new pyridobenzoindole derivative of formula general:

in which R represents a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms, alk represents a straight or branched alkylene radical containing 2 to 4 carbon atoms, R1 represents a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms, and R2 represents a hydroxy or methoxy radical, as well as its addition salts with acids, and where appropriate its hydrates and isomeric forms thereof and mixtures thereof. 2 - A new pyridobenzoindole derivative according to the claim 1 for which:
R is a methyl radical, alk is a straight or branched alkylene radical containing 2 to 4 atoms of carbon, R1 is a hydrogen atom or a methyl radical, and R2 is hydroxy radical as well as its addition salts with acids, and where appropriate its hydrates and isomeric forms thereof and mixtures thereof. 3 - [(3-Dimethylamino)propyl]amino-1-hydroxy-9-5H-pyrido[4,3-b]benzo[e]indole, and its salts and forms hydrated. 4 - A process for the preparation of a derivative of pyridobenzo-indole according to Claim 1, characterized in that one makes act an amine of general formula:

H2N - alk - N(R)2 wherein alk and R are defined as in claim 1, on a chlorinated derivative of formula:

wherein R1 is defined as in claim 1, then transforms, where appropriate, the methoxylated product obtained, of formula general:

wherein R1 is defined as in claim 1, in a ?? 92/09602 PCT/FR91/00926 9-hydroxy-pyrido[4,3-b]benzo[e]indole derivative and transforms optionally the product obtained into an addition salt with an acid. 5 - Pharmaceutical composition characterized in that it contains a product according to claim 1 in the pure state or in form of association with any compatible diluent or adjuvant and pharmaceutically acceptable.