ZA200404390B - 1,3-Diarylprop-2-en-1-ones, compositions containing same and use thereof. - Google Patents

1,3-Diarylprop-2-en-1-ones, compositions containing same and use thereof. Download PDF

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Publication number
ZA200404390B
ZA200404390B ZA200404390A ZA200404390A ZA200404390B ZA 200404390 B ZA200404390 B ZA 200404390B ZA 200404390 A ZA200404390 A ZA 200404390A ZA 200404390 A ZA200404390 A ZA 200404390A ZA 200404390 B ZA200404390 B ZA 200404390B
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methyl
trimethoxyphenyl
propenone
product
amino
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ZA200404390A
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Patrick Mailliet
Marie-Christine Bissery
Thomas Caulfield
Cecile Combeau
Marie-Pierre Cherrier
Gilles Tiraboshi
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Aventis Pharma Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/30—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to nitro or nitroso groups
    • C07C279/32—N-nitroguanidines
    • C07C279/36—Substituted N-nitroguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

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Description

® 200454 1, 3-DIARYLPROP~-2-EN-1-ONES, COMPOSITIONS CONTAINING
THEM AND USE THEREOF
The present invention relates to novel chemical compounds, particularly novel 1,3-diarylprop- 2-en-l-ones, to compositions containing them and to their use as medicinal products.
More particularly, the invention relates to novel specific 1,3-diarylprop-2-en-l-ones with anticancer activity, and in particular inhibitory activity on tubulin polymerization. 1,3-diarylprop-2-en-1-ones, or “chalcones”, : have been widely described in the literature for more than a century. However, although certain publications deal with therapeutic applications of chalcones, few of them mention their use in oncology.
Among the documents describing the use of chalcones in oncology, mention may be made of the following patents and publications: - WO 01/72980, discloses substituted chalcones with anticancer and anti-inflammatory activity. These chalcones are characterized in that they are 1-(3,5-dimethoxyphenyl)prop-2-en-1l-one derivatives in which the 3-phenyl group is never substituted with an amino group. - WO 98/22728, especially claims, in general, substituted chalcones, for inhibiting the S5a-reductase activity towards steroid hormones, for the purpose of treating pathologies such as alopecia, baldness,
Le]
® ¢ 2 £-20047 39g obesity, skin diseases, prostate cancer and breast cancer. No specific example of a chalcone is presented in the description, only the structure of the reference product HZIV 82 (E-3-(4-N,N-dimethylaminophenyl)- 1-(3,4,5-trimethoxyphenyl)prop-2-en-l-one) is presented in Figure 2. - WO 99/00114, claims the use of chalcones in which the prop-2-en-1l-one chain may be saturated or unsaturated. The preparation examples are limited to certain families of chalcones. For each of the examples presented, one of the two phenyl nuclei is mono- substituted. When an amino group is present, it is in the N,N-dimethylamino form and it is the only substituent of one of the two phenyl nuclei borne by the propenone chain. :
Two products are cited as having anticancer activity. These are 1-(4-hydroxyphenyl)-3-(2,3-di- methoxyphenyl) -prop-2-en-1-one and 1-(4-hydroxyphenyl)- 3-(2,5-dimethoxyphenyl) -prop-2-en-1-one. - WO 98/58913, presents chalcones derived from 1-(2-hydroxyphenyl)-3-arylprop-2-en-l-one with antiproliferative activity. - EP 288 794-Bl, claims the use in oncology of 1l-(aryl)-3-(4-X-phenyl)prop-2-en-l-ones in which X represents a substituent NR; or NHCOR, where R = alkyl. - WO 91/17749, claims a method for treating cancer especially using chalcones. These chalcones are described and claimed in very general terms. Thus, any
I 1
: PY : ® 3 substituents can replace any hydrogen, whether said hydrogen is on the prop-2-en-l-one chain or on a phenyl nucleus. None of the chalcones described bear amino groups on either of the aryl groups. - Michael L. Edwards et al., in the article published in J. Med. Chem. 1990, vol. 33, pp. 1948-1954, present chalcones that may be used as antimitotic agents. Chalcones in which the phenyl in position 3 on the prop-2-en-1l-one chain is substituted either (i) in position 4 with NHC (O)CHs, C(CHs);, SCHs,
S(0)CH3, N(CHs3),, NH, NO,, F, CN, OCH(CHs3),, Br, CFs,
N-morpholino, NH-butyl, O-butyl, NHC(O)OCH3;, O-butyl or
N(CzHs)2, or (ii) in position 3 with NHC(O)CHs, N(CHj3)g,
NH; or NO,;, are presented and tested in vitro on cancer cell lines. None of the chalcones bears another group in addition to the amino group on one of the aryl nuclei. - Sylvie Ducki et al., in the article published in Bioorg. Med. Chem. Letters 1988, vol. 8 pp 1051-1056, present chalcones with antimitotic activity.
Their study is based on the work by Michael L. Edwards et al. cited above. The authors observed that the replacement of a 4-N,N-dimethylamino substituent with 4-methoxy and 3-hydroxy substituents considerably improves the antimitotic activity, especially with respect to K562 cells.
Now, it has been found, surprisingly, that products containing the 1, 3-diphenyl-prop-2-en-1l-one
Oo
® ¢ 4 Bb-2004/439p unit in which the phenyl in position 3 is substituted with two different groups, at least one of which is an amine or an amine precursor, have large inhibitory activity on tubulin polymerization.
Furthermore, these products very strongly induce necrosis in vivo, which is a highly favorable result with regard to the subsequent development of medicinal products that are effective for treating cancers. : 10 Next, it has been observed that, with the products of the invention, the tumor necrosis survives in the minutes following the injection of the test product, and that the core of the tumor is totally destroyed within a day, with no apparent effect on the neighboring healthy cells. These products might consequently be useful for treating patients suffering from inoperable tumors, that is to say tumors whose surgical removal presents a very major risk (i) to the immediate survival of the patient, or (ii) to the possible consequences on his quality of life (invalidation).
Finally, the products of the invention are generally rapidly metabolized by the body, which limits their long-term effect.
These products correspond to formula (I) below: ip
®
NP
: Y 0) in which a) Y is selected from the group consisting of halogen, C;-C; linear alkyl, C;-C; branched alkyl, substituted C;-C; linear alkyl, substituted C;-C, branched alkyl, cycloalkyl, substituted cycloalkyl, NH;, NH(R4), N(R4),, aralkyl, substituted aralkyl, COOH, COO(R4), CONH,,
CONH(R4), CON(R4),, CN, in which R4 represents an optionally substituted C;-C; alkyl or cycloalkyl group and, when two radicals R4 are present, they may be linked together to form a ring; b) Ar2 is selected from the group consisting of:
CC
R2 in which:
R1 =X 1) when Ar2 is R2 then one of the radicals Rl and R2 is selected from the group consisting of NH, NH,-HZ, NHC(O)-amino acid,
NH- (GP); N=(GP); in which the amino acid is preferably serine; in which GP is a metabolizable substituent allowing the functional group to be changed: /
o ;
NH- (GP) — NH, or N=(GP) — NH, and in which HZ is an organic or mineral acid; and the other radical R1 or R2 is selected from the group consisting of CHj;, C,;Hs, .OCHs, OC:Hs,
SCH3;, NH(R5)}, N(R5)2, N(R5) (GP), N(R5)C(O)~- amino acid, in which R5 represents a C;-C; alkyl group and, when two radicals R5 are present, they may be linked together to form a ring; oo 2) when Ar2 is , then A is a 5- or 6-membered heterocycle, fused to a benzene ring B, said heterocycle A is aromatic or non-aromatic, comprising one or two hetero atoms, at least one of which is a nitrogen atom linked directly to B and bearing a side chain R8, in which R8 is chosen from the group consisting of H, (C1-C3)alkyl, (C1-C3)alkyl-OH, (C1-Cs) alkyl-0(C;-Cs3) alkyl, (C1-C3) alkyl-NHg, (C;-C3)alkyl-NH(R7), (C1-C3)alkyl~-N(R7),, —(CCalky()
Re” Co , in which R9 is chosen from
H, (C;-C3) alkyl, in which each R7 independently represents a (C;-Cs)alkyl or
) [J 7 (C3-C7) cycloalkyl group, OI alternatively, when two radicals R7 are present, they are linked together to form a S-membered heterocycle; c) X is selected from the group consisting of O, NOH,
NO(R3), in which R3 is selected from the group consisting of H, C;-C; linear alkyl, Ci-Cy branched alkyl, cycloalkyl, C;-C; linear haloalkyl, C;-C, branched haloalkyl, substituted cycloalkyl, halocycloalkyl, aralkyl, substituted aralkyl; and d) Ar is selected from the group consisting of 2,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3, 5-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,3,4,5-tetramethoxyphenyl, 3-methoxy- 4,5-methylenedioxy, 3-methoxy-4, 5-ethylenedioxy, 2-methoxy-4, 5-methylenedioxy, 2-methoxy- 4,5-ethylenedioxy, 2-methoxy-3, 4-methylenedioxy and 2-methoxy-3, 4-ethylenedioxy radicals.
Preferably, X is oxygen.
Ar is preferably 3,4, 5-trimethoxyphenyl or 3-methoxy-4, 5-methylenedioxy.
Y is preferably selected from the group consisting of Cl, Br, CH3 and CH;CHs.
A first preferred product in accordance with the invention preferably contains a substituent Ar2
NL
—CC : such that Ar2 = R2 in which R1 and R2 are selected from the group of combinations (Rl, R2) consisting of, respectively, (NH;, OCHj), (NH, OC.Hs), (NHz, N(R5)2), (N(RS5)z, OCHs), (N(RS),, OCzHs), (N(RS)2,
NH), (OCHs, NH), (OC,Hs, NH). :
A first more preferred product in accordance with the invention contains a substituent Ar2 such that —CC
Ar2 = R2 in which one of the radicals R1 and R2 is NHC(O)-amino acid, and in that the amino acid is selected from natural amino acids and unnatural amino acids. Preferred amino acids are chosen from the group consisting of glycine, N-methylproline, serine, lysine and N-w-nitroarginine, and the amino acid is in enantiomerically pure or racemic form, or is enriched in one enantiomer.
The products in accordance with the invention are present in free or salified form, preferably in salified form. One preferred salified form is a hydrochloride.
A second preferred product in accordance with the invention preferably contains a substituent Ar2 oO. such that Ar2 = , in which Ar2 is selected from the group consisting of
0) : ® 9 on TCR
N N
R8 ; R8
R8 preferably represents a methyl, hydroxymethyl or 2-dimethylaminoethyl group.
A preferred product in accordance with the invention may be chosen from the group consisting of
E-3-(3-Amino-4-methoxyphenyl)-2-methyl-1-(3, 4, 5- trimethoxyphenyl)propenone;
E-3- (4-Amino-3-methoxyphenyl)-2-methyl-1-(3,4,5~ : trimethoxyphenyl)propenone;
E-3-(3~-Amino-4-methoxyphenyl)-2-methyl-1-(2,5- dimethoxyphenyl)propenone hydrochloride;
E-3-(3-Amino-4-methoxyphenyl)-2-bromo-1-(3,4, 5- trimethoxyphenyl)propenone;
E-2-Methyl-3-(1l-methyl-1-H-indol-5-y1)-1-(3,4,5- trimethoxyphenyl)propenone;
E-2-Methyl-3-(l-methyl-2, 3-dihydro-1-H~-indol-5-yl)-1- (3,4,5-trimethoxyphenyl)propenone;
E-2-Methyl-3-(l1-methyl-1-H-indol-5-yl)-1-(3,4, 5- trimethoxyphenyl)propenoneoxime;
E-2-Methyl-3-[1-(2-dimethylaminoethyl)-1-H-indol-5-yl]- : 1-(3,4,5-trimethoxyphenyl) propenone hydrochloride;
E-2-Methyl-3-(1-hydroxymethyl-1-H-indol-5-yl)-1-(3, 4, 5- trimethoxyphenyl)propenone;
E-2-Methyl-3- (1-methyl-1-H-indol-5-yl)~1- (3-methoxy- 4,5-methylenedioxyphenyl)propenone;
® Co 7) lo BE .2004/,39p
E-2-Methyl-3-[1- (2-dimethylaminoethyl) -1-H-indol-5-y1]- 1- (3-methoxy-4, 5-methylenedioxyphenyl)propenone; (S)-2, 6-Diaminohexanoic acid {2-methoxy-5-[{2-methyl-3- oxo-3-(3,4,5-trimethoxyphenyl)propenyl] phenyl }amide dihydrochloride; 3- (3- [N-@-nitro-L-arginineamido] - 4-methoxyphenyl) -2- methyl-1-(3,4,5-trimethoxyphenyl)propenone; 1-Methylpyrrolidine-2-carboxylic acid {2-methoxy-5-[2- methyl-3-oxo-3-(3,4,5-trimethoxyphenyl)propenyl]- phenyl}amide hydrochloride;
Aminoacetic acid {2-methoxy-5-[2-methyl-3-oxo-3-(3,4,5- trimethoxyphenyl)propenyl] phenyl }amide hydrochloride.
A more preferred product in accordance with the invention is (S)-2-amino-3-hydroxypropanoic acid {2-methoxy-5-[2-methyl-3-oxo-3-(3,4,5~-trimethoxy- phenyl) propenyl] phenyl }amide hydrochloride.
The list of products below is also representative of the invention:
E-3-(3-Amino-4-methoxyphenyl) -2-chloro-1-(3, 4,5-tri- methoxyphenyl)propenone
E-3-(3-Amino-4-methoxyphenyl)-2-bromo-1-(3,4,5-trimeth- oxyphenyl)propenone
E-3-(3-Amino-4-methoxyphenyl)-2-methyl-1-(3,4,5-tri- methoxyphenyl)propenone
E-3-(3-Amino-4-methoxyphenyl)-2-ethyl-1-(3,4,5-tri- methoxyphenyl)propenone
E-3-(3-Amino-4-methoxyphenyl) -2-propyl-1-(3,4,5-tri- methoxyphenyl)propenone
® ® 11
E-3- (3-Amino-4-methoxyphenyl)-2-(1-methylethyl)-1- (3,4, 5-trimethoxyphenyl)propenone
E-3- (3-Amino-4-ethoxyphenyl)-2-chloro-1-(3,4,5-tri- methoxyphenyl)propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-bromo-1-(3,4,5~-trimeth- oxyphenyl)propenone
E-3- (3-Amino-4-ethoxyphenyl)-2-methyl-1-(3,4,5-trimeth~ oxyphenyl)propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-ethyl-1-(3,4,5-trimeth- oxyphenyl)propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-propyl-1-(3,4,5-trimeth- oxyphenyl)propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-(l-methylethyl)-1- (3,4,5-trimethoxyphenyl) propenone
E-3-[3-Amino-4-(N,N-dimethylamino)phenyl]-2-chloro- 1-(3,4,5-trimethoxyphenyl)propenone
E-3-[3-Amino-4- (N,N-dimethylamino) phenyl] -2-bromo- 1-(3,4,5~-trimethoxyphenyl)propenone
E-3-[3-Amino-4- (N,N-dimethylamino) phenyl] -2-methyl- 1-(3,4,5-trimethoxyphenyl)propencne
E-3-[3-Amino-4- (N,N-dimethylamino) phenyl] -2-ethyl- 1-(3,4,5-trimethoxyphenyl)propenone
E-3-[3-Amino-4-(N,N-dimethylamino) phenyl] -2-propyl- 1-(3,4,5-trimethoxyphenyl)propenone
E-3-[3-Amino-4-(N,N-dimethylamino) phenyl] -2-(l-methyl- ethyl) -1-(3,4, 5-trimethoxyphenyl)propenone
E-3-[4-Amino-3-methoxyphenyl)-2-chloro-1-(3,4,5-tri- methoxyphenyl) propenone
-@ oo ® 12
E-3-[4-Amino-3-methoxyphenyl) -2-bromo-1- (3, 4, 5-trimeth- oxyphenyl) propenone
E-3-[4-Amino-3-methoxyphenyl)-2-methyl-1-(3,4, 5-tri- methoxyphenyl)propenone
E-3-[4-Amino-3-methoxyphenyl)-2-ethyl-1-(3,4,5-tri- methoxyphenyl)propenone
E-3-[4-Amino-3-methoxyphenyl)-2-propyl-1-(3,4,5-tri- methoxyphenyl)propenone
E-3-[4-Amino-3-methoxyphenyl)-2- (l-methylethyl) - 1-(3,4,5-trimethoxyphenyl)propenone
E-3-[4-Amino-3-ethoxyphenyl) -2-chloro-1- (3,4, 5~tri- methoxyphenyl)propenone
E-3-[4-Amino-3-ethoxyphenyl)-2-bromo-1-(3,4,5-trimeth- oxyphenyl)propenone
E-3-[4-Amino-3-ethoxyphenyl)-2-methyl-1-(3,4,5-trimeth- oxyphenyl) propenone
E-3-[4-Amino-3-ethoxyphenyl)-2-ethyl-1~(3,4,5-trimeth- oxyphenyl)propenone
E-3-[4-Amino-3-ethoxyphenyl)-2-propyl-1-(3,4,5-trimeth- oxyphenyl)propenone
E-3-[4-Amino-3-ethoxyphenyl)-2-(l-methylethyl) - : 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[4-Amino-3- (N,N-dimethylamino)phenyl]-2-chloro- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[4-Amino-3-(N,N-dimethylamino)phenyl]-2-bromo- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[4-Amino-3- (N,N-dimethylamino) phenyl] -2-methyl- 1-(3,4,5-trimethoxyphenyl) propenone
C
E-3- [4-Amino-3- (N, N-dimethylamino) phenyl] -2-ethyl- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[4-Amino-3- (N, N-dimethylamino) phenyl] -2-propyl- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[4-Amino-3-(N,N-dimethylamino)phenyl]-2-(l-methyl- ethyl) -1-(3,4,5-trimethoxyphenyl)propenone
E-3-[3-(N,N-Dimethylamino)-4-methoxyphenyl]-2-chloro- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[3-(N,N-Dimethylamino) -4-methoxyphenyl] -2-bromo-1- (3,4,5-trimethoxyphenyl)propenone
E-3-[3-(N,N-Dimethylamino)-4-methoxyphenyl]-2-methyl- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[3-(N,N-Dimethylamino) ~4-methoxyphenyl] -2-ethyl- 1- (3,4, 5-trimethoxyphenyl) propenone
E-3-[4-Amino-3-(N,N-dimethylamino)-4-methoxyphenyl]- 2-propyl-1-(3,4, 5-trimethoxyphenyl) propenone
E-3-[4-Amino-3- (N,N-dimethylamino) -4-methoxyphenyl] - 2-(l1-methylethyl)-1-(3,4,5-trimethoxyphenyl)propenone
E-3-[3-(N,N-Dimethylamino)-4-ethoxyphenyl]-2-chloro- 1-(3,4,5-trimethoxyphenyl)propenone oo
E-3-[3- (N,N-Dimethylamino) -4-ethoxyphenyl] -2-bromo- : 1- (3,4, 5-trimethoxyphenyl)propenone
E-3-[3-(N,N-Dimethylamino) ~4-ethoxyphenyl]-2-methyl- 1-(3,4,5-trimethoxyphenyl)propenone
E-3-[3-(N,N-Dimethylamino)-4-ethoxyphenyl]-2-ethyl- 1-(3,4,5-trimethoxyphenyl) propenone
E-3-[4-Amino-3~ (N,N~-dimethylamino)-4-ethoxyphenyl]- : 2-propyl-1-(3, 4, 5-trimethoxyphenyl)propenone o * 14
E-3-[4-Amino-3-(N,N-dimethylamino) -4-ethoxyphenyl] - 2-(l-methylethyl)-1-(3, 4, 5-trimethoxyphenyl) propenone
E-3- (3-Amino-4-methoxyphenyl)-2-chloro-1-(2, 5-dimeth- oxyphenyl)propenone
E~-3-(3-Amino-4-methoxyphenyl)~-2-bromo-1-(2,5-dimethoxy- phenyl) propenone
E-3- (3-Amino-4-methoxyphenyl) -2-methyl-1-(2, 5-di- methoxyphenyl)propenone hydrochloride
E-3-~(3-Amino-4-methoxyphenyl) -2-methyl-1-(2, 5-dimeth- oxyphenyl)propenone
E-3-(3-Amino-4-methoxyphenyl)-2-ethyl-1-(2, 5-dimeth- oxyphenyl) propenone
E-3- (3-Amino-4-methoxyphenyl) -2-propyl-1- (2, 5-dimeth- oxyphenyl) propenone
E-3-(3-Amino-4-methoxyphenyl)-2~(l-methylethyl)-1-(2,5~ dimethoxyphenyl) propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-chloro-1- (2, 5-dimethoxy- phenyl) propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-bromo-1- (2, 5-dimethoxy- phenyl)propenone
E-3-(3-Amino-4-ethoxyphenyl) -2-methyl-1-(2,5-dimethoxy- phenyl) propenone
E-3- (3-Amino-4-ethoxyphenyl)-2-ethyl-1- (2, 5-dimethoxy- phenyl) propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-propyl-1-(2,5-dimeth- oxyphenyl)propenone
E-3-(3-Amino-4-ethoxyphenyl)-2-(l-methylethyl)-1-(2, 5- dimethoxyphenyl)propenone

Claims (19)

- Co PCT/FRO2/04143 117 | to CLAIMS :
1. A product corresponding to the following formula (I): oo - X
NP . v ow oo : in which: a) Y is selected from the group consisting of halogen, linear C4-C; alkyl, branched C4-C; alkyl, substituted linear C4-C; alkyl, substituted branched C;-C; alkyl, cycloalkyl, substituted cycloalkyl, NH, NH(R4), N(R4),, aralkyl, substituted aralkyl, COOH, COO(R4), CONH,, CONH(R4), CON(R4),, CN, in which R4 represents an optionally substituted C-C7 alkyl or cycloalkyl group, and when two R4 groups are present, they may be linked to each other to form a ring; b) Ar2is B —CC
: . in which: one of R1 and R2 is selected from the group consisting of NH», NHz.HZ, NHC(O)-amino acid, NH-(GP); N=(GP); in which the amino acid is = preferably serine; in which GP is a metabolizable substituent which makes - it possible to change the functional group: NH-(GP) — NH; or N=(GP) — NH> and in which HZ is an organic or inorganic acid; and AMENDED SHEET : CLEAN COPY a 118 oo PCT/FRO2/04143 the other of R1 and R2 is selected from the group consisting of CHz, CoHs, OCHg3;, OCgHs, SCHj, NH(R5), N(R5)2, N(R5)(GP), N(R5)C(O)-amino acid, in which R5 represents a C4-C; alkyl group and when two R5 groups are oo present, they may be linked to each other to form a ring; c) X is selected from the group consisting of O, NOH, NO(RS), in which R3 is selected from the group consisting of H, linear C4-C- alkyl, branched Ci-C; alkyl, cycloalkyl, halogenated linear C4-C; alkyl, halogenated branched C;-C; alkyl, substituted cycloalkyl, halogenated cycloalkyl, aralkyl, substituted aralkyl; and d) Ar is selected from the group consisting of 2,5-dimethoxyphenyl,- : 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, - 2,4,5-trimethoxyphenyi, 2,3,4,5-tetramethoxyphenyl, 3-methoxy-4,5- methylenedioxy, 3-methoxy-4,5-ethylenedioxy, 2-methoxy-4,5-methylene- dioxy, 2-methoxy-4,5-ethylenedioxy, 2-methoxy-3,4-methylenedioxy, 2-methoxy-3,4-ethylenedioxy.
2. The product as claimed in claim 1, characterized in that X is oxygen.
3. The product as claimed in claim 1 or 2, characterized in that Ar is 3,4,5-trimethoxyphenyl or 3-methoxy-4,5-methylenedioxy.
4, The product as claimed in claim 1, 2 or 3, characterized in that Y is selected from the group consisting of Cl, Br, CH3, CH2CHj.
5. The product as claimed in any one of claims 1 to 4, characterized in that R1 and R2 are selected from the group of combinations (R1, R2) consisting of, respectively, (NHs, OCHg), (NHz, OC:Hs), (NHz, N(R5)2), (N(R5)2, OCHa), (N(R5)2, OC2Hs), (N(R5)2, NHz), (OCHa, NHz), (OC2Hs,
NH).
6. The product as claimed in claim 1, characterized in that it is chosen - from the group consisting of E-3-(3-amino-4-methoxyphenyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)- propenone; oo AMENDED SHEET B : CLEAN Copy
. 119 : PCT/FR02/04143 E-3-(4-amino-3-methoxyphenyl)-2-methyl-1,-(3,4,5-trimethoxyphenyl)- propenone; : E-3-(3-amino-4-methoxyphenyl)-2-methyl-1-(2,5-dimethoxy)phenyl)-
propenone hydrochloride; E-3-(3-amino-4-methoxyphenyl)-2-bromo-1-(3,4,5-trimethoxyphenyl)- propenone;
E-2-methyl-3-(1-methyl-1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)- propenone; E-2-methyl-3-(1-methyl-2,3-dihydro-1H-indoi-5-yl)-1 -(3,4,5-trimethoxy-
phenyl)propenone;
E-2-methyl-3-(1-methyl-1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)propenone oxime;
E-2-methyl-3-[1 -(2-dimethylaminoethyl)-1H-indol-5-yl]-1-(3,4,5-
trimethoxyphenyl)propenone hydrochloride; E-2-methyl-3-(1-hydroxymethyl-1H-indol-5-yf)-1-(3,4,5-trimethoxyphenyl)- propenone;
E-2-methyl-3-(1-methyl-1H-indol-5-yl)-1-(3-methoxy-4,5-methylenedioxy-
~ phenyl)propenone; E-2-methyl-3-[1-(2-dimethylaminoethyl)-1H-indol-5-yl}-1-(3-methoxy-4,5- methylendioxypheny!)propenone; :
(S)-2,6-diaminohexanocic acid ~~ {2-methoxy-5-[2-methyl-3-0x0-3-(3,4,5- trimethoxyphenyl)propenyl]phenyl}amide dihydrochloride; 3-(3-Nw-nitro-L-arginineamido]-4-methoxyphenyl)-2-methyl-1-(3,4,5-
trimethoxyphenyl)propenone;
aminoacetic acid {2-methoxy-5-[2-methyl-3-ox0-3-(3,4,5-trimethoxyphenyl)- propenyl]phenyl}amide hydrochloride; AMENDED SHEET CLEAN COPY
. 120 . PCT/FR02/04143 (S)-2-amino-3-hydroxypropanoic acid {2-methoxy-5-[2-methyl-3-0x0-3- (3,4,5-trimethoxyphenyl)propenyl]phenyllamide hydrochloride; and 1-methylpyrrolidine-2-carboxylic acid ~~ {2-methoxy-5-[2-methyl-3-ox0-3- (8,4,5-trimethoxyphenyl)propenyljphenyl}amide hydrochloride.
7. The product as claimed in any one of claims 1 to 4, characterized in that one of R1 and R2 is NHC(O)-amino acid, and in that the amino acid is selected from natural amino acids and unnatural amino acids.
8. The product as claimed in claim 7, characterized in that the amino acid is chosen from glycine, lysine, N-methylproline, serine, Na-nitro-: ‘arginine, and in that the amino acid is in enantiomerically pure form, in racemic form or in a form enriched with one enantiomer.
9. The product as claimed in any one of claims 1 to 5, characterized in that it is present in free or salified form. :
10. The product as claimed in claim 9, characterized in that it is present in salified form.
11. The product as claimed in claim 10, characterized in that the salified form is a hydrochloride.
12. The product as claimed in claim 8, characterized in that it is (S)-2- amino-3-hydroxypropanoic acid {2-methoxy-5-[2-methyl-3-0x0-3-(3,4,5- trimethoxyphenyl)propenyl]phenyl}amide hydrochloride.
13. A pharmaceutical composition comprising a product as claimed in any one of the preceding claims, in combination with a pharmaceutically acceptable excipient.
14. The pharmaceutical composition as claimed in clam 13, - characterized in that it comprises the product as claimed in claim 11.
15. The use of a product as claimed in any one of claims 1 to 11, as an agent which inhibits the polymerization of tubulin. AMENDED SHEET ~ CLEAN copy
} | 3 a PCT/FRO2/04143
16. The use of a product as claimed in any one of claims 1 to 12, for promoting the detachment of endothelial cells forming the wall of the vessels supplying a tumor. .
17. The use of a product as claimed in any one of claims 1 to 12, for promoting tumor necrosis.
18. The use of a product as claimed in any one of claims 1 to 12, for the manufacture of a medicament useful for treating a pathological state.
19. The use as claimed in claim 18, in which the pathological stage is cancer. : AMENDED SHEET ~ : CLEAN COPY
ZA200404390A 2001-12-05 2004-06-03 1,3-Diarylprop-2-en-1-ones, compositions containing same and use thereof. ZA200404390B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4904697A (en) * 1987-04-09 1990-02-27 Merrell Dow Pharmaceuticals Inc. Controlling the growth of certain tumor tissue with chalcone derivatives
EP0996432A2 (en) * 1997-06-26 2000-05-03 Statens Seruminstitut Biologically active 1,3-bis-aromatic-prop-2-en-1-ones, 1,3-bis-aromatic-propan-1-ones, and 1,3-bis-aromatic-prop-2-yn-1-ones

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FR2833008B1 (en) 2004-05-21
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GT200200252A (en) 2003-11-11

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