CN1612856A - 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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CN1612856A
CN1612856A CNA028268601A CN02826860A CN1612856A CN 1612856 A CN1612856 A CN 1612856A CN A028268601 A CNA028268601 A CN A028268601A CN 02826860 A CN02826860 A CN 02826860A CN 1612856 A CN1612856 A CN 1612856A
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propenone
amino
methoxy
methyl
trimethoxyphenyl
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P·马耶
C·孔博
M-C·比斯里
M-P·谢里耶
T·考尔菲勒
G·蒂拉博斯奇
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Aventis Pharma SA
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Aventis Pharma SA
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • 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
    • C07C225/02—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 acyclic carbon atoms of the carbon skeleton
    • C07C225/14—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 acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—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 acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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

Abstract

1,3-Diarylprop-2-en-1-ones and derivatives, compositions containing them, manufacturing process and use. Substituted 1,3-diarylprop-2-en-1-ones with therapeutic activity may be used in oncology.

Description

1, 3-diarylprop-2-en-1-ones, compositions containing them and their use
The present invention relates to novel compounds, in particular novel 1, 3-diarylprop-2-en-1-ones, to compositions containing them and to their use as pharmaceutical products.
More particularly, the present invention relates to novel specific 1, 3-diarylprop-2-en-1-ones having anticancer activity, in particular, inhibitory activity against tubulin polymerization.
1, 3-diarylprop-2-en-1-ones or "chalcones" have been widely described in the literature for over a century. However, although some publications refer to the therapeutic use of chalcones, few mention is made of their use in oncology.
Among the documents describing the use of chalcones in oncology, the following patents and publications may be mentioned:
-WO 01/72980 discloses substituted chalcones with anti-cancer and anti-inflammatory activity, which chalcones are characterized in that they are 1- (3, 5-dimethoxyphenyl) prop-2-en-1-one derivatives wherein the 3-phenyl group is not substituted by an amino group.
WO 99/22728 claims in particular generally substituted chalcones for inhibiting the activity of 5 α -reductase on steroid hormones, aimed at treating diseases such as alopecia, obesity, skin diseases, prostate cancer and breast cancer, specific examples of chalcones are not given in this specification, and the structure of the control product HZIV 82(E-3- (4-N, N-dimethylaminophenyl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one) is given only in fig. 2.
WO 99/00114 claims the use of chalcones in which the prop-2-en-1-one chain may be saturated or unsaturated. The preparation examples are limited to certain families of chalcones. For each of the examples given, one of the two benzene nuclei was monosubstituted. When present, the amino group is in the form of an N, N-dimethylamino group and is the only substituent for one of the two benzene nuclei present in the acrylic chain.
Two products with anticancer activity are listed, which are 1- (4-hydroxyphenyl) -3- (2, 3-dimethoxyphenyl) -prop-2-en-1-one and 1- (4-hydroxyphenyl) -3- (2, 5-dimethoxyphenyl) -prop-2-en-1-one.
WO 98/58913 discloses chalcones with antiproliferative activity derived from 1- (2-hydroxyphenyl) -3-arylprop-2-en-1-ones.
EP 288794-B1 claims in which X represents the substituent NR2Or NHCOR, 1- (aryl) -3- (4-X-phenyl) prop-2-en-1-one wherein R is alkyl, in oncology.
WO 91/17749 claims a method for treating cancer, in particular using chalcones. These chalcones described and claimed are very broad. Thus, any substituent may be substituted for any hydrogen, whether on the prop-2-en-1-one chain or on the benzene nucleus. None of the chalcones have an amino group on any of the aryl groups.
Chalcones useful as antimitotic agents are given in Michael L.Edwards et al, J.Med.chem.1990, Vol.33, 1948-page 1954. Wherein the phenyl group in position 3 of the prop-2-en-1-one chain or (i) in position 4 is substituted by NHC (O) CH is given3、C(CH3)3、SCH3、S(O)CH3、N(CH3)2、NH2、NO2、F、CN、OCH(CH3)2、Br、CF3N-morpholino, NH-butyl, O-butyl, NHC (O) OCH3O-butyl or N (C)2H5)2Substituted, or (ii) at position 3 with NHC (O) CH3、N(CH3)2、NH2Or NO2Substituted chalcones and cancer cell lines were tested in vitro. None of the chalcones contain, in addition to the amino group on one of the aromatic nuclei, an additional group.
Chalcones with antimitotic activity are given in Sylvie Ducki et al, Bioorg.Med.chem.letters 1988, Vol.8, page 1051-1056. Their research is based on the above described work by Michael l. The authors found that: replacement of the 4-N, N-dimethylamino substituent with 4-methoxy and 3-hydroxy substituents significantly improved antimitotic activity, especially for K562 cells.
It has now surprisingly been found that: products containing 1, 3-diphenyl-prop-2-en-1-one units in which the phenyl group in position 3 is substituted with two different groups and at least one of which is an amine or an amine precursor have a greater inhibitory activity on tubulin polymerization.
Furthermore, these products induce necrosis very strongly in vivo, which is a very advantageous result for the subsequent development of pharmaceutical products effective for the treatment of cancer.
It has been found next that: with the product of the invention, tumor necrosis began several minutes after injection of the test product and the tumor nuclei were completely destroyed within one day without significant effect on adjacent normal cells. These products may then be used to treat patients with inoperable tumors, i.e., surgical removal of the tumor poses a very serious risk to (i) the immediate survival of the patient or (ii) the possible consequences (disability) to the quality of life of the patient.
Finally, the products of the invention are usually metabolized rapidly by the body, which limits their long-term effectiveness.
These products correspond to the following formula (I):
Figure A0282686000091
wherein:
a) y is selected from halogen and C1-C7Straight chain alkyl, C1-C7Branched alkyl, substituted C1-C7Straight chain alkyl, substituted C1-C7Branched alkyl, cycloalkylSubstituted cycloalkyl, NH2、NH(R4)、N(R4)2Aralkyl, substituted aralkyl, COOH, COO (R4), CONH2、CONH(R4)、CON(R4)2CN, wherein R4 represents optionally substituted C1-C7Alkyl or cycloalkyl, and when two groups R4 are present, they may be linked together to form a ring;
b) ar2 is selected from:
Figure A0282686000092
wherein
1) When Ar2 isWhen, then one of the radicals R1 and R2 is chosen from NH2、NH2HZ, NHC (O) -amino acid, NH- (GP), N ═ N (GP), wherein the amino acid is preferably serine, wherein GP is a metabolisable substituent that allows a change in the functional group:
or N ═ N (GP) → NH2
And wherein HZ is an organic or inorganic acid; and is
The other group R1 or R2 is selected from CH3、C2H5、OCH3、OC2H5、SCH3、NH(R5)、N(R5)2N (R5) (GP), N (R5) C (O) -amino acid, wherein R5 represents C1-C2Alkyl, and when two groups R5 are present, they may be linked together to form a ring;
2) when Ar2 isWhen A is a 5-or 6-membered heterocyclic ring fused to the phenyl ring B,
the heterocycle A is aromatic or non-aromatic and comprises 1 or 2 heteroatoms, at least one of whichOne is a nitrogen atom directly bonded to B and has a side chain R8, wherein R8 is selected from H, (C)1-C3) Alkyl, (C)1-C3) alkyl-OH, (C)1-C3) alkyl-O (C)1-C3) Alkyl, (C)1-C3) alkyl-NH2、(C1-C3) alkyl-NH (R7), (C)1-C3) alkyl-N (R7)2、
Figure A0282686000101
Wherein R9 is selected from H, (C)1-C3) Alkyl, wherein each R7 independently represents (C)1-C3) Alkyl or (C)3-C7) Cycloalkyl or, alternatively, when two groups R7 are present, they may be linked together to form a 5-membered heterocyclic ring;
c) x is selected from O, NOH, NO (R3), wherein R3 is selected from H, C1-C7Straight chain alkyl, C1-C7Branched alkyl, cycloalkyl, C1-C7Straight-chain haloalkyl, C1-C7Branched haloalkyl, substituted cycloalkyl, halocycloalkyl, aralkyl, substituted aralkyl; and is
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.
X is preferably oxygen.
Ar is preferably 3, 4, 5-trimethoxyphenyl or 3-methoxy-4, 5-methylenedioxy.
Y is preferably selected from Cl, Br, CH3And CH2CH3。
The first preferred product of the invention preferably contains the substituent Ar2, i.e.
Figure A0282686000102
Wherein R1 and R2 are selected from the group consisting of the following combinations (R1, R2), respectively:
(NH2，OCH3)、(NH2，OC2H5)、(NH2，N(R5)2)、(N(R5)2，OCH3)、(N(R5)2，OC2H5)、(N(R5)2，NH2)、(OCH3，NH2)、(OC2H5，NH2)。
the first more preferred product of the invention contains the substituent Ar2, i.e. Ar2Wherein one of the groups R1 and R2 is an NHC (O) -amino acid, and the amino acid is selected from a natural amino acid and an unnatural amino acid. Preferred amino acids are selected from glycine, N-methylProline, serine, lysine and N- ω -nitroarginine, and the amino acid is enantiomerically pure or in racemic form or enriched in one enantiomer.
The products of the invention are present in free or salified form, preferably in salified form. One preferred salt-forming form is the hydrochloride salt.
The second preferred product of the invention preferably contains the substituent Ar2, i.e.
Figure A0282686000111
Wherein Ar2 is selected from
R8 preferably represents methyl, hydroxymethyl or 2-dimethylaminoethyl.
Preferred products of the invention may be selected from:
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- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone;
e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone;
e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone oxime;
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;
e-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl ] -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- ω -nitro-L-argininamido ] -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 of the invention is (S) -2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride.
The following products are also representative of the invention:
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
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-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-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) propenone,
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- (1-methylethyl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-chloro-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-bromo-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-ethyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-propyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2- (1-methylethyl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-chloro-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-bromo-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-ethyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-propyl-1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2- (1-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,
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- (1-methylethyl) -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- (1-methylethyl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (3, 4, 5-trimethoxyphenyl) propenone,
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,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone hydrochloride,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2, 5-dimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 5-dimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N, -dimethylamino) phenyl ] -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N, -dimethylamino) phenyl ] -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N, -dimethylamino) phenyl ] -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N, -dimethylamino) phenyl ] -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N, -dimethylamino) phenyl ] -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N, -dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 4, 5-trimethoxyphenyl) propenone,
e-3- [ 3-amino-4-methoxyphenyl ] -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-methoxyphenyl ] -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-methoxyphenyl ] -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-methoxyphenyl ] -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-methoxyphenyl ] -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-ethoxyphenyl ] -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-ethoxyphenyl ] -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-ethoxyphenyl ] -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-ethoxyphenyl ] -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-ethoxyphenyl ] -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2, 3, 4, 5-tetramethoxyphenyl) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (3-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-3, 4-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-methylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (3-amino-4-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 3-amino-4- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-methoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- (4-amino-3-ethoxyphenyl) -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) phenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2-propyl-1- (2, 3, 4-trimethoxyphenyl) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-methoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-chloro-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-bromo-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-methyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-ethyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2-propyl-1- (2-methoxy-4, 5-ethylenedioxy) propenone,
e-3- [ 4-amino-3- (N, N-dimethylamino) -4-ethoxyphenyl ] -2- (1-methylethyl) -1- (2-methoxy-4, 5-ethylenedioxy) propenone,
2-aminoacetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-aminopropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-5-guanidinopentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-aminosuccinamic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-aminosuccinic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-mercaptopropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-aminoglutamic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-methylpentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2, 6-diaminohexanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-4-methylthiobutanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-aminocaproic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-phenylpropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
pyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-hydroxybutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3- (1-H-indol-5-yl) propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3- (4-hydroxyphenyl) propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-2-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2- (N-methylamino) acetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-5- [3- (1-nitroguanidino) ] pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) -propenyl ] phenyl } amide,
1-methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide,
e-2-methyl-3- (1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1-hydroxymethyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1-hydroxyethyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1-methoxymethyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1- (N, N-dimethylaminoethyl) -1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- (1- (N, N-dimethylaminopropyl) -1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone,
e-2-methyl-3- [1- (2-pyrrolidinylethyl) -1-H-indol-5-yl ] -1- (3, 4, 5-trimethoxyphenyl) propenone,
2-aminoacetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-aminopropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-5-guanidinopentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-aminosuccinamic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-aminosuccinic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-mercaptopropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-aminoglutamic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-methylpentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2, 6-diaminohexanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-4-methylthiobutanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-aminocaproic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-phenylpropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
pyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3-hydroxybutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3- (1-H-indol-5-yl) propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-3- (4-hydroxyphenyl) propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-2-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2- (N-methylamino) acetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
2-amino-5- [3- (1-nitroguanidino) ] -pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
1-methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (2, 5-dimethoxyphenyl) propenyl ] phenyl } amide,
e-2-methyl-3- (1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (2, 3-dihydro-1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1-hydroxymethyl-1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1-hydroxyethyl-1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1-methoxymethyl-1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1- (N, N-dimethylaminoethyl) -1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- (1- (N, N-dimethylaminopropyl) -1-H-indol-5-yl) -1- (2, 5-dimethoxyphenyl) propenone,
e-2-methyl-3- [1- (2-pyrrolidinylethyl) -1-H-indol-5-yl ] -1- (2, 5-dimethoxyphenyl) propenone,
2-aminoacetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-ethoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-aminopropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-5-guanidinopentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-aminosuccinamic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-aminosuccinic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-3-mercaptopropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-aminoglutamic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) -propenyl ] phenyl } amide,
2-amino-3-methylpentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2, 6-diaminohexanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-4-methylthiobutanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-aminocaproic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-3-phenylpropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
pyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-3-hydroxybutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-3- (1-H-indol-5-yl) -propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-3- (4-hydroxyphenyl) propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxy-phenyl) propenyl ] phenyl } amide,
2-amino-2-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2- (N-methylamino) acetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
2-amino-5- [3- (1-nitroguanidino) ] pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
1-methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3-methoxy-4, 5-methylenedioxyphenyl) propenyl ] phenyl } amide,
e-2-methyl-3- (1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (2, 3-dihydro-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1-hydroxymethyl-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1-hydroxyethyl-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1-methoxymethyl-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1- (N, N-dimethylaminoethyl) -1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- (1- (N, N-dimethylaminopropyl) -1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone,
e-2-methyl-3- [1- (2-pyrrolidinylethyl) -1-H-indol-5-yl ] -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone.
The products of the invention may preferably be selected from:
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- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone;
e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone;
e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone oxime;
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;
e-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl ] -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;
2-amino-5- [3- (1-nitroguanidino) ] pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride;
glycine { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride;
(S) -2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride;
1-methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride.
When the products of the invention comprise at least one salifiable substituent, they may be present in free or salifiable form. The product comprising at least one salifiable substituent may preferably be salified. Examples of suitable salifiable substituents are amino, alkylamino, dialkylamino, imino, guanidino, hydrazino, imidazolinyl (imidazolino), pyridyl (pyridido), pyrimidinyl (pyridimido), and pyridazinyl (pyridazino).
The preferred salt form is the hydrochloride salt.
A preferred salified form of the product of the invention with particularly advantageous properties is (S) -2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride having the following structure:
Figure A0282686000551
a hydrochloride salt.
The products of the invention can be used for the preparation of pharmaceutical products useful for the treatment of pathological conditions, in particular cancer.
The invention also relates to therapeutic compositions comprising a compound of the invention and a pharmaceutically acceptable excipient according to the chosen mode of administration. The pharmaceutical composition may be in solid or liquid form or in liposome form.
Among solid compositions, mention may be made of powders, gel capsules and tablets. In oral form, solid forms which are protected from the acidic media of the stomach are also included. Carriers for solid forms include, inter alia, inorganic carriers, such as phosphates or carbonates, or organic carriers, such as lactose, cellulose, starch or polymers. Liquid forms include solutions, suspensions or dispersions. They contain water or an organic solvent (ethanol, NMP, etc.), or a mixture of surfactants, and a solvent or a mixture of a compounding agent and a solvent as a dispersion carrier.
The liquid form is preferably injectable and therefore has a formulation acceptable for this use.
Acceptable routes of administration by injection include intravenous, intraperitoneal, intramuscular and subcutaneous routes, with intravenous routes being preferred.
The dosage of the compounds of the invention to be administered is adjusted by the physician in accordance with the route of administration to the patient and the condition of the patient.
The compounds of the present invention may be administered alone or as a mixture with other anticancer agents. Among the possible combinations, mention may be made of:
alkylating agents, in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, cermetin, streptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine;
platinum derivatives, such as in particular cisplatin, carboplatin or oxaliplatin;
antibiotic agents, such as bleomycin, mitomycin or actinomycin D, among others;
antimicrotubule agents, such as vinblastine, vincristine, vindesine, vinorelbine and the taxoids (paclitaxel and docetaxel), among others;
anthracyclines, such as, in particular, doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone and losoxantrone;
group I and II topoisomerases, such as etoposide, teniposide, amfenadine, irinotecan, topotecan and tomodex;
fluoropyrimidines, such as 5-fluorouracil, UFT and floxuridine;
cytidine analogs, such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptopurine, and 6-thioguanine;
adenosine analogues such as pentostatin, cytarabine or fludarabine phosphate;
methotrexate and leucovorin;
various enzymes and compounds, such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazimine, amifostine, monoclonal antibodies, and female and male hormones;
antiangiogenic agents, such as combretastatin derivatives or colchicine derivatives and prodrugs thereof.
The compounds of the invention may also be combined with radiation therapy. These treatments may be administered simultaneously, separately or sequentially. The treatment can be adjusted by the physician according to the specific circumstances of the patient to be treated.
The product of the invention can promote the disintegration of cell masses derived from vascular tissue. More specifically, the products of the invention are useful in their first therapeutic application for inhibiting the growth of cancer cells and simultaneously destroying existing blood vessels. Inhibition of angiogenesis was determined by the cell shedding assay described below.
Assays for inhibition of angiogenesis
Assays to determine endothelial cell shedding were established to select products based on their "in vitro" activity. The test for determining endothelial cell shedding is characterized in that: endothelial cells seeded on a plate coated on the bottom with a binder preferably selected from gelatin, fibronectin or vitronectin are supplemented after culture with a medium containing the test compound, these cells are then labeled with a fluorescent substance, the exfoliated cells are removed by washing, and the fluorescence of the remaining cells is counted in a fluorimeter.
The assay involves measuring the shedding of endothelial cells cultured in a substrate based on a binder preferably selected from fibronectin, vitronectin and gelatin. Preferably, after one day of seeding the cells in a 96-well plate, the culture medium is replaced, for example, with serum-free medium containing the test compound. The same formulation was prepared in 6 parts at three different concentrations (0.1, 0.3 and 0.6 μ M) and a control was prepared in 6 parts without the addition of anti-vascular product. After 2 hours of treatment with the test substances, the cells were labeled with calcein-AM (1.6. mu.l/ml) in a medium supplemented with 0.1% BSA. The exfoliated cells were removed by washing with a medium containing 0.1% bovine serum albumin; to each well 100. mu.l of medium was added. The fluorescence of the remaining cells was counted in a fluorimeter. The data obtained are presented relative to the control (untreated cells).
The assessment of endothelial cell shedding in vitro was determined as follows. HDMEC cells (human dermal microvascular endothelial cells, Promocell, c-122102) were cultured in ECGM-MV medium containing 5% fetal bovine serum, growth factors (EGF10ng/ml, hydrocortisone 1. mu.g/ml, 0.4% growth supplement containing heparin), and antibiotics (amphotericin 50ng/ml, gentamicin 50. mu.g/ml). In performing this detachment assay, HDMECs were seeded at a rate of 5000 cells in clear-bottom 96-well plates (Costar) pre-coated with fibronectin (10. mu.g/ml) or vitronectin (1. mu.g/ml) or gelatin. After 24 hours, the medium was replaced with 0.1% BSA ECGM-MV medium containing the indicated product. The tested concentrations of each product were 0.1-0-3 and 1. mu.M. After 2 hours of treatment, cells were labeled with calcein (1.6. mu.g/ml, molecular probe) in 0.1% BSA ECGM-MV medium for 1 hour. The exfoliated cells were then removed by washing with 0.1% BSA ECGM-MV medium; to each well 100. mu.l of medium was added. The fluorescence of the cells still adhering to the bottom of the wells was counted using a fluorometer Spectrafluor Plus (Tecan, excitation: 485nm, emission: 535 nm). Data are the average of six different samples and are expressed as a percentage relative to the control (untreated cells).
Cell shedding greater than or equal to 15% was considered significant.
The products of the invention are useful for inhibiting tubulin polymerization in vitro.
Evaluation of inhibition of tubulin polymerization
Tubulin was purified from porcine brain according to published methods (Shelanski et al, 1973, Proc. Natl, Acad. Sci. USA, 70, 765-768; Weingarten et al, 1975, Proc. Natl, Acad. Sci. USA, 72, 1858-1862). Briefly, pig brain was triturated in extraction buffer and centrifuged. Tubulin contained in the extraction supernatant was subjected to two successive polymerization cycles at 37 ℃ and depolymerized at 4 ℃ before being chromatographed on a phosphocellulose P11 column (Whatman) with MAP (microtubules)Related proteins) are isolated. Tubulin thus isolated is more than 95% pure. It was stored in a buffer called RB/230% glycerol consisting of MES-NaOH [2- (N-morpholino) ethanesulfonic acid]，50mM，pH6.8；MgCl20.25 mM; EGTA, 0.5 mM; 30% glycerol (v/v); GTP (guanosine 5' -triphosphate), 0.2 mM.
The polymerization of tubulin into microtubules can be monitored by turbidimetry as follows; tubulin was adjusted to a concentration of 10. mu.M (1mg/ml) in RB/230% glycerol buffer to which 1mM GTP and 6mM MgCl were added2. The polymerization is initiated in a cuvette having an optical path length by raising the temperature from 6 ℃ to 37 ℃The mixture was measured at a temperature of 1cm and placed in an Uvikon931 spectrophotometer (Kontron) equipped with thermostatically regulated cuvette holders. The increase in turbidity of the solution was monitored at 350 nm.
The product was dissolved in DMSO at 10mM and added to the tubulin solution at various concentrations (0.5 to 10 μ M) prior to polymerization. IC (integrated circuit)50The value is defined as the concentration of product inhibiting 50% of the polymerization rate. IC (integrated circuit)50Products with values less than or equal to 3 μ M are considered to be very active.
Evaluation of inhibition of HeLa cell proliferation
Proliferation of HeLa cells was measured by14C]-thymidine incorporation was evaluated. HeLa cells (from human epithelial tumor cells) were cultured in DMEM medium (Gibco) containing 10% fetal bovine serum and antibiotics (1% penicillin, 1% streptomycin). For proliferation assays, cells were seeded in 96-well cytostar microplates (Amersham) at a rate of 5000 cells per well. Then, add [2 ]14C]Thymidine (0.1. mu. Ci/well) and the product to be assessed. Using different concentrations of product not exceeding 10 μ M; DMSO (solvent used to dissolve the product) should not exceed 0.5% in the medium. After incubation for 48 hours at 37 ℃, the radioactivity introduced into the cells was determined by counting the plates in a TRI-LUX counter (Wallac). IC (integrated circuit)50Values are defined as the concentration of product that reduces radioactivity by 50% relative to untreated controls. IC (integrated circuit)50Products with values less than 1 μ M are considered cytotoxic.
Evaluation of the shedding Effect of HDMEC endothelial cells
The assessment of endothelial cell shedding in vitro was determined in the following manner. HDMEC cells (human dermal microvascular endothelial cells, Promocell, c-122102) were cultured in ECGM-MV medium containing 5% fetal bovine serum, growth factors (EGF10ng/ml, hydrocortisone 1. mu.g/ml, 0.4% growth supplement containing heparin), and antibiotics (amphotericin 50ng/ml, gentamicin 50. mu.g/ml). In performing this shedding assay, HDMECs were seeded at a rate of 5000 cells in clear-bottom 96-well plates (Costar) pre-coated with fibronectin (10. mu.g/ml) or vitronectin (1. mu.g/ml) or gelatin. After 24 hours, the medium was replaced with 0.1% BSA ECGM-MV medium containing the indicated product. The tested concentrations of the respective products were 0.1-0.3 and 1. mu.M. After 2 hours of treatment, cells were labeled with calcein (1.6 μ g/ml, molecular probe) in 0.1% BSAECGM-MV medium for 1 hour. The exfoliated cells were then removed by washing with 0.1% BSA ECGM-MV medium; to each well 100. mu.l of medium was added. The fluorescence of the cells still adhering to the bottom of the wells was counted using a fluorometer Spectrafluor Plus (Tecan, excitation: 485nm, emission: 535 nm). Data are the average of six different samples and are expressed as a percentage relative to the control (untreated cells).
Cell shedding greater than or equal to 15% was considered significant.
Assessment of in vivo tumor necrosis
Mice were bred by either IFFA-CREDO (Domaine nes, 69210L' Arbresle, France) from Jackson laboratories, Bar Harbor, Me. USA, or by Charles River France (76410 St Aubin les Elbeuf, France) from Charles River, USA. At the beginning of the experiment, the initial body weight of the mice exceeded 18 g. They have free access to food (UAR reference 113, Villemoisson, 91160 epicay sur orange, france) and water.
The tumors used were recently transplanted in our laboratory. All of these tumors were either deposited at the Frederick cancer research center (Frederick, Md., USA) of the frozen tumor Collection of the national cancer institute (NCl) or maintained at the American type culture Collection (ATCC, Rockville, Md., USA).
Tumor transplantation techniques, chemotherapy and data analysis are detailed in (Corbeta et al, 1982 a; Corbeta et al, 1982 b).
In summary, animals required for this experiment were pooled on day 0 and implanted bilaterally with tumors.
The growth of solid tumors is free to progress to the desired size. Mice were then treated by intravenous injection of test compound solutions.
Tumor sampling is usually (but not necessarily) performed 24 hours after treatment.
Mice were sacrificed by dislocating the brain. Implanted tumors, along with the skin and adjacent tissues that coat them, were collected and stored in 10% formaldehyde (v/v) (Carlo Erba, Val de Reuil, France).
The samples were then processed, sectioned, stained with hematoxylin, eosin and saffron yellow, and then visually inspected. Tumor necrosis was assessed microscopically using a 0 to 5 scale score (necrosis ± regression):
0-absence of necrosis;
1 is extremely small and less than 5 percent;
2 is small, 5-25%;
medium, 25-50%;
significant 4, 50-75%;
5 is large and > 75%.
The score for tumor necrosis 24 hours after administration of the test compound only corresponded to necrosis due to the product, which is believed to be different from any existing necrosis caused by the experiment.
Experimental necrosis was assessed based on untreated controls.
The tumor model was a C51 murine adenoma. The colon tumor is grade III mucinous colon adenoma. The tumor was maintained in female BALB/c mice by serial subcutaneous passages every 18 days. The experiments were performed in female BALB/c mice.
Results
Under the conditions described, the following results were obtained for the following examples:
example 1: the dose of 24.5 mg/kg/injection-grade 5 necrosis was selected,
example 2: the dose 50 mg/kg/injection-grade 5 necrosis was selected.
Reference to the literature
Corbert, t.h., LEOPOLD, w.r., DYKES d.j., ROBERTS, b.j., GRISWOLD, d.p., Jr and SCHABEL, f.m., Jr., "toxicity and anticancer activity of novel triazine antifolates (NSC 127755)", Cancer res, 1982a, 42, 1707-one 1715.
Corbert, t.h., ROBERTS, b.j., TRADER, m.w., last, w.r., Jr, GRISWOLD, d.p., Jr and SCHABEL, f.m., Jr., "response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinical drugs", Cancer treat.rep., 1982b, 66, 1187-.
Definition of
"halogen" is an element selected from the group consisting of F, Cl, Br and I.
“C1-C7Straight chain alkyl "is a substituent selected from the group consisting of: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-heptyl.
“C1-C7Branched alkyl "is a substituent selected from the group consisting of: 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, 1-dimethylethyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2, 2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2, 2-dimethylbutyl group, 2, 3-dimethylbutyl group, 3-dimethylbutyl group, 1, 2-trimethylpropyl group, 1, 2, 2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-dimethylpentyl group, 1, 2-dimethylpentyl group, 1, 3-dimethylpentyl group, 1, 4-dimethylpentyl group, 2, 2-dimethylpentyl group, 2, 3-dimethylpentyl group, 2, 4-dimethylpentyl group, 3, 3-dimethylpentyl group, 4-dimethylpentyl group, 1, 2-trimethylbutyl group, 1, 3-trimethylbutyl group, 1, 2, 2-trimethylbutyl group, 1, 2, 3-trimethylbutyl group, 1,3, 3-trimethylbutyl group, 2, 3-trimethylbutyl, 2, 3, 3-trimethylbutyl, 1, 2, 2-tetramethylpropyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-ethyl-1-methylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 2-ethyl-1-methylbutyl, 2-ethyl-2-methylbutyl, 2-ethyl-3-methylbutyl, 1-propylbutyl, 1- (1-methylethyl) butyl, 1- (1-methylethyl) -2-methylpropyl.
"cycloalkyl" may be a substituent selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo [2.2.1] heptyl.
"aryl" may be a substituent selected from: phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, pyrimidinyl, piperazinyl, triazinyl, carbazolyl, imidazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, triazolyl, tetrazolyl, benzotriazolyl, thienyl, furyl, pyrrolyl, benzothienyl, benzofuryl and indolyl.
"aralkyl" is an alkyl substituent which is itself substituted with an aryl group as described above. Benzyl is an example of an aralkyl substituent.
The term "substituted" is especially present in the expression "substituted C1-C7Straight chain alkyl "," substituted C1-C7In the branched alkyl group, the "substituted cycloalkyl group" and the "substituted aralkyl group", it is necessarily referred to a substituent other than hydrogen, and these substituents may be selected from F, Cl, Br, I, N (R7, R8), N (O) (R7, R8), NO2、O(R7)、S(R7)、SO(R7)、SO2(R7)、OSO2(R7)、PO3(R7)、OPO3(R7), CO (R7), COO- (R7), CONH- (R7), CON (R7, R8), CN, C ≡ C- (R7), N ≡ C- (R9), aryl, aralkyl, heteroaryl and heteroaralkyl where R7, R8 are independently selected from H, alkyl, alkylene, aryl, heteroaryl, aralkyl, C (O) - (R7), C (S) - (R7), alkyl-O (R7), alkyl-S (R7) and alkyl-N (R7, R8), where R7 and R8, when both are present, may be linked together to form a ring, R9 is selected from alkyl, alkylene, aryl, heteroaryl, aralkyl, alkyl-O (R7), alkyl-S (R7) and alkyl-N (R7, R8); it also relates to any other acceptable substituent known to those skilled in the art at the time of the filing date of the present application.
"amino acids" include natural and artificial amino acids in enantiomerically pure form or as mixtures.
"metabolizable substituent" includes any substituent that contains at least one functional group that is cleavable by the metabolism of the organism. Examples of cleavable functional groups include amides, imides, imines, esters, lactones, lactams, acetals, hemiacetals, carbonates, carbamates, and ureas.
"organic acid" includes organic molecules containing at least one proton-donating functional group, e.g., COOH, SO3H、OSO3H、PO3H2、OPO3H2And optionally OH, in which case the latter functional group is directly linked to the aromatic or heteroaromatic core.
"inorganic acid" includes proton donor (H)+) Inorganic substances, e.g. HCl, HBr, HI, HIO4、H2S、H2SO4、H3PO2、H3PO4And HNO3(ii) a Or substances which give mineral acids by reaction, e.g. AlCl3、AlBr3、SnCl4、SiCl4、TiCl4、FeCl3Or RuCl3They can be reacted in protic solvents such as water according to the following formula:
MaZb+bH2O→a{M(OH)band/or [ MOn(OH)b-2n+nH2O]}+bHZ
Wherein a, b and n are integers or real stoichiometric coefficients, M is selected from the metals given above as examples and Z is halogen.
Hereinafter, the products corresponding to formula (I) will be represented by general formula (I) wherein Ar is replaced by phenyl substituted with n methoxy groups, with the proviso that: n has the value 2, 3 or 4 and the position of the methoxy group on the phenyl group is as defined above.
Chalcones of general formula (I):
Figure A0282686000631
wherein X represents an oxygen atom, Y is not a halogen atom, and n, R1 and R2 are as defined above, wherein R1 or R2 represents an amino group, which can be prepared by coupling an aromatic ketone of the general formula (II) wherein Y is not a halogen atom with an aromatic aldehyde of the general formula (III) under the conditions described in j.med.chem., 1990, 33, 1948. After coupling, the nitro group is reduced to an amino group according to scheme (I):
scheme (I)
The process is typically carried out in a Soxhlet type apparatus in the presence of piperidine, acetic acid and molecular sieves at the reflux point of an alcohol such as ethanol.
It should be understood that: the coupling between the ketones of the general formula (II) and the aldehydes of the general formula (III) can also be carried out with replacement of the amino group in R1 or R2 by a nitro group. It should be understood that: the coupling can also be carried out with R1 or R2 representing any protected form of the aromatic amine function such as, as a non-limiting example, tert-butoxycarbonylamino (NHBoc). The cleavage of the protecting group on the aromatic amine function can be carried out under the conditions described in protecting groups in organic chemistry (edited by Wiley). In the particular case of reduction of the nitro group to an amino group, a catalytic reduction process may be used, for example reduction with hydrogen in the presence of a catalyst such as 3% palladium on carbon, or a chemical reduction process, for example reduction with iron in the presence of hydrochloric acid or stannous chloride.
Aromatic aldehydes of the general formula (III) are commercially available or have been described in the literature.
Aromatic ketones of the general formula (II) are described in the literature and are usually prepared from the corresponding aromatic aldehydes which are commercially available. When Y represents an optionally substituted alkyl or aralkyl group, the process is advantageously carried out by reacting the aldehyde with a suitably selected organometallic reagent, followed by oxidation of the benzyl alcohol thus obtained, under the conditions described in j.med.chem., 1990, 33, 1948. When Y represents a carboxyl group, a carboxylate group or a carboxamide group, the aldehyde may advantageously be reacted with a diazoacetate under the conditions described in Synlett, 1996, 369.
Chalcones of general formula (I):
Figure A0282686000641
wherein X represents an oxygen atom, Y represents a halogen atom, preferably a bromine or chlorine atom, and n, R1 and R2 are as defined above, wherein R1 or R2 represent an amino group, which can be prepared according to scheme (II) by addition of a chalcone in which Y represents a hydrogen atom to a halogen followed by dehydrohalogenation. It is particularly advantageous to carry out this addition-elimination procedure on protected forms of amino groups, such as nitro or NHBoc groups, followed by reduction or deprotection.
Figure A0282686000642
Scheme (II)
The addition of halogen, preferably bromine or chlorine, is usually carried out at a temperature of from 0 to 50 ℃ in a solvent such as chloroform or carbon tetrachloride. Dehydrohalogenation is generally carried out at a temperature ranging from 0 ℃ to the reflux point of the reaction medium, in the presence of an organic or inorganic base, such as triethylamine, sodium hydroxide or potassium carbonate, in a solvent such as dichloromethane.
Chalcones of general formula (I):
Figure A0282686000651
wherein X represents an oxygen atom, Y is not a halogen atom, and n, R1 and R2 are as defined above, wherein R1 or R2 represent an amino group, which can also be prepared by nucleophilic substitution of a product of general formula (I) wherein Y represents a halogen atom, preferably a bromine atom. In this case, the ketone function can advantageously be protected beforehand according to scheme (III):
Figure A0282686000652
scheme (III)
Chalcones of general formula (I):
Figure A0282686000653
wherein X represents an oxygen atom, Y represents a substituted methylene group, and n, R1 and R2 are as defined above, wherein R1 or R2 represent an amino group, which can also be prepared by nucleophilic substitution of a product of general formula (I) wherein Y represents a bromomethyl group, according to scheme (IV) under conditions described in j.org.chem., 1967, 3830:
Figure A0282686000661
scheme (IV)
Schemes (III) and (IV) illustrate, in a non-limiting manner, methods of altering the substituent Y on the preformed chalcone, which may be altered using any other method known to those skilled in the art.
Chalcones of general formula (I):
Figure A0282686000662
wherein X represents a group N-OR3And Y, n, R1 and R2 are as defined above, wherein R1 or R2 represent amino groups, which can be prepared according to scheme (V) by the action of hydroxylamine and a product of general formula (I) wherein X represents an oxygen atom:
Figure A0282686000663
scheme (V)
It should be understood that: the invention also relates to prodrugs, in particular water-soluble prodrugs, of chalcones of the general formula (I):
Figure A0282686000671
wherein X represents an oxygen atom OR a group N-OR3And Y, n, R1 and R2 are as defined above, wherein R1 or R2 represents a cleavable derivative of an amino group. Among the cleavable derivatives of amino groups, more particularly desirable are amino acid derivatives, which can be prepared according to scheme (VI) by peptide-type coupling between:
(i) a product of general formula (I) in which X represents an oxygen atom OR a group N-OR3Wherein Y, n, R1 and R2 are as defined above, wherein R1 or R2 represents amino, and
(ii) natural or modified amino acids, optionally in protected form, with the exception of their carboxylic acid functions, wherein it is understood that: when the amino acid is partially protected, the coupling is followed by a deprotection step as follows:
Figure A0282686000672
scheme (VI)
Peptide-based coupling is carried out in the presence of a coupling and/or activating agent such as, by way of non-limiting example, an EDCI/HOBT mixture, in an organic solvent such as dichloromethane under standard conditions.
The following examples are given to illustrate the invention.
Example 1: e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone
Step 1: 2.24g of 1- (3, 4, 5-trimethoxyphenyl) propenone (which can be according to Biorg. Med. chem.1998, 8(9), 1051 preparation), 1.85g of 3-nitro-4-methoxybenzaldehyde and 2mL of piperidine and 1mL of acetic acid in 20mL of ethanol were added sequentially to a 25mL three-necked flask fitted with a soxhlet. medium reflux filled with 3 Å molecular sieves for 48 hours after cooling, the reaction medium was concentrated under reduced pressure and then dissolved in 100mL of ethyl acetate and the organic phase was washed with water, dried over magnesium sulphate and concentrated under reduced pressure the crude product was purified by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of cyclohexane and ethyl acetate (80/20 (vol.). the 2g E-3- (3-nitro-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone was obtained containing about 5% of the Z isomer as a yellow solid with a melting point of 45-50 ℃.
Step 2: 485mg of 3- (3-nitro-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone obtained in the previous step were suspended in 20mL of ethanol and 2.5mL of water in a 50mL three-necked flask. The mixture was refluxed, then 0.25mL of 37% hydrochloric acid was added, followed by addition of 2.09g of iron filings in portions. Reflux was maintained for 30 minutes and the mixture was then cooled. After addition of 2g of potassium carbonate, the insoluble material was filtered and washed 3 times with 25mL of ethanol. After concentrating the filtrate under reduced pressure, the residue was dissolved in 50mL of water and extracted 3 times with 50mL of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The orange residue thus obtained was purified by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (70/30 vol). This gives 0.35g of pure E-3- (3-amino-4)-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone, as a pale yellow powder, having the following characteristics:
melting point (Kofler) 142 ℃.
-elemental analysis: 67.26% C; % H6.80; % N is 3.97.
Example 2: e-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone
Figure A0282686000681
Step 1: the procedure is as in step 1 of example 1, but 2.24g of 1- (3, 4, 5-trimethoxyphenyl) propenone and 1.81g of 4-nitro-3-methoxybenzene are taken from 75mL of ethanol containing 2mL of piperidine and 1mL of acetic acidThe aldehyde started to reflux for 96 hours and after purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (80/20 vol), 0.7g E-3- (4-nitro-3-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone was obtained, free of Z isomer, as a very viscous yellow oil.
Step 2: following step 2 of example 1, but starting from 700mg of 3- (4-nitro-3-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone and 3.09g of iron, after purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (70/30 vol)), 0.55g of pure E-3- (4-amino-3-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone was obtained as a pale yellow powder with the following characteristics:
melting point (Kofler) 140 ℃.
-elemental analysis: % C67.27; % H6.68; % N is 3.93.
Example 3: e-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone hydrochloride
Figure A0282686000691
Step 1: the procedure is as in step 1 of example 1, but 3.8g of 1- (2, 5-dimethoxyphenyl) are dissolved in 75mL of ethanol containing 4mL of piperidine and 2mL of acetic acidStarting from acrylketone and 3.7g of 3-nitro-4-methoxybenzaldehyde, reflux was carried out for 96 hours, and after purification by flash chromatography using silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (80/20 vol), followed by recrystallization from isopropyl acetate, 0.3g of E-3- (3-nitro-4-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) acrylketone was obtained, free of the Z isomer, as yellow crystals, melting point 104 ℃.
Step 2: the procedure is as in step 2 of example 1, but starting from 280mg of 3- (3-nitro-4-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone and 1.03g of iron, after purification by recrystallization from a mixture of ethanol and diethyl ether in the form of the hydrochloride, 0.25g of pure E-3- (3-amino-4-methoxyphenyl) -2-methyl-1- (2, 5-dimethoxyphenyl) propenone hydrochloride is obtained in the form of pale yellow crystals, which have the characteristics such asThe following:
melting point (Kofler) 178 ℃.
-elemental analysis: % C62.47; % H ═ 6.01; % N ═ 3.77; % Cl 9.14.
Example 4: e-3- (3-amino-4-methoxyphenyl) -2-bromo-1- (3, 4, 5-trimethoxyphenyl) propenone
Step 1: proceeding as in step 1 of example 1, but starting from 3.8g of 3, 4, 5-trimethoxyacetophenone and 3.44g of 3-nitro-4-methoxybenzaldehyde in 95mL of methanol containing 2.37mL of sodium hydroxide, after purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (80/20 vol) overnight at room temperature, 6.27g E-3- (3-nitro-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) propenone is obtained, free of the Z isomer, as a viscous yellow oil.
Step 2: 500mg of E-3- (3-nitro-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) propenone was dissolved in 8mL of chloroform in a 50mL three-necked flask. Then 40. mu.L of bromine dissolved in 3mL of chloroform was added dropwise. After stirring at room temperature for 3 hours, 40. mu.L of bromine dissolved in 3mL of chloroform was added dropwise and further stirred at room temperature for 3 hours. Concentrating under reduced pressure, mixingThe residue was purified by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of dichloromethane and cyclohexane (50/50 (vol)). This gave 554mg of 2, 3-dibromo-3- (3-nitro-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) acetone, whose characteristics were as follows:
mass Spectrometry (EI/DCI) M+＝533。
Step 3153mg of 2, 3-dibromo-3- (3-nitro-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) acetone was dissolved in 6mL of methylene chloride dried over a 4 Å molecular sieve in a 10mL three-necked flask, 81. mu.L of anhydrous triethylamine was then added, and the mixture was stirred at room temperature for 24 hours, then 40. mu.L of anhydrous triethylamine was added, and the mixture was stirred at room temperature for 72 hours, after adding 5mL of distilled water, the organic phase was separated by settling, washed with 5mL of water 2 times, dried over magnesium sulfate, and concentrated under reduced pressure, whereby 116mg of E-2-bromo-3- (3-nitro-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) acetone was obtainedMethoxyphenyl) acrylketone, containing about 10% of the Z isomer, which was used in the rest of the synthesis without further purification.
Step 4: 67.2mg of E-2-bromo-3- (3-nitro-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) propenone were suspended in 2mL of ethanol, then 167.5mg of stannous chloride dihydrate were added and the mixture was heated at 80 ℃ for 1 hour. After cooling and dilution with 2mL of water, the pH was adjusted to 8 by addition of saturated sodium bicarbonate solution and the resulting mixture was extracted 3 times with 5mL of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (70-230 mesh) eluting with dichloromethane. This gave 34.4mg of E-2-bromo-3- (3-amino-4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) propenone, free of the Z isomer, having the following characteristics:
-silica gel plate chromatography: rf ═ 0.16 (solvent: dichloromethane)
Mass Spectrometry (EI/DCI) M+＝422。
Example 5: e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone
The process is carried out as in step 1 of example 1, but starting from 4.49g of 1- (3, 4, 5-trimethoxyphenyl) acetone and 3.18g of 1-methylindole-5-carbaldehyde (which can be prepared according to Terent' ew et al, J.Gen.chem USSR (1962), 32, 1311) in 100mL of ethanol containing 4mL of piperidine and 2mL of acetic acid, under reflux for 48 hours. After purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (80/20 vol), followed by recrystallization from ethanol, 2.5g of pure E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone are obtained as pale yellow crystals, the characteristics of which are as follows:
melting point (Kofler) ═ 136 ℃.
-elemental analysis: % C72.52; % H6.45; % N is 3.87.
Example 6: e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone
The process is carried out as in step 1 of example 1, but starting from 4.49g of 1- (3, 4, 5-trimethoxyphenyl) propenone and 3.22g of 1-methyl-2, 3-indoline-5-carbaldehyde (which can be prepared according to Gavinecki et al, org.Prep.proced.int. (1998), 30, 455-60) in 100mL of ethanol containing 4mL of piperidine and 2mL of acetic acid, refluxing for 48 hours. After purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (70/30 vol), followed by crystallization from isopropyl ether, 1.2g of pure E-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) -propenone are obtained as pale yellow crystals, whose characteristics are as follows:
melting point (Kofler) ═ 85 ℃.
-elemental analysis: % C71.91; % H ═ 7.04; % N3.79.
Example 7: e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone oxime
Figure A0282686000722
100mg of E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone obtained in example 5, 29mg of hydroxylamine hydrochloride, 0.5mL of piperidine and 5mL of ethanol were placed in a 25mL three-necked flask. The mixture was refluxed for 5 hours with stirring and then stirred for another 20 hours at room temperature. After concentration under reduced pressure, the reaction medium is dissolved in 20mL of water and 25mL of ethyl acetate. The organic phase was separated by settling, washed with water and concentrated to dryness under reduced pressure. After purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture of cyclohexane and ethyl acetate (80/20 vol), followed by recrystallization from ethanol, 70mg of 60/40 mixture of the Z and E isomers of E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone oxime were obtained as white crystals, which were characterized as follows:
melting point (Kofler) ═ 150 ℃.
-elemental analysis: % C68.63; % H6.30; % N7.03.
Example 8: e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone Z-oxime
820mg of 60/40 mixture of Z and E isomers of E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone oxime, prepared as in example 7, can be separated on a Whelk 01S, S10. mu.M type chiral column containing 700g of chiral stationary phase, eluting with n-heptane/ethanol/dichloromethane (68/2/30 (vol)) containing 0.1% trifluoroacetic acid at a flow rate of 100 mL/min. By separating the eluted first fraction (retention time ═ 22 minutes), 434mg of E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone Z-oxime were obtained.
Example 9: e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone E-oxime
Proceeding as in example 8, but isolating the eluted second fraction (retention time 28 min), 328mg of E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone E-oxime are obtained.
Example 10: (S) -2, 6-Diaminohexanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide dihydrochloride
Step 1: 1g of Boc-Lys (Boc) -OH. DCHA was dissolved in 10mL of ethyl acetate in a 50mL round-bottomed flask, after which 1.2 equivalents of 2M aqueous sulfuric acid (i.e., 2.2mL) was added. Clear two phases were obtained. The organic phase was removed, 5mL of cold distilled water was added to the aqueous phase, and the resulting mixture was extracted with 2X 5mL of ethyl acetate. The organic phases are combined and washed with 2X 10mL of distilled water, then dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator (bath temperature below 40 ℃). The colorless oil was dried under vacuum to give 0.47g Boc-Lys (Boc) -OH.
Step 2: Boc-Lys (Boc) -OH (458mg, 1.319mmol) prepared in step 1 was dissolved in 7mL ethyl acetate in a 50mL three-necked flask equipped with thermometer and bubble counter. The colorless solution was cooled to 6 deg.C (water bath + ice) before N-methylmorpholine (1.2 eq, 146.5. mu.l) and pivaloyl chloride (1.2 eq, 163. mu.l) were added. The resulting white suspension was kept at 5 ℃ for 2 h 30 min, then 3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxy-phenyl) propenone (392.9mg, 1 eq) suspended in 10mL ethyl acetate was added. The suspension was stirred at room temperature for 72 hours. The suspension was filtered through a sintered funnel and the solid was then rinsed with ethyl acetate. The filtrate was washed with 10mL of distilled water, and then with 5mL of 1N aqueous sodium hydroxide solution, 10mL of distilled water and 10mL of saturated NaCl solution. The organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator. The crude reaction product thus obtained was dissolved in 5mL of ethyl acetate and 3mL of anhydrous ethanol, followed by addition of 1mL of 4.8N ethanol hydrochloride. Heating the medium at 49 ℃ until the desired product is obtained, wherein the reaction is carried outProgress was monitored by LC/MS. When cooled. A white solid precipitated. The solid was filtered on a sintered funnel and washed with ethyl acetate. 299.3mg of a white solid are obtained in the form of a powder, the characteristics of which are as follows:
LC/MS (50X 4.6mm Hypersil BDS 3 μm silica C18 column; linear elution gradient: acetonitrile 5% to 90% containing 0.05% trifluoroacetic acid in 3.5 min/water also containing 0.05% trifluoroacetic acid at a flow rate of 1 mL/min); retention time 2.67 minutes; MS: 486.3([ M + H)]+)。
-elemental analysis: % C52.06; % H6.73; % N ═ 7.02; % Cl 12.7.
Example 11: 2-amino-5- [3- (1-nitroguanidino)]-pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide hydrochloride
Figure A0282686000751
Step 13- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone (1g, 0.279mmol) is dissolved in 150mL of dichloromethane after which EEDQ (760.1mg, 1.1 equiv.) and N α -Boc-N- ω -nitro-L-arginine (980.2mg, 1.1 equiv.) are added, the suspension is stirred at room temperature for 20 h the resulting solution is concentrated in vacuo on a rotary evaporator the crude reaction product is purified by flash chromatography on silica gel (AC.C 35-70 μm silica gel 60) eluting with a mixture of ethyl acetate and cyclohexane (80/20 vol.) to yield 1.5g 2- (1, 1-dimethylethyloxycarbonylamino) -5- [3- (1-nitroguanidino)]Pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide as brown oil.
Step 2: the oil was dissolved in 10mL ethyl acetate, after which 4mL ethanol and 2mL 4.8N ethanolic hydrochloride solution were added. The medium is heated at 60 ℃ (temperature of the oil bath) for 12 hours. The resulting white solid was filtered off on a sintered funnel, then rinsed with ethyl acetate and dried in vacuo. This gave 1.07g 2-amino-5- [3- (1-nitroguanidino)]Pentanoic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } acylAmine hydrochloride, as a white powder, with the following characteristics:
-mass spectrum (EI): and m/z is 558.
-elemental analysis: % C52.84; % H6.22; 14.14% N; % Cl 6.12.
Example 12: 1-Methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethyl)Oxyphenyl) propenyl group]Phenyl } amide hydrochloride
3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone (450mg, 1.259mmol) was dissolved in 45mL DMF before HOBT (578.3mg, 3 equiv.), HBTU (1.43g, 3 equiv.), N-methyl-L-proline (487.9mg, 3 equiv.) and N, N-diisopropylethylamine (1.31mL, 6 equiv.) were added. The medium is stirred at room temperature for 3 hours. The solvent was distilled off under vacuum (P9 mbar, bath temperature T44 ℃). The crude product was dissolved in 30mL of distilled water and the aqueous phase was extracted with 5X 60mL of dichloromethane. The organic phase was washed with saturated NaCl solution and then dried over magnesium sulfate. The solvent was distilled off under vacuum. The crude reaction product was purified by flash chromatography on silica gel, eluting with a dichloromethane/methanol mixture (95/5 (vol)). 197mg of the thus purified product were dissolved in ethyl acetate (2mL), after which a 4.8N ethanol solution of hydrochloric acid (17. mu.l) was added and the medium was stirred at room temperature for 18 hours. After concentration of the solvent, drying, 205mg of 1-methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide was obtained, having the following characteristics:
LC/MS (50X 4.6mm Hypersil BDS 3 μm silica C18 column; linear elution gradient: acetonitrile 5% to 90% containing 0.05% trifluoroacetic acid in 3.5 min/water also containing 0.05% trifluoroacetic acid at a flow rate of 1 mL/min); retention time 3.03 minutes.
-mass spectrometry: 486.32([ M + H)]+)。
Example 13: (S) -2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide hydrochloride
Figure A0282686000762
Step 1: 3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone (700mg, 1.96mmol) was dissolved in 25mL of dichloromethane before HOBT (298mg, 1.2 equiv.), EDCI (422mg, 1.2 equiv.) and N-Boc-L-serine (452mg, 1.2 equiv.) were added. The medium is stirred at room temperature for 3 days. 50mL of methylene chloride and 25mL of water were added. After settling the phases the organic phase was separated, washed with saturated NaCl solution and then dried over magnesium sulfate. The solvent was distilled off under vacuum. The crude reaction product was purified by flash chromatography on silica gel eluting with methylene chloride/ethyl acetate (7/3 (vol)). Thus, 800mg of (S) -2-Boc-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide as an orange oil which was used in the following step without further modification, the properties of the product being as follows:
-mass spectrum (EI): m/z 544.
Step 2: reacting (S) -2-Boc-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide (800mg) was dissolved in 2.5mL of dioxane, followed by the dropwise addition of 2.5mL of a 4M solution of hydrochloric acid in dioxane. The reaction medium is stirred at room temperature for 20 hours; after the solvent was concentrated under reduced pressure, the residue was dissolved in 50mL of water, the pH was adjusted to 8 by adding saturated aqueous sodium bicarbonate solution, and then extracted 3 times with 25mL of dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a dichloromethane/methanol mixture (95/5 (vol)). Thus 360mg of (S) -2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide as an amorphous beige solid.
240mg (0.54mmol) of the base obtained above are dissolved in 5mL of diisopropyl ether and 1mL of methanol. Then 0.54mL of a 1M solution of hydrochloric acid in diisopropyl ether is added dropwise and the mixture is crystallized for 3 hours. After filtration and subsequent air drying, 200mg of { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride(s) -2-amino-3-hydroxypropionic acid are obtained as white crystals, whose characteristics are as follows:
-mass spectrum (EI): 494, m/z.
-elemental analysis: % C56.93; % H6.58; 5.61% N; % Cl 7.12.
Example 14: aminoacetic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propaneAlkenyl radical]Phenyl } amide hydrochloride
Step 1: 3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone (175mg, 0.5mmol) was dissolved in 10mL of dichloromethane before HOBT (75mg, 1.1 equiv.), EDCI (106mg, 1.1 equiv.) and N-Boc-glycine (96mg, 1.1 equiv.) were added. The medium is stirred at room temperature for 3 days. 10mL of methylene chloride and 10mL of water were added. After settling the phases the organic phase was separated, washed with saturated NaCl solution and then dried over magnesium sulfate. The solvent was distilled off under vacuum. The crude reaction product was purified by flash chromatography on silica gel, eluting with a dichloromethane/ethyl acetate mixture (6/4 (vol)). This gave 250mg of Boc-glycine { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide, as a beige foam, which was used in the following step without further modification, the properties of the product were as follows:
-mass spectrum (EI): m/z 514.
Step 2: 250mg of Boc-glycine { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide was dissolved in 2mL of dioxane, after which 1.1mL of a 4M solution of hydrochloric acid in dioxane was added dropwise. The reaction medium is stirred at room temperature for 20 hours; after the solvent was concentrated under reduced pressure, the residue was dissolved in 5mL of diisopropyl ether and 1mL of methanol, followed by crystallization for 2 hours. After filtration and subsequent air drying, 130mg of { 2-methoxy-5- [2-Methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide hydrochloride as white crystals, having the following characteristics:
-mass spectrum (EI): and m/z is 450.
-elemental analysis: % C58.03; % H6.17; % N ═ 6.11; % Cl 8.29.
Example 15: (S) -2-amino-3-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide hydrochloride
Figure A0282686000791
Step 1: 3- (3-amino-4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone (176mg, 0.5mmol) was dissolved in 10mL of dichloromethane before HOBT (75mg, 1.1 equiv.), EDCI (106mg, 1.1 equiv.) and N-Boc-L-valine (120mg, 1.1 equiv.) were added. The medium is stirred at room temperature for 3 days. 15mL of methylene chloride and 10mL of water were added. After settling the phases the organic phase was separated, washed with saturated NaCl solution and then dried over magnesium sulfate. The solvent was distilled off under vacuum. The crude reaction product was purified by flash chromatography on silica gel, eluting with a dichloromethane/ethyl acetate mixture (8/2 (vol)). Thus, 260mg of (S) -2-Boc-amino-3-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide, as a beige foam, which was used in the following step without further modification, the properties of the product were as follows:
mass spectrum (EI): m/z 556.
Step 2: reacting (S) -2-Boc-amino-3-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl]Phenyl } amide (260mg) was dissolved in 2mL of dioxane, after which 1.05mL of a 4M solution of hydrochloric acid in dioxane was added dropwise. The reaction medium is stirred at room temperature for 20 hours. After the solvent was concentrated under reduced pressure, the residue was dissolved in 5mL of diisopropyl ether and 0.5mL of methanol, followed by crystallization for 3 hours. After filtration and then air-drying, 170mg of (S) -2-amino-3-methylbutyric acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4)5-trimethoxyphenyl) propenyl group]Phenyl } amide hydrochloride as white crystals, having the following characteristics:
-mass spectrum (EI): 493/z.
-elemental analysis: % C60.56; % H ═ 7.03; 5.16% N; % Cl 7.84.
Example 16: e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone
Figure A0282686000801
The process is carried out as in step 1 of example 1, but starting from 2.1g of 1- (3-methoxy-4, 5-methylenedioxyphenyl) acetone (which can be prepared according to J.org.chem.1981, 46(14), 2969-71) and 3.18g of 1-methylindole-5-carbaldehyde (which can be prepared according to Terent' ew et al, J.Gen.chem USSR (1962), 32, 1311) in 100mL of ethanol containing 2mL of piperidine and 1mL of acetic acid, under reflux for 96 hours. After purification by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of cyclohexane and ethyl acetate (80/20 vol), followed by recrystallization from isopropanol, 1.05g of pure E-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone was obtained as pale yellow crystals, having the following characteristics:
melting point (Kofler) ═ 129 ℃.
-elemental analysis: % C ═ 72.10; 5.28% H; % N4.06.
Example 17: e-2-methyl-3- (1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone
Figure A0282686000802
Step 1: 5g of 5-indolylaldehyde are dissolved in 90mL of DMF and 18mL of DMSO in a 250mL three-necked flask under argon, and the mixture is then cooled to 0 ℃. Thereafter, 2.06g of 60% sodium hydride in oil were added in portions, and then stirring was continued while the mixture was allowed to return to room temperature until gas evolution ceased. Then 8.6g of (2-trimethylsilylethyl) oxymethyl chloride were added dropwise, after which the mixture was stirred at room temperature for 20 hours. Then will beThe reaction medium is poured into a mixture of 300mL of water and 100g of crushed ice and then extracted three times with 150mL of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The obtained brown colorThe oil was purified by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of cyclohexane and ethyl acetate (70/30 (vol)) to give 9g of 1- (2-trimethylsilylethyl) oxymethylindole-5-carbaldehyde as an orange oil, which was used in the next step without further modification.
Step 2: the process is carried out as in step 1 of example 1, but starting from 2.1g of 1- (3-methoxy-4, 5-methylenedioxyphenyl) acetone (which can be prepared according to J.org.chem.1981, 46(14), 2969-71) and 2.76g of 1- (2-trimethylsilylethyl) oxymethylindole-5-carbaldehyde in 100mL of ethanol with 2mL of piperidine and 1mL of acetic acid, under reflux for 96 hours. Purification by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of cyclohexane and ethyl acetate (70/30 vol), followed by crystallization from diisopropyl ether, gave 2g of pure E-2-methyl-3- [1- (2-trimethylsilylethyl) oxymethyl-1-H-indol-5-yl]-1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone, as white crystals, having the following characteristics:
melting point (Kofler) ═ 90 ℃.
Step 3: 2g E-2-methyl-3- [1- (2-trimethylsilylethyl) oxymethyl-1-H-indol-5-yl]-1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone was dissolved in 42mL of THF, after which 4.3mL of a 1M solution of tetra-N-butylammonium fluoride in THF was added and the mixture was refluxed for 20 hours. After concentration under reduced pressure, the reaction medium is dissolved in 75mL of ethyl acetate and 75mL of water. After settling the phases the organic phase is separated, washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The resulting red oil was purified by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of cyclohexane and ethyl acetate (70/30 vol), followed by recrystallization from isopropanol to give 420mg of pure E-2-methyl-3- (1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone as an off-white solid having the following characteristics:
melting point (Kofler) 140 ℃.
Example 18: e-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl]-1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone
Figure A0282686000821
336mg of E-2-methyl-3- (1-H-indol-5-yl) -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone obtained in example 17 were dissolved in 10.5mL of pyridine in a 250mL three-necked flask under an argon atmosphere, then the solution was cooled to 0 ℃ and 90mg of 60% sodium hydride in oil were added. After stirring at room temperature for 1 hour, the mixture was cooled to 0 ℃ and 144mg of (2-chloroethyl) dimethylamine hydrochloride were added dropwise. The mixture was then held at 60 ℃ for 5 hours. After concentration under reduced pressure, the reaction medium is dissolved in 50mL of ethyl acetate, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification of the resulting yellowish-brown foam by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of methanol and dichloromethane (2/98 vol), followed by crystallization from diisopropyl ether, 400mg of pure E-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl ] -1- (3-methoxy-4, 5-methylenedioxyphenyl) propenone are obtained as beige solid which is characterized as follows:
melting point (Kofler) ═ 118 ℃.
Example 19: e-2-methyl-3- (1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone
Step 1: the process is carried out as in step 1 of example 1, but starting from 2.24g of 1- (3, 4, 5-trimethoxyphenyl) acetone and 2.76g of 1-tert-butyloxycarbonyl-indole-5-carbaldehyde (which can be prepared according to J.org.chem.2002, 67(17), 6256-59) in 100mL of ethanol containing 2mL of piperidine and 1mL of acetic acid, under reflux for 48 hours. After purification by flash chromatography on silica gel (70-230 mesh) eluted with a mixture (70/30 vol.) of cyclohexane and ethyl acetate, 2.2g of pure E-2-methyl-3- [1- (1-tert-butyloxycarbonyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone as a pale yellow oil, which isThe oil was used in the following step without further modification.
Step 2: 0.7g E-2-methyl-3- [1- (1-tert-butyloxycarbonyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone was dissolved in 15mL THF. Then, 1.5mL of methanol and 0.25g of sodium methoxide were sequentially added, and the mixture was stirred at room temperature for 18 hours. After concentration under reduced pressure, the reaction medium is dissolved in 75mL of ethyl acetate and 35mL of water. After settling the phases the organic phase is separated, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of dichloromethane and diisopropyl ether (50/50 vol)) gave 505mg of pure E-2-methyl-3- (1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone as an orange oil, which was characterized as follows:
-mass spectrum (EI): and m/z is 351.
-elemental analysis: % C71.26; % H6.54; % N is 3.72.
Example 20: e-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl]-1- (3, 4, 5-trimethoxyphenyl) propenone hydrochloride
Figure A0282686000831
The process is carried out as in example 18, but starting from 350mg of 2-methyl-3- (1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone obtained in example 19, 90mg of 60% sodium hydride in oil and 143mg of (2-chloroethyl) dimethylamine hydrochloride in 10mL of pyridine. After purification by flash chromatography on silica gel (70-230 mesh) eluting with a mixture of ethanol and dichloromethane (5/95 vol), 150mg of pure E-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl ] -1- (3, 4, 5-trimethoxyphenyl) propenone was obtained as a yellow oil. The oil was redissolved in 2.5mL of diethyl ether, after which 0.4mL of a 1M solution of hydrochloric acid in diethyl ether was added and the mixture was crystallized for 20 hours. After filtration, washing with ether and drying under reduced pressure in the presence of phosphorus pentoxide yield 120mg of E-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl ] -1- (3, 4, 5-trimethoxyphenyl) propenone hydrochloride as beige crystals with the following characteristics:
melting point (Kofler) ═ 127 ℃.
-elemental analysis: % C ═ 65.17; % H ═ 7.09; 5.68% N; % Cl 7.88.
Example 21: e-2-methyl-3- (1-hydroxymethyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone
Figure A0282686000841
To a solution of 176mg of E-2-methyl-3- (1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) -propenone obtained in example 19 in 3mL of ethanol were added 2.5mL of 37% aqueous formaldehyde solution and 0.55mL of 1N aqueous sodium hydroxide solution in this order. After stirring at room temperature for 20 hours, 25mL of water was added to the resulting suspension, and the mixture was extracted 3 times with 15mL of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by recrystallization from ethyl acetate, 35mg of pure E-2-methyl-3- (1-hydroxymethyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone are obtained as beige crystals, which have the following characteristics:
melting point (Kofler) 185 ℃.
-elemental analysis: % C69.13; % H6.14; % N is 3.36.
Biological test results
Practice of Example sequence Number (C) Tubulin: for polymerization Inhibit IC50 (μM) Inhibition of cell proliferation System IC50(μM) The following concentrations are used in the examples Compound-induced HDMEC finesse Percentage of cell shedding C51 Colon In vivo tumor Necrosis (necrosis)
HDMEC Hela 1μM 0.3μM 0.1μM
1 0.3 0.0025- 0.0032 0.0036- 0.0043 37-42 18-38 21-36 In the 5 th stage, the first stage, 24.5mg/kg
2 2.5 0.0019- 0.0040 0.039- 0.104 31-49 17-32 16-21 in the 5 th stage, the first stage, 50mg/kg
3 0.5 ＜0.019 ＜0.019 34 37 31 nd
4 0.6 nd nd nd nd nd nd
5 0.7 0.03 0.005- 0.01 32 nd nd in the 5 th stage, the first stage, 25mg/kg
6 0.8 0.017- 0.02 nd 28 nd nd in the 5 th stage, the first stage, 50mg/kg
7 2.0 0.3- 0.5 nd nd nd nd nd
8 0.8 nd nd nd nd nd nd
9 3.5 nd nd nd nd nd nd
10 np 0.207- 0.225 nd 36 nd nd in the 5 th stage, the first stage, 25mg/kg
11 np 0.4 nd nd nd nd nd
12 nr 0.32 nd nd nd nd nd
13 10(np) 0.03 0.1 31 nd nd in the 5 th stage, the first stage, 12.5mg/kg
14 25(np) 0.01 nd 36 nd nd in the 5 th stage, the first stage, 25mg/kg
15 9(np) 0.03- 0.06 nd nd nd nd nd
16 0.5 nd nd nd nd nd nd
17 0.8 nd nd nd nd nd nd
18 2.0 nd nd nd nd nd nd
19 0.8 nd nd nd nd nd nd
20 2.0 nd nd nd nd nd nd
21 0.5 nd nd nd nd nd nd
nd: not testing
np: is not related

Claims (23)

1. A product corresponding to the following formula (I):
Figure A028268600002C1
wherein:
a) y is selected from halogen and C1-C7Straight chain alkyl, C1-C7Branched alkyl, substituted C1-C7Straight chain alkyl, substituted C1-C7Branched alkyl, cycloalkyl, substituted cycloalkyl, NH2、NH(R4)、N(R4)2Aralkyl, substituted aralkyl, COOH, COO (R4), CONH2、CONH(R4)、CON(R4)2CN, wherein R4 represents optionally substituted C1-C7Alkyl or cycloalkyl, and when two groups R4 are present, they may be linked together to form a ring;
b) ar2 is selected from:
Figure A028268600002C2
wherein:
1) when Ar2 isWhen, then one of the radicals R1 and R2 is chosen from NH2、NH2HZ, NHC (O) -amino acid, NH- (GP), N ═ N (GP), wherein the amino acid is preferably serine, wherein GP is a metabolisable substituent that allows a change in the functional group:
NH-(GP)→NH2or N ═ N (GP) → NH2
And wherein HZ is an organic or inorganic acid; and is
The other group R1 or R2 is selected fromCH3、C2H5、OCH3、OC2H5、SCH3、NH(R5)、N(R5)2N (R5) (GP), N (R5) C (O) -amino acid, wherein R5 represents C1-C2Alkyl, and when two groups R5 are present, they may be linked together to form a ring;
2) when Ar2 is
Figure A028268600002C4
When A is a 5-or 6-membered heterocyclic ring fused to a phenyl ring B, said heterocyclic ring A being aromatic or non-aromatic, containing 1 or 2 heteroatoms, at least one of which is a nitrogen atom directly attached to B and having a side chain R8, wherein R8 is selected from H, (C)1-C3)Alkyl, (C)1-C3) alkyl-OH, (C)1-C3) alkyl-O (C)1-C3) Alkyl, (C)1-C3) alkyl-NH2、(C1-C3) alkyl-NH (R7), (C)1-C3) alkyl-N (R7)2、
Wherein R9 is selected from H, (C)1-C3) Alkyl, wherein each R7 independently represents (C)1-C3) Alkyl radical
Or (C)3-C7) Cycloalkyl groups or, alternatively, when two groups R7 are present, they are linked
Taken together to form a 5-membered heterocyclic ring;
c) x is selected from O, NOH, NO (R3), wherein R3 is selected from H, C1-C7Straight chain alkyl, C1-C7Branched alkyl, cycloalkyl, C1-C7Straight-chain haloalkyl, C1-C7Branched haloalkyl, substituted cycloalkyl, halocycloalkyl, aralkyl, substituted aralkyl; and is
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.
2. The product as claimed in claim 1, characterized in that X is oxygen.
3. A product as claimed in claim 1 or 2, characterized in that Ar is 3, 4, 5-trimethoxyphenyl or 3-methoxy-4, 5-methylenedioxy.
4. A product as claimed in claim 1, 2 or 3, characterized in that Y is selected from Cl, Br, CH3And CH2CH3。
5. A product as claimed in any one of claims 1 to 4, characterised in that Ar2 is:
Figure A028268600003C2
6. a product as claimed in claim 5, characterized in that R1 and R2 are selected from the following combinations of radicals (R1, R2), respectively: (NH)2，OCH3)、(NH2，OC2H5)、(NH2，N(R5)2)、(N(R5)2，OCH3)、(N(R5)2，OC2H5)、(N(R5)2，NH2)、(OCH3，NH2)、(OC2H5，NH2)。
7. A product as claimed in any one of claims 1 to 4, characterised in that Ar2 is:
Figure A028268600004C1
8. the product as claimed in claim 7, characterized in that Ar2 is selected from:
9. the product as claimed in claim 8, characterized in that R8 is selected from the group consisting of methyl, hydroxymethyl and 2-dimethylaminoethyl.
10. The product as claimed in claim 1, which is selected from:
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- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone;
e-2-methyl-3- (1-methyl-2, 3-dihydro-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone;
e-2-methyl-3- (1-methyl-1-H-indol-5-yl) -1- (3, 4, 5-trimethoxyphenyl) propenone oxime;
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;
e-2-methyl-3- [1- (2-dimethylaminoethyl) -1-H-indol-5-yl ] -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- ω -nitro-L-argininamido ] -4-methoxyphenyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propenone;
glycine { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride;
(S) -2-amino-3-hydroxypropionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride;
1-methylpyrrolidine-2-carboxylic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride.
11. Product as claimed in any one of claims 1 to 5, characterized in that one of the radicals R1 and R2 is an NHC (O) -amino acid and in that the amino acid is selected from natural amino acids and unnatural amino acids.
12. Product as claimed in claim 11, characterized in that the amino acid is selected from glycine, lysine, N-methylproline, serine and N- ω -nitroarginine and is enantiomerically pure or in racemic form or enriched in one enantiomer.
13. The product as claimed in any of claims 1 to 9, characterized in that it is in free or salified form.
14. The product as claimed in claim 13, characterized in that it is in salified form.
15. The product as claimed in claim 14, characterized in that the salified form is the hydrochloride.
16. The product as claimed in claim 12, characterized in that it is (S) -2-amino-3-hydroxy-propionic acid { 2-methoxy-5- [ 2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) propenyl ] phenyl } amide hydrochloride.
17. A pharmaceutical composition comprising a product as claimed in any one of the preceding claims together with a pharmaceutically acceptable excipient.
18. A pharmaceutical composition as claimed in claim 17, characterized in that it comprises a product as claimed in claim 15.
19. Use of a product as claimed in any one of claims 1 to 15 as an inhibitor of tubulin polymerization.
20. Use of a product as claimed in any of claims 1 to 16 for promoting the shedding of endothelial cells forming the vessel wall of blood vessels supplying a tumor.
21. Use of a product as claimed in any one of claims 1 to 16 for promoting tumor necrosis.
22. Use of a product as claimed in any one of claims 1 to 16 in the manufacture of a pharmaceutical product useful in the treatment of a pathological condition.
23. The use as claimed in claim 22, wherein the pathological condition is cancer.
CNA028268601A 2001-12-05 2002-12-03 1,3-diarylprop-2-en-1-ones, compositions containing same and use thereof Pending CN1612856A (en)

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EP1598353A1 (en) * 2004-05-17 2005-11-23 Boehringer Ingelheim International GmbH Pyrrolobenzimidazolones and their use as antiproliferative agents
WO2017103637A1 (en) 2015-12-18 2017-06-22 Blirt S.A. Diphenylpropane compounds and their cytotoxic activity

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