Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-18
2004-06-22
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S465000, C546S278100
Reexamination Certificate
active
06753342
ABSTRACT:
The present invention relates to 2-(1H-indol-3-yl)-2-oxo-acetamides having antitumor activity, particularly against solid tumors, more precisely colon and lung tumors.
Colo-rectal carcinoma is one of the most common tumors in Western countries as it accounts for about 421,000 new cases each year in the world, and it is the most frequent cause of death, except lung and breast cancers.
Surgical cure is possible in about 40-50% of patients, the remaining patients can be treated with combined chemotherapy, to obtain complete remission in a percentage not higher than 5%.
Colo-rectal tumors are usually refractory or poorly sensitive to the presently available chemotherapy, and the only agent who has some efficacy for this type of cancer is 5-fluorouracil.
No therapeutical alternatives are at present available in case of failure of the combination chemotherapy based on 5-FU. There is therefore strong need for novel medicaments active against this type of tumors.
WO 99712917 in the name of Roche Diagnostics discloses 4-ureido and thioureido 2(5H)-furanone or 2(5H)-thiophenone derivatives with antitumor activity, particularly against colon tumors.
WO 98/09946 in the name of Asta Medica discloses indol-3-glyoxylamide derivatives. The compounds are substituted at the amido nitrogen with aromatic and pyridyl residues and are reported to have antiasthmatic, antiallergic, immunosuppressive and immunomodulating activities.
In
Proceedings of the American Association for Cancer Research
, volume 40, abstract 1893 and 4110, 1999, the compound N-(4-pyridyl)-2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-glyoxylamide (D-24,851) is described to have in vitro and in vivo antitumor effects.
It has now been found that N-(5-oxo-2,5-dihydrofuran-3-yl) or N-(5-oxo-2,5-dihydrothiophen-3-yl)-2-(1H-indol-3-yl)-2-oxo-acetamido derivatives have marked antitumor activity, particularly against human solid tumors.
The compounds of the invention can be represented by the general formula (I):
wherein:
R1, R2 and R5 are independently hydrogen or a C1-C6 alkyl group;
R3 is hydrogen, C1-C4 alkyl, aralkyl, optionally substituted phenyl;
R4 is hydrogen, straight or branched C1-C8 alkyl, C5-C6 cycloalkyl; aralkyl; heteroaralkyl;
X is one or more groups, at most four, independently selected from hydrogen; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C1-C6-aminoalkyl; C1-C6-alkoxy-C1-C6-alkyl; C1-C18-acyloxy-C1-C6-alkyl; hydroxy; C1-C4 alkoxy; C1-C3 haloalkoxy; phenoxy; aralkoxy; C1-C3 acyloxy; amino; C1-C3 alkylamino; C1-C3-acylamino; C1-C3-alkylsulfonylamino; aroylamino; halogen; nitro; cyano; trifluoromethyl; carboxy; C1-C6 alkoxycarbonyl; a RaRbN(CH
2
)
n
C(═O)— group wherein Ra and Rb are independently hydrogen, C1-C3-alkyl or Ra and Ro together with the nitrogen atom they are linked to form a pyrrolidino, piperidino, piperazino or morpholino ring and n=0 or an integer from 1 to 4; a RaRcN(CH
2
)
n
C(═O)— group wherein Ra and n are as above defined and Rc is a C1-C4-alkoxycarbonyl group; a R1C(═O)— group wherein R1 is as above defined; sulfonyl; mercapto; C1-C4-alkylthio; C1-C4-alkylsulfinyl; C1-C4-alkylsulfonyl; aminosulfonyl; C1-C3-alkylamiosulfonyl; a group —P(═O)(OR1)(OR2) being R1 and R2 as above defined; a group (E)— or (Z)—C(R1)═C(R2)—C(═O)R6 wherein R6 is hydroxy, C1-C6-alkoxy, NRaRb or a group of formula RaRbN(CH
2
)
m
NR1—, being m an integer from 2 to 4 and R1, R2, Ra, and Rb as above defined;
Y is an oxygen or sulfur atom, and the isomers, enantiomers and mixtures thereof.
The invention also relates to the salts of compounds of formula (I) obtainable by reacting non toxic acids or bases with the ionisable groups present in compounds (I).
Optionally substituted phenyl preferably means phenyl, 4-methylphenyl, 2,4-dimethoxy-phenyl, 4-methoxy-phenyl, 4-nitro-phenyl, 3-chlorophenyl, 4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxy-phenyl, 3-cyano-phenyl, 2-hydroxyphenyl, 2-carboxyphenyl.
Aralkyl preferably means benzyl, phenethyl, naphthylmethyl, biphenylmethyl, optionally substituted with one or more chloro, fluoro, trifluoromethyl, nitro, cyano, methylsulfonyl, tert-butyl groups.
Heteroaralkyl preferably means pyridylmethyl.
R1 and R2 and R3 and R5 are preferably hydrogen and methyl.
R4 is preferably hydrogen; methyl; benzyl substituted on the benzene ring with one or more groups selected from methyl, t-butyl, fluorine, chlorine, bromine, hydroxy, acetoxy, methoxy, trifluoromethoxy, benzyloxy, trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino, methylmercapto, methylsulfinyl, methylsulfonyl, phenyl, ethoxycarbonyl, carboxy, carboxymethyl, (ethoxycarbonyl)methyl, (tert-butoxycarbonyl)methyl, (benzyloxycarbonyl)methyl, (dimethylcarbamoyl)methyl; &agr;-naphthyl, &bgr;-naphthyl; 4-pyridyl; 4-pyridyl-N oxide.
X is preferably methyl, ethyl, fluorine, chlorine, bromine, hydroxy, acetoxy, methoxy, phenoxy, trifluoromethoxy, trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino, methylmercapto, methylsulfinyl, methylsulfonyl, carboxy, methoxycarbonyl, tert-butoxycarbonyl, diethylcarbamoyl, (2-aminoethyl)carbamoyl, (2-dimethylaminoethyl)carbamoyl, (E)- and (Z)-2-carboxyethen-1-yl, (E)- and (Z)-(2-tert-butoxycarbonyl)ethen-1-yl, (E)- and (Z)—(ethoxycarbonyl)ethenyl, hydroxymethyl, and allyloxymethyl.
Y is preferably an oxygen atom.
The compounds of the invention can be prepared by reacting compounds of formula (II)
wherein R3, and R4 and X are as defined above,
with a compound of formula (HI)
wherein Y, R1 and R2 are as defined above.
The reaction is carried out in a solvent such as ethyl ether, isopropyl ether, methyl-tert-butyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, toluene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, at a temperature ranging from 0° C. to the reflux temperature of the solvent, and using 1 to 3 molar equivalents of compounds of formula (III). Optionally, the reaction can be performed in the presence of the carbonate of an alkaline- or alkaline-earth metal.
The reaction is preferably carried out in an ether solvent such as ethyl ether, THF, or 1,2-dimethoxyethane, at a temperature ranging from room temperature to 80° C., in the presence of at least one equivalent of potassium carbonate.
The resulting compounds of formula (I) can subsequently be transformed into other compounds of formula (I) according to the procedures conventionally used for the transformation of functional groups, for example reactions such as hydrolysis of ester groups, esterification of carboxylic acids, amidation, and the like. For example, when in compounds of formula (II) X and R4 contain substituents which interfere with the reaction of compounds of formula (II) with compounds of formula (III), suitable protective groups will be used and subsequently removed according to conventional methods.
The compounds of formula I in which R5 is a C1-C6 alkyl group are obtained by alkylation of the compounds of formula I in which R5 is hydrogen with a R5-Hal derivative, wherein Hal is preferably chlorine, bromine or iodine, in the presence of the hydride of an alkali- or alkaline-earth metal.
Compounds of formula (II) are obtained by reacting compounds of formula (IV)
wherein X, R3 and R4 are as defined above, with oxalyl chloride.
The reaction is usually carried out in a solvent such as ethyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dichloromethane, at a temperature ranging from −10° C. to 25° C. and using from one to two molar equivalents of oxalyl chloride, preferably at 0° C. to 25° C. in ethyl ether or in tetrahydrofuran and using a slight excess (1.2 molar equivalents) of oxalyl chloride. The reaction is usually completed in 3 hours.
Compounds of formula (IV) are obtained by reacting indoles of formula (V)
with halides of formula R4-Hal (VI), wherein Hal is preferably chlorine, bromine or iodine, in the presence of acid-binding agents.
The reaction is usually carried out using an equimolar amount or a slight excess of the halide (VI), in a protic, dipolar aproti
Menta Ernesto
Pescalli Nicoletta
McKane Joseph K.
Novuspharma S.p.A.
Rothwell Figg Ernst & Manbeck
Shameem Golam M M
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