Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-22
2001-05-08
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S455000
Reexamination Certificate
active
06228877
ABSTRACT:
BRIEF SUMMARY OF THE INVENTION
The invention relates to substituted pyrroles. More particularly, the invention relates to substituted pyrroles of the formula
wherein
R
1
and R
1′
are independently alkyl, aryl, alkenyl or alkynyl;
R
2
and R
2′
are independently hydrogen or alkyl;
R
4
, R
5
, R
6
, R
7
, R
4′
, R
5′
, R
6′
, and R
7′
each independently are hydrogen,
CO
2
R
9
, CH
2
OR
10
, CHO, CH
2
NR
11
R
12
, CON(R
13
)
2
, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amnino, aralkyloxy, acylamnino, monoalkylarnino, dialkylamino, thio, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, azide, phosphate or phosphonate provided that at least one of R
4
, R
5
, R
6
and R
7
and at least one of R
4′
, R
5′
, R
6′
, and R
7′
are other than hydrogen;
R
8
is alkyl or aryl;
R
9
is alkyl or aryl;
R
10
is hydrogen, alkyl or aryl;
R
11
and R
12
are independently hydrogen, alkyl, aryl, aralkyl or acyl;
R
13
is hydrogen, alkyl, aryl or aralkyl; and
one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); with the proviso that when R
6
is methoxy, R
5
or R
5′
can not be methoxy, as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts of acidic compounds of formula I with bases and or basic compounds of formula I with acids.
The compounds of the invention are anti-proliferative agents useful in the treatment or control of cancer, particularly in the treatment or control of solid tumors. The compounds of the invention are especially useful in the treatment or control of breast tumors.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to substituted pyrroles. More particularly, the invention relates to substituted pyrroles of the formula
wherein
R
1
and R
1′
are independently alkyl, aryl, alkenyl or alkynyl;
R
2
and R
2′
are independently hydrogen or alkyl;
R
4
, R
5
, R
6
, R
7
, R
4′
, R
5′
, R
6′
, and R
7′
each independently are hydrogen,
CO
2
R
9
, CH
2
OR
10
, CHO, CH
2
NR
11
R
12
, CON(R
13
)
2
, halogen, cyano, aryl, aralkyloxy, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, azide, phosphate or phosphonate provided that at least one Of R
4
, R
5
, R
6
and R
7
and at least one of R
4′
, R
5′
, R
6′
, and R
7′
are other than hydrogen;
R
8
is alkyl or aryl;
R
9
is alkyl or aryl;
R
10
is hydrogen, alkyl or aryl;
R
11
and R
12
are independently hydrogen, alkyl, aryl, aralkyl or acyl;
R
13
is hydrogen, alkyl, aryl or aralkyl; and
one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); with the proviso that when R
6
is methoxy, R
5
or R
5
′ are not methoxy, as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts of acidic compounds of formula I with bases and or basic compounds of formula I with acids.
As used herein, the term “alkyl”, alone or in combinations, means a straight or branched-chain alkyl group containing a maximum of 10, preferably a maximum of 5, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and pentyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, halogen, thioalkyl or alkylsulphinyl. The term “alkoxy” denotes a group wherein the alkyl residue is as defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like. A haloalkyl group can carry one or more halogen atoms, with examples of such groups being chloromethyl and trifluoromethyl. The term “acyl”, alone or in combination, means a group derived from an alkanoic acid containing a maximum of 10, preferably a maximum of 5, carbon atoms for example, acetyl, propionyl or butyryl, or from an aromatic carboxylic acid for example, benzoyl. Examples of substituents on alkanoic acid include one or more of the following: hydroxy, alkoxy, amino, halogen, thioalkyl, carboxy, carboxylic acid derivative or alkyl sulphinyl and the like. Examples of substituents on aromatic carboxylic acid include one or more of the following: halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, amino, cyano and the like. The term “aryl”, alone or in combinations means an unsubstituted phenyl group or a phenyl group carrying one or more, preferably one to three, substituents, examples of which are halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, amino and cyano. The term “halogen” means fluorine, chlorine, bromine or iodine. The term “amino”, alone or in combination means an unsubstituted amine group or an amine substituted by one or more substituents selected from alkyl, aryl, acyl, alkylsulfonyl or arylsulfonyl . The term “alkenyl” refers to straight or branched chain hydrocarbon groups of 2 to 5 carbon atoms having at least one double bond. Groups of 3 to 5 carbon atoms are preferred. The term “alkynyl” refers to straight or branched chain groups of 2 to 5 carbon atoms having at least one triple bond. Groups of 3 to 5 carbon atoms are preferred.
The term “amino protecting group” means any conventional amino protecting group such as alkyl, preferably methyl, substituted alkyl, such as trityl and trialkylsilylethyl, acyl and the like.
As used herein, the term “pharmaceutically acceptable prodrug” means a compound that may be converted under physiological conditions or by solvolysis to a compound of formula I or to a pharmaceutically acceptable salt thereof.
In formula I above, R
1
and R
1′
are preferably alkyl. In an especially preferred embodiment, R
1
and R
1′
are methyl. Preferably, R
2
and R
2′
are hydrogen.
At least one of R
4
, R
5
, R
6
and R
7
and at least one of R
4′
, R
5′
, R
6′
and R
7′
are preferably nitro, alkoxy, alkyl, halogen, cyano,
CO
2
R
9
, CH
2
OR
10
, CH
2
NR
11
R
12
, CHO, CON(R
13
)
2
, alkylthio or aralkyloxy.
In a preferred embodiment, at least one of R
4
, R
5
, R
6
, R
7
and one of R
4′
, R
5′
R
6′
and R
7′
are cyano,
CO
2
R
9
, CH
2
OR
10
, CH
2
NR
11
R
12
, CHO, or CON(R
13
)
2
.
In a particularly preferred embodiment, one of R
4
, R
5
, R
6
, R
7
and one of R
4′
, R
5′
R
6′
and R
7′
are nitro, alkoxy, alkyl, halogen, cyano,
CO
2
R
9
, CH
2
OR
10
, CH
2
NR
11
R
12
, CHO, CON(R
13
)
2
, alkylthio, or aralkyloxy and the others are hydrogen.
In an especially preferred embodiment, R
6
and R
6′
are independently nitro, alkoxy, alkyl, halogen, cyano,
CO
2
R
9
, CH2OR
10
, CH
2
NR
11
R
12
, alkylthio, aralkyloxy, CHO or CON(R
13
)
2
, and R
4
, R
5
, R
7
and R
4′
, R
5′
and R
7′
are hydrogen.
Preferably R
8
and R
9
are independently alkyl, particularly preferred is methyl, R
10
is hydrogen or alkyl, preferably methyl, R
11
and R
12
are hydrogen or alkyl and R
13
is hydrogen or alkyl.
Preferred compounds of formula I are those in which R
1
and R
1′
are alkyl; R
2
and R
2′
are hydrogen, at least one R
4
, R
5
, R
6
and R
7
and at least one of R
4′
, R
5′
R
6′
and R
7′
are nitro, alkoxy, alkyl, halogen, cyano,
CO
2
R
9
, CH
2
OR
10
, CH
2
NR
11
R
12
, CHO, CON(R
13
)
2
, alkylthio, or aralkyloxy, R
8
and R
9
are alkyl; R
10
is alkyl; R
11
and R
12
are alkyl; and R
13
is alkyl.
In a particularly preferred embodiment, R
1
and R
1′
are methyl; R
2
and R
2′
are hydrogen, one of R
4
, R
5
, R
6
, R
7
and one of R
4′
, R
5′
R
6′
and R
7′
is nitro, alkoxy, alkyl, halogen, cyano,
CO
2
R
9
, CH
2
OR
10
, alkylthio, aralkyloxy, CH
2
NR
11
R
2
, CHO or CON(R
13
)
2
and the others are hydrogen; R
8
and R
9
are methyl; R
10
is methyl; R
11
and R
12
are methyl; and R
13
is methyl.
In another preferred embodiment, R
1
and R
1′
are alkyl; R
2
and R
2′
are hydrogen, at least one of R
4
, R
5
, R
6
Dhingra Urvashi Hooda
Huryn Donna Mary
Keith Dennis Dalton
Hoffmann-La Roche Inc.
Johnston George W.
Morris Patricia L.
Rocha-Tramaloni Patricia S.
Silverman Robert A.
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