Substituted pyrroles

Details Substituted pyrroles Substituted pyrroles

2000-11-07

2001-11-06

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S414000, C548S414000, C548S455000, C548S111000, C546S201000

Reexamination Certificate

active

06313143

ABSTRACT:

BRIEF SUMMARY OF THE INVENTION
The present invention is directed to certain substituted pyrroles that are antiproliferative agents. These compounds and their pharmaceutically acceptable salts are useful in the treatment or control of cell proliferative disorders, in particular cancer. The invention is also directed to pharmaceutical compositions containing such compounds, and to methods for the treatment and/or prevention of cancer, particularly the treatment or control of solid tumors.
BACKGROUND OF THE INVENTION
Uncontrolled cell proliferation is the hallmark of cancer. Cancerous tumor cells typically have some form of damage to the genes that directly or indirectly regulate the cell-division cycle. Much research has been expended in the study of antiproliferative agents. While many agents have been identified having desired antiproliferative activities, many of these agents have various drawbacks, including poor solubility, molecular complexity, etc., which may render them either unsuitable or inconvenient for therapeutic use in human patients. There continues to be a need for small molecule compounds that may be readily synthesized, are effective as cancer therapeutic agents and are suitable for continuous infusion delivery to patients. It is thus an object of this invention to provide such compounds as well as pharmaceutical compositions containing such compounds.
Definitions
As used herein, the following terms shall have the following definitions.
“Alkenyl” means a straight-chain or branched aliphatic unsaturated hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, most preferably 1 to 6 carbon atoms.
“Alkoxy” means an alkyl or alkenyl group that is attached to the remainder of the molecule by oxygen (e.g. RO—, such as methoxy, ethoxy, etc.).
“Aryl” means an aromatic ring having 5 to 10 atoms and consisting of 1 or 2 rings, which optionally may include one or more heteroatoms that are the same or different. For the purposes of this definition, aryl includes heteroaryl. Preferred heteroatoms include nitrogen, sulfur, or oxygen, singly or in any combination, in place of one or more of the carbons. Examples of aryl groups within this definition are phenyl, pyridine, imidazole, pyrrole, triazole, furan, pyrimidine.
“Cycloalkyl” means a non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.
“Effective amount” means an amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.
“Hetero atom” means an atom selected from nitrogen, sulfur and oxygen. Hetero atoms are independently selected and may replace one or more carbon atoms.
“Heterocycle” means a 3- to 10- membered non-aromatic, partially or completely saturated hydrocarbon group that contains at least one hetero atom. Such ring systems include, morpholine, pyrrolidine, piperidine, piperazine
“IC
50
” refers to the concentration of a particular compound according to the invention required to inhibit 50% of a specific measured activity. IC
50
can be measured, inter alia, as is described in Example 15, infra.
“Lower alkyl” denotes a straight-chain or branched saturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Lower alkyl groups may be substituted as specifically provided infra. In addition the alkyl chain may include one or more hetero atoms in lieu of one or more carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like.
“Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid, and those derived from organic acids such as acetic acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
“Pharmaceutically active metabolite” means a metabolic product of a compound of formula I which is pharmaceutically acceptable and effective.
“Polyethylene glycol” or “PEG” groups represent structures of the general formula
−
R
9
(OCH
2
CH
2
)
n
OH, where n is on average between 2 and 1500, preferably 15 to 150, with an average molecular weight of 500 to 5000 Daltons, and wherein R
9
is carboxy or lower alkyl, preferably methyl or ethyl.
“Prodrug” refers to a compound that may be converted under physiological conditions or by solvolysis to a pharmaceutical active compound. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound.
“Substituted,” as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
“Substituted amino” means an amino group, which is mono- or di-substituted with another group, preferably lower alkyl (e.g. methyl, or ethyl).
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the invention relates to substituted pyrroles having the formula:
and pharmaceutically acceptable salts of the foregoing compounds, wherein:
R is selected from the group consisting of —PO
3
R
1
R
2
, —CHR
3
OCOR
4
, —CHR
3
OCO
2
R
4
, —CHR
3
OCONHR
4
and —COR
4
;
R
1
and R
2
are selected from the group consisting of H, Na and NH
4
, and are the same unless either R
1
or R
2
is H, in which case the other can be different, or alternatively, R
1
and R
2
together represent Ca;
R
3
is selected from the group consisting of H or methyl;
R
4
is selected from a group consisting of
lower alkyl, which may be optionally substituted by one or more substituents selected from the group consisting of —CO
2
R
5
, —NR
6
R
7
, polyethylene glycol, —OPO
3
R
1
R
2
, hydroxy, alkoxy, and aryl,
alkenyl, which may be optionally substituted by one or more substituents selected from the group consisting of —CO
2
R
5
, —NR
6
R
7
, polyethylene glycol, —OPO
3
R
1
R
2
, hydroxy, alkoxy, and aryl,
cycloalkyl, which may be optionally substituted by one or more substituents selected from the group consisting of —CO
2
R
5
, —NR
6
R
7
, polyethylene glycol, —OPO
3
R
1
R
2
, hydroxy, alkoxy, and aryl.
heterocycle, which when including N as a hetero atom the N optionally may be substituted with —COR
8
, and
aryl which optionally may be substituted by one or more substituents selected from the group consisting of —CO
2
R
5
, hydroxy, alkoxy, polyethylene glycol, —OPO
3
R
1
R
2
, and lower alkyl which itself may be substituted with hydroxy, carboxy, and substituted amino;
R
5
is selected from the group consisting of H, Na, or lower alkyl;
R
6
and R
7
are each independently selected from H, lower alkyl, and —COR
8
, or alternatively, the group —NR
6
F
7
forms a 5 or 6 membered heterocyclic ring; and
R
8
is lower alkyl, which optionally may be substituted with a polyethylene glycol.
The compounds of this invention have antiproliferative activity, specifically, they inhibit cell division in G2/M phase of the cell cycle and are generally referred to as “G2/M phase cell-cycle” inhibitors. These compounds are soluble prodrugs of an active metabolite of an anticancer therapeutic agent withi

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