Substituted pyrroles suitable for continuous infusion

Details Substituted pyrroles suitable for continuous infusion Substituted pyrroles suitable for continuous infusion

2000-10-03

2003-05-06

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...

C514S339000, C514S414000, C514S323000, C546S251000, C546S201000, C548S415000, C548S455000

Reexamination Certificate

active

06559164

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 having desired antiproliferative activities have been identified, 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.
“Alkyl” denotes a straight-chain or branched saturated aliphatic hydrocarbon having 1 to 15, preferably 1 to 10, carbon atoms. 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. “Lower alkyl” groups having from 1 to 6, preferably 1 to 4, carbon atoms are preferred. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like.
“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 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 26, infra.
“Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts which 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.
“Plasma conversion” with respect to compounds of formula I means the degradation (enzymatic and/or non-enzymatic) of such compound in human or rodent plasma at 37° C. from 30 minutes to 6 hours to give 3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione, a pharmaceutically active metabolite of compounds of formula I, as well as pharmaceutically active metabolites thereof. This conversion is typically given as the percent degradation over a specified time frame.
“Polyethylene glycol” or “PEG” groups represent structures of the general formula HO(CH
2
CH
2
O)
n
R
8
, 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
8
is carboxy or lower alkyl, preferably methyl or ethyl. PEG groups may be reacted with compounds according to this invention to yield pegylated compounds also within the scope of this invention.
“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.
“Stability” is an overall assessment of the ability of a compound of formula I to withstand degradation in a typical solution used for the administration of drugs intravenously. Specifically, it refers to the ability of any given compound of formula I to release 3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione, over a 72 hour period in a mixture of acetonitrile and saline or dextrose water. The
“stability” of a compound of formula I is “very good” if the less than 1% 3-(1-Methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione is detected, “good” if less than 2.5% 3-(1-Methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione is detected, and “fair” if less than 5% 3-(1-Methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione is detected after 72 hours incubation at room temperature.
“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 —CH
2
OPO
3
R
1
R
2
, —CH
2
OH, —CH
2
OCOR
3
, —CH
2
OCO
2
R
3
, —CH
2
OCONHR
3
, and —CONHR
3
;
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 calcium.
R
3
is selected from the group consisting of
alkyl which optionally may be substituted by one or more substituents selected from the group consist

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