Substituted phenanthridinones and methods of use thereof

Details Substituted phenanthridinones and methods of use thereof Substituted phenanthridinones and methods of use thereof

1999-12-07

2001-08-21

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S112000, C546S139000, C546S152000, C514S187000, C514S277000

Reexamination Certificate

active

06277990

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to substituted phenanthridinones.
BACKGROUND OF THE INVENTION
Inflammation disorders, such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct form those associated with reperfusion injury, e.g., stroke and heart attack, and can clinically manifest themselves as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammation and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis. Induction of pro-inflammatory cytokines can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO
−
) (Szabó et al., Shock 6:79-88, 1996).
The peroxynitrite-induced cell necrosis observed in inflammation and reperfusion injury involves, in significant part, the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabó et al., Trends Pharmacol. Sci. 19: 287-98, 1998).
SUMMARY OF THE INVENTION
The invention is based in part on the discovery of novel substituted 6(5H)phenanthridinone derivatives and their unexpected effects in inhibiting inflammation and in treating reperfusion injuries.
Accordingly, in one aspect the invention provides novel substituted 6(5H)phenanthridinone derivatives falling within formula I, as set forth in the Detailed Description of the Invention, below.
Also provided is a method of treating inflammatory and reperfusion conditions in mammals by administering to a mammal in need of such treatment an effective amount of a compound according to formula I.
In a further aspect, the invention also includes a method for the production of compounds of formula I.
The substituted 6(5H)phenanthridinone compounds of the invention are potent, pharmaceutical compounds that can be used to treat a variety of conditions and diseases, typically those known to involve inflammatory mediator production and cell death.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials arc now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patcnts and publications cited in this specification are incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel class of 2-substituted 6(5H)phenanthridinone compounds falling within the formula I, as set forth below:
where
X is C═O, C═S, SO
2
, C═NH, C═NR
6
; C—Cl
Q is NHCO, O, CO, OCO
2
, OCO, OCONH, NR
2
, NHCO
2
, S, SO
2
, CS, SO;
R
1
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, are, independently, hydrogen or lower alkyl; halogen, nitro, amino, alkylamino, carboxy, ester
Y
1
and Y
2
are, independently: hydrogen, halo, alkylhalo, hydroxy, C
1
-C
10
straight or branched chain alkyl, C
2
-C
10
straight or branched chain alkenyl group, C
3
-C
8
carbocyclic, aryl, alkylamino, amino, carboxy, ester, arylalkyl, nitro;
n is 0 to 10; and
Z
1
and Z
2
are, independently: hydrogen, alkylhalo, aklylhydroxy, C
1
-C
10
straight or branched chain alkyl, C
2
-C
10
straight or branched chain alkenyl group, C
2
-C
10
straight or branched chain alkynyl group, aryl, benzyl, alkylamino, alkylcarboxy, alkylester, arylalkyl, or Z
1
or Z
2
taken together form a fused ring, wherein the ring has 4-8 ring members.
In addition to the compounds of Formula I, the invention also provides a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixture thereof. The invention also includes pharmaceutical formulations comprising a compound of Formula I in association with a pharmaceutically acceptable carrier, diluent, or excipient.
As used herein:
“Alkyl” refers to saturated or unsaturated branched or straight chain hydrocarbon radical. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
“Alkylhalo” refers an alkyl group containing a halogen substituent; “alkylhydroxy” refers to an alkyl group having a hydroxyl substituent; “alkylamino” refers to an alkyl group having an amino substituent; “alkylester” refers to an alkyl group having an ester functionality appended thereto; “alkylcarboxy” refers to an alkyl group having a carboxyl functionality appended thereto.
“Alkenyl” refers to unsaturated branched or straight chain hydrocarbon radical, having at least one carbon-carbon double bond.
“Alkynyl” refers to unsaturated branched or straight chain hydrocarbon radical having at least one carbon-carbon triple bond.
“Alkoxy” refers to the radical —O-alkyl. Typical alkoxy radicals are methoxy, ethoxy, propoxy, butoxy and pentoxy and the like.
“Cycloalkyl” refers to saturated monocyclic hydrocarbon radical containing 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
“Aryl” refers to unsaturated cyclic, hydrocarbon radical.
“Substituted phenyl” refers to all possible isomeric phenyl radicals such as mono or disubstituted with a substituent selected from the group consisting of alkyl, alkoxy, hydroxy, or halo.
“Halo” refers to chloro, fluoro, bromo or iodo.
The carrier must be “acceptable” in the sense of being compatible with the active ingredient of the formulation and not deleterious to the subject to be treated. Preferably, the carrier is also capable of stabilizing the compound or composition.
Whenever the term “alkyl” or its prefix root appears in a name of a substituent (e.g. aralkoxyaryloxy) it shall be interpreted as including those limitations given above for “alkyl”.
In some embodiments, X is C═O.
In some embodiments, one or more R
1
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, Y
1
, or Y
2
are hydrogen.
In some embodiments, Q is NHCO.
In some embodiments, n is 1.
In some embodiments, one or both of Z
1
and Z
2
are methyl groups (PJ-34).
In some embodiments, one or both of Z
1
and Z
2
are ethyl groups (PJ-44).
In some embodiments, Z
1
is a methyl group and Z
2
is a benzyl group (PJ-45).
In some embodiments, N, Z
1
and Z
2
taken together, form piperidine, piperazine, N-alkylated or alkylcarbonylated piperazine, pyrole, imidazole, indole, or other C
2
to C
10
branched or cyclic or cycloalkenyl amines.
In some embodiments, Z
1
, N, and Z
2
taken together form a fused ring having, six ring members.
In some embodiments, Z
1
and Z
2
taken together form —CH
2
—CH
2
—CH
2
—CH
2
—CH
2
— (PJ-36).
In some embodiments, at least one of the ring members is oxygen.
In some embodiments, Z
1
and Z
2
taken together form —CH
2
—CH
2
—O—CH
2
—CH
2
— (PJ-38).
In some embodiments, two of the ring members are nitrogen atoms.
In some embodiments, Z
1
and Z
2
taken together form —CH
2
—CH
2
—N(CH
3
)—CH
2
—CH
2
— (PJ-46).
In particularly preferred embodiments, the compounds have the structures represented by PJ 34, 36, 38, 44 and 46.
Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid to produce “pharmaceutically-acceptable acid addition salts” of the compounds described herein. These compounds retain the biological effectiveness and properties of the free bases. Representative of such

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