Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1995-05-01
2003-08-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S169000, C552S610000
Reexamination Certificate
active
06610675
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to novel soft steroids having anti-inflammatory activity, pharmaceutical compositions containing said soft steroids, novel chemical intermediates useful in the preparation of the steroids, and methods of administering said steroids to mammals in the treatment of inflammation.
BACKGROUND ART
Successful predictions on a rational basis of the biological activity of compounds leading to new drugs are the main objective of drug designers. This has usually been achieved by considering a known bioactive molecule as the basis for structural modifications, either by the group or biofunctional moieties approach or by altering the overall physical-chemical properties of the molecule. Thus, the main aim has been to design, synthesize, and test new compounds structurally analogous to the basic bioactive molecule which have, however, improved therapeutic and/or pharmacokinetic properties. Although “vulnerable” moieties have been identified as the ones whose role is the bioinactivation or metabolic elimination of the drug after it has performed its role, little or no attention has been paid in the drug-design process to the rational design of the metabolic disposition of the drugs. This has been the case despite the fact that the toxicity of a number of bioactive molecular is due to their increased elimination half-life, stability, or other factors introduced during the design of increasing their activity. Drugs and particularly their metabolic processes contribute to the various toxic processes by formation of active metabolites. The phenomenon of metabolic activation to reactive intermediates which covalently bind to tissue macromolecules is the initial step in cell damage. It is also clear that the most toxic metabolites will not survive long enough to be excreted and identified; thus, studies of the stable metabolites may provide misleading information.
It is clear that, in order to prevent and/or reduce toxicity problems related to drugs, the metabolic disposition of the drugs should be considered at an early stage of the drug-design process. This is true particularly when one considers that the body can attack and alter chemically quite stable structures and that, even if a drug is 95% excreted unchanged, the unaccounted small portion can, and most likely will, cause toxicity.
“Soft drugs” can be defined as biologically active chemical compounds (drugs) which might structurally resemble known active drugs (soft analogues) or could be entirely new types of structures, but which are all characterized by a predictable in vivo destruction (metabolism) to nontoxic moieties, after they achieve their therapeutic role. The metabolic disposition of the soft drugs takes place with a controllable rate in a predictable manner.
The present inventor has found five major classes of soft drugs. One of the most useful classes was termed the “inactive metabolite” approach which can be advantageously employed to design especially valuable “soft drugs”. This approach starts with a known inactive metabolite of a drug or a drug class; followed by modifying the metabolite to resemble structurally (isosteric and/or isoelectronic) the active drug (i.e., activation); and designing the metabolism of the activated species to lead to the starting inactive metabolite after achieving the desired therapeutic role, without the formation of toxic intermediates (i.e., predictable metabolism). The “inactive metabolite” approach further allows controlling the rate of metabolism and pharmacokinetic properties by molecular manipulation in the activation stage. Also, if no useful inactive metabolite is known, one can be designed by the introduction of transporting groups in noncritical structural parts.
SUMMARY OF THE INVENTION
The present inventor has now applied his inactive metabolite approach to the case of the natural and synthetic glucocorticosteroids and has designed the soft steroidal anti-inflammatory agents of the present invention, beginning with the known inactive natural metabolites of the glucocorticosteroids. Thus, for example, in the case of hydrocortisone, one of its major, inactive metabolites, cortienic acid, i.e., 11&bgr;,17&agr;-dihydroxyandrost-4-en-3-one-17&bgr;-carboxylic acid, has been used as a starting point and activated by the introduction of suitable non-toxic 17&agr;- and 17&bgr;-substituents, which activated derivatives will cleave in vivo, after accomplishment of their therapeutic role, to the starting inactive metabolite and other nontoxic moieties.
In accord with the foregoing, the present invention provides novel soft steroids having anti-inflammatory activity, said steroids having the structural formula
wherein:
R
1
is C
1
-C
10
alkyl; C
2
-C
10
(monohydroxy or polyhydroxy)alkyl; C
1
-C
10
(monohalo or polyhalo)alkyl; or —CH
2
COOR
6
wherein R
6
is unsubstituted or substituted C
1
-C
10
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl or C
2
-C
10
alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,
or R
6
is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; or R
1
is —CH
2
CONR
7
R
8
wherein R
7
and R
8
, which can be the same or different, are each hydrogen, lower alkyl, C
3
-C
8
cycloalkyl, phenyl or benzyl, or R
7
and R
8
are combined such that —NR
7
R
8
represents the residue of a saturated monocyclic secondary amine; or R
1
is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove with respect to R
6
; or R
1
is
wherein Y is —S—, —SO—, —SO
2
—or —O— and R
9
is hydrogen, lower alkyl or phenyl, or R
9
and the lower alkyl group adjacent to Y are combined so that R
1
is a cyclic system of the type
wherein Y is defined as above and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms; or R
1
is
wherein R
6
is defined as hereinabove and R
10
is hydrogen, lower alkyl, phenyl or haloalkyl;
R
2
is unsubstituted or substituted C
1
-C
10
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl or C
2
-C
10
alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,
or R
2
is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl;
R
3
is hydrogen, &agr;-hydroxy, &bgr;-hydroxy, &agr;-methyl, &bgr;-methyl, ═CH
2
, or &agr;- or
wherein R
2
is identical to R
2
as defined hereinabove;
R
4
is hydrogen, fluoro or chloro;
R
5
is hydrogen, fluoro, chloro or methyl;
X is —O— or —S—;
Z is carbonyl or &bgr;-hydroxymethylene;
and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated.
A group of preferred compounds of formula (I) consists of those wherein:
R
1
is C
1
-C
6
alkyl; C
1
-C
6
(monohalo or polyhalo)alkyl; —CH
2
COOR
6
wherein R
6
is C
1
-C
6
alkyl; —CH
2
—Y—(C
1
-C
6
alkyl) wherein Y is —S—, —SO—, —SO
2
— or —O—; or
wherein R
6
′ is C
1
-C
6
alkyl or phenyl;
R
2
is C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, phenyl, benzyl or C
1
-C
6
(monohalo or polyhalo)alkyl;
R
3
is hydrogen, &agr;-hydroxy, &agr;-methyl, &bgr;-methyl or
wherein R
2
is identical to R
2
as defined hereinabove;
R
4
is hydrogen or fluoro;
R
5
is hydrogen or fluoro;
Z is &bgr;-hydroxymethylene;
and X and the dotted line in ring A are defi
Bodor Nicholas S.
Burns Doane Swecker & Mathis L.L.P.
Raymond Richard L.
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