Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-29
2001-03-20
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S253020, C514S256000, C514S258100, C514S259500, C514S266400, C544S236000, C544S256000, C544S264000, C544S279000, C544S283000, C544S295000, C544S296000, C544S316000, C544S333000, C544S336000, C544S405000, C544S407000, C546S014000, C546S077000, C546S078000
Reexamination Certificate
active
06204273
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action rely on the selective inhibition of the isozyme 5&agr;-reductase 1.
BACKGROUND OF THE INVENTION
Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenetic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyper-androgenic stimulation caused by an excessive accumulation of testosterone (“T”) or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4′-nitro-3′-trifluoromethylisobuty-ranilide. See Neri, et al.,
Endocrinol
. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in some target organs, e.g., the prostate, is 5&agr;-dihydrotestosterone (“DHT”), formed locally in the target organ by the action of testosterone-5&agr;-reductase (or simply 5&agr;-reductase). Inhibitors of 5&agr;-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. Nos. 4,377,584, issued Mar. 22, 1983, and 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5&agr;-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al.,
Proc. Natl. Acad. Sci. USA
, Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5&agr;-reductase 1 (or 5&agr;-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5&agr;-reductase 2 (or 5&agr;-reductase type 2).
In the treatment of androgenic sensitive disease conditions, e.g., benign prostatic hyperplasia (BPH) and/or the prevention and treatment of prostatic cancer, it would be desirable to have one drug entity which is active against both isozymes in the prostate to significantly inhibit all dihydrotestosterone production. It would also be desirable to have another drug entity which is highly selective for inhibiting the isozyme 5&agr;-reductase 1 associated with the scalp, for use in treating conditions of the skin and scalp, e.g., acne vulgaris, male pattern baldness and hirsutism in females. Additionally, a selective 5&agr;-reductase 1 inhibitor could be used in combination with a 5&agr;-reductase 2 inhibitor such as, e.g., finasteride (PROSCAR®), for therapy in the treatment of hyperandrogenic conditions such as BPH and/or the prevention and treatment of prostatic cancer, and for the treatment of skin and scalp-related disorders such as acne vulgaris, seborrhea, female hirsutism, and androgenic alopecia. Still further, the 5&agr;-reductase 1 inhibitors of this invention could be used in combination with a potassium channel opener such as minoxidil for the treatment of these skin and scalp-related disorders. Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of 5&agr;-reductase isozyme 1.
SUMMARY OF THE INVENTION
The novel compounds of this invention have the formula
and are selective 5&agr;-reductase 1 inhibitors. It is an object of this invention to provide compounds that alone or in combination with inhibitors of 5&agr;-reductase 2 are useful in the treatment of benign prostatic hyperplasia, prostatitis, and/or the prevention and treatment of prostatic cancer. It is an additional object of this invention to provide compounds that alone or in combination with inhibitors of 5&agr;-reductase 2 are useful in the treatment of acne vulgaris, female hirsutism, androgenic alopecia (also known as androgenetic alopecia and human pattern baldness), and insufficient plasma levels of high density lipoproteins. The compounds of the invention have utility in one or more of the aforementioned areas.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention have the general structural Formula I:
or a pharmaceutically acceptable salt or ester thereof wherein:
the C1—C2 carbon-carbon bond may be a single bond, or a double bond as indicated by the dashed line;
R
1
is selected from the group consisting of hydrogen and C
1-10
alkyl;
R
2
is selected from the group consisting of hydrogen and C
1-10
alkyl;
one of R
3
and R
4
is selected from the group consisting of hydrogen and methyl, and the other is selected from the group consisting of:
(a) amino;
(b) cyano;
(c) fluoro;
(d) methyl;
(e) OH;
(f) —C(O)NR
b
R
c
, where R
b
and R
c
are independently H, C
1-6
alkyl, aryl, or arylC
1-6
alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C
1-4
alkyl; C
1-4
alkoxy; or trifluoromethyl;
(g) C
1-10
alkyl-X—;
(h) C
2-10
alkenyl-X—;
wherein the C
1-10
alkyl in (g) and C
2-10
alkenyl in (h) can be unsubstituted or substituted with one to three of:
i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; oxo; hydroxysulfonyl; carboxy;
ii) hydroxyC
1-6
alkyl; C
1-6
alkyloxy; C
1-6
alkylthio; C
1-6
alkylsulfonyl; C
1-6
alkyloxycarbonyl; in which the C
1-6
alkyl moiety can be further substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl;
iii) arylthio; aryl; aryloxy; arylsulfonyl; aryloxycarbonyl; in which the aryl moiety can be further substituted with 1-3 of: halo; C
1-4
alkyl; C
1-4
alkoxy; or trifluoromethyl;
iv) —C(O)NR
b
R
c
; —N(R
b
)—C(O)—R
c
; —NR
b
R
c
;
where R
b
and R
c
are defined above;
(i) aryl-X—;
(j) heteroaryl-X—, wherein heteroaryl is a 5, 6 or 7 membered heteroaromatic ring containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms , or combinations thereof; in which the heteroaromatic ring can also be fused with one benzo or heteroaromatic ring;
wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to three of:
v) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; mono-, di- or trihalomethoxy; C
2-6
alkenyl; C
3-6
cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;
vi) C
1-6
alkyl; hydroxy C
1-6
alkyl; C
1-6
alkyloxy; C
1-6
alkyloxy C
1-6
alkyl; C
1-6
alkylcarbonyl; C
1-6
alkylsulfonyl; C
1-6
alkylthio; C
1-6
alkylsulfinyl; C
1-6
alkylsulfonamido; C
1-6
alkylarylsulfonamido; C
1-6
alkyloxy-carbonyl; C
1-6
alkyloxycarbonyl C
1-6
alkyl; R
b
R
c
N—C(O)—C
1-6
alkyl; C
1-6
alkanoylamino C
1-6
alkyl; aroylamino C
1-6
alkyl; wherein the C
1-6
alkyl moiety can be substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl;
vii) aryl; aryloxy; arylcarbonyl; arylthio; arylsulfonyl; arylsulfinyl; arylsulfonamido; aryloxycarbonyl; wherein the aryl moiety can be substituted with 1-3 of: halo; C
1-4
alkyl; C
1-4
alkoxy; or trifluoromethyl;
viii) —C(O)NR
b
R
c
; —O—C(O)—NR
b
R
c
; —N(R
b
)—C(O)—R
c
; —NR
b
R
c
; R
b
—C(O)—N(R
c
)—; where R
b
and R
c
are defined in (f) above; and —N(R
b
)—C(O)—OR
g
, wherein R
g
is C
1-6
alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo; C
1-4
alkyl; C
1-4
alkoxy, or trifluoromethyl; —N(R
b
)—C(O)NR
c
R
d
, wherein R
d
i
Durette Philippe L.
Hagmann William K.
Langen Derek Von
Lanza, Jr. Thomas J.
Rasmusson Gary H.
Coleman Brenda
Durette Philippe L.
Fitch Catherine D.
Merck & Co. , Inc.
Shah Mukund J.
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