Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-16
2001-02-13
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S238000, C544S276000, C544S316000, C544S319000
Reexamination Certificate
active
06187925
ABSTRACT:
BACKGROUND OF THE INVENTION
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 5&agr;-reductase, which converts testosterone to DHT. Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia (also called androgenetic alopecia) which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone (“T”) or similar androgenic hormones in the metabolic system. Inhibitors of 5&agr;-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. No. 4,377,584, issued Mar. 22, 1983, and U.S. Pat. No. 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).
U.S. Pat. No. 5,237,064 describes a process for producing 7&bgr;-substituted 5&agr;-androstan-3-ones. U.S. Pat. No. 5,470,976 describes the stereoselective hydrogenation of the delta-5 double bond of a 17-substituted azasteroid. U.S. Pat. No. 5,120,847 and U.S. 5,021,575 relate to the insertion of a double bond at the 1,2 position of a 4-azasteroid.
The instant invention provides an improved process for the synthesis of 16-substituted 7-&bgr;-methyl-4-aza-5&agr;-androst-1-en-3-ones. 16&bgr;-substituted 7-&bgr;-methyl-4-aza-5&agr;-androst-1-en-3-ones are described in PCT publication WO 95/11254. Also provided by the present invention are intermediates useful in the present process.
SUMMARY OF THE INVENTION
The novel process of this invention involves the stereoselective synthesis of certain 16-substituted 4-aza-5&agr;-androst-1-en-3-ones, and the useful intermediates obtained therein. These novel intermediates and this novel process can be exemplified in the following embodiment.
The products of the present process are useful as a inhibitors of 5&agr;-reductase, particularly 5&agr;-reductase type 1. 5&agr;-reductase inhibitors are useful in the treatment of hyperandrogenic disorders such as benign prostatic hyperplasia, acne vulgaris, seborrhea, female hirsutism, androgenic alopecia (androgenetic alopecia), including male pattern baldness, and the prevention and treatment of prostatic carcinoma.
DETAILED DESCRIPTION OF THE INVENTION
A general procedure for the process of the present invention is shown below:
wherein Ar is:
unsubstituted or mono- or di-substituted phenyl, naphthyl, or 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.
When Ar is heteroaryl, the heteroaryl ring may be attached within structural formula I or substituted on any carbon atom in the ring which results in the creation of a stable structure.
The substituents on the aryl and heteroaryl groups named above are independently selected from:
i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; mono-, di- or trihalomethoxy; C
2-6
alkenyl; C
3-6
cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;
ii) 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 is unsubstituted or substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl;
iii) aryl; aryloxy; arylcarbonyl; arylthio; arylsulfonyl; arylsulfinyl; arylsulfonamido; aryloxycarbonyl; wherein the aryl moiety is unsubstituted or substituted with 1-3 of: halo; C
1-4
alkyl; C
1-4
alkoxy; or trifluoromethyl;
iv) —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
R
b
and R
c
are independently H, C
1-6
alkyl, aryl, or arylC
1-6
alkyl; wherein the alkyl moiety is unsubstituted or 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; and —N(R
b
)—C(O)FIG.OR
g
, wherein R
g
is C
1-6
alkyl or aryl, in which the alkyl moiety is unsubstituted or substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl, and the aryl moiety is unsubstituted or 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
is selected from H, C
1-6
alkyl, and aryl; in which said C
1-6
alkyl and aryl is unsubstituted or substituted as described above for R
b
and R
c
;
v) a heterocyclic group, wherein the heterocyclic ring can be fused with a benzo ring, and wherein said heterocyclic ring is unsubstituted or substituted with one to three substituents, as defined above for i), ii), iii) and iv), excluding v) a heterocyclic group.
Preferably, Ar is selected from: unsubstituted or mono- or di-substituted phenyl, naphthyl, pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl.
In another embodiment, Ar is selected from: unsubstituted or mono- or di-substituted phenyl, naphthyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, and oxazolyl.
Preferably, the aryl and heteroaryl substituents are selected from:
vi) halo; cyano; nitro; trihalomethyl; trihalomethoxy; C
1-6
alkyl; aryl; C
1-6
alkylsulfonyl; C
1-6
alkyl-arylsulfonamino;
vii) —NR
b
R
c
; R
b
—C(O)—N(R
c
)—; wherein R
b
and R
c
are independently H, C
1-6
alkyl, aryl, or arylC
1-6
alkyl;
wherein the alkyl moiety is unsubstituted or substituted with 1-3 of: halo; C
1-4
alkoxy; or trifluoromethyl; and the aryl moiety is unsubstituted or substituted with 1-3 of: halo; C
1-4
alkyl; C
1-4
alkoxy; or trifluoromethyl;
viii) a heterocyclic group, which is a 5 membered aromatic ring, containing one ring nitrogen atom, or one ring oxygen and one ring nitrogen atom.
The starting material for the process is produced according to the procedures in Miller et al., Tetrahedron Letters 37(20) 3429-3432 (1996) and those in PCT publication WO 95/32215, and is generally known and available in the art.
Addition of methyl magnesium chloride to the 7-keto-3,16 bis acetate starting material (1) cleaves the 3 and 16 acetates with concurrent addition to the 7-ketone to produce (2). Anhydrous cerium trichloride, in the proper needle form, was added to the Grignard before addition to the 7-ketone and improved the yield of the reaction by >15%. The triol (2) can be carried on to the next step without purification, or it may be isolated.
Oxidation of the triol (2) to the dienedione (3) was carried out under Oppenauer conditions with 2-butanone, aluminum isopropoxide, and triethylamine. Concurrent hydrolysis of the aluminum salts and elimination of the 7-OH occurred upon aging with concentrated HCl. Butanone dimers can be removed from the reaction mixture by a water distillation before carrying on to the next step, or the dienedione (3) may be isolated.
A chemo- and stereoselective reduction of the dienone (3) to the 7-P methyl enone (4) was achieved under transfer hydrogenation conditions using
Humphrey Guy R.
Li Wenjie
Miller Ross A.
Coleman Brenda
Fitch Catherine D.
Merck & Co. , Inc.
Shah Mukund J.
Winokur Melvin
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