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Last Updated: March 29, 2024

Claims for Patent: 5,945,412


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Summary for Patent: 5,945,412
Title: Methods and compositions for preventing and treating bone loss
Abstract:The present invention provides for a method of inhibiting bone loss in a subject in need of such treatment comprising administration to the subject of a therapeutically effective amount of a compound of structural formula I: ##STR1## The present invention further provides for a method for treating and preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget\'s disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, comprising administration of therapeutically effective amount of a compound of structural formula I to the subject. Further, the present invention provides for compositions useful in the methods of the present invention, as well as a method of manufacture of a medicament useful for inhibiting bone loss and treating or preventing osteoporosis and osteopenia.
Inventor(s): Fuh; Vivian L. (New York, NY), Kaufman; Keith D. (Westfield, NJ), Waldstreicher; Joanne (Scotch Plains, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:08/984,425
Patent Claims:1. A method of inhibiting bone loss in a subject in need of such treatment comprising administration to the subject of an effective amount of a compound of structural formula I: ##STR10## 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.sup.1 is selected from the group consisting of hydrogen and C.sub.1-10 alkyl;

R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-10 alkyl;

one of R.sup.3 and R.sup.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.sub.b R.sub.c, where R.sub.b and R.sub.c are independently H, C.sub.1-6 alkyl, aryl, or arylC.sub.1-6 alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

(g) C.sub.1-10 alkyl--X--;

(h) C.sub.2-10 alkenyl--X--;

wherein the C.sub.1-10 alkyl in (g) and C.sub.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.sub.1-6 alkyl; C.sub.1-6 alkyloxy; C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkyloxycarbonyl; in which the C.sub.1-6 alkyl moiety can be further substituted with 1-3 of: halo; C.sub.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.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

iv) --C(O)NR.sub.b R.sub.c ; --N(R.sub.b)--C(O)--R.sub.c ; --NR.sub.b R.sub.c ; where R.sub.b and R.sub.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.sub.2-6 alkenyl; C.sub.3-6 cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;

vi) C.sub.1-6 alkyl; hydroxy C.sub.1-6 alkyl; C.sub.1-6 alkyloxy; C.sub.1-6 alkyloxy C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfinyl; C.sub.1-6 alkylsulfonamido; C.sub.1-6 alkylarylsulfonamido; C.sub.1-6 alkyloxy-carbonyl; C.sub.1-6 alkyloxycarbonyl C.sub.1-6 alkyl; R.sub.b R.sub.c N--C(O)--C.sub.1-6 alkyl; C.sub.1-6 alkanoylamino C.sub.1-6 alkyl; aroylamino C.sub.1-6 alkyl; wherein the C.sub.1-6 alkyl moiety can be substituted with 1-3 of: halo; C.sub.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.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

viii) --C(O)NR.sub.b R.sub.c ; --O--C(O)--NR.sub.b R.sub.c ; --N(Rb)--C(O)--R.sub.c ; --NR.sub.b R.sub.c ; R.sub.b --C(O)--N(R.sub.c)--; where R.sub.b and R.sub.c are defined in (f) above; and --N(R.sub.b)--C(O)--OR.sub.g, wherein R.sub.g is C.sub.1-6 alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkyl; C.sub.1-4 alkoxy, or trifluoromethyl; --N(R.sub.b)--C(O) NR.sub.c R.sub.d, wherein R.sub.d is selected from H, C.sub.1-6 alkyl, and aryl; in which said C.sub.1-6 alkyl and aryl can be substituted as described above in (f) for R.sub.b and R.sub.c ;

ix) a heterocyclic group, which is a 5, 6 or 7 membered 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 heterocyclic ring can be aromatic, unsaturated, or saturated, wherein the heterocyclic ring can be fused with a benzo ring, and

wherein said heterocyclic ring can be substituted with one to three substituents, as defined above for v), vi), vii) and viii), excluding ix) a heterocyclic group; and

(k) R.sup.3 and R.sup.4 taken together can be carbonyl oxygen;

(l) R.sup.3 and R.sup.4 taken together can be .dbd.CH--R.sub.g, wherein R.sub.g is defined in viii); and wherein:

X is selected from the group consisting of:

--O--; --S(O).sub.n --; --C(O)--; --CH(R.sub.e)--; --C(O)--O--.sup.* ; --C(O)--N(R.sub.e)--.sup.* ;

--N(R.sub.e)--C(O)--O--.sup.* ; --O--C(O)--N(R.sub.e)--.sup.* ; --N(R.sub.e)C(O )--N(R.sub.e)--;

--O--CH(R.sub.e)--.sup.* ; --N(R.sub.e)--; wherein R.sub.e is H, C.sub.1-3 alkyl, aryl, aryl- C.sub.1-3 alkyl, or unsubstituted or substituted heteroaryl, as defined above in (j); wherein the asterisk (.sup.*) denotes the bond which is attached to the 16-position in Structure I; and n is zero, 1 or 2.

2. The method of claim 1 wherein the compound of structural formula I is selected from:

4-aza-4,7.beta.-dimethyl-5.alpha.-androstane-3,16-dione;

4-aza-4-methyl-5.alpha.-androstan- 3, 16-dione;

3-oxo-4-aza-4-methyl-16.beta.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(benzylaminocarbonyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-benzoylamino-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-allyloxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(n-propyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.alpha.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(phenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(phenoxy)-5.alpha.-androst- 1-ene;

3-oxo-4-aza-4-methyl-16.alpha.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst-1-en e;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-en e;

3-oxo-4-aza-7.beta.-methyl-16.beta.-[4-(1-pyrrolyl)phenoxy]-5.alpha.-andros t-1-ene;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-allyloxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3,3-dimethylallyloxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16,.beta.-(n-propyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(iso-pentoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,16.alpha.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethyloxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-benzyloxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-methylthio-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propylthio)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-fluoro-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-cyano-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(1-hexyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7 .beta.-dimethyl-16.beta.-benzyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorobenzyl)-5.alpha.-androstan e;

3-oxo-4-aza-4,16.alpha.-dimethyl-16.beta.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-nitrophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-( 1-naphthyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylphenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(tert-butyloxy)-5.alpha.-androstane

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-methyl-1-butyloxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-(n-propyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-tiifluoromethoxyphenoxy)-5.alpha .-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethylthio-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethylsulfonyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylsulfonylphenoxy)-5.alpha.- androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(4-tolylsulfonylamino)phenoxy]-5 .alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-pyridyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[(4-phenyl)phenoxy)-5.alpha.-andros tane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-pyrazinyloxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(5-oxazolyl)phenoxy]-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-pyrinidinyloxy)-5.alpha.-androst ane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-aminophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-acetylaminophenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-benzoylaminophenoxy)-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst- 1-ene;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorobenzylidene)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-benzylidene-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-methylbenzylidene)-5.alpha.-androstane ;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-chlorobenzyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-methylbenzyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(3-pyridylmethyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-methanesulfonyl-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-thiophenoxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorothiophenoxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorothiophenoxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylthiophenoxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methoxythiophenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-phenylsulfinyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-phenylsulfonyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-(4-trifluoromethylphenox y)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-hydroxy-5.alpha.-androst ane;

3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-methoxy-5.alpha.-androst ane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-nitrophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(1-naphthyloxy)-5.alpha.-androstane ;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylphenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethoxyphenoxy)-5.alpha .-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylsulfonylphenoxy)-5.alpha.- androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(4-tolylsulfonylamino)phenoxy]-5 .alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[(4-phenyl)phenoxy)-5.alpha.-andros tane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(5-oxazolyl)phenoxy]-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-aminophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-acetylaminophenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-benzoylaminophenoxy)-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chlorophenoxy)-5.alpha.-androsta ne; and the pharmaceutically acceptable salts thereof.

3. The method of claim 1 wherein the compound of structural formula I selected from:

(a) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst ane,

(b) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane, and

(c) 3-oxo-4-aza-7-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene, or pharmaceutically acceptable salts thereof.

4. The method of claim 1 wherein the subject is a human.

5. The method of claim 1 wherein the compound of structural formula I is administered at a dose of 0.01 to 1000 mg per day.

6. The method of claim 5 wherein the compound of structural formula I is administered at a dose of 0.1 to 50 mg per day.

7. The method of inhibiting bone loss in a subject in need of such treatment according to claim 1 comprising administration of an effective amount of the compound of structural formula I and an effective amount of a bone anabolic agent or a bone antiresorptive agent or an inhibitor of 5.alpha.-reductase type 2 or a dual 5.alpha.-reductase inhibitor.

8. The method according to claim 7 wherein the bone anabolic agent is selected from a form of parathyroid hormone and a growth hormone secretagogue, growth hormone, growth hormone releasing hormone and insulin-like growth factor.

9. The method according to claim 8 wherein the growth hormone secretagogue is selected from:

(a) N-[1(R)-[( 1,2-Dihydro- 1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenyl methyloxy)ethyl]-2-amino-2-methylpropanamide; and

(b) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'- yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate.

10. The method according to claim 7 wherein the bone antiresorptive agent is selected from:

(1) an estrogen,

(2) a bisphosphonate compound, and

(3) an antiestrogenic compound.

11. The method according to claim 10 wherein:

(1) the estrogen is selected from:

(a) 17.beta.-estradiol,

(b) estrone,

(c) conjugated estrogen, equine estrogen, and

(d) 17.beta.-ethynyl estradiol;

(2) the bisphosphonate compound is selected from:

(a) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,

(b) N-methyl-4-amino-hydroxybutylidene-1,1-bisphosphonic acid,

(c) 4-(N,N-dimethylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,

(d) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,

(e) 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid,

(f) 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,

(g) 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid, and

(h) 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine; and

(3) the antiestrogenic compound is selected from:

(a) raloxifene,

(b) clomiphene,

(c) zuclomiphene,

(d) enclomiphene,

(e) nafoxidene,

(f) CI-680,

(g) CI-628,

(h) CN-55,945-27,

(i) Mer-25,

(j) U-11,

(k) 555A, and

(l) U-100A; and pharmaceutically acceptable salts thereof.

12. The method of inhibiting bone loss in a subject in need of such treatment according to claim 11 comprising administration of 0.1 to 50 mg/day of a compound of structural formula I selected from:

compound of structural formula I selected from:

(a) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst ane,

(b) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane,and

(c) 3-oxo-4-aza-7-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene, and pharmaceutically acceptable salts thereof;

together with 2.5 to 100 mg/day of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.

13. The method according to claim 7 wherein:

the 5.alpha.-reductase type 2 inhibitor is selected from:

(a) finasteride, and

(b) epristeride; and

the dual 5.alpha.-reductase inhibitor is:

(a) 17.beta.-N-(2,5-bis(trifluoromethyl))phenyl carbamoyl-4-aza-5.alpha.-androst-1-en-3-one.

14. A method of treating and preventing a disease involving bone resorption selected from: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease which comprises the administration to a subject in need thereof of an effective amount of a compound of structural formula I: ##STR11## 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.sup.1 is selected from the group consisting of hydrogen and C.sub.1-10 alkyl;

R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-10 alkyl;

one of R.sup.3 and R.sup.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.sub.b R.sub.c, where R.sub.b and R.sub.c are independently H, C.sub.1-6 alkyl, aryl, or arylC.sub.1-6 alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

(g) C.sub.1-10 alkyl--X--;

(h) C.sub.2-10 alkenyl--X--;

wherein the C.sub.1-10 alkyl in (g) and C.sub.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.sub.1-6 alkyl; C.sub.1-6 alkyloxy; C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkyloxycarbonyl; in which the C.sub.1-6 alkyl moiety can be firther substituted with 1-3 of: halo; C.sub.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.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

iv) --C(O)NR.sub.b R.sub.c ; --N(R.sub.b)--C(O)--R.sub.c ; --NR.sub.b R.sub.c ; where R.sub.b and R.sub.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.sub.2-6 alkenyl; C.sub.3-6 cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;

vi) C.sub.1-6 alkyl; hydroxy C.sub.1-6 alkyl; C.sub.1-6 alkyloxy; C.sub.1-6 alkyloxy C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfinyl; C.sub.1-6 alkylsulfonamido; C.sub.1-6 alkylarylsulfonamido; C.sub.1-6 alkyloxy-carbonyl; C.sub.1-6 alkyloxycarbonyl C.sub.1-6 alkyl; R.sub.b R.sub.c N--C(O)--C.sub.1-6 alkyl; C.sub.1-6 alkanoylamino C.sub.1-6 alkyl; aroylamino C.sub.1-6 alkyl; wherein the C.sub.1-6 alkyl moiety can be substituted with 1-3 of: halo; C.sub.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.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

viii) --C(O)NR.sub.b R.sub.c ; --O--C(O)--NR.sub.b R.sub.c ; --N(R.sub.b)--C(O)--R.sub.c ; --NR.sub.b R.sub.c ; R.sub.b --C(O)--N(R.sub.c)--; where R.sub.b and R.sub.c are defined in (f) above; and --N(R.sub.b)--C(O)--OR.sub.g, wherein R.sub.g is C.sub.1-6 alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkyl; C.sub.1-4 alkoxy, or trifluoromethyl; --N(R.sub.b)--C(O) NR.sub.c R.sub.d, wherein R.sub.d is selected from H, C.sub.1-6 alkyl, and aryl; in which said C.sub.1-6 alkyl and aryl can be substituted as described above in (f) for R.sub.b and R.sub.c ;

ix) a heterocyclic group, which is a 5, 6 or 7 membered 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 heterocyclic ring can be aromatic, unsaturated, or saturated, wherein the heterocyclic ring can be fused with a benzo ring, and wherein said heterocyclic ring can be substituted with one to three substituents, as defined above for v), vi), vii) and viii), excluding ix) a heterocyclic group; and

(k) R.sup.3 and R.sup.4 taken together can be carbonyl oxygen;

(l) R.sup.3 and R.sup.4 taken together can be .dbd.CH--R.sub.g, wherein R.sub.g is defined in viii); and wherein:

X is selected from the group consisting of:

--O--; --S(O).sub.n --; --C(O)--; --CH(R.sub.e)--; --C(O)--O--.sup.* ; --C(O)--N(R.sub.e)--.sup.* ;

--N(R.sub.e)--C(O)--O--.sup.* ; --O--C(O)--N(R.sub.e)--.sup.* ; --N(R.sub.e)C(O )--N(R.sub.e)--;

--O--CH(R.sub.e)--.sup.* ; --N(R.sub.e)--; wherein R.sub.e is H, C.sub.1-3 alkyl, aryl, aryl- C.sub.1-3 alkyl, or unsubstituted or substituted heteroaryl, as defined above in (j); wherein the asterisk (.sup.*) denotes the bond which is attached to the 16-position in Structure I; and n is zero, 1 or 2.

15. The method of claim 14 wherein the compound of structural formula I is selected from:

4-aza-4,7.beta.-dimethyl-5.alpha.-androstane-3,16-dione;

4-aza-4-methyl-5.alpha.-androstan- 3, 16-dione;

3-oxo-4-aza-4-methyl-16.beta.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(benzylaminocarbonyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-benzoylamino-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-allyloxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(n-propyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.alpha.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(phenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(phenoxy)-5.alpha.-androst- 1-ene;

3-oxo-4-aza-4-methyl-16.alpha.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst-1-en e;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androstane;

3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-en e;

3-oxo-4-aza-7.beta.-methyl-16.beta.-[4-(1-pyrrolyl)phenoxy]-5.alpha.-andros t-1-ene;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-allyloxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3,3-dimethylallyloxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16,.beta.-(n-propyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(iso-pentoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,16.alpha.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethyloxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-benzyloxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-hydroxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-methylthio-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propylthio)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-fluoro-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-cyano-5.alpha.-androstane;

3-oxo-4-aza-4-methyl-16.beta.-(1-hexyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7 .beta.-dimethyl-16.beta.-benzyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorobenzyl)-5.alpha.-androstan e;

3-oxo-4-aza-4,16.alpha.-dimethyl-16.beta.-methoxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-nitrophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-( 1-naphthyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylphenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(tert-butyloxy)-5.alpha.-androstane ;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-methyl-1-butyloxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-(n-propyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-tiifluoromethoxyphenoxy)-5.alpha .-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethylthio-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethylsulfonyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylsulfonylphenoxy)-5.alpha.- androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(4-tolylsulfonylamino)phenoxy]-5 .alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-pyridyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[(4-phenyl)phenoxy)-5.alpha.-andros tane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-pyrazinyloxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(5-oxazolyl)phenoxy]-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-pyrinidinyloxy)-5.alpha.-androst ane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-aminophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-acetylaminophenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-benzoylaminophenoxy)-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst- 1-ene;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorobenzylidene)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-benzylidene-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-methylbenzylidene)-5.alpha.-androstane ;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-chlorobenzyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-methylbenzyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16-(3-pyridylmethyl)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-methanesulfonyl-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-thiophenoxy-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorothiophenoxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorothiophenoxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylthiophenoxy)-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methoxythiophenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-phenylsulfinyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-phenylsulfonyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-(4-trifluoromethylphenox y)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-hydroxy-5.alpha.-androst ane;

3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-methoxy-5.alpha.-androst ane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-cyanophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-nitrophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(1-naphthyloxy)-5.alpha.-androstane ;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylphenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha. -androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethoxyphenoxy)-5.alpha .-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylsulfonylphenoxy)-5.alpha.- androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(4-tolylsulfonylamino)phenoxy]-5 .alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[(4-phenyl)phenoxy)-5.alpha.-andros tane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(5-oxazolyl)phenoxy]-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-andr ostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-aminophenoxy)-5.alpha.-androstan e;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-acetylaminophenoxy)-5.alpha.-and rostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-benzoylaminophenoxy)-5.alpha.-an drostane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-chlorophenoxy)-5.alpha.-androsta ne;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chlorophenoxy)-5.alpha.-androsta ne; and the pharmaceutically acceptable salts thereof.

16. The method of claim 14 wherein the compound of structural formula I is selected from:

(a) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst ane,

(b) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane, and

(c) 3-oxo-4-aza-7-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene, or pharmaceutically acceptable salts thereof.

17. The method of claim 14 wherein the compound of structural formula I is administered at a dose of 0.01 to 1000 mg per day.

18. The method of claim 14 wherein the compound of structural formula I is administered at a dose of 0.1 to 50 mg per day.

19. The method of treating and preventing a disease involving bone resorption selected from: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease in a subject in need thereof according to claim 14 comprising administration of an effective amount of the compound of structural formula I and an effective amount of a bone anabolic agent or a bone antiresorptive agent or a 5.alpha.-reductase type 2 inhibitor or a dual 5.alpha.-reductase inhibitor.

20. The method according to claim 19 wherein the bone anabolic agent is selected from a form of parathyroid hormone and a growth hormone secretagogue, growth hormone, growth hormone releasing hormone and insulin-like growth factor.

21. The method according to claim 20 wherein the growth hormone secretagogue is selected from:

(a) N-[1(R)-[( 1,2-Dihydro- 1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenyl methyloxy)ethyl]-2-amino-2-methylpropanamide; and

(b) N-[1(R)-[( 1,2-Dihydro- 1-methanesulfonylspiro[3H-indole-3,4'-piperidin]- 1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate.

22. The method according to claim 19 wherein the bone antiresorptive agent is selected from:

(1) an estrogen,

(2) a bisphosphonate compound, and

(3) an antiestrogenic compound.

23. The method according to claim 22 wherein:

(1) the estrogen is selected from:

(a) 17.beta.-estradiol,

(b) estrone,

(c) conjugated estrogen, equine estrogen, and

(d) 17.beta.-ethynyl estradiol;

(2) the bisphosphonate compound is selected from:

(a) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,

(b) N-methyl-4-amino-hydroxybutylidene-1,1-bisphosphonic acid,

(c) 4-(N,N-dimethylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,

(d) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,

(e) 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid,

(f) 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,

(g) 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid, and

(h) 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine; and

(3) the antiestrogenic compound is selected from:

(a) raloxifene,

(b) clomiphene,

(c) zuclomiphene,

(d) enclomiphene,

(e) nafoxidene,

(f) CI-680,

(g) CI-628,

(h) CN-55,945-27,

(i) Mer-25,

(j) U-11,

(k) 555A, and

(l) U-100A; and pharmaceutically acceptable salts thereof.

24. The method according to claim 23 comprising administration of 0.1 to 50 mg/day of the compound of structural formula I selected from:

(a) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst ane,

(b) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane, and

(c) 3-oxo-4-aza-7-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene, or a pharmaceutically acceptable salt thereof;

together with 2.5 to 100 mg/day of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.

25. The method according to claim 19 wherein:

the 5.alpha.-reductase type 2 inhibitor is selected from:

(a) finasteride, and

(b) epristeride; and

the dual 5.alpha.-reductase inhibitor is:

(a) 17.beta.-N-(2,5-bis(trifluoromethyl))phenyl carbamoyl-4-aza-5.alpha.-androst-1-en-3-one.

26. The method according to claim 14 wherein the bone resorption disease being prevented or treated is osteoporosis.

27. The method of claim 3 wherein the compound of structural formula I is 3-oxo-4-aza-7-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a therapeutically effective amount of a compound of structural formula I: ##STR12## 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.sup.1 is selected from the group consisting of hydrogen and C.sub.1-10 alkyl;

R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-10 alkyl;

one of R.sup.3 and R.sup.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.sub.b R.sub.c, where R.sub.b and R.sub.c are independently H, C.sub.1-6 alkyl, aryl, or arylC.sub.1-6 alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

(g) C.sub.1-10 alkyl--X--;

(h) C.sub.2-10 alkenyl--X--;

wherein the C.sub.1-10 alkyl in (g) and C.sub.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.sub.1-6 alkyl; C.sub.1-6 alkyloxy; C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkyloxycarbonyl; in which the C.sub.1-6 alkyl moiety can be firther substituted with 1-3 of: halo; C.sub.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.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

iv) --C(O)NR.sub.b R.sub.c ; --N(R.sub.b)--C(O)--R.sub.c ; --NR.sub.b R.sub.c ; where R.sub.b and R.sub.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.sub.2-6 alkenyl; C.sub.3-6 cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;

vi) C.sub.1-6 alkyl; hydroxy C.sub.1-6 alkyl; C.sub.1-6 alkyloxy; C.sub.1-6 alkyloxy C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfinyl; C.sub.1-6 alkylsulfonamido; C.sub.1-6 alkylarylsulfonamido; C.sub.1-6 alkyloxy-carbonyl; C.sub.1-6 alkyloxycarbonyl C.sub.1-6 alkyl; R.sub.b R.sub.c N--C(O)--C.sub.1-6 alkyl; C.sub.1-6 alkanoylamino C.sub.1-6 alkyl; aroylamino C.sub.1-6 alkyl; wherein the C.sub.1-6 alkyl moiety can be substituted with 1-3 of: halo; C.sub.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.sub.1-4 alkyl; C.sub.1-4 alkoxy; or trifluoromethyl;

viii) --C(O)NR.sub.b R.sub.c ; --O--C(O)--NR.sub.b R.sub.c ; --N(R.sub.b)--C(O)--R.sub.c ; --NR.sub.b R.sub.c ; R.sub.b --C(O)--N(R.sub.c)--; where R.sub.b and R.sub.c are defined in (f) above; and --N(R.sub.b)--C(O)--OR.sub.g, wherein R.sub.g is C.sub.1-6 alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo; C.sub.1-4 alkyl; C.sub.1-4 alkoxy, or trifluoromethyl; --N(R.sub.b)--C(O) NR.sub.c R.sub.d, wherein R.sub.d is selected from H, C.sub.1-6 alkyl, and aryl; in which said C.sub.1-6 alkyl and aryl can be substituted as described above in (f) for R.sub.b and R.sub.c ;

ix) a heterocyclic group, which is a 5, 6 or 7 membered 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 heterocyclic ring can be aromatic, unsaturated, or saturated, wherein the heterocyclic ring can be fused with a benzo ring, and wherein said heterocyclic ring can be substituted with one to three substituents, as defined above for v), vi), vii) and viii), excluding ix) a heterocyclic group; and

(k) R.sup.3 and R.sup.4 taken together can be carbonyl oxygen;

(l) R.sup.3 and R.sup.4 taken together can be .dbd.CH--R.sub.g, wherein R.sub.g is defined in viii); and wherein:

X is selected from the group consisting of:

--O--; --S(O).sub.n --; --C(O)--; --CH(R.sub.e)--; --C(O)--O--.sup.* ; --C(O)--N(R.sub.e)--.sup.* ;

--N(R.sub.e)--C(O)--O--.sup.* ; --O--C(O)--N(R.sub.e)--.sup.* ; --N(R.sub.e)C(O )--N(R.sub.e)--;

--O--CH(R.sub.e)--.sup.* ; --N(R.sub.e)--; wherein R.sub.e is H, C.sub.1-3 alkyl, aryl, aryl- C.sub.1-3 alkyl, or unsubstituted or substituted heteroaryl, as defined above in (j); wherein the asterisk (.sup.*) denotes the bond which is attached to the 16-position in Structure I; and n is zero, 1 or 2.

29. The pharmaceutical composition according to claim 28 comprising 0.1 to 50 mg of a compound of structural formula I selected from:

(a) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst ane,

(b) 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane, and

(c) 3-oxo-4-aza-7-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene, or a pharmaceutically acceptable salt thereof; and

2.5 to 100 mg 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

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