This invention relates to the field of pharmaceutical and organic chemistry and provides benzothiophene compounds, intermediates, formulations, and methods.

BACKGROUND OF THE INVENTION 
This invention relates to the field of pharmaceutical and organic chemistry 
and provides benzob!thiophene compounds, intermediates, formulations, and 
methods. 
Osteoporosis describes a group of diseases which arises from diverse 
etiologies, but which are characterized by the net loss of bone mass per 
unit volume. The consequence of this loss of bone mass and resulting bone 
fracture is the failure of the skeleton to provide adequate support for 
the body. One of the most common types of osteoporosis is associated with 
menopause. Most women lose from about 20% to about 60% of the bone mass in 
the trabecular compartment of the bone within 3 to 6 years after the 
cessation of menses. This rapid loss is generally associated with an 
increase of bone resorption and formation. However, the resorptive cycle 
is more dominant and the result is a net loss of bone mass. Osteoporosis 
is a common and serious disease among postmenopausal women. 
There are an estimated 25 million women in the U.S. alone who are afflicted 
with this disease. The results of osteoporosis are personally harmful, and 
also account for a large economic loss due to its chronicity and the need 
for extensive and long term support (hospitalization and nursing home 
care) from the disease sequelae. This is especially true in more elderly 
patients. Additionally, although osteoporosis is generally not thought of 
as a life threatening condition, a 20% to 30% mortality rate is related to 
hip fractures in elderly women. A large percentage of this mortality rate 
can be directly associated with postmenopausal osteoporosis. 
The most generally accepted method for the treatment of postmenopausal 
osteoporosis is estrogen replacement therapy. Although therapy is 
generally successful, patient compliance with the therapy is low, 
primarily because estrogen treatment frequently produces undesirable side 
effects. An additional method of treatment would be the administration of 
a bisphosphonate compound, such as, for example, Fosomax.RTM. (Merck & 
Co., Inc.). 
Throughout premenopausal time, most women have less incidence of 
cardiovascular disease than men of the same age. Following menopause, 
however, the rate of cardiovascular disease in women slowly increases to 
match the rate seen in men. This loss of protection has been linked to the 
loss of estrogen and, in particular, to the loss of estrogen's ability to 
regulate the levels of serum lipids. The nature of estrogen's ability to 
regulate serum lipids is not well understood, but evidence to date 
indicates that estrogen can up regulate the low density lipid (LDL) 
receptors in the liver to remove excess cholesterol. 
It has been reported in the literature that serum lipid levels in 
postmenopausal women having estrogen replacement therapy return to 
concentrations found in the premenopausal state. Thus, estrogen would 
appear to be a reasonable treatment for this condition. However, the side 
effects of estrogen replacement therapy are not acceptable to many women, 
thus limiting the use of this therapy. An ideal therapy for this condition 
would be an agent which regulates serum lipid levels in a manner analogous 
to estrogen, but which is devoid of the side effects and risks associated 
with estrogen therapy. 
Estrogen dependent cancers are major diseases affecting both women and to a 
lesser extent men. Cancer cells of this type are dependent on a source of 
estrogen to maintain the original tumor as well as to proliferate and 
metastasize to other locations. The most common forms of estrogen 
dependent cancer are breast and uterine carcinomas. Current chemotherapy 
of these diseases relies primarily on the use of anti-estrogens, 
predominately tamoxifen. The use of tamoxifen, although efficacious, is 
not without undesirable side-effects, e.g., estrogen agonist properties, 
such as uterine hypertrophy and carcinogenic potential. Compounds of the 
current invention while showing the same or better potential for 
anti-cancer activity also demonstrate a lower potential for estrogen 
agonist activity. 
Thus, it would be a significant contribution to the art to provide novel 
compounds useful, for example, in the treatment or prevention of the 
disease states as indicated herein. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds of formula I 
##STR1## 
wherein R.sup.1 is --P(O)(OR.sup.6).sub.2 ; 
R.sup.2 is --H, --Cl, --F, C.sub.1 -C.sub.4 alkyl, --OH, --O(C.sub.1 
-C.sub.4 alkyl), --OCO(C.sub.1 -C.sub.6 alkyl), --O--CO--O(C.sub.1 
-C.sub.6 alkyl), --O--CO--AR, --OSO.sub.2 (C.sub.2 -C.sub.6 alkyl), or 
--O--CO--OAR, where AR is optionally substituted phenyl; 
R.sup.3 and R.sup.4 are, independently, R.sup.2 ; 
R.sup.5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, 
dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, 
diisopropylamino, or 1-hexamethyleneimino; 
R.sup.6 is --H or C.sub.1 -C.sub.4 alkyl; 
X is --CO-- or --CH.sub.2 --; and 
n is 2 or 3; 
or a pharmaceutically acceptable salt or solvate thereof. 
The present invention further relates to pharmaceutical compositions 
containing compounds of formula I and methods for the therapeutic use of 
such compounds and compositions. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention further provides intermediate compounds of formula II 
which are novel and useful for preparing the pharmaceutically active 
compounds of the present invention, and are shown below. 
##STR2## 
wherein R.sup.2a, R.sup.3a, and R.sup.4a are, independently, --H, --Cl, 
--F, C.sub.1 -C.sub.4 alkyl, or --OR.sup.7, where R.sup.7 is a hydroxyl 
protecting group; and 
R.sup.5, X and n have their previous meanings. 
A preferred compound of formula II is 
2-4-(t-Butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxy 
benzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl! methanone. 
General terms used in the description of compounds herein described bear 
their usual meanings. For example, "C.sub.1 -C.sub.6 alkyl" refers to 
straight or branched aliphatic chains of 1 to 6 carbon atoms including 
moieties such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, 
isopentyl, hexyl, isohexyl, and the like. Similarly, the term "--OC.sub.1 
-C.sub.4 alkyl" represents a C.sub.1 -C.sub.4 alkyl group attached through 
an oxygen molecule and include moieties such as, for example, methoxy, 
ethoxy, n-propoxy, isopropoxy, and the like. Of these alkoxy groups, 
methoxy is highly preferred in most circumstances. 
Optionally substituted phenyl includes phenyl and phenyl substituted once 
or twice with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, 
nitro, chloro, fluoro, or tri (chloro or fluoro)methyl. 
The term, "hydroxyl protecting group (R.sup.7)" contemplates numerous 
functionalities used in the literature to protect a hydroxyl function 
during a chemical sequence and which can be removed to yield the phenol. 
Included within this group would be acyls, mesylates, tosylates, benzyl, 
alkylsilyloxys, --OC.sub.1 -C.sub.4 alkyls, and the like. Numerous 
reactions for the formation and removal of such protecting groups are 
described in a number of standard works including, for example, Protective 
Groups in Organic Chemistry, Plenum Press (London and New York, 1973); 
Green, T. W., Protective Groups in Organic Synthesis, Wiley, (New York, 
1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press 
(London and New York, 1965). A preferred hydroxyl protecting group for the 
current invention is tert-butyl-dimethylsilyloxy (TBDMS), (see: examples 
and preparations, below). 
The term "inhibit" includes its generally accepted meaning which includes 
prohibiting, preventing, restraining, alleviating, ameliorating, and 
slowing, stopping or reversing progression, severity, or a resultant 
symptom. As such, the present method includes both medical therapeutic 
and/or prophylactic administration, as appropriate. 
The compounds of the current invention are named as derivatives of 
centrally located carbon, i.e., the "--CO--" or "--CH.sub.2 --" moiety in 
formula I, thus derivatives are methanones or methanes, e.g. a compound of 
A--CO--B, would be named A!B!methanone. Further the compounds of formula 
I are derivatives of benzob!thiophene which is named and numbered 
according to the Ring Index, The American Chemical Society, as follows: 
##STR3## 
The starting material for preparing compounds of the present invention is a 
compound of formula III or IIIa. 
##STR4## 
wherein R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5, and n have their previous 
meanings. 
Compounds of formula III are generally known in the art and are prepared 
essentially as described by Jones, et al., in U.S. Pat. Nos. 4,400,543 and 
4,418,068 each of which is herein incorporated by reference. See also 
Jones, et al., J. Med. Chem., 27, p. 1057-1066 (1984). The compounds of 
formula IIIa are prepared as described by Bryant, et al., in U.S. Pat. 
Nos. 5,484,798 and 5,492,921, each of which is incorporated by reference 
herein. Compounds of formula III or IIIa, where R.sup.2a-4a are --OR.sup.7 
may be prepared by reacting their hydroxy precursors with the proper 
number of equivalents of protecting reagent which will allow the C.sub.6 
hydroxyl group to remain unprotected. This protection synthesis usually 
results in a statistical distribution of protecting groups on the various 
hydroxyl functions. These products can be separated by chromatographic 
techniques to yield the desired compound of III or IIIa, i.e., a compound 
with an unprotected 6-hydroxyl. An example of this preparation, using the 
preferred TBDMS protecting group, is given below. 
The compounds of formula III or IIIa are converted into their triflate 
analogs, i.e., the compounds of formula II, by reaction of the phenol with 
a trifluoromethylsulfonoylating agent in the presence of an acid 
scavenger. Commonly used sulfonoylating reagents would be halides, e.g., 
trifluoromethylsulfonoyl-chloride, -bromide, or -iodide, anhydrides mixed 
or homogeneous, e.g,. triflic anhydride, or imides, e.g., N-alkyl or aryl 
trifluoromethylsulfonylimide. A preferred reagent is 
N-phenyltrifluoromethanesulfonimide. 
Acid scavengers used in the synthesis of the compounds of formula II 
include alkali metal base, e.g., Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, etc. 
or organic tertiary amines, e.g., trimethylamine, pyridine, lutidine, 
triethylamine, etc. A preferred acid scavenger is triethylamine. 
This reaction may be run in a variety of inert solvents, such ether, THF, 
dioxane, methylene chloride, and the like. Of these, THF is preferred and 
especially preferred is the anhydrous form of THF. 
The sulfonoylation reaction may be run at temperatures between 0-50.degree. 
C., with ambient temperature adequate and most convenient. Under these 
reaction conditions, the reaction is usually complete within one to twenty 
hours. The optimal time can be determined by monitoring the progress of 
the reaction via conventional chromatographic techniques, such as tlc. 
Application of the chemistry described, supra, enables the preparation of 
the compounds of formula II. Examples of the compounds of formula II 
include, but are not limited to: 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methane 
2-3-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-2-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-pyrrolidinyl)ethoxy!phenyl!methanone 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-3-(1-piperidinyl)propoxy!phenyl!methanone 
2-3-chloro-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoylo 
xybenzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-3-(t-butyldimethylsilyloxy)-4-fluorophenyl!-6-trifluoromethylsulfonoylo 
xybenzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methane 
2-2-methyl-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoylo 
xybenzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-hexamethyleneimino)ethoxy!phenyl!methanone 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(N,N-dimethylamino)ethoxy!phenyl!methane 
2-3-fluoro-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoylo 
xybenzob!thien-3-yl!4-3-(1-piperidinyl)propoxy!phenyl!methanone 
2-3,4-di-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybe 
nzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-2,4-di-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybe 
nzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methane 
2-2,3-di-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybe 
nzob!thien-3-yl!4-2-(1-pyrrolidinyl)ethoxy!phenyl!methanone 
2-2,3-di-chlorophenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-yl!4 
-2-(1-pyrrolidinyl)ethoxy!phenyl!methanone 
2-4-fluorophenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-yl!4-2-( 
1-pyrridinyl)ethoxy!phenyl!methanone 
2-2-methyl-3-fluorophenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-y 
l!4-2-(1-pyrridinyl)ethoxy!phenyl!methanone 
2-3-methyl-4-chlorophenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-y 
l!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-3,4-di-methoxyphenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-yl! 
4-2-(1-pyrridinyl)ethoxy!phenyl!methanone 
2-4-methoxyphenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-yl!4-2- 
(1-piperidinyl)ethoxy!phenyl!methanone 
2-4-methoxyphenyl!-6-trifluoromethylsulfonoyloxybenzob!thien-3-yl!4-2- 
(1-piperidinyl)ethoxy!phenyl!methane 
The triflate compounds of formula II are converted to the compounds of 
formula Ia by a transition metal coupling reaction. Transition metals such 
as, but not limited to, palladium and nickel, in various oxidation states, 
are generally employed. Typically, these reactions are run in inert 
solvents which would include toluene, DMF, acetonitrile, and the like. 
Catalytic amounts of phosphorous-bearing ligands are used to facilitation 
these reactions, e.g., triarylphosphines, bis-diphenylphosphoalkanes, 
bis-diphenylphosphinoferrocenes and the like. A preferred 
phospho-ligand/transition metal catalyst is Pd(0)(PPh.sub.3).sub.4. 
Organic bases are also employed to facilitate the reaction, e.g., 
trialkylamines, pyridine, etc. A preferred base is triethylamine. The 
temperature employed in this coupling is that which is sufficient to 
effect completion of the reaction, generally, in the range from 
50-100.degree. C. The length of time required for the reaction to run to 
completion is typically from four to seventy-two hours. However, the 
optimal time can be determined by monitoring the progress of the reaction 
via conventional chromatographic techniques. 
When the preferred hydroxyl protecting group (R.sup.7), i.e., TBDMS, is 
present in a compound of formula II, this protecting group is cleaved 
during the coupling reaction and subsequent workup. Thus, the products 
(Ia) are isolated as the free hydroxyl derivatives. This chemistry is 
illustrated in Scheme I, below. 
##STR5## 
wherein R.sup.2b, R.sup.3b, and R.sup.4b are, independently, --H, --Cl, 
--F, C.sub.1 -C.sub.4 alkyl, or --OH; R.sup.6a is C.sub.1 -C.sub.4 alkyl; 
and R.sup.2a,R.sup.3a, R.sup.4a,R.sup.5, n, and X have their previous 
meanings. 
The compounds of formula Ia, where the triflate has been replaced by a 
phosphonate (ester or acid), are prepared by running the metal coupling 
reaction in the presence of a phosphite, (R.sup.6a O).sub.2 P(O)H. A 
specific example of this reaction enabling the preparation of the 
compounds of formula Ia, is given below. Further information regarding 
this chemistry may be found in Thurieau, et al., J. Med. Chem., 37, 
625-629 (1994). Application of the chemical synthesis described, supra, 
enables the preparation of the compounds of formula Ia. Compounds of 
formula Ia include, but are not limited to: 
2-(4-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piper 
idinyl)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piper 
idinyl)ethoxy!phenyl!methane 
2-(4-hydroxyphenyl)-6-di-methylphosphonoylbenzob!thien-3-yl!4-2-(1-pipe 
ridinyl)ethoxy!phenyl!methanone 
2-(4-chlorophenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piperi 
dinyl)ethoxy!phenyl!methanone 
2-(4-fluorophenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piperi 
dinyl)ethoxy!phenyl!methanone 
2-(3-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piper 
idinyl)ethoxy!phenyl!methanone 
2-(2-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-pyrro 
lidinyl)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-di-propylphosphonoylbenzob!thien-3-yl!4-2-(1-pipe 
ridinyl)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-di-i-butylphosphonoylbenzob!thien-3-yl!4-2-(1-pip 
eridinyl)ethoxy!phenyl!methanone 
2-(2-methyl-4-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2 
-(1-piperidinyl)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-3-(1-piper 
idinyl)propoxy!phenyl!methanone 
2-(3,4-di-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1- 
piperidinyl)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(N,N-die 
thyl)ethoxy!phenyl!methanone 
and the like. 
The compounds of formula Ia are used to synthesize the phosphonic acids, 
formula Ib, i.e., where R.sup.6 is --OH. This conversion is accomplished 
by hydrolyzing the ester moieties of a Ia compound. This chemistry is well 
known in the art and is usually done under basic conditions. Bases 
commonly employed for this hydrolysis are NaOH, KOH, Na.sub.2 CO.sub.3, 
and the like. Such reactions are carried out in a mixed aqueous solvent, 
e.g., aqueous alcohol mixtures, biphasic water-organic systems, and the 
like. The reaction are usually run at temperature between 50-100.degree. 
C. for two to twenty-four hours. Application of the chemical synthesis 
described, supra, enables the preparation of the compounds of formula Ib. 
Compounds of formula Ib include, but are not limited to: 
2-(4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-piperidinyl)e 
thoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-piperidinyl)e 
thoxy!phenyl!methane 
2-(3-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-piperidinyl)e 
thoxy!phenyl!methanone 
2-(2-methyl-4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-pipe 
ridinyl)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-pyrrolidinyl) 
ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-N,N-di-methyl 
)ethoxy!phenyl!methanone 
2-(4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-3-(1-piperidinyl)p 
ropoxy!phenyl!methanone 
2-(3-chloro-4-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-pipe 
ridinyl)ethoxy!phenyl!methanone 
2-(3,4-di-hydroxyphenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-piperidi 
nyl)ethoxy!phenyl!methanone 
2-(4-fluorophenyl)-6-phosphonatobenzob!thien-3-yl!4-2-(1-piperidinyl)et 
hoxy!phenyl!methanone 
2-phenyl-6-phosphonatobenzob!thien-3-yl!4-2-(1-piperidinyl)ethoxy!pheny 
l!methanone 
Other compounds of formula I, i.e., those of formula Ic, where the hydroxyl 
functions (R.sup.2b-4b), when present, are substituted with acyl or 
sulfonoyl moieties, are also apart of the current invention. Compounds of 
formula Ic are prepared by replacing the 2', 3', and/or 4'-position 
hydroxy moieties of Ia or Ib compounds, when present, with a moiety of the 
formula --O--CO--(C.sub.1 -C.sub.6 alkyl), --O--CO--Ar, or --O--SO.sub.2 
--(C.sub.2 -C.sub.6 alkyl) via well known procedures. See, e.g., U.S. Pat. 
Nos. 5,393,763 or 5,482,949, each of which is included by reference 
herein. 
For example, when an --O--CO(C.sub.1 -C.sub.6 alkyl) or --O--CO-phenyl 
group is desired, a mono-, di-, trihydroxy compound of formula Ia or Ib is 
reacted with an agent such as acyl chloride, bromide, cyanide, or azide, 
or with an appropriate anhydride or mixed anhydride. The reactions are 
conveniently carried out in a basic solvent such as pyridine, lutidine, 
quinoline or isoquinoline, or in a tertiary amine solvent such as 
triethylamine, tributylamine, methylpiperidine, and the like. The reaction 
also may be carried out in an inert solvent such as ethyl acetate, 
dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, 
acetonitrile, acetone, methyl ethyl ketone, and the like, to which at 
least one equivalent of an acid scavenger, such as a tertiary amine, has 
been added. If desired, acylation catalysts such as 
4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g., 
Haslam, et al., Tetrahedron, 36:2409-2433 (1980). 
The present reactions are carried out at moderate temperatures, in the 
range from about -25.degree. C. to about 100.degree. C., frequently under 
an inert atmosphere such as nitrogen gas. However, ambient temperature is 
usually adequate for the reaction to run. 
Acylation of a 2', 3', and/or 4'-position hydroxy group also may be 
performed by acid-catalyzed reactions of the appropriate carboxylic acids 
in inert organic solvents. Acid catalysts such as sulfuric acid, 
polyphosphoric acid, methanesulfonic acid, and the like are used. 
When a formula I compound is desired in which the 2',3', and/or 4'-position 
hydroxy group of a formula Ia or Ib compound is converted to a group of 
the formula --O--SO.sub.2 --(C.sub.2 -C.sub.6 alkyl), the mono-, di-, or 
trihydroxy compound is reacted with, for example, a sulfonic anhydride or 
a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, 
bromide, or sulfonyl ammonium salt, as taught by King and Monoir, J. Am. 
Chem. Soc., 97:2566-2567 (1975). The hydroxy compounds also can be reacted 
with the appropriate sulfonic anhydride or mixed sulfonic anhydrides. Such 
reactions are carried out under conditions such as were explained above in 
the discussion of reaction with acid halides and the like. 
Applying the chemical synthetic schemes, supra, compounds of formula Ic may 
be prepared, and such compounds include, but are not limited to: 
2-(4-acetoxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piper 
idinyl)ethoxy!phenyl!methanone 
2-(4-benzoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-pi 
peridinyl)ethoxy!phenyl!methanone 
2-(4-butanoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-p 
iperidinyl)ethoxy!phenyl!methanone 
2-(4-hexanoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-p 
iperidinyl)ethoxy!phenyl!methane 
2-(4-benzoyloxyphenyl)-6-di-methylphosphonoylbenzob!thien-3-yl!4-2-(1-p 
iperidinyl)ethoxy!phenyl!methanone 
2-(2-acetoxy-4-chlorophenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2 
-(1-piperidinyl)ethoxy!phenyl!methanone 
2-(3-benzoyloxy-4-fluorophenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4 
-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-(3-benzoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-pi 
peridinyl)ethoxy!phenyl!methanone 
2-(2-butanoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-p 
yrrolidinyl)ethoxy!phenyl!methanone 
2-(4-n-butylsulfonoyloxyphenyl)-6-di-propylphosphonoylbenzob!thien-3-yl! 
4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-(4-n-butylsulfonoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4 
-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-(4-acetoxyphenyl)-6-di-i-butylphosphonoylbenzob!thien-3-yl!4-2-(1-pip 
eridinyl)ethoxy!phenyl!methanone 
2-(2-methyl-3-acetyl-4-hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3 
-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
2-(4-benzoyloxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-3-(1-pi 
peridinyl)propoxy!phenyl!methanone 
2-(3,4-di-acetoxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1- 
piperidinyl)ethoxy!phenyl!methanone 
and the like. 
A preferred embodiment of the current invention is 
2-(4-hydroxyphenyl)-6-diethylphosphonoylbenzob!thien-3-yl!4-2-(1-piper 
idinyl)ethoxy!phenyl!methanone. 
Together, the compounds of formulae Ia, Ib, and Ic comprise the genus of 
the compounds of formula I, are novel, and useful for the pharmacologic 
methods described herein. 
Although the free-base form of formula I compounds can be used in the 
methods of the present invention, it is preferred to prepare and use a 
pharmaceutically acceptable salt form. Thus, the compounds used in the 
methods of this invention primarily form pharmaceutically acceptable acid 
addition salts with a wide variety of organic and inorganic acids, and 
include the physiologically acceptable salts which are often used in 
pharmaceutical chemistry. Such salts are also part of this invention. 
Typical inorganic acids used to form such salts include hydrochloric, 
hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and 
the like. Salts derived from organic acids, such as aliphatic mono and 
dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and 
hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic 
acids, may also be used. Such pharmaceutically acceptable salts thus 
include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, 
benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, 
methoxybenzoate, methylbenzoate, o-acetoxybenzoate, 
naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, 
.beta.-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, 
caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, 
heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, 
mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, 
phthalate, terephthalate, phosphate, monohydrogenphosphate, 
dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, 
phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, 
bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, 
p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 
2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, 
naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, 
and the like. Preferred salts are the hydrochloride and oxalate salts. 
The pharmaceutically acceptable acid addition salts are typically formed by 
reacting a compound of formula I with an equimolar or excess amount of 
acid. The reactants are generally combined in a mutual solvent such as 
diethyl ether or ethyl acetate. The salt normally precipitates out of 
solution within about one hour to 10 days and can be isolated by 
filtration or the solvent can be stripped off by conventional means. 
The pharmaceutically acceptable salts generally have enhanced solubility 
characteristics compared to the compound from which they are derived, and 
thus are often more amenable to formulation as liquids or emulsions. 
The term "solvate" represents an aggregate that comprises one or more 
molecules of the solute, such as a formula I compound, with one or more 
molecules of solvent. 
The following examples are presented to further illustrate the preparation 
of compounds of the present invention. It is not intended that the 
invention be limited in scope by reason of any of the following examples. 
NMR data for the following Examples were generated on a GE 300 MHz NMR 
instrument, and anhydrous d-6 DMSO was used as the solvent unless 
otherwise indicated.

PREATION 1 
2-4-(t-Butyldimethylsilyloxy)phenyl!-6-hydroxybenzob!thien-3-yl!4-2-(1 
-piperidinyl)ethoxy!phenyl!methanone 
A solution was prepared consisting of 10 g (21.1 mmol) of 
2-(4-hydroxyphenyl)-6-hydroxybenzob!thien-3-yl!4-2-(1-piperidinyl)etho 
xy!phenyl!methanone and 6 g (49.1 mmol) of dimethylaminopyridine in 700 mL 
of THF-DMF (6:1)(v/v). This solution was stirred for one hour at ambient 
temperature and then cooled to 0.degree. C. in an ice bath. To this 
solution was added 2.9 g (19.3 mmol) of tert-butyl-dimethylsilylchloride. 
The reaction mixture was stirred under a nitrogen atmosphere and allowed 
to warm to ambient temperature. After seventy-two hours, the reaction was 
quenched with the addition of a saturated solution of aqueous NH.sub.4 Cl. 
The organic layer was separated and washed with water, brine, and finally 
dried by filtration through anhydrous Na.sub.2 SO.sub.4 and evaporated to 
dryness. The crude product was triturated with CH.sub.2 Cl.sub.2, allowed 
to stand for three hours, and filtered to remove unreacted starting 
material. This resulting product is a mixture of isomers, which are 
separated by chromatography on a silica gel column eluted with a linear 
gradient beginning with CHCl.sub.3 and ending with CHCl.sub.3 --MeOH 
(19:1)(v/v). The desired fractions were determined by tlc, combined, and 
evaporated to dryness. This yielded 5.1 g of the title compound, isolated 
as a yellow crystalline solid. 
PMR: .delta.0.12(s,6H); 0.92(s,9H); 1.46(m,2H); 1.67(m,4H); 2.56(m,5H); 
2.79(t, J=5.6 Hz, 2H); 4.07(t, J=5.7 Hz, 2H); 6.55(d, J=8.9 Hz, 2H); 
6.66(d, J=8.5 Hz, 2H); 6.77(dd, J.sub.1 =8.7 Hz, J.sub.2 =2.2 Hz, 1H); 
7.17(d, J=2.2 Hz, 1H); 7.20(d, J=8.6 Hz, 3H); 7.44 (d, J=8.8 Hz, 1H); 
7.63(d, J=8.9 Hz, 2H) 
MS: m/e=587 (M) FD 
EA: Calc. for C.sub.34 H.sub.41 NO.sub.4 SSi: C, 69.47; H, 7.03; N, 2.38 
Found: C, 69.19; H, 6.98; N, 2.57. 
PREATION 2 
2-4-(t-Butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzob 
!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone 
A solution was prepared of 10 g (17.5 mmol) of 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-hydroxybenzob! 
thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone in 100 mL of 
CH.sub.2 Cl.sub.2, which was placed under a nitrogen atmosphere and cooled 
to 0.degree. C. in an ice bath. Triethylamine (5 mL, 3.6 g, 35.9 mmol) was 
added followed by the addition of 7 g (19.5 mmol) of 
N-phenyltrifluoromethanesulfonimide. The reaction was allowed to warm 
slowly to ambient temperature over a period of sixteen hours. The reaction 
mixture was filtered and evaporated to a red oil. The crude product was 
chromatographed on a silica gel column eluted with CH.sub.2 Cl.sub.2. This 
yielded 11 g of the title compound isolated as a tan amorphous solid. 
PMR: (CDCl.sub.3) .delta.0.05 (s, 6H); 0.85(s, 9H); 1.35(m, 2H); 1.55(m, 
4H); 2.40(m, 4H); 2.65(t, J=7 Hz, 2H); 4.00(t, J=7 Hz, 2H); 6.65(m, 4H); 
7.20(m, 3H); 7.65(d, J=10 Hz, 2H); 7.75(m,2H) 
MS: m/e=720 (M) FD 
EXAMPLE 1 
2-(4-Hydroxyphenyl)-6-di-ethylphosphonoylbenzob!thien-3-yl!4-2-(1-piper 
idinyl)ethoxy!phenyl!methanone 
A solution was prepared of 2 g (2.8 mmol) of 
2-4-(t-butyldimethylsilyloxy)phenyl!-6-trifluoromethylsulfonoyloxybenzo 
b!thien-3-yl!4-2-(1-piperidinyl)ethoxy!phenyl!methanone, 0.58 g (0.54 mL, 
4.2 mmol) of diethylphosphite, and 5 mL of triethylamine in 15 mL of MeCN. 
The reaction was purged with nitrogen for fifteen minutes and 100 mg of 
Pd(0)(Ph.sub.3 P).sub.4 was added. The reaction mixture turned a bright 
yellow color. The reaction mixture was heated to 75.degree. C. for 
thirty-six hours. The reaction was allowed to cool, evaporated to dryness 
in vacuo, the residue resuspended in 100 mL of THF, and filtered. The 
crude product was partitioned between 100 mL of EtOAc and 100 mL of 1N HCl 
and stirred, vigorously, for two hours at ambient temperature. The organic 
layer was separated and dried by filteration through anhydrous Na.sub.2 
SO.sub.4 and evaporated to dryness. This yielded 800 mg of the title 
compound as yellow solid, mp: 75-78.degree. C. 
PMR: .delta.1.25 (t, J=4 Hz,6H); 1.40 (s br, 2H); 1.50 (s br, 4H); 2.45 (s 
br, 4H); 2.70 (t, J=3 Hz, 2H); 4.05-4.25 (m, 6H); 6.80 (d, J=8 Hz, 2H); 
7.00 (d, J=8 Hz, 2H); 7.35 (d, J=8 Hz, 2H); 7.65-7.70 (m, 2H); 7.75 (d, 
J=8 Hz, 2H); 8.55 (d, J=15 Hz, 1H); 10.05 (s br, 1H) 
MS: m/e=594 FD 
EA: Calc. for C.sub.32 H.sub.36 NO.sub.6 PS-3/2H.sub.2 O: C, 63.47; H, 
6.21; N, 2.31 Found: C, 63.10; H, 6.08; N, 2.20. 
TEST PROCEDURE 
General Preparation Procedure 
In the examples illustrating the methods, a post-menopausal model was used 
in which effects of different treatments upon circulating lipids were 
determined. 
Seventy-five day old female Sprague Dawley rats (weight range of 200 to 225 
g) are obtained from Charles River Laboratories (Portage, Mich.). The 
animals are either bilaterally ovariectomized (OVX) or exposed to a Sham 
surgical procedure at Charles River Laboratories, and then shipped after 
one week. Upon arrival, they are housed in metal hanging cages in groups 
of 3 or 4 per cage and have ad libitum access to food (calcium content 
approximately 0.5%) and water for one week. Room temperature is maintained 
at 22.2.degree..+-.1.7.degree. C. with a minimum relative humidity of 40%. 
The photoperiod in the room is 12 hours light and 12 hours dark. 
Dosing Regimen Tissue Collection. After a one week acclimation period 
(therefore, two weeks post-OVX) daily dosing with test compound is 
initiated. 17.alpha.-ethynyl estradiol or the test compound are given 
orally, unless otherwise stated, as a suspension in 1% 
carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals are dosed 
daily for 4 days. Following the dosing regimen, animals are weighed and 
anesthetized with a ketamine: Xylazine (2:1, V:V) mixture and a blood 
sample is collected by cardiac puncture. The animals are then sacrificed 
by asphyxiation with CO.sub.2, the uterus is removed through a midline 
incision, and a wet uterine weight is determined. 
Cholesterol Analysis. Blood samples are allowed to clot at ambient 
temperature for 2 hours, and serum is obtained following centrifugation 
for 10 minutes at 3000 rpm. Serum cholesterol is determined using a 
Boehringer Mannheim Diagnostics high performance cholesterol assay. 
Briefly, the cholesterol is oxidized to cholest-4-en-3-one and hydrogen 
peroxide. The hydrogen peroxide is then reacted with phenol and 
4-aminophenazone in the presence of peroxidase to produce a p-quinone 
imine dye, which is read spectrophotemetrically at 500 nm. Cholesterol 
concentration is then calculated against a standard curve. 
Uterine Eosinophil Peroxidase (EPO) Assay. Uteri are kept at 4.degree. C. 
until time of enzymatic analysis. The uteri are then homogenized in 50 
volumes of 50 mM Tris buffer (pH-8.0) containing 0.005% Triton X-100. Upon 
addition of 0.01% hydrogen peroxide and 10 mM o-phenylenediamine (final 
concentrations) in Tris buffer, increase in absorbance is monitored for 
one minute at 450 nm. The presence of eosonophils in the uterus is an 
indication of estrogenic activity of a compound. The maximal velocity of a 
15 second interval is determined over the initial, linear portion of the 
reaction curve. 
Source of Compound: 17.alpha.-ethynyl estradiol was obtained from Sigma 
Chemical Co., St. Louis, Mo. 
The pharmacologic activity for the methods of the current invention, i.e., 
the compounds of formula I, are illustrate in Table 1, below. 
Osteoporosis Test Procedure 
Following the General Preparation Procedure, infra, the rats are treated 
daily for 35 days (6 rats per treatment group) and sacrificed by carbon 
dioxide asphyxiation on the 36th day. The 35 day time period is sufficient 
to allow maximal reduction in bone density, measured as described herein. 
At the time of sacrifice, the uteri are removed, dissected free of 
extraneous tissue, and the fluid contents are expelled before 
determination of wet weight in order to confirm estrogen deficiency 
associated with complete ovariectomy. Uterine weight is routinely reduced 
about 75% in response to ovariectomy. The uteri are then placed in 10% 
neutral buffered formalin to allow for subsequent histological analysis. 
The right femurs are excised and digitized x-rays generated and analyzed by 
an image analysis program (NIH image) at the distal metaphysis. The 
proximal aspect of the tibiae from these animals are also scanned by 
quantitative computed tomography. 
In accordance with the above procedures, compounds of the present invention 
and ethynyl estradiol (EE.sub.2) in 20% hydroxypropyl .beta.-cyclodextrin 
are orally administered to test animals. 
TABLE 1 
______________________________________ 
Serum 
Dose Uterine Wt. 
Uterine EPO 
Cholesterol 
Compound mg/kg).sup.a 
(% Inc.).sup.b 
(Vmax).sup.c 
(% Dec.).sup.d 
______________________________________ 
EE.sub.2.sup.e 
0. 171.2* 142.4* 85.1* 
Example 1 
0.1 -.08 3.9 -20.4 
1 0.9 2.7 6.3 
10 36.6* 7.2 48.9* 
______________________________________ 
*p &lt; 0.05 
.sup.a mg/kg PO 
.sup.b Uterine Weight, % increase versus the ovariectomized controls 
.sup.c Eosinophil peroxidase, .sup.V maximum 
.sup.d Serum cholesterol decrease versus ovariectomized controls 
.sup.e 17Ethynyl-estradiol 
As evidence of the current invention treat estrogen dependent cancer, the 
following assay was performed. 
MCF-7 Proliferation Assay 
MCF-7 breast adenocarcinoma cells (ATCC HTB 22) were maintained in MEM 
(minimal essential medium, phenol red-free, Sigma, St. Louis, Mo.) 
supplemented with 10% fetal bovine serum (FBS) (V/V), L-glutamine (2 mM), 
sodium pyruvate (1 mM), HEPES 
{(N-2-hydroxyethyl!piperazine-N'-2-ethanesulfonic acid! 10 mM}, 
non-essential amino acids and bovine insulin (1 ug/mL) (maintenance 
medium). Ten days prior to assay, MCF-7 cells were switched to maintenance 
medium supplemented with 10% dextran coated charcoal stripped fetal bovine 
serum (DCC-FBS) assay medium) in place of 10% FBS to deplete internal 
stores of steroids. MCF-7 cells were removed from maintenance flasks using 
cell dissociation medium Ca++/Mg++ free HBSS (phenol red-free) 
supplemented with 10 mM HEPES and 2 mM EDTA!. Cells were washed twice with 
assay medium and adjusted to 80,000 cells/mL. Approximately 100 mL (8,000 
cells) were added to flat-bottom microculture wells (Costar 3596) and 
incubated at 37.degree. C. in a 5% CO.sub.2 humidified incubator for 48 
hours to allow for cell adherence and equilibration after transfer. Serial 
dilutions of drugs or DMSO as a diluent control were prepared in assay 
medium and 50 mL transferred to triplicate microcultures followed by 50 mL 
assay medium for a final volume of 200 mL. After an additional 48 hours at 
37.degree. C. in a 5% CO.sub.2 humidified incubator, microcultures were 
pulsed with tritiated thymidine (1 .mu.Ci/well) for 4 hours. Cultures were 
terminated by freezing at -70.degree. C. for 24 hours followed by thawing 
and harvesting of microcultures using a Skatron Semiautomatic Cell 
Harvester. Samples were counted by liquid scintillation using a Wallac 
BetaPlace .beta. counter. The compounds of formula I are active and potent 
in inhibiting the tumor cell growth. 
The Example 1 compound has an IC.sub.50 of 100 nM for the inhibition of the 
MCF-7 tumor cell line. 
As used herein, the term "effective amount" means an amount of compound of 
the present invention which is capable of inhibiting the symptoms of the 
various pathological conditions herein described. The specific dose of a 
compound administered according to this invention will, of course, be 
determined by the particular circumstances surrounding the case including, 
for example, the compound administered, the route of administration, the 
state of being of the patient, and the pathological condition being 
treated. 
The compounds of this invention can be administered by a variety of routes 
including oral, rectal, transdermal, subcutaneous, intravenous, 
intramuscular, and intranasal. These compounds preferably are formulated 
prior to administration, the selection of which will be decided by the 
attending physician. Thus, another aspect of the present invention is a 
pharmaceutical composition comprising an effective amount of a compound of 
Formula I, or a pharmaceutically acceptable salt thereof. 
The total active ingredients in such formulations comprises from 0.1% to 
99.9% by weight of the formulation. By "pharmaceutically acceptable" it is 
meant the carrier, diluent, excipients and salt must be compatible with 
the other ingredients of the formulation, and not deleterious to the 
recipient thereof. 
Pharmaceutical formulations of the present invention can be prepared by 
procedures known in the art using well known and readily available 
ingredients. For example, the compounds of formula I, with or without an 
estrogen or progestin compound, can be formulated with common excipients, 
diluents, or carriers, and formed into tablets, capsules, suspensions, 
powders, and the like. Examples of excipients, diluents, and carriers that 
are suitable for such formulations include the following: fillers and 
extenders such as starch, sugars, mannitol, and silicic derivatives; 
binding agents such as carboxymethyl cellulose and other cellulose 
derivatives, alginates, gelatin, and polyvinyl-pyrrolidone; moisturizing 
agents such as glycerol; disintegrating agents such as calcium carbonate 
and sodium bicarbonate; agents for retarding dissolution such as paraffin; 
resorption accelerators such as quaternary ammonium compounds; surface 
active agents such as cetyl alcohol, glycerol monostearate; adsorptive 
carriers such as kaolin and bentonite; and lubricants such as talc, 
calcium and magnesium stearate, and solid polyethyl glycols. 
The compounds also can be formulated as elixirs or solutions for convenient 
oral administration or as solutions appropriate for parenteral 
administration, for example, by intramuscular, subcutaneous or intravenous 
routes. Additionally, the compounds are well suited to formulation as 
sustained release dosage forms and the like. The formulations can be so 
constituted that they release the active ingredient only or preferably in 
a particular physiological location, possibly over a period of time. The 
coatings, envelopes, and protective matrices may be made, for example, 
from polymeric substances or waxes. 
Compounds of formula I, alone or in combination with another pharmaceutical 
agent, generally will be administered in a convenient formulation. A 
typical dosage amount is from about 5 mg to about 600 mg, 1 to 3 times a 
day. More typically, the dose will be about 15 mg to 80 mg/day. The term 
of administration will be for a period of at least 2 months. More 
typically, administration will be at least 6 months, or chronically. The 
following formulation examples only are illustrative and are not intended 
to limit the scope of the present invention. 
FORMULATIONS 
In the formulations which follow, "active ingredient" means a compound of 
formula I, or a salt or solvate thereof. 
Formulation 1: Gelatin Capsules 
Hard gelatin capsules are prepared using the following: 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Active ingredient 0.1-1000 
Starch, NF 0-650 
Starch flowable powder 
0-650 
Silicone fluid 350 centistokes 
0-15 
______________________________________ 
The formulation above may be changed in compliance with the reasonable 
variations provided. 
A tablet formulation is prepared using the ingredients below: 
Formulation 2: Tablets 
______________________________________ 
Ingredient Quantity (mg/tablet) 
______________________________________ 
Active ingredient 
2.5-1000 
Cellulose, microcrystalline 
200-650 
Silicon dioxide, fumed 
10-650 
Stearate acid 5-15 
______________________________________ 
The components are blended and compressed to form tablets. 
Alternatively, tablets each containing 2.5-1000 mg of active ingredient are 
made up as follows: 
Formulation 3: Tablets 
______________________________________ 
Ingredient Quantity (mg/tablet) 
______________________________________ 
Active ingredient 25-1000 
Starch 45 
Cellulose, microcrystalline 
35 
Polyvinylpyrrolidone 
4 
(as 10% solution in water) 
Sodium carboxymethyl cellulose 
4.5 
Magnesium stearate 0.5 
Talc 1 
______________________________________ 
The active ingredient, starch, and cellulose are passed through a No. 45 
mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone 
is mixed with the resultant powders which are then passed through a No. 14 
mesh U.S. sieve. The granules so produced are dried at 
50.degree.-60.degree. C. and passed through a No. 18 mesh U.S. sieve. The 
sodium carboxymethyl starch, magnesium stearate, and talc, previously 
passed through a No. 60 U.S. sieve, are then added to the granules which, 
after mixing, are compressed on a tablet machine to yield tablets. 
Suspensions each containing 0.1-1000 mg of medicament per 5 ml dose are 
made as follows: 
Formulation 4: Suspensions 
______________________________________ 
Ingredient Quantity (mg/5 ml) 
______________________________________ 
Active ingredient 0.1-1000 mg 
Sodium carboxymethyl cellulose 
50 mg 
Syrup 1.25 mg 
Benzoic acid solution 
0.10 mL 
Flavor q.v. 
Color q.v. 
Purified water to 5 mL 
______________________________________ 
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with 
the sodium carboxymethyl cellulose and syrup to form a smooth paste. The 
benzoic acid solution, flavor, and color are diluted with some of the 
water and added, with stirring. Sufficient water is then added to produce 
the required volume. 
An aerosol solution is prepared containing the following ingredients: 
Formulation 5: Aerosol 
______________________________________ 
Quantity (% by 
Ingredient weight) 
______________________________________ 
Active ingredient 0.25 
Ethanol 25.75 
Propellant 22 (Chlorodifluoromethane) 
70.00 
______________________________________ 
The active ingredient is mixed with ethanol and the mixture added to a 
portion of the propellant 22, cooled to 30.degree. C., and transferred to 
a filling device. The required amount is then fed to a stainless steel 
container and diluted with the remaining propellant. The valve units are 
then fitted to the container. 
Suppositories are prepared as follows: 
Formulation 6: Suppositories 
______________________________________ 
Ingredient Quantity (mg/suppository) 
______________________________________ 
Active ingredient 
250 
Saturated fatty acid 
2,000 
glycerides 
______________________________________ 
The active ingredient is passed through a No. 60 mesh U.S. sieve and 
suspended in the saturated fatty acid glycerides previously melted using 
the minimal necessary heat. The mixture is then poured into a suppository 
mold of nominal 2 g capacity and allowed to cool. 
An intravenous formulation is prepared as follows: 
Formulation 7: Intravenous Solution 
______________________________________ 
Ingredient Quantity 
______________________________________ 
Active ingredient 50 mg 
Isotonic saline 1,000 mL 
______________________________________ 
The solution of the above ingredients is intravenously administered to a 
patient at a rate of about 1 mL per minute. 
Formulation 8: Combination Capsule I 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Active ingredient 
50 
Premarin 1 
Avicel pH 101 50 
Starch 1500 117.50 
Silicon Oil 2 
Tween 80 0.50 
Cab-O-Sil 0.25 
______________________________________ 
Formulation 9: Combination Capsule II 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Active ingredient 
50 
Norethylnodrel 
5 
Ayicel pH 101 82.50 
Starch 1500 90 
Silicon Oil 2 
Tween 80 0.50 
______________________________________ 
Formulation 10: Combination Tablet 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Active ingredient 
50 
Premarin 1 
Corn Starch NF 50 
Povidone, K29-32 
6 
Avicel pH 101 41.50 
Avicel pH 102 136.50 
Crospovidone XL10 
2.50 
Magnesium Stearate 
0.50 
Cab-O-Sil 0.50 
______________________________________