The current invention provides methods and pharmaceutical formulations that are useful for inhibiting the loss of bone. These methods and formulations can be used without the associated adverse effects of estrogen therapy, and thus serve as an effective and acceptable treatment for osteoporosis.
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1. A method of inhibiting post-menopausal bone loss in a postmenopausal woman in need of treatment to prevent or to treat post-menopausal osteoporosis comprising administering to a human said woman in need of said treatment an amount of a compound of Formula I
##STR00011##
wherein
X is a bond, CH2, or CH2CH2;
R and R1, independently, are hydrogen, hydroxyl, C1-C6-alkoxy, C1-C6-acyloxy, C1-C6-akoxy-C2-C6-acyloxy, R3-substituted aryloxy, R3-substituted aroyloxy, R4-substituted carbonyloxy, chloro, or bromo;
R2 is a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, and hexamethyleneimino;
R3 is C1-C3-alkyl, C1-C3-alkoxy, hydrogen, or halo; and
R4 is C1-C6-alkoxy or aryloxy; or a pharmaceutically acceptable salt thereof, that is effective to inhibit post-menopausal bone loss in a human said woman.
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This application is a continuation of application Ser. No. 07/920,933, filed on Jul. 28, 1992, now abandoned.
This invention relates to the discovery that a group of 2-phenyl-3-aroylbenzothiophenes is useful in the prevention of bone loss.
The mechanism of bone loss is not well understood, but in practical effect, the disorder arises from an imbalance in the formation of new healthy bone and the resorption of old bone, skewed toward a net loss of bone tissue. This bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased fracture rate of, predominantly, femoral bones and bones in the forearm and vertebrae. These fractures, in turn, lead to an increase in general morbidity, a marked loss of stature and mobility, and, in many cases, an increase in mortality resulting from complications.
Bone loss occurs in a wide range of subjects, including post-menopausal women, patients who have undergone hysterectomy, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patients having gonadal —OC(O)CH2CH2OCH3
In the following Preparations, the compound numbers correspond to those given in Table 1
Raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl-4-[2-(piperidin-1-yl)ethoxyphenyl]methanone hydrochloride, (5.1 g, 10 mmol) was suspended in 250 mL of dry tetrahydrofuran (THF) and 7.1 g (70 mmol) of triethylamine, and approximately 10 mg of 4-(N,N-dimethylamino)pyridine were added. The suspension was cooled in an ice bath and placed under an atmosphere of nitrogen. 4-Fluorobenzoyl chloride (4.75 g, 30 mmol), dissolved in 20 mL of dry THF, was slowly added over a twenty minute period. The reaction mixture was stirred and allowed to slowly warm to room temperature over a period of eighteen hours. It was then filtered, and the filtrate was evaporated to a gum in vacuo. The crude product thus obtained was dissolved in a small volume of chloroform and chromatographed (HPLC) on a silica gel column eluted with a linear gradient of solvent, starting with chloroform and ending with a mixture of chloroform-methanol (19:1 (v/v)). The fractions containing the desired product as determined by thin layer chromatography (silica, chloroform-methanol (9:1)) were combined and evaporated to a gum. The final product was crystallized from ether to give 3.21 g of compound 1.
PMR: consistent with the structure FDMS: m/e=717 M+
Elemental Analysis for C42H33F2NO6S: Theor: C, 70.29; H, 4.60; N, 1.95 Found: C, 70.05; H, 4.60; N, 1.89 Mol. Wt.: 717.
Compound 1 (5.15 g, 7.18 mmol) was dissolved in 25 mL THF, and 150 mL ether was added. Dry HCl gas was bubbled into the solution, and a white gummy precipitate formed. The liquid was removed by decanting, and the residue was crystallized from ethyl acetate with a small amount of ethanol added to effect solution. The product was filtered, washed with ether, and dried to give 4.41 g of Compound 2 as a white powder.
PMR: consistent with the structure
Elemental Analysis for C42H34ClF2NO6S: Theor: C, 66.88; H, 4.54; N, 1.86 Found: C, 66.59, H, 4.39; N, 1.60 Mol. Wt.: 753.5.
The title compound was prepared using procedures analogous to those in Preparation 1, but using cyclopropylcarbonyl chloride, except that the product was not crystallized. Yield=2.27 g.
PMR: consistent with the structure FDMS: m/e=610 M+
Compound 4 was prepared from Compound 3 as described in Preparation 2.
Compound 5 was prepared using the method of Preparation 1, but starting with n-butanoyl chloride, to give 4.12 g of final product as an oil.
PMR: consistent with the structure FDMS: m/e=614 (M+1)
Compound 5 (4.12 g) was dissolved in ethyl acetate (50 mL), and a solution of HCl in ether was added until the precipitation stopped. The liquid was decanted off, and the white, gummy residue was triturated with diethyl ether and filtered. The residue was dried to give 1.33 g of Compound 6.
PMR: consistent with the structure
Elemental Analysis of for C36H40ClNO6S: Theor.: C, 66.50; H, 6.20; N, 2.15 Found: C, 66.30; H, 6.28; N, 1.98 Mol. Wt.: 650.24.
Compound 7 was prepared using the procedure of Preparation 1, but using 2,2-dimethylpropanoyl chloride.
Compound 8 was Prepared from Compound 7, as described in Preparation 2.
FDMS: m/e=641 (M-HCl-1)
Elemental Analysis of C38H44ClNO6S: Theor.: C, 67.29; H, 6.54; N, 2.07 Found: C, 67.02; H, 6.54; N, 1.90 Mol. Wt.: 678.29.
Compound 9 was prepared using the procedures of Preparation 1, but with 3,3-dimethylbutanoyl chloride.
Compound 10 was prepared from Compound 9 as described in Preparation 2.
FDMS: m/e=669 (M-HCl-1)
Elemental Analysis of C40H48ClNO6S: Theor.: C, 68.02; H, 6.85; N, 1.98 Found: C, 67.75; H, 6.83; N, 2.04 Mol. Wt.: 706.35.
Compound 11 was prepared from the free base using a procedure similar to that of Preparation 2.
FDMS: m/e=710 (M-HCl-1)
Elemental Analysis of C44H40ClNO6S: Theor.: C, 70.81; H, 5.39; N, 1.88 Found: C, 71.10; H, 5.39; N, 1.94 Mol. Wt.: 746.33.
Compound 12 was prepared from the appropriate acid chloride as described in Preparation 1.
FDMS: m/e=682 (M+1)
Element Analysis of C42H35NO6S: Calc: C, 73.80; H, 5.14; N, 2.05 Found: C, 73.27; H, 5.27; N, 1.94 Mol. Wt.: 681.8.
Compound 13 was prepared in a manner analogous to that described in Preparation 1, except that n-butylchloroformate was used in place of the acid chloride. Yield=6.13 g in form of oil.
PMR: consistent with structure FDMS: m/e=674 (M+1)
Compound 13 was converted to the hydrochloride salt in a manner analogous to that described in Preparation 6.
PMR: consistent with structure
Elemental Analysis of C38H44ClNO8S: Calc: C, 64.26; H, 6.24; N, 1.97 Found: C, 63.97; H, 6.34; N, 1.98 Mol. Wt.: 710.29.
This compound was prepared in a manner analogous to that described in Preparation 13, but using the appropriate acyl ester. Yield=3.59 g of final product as a tan amorphous powder.
PMR: consistent with structure FDMS: m/e=713 (M+)
Compound 15 was converted to the hydrochloride salt in a manner analogous to that described in Preparation 6.
PMR: consistent with structure
Elemental Analysis of C38H44ClNO8S: Calc: C, 67.24; H, 4.84; N, 1.87 Found: C, 66.94; H, 4.96; N, 1.84 Mol. Wt.: 750.27.
Compound 17 was prepared as described in Preparation 1 using the appropriate acid halide. Yield=3.5 g of a white amorphous powder.
PMR: consistent with structure FDMS: m/e=781 (M+)
Elemental Analysis of C50H39NO6S: Calc: C, 76.80; H, 5.03; N, 1.79 Found: C, 76.53; H, 5.20; N, 1.53 Mol. Wt.: 781.94.
Compound 18 was prepared as described in Preparation 1 using the appropriate acid halide. Yield=3.61 g of a gummy solid.
PRM: consistent with structure FDMS: m/e=618 (M+1)
Compound 19 was prepared from 3.5 g of Compound 18 as described in Preparation 2. Yield=1.65 g of amorphous white powder.
PMR: consistent with structure FDMS: m/e=618 (M+1)
Elemental Analysis of C34H36NO8S: Calc: C, 62.43; H, 5.55; N, 2.14 Found: C, 62.23; H, 5.63; N, 2.15.
The following nonlimiting examples illustrate the methods and formulations of this invention.
In the examples illustrating the methods, a model of post-menopausal osteoporosis was used in which effects of different treatments upon femur density were determined.
Seventy-five day old female Sprague Dawley rats (weight range of 225 to 275 g) were obtained from Charles River Laboratories (Portage, Mich.). They were housed in groups of 3 and had ad libitum access to food (calcium content approximately 1%) and water. Room temperature was maintained at 22.2°±1.7° C. with a minimum relative humidity of 40%. The photoperiod in the room was 12 hours light and 12 hours dark.
One week after arrival, the rats underwent bilateral ovariectomy under anesthesia (44 mg/kg Ketamine and 5 mg/kg Xylazine (Butler, Indianapolis, Ind.) administered intramuscularly). Treatment with vehicle, estrogen, or a compound of formula I was initiated on the day of surgery following recovery from anesthesia. Oral dosage was by gavage in 0.5 mL of 1% carboxymethylcellulose (CMC). Body weight was determined at the time of surgery and weekly thereafter and the dosage was adjusted with changes in body weight. Vehicle or estrogen treated ovariectomized (ovex) rats and non-ovariectomized (intact) rats were evaluated in parallel with each experimental group to serve as negative and positive controls.
The rats were treated daily for 35 days (6 rats per treatment group) and sacrificed by decapitation on the 36th day. The 35 day time period was sufficient to allow maximal reduction in bone density, measured as described herein. At the time of sacrifice, the uteri were removed, dissected free of extraneous tissue, and the fluid contents were expelled before determination of wet weight in order to confirm estrogen deficiency associated with complete ovariectomy. Uterine weight was routinely reduced about 75% in response to ovariectomy. The uteri were then placed in 10% neutral buffered formalin to allow for subsequent histological analysis.
The right femurs were excised and scanned at the distal metaphysis 1 mm from the patellar groove with single photon absorptiometry. Results of the densitometer measurements represent a calculation of bone density as a function of the bone mineral content and bone width.
The results of control treatments from five separate experiments are accumulated in Table 2. In summary, ovariectomy of the rats caused a reduction in femur density of about 25% as compared to intact vehicle treated controls. Estrogen, administered in the orally active form of ethynyl estradiol (EE2), prevented this loss of bone in a dose dependent manner, but it also exerted a stimulatory action on the uterus resulting in uterine weights approaching that of an intact rat when administered at 100 μg/kg. Results are reported as the mean of measurements from thirty rats ±the standard error of the mean.
In these studies, raloxifene also prevented bone loss in a dose dependent manner; however, only minimal increase of uterine weight over the ovariectomized controls was present in these animals. The results of five assays using raloxifene are combined in Table 3. Accordingly, each point reflects the responses of thirty rats and depicts a typical dose response curve for raloxifene in this model. Results are reported as the mean + the standard error of the mean.
TABLE 2
Bone Density
Uterine Weight
(mg/cm/cm)
(mg)
ovariectomy control
170 ± 3
127 ± 5
(0.5 mL CMC oral)
Intact control
220 ± 4
545 ± 19
(0.5 mL CMC oral)
EE2 100 μg/kg, oral
210 ± 4
490 ± 11
TABLE 3
Bone Density
Uterine Weight
(mg/cm/cm)
(mg)
ovariectomy control
171 ± 3
127 ± 5
(0.5 mL CMC oral)
Intact control
222 ± 3
540 ± 22
(0.5 mL CMC oral)
raloxifene 0.01 mg/kg, oral
176 ± 3
150 ± 5
raloxifene 0.10 mg/kg, oral
197 ± 3
196 ± 5
raloxifene 1.00 mg/kg, oral
201 ± 3
199 ± 5
raloxifene 10.00 mg/kg, oral
199 ± 3
186 ± 4
Raloxifene was administered alone or in combination with ethynyl estradiol. Rats treated with raloxifene alone had uterine weights which were marginally higher than the overiectomized controls and much less than those of ethynyl estradiol treated rats, which approached those of the intact controls. Conversely, raloxifene treatment significantly reduced bone loss in ovariectomized rats, and when given in combination with ethynyl estradiol it did not appreciably reduce the protective effect of the estrogen on bone density. The results are shown in Table 4.
TABLE 4
Bone Density
Uterine Weight
(mg/cm/cm)
(mg)
Experiment A
Ovariectomy control
162 ± 4
142 ± 18
(0.5 mL CMC oral)
Intact control
219 ± 5
532 ± 49
(0.5 mL CMC oral)
EE2 100 μg/kg, oral
202 ± 6
450 ± 17
EE2 100 μg/kg +
204 ± 2
315 ± 10
raloxifene 0.10 mg/kg, oral
EE2 100 μg/kg +
200 ± 5
250 ± 21
raloxifene 1 mg/kg, oral
Experiment B
Ovariectomy control
165 ± 8
116 ± 6
(0.5 mL CMC oral)
Intact control
220 ± 4
605 ± 69
(0.5 mL CMC oral)
EE2 100 μg/kg, oral
215 ± 11
481 ± 24
raloxifene 1 mg/kg +
197 ± 7
263 ± 17
EE2 100 μg/kg, oral
raloxifene 1 mg/kg
198 ± 11
202 ± 5
The ability of raloxifene to inhibit bone loss was compared to that of tamoxifen (SIGMA, St. Louis, Mo.). Tamoxifen, a well known antiestrogen currently used in the treatment of certain cancers, has been shown to inhibit bone loss (see for example, Love, R., et al. 1992 “Effects of tamoxifen on bone mineral density in post-menopausal women with breast cancer”, N Eng J Med 326:852; Turner, R., et al. 1988 “Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats”, Endo 122:1146). A relatively narrow range of doses of raloxifene and tamoxifen was administered orally to ovariectomized rats as in the previous example. Although both of these agents displayed the ability to prevent reduction of femur density while evoking only modest uterotrophic activity, as identified by gains in uterine weight (Table 5), a comparison of several histological parameters demonstrated a marked difference between the rats treated with these agents (Table 6).
Increases in epithelial height are a sign of estrogenicity of therapeutic agents and may be associated with increased incidence of uterine cancer. When raloxifene was administered as described in Example 1, only at one dose was there any statistically measurable increase in epithelial height over the ovariectomized controls. This was in contrast to the results seen with tamoxifen and estrogen. At all doses given, tamoxifen increased epithelial height equal to that of an intact rat, about a six-fold increase over the response seen with raloxifene. Estradiol treatment increased epithelial height to a thickness greater than intact rats.
Estrogenicity was also assessed by evaluating the adverse response of eosinophil infiltration into the stromal layer of the uterus (Table 6). Raloxifene did not cause any increase in the number of eosinophils observed in the stromal layer of ovariectomized rats while tamoxifen caused a significant increase in the response. Estradiol, as expected, caused a large increase in eosinophil infiltration.
Little or no difference was detectable between raloxifene and tamoxifen effects on thickness of the stroma and myometrium. Both agents caused an increase in these measurements that was much less than the effect of estrogen.
A total score of estrogenicity, which was a compilation of all four parameters, showed that raloxifene was significantly less estrogenic than tamoxifen.
TABLE 5
Bone Density
Uterine Weight
(mg/cm/cm)
(mg)
Ovariectomy control
171 ± 5
126 ± 17
(0.5 mL CMC oral)
Intact control
208 ± 4
490 ± 6
(0.5 mL CMC oral)
EE2 100 μg/kg, oral
212 ± 10
501 ± 37
raloxifene 1 mg/kg, oral
207 ± 13
198 ± 9
tamoxifen 1 mg/kg, oral
204 ± 7
216 ± 18
TABLE 6
Epithelial
Stromal
Myometrial
Stromal
Height
Eosinophils
Thickness
Expansion
Ovariectomy control
1.24
1.00
4.42
10.83
(0.5 mL CMC oral)
Intact control
2.71
4.17
8.67
20.67
(0.5 mL CMC oral)
EE2 100 μg/kg, oral
3.42
5.17
8.92
21.17
raloxifene 1 mg/kg
1.67
3.17
5.42
14.00
tamoxifen 1 mg/kg
2.58
2.83
5.50
14.17
Other compounds of formula I were administered orally in the rat assay described in Example 1. Table 7 reports the effect of a 1 mg/kg dose of each compound in terms of a percent inhibition of bone loss and percent uterine weight gain.
TABLE 7
Compound
% Inhibition
% Uterine
Number
of Bone Lossa
Weight Gainb
2
26
26
6
24
19
8
66
24
10
52
24
11
26
28
12
60
15
14
121
32
16
108
25
18
21
17
27
25
1
34
26
−6
aPercent inhibition of bone loss = (bone density of treated ovex animals − bone density of untreated ovex animals) − (bone density of estrogen treated ovex animals − bone density of untreated ovex animals) × 100.
bPercent uterine weight gain = (uterine weight of treated ovex animals − uterine weight of ovex animals) − (uterine weight of estrogen treated ovex animals − uterine weight of ovex animals) × 100.
Fracture rate as a consequence of osteoporosis is inversely correlated with bone mineral density. However, changes in bone density occur slowly, and are measured meaningfully only over many months or years. It is possible, however, to demonstrate that the formula I compounds, such as raloxifene, have positive effects on bone mineral density and bone loss by measuring various quickly responding biochemical parameters that reflect changes in skeletal metabolism. To this end, in a current test study of raloxifene at least one hundred-sixty patients are enrolled and randomized to four treatment groups: estrogen, two different doses of raloxifene, and placebo. Patients are treated daily for eight weeks.
Blood and urine are collected before, during, and at the conclusion of treatment. In addition, an assessment of the uterine epithelium is made at the beginning and at the conclusion of the study. Estrogen administration and placebo serve as the positive and negative controls, respectively.
The patients are healthy post-menopausal (surgical or natural) women, age 45-60 who would normally be considered candidates for estrogen replacement in treatment for osteoporosis. This includes women with an intact uterus, who have had a last menstrual period more than six months, but less than six years in the past.
Patients who have received any of the following medications systematically at the beginning of the study are excluded from the study: vitamin D, corticosteroids, hypolipidemics, thiazides, antigout agents, salicylates, phenothiazines, sulfonates, tetracyclines, neomycin, and antihelmintics. Patients who have received any estrogen, progestin, or androgen treatment more recently than three months prior to the beginning of the study; patients who have ever received calcitonin, fluoride, or bisphosphonate therapy; patients who have diabetes mellitus; patients who have a cancer history anytime any time within the previous five years; patients with any undiagnosed or abnormal genital bleeding; patients with active, or a history of, thromboembolic disorders; patients who have impaired liver or kidney function; patients who have abnormal thyroid function; patients who are poor medical or psychiatric risks; or patients who consume an excess of alcohol or abuse drugs.
Patients in the estrogen treatment group receive 0.625 mg/day and the two raloxifene groups receive dosages of 200 and 600 mg/day, all groups receiving oral capsule formulations. Calcium carbonate, 648 mg tablets, is used as calcium supplement with all patients taking 2 tablets each morning during the course of the study.
The study is a double-blind design. The investigators and the patients do not know the treatment group to which the patient is assigned.
A baseline examination of each patient includes quantitative measurement of urinary calcium, creatinine, hydroxyproline, and pyridinoline crosslinks. Blood samples are measured for serum levels of osteocalcin, bone-specific alkaline phosphatase, raloxifene, and raloxifene metabolites. Baseline measurements also include examination of the uterus including uterine biopsy.
During subsequent visits to the investigating physician, measurements of the above parameters in response to treatment are repeated. The biochemical markers listed above that are associated with bone resorption have all been shown to be inhibited by the administration of estrogen as compared to an untreated individual. Raloxifene is also expected to inhibit the markers in estrogen deficient individuals as an indication that raloxifene is effective in inhibiting bone loss from the time that treatment is begun.
Subsequent longer term studies can incorporate the direct measurement of bone density by the use of a photon absorptiometry and the measurement of fracture rates associated with therapy.
Cullinan, George J., Black, Larry J.
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