MXPA00012727A - Therapeutic combinations of (selective) estrogen receptor modulators (serm) and growth hormone secretagogues (ghs) for treating musculoskeletal frailty - Google Patents
Therapeutic combinations of (selective) estrogen receptor modulators (serm) and growth hormone secretagogues (ghs) for treating musculoskeletal frailtyInfo
- Publication number
- MXPA00012727A MXPA00012727A MXPA/A/2000/012727A MXPA00012727A MXPA00012727A MX PA00012727 A MXPA00012727 A MX PA00012727A MX PA00012727 A MXPA00012727 A MX PA00012727A MX PA00012727 A MXPA00012727 A MX PA00012727A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- oxo
- compound
- bone
- pharmaceutically acceptable
- Prior art date
Links
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Abstract
This invention is directed to pharmaceutical combination compositions and methods containing (-)-cis-6-phenyl- 5-(4-(2-pyrrolidin-1-yl-ethoxy) -phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt thereof and 2-amino-N-(2-(3a(R)-benzyl- 2-methyl-3-oxo-2,3, 3a, 4,6, 7-hexahydro-pyrazolo -[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl- 2-oxo-ethyl)-isobutyramide or a pharmaceutically acceptable salt thereof, methods of using such compositions and kits containing such compositions. The compositions are useful for treating musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass, frailty and low muscle mass.
Description
COMBINATION THERAPY FOR MUSCULOSKELETAL FRAGILITY
BACKGROUND OF THE INVENTION
This invention relates to a pharmaceutical combination of a selective estrogen receptor modulator (SERM) and a growth hormone secretagogue (GHS) that stimulates bone formation, increases bone mass, decreases serum lipid levels and increases muscle mass The invention further relates to kits containing such combinations and to the use of such combinations to treat musculoskeletal fragility, including osteoporosis, osteoporotic fracture, reduced bone mass, frailty, reduced muscle mass and similar disorders in mammals, including humans. In particular, this invention relates to a combination of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene -2-ol or one of its pharmaceutically acceptable salts and 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro -pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide or one of its pharmaceutically acceptable salts, or kits containing said combination and to the use of said combination to treat musculoskeletal fragility, including osteroporosis, osteoporotic fracture, reduced bone mass, frailty, reduced muscle mass and similar disorders in mammals, including humans.
Osteoporosis is a systemic skeletal disease, characterized by reduced bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures. In the United States, the disease affects more than 25 million people and causes more than 1.3 million fractures every year, including 500,000 spine fractures, 250,000 hip fractures and 240,000 wrist fractures each year. Hip fractures are the most serious, with 5-20% of patients dying within a one-year period and more than 50% of survivors being incapacitated. The elderly have an increased risk of osteoporosis and, therefore, it is expected that the problem will increase significantly with the aging of the population. The incidence of fractures worldwide is estimated to increase three times over the next 60 years and one study estimates that there will be 4.5 million hip fractures worldwide by the year 2050. Although both men and women are susceptible of musculoskeletal fragility, including osteoporosis, women have a higher risk of osteoporosis than men. Women experience a sudden acceleration of bone loss immediately after menopause. Other factors that increase bone loss that leads to osteoporosis include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Estrogens are the agents of choice in the prevention of osteoporosis or postmenopausal bone loss in women. In addition, Black et al., In EP 0605193A1, mention that estrogens, particularly when taken orally, lower plasma levels of LDL and increase those of high density lipoproteins (HDL), which are beneficial. However, long-term estrogen therapy has been linked to a number of disorders that include an increased risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment or take medication only for a short period of time. Although it is believed that the risk of endometrial cancer is reduced by the concurrent use of progesterone, there is still the problem about the possible increased risk of breast cancer due to the use of estrogen. The recently suggested therapeutic guidelines, which aim to reduce the risk of cancer, such as the administration of combinations of progesterone and estrogen, cause the patient to suffer from unacceptable bleeding. In addition, the combination of progesterone with estrogen seems to weaken the effects of lowering serum cholesterol of estrogen. Undesirable side effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable beneficial effect on serum LDL but do not cause undesirable side effects. Recently, a series of selective estrogen receptor modulators have been proposed for the treatment of osteoporosis. It has been described (Osteoporosis Conference Scrip No. 1812/13 April 16/20, 1993, p.29), that raloxifene, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) Benzoyl] benzo [b] -thiophene, emulates the favorable action of estrogen on bone and lipids but, unlike estrogen, has a minimal effect of uterine stimulation. [Black, L. J. et al., Raloxifene (LY139481 HCl) Prevents Bone Loss and Reduces Cholesterol Serum Without Causing Uterine Hypertrophy in Ovariectomized Rats, J. Clin Invest. 1994, 93: 63-69 and Delmas, P. D. et al., Effets of Raloxifene on Bone Mineral Density, Cholesterol Concentration Serum, and Uterine Endometrium in Postmenopausal Women, New England Journal of Medicine, 1997, 337: 1641-1647]. Agents such as droloxifene, United States Patent No. 5,254,595, prevent bone loss and therefore reduce the risk of fracture without the side effects of estrogen. However, estrogen and estrogen agonists alone can only be expected to reduce the risk of fracture by approximately 50%, with approximately 50% of osteoporotic women still at risk of osteoporotic fracture. U.S. Patent No. 5,552,412, commonly assigned, which is incorporated herein by reference, discloses SERM compound of formula
in which the variables are defined as described therein. The growth hormone (GH) that secretes in the pituitary gland stimulates the growth of all the tissues of the body that have the capacity to grow. In addition, GH is known to have the following basic effects on the body's metabolic processes: 1. Increase in the rate of protein synthesis in virtually all cells of the body; 2. Decrease in the rate of utilization of carbohydrates in body cells; 3. Increased mobilization of free fatty acids and use of fatty acids to produce energy. GH deficiency leads to a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of an acquired GH deficiency include a profound reduction in lean body mass and a concomitant increase in total body fat, particularly in the trunk region. The reduction of skeletal and muscular mass and muscular endurance lead to a significant reduction in exercise capacity. Bone density is also reduced. The administration of exogenous GH has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included lowering LDL cholesterol and improving psychological mood. In cases where higher levels of GH were desired, the problem was usually solved by administering exogenous GH or administering an agent that stimulates GH production and / or releases it. In any case, the peptide nature of the compound requires that it be administered by injection. Initially, the origin of GH was the removal of pituitary glands from corpses. This resulted in a costly product, and there was a risk that a disease associated with the donor of the pituitary gland could be transmitted to the GH receptor (eg, Jacob-Creutzfeld disease). Recently, recombinant GH has begun to be available which, although it no longer implies the risk of disease transmission, is still a very expensive product that must be administered by injection or by nasal spray. Most deficiencies of GH are caused by defects in the release of GH, not in primary defects in the synthesis of GH in the pituitary. Therefore, an alternative strategy to normalize serum GH levels is by stimulating their release from somatotropes. Increased GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of agents that release synthetic GH to stimulate the pituitary secretion of GH is being sought, and may have several advantages over costly and inconvenient GH replacement therapy. Acting along the physiological regulatory pathways, the most desirable agents would stimulate GH pituitary secretion and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by means of feedback loops negative intact. Physiological and pharmacological stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin hypoglycemia, as well as activities such as sleep and exercise, indirectly cause GH release of the pituitary acting in some way on the hypothalamus, perhaps by decreasing the secretion of somatostatin or increasing the secretion of a known secretagogue, the GH releasing factor (GHRF) or of an unknown endogenous GH releasing hormone, or all of them. The international patent application, publication number WO97 / 24369, of common assignment and designating, inter alia, the United States, describes secretagogues of the formula GH
in which the variables are defined as described therein. The international patent application number WO97 / 24369 is incorporated herein by reference. Tang et al., Restoring and Maintainiq Bone in Osteoqenic Female Rat Skeleton: I. Chanqes in Bone Mass and Structure, J. Bone Mineral Research 7 (9), p1093-1 104, 1992 describe data for the concept of loss, restoration and maintenance (LRM) , a practical approach to reverse existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, maintain the new bone (phase +/-). The study in rats used PGE2 and risendronate, a bisphosphonate, to show that most of the new spongy and cortical bone induced by PEG2 could be maintained for at least 60 days after discontinuing PGE2 by administering risedronate. Shen et al., Effets of Reciprocal Treatment with Estrogen and
Estrogen plus Parathyroid Hormone on Bone Structure and Strength in Ovariectomized Rats, J. Clinical Investigation, 1995, 96: 2331-2338 describes data for the combination and / or sequential use of antiresorptive agents and anabolic agents for the treatment of osteoporosis. The international patent application publication number
WO97 / 31640, commonly assigned and designating, inter alia, the United States, describes the use of certain GH secretagogues in combination with certain SERMs to treat osteoporosis. The international patent application publication number WO97 / 31640 is incorporated herein by reference.
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to a pharmaceutical composition comprising: a. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts; and b. a second compound, said second compound being 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4 , 3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide or one of its pharmaceutically acceptable salts. This invention further relates to a pharmaceutical composition as cited in the immediately preceding paragraph further comprising a pharmaceutical carrier. This invention also relates to a pharmaceutical composition as described in any of the first two paragraphs of this disclosure, wherein said first compound is (-) - cis-6-phenyl-5- (4- ( 2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound the L-tartrate of 2-amino-N- (2-3a (R) - benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-haxahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo- ethyl) -isobutyramide. This invention further relates to a method called process A, for treating a mammal suffering from musculoskeletal fragility, which comprises administering to said mammal a pharmaceutical composition as cited in any of the first three paragraphs of this summary. A preferred method within method A, called method B, is when the mammal suffers from osteoporosis. Another preferred method within procedure A, called procedure C, is when the mammal suffers osteotomy, idiopathic bone loss of childhood or bone loss associated with periodontitis. This invention also relates to a method, called method A1, for treating a mammal suffering from musculoskeletal fragility, which comprises administering said mammal. to. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts, and b. a second compound, said second compound being 2-amino-N- (1 (R) - (2,4-d-fluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin- 2-ylmethyl) -2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -ethyl) -2 -methylpropionamide or one of its pharmaceutically acceptable salts.
This invention relates particularly to a process of process A1, wherein the first compound and the second compound are administered substantially at the same time. This invention particularly relates to a process of process A1, hereinafter referred to as method D, wherein the second compound is administered over a period of from about three months to about three years. This invention relates more particularly to a method of process D, followed by administration of the first compound for a period of about three months to about three years, without the administration of the second compound for the period of about three months to about three years. This invention also relates more particularly to a procedure of process D, followed by administration of the first compound for a period greater than about three years, without the administration of the second compound during the period greater than approximately three years. This invention also relates to a method, hereinafter referred to as method E, for treating musculoskeletal fragility in a mammal suffering from it, which comprises administering to said mammal a therapeutically effective amount of a composition as cited in any of the three first paragraphs of this description. A preferred procedure within procedure E is when bone healing is enhanced after facial reconstruction, maxillary reconstruction or mandibular reconstruction, spinal synostosis is induced, the extension of the long bones is enhanced, the healing speed of a bone is enhanced. bone graft or a fracture of a long bone or prosthetic incarnation is enhanced. A further preferred method is that which comprises administering said mammal. to. a first compound, said first compound being (-) - cis-d-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts, and b. a second compound, said second compound being 2-amino-N- (1 (R) - (2,4-d-fluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) - pyridin-2-ylmethyl) -2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -ethyl) -2-methylpropionamide or one of its pharmaceutically acceptable salts. This invention relates particularly to a process of the method for increasing muscle mass in a mammal comprising, administering to said mammal an amount effective to increase the muscle mass of a composition as cited in any of the first three paragraphs of this disclosure. A further preferred method is that which comprises administering said mammal a. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene- 2-ol or one of its pharmaceutically acceptable salts, and b. a second compound, said second compound being 2-amino-N- (1 (R) - (2,4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin- 2-ylmethyl) -2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -ethyl) -2-methylpropionamide or one of its pharmaceutically acceptable salts. In all the methods of this invention, it is particularly preferred that the mammal be a human being. This invention also relates to a kit comprising a treatment for a mammal suffering from musculoskeletal fragility, comprising: a. in a first unit dose form, a therapeutically effective amount of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -pheni) -5,6,7,8 -tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and b. in a second unit dose form, a therapeutically effective amount of 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide or one of its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier; and c. a container.
This invention particularly relates to a kit as described in the immediately preceding paragraph, wherein said first unit dosage form comprises (-) - cis-6-phenyl-5- (4- (2- pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second unit dosage form comprises L-tartrate 2-amino-N- (2- (3a- ( R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2 -oxo-ethyl) -isobutyramide. In all of the compositions, methods and kits of this invention, it is particularly preferred that the salt D-tartrate of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) is used) phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and the salt is used L-tartrate 2-amino-N- (2- (3a- (R) -benzyl-2-methyl-3 -oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide. The term "disorder with reduced bone mass" refers to a condition in which the level of bone mass is below the specific normal for that age, as defined in the rules of the World Health Organization "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994), Report of a Study Group of the World Health Organization, World Health Organization, Technical Series 843. Idiopathic childhood and primary osteoporosis are also included The prevention or attenuation of long-term complications such as curvature of the spine, weight loss, prosthetic surgery and prevention of prostate malfunction is included in the treatment of osteoporosis. the rate of healing of bone fractures and the enhancement of the success rate of bone grafts, it also includes periodontal disease and alveolar bone loss The term "disorder with reduced bone mass" also refers to a mammal known to have a significantly higher than average chance of developing diseases such as those described above, including osteoporosis (for example, postmenopausal women, men over 60 and people who are being treated with drugs that cause osteoporosis as a side effect (such as glucocorticoids)). Those skilled in the art will recognize that the term "bone mass" actually refers to bone mass per unit surface, which is sometimes (although not entirely correct) called bone mineral density. The term "musculoskeletal fragility" refers to a disorder in which a subject has reduced bone mass and / or reduced muscle mass, and includes diseases, disorders and conditions such as, but not limited to, disorders involving reduced bone mass, osteoporosis, disorders that involve reduced muscle mass, osteotomy, idiopathic bone loss in childhood, bone loss associated with periodontitis, bone healing after facial reconstruction, maxillary reconstruction or mandibular reconstruction and bone fracture. In addition, musculoskeletal fragility includes disorders such as contact zones between newly implanted prostheses and bone, which require bone incarnation. The terms "treat", "treatment" or "treatment" as used herein, include curative, preventive (eg, prophylactic) and palliative treatment. The positive or negative sign in parentheses used in the present nomenclature represents the direction in which the polarized light in the plane is rotated by the particular stereoisomer. The compositions of this invention may include hydrates of the compounds used therein. The pharmaceutical compositions and methods of this invention result in a faster and larger increase in bone mass than can be achieved with the same doses of (-) - cis-6-phenyl-5- (4- ( 2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7, 8-tetrahydronaphthalen-2-ol as described above, alone, or 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6 , 7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide as described above, alone. In addition, these combinations increase bone density and muscle mass, while reducing fat mass and total serum cholesterol. Thus, these combinations increase bone mass and decrease fracture rates to a greater degree than can be achieved with the use of any of the agents alone. This invention has an important contribution to the art by providing compositions and methods that increase and maintain bone mass, resulting in the prevention, delay and / or reversal of osteoporosis and related bone disorders. Other features and advantages will be apparent from the specification and the claims describing the invention.
DETAILED DESCRIPTION OF THE INVENTION
The first compound of this invention is (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8- tetrahydronaphthalen-2-ol or a pharmaceutically acceptable salt thereof, having the structure of formula I:
(-) - Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -fenii] -5,6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts are they are prepared as described in U.S. Patent 5,552,412, commonly assigned and cited above.
D - tartrate of (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol is prepared as described in the immediately preceding paragraph or, alternatively, as described in the international patent application, publication number WO97 / 16434, which designates the United States and which is incorporated herein by reference. The second compound of this invention is 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxo-ethyl] -isobutyramide or one of its pharmaceutically acceptable salts, having the structure of formula II:
2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyrid) n-5-yl) -1 (R) benzyloxymethyl-2-oxo-ethyl] -isobutyramide and its pharmaceutically acceptable salts are prepared as described in the international patent application, publication number WO97 / 24369, of common cession, which It has been quoted before.
In addition, when the compounds, or their pharmaceutically acceptable salts, of this invention form hydrates or solvates, they are also within the scope of the invention. The pharmaceutical combinations and methods of this invention are all adapted to therapeutic use as agents that activate bone turnover or that prevent bone resorption or enhance formation in mammals, particularly in humans. Since these functions are closely related to the development of osteoporosis and bone-related disorders, these combinations, by virtue of their action on bone, prevent, stop, delay or reverse osteoporosis. The utility of the compositions and methods of the present invention as medical agents in the treatment of musculoskeletal fragility (e.g., disorders that involve reduced bone mass or reduced muscle mass, including osteoporosis) in mammals (e.g., humans) is demonstrated by the activity of the compounds of this invention in conventional tests such as those described in the US patent 5,552,412 and in the international patent application, publication number WO97 / 24369. Further evidence of the utility of the present combination is shown in Example 1, below. Such assays also provide a means by which the activities of the compounds of this invention, among themselves, and with the activities of other known compounds can be compared. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases. The administration of the compounds of this invention can be carried out by any method that releases a compound of the combination of this invention systemically and / or locally. These methods include the oral, parenteral, intraduodenal and the like. In general, the compounds of this invention are administered orally, although parenteral administration (eg, intravenous, intramuscular, transdermal, subcutaneous or intramedullary) can be used, for example, when oral administration is inappropriate for the particular object or when the patient is unable to ingest the drug. The two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition can be administered comprising a first compound as described above and a second compound as described above in a pharmaceutically acceptable carrier. In any case, the amount and pattern of administration of the administered compounds will, of course, depend on the subject being treated, the intensity of the condition, the manner of administration, and the opinion of the prescribing physician. Thus, due to the variability between patients, the doses indicated below are a guideline and the doctor can increase or decrease the dose of the drug to achieve the activity (for example, increase in bone mass) that the doctor considers appropriate for the patient individual. Considering the desired degree of activity, the doctor must assess a number of factors such as the initial level of bone mass, age of the patient, presence of pre-existing disease, as well as the presence of other diseases (for example, cardiovascular disease). For example, administration of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol may provide cardiovascular benefits, particularly for postmenopausal women. The following paragraphs provide preferred dosage ranges for the different components of this invention. An effective dose for (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol varies in the range from 0.0001 to 100 mg / kg / day, preferably from 0.001 to 10 mg / kg / day. An effective dose for 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrrazolo [4,3 -c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl-isobutyramide varies in the range of 0.0001 to 100 mg / kg / day, preferably 0.01 to 5 mg / kg / day. When the tartrate salt or other pharmaceutically acceptable salt of any of the above compounds is used in this invention, the skilled person will be able to calculate the effective dosage amounts by calculating the molecular weight of the salt form and performing simple stoichiometric ratios.
The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds, or their pharmaceutically acceptable salts, of this invention, together with a pharmaceutically acceptable carrier or diluent. Thus, the compounds and their pharmaceutically acceptable salts of this invention can be administered separately or together in a conventional oral, parenteral or transdermal dosage form. When administered separately, the administration of the other compound, or its pharmaceutically acceptable salt, of the invention is below. For oral administration, a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used, together with various disintegrants such as starch and preferably potato starch or tapioca and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are frequently useful for preparing tablets. Solid compositions of a similar type are also employed as fillers in hard filled gelatin capsules; including the preferred materials in this sense also lactose and milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds, or their pharmaceutically acceptable salts, of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts can be used. Such aqueous solutions can be suitably buffered if necessary and the liquid diluent first made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for the purposes of intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used can all be obtained easily by conventional techniques well known to those skilled in the art. For the purposes of transdermal administration, for example topical, diluted sterile aqueous or partially aqueous solutions are prepared (usually in a concentration of about 0.1% to 5%), or similar to the above parenteral solutions. The methods for preparing the different pharmaceutical compositions with a certain amount of each active ingredient are known or will be apparent in the light of this description for those skilled in the art. Examples can be found in Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1990).
The pharmaceutical compositions according to the invention may contain 0.1% -95% of a combination of the compounds, or their pharmaceutically acceptable salts, of this invention, preferably 1% -70%. In any case, the composition or formulation to be administered will contain an amount of the compounds, or their pharmaceutically acceptable salts, of the invention in an amount effective to treat the disease / disorder of the subject being treated. Since the present invention relates to treatment with a combination of the two active ingredients that can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5, 6,7,8-tetrahydronaphthalene-2-ol or one of its pharmaceutically acceptable salts and 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a , 4,6,7-hexahydro-prazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide or one of its pharmaceutically acceptable salts. The kit includes a package for containing the separate compositions, such as a divided bottle or a package of a thin divided sheet, however, the separate compositions may also be contained in a single undivided package. Typically, the kit includes instructions for administration of the separate components. The case form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different intervals, or when the prescribing physician wishes to increase or decrease the dose of the individual components. of the combination. An example of such a case is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging dosage unit dosage forms (tablets, capsules and the like). The blister packs are generally formed by a sheet of relatively rigid material covered with a thin sheet of a preferably transparent plastic material. During the packaging process, alveoli are formed in the thin sheet of the plastic. The alveoli have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the alveoli and the sheet of relatively rigid material is sealed to the thin sheet of plastic on the face opposite to the direction in which the alveoli have been formed. As a result, the tablets or capsules are hermetically sealed in the alveoli between the thin sheet of plastic and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying a manual pressure on the sockets, by which an opening is formed in the sheet in the position of the socket. The tablet or capsule can then be extracted through said opening. It would be desirable to provide a memory aid means in an inserted card, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of the administration schedule in which the tablets should be ingested or specified capsules. Another example of said means of memory aid is a calendar printed on the card, for example, as follows "first week, Monday, Tuesday, and so on. Second week, Monday, Tuesday and so on": Other variations of Means of memory aid will be evident. A "daily dose" may be a single tablet or capsule or several pills or capsules that must be taken on a given day. In addition, a daily dose of SERM may consist of a tablet or capsule, while a daily dose of GH secretagogue may consist of several tablets or capsules. The means of memory aid should reflect this. In another preferred embodiment of the invention, a dispenser designed to dispense daily doses at each time in the order of its intended use is provided. Preferably, the dispenser is provided with a means of memory aid, to facilitate compliance with the dosing schedule. An example of said memory aid means is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of said memory aid means is a battery-operated microprocessor memory coupled to a liquid crystal display to an audible recall signal that, for example, displays the date on which the last dose was taken and / or remember when the next dose should be taken.
The following test is used to demonstrate that the combination and method of this invention increase lean body mass and decrease body fat mass, while the GH secretagogue can only be expected to only decrease body fat mass, without changes in body mass. lean and it is expected that the SERM only increases both lean body mass and fat. In addition, the combination increases bone density and decreases total serum cholesterol.
EXAMPLE 1
S-D female rats (Harian) were operated on simulated or ovariectomized (OVX) at 3.5 months of age. Drug administration was initiated when the rats were 9 months and 5.5 months after surgery. The sham-operated rats received daily vehicle (10% ethanol in water) by esophageal tube, while the OVX rats received daily, by esophageal tube, vehicle or only 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo -ethyl) -isobutyramide at 5 mg / kg / day, or alone (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7 , 8-tetrahydronaphthalen-2-ol at 0.1 mg / kg / day, or a combined treatment of 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3, 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide and (-) - cis-6-phenyl -5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol for 4 weeks. In the combination group, 2-amino-N- (2- (3a (R) -benzy-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3 -c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide was administered 2 hours before (-) - cis-6-phenyl-5- (4- (2 -pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol. In each subgroup there were 8 to 10 rats. All rats received subcutaneous injections of 10 mg / kg calcein (Sigma Chemical Co. St. Louis, MO) on days 13 and 3 before autopsy. It will be appreciated by those skilled in the art that the compounds used in this assay can be administered in the form of a pharmaceutically acceptable salt and that the amount of the dose can be easily determined by calculating the molecular weight of the salt and performing simple proportions. Prior to autopsy on the day of the end of the trial, all rats under ketamine / xylazine anesthesia underwent double-hash X-ray absorptiometry (DXA QDR-1000 / W, Hologic Inc., Waltham, MA) equipped with a program of the rat's entire body scan (Hologic Inc., Waltham, MA) to determine lean body mass and fat. The rats were then autopsied and the blood was removed by cardiac puncture. Total serum cholesterol was determined using a high resolution colorimetric cholesterol assay (Boehringer Mannheim Biochemicals, Indianapolis, IN). Body weight gain was calculated as body weight at autopsy minus body weight on day 0. Wet uterine weight was determined immediately at autopsy. The right femur of each rat was excised at autopsy and explored using double-beam X-ray absorptiometry (DXA, QDR 1000 / W, Hologic Inc., Waltham, MA) equipped with the "Regional High Resolution Sean" program (Hologic Inc., Waltham, MA). The size of the exploration field was 5.08 x 1.902 cm, the resolution was 0.0254 x 0.0127 cm and the scanning speed was 7.25 mm / second. The images of the femoral examination were analyzed and the total femoral bone area, the mineral content of the bone and the bone mineral density were determined according to the procedure described in HZ Ke et al., Droloxifene, a New Estrogen Antagonist / Agonist, Prevents Bone Loss in Ovariectomized Rats. ENDO? RINOLOGY 136; 2435-2441, 1995.
Results and discussion of the study Compared with the controls, 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazole [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl) -sobutyramide alone, increased lean body mass and fat, while ( -) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenl) -5, 6,7,8-tetrahydronaphthalen-2-ol alone, decreased body fat mass, without any change in lean body mass. The combination of 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide and (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) - feniI) -5,6,7,8-tetrahydronaphthalen-2-ol increased lean body mass and reduced body fat mass. Therefore, the combination of both compounds has a better body composition profile than 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a , 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide alone or (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol alone. A 5-6% increase in total femoral bone area was observed in subjects who received the combination compared to subjects who received placebo. This result is similar to the increase in the area of the total femoral bone that was observed in subjects who received (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) - 5,6,7,8-tetrahydronaphthalen-2-ol or 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6 , 7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -ber) cycloxymethyl-2-oxo-ethyl) -sobutyramide and (-) -cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol alone. The mineral content of the total femoral bone increased by 8.5% with 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide alone, and in 7.7% with (-) -cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol alone. However, in the combination group, the mineral content of the femoral bone increased by 12.5%, which was a significant increase compared to its administration alone. A similar trend was found in the mineral density of the total femoral bone. Total serum cholesterol decreased in the group of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrah dronaftalen-2-ol alone and in the combination group. These data indicate that the combination of 2-amino-N- (2- (3a (R) -benzyl-2-methyl-2-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4, 3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide and (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1 -yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol has multiple benefits. These benefits include an increase in lean mass and a decrease in fat mass and serum lipids. In addition, an increase in bone mass was observed. It will be appreciated that the invention is not limited to the particular embodiments described herein, but that types of changes and modifications may be made without departing from the spirit and scope of the invention, as defined by the following claims.
Claims (22)
1. - A pharmaceutical composition comprising: a. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts; and b. a second compound, said second compound being 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4 , 3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide or one of its pharmaceutically acceptable salts.
2. The pharmaceutical composition according to claim 1, further comprising a pharmaceutical carrier.
3. The pharmaceutical composition according to claim 1, wherein said first compound is (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl ) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound is L-tartrate of 2-amino-N- (2- (a (R) -benzyl-2-methyl-3-oxo-2 3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide.
4. The use of a pharmaceutical composition as claimed in claim 1, for preparing a medicament for treating a mammal suffering from musculoskeletal fragility.
5. The use as claimed in claim 4, wherein said first compound is D-tartrate of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl- ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound is 2-amino-N- (2- (3a (R) -benzyl-2-methyl L-tartrate -3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-eti ) -isobutyramide.
6. The use as claimed in claim 4, wherein said mammal suffers from osteoporosis.
7. The use as claimed in claim 4, in which osteotomy is treated, idiopathic bone loss of childhood or bone loss associated with periodontitis.
8. The use as claimed in claim 4, in which bone healing is treated after a facial reconstruction, a maxillary reconstruction or a mandibular reconstruction, spinal synostosis or power is induced the extension of the long bones , the speed of healing of a bone graft is enhanced or the prosthetic incarnation is enhanced.
9. Use as claimed in claim 8, in which a bone bill is treated in a human being.
10. The use as claimed in claim 6, wherein said mammal is a human being.
11.- A case that includes: a. in a first unit dose form, (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; b. in a second unit dose form, 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4 , 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-yl) -isobutyramide or one of its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier or diluent; and c. a container.
12. The kit according to claim 1, wherein said first unit dosage form comprises (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl) -tartrate) - ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second unit dosage form comprises 2-amino-N- (2- (3a (R) -benzyl-2-L-tartrate methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide .
13.- The use of a. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts; and b. a second compound, said second compound being 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro -pyzozoo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxo-ethyl) -isobutyramide or one of its pharmaceutically acceptable salts for preparing a first and a second drug respectively to treat a mammal suffering from musculoskeletal fragility.
14. The use as claimed in claim 13, wherein the first medicament and the second medicament are administered substantially at the same time.
15. - The use as claimed in claim 13, wherein the second medicament is administered for a period of from about three months to about three years.
16. The use as claimed in claim 15, followed by the administration of the first medicament for a period of about three months to about three years without the administration of the second medicament for the period of about three months to about three years .
17. The use as claimed in claim 15, followed by the administration of the first medication for a period greater than about three years without the administration of the second medication during the period of approximately three years.
18. The use as claimed in claim 13, wherein said mammal suffers from osteoporosis.
19. The use as claimed in claim 13, wherein said mammal suffers osteotomy, idiopathic bone loss of childhood or bone loss associated with periodontitis.
20. The use as claimed in claim 13, in which bone healing is treated after a facial reconstruction, a maxillary reconstruction or a mandibular reconstruction, vertebral synostosis is induced or the extension of the long bones is enhanced , the healing speed of a bone graft is enhanced or the prosthetic incarnation is potentiated.
21. - The use as claimed in claim 20, wherein a bone fracture is treated in a human being.
22. The use of a composition according to claim 1 for preparing a medicament for increasing muscle mass in a mammal.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/089,469 | 1998-06-16 |
Publications (1)
Publication Number | Publication Date |
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MXPA00012727A true MXPA00012727A (en) | 2001-07-31 |
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