HRP20000857A2 - Therapeutic combinations of (selective) estrogen receptor modulators (serm) and growth hormone secretagogues (ghs) for treating musculoskeletal frailty - Google Patents

Description

Background of the invention

This invention relates to a pharmaceutical combination of selective estrogen receptor modulator (SERM) and growth hormone secretagogue (GHS) which stimulates bone formation, increases bone mass, lowers serum lipid content and increases muscle mass. This invention also relates to a kit containing such combinations and to the use of such combinations for the treatment of musculoskeletal weakness, including osteoporosis, osteoporotic fractures, low bone mass, bone weakness, low muscle mass, and the like, in mammals, including humans. This invention particularly relates to the combination (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or its pharmaceutically acceptable salts and 2-amino-N-(1R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2 -(2,2,2,-trifluoro-ethyl)-2,3,3a,4,6,7-hexhydro-pyrazolo[4,3-c]pyridin-5-yl)ethyl)-2-methyl-propionamide or a pharmaceutically acceptable salt thereof, to a kit containing such combination and to the use of said combination for the treatment of musculoskeletal weakness, including osteoporosis, osteoporotic fractures, low bone mass, bone weakness, low muscle mass, and the like, in mammals, including humans .

Osteoporosis is a disease of the skeletal system characterized by low bone mass and deterioration of bone tissue, and as a result increases bone fragility and susceptibility to fractures. In the US, the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine fractures, 250,000 hip fractures, and 240,000 wrist fractures annually. The most serious are hip fractures, as 5-20% of patients die within one year, with over 50% of survivors becoming incapacitated.

The greatest risk of osteoporosis is in the elderly, so it can be predicted that the problem will increase significantly with the aging of the population. The global incidence of fractures is predicted to triple over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.

Although both men and women are susceptible to musculoskeletal weakness, including osteoporosis, women are at greater risk of osteoporosis than men. In women, bone loss accelerates immediately after menopause. Other factors that increase bone loss, which leads to osteoporosis, are smoking, alcohol abuse, an inactive lifestyle and too little calcium intake.

Estrogen is an indispensable factor in preventing osteoporosis or bone loss in women after menopause. In addition, Black et al in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma LDL levels and increases favorable high density lipoproteins (HDL). However, long-term estrogen therapy implies a variety of disorders, including an increased risk of uterine cancer, endometrial cancer, and possibly breast cancer, which causes many women to either avoid this treatment or undertake treatment only for a short period of time. Although the risk of endometrial cancer is thought to be reduced through the parallel use of progesterone, there is still concern about a possible increase in breast cancer due to the use of estrogen. Recently proposed therapeutic regimens, which aim to reduce the risk of cancer, such as the administration of combinations of progesterone and estrogen, cause unacceptable bleeding in patients. In addition, combining progesterone with estrogen appears to reverse the serum cholesterol-lowering effects of estrogen. Significant adverse side effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have a beneficial effect on serum LDL but do not cause adverse side effects.

Recently, a number of selective estrogen receptor modulators have been proposed for the treatment of osteoporosis. It has been described ("Osteoporosis Conference Scrip", No. 1812/13, p. 29, April 16-20, 1993) that raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2 -piperidinoethoxy)benzolyl]benzo[b]thiophene, mimics the beneficial effect of estrogen on bones and lipids, but unlike estrogen, it has a minimal stimulatory effect on the uterus. (L.J. Black et al.: "Raloxifene (LY139481 Hcl) Prevents Bone Loss and Reduces Serum Cholesterol Without Causing Uterine Hypertrophy in Ovariectomized Rats", J. Clin. Invest., 93, 63-69, (1994); and P.D. Delmas et al. another: "Effects of Ralixifene on Bone Mineral Density, Serum Cholesterol Concentration, and Uterine Endometrium in Postmenopausal Women", New England Journal of Medicine, 337, 1641-1647, (1997)).

Agents such as droloxifene, US Pat. 5,254,595, prevent bone loss and thereby reduce the risk of fracture, without estrogenic side effects. However, estrogen and estrogen agonists administered alone are expected to reduce the risk of fracture by 50%, still leaving 50% of osteoporotic women at risk of osteoporotic fracture.

US patent no. 5,552,412, which is incorporated herein by reference, discloses the discovery of SERM compounds of the formula

[image]

where the variables are defined as described therein.

Growth hormone (GH), secreted by the pituitary gland, stimulates the growth of all tissues in the body that can grow. In addition, it is known that GH has the following basic effects on the metabolic process in the body:

1. It increases the speed of protein synthesis, in principle in all cells of the body;

2. Reduces the rate of utilization of carbohydrates in body cells;

3. It increases the mobilization of free fatty acids and the use of fatty acids for energy.

GH deficiency leads to a number of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include a serious reduction in body muscle mass and an accompanying increase in total body fat, especially in the trunk. A decrease in body and cardiac muscle mass and muscle strength leads to a significant decrease in motor capacities. Bone density is also reduced. Administration of exogenous GH has been shown to reverse many of these metabolic changes. Additional benefits of such therapy are a reduction in LDL cholesterol and an improved psychological sense of satisfaction.

In cases where elevated GH levels are desired, the problem is usually solved by administering exogenous GH, or by administering an agent that stimulates GH production and/or release. In any case, the peptide nature of the injectable compound is essential. Originally, the source of GH was the extraction of pituitaries from cadavers. This led to an expensive product, and was associated with the risk that a pituitary-related disease could be transmitted to the recipient of such GH (eg, Jacob-Creutzfeldt disease). Recombinant GH has recently become available, and although it no longer carries any risk of disease transmission, it is still an expensive product that must be given by injection or as a nasal spray.

Most GH deficiency is caused by defects in GH release rather than primary defects in pituitary GH synthesis. Therefore, an alternative strategy for normalizing the content of GH in the serum is to stimulate its release from somatotropin. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, efforts are being made to develop synthetic agents to release GH via stimulation of GH secretion from the pituitary gland, which may have several advantages over expensive and inappropriate GH replacement therapy. By acting on physiological regulatory pathways, the most desirable agents will stimulate GH secretion in pulses, so elevated GH levels associated with the undesirable effects of exogenous GH administration can be avoided via intact negative feedback loops.

Physiological and pharmacological stimulators of GH secretion are arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin and insulin-induced hypoglycemia, but also activities such as sleep and exercise, indirectly cause the release of GH from the pituitary gland by acting in some way on the hypothalamus, either by lowering somatostatin, or by increasing the secretion of a known secretory GH-releasing factor (GHRF), or an unknown endogenous GH-releasing hormone, or all of them.

The international patent application published as WO97/24369, designated inter alia for the USA, describes secretors of the GH formula:

[image]

where the variables are defined as described therein. Said WO97/24369 is incorporated herein by reference.

Tang et al in "Restoring and Maintaining Bone in Osteogenic Female Rat Skeleton. I. Changes in Bone Mass and Structure", J. Bone Mineral Research, 7(9), 1093-1104, (1992), describe data for loss, restoration and maintenance concept (GOO), and a practical procedure for reversing existing osteoporosis. The GOO concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with established bone maintenance ability to maintain new bone (+/- phase). A study in rats used PGE22 and risedronate, a bisphosphonate, to show that most of the new porous and cortical bone that was induced with PGE2 could be maintained for at least 60 days after withdrawal of PGE2, by administration of risedronate.

Shen et al in "Effects of Reciprocal Treatment with Estrogen and Estrogen plus Parathyroid Hormone on Bone Structure and Strength in Ovariectomized Rats", J. Clinical Investigation, 96, 2331-2338, (1995), describe data for this combined and/or the sequential use of antiresorptive agents and anabolic agents in the treatment of osteoporosis.

International patent application published as WO97/31640, assigned inter alia to the USA, describes the use of some GH secretors in combination with some SERMs for the treatment of osteoporosis. Said WO97/31640 is incorporated herein by reference.

The essence of invention

This invention is directed to a pharmaceutical composition containing:

a. first compound, where said first compound is (-)-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

b. second compound, where said second compound is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridine- 2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl) -2-methyl-propionamide, or a pharmaceutically acceptable salt thereof.

This invention is still further directed to the pharmaceutical composition defined in the previous paragraph, which additionally contains a pharmaceutical carrier.

This invention is still further directed to the composition defined in one of the first two paragraphs of this section, in which the first compound is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol D-tartrate, and said second compound is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo -2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[ 4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide L-tartrate.

The present invention is still further directed to a method, designated as method A, for treating a mammal suffering from musculoskeletal weakness, which comprises administering to said mammal said pharmaceutical composition of any of the first three paragraphs of this section.

Within procedure A, a procedure, denoted as procedure B, wherein said mammal suffers from osteoporosis, is preferred.

The next preferred procedure within procedure A, denoted as procedure C, is in the case where the mammal is suffering from osteotomy, childhood idiopathic bone loss, or periodontitis-related bone loss.

The present invention is further directed to a method, denoted as method A1, for treating a mammal suffering from musculoskeletal weakness, which comprises administering to said mammal

a. of the first compound, where said first compound is (-)-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

b. a second compound, where said second compound is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridine- 2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl) -2-methyl-propionamide or a pharmaceutically acceptable salt thereof.

This invention is particularly directed to the process of process A1 in which the first compound and the second compound are administered essentially simultaneously.

This invention is also particularly directed to the process from process A1, designated as process D, according to which the second compound is administered over a period of about 3 months to about 3 years.

This invention is particularly directed to the method of method D, which follows the administration of the first compound for a period of about 3 months to about 3 years, without the administration of the second compound for a period of about 3 months to about 3 years.

This invention is also particularly directed to the method of method D, which follows the administration of the first compound for a period longer than about 3 years, without the administration of the second compound for a period longer than about 3 years.

This invention is also directed to a method, herein designated as method E, for treating a mammal suffering from musculoskeletal weakness, which consists in administering to said mammal a therapeutically effective amount of the composition described in the first three paragraphs of this section.

Within procedure E, the preferred procedure is when bone healing is improved after facial reconstruction, maxillary reconstruction, or mandibular reconstruction, when vertebral fusion is induced, when long bone extension is improved, bone graft healing speed is improved, or long bone fracture is improved, or prosthetic fusion is improved.

This invention is also directed to a method of increasing muscle mass in a mammal comprising administering to said mammal an effective amount for increasing muscle mass of a composition described in any of the first three paragraphs of this section.

In all methods of this invention, a particularly preferred mammal is a human.

The present invention is also directed to a kit for the treatment of a mammal suffering from musculoskeletal weakness, comprising:

a. (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, in the form of a first dosage unit;

b. 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-( 2,2,2-thifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide or its pharmaceutically acceptable salts, in the form of a second dosage unit; and

c. container.

This invention is particularly directed to the kit, which is described in the previous paragraph, in which said first dosage unit contains (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl ]-5,6,7,8-tetrahydronaphthalen-2-ol D-tartrate, and said second dosage unit contains 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo -2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[ 4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide L-tartrate.

In each of the preparations, methods and kits of this invention, it is particularly preferable to use D-tartrate salt (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 5,6,7,8-tetrahydronaphthalen-2-ol, and the L-tartrate salt of 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3- oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c] pyridin-5-yl)-ethyl)-2-methyl-propionamide.

The term "condition represented by low bone mass" refers to a condition in which the content of bone mass is below the age-specific normal, which is defined in the standards of the World Health Organization "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis" (1994). , Report of a World Health Organization Study Group. World Health Organization Technical Series 843. Idiopathic childhood and primary osteoporosis are also covered. Treatment of osteoporosis includes prevention or reduction of long-term complications, such as spinal curvature, loss of height, prosthetic surgery and prevention of prostate dysfunction. Also included is an increase in the rate of fracture healing and an increase in the rate of successful bone grafting. Periodontal disease and alveolar ridge loss are also included.

The term "condition represented by low bone mass" refers to a mammal known to have a significantly higher than average chance of developing such diseases as those described above, including osteoporosis (eg, postmenopausal women, men over 60 years of age and people treated with drugs known to cause osteoporosis as a side effect (such as glucocorticoids)).

Those skilled in the art understand that the term bone mass essentially refers to bone mass per unit area, which sometimes (although not strictly correctly) refers to bone mineral density.

The term "musculoskeletal weakness" refers to a condition in which a subject has low bone mass and/or low muscle mass, and includes diseases such as diseases and conditions such as, but not limited to, conditions characterized by low bone mass , osteoporosis, conditions presenting with low muscle mass, osteotomy, pediatric idiopathic bone loss, bone loss associated with periodontitis, bone healing after facial reconstruction, maxillary reconstruction, mandibular reconstruction and bone fracture. Furthermore, musculoskeletal weakness includes such conditions as the boundary surface between the newly attached prosthesis and the bone, when bone ingrowth is required.

The term "treatment", "treat" or "treatment" as used herein includes curative, preventive (eg, prophylactic) and palliative treatment.

Parenthetically negative or positive, as used herein, indicates that in a particular stereoisomer the direction of linearly polarized light is rotated.

The compounds of this invention also include hydrates of the compounds used herein.

The pharmaceutical preparations and methods of this invention lead to a higher content of increased bone mass more quickly than is achieved with the same doses of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy) alone )-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol, as described above, or 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2 itself -oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro- pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, as described above. Thus, these combinations increase bone mass and reduce the number of fractures to a greater extent than when either of these agents is used alone. Furthermore, these combinations increase bone density and muscle mass, while simultaneously reducing fat mass and total serum cholesterol. This invention represents a significant contribution to the state of the art by providing compositions and procedures that increase and maintain bone mass, leading to the prevention, retardation and/or reversal of osteoporosis and related bone disorders.

Other features and advantages will be apparent from the detailed description and claims of this 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:

[image]

(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salt are obtained according to the procedure described in US patent no. 5,552,412, which is cited above.

(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol D-tartrate is obtained as is set forth in the preceding paragraph, or alternatively, as set forth in the publication of International Patent Application no. WO97/16434, assigned to the USA, which is incorporated herein by reference.

Another compound of this invention is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl) -2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl -propionamide or its pharmaceutically acceptable salt, having the structural formula II:

[image]

2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2, 2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide and its pharmaceutically acceptable the salts are prepared as disclosed in International Patent Application Publication WO97/24369, assigned inter alia to the US, cited above.

2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2, 2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide L-tartrate is obtained as disclosed in International Patent Application Publication WO97/24369, cited above. Alternatively, 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-( 2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide L- tartrate is prepared as described herein in Example 1.

In addition, when these compounds and their pharmaceutically acceptable salts, which are used in the compositions and methods of this invention, form hydrates or solvates, such hydrates or solvates are also within the scope of this invention.

The pharmaceutical compositions and methods of this invention are all adapted for therapeutic use as agents that either activate bone regeneration or prevent bone resorption or increase bone formation in mammals, particularly humans. Since these functions are closely related to the development of osteoporosis and related bone disorders, these combinations prevent, stop, reduce and reverse osteoporosis by acting on the bones themselves.

The utility of the compositions and methods of this invention as medicinal agents for the treatment of musculoskeletal weakness (e.g., conditions characterized by low bone mass, or low muscle mass, including osteoporosis) in mammals (e.g., humans) has been demonstrated through the activity of the compounds of this invention in the conventional tests set forth in US Pat. 5,552,412 and International Patent Application published as WO97/24369. Further evidence of the utility of this combination is set forth in Example 2 below. These tests also represent a means by which the activities of the compounds of this invention can be compared with each other and with the activities of other known compounds. The results of these comparisons are useful for determining dose content in mammals, including humans, when treating such diseases.

The compounds of the present invention may be administered by any method that delivers the compound of the combination of the present invention systemically and/or locally. The compounds of the present invention can be administered by the oral route, parenteral routes, intraduodenal routes, etc. Typically, the compounds of the present invention are administered orally, but for example, parenteral administration (eg, intravenous, intramuscular, transcutaneous, subcutaneous, or intramedullary) can be used, if is oral administration inappropriate for the chosen goal, or if the patient is unable to swallow the medicine. Two different compounds of this invention may be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition may be administered comprising the first compound described above, and the second compound described above, in a pharmaceutically acceptable carrier.

In any case, the amount and time of administration of the compounds will, of course, depend on the subject being treated, on the severity of the suffering, on the method of administration and on the assessment of the competent physician. Therefore, due to the variability from patient to patient, the doses given below are guidelines, and the competent doctor can adjust the doses of the drug until he achieves the activity (eg, increase in bone mass) that he considers appropriate for the individual patient. When considering the desired level of activity, the doctor must balance a number of factors, such as the starting content of the bone mass, the age of the patient, the presence of previous diseases, as well as the existence of other diseases (eg cardiovascular). For example, administration of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol can provide cardiovascular benefits, especially in women after menopause. The following paragraphs provide preferred dosage levels for the various components of this invention.

The effective dose of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol is in the range of 0 .0001 to 100 mg/kg/day, preferably 0.001 to 20 mg/kg/day.

Effective dose of 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-( 2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide is in range from 0.0001 to 100 mg/kg/day, preferably from 0.01 to 5 mg/kg/day.

If a tartrate salt or other pharmaceutically acceptable salt of any of the above compounds is used according to this invention, the skilled person is able to determine the amount of effective dose by calculating the molar mass of the salt form and using simple stoichiometric relationships.

The compounds of the present invention are usually administered in the form of a pharmaceutical composition containing at least one of the compounds or a pharmaceutically acceptable salt thereof of the present invention, together with a pharmaceutically acceptable carrier or diluent. Thus, the compounds and their pharmaceutically acceptable salts of the present invention may be administered separately or together in any conventional oral, parenteral or transdermal dosage form. When administered separately, administration of the second compound or a pharmaceutically acceptable salt thereof follows subsequently.

For oral administration, the pharmaceutical preparation can be in the form of solutions, suspensions, tablets, pills, capsules, powders and the like. The tablets, which contain various additives, such as sodium citrate, calcium carbonate and calcium phosphate, are used together with various disintegrants, such as starch, preferably potato or tapioca starch, and some complex silicates, together with agents for binders, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tableting purposes. Solid preparations of a similar type are also used as fillers for soft and hard gelatin capsules; preferred materials in this regard also include lactose or milk sugar, as well as high molar mass polyethylene glycols. If aqueous suspensions and/or elixirs are desired orally, the compounds or their pharmaceutically acceptable salts from this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying and/or suspending agents, as well as with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For the purpose of 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 is first made isotonic with sufficient salt or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration of injections. In this regard, the sterile aqueous media used are readily obtained by standard techniques well known to those skilled in the art.

For purposes of transdermal (eg, surface) administration, dilute, sterile, aqueous or partially aqueous solutions (usually about 0.1% to 5% concentration) are prepared, which are similar to the above parenteral solutions.

Procedures for obtaining various pharmaceutical preparations with a certain amount of each active ingredient are known, which are clear to those skilled in the art in light of the description of the present invention. For example, see "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., 18th ed., (1990).

Pharmaceutical preparations according to the present invention may contain 0.1%-95% of a combination of these compounds or their pharmaceutically acceptable salts from the present invention, preferably 1%-70%. In any case, the preparation or formulation to be administered will contain an amount of the compound or its pharmaceutically acceptable salt of this invention in an amount that is effective for treating the disease/condition of the subject being treated.

Since this invention relates to treatment with a combination of two active ingredients that can be administered separately, this invention also relates to combining separate pharmaceutical preparations in kit form. The kit includes two separate pharmaceutical preparations: (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmaceutically acceptable salt thereof, and 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl) )-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2- methyl-propionamide, or a pharmaceutically acceptable salt thereof. This kit also includes a container containing separate preparations, such as a divided vial, or a divided package under foil, and separate preparations can also be contained within a single undivided container. Typically, the kit contains instructions for providing the separate components. The form of the kit is particularly suitable when it is necessary that the separate components are applied in different dosage forms (eg oral and parenteral), when they are given at different dosing intervals, or when the competent physician adjusts the individual components of the combination.

An example of such a set is the so-called blister pack. Blister packs are well known in the packaging industry, and are widely used for packaging pharmaceutical unit dose forms (tablets, capsules and the like). Blister packs usually consist of a thin tablet made of a relatively rigid material covered with a plastic film, preferably transparent. During the packaging process, depressions are formed in the plastic film. These indentations are the size and shape of the tablet or capsule being packaged. After that, tablets or capsules are placed in these depressions, and a thin plate of relatively rigid material is sealed with the face of the plastic film, on the side of the film that is opposite to the direction in which the depressions are formed. As a result, the tablets or capsules are hermetically sealed in the recesses between the plastic film and the thin plate. It is desirable that the strength of this plate should be such that tablets or capsules can be removed from the blister pack by manually pressing the indentation, which creates an opening in this plate at the place of the indentation. The tablet or capsule can then be removed through this opening.

It is desirable to provide a reminder on the inserted paper, for example in the form of numbers next to the tablets or capsules, where these numbers correspond to the days of the regimen by which the tablets or capsules so marked should be swallowed. An example of such a reminder is a calendar printed on paper, for example, as follows: "First week, Monday, Tuesday, ..., etc., Second week, Monday, Tuesday, ..., etc., ...". Other variants of reminders are also possible. "Daily dose" can be one pill or capsule, or several pills or capsules to be taken in a given day. Also, a daily dose of a SERM can consist of one tablet or capsule, while a daily dose of a GH secreter can consist of several tablets or capsules. The reminder should indicate this.

In the following specific embodiment of this invention, the machine is designed so that it gives daily doses, one each time, in the order in which the intended use is foreseen. This machine is preferably equipped with a reminder, in order to further facilitate adaptation to the regimen. An example of such a reminder is a mechanical counter that shows the number of daily doses taken. Another example of such a reminder is a battery-powered electronic memory to which a liquid crystal reading unit or an audible reminder unit is connected, by means of which, for example, the date when the last daily dose was taken is read and/or a reminder when the next dose should be taken.

Example 1

2-amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-]3-oxo-3a-pyridin-2-ylmethyl)-2-(2,2,2-(2 ,4-difluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide L-(+) tartrate

A. 4-oxo-3-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester

To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (10.34 g, 38.2 mmol) in DMF (40 mL) at about 0 °C, picolyl chloride hydrochloride (5 .7 g, 34.7 mmol, potassium carbonate (14.4 g, 104.1 mmol) and potassium iodide (5.76 g, 34.7 mmol). After about 2 hours of stirring at about 0°C, the ice bath was removed, and DABCO (973 mg, 8.68 mmol) was added. The reaction mixture was stirred for about 30 minutes, then poured into a mixture of water and IPE. The organic layer was separated and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo The crude residue was crystallized from hexane to give a white solid (8.19 g, 65% yield).

1H-NMR (CDCl 3 ) δ 1.17 (t, 3H); 1.48 (s, 9H); 1.55 (s, 2H); 2.61 (m, 1H); 2.71 (m, 1H); 3.31-3.50 (m, 3H); 4.11 (d, 2H); 4.49 (d, 1H); 7.06 (bs, 1H); 7.17 (d, 1H); 7.54 (m, 1H); 8.40 (s, 2H).

B. 3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c] pyridine-5-carboxylic acid tert-butyl ester

An aqueous solution of CF3CH2NHNH2 (325 ml, 1.986 mol) (obtained from Aldrich) was extracted with toluene (3 x 1,200 ml). To a solution of the product made according to step A (600 g, 1.655 mol) in toluene (900 mL) was first added the combined toluene extracts containing anhydrous 2,2,2-trifluoroethylhydrazine, followed by acetic acid (121.4 g, 1.986 mol ). The reaction mixture is heated to about 70°C for about 2 hours, and then a second extraction of 70% aqueous 2,2,2-trifluoroethylhydrazine (50 g) is added. The reaction mixture is heated to about 80°C for about 3.5 hours, cooled to room temperature, and then diluted with saturated aqueous NaHCO3 (2 l). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na 2 SO 4 and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol/water gave the desired product as a white solid (609.5 g).

1H-NMR (CDCl 3 ) δ 1.50 (s, 9H); 2.53 (d, 1H); 2.70 (bs, 2H); 2.88 (bs, 1H); 3.31 (m, 2H); 3.97 (m, 1H); 4.19 (m, 1H); 4.46 (bs, 1H); 4.63 (bs, 1H); 7.06 (m, 2H); 7.51 (m, 1H); 8.34 (m, 1H).

C. 3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise over 30 min to a solution of the product from step B (10 g, 24.2 mmol) in CH 2 Cl 2 (100 mL). The reaction mixture was stirred for 1 hour, then cooled to about 0°C, and triethylamine (18.6 ml, 133.1 mmol) was added through the dropping funnel. The mixture was allowed to warm to room temperature over 1 hour, diluted with more CH 2 Cl 2 , and washed with saturated aqueous NaCl, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the product as a white solid.

(7.2 g).

1H-NMR (CDCl 3 ) δ 2.51-2.72 (m, 4H); 3.35 (m, 2H); 3.49 (m, 2H); 4.03 (m, 1H); 4.25 (m, 1H);

7.08 (d, 2H); 7.51 (t, 1H); 8.37 (d, 1H).

D. 3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoroeorethyl)-2, 3a, 4,5,6,7-hexahydro-pyrazolo[3,4-c]pyridin-3-one ( D)-tartrate

In a dry nitrogen-purged 5 L round-bottomed flask equipped with a mechanical stirrer, D-(-)tartaric acid (129 g, 0.86 mol) is added to the compound made according to step C (243 g, 0.78 mol ) in acetone/water (9:1, 2430 ml) at about 17°C. The mixture is stirred overnight at room temperature and filtered, after which the precipitate is collected and washed with cold acetone, and dried under vacuum. The product is obtained as a yellow substance (284 g, yield 78.8 %).

E. 2-tert-butoxycarbonylamino-3-(2,4-difluoro-benzyloxy)propionic acid

To a solution of N-Boc-(D)-serine (452 g, 2.026 mol) in a mixture of THF (7 L) and DMF (3 L) at about 0°C, a solution of potassium tert-butoxide (515.8 g, 4.5963 mol). The reaction mixture was stirred for about 30 minutes at about 0°C, and then 2,4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After warming to room temperature, the reaction mixture was concentrated under vacuum and the THF was removed. The reaction mixture was distributed between 4.5 l of water and 4.5 l of IPE. The layers are separated, and the pH of the aqueous layer is adjusted to about 3 with 1N HCl. The aqueous layer is extracted twice, each time with 4 l of IPE. The organic solution was dried over Na2SO4 and concentrated under vacuum to give a yellow waxy substance (518.0 g, yield: 70.9 %).

1H-NMR (CDCl 3 ) δ 1.44 (s, 9H); 3.73 (m, 1H); 3.94 (d, 1H); 4.44 (bs, 1H); 4.54 (s, 2H); 5.34 (m, 1H); 6.78 (m, 1H); 6.84 (m, 1H); 7.30 (m, 1H).

F. 2-amino-2-(2,4-difluorobenzyloxy)-propionic acid methanesulfonic acid salt

Methanesulfonic acid (1.72 g, 17.95 mmol) was added via syringe to a solution of the product from step E (1.19 g, 3.59 mmol) in CH 2 Cl 2 /IPE (1:1, 12 ml) over 10 min. A solid substance immediately precipitates from the solution. After about 1 hour, the precipitate is filtered and washed with a CH2Cl2/IPE mixture (1:1), giving 939 mg of product (80% yield).

G. 2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-3-(2,4-difluoro-benzyloxy)-propionic acid

2-tert-butoxycarbonylamino-2-methyl-propionic acid-2,5-dioxo-pyrrolidine- 1-yl ester (438 mg, 1.46 mmol) and triethylamine (369 mg, 3.65 mmol). The reaction mixture is stirred for about 1 hour at room temperature, then quenched with a 10% aqueous solution of citric acid (10 ml). After about 15 minutes, ethyl acetate (50 ml) was added, after which the organic layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under vacuum to give a foam (534.1 mg, 88% yield).

1H-NMR (CD3OD) δ 1.38 (bs, 15H); 3.77 (d, 1H); 3.92, (d, 1H); 4.52 (m, 3H); 6.92 (m, 1H);

7.41 (m, 1H); 7.58 (d, 1H).

H. (1-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl) - 2,3,3a,4,6,7

-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethylcarbamoyl}-1-methyl-ethyl-carbamic acid tert-butyl ester

(a) To the compound made according to step D (517 g, 1.12 mol) was added at about -6 °C ethyl acetate (5170 ml) in a dry 12 L round-bottomed flask equipped with a mechanical stirrer, which had previously been purged with nitrogen . The solution is cooled to about -40°, and triethylamine (398 ml, 2.86 mol) is added over about 45 minutes. The reaction mixture is stirred for about 90 minutes at a temperature between about -50°C and about -40°C, filtered into a 22 l round bottom flask, purged with nitrogen and washed with ethyl acetate (2,068 ml, previously cooled to about -50°C) , giving the free base as a white solid.

(b) The compound made according to step G (425 g, 1.02 mol) is added at about -30°C to an ethyl acetate solution containing the product of step H(a), triethylamine (654 ml, 4.69 mol) and PPAA (1-propanephosphonic acid, cyclic anhydride) (50% in ethyl acetate, 916 ml, 1.53 mol). The reaction mixture was stirred for about 1 hour, washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated under vacuum to give the product as an oil (636 g, yield: 87.8 %).

I. 2-amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl)-2-(2,2,2- (2,4-difluoro-ethyl)

-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide

Methanesulfonic acid (258.3 mL, 3.98 mol) was added dropwise over about 55 min at about 15°C to the product from step H (566 g, 0.796 mol) in CH2Cl2 (11,320 mL), in a dry 22 L flask. with a round bottom equipped with a mechanical stirrer, which was previously blown with nitrogen. The mixture is stirred for about 40 minutes at about 20°C, and then saturated aqueous NaHCO3 (8,490 ml) is added until the pH is 7.8. The organic layer is separated, washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated under vacuum to give an oily product (388.8 g, 80% yield).

J. 2-amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl)-2-(2,2,2- (2,4-difluoro

-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide L-(+) tartrate

To a solution of the product from step I (370 g, 0.6 mol) in methanol (4,070 ml) in a 12 L round-bottomed flask equipped with a mechanical stirrer, L-(+) tartaric acid (90 g, 0.6 mol) is added ). The reaction mixture is stirred for about 90 minutes at about 22°C, filtered and concentrated. The crude residue is diluted with ethyl acetate (4,560 ml), heated to about 70°C, and allowed to cool slightly to room temperature for about 17 hours. The precipitate is separated by filtration and dried, giving white crystals, m.p. melting point 188-189 °C (348.46 g, yield 76 %).

1H-NMR (MerOH, d4) δ 8.28 (d, 1H); 7.59 (t, 1H); 7.41-7.39 (m, 1H); 7.18-7.13 (m, 1H); 6.92 (t, 1H); 5.2 (t, 1H); 4.56 (bs, 3H); 4.36 (s, 2H); 4.31-4.25 (m, 1H); 4,134.06 (m, 1H); 3.78 (d, 2H); 3.21 (7.1H); 3.18-2.96 (m, 2H); 2.65-2.55 (m, 2H); 1.57 (d, 6H).

MS: MH+ 611.

[�]589 +22.03° (c=11.9, MeOH).

In the rest of the text, it is shown that the combinations and methods of this invention increase muscle body mass, and reduce body fat mass, while the GH secreter itself would be expected to reduce body fat mass without a change in body muscle mass, and SERM itself is expected to to increase the mass of both muscles and fat in the body. In addition, this combination increases bone density and reduces total serum cholesterol.

Example 2

Female S-D rats (Harlan) at 3.5 months of age were sham-operated or ovariectomized (OVX). Administration of the drug begins when the rats are 9 months old, and 5.5 months after surgery. Sham-operated rats received daily via pecking tube vehicle (10% ethanol in water), while OVX rats received daily via pecking tube vehicle or 2-amino-N-(1(R)-(2,4-difluoro- benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6, 7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide 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 co-treatment with 2-amino-N-( 1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl) )-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide 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-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2- (2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide is given 2 hours before (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol. There were 8 to 10 rats in each subgroup. All rats were injected subcutaneously with 10 mg/kg calein (Sigma Chemical Co., St. Louis, MO) at 13 and 3 days before necropsy. It will be understood 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 dosage can be easily determined by calculating the molar mass of the salt and applying simple stoichiometric relationships.

Before necropsy on the final test day, all rats underwent a dual-energy X-ray absorptiometer (DXA, QDR-1000/W, Hologic Inc., Waltham, MA) equipped with whole-body scanning software under ketamine/xylazine anesthesia. rat (Hologic Inc., Waltham, MA) to determine muscle mass and body fat. Rats were then necropsied, and blood was obtained by cardiac puncture. Total serum cholesterol was determined using a high-performance cholesterol colorimetric assay (Boehringer Mannheim Biochemicals, Indianapolis, IN). Body weight gain was calculated as body weight at autopsy minus body weight on day 0. The wet mass of the uterus was determined immediately after the autopsy.

The right femur from each rat was removed at necropsy and scanned with a dual-energy X-ray absorptiometer (DXA, QDR 1000/W, Hologic Inc, Walthan, MA) equipped with “High Resolution Regional Scanning” software (Hologic Inc., Waltham, MA). The size of the scanning field was 5.08 × 0.0127 cm, and the scanning speed was 7.25 mm/s. Femur scan images were analyzed, and the total femur bone surface, bone mineral content and bone mineral density were determined according to the procedure described in H.Z. Ke et al.: "Droloxifene, a New Estrogen Antagonist/Agonist, Prevents Bone Loss in Ovariectomized Rats", Endocrinology, 136, 2435-2441, (1995).

It is understood that this invention is not limited to the specific embodiments described, but that various changes and modifications may be made without departing from the spirit and scope of this new concept as defined in the patent claims that follow.

Claims (29)

1. Pharmaceutical preparation, characterized in that it contains: a. first compound, where said first compound is (-)-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 b. second compound, where said second compound is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridine- 2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl) -2-methyl-propionamide or a pharmaceutically acceptable salt thereof. 2. Pharmaceutical preparation according to claim 1, characterized in that it additionally contains a pharmaceutically acceptable carrier. 3. Pharmaceutical preparation according to claim 1, characterized in that said first compound is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7 ,8-tetrahydronaphthalen-2-ol D-tartrate, and said second compound is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo- 3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine- 5-yl)-ethyl)-2-methyl-propionamide L-tartrate. 4. A method of treating a mammal suffering from musculoskeletal weakness, characterized in that said mammal is given a pharmaceutical preparation according to claim 1. 5. The method according to claim 4, characterized in that said first compound is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7, 8-tetrahydronaphthalen-2-ol D-tartrate, and said second compound 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a( R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5- yl)-ethyl)-2-methyl-propionamide L-tartrate. 6. The method according to claim 4, characterized in that said mammal suffers from osteoporosis. 7. The method according to claim 4, characterized in that said mammal suffers from osteotomy, pediatric bone idiopathy or bone loss associated with periodontitis. 8. Procedure according to claim 4, indicated by the fact that it is treated: bone healing after facial reconstruction, maxillary reconstruction or mandibular reconstruction, inducing vertebral fusion or supporting bone extension, increasing the speed of bone graft healing or supporting prosthesis integration. 9. The method according to claim 8, characterized in that a bone fracture in a human is treated. 10. The method according to claim 6, characterized in that osteoporosis in humans is treated. 11. A method for treating a mammal suffering from musculoskeletal weakness, characterized in that said mammal is given: a. first compound, where said first compound is (-)-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 b. second compound, where said second compound is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridine- 2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl) -2-methyl-propionamide or a pharmaceutically acceptable salt thereof. 12. The method according to claim 11, characterized in that the first compound and the second compound are administered essentially simultaneously. 13. The method according to claim 11, characterized in that the second compound is administered over a period of about 3 months to about 3 years. 14. The method according to claim 13, characterized in that the administration of the first compound is followed for a period of about 3 months to about 3 years, without the administration of the second compound for a period of about 3 months to about 3 years. 15. The method according to claim 13, characterized in that the administration of the first compound is followed for a period longer than about 3 years, without the administration of the second compound for a period longer than about 3 years. 16. The method according to claim 11, characterized in that said mammal suffers from osteoporosis. 17. The method according to claim 11, characterized in that said mammal suffers from osteotomy, pediatric bone idiopathy or bone loss associated with periodontitis. 18. The procedure according to claim 11, characterized by treating: bone healing after facial reconstruction, maxillary reconstruction or mandibular reconstruction, inducing vertebral fusion or supporting bone extension, increasing the speed of bone graft healing or supporting prosthesis integration. 19. The method according to claim 18, characterized in that a bone fracture in a human is treated. 20. A method of increasing muscle mass in a mammal that needs the same, characterized in that said mammal is given an amount of preparation according to claim 1 that is effective for increasing muscle mass. 21. A set, characterized by the fact that it contains: a. (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, in the form of a first dosage unit; b. 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-( 2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide or its a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, in the form of a second dosage unit; and c. tank. 22. Kit according to claim 21, characterized in that said first dosage unit contains (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7 ,8-tetrahydronaphthalen-2-ol D-tartrate, and said second dosage unit contains 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo -3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine -5-yl)-ethyl)-2-methyl-propionamide L-tartrate. 23. Pharmaceutical preparation according to claim 1, characterized in that it is used to obtain a medicine for the treatment of a mammal suffering from musculoskeletal weakness. 24. Application according to claim 23, characterized in that the mentioned first compound is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7, 8-tetrahydronaphthalen-2-ol D-tartrate, and the second compound mentioned is 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a (R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5 -yl)-ethyl)-2-methyl-propionamide L-tartrate. 25. Use according to claim 23, characterized in that said mammal suffers from osteoporosis. 26. Use according to claim 23, characterized in that said mammal suffers from osteotomy, pediatric bone idiopathy or bone loss associated with periodontitis. 27. Application according to claim 23, indicated by the fact that it treats: bone healing after facial reconstruction, maxillary reconstruction or mandibular reconstruction, inducing vertebral fusion or supporting bone extension, increasing the speed of bone graft healing or supporting prosthesis integration. 28. Application according to claim 27, characterized in that it is used for the treatment of bone fractures in humans. 29. Use according to claim 25, characterized in that it is used to treat osteoporosis in humans.