OA11569A - Therapeutic combinations of (selective) estrogen receptor modulators (serm) and growth hormone secretagogues(GHS) for treating musculoskeletal frailty. - Google Patents

Abstract

This invention is directed to pharmaceutical combination compositions and methods comprising (-)-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-(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, 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

011569

THERAPEUTIC COMBINATIONS OF (SELECTIVE) ESTROGEN RECEPTOR MODULATORS (SERM) AND GROWTHHORMONE SECRETAGOGUES (GHS) FOR TREATING MUSCULOSKELETAL FRAILTY

BACKGROUND OF THE INVENTION

This invention relates to a pharmaceutical combination of a sélective5 estrogen receptor modulator (SERM) and a growth hormone secretagogue (GHS)that stimulâtes bone formation, increases bone mass, decreases sérum lipid levelsand increases muscle mass. The invention also relates to kits containing suchcombinations and the use of such combinations to treat musculoskeletal frailty,including osteoporosis, osteoporotic fracture, low bone mass, frailty, low muscle 10 mass and the like in mammals, including humans. In particular, this inventionrelates to a combination of (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable sait thereofand 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- 15 5-yl)-ethyl)-2-methyl-propionamide or a pharmaceutically acceptable sait thereof,kits containing such a combination and the use of such a combination to treatmusculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bonemass, frailty, low muscle mass and the like in mammals, including humans.

Osteoporosis is a systemic skeletal disease, characterized by low bone 20 mass and.détérioration of bone tissue, with a conséquent increase in bone fragilityand susceptibilité to fracture. In the U.S., the condition affects more than 25million people and causes more than 1.3 million fractures each year, including500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fracturesare the most serious, with 5-20% of patients dying within one year, and over 50% 25 of survivors being incapacitated.

The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.Worldwide fracture incidence is forecast to increase three-fold over the next 60years, and one study estimâtes that there will be 4.5 million hip fractures 30 worldwide in 2050.

Although both men and women are susceptible to musculoskeletal frailty, including osteoporosis, women are at greater risk of osteoporosis than men.

Women expérience a Sharp accélération of bone loss immediately following -2- 01 1 569 ménopausé. Other factors that increase bone loss leading to osteoporosis includesmoking, alcohol abuse, a sedentary lifestyle and low calcium intake.

Estrogen is the agent of choice in preventing osteoporosis or postmenopausal bone loss in women. In addition, Black, et al. in EP 0605193A1 5 report that estrogen, particularly when taken orally, lowers plasma levels of LDLand raises those of the bénéficiai high density lipoproteins (HDL's). Long-termestrogen therapy, however, has been implicated in a variety of disorders, includingan increase in the risk of uterine cancer, endométrial cancer and possibly breastcancer, causing many women to either avoid this treatment or take the médication 10 for only a short period of time. Although the risk of endométrial cancer is thoughtto be reduced by a concurrent use of a progestérone, there is still concem aboutpossible increased risk of breast cancer with the use of estrogen. Recentlysuggested therapeutic regimens, which seek to lessen the cancer risk, such asadministering combinations of progestérone and estrogen, cause the patient to 15 expérience unacceptable bleeding. Furthermore, combining progestérone withestrogen seems to blunt the sérum cholestérol lowering effects of estrogen. Thesignificant undesirable side effects associàted with estrogen therapy support theneed to develop alternative thérapies for osteoporosis that hâve the désirablebénéficiai effect on sérum LDL but do not cause undesirable side effects. 20 Recently, a number of sélective estrogen receptor modulators hâve been proposed for treatment of osteoporosis. It has been reported (OsteoporosisConférence 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, mimicsthe favorable action of estrogen on bone and lipids but, unlike estrogen, has 25 minimal uterine stimulatory effect. [Black, L.J. et al., Raloxifene (LY139481 Hcl)Prevents Bone Loss and Reduces Sérum Cholestérol Without Causing UterineHypertrophy in Ovariectomized Rats, J. Clin. Investi, 1994, 93:63-69 and Delmas,P.D. et al., Effects of Raloxifene on Bone Minerai Density, Sérum CholestérolConcentration, and Uterine Endometrium in Postmenopausal Women, New 30 England Journal of Medicine, 1997, 337:1641-1647).

Agents such as droloxifene, U.S. pat. no. 5,254,595, prevent bone loss and thereby reduce the risk of fracture without estrogen's side effects. However, estrogen and estrogen agonists alone are only expected to reduce the fracture risk -3- 011569 by about 50% leaving approximately 50% of ostéopénie women still at risk for anosteoporotic fracture.

Commonly assigned U.S. pat. no. 5,552,412, which is incorporated hereinby référencé, discloses SERM compounds of the formula

wherein the variables are defined as set forth therein.

Growth hormone (GH), which is secreted from the pituitary gland, stimulâtes growth of ail tissues of the body that are capable of growing. Inaddition, GH is known to hâve the following basic effects on the metabolic process 10 of the body: 1. Increased rate of protein synthesis in substantially ail cells of thebody; 2. Decfeased rate of carbohydrate utilization in cells of the body; 3. Increased mobilization of free fatty acids and use of fatty acids for 15 energy.

Delïciency in GH results in a variety of medical disorders. In children, itcauses dwarfism. In adults, the conséquences of acquired GH deficiency includeprofound réduction in lean body mass and concomitant increase in total body fat,particularly in the truncal région. Decreased skeletal and cardiac muscle mass 20 and muscle strength lead to a significant réduction in exercise capacity. Bonedensity is also reduced. Administration of exogenous GH has been shown toreverse many of the metabolic changes. Additional benefits of therapy hâveincluded réduction in LDL cholestérol and improved psychological well-being.

In cases where increased levels of GH were desired, the problem was 25 generally solved by providing exogenous GH or by administering an agent which stimulated GH production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of -4- 011569 GH was the extraction of the pituitary glands of cadavers. This resulted in anexpensive product, and carried with it the risk that a disease associated with thesource of the pituitary gland could be transmitted to the récipient of the GH (e.g.,Jacob-Creutzfeld disease). Recently, recombinant GH has become availablewhich, while no longer carrying any risk of disease transmission, is still a veryexpensive product which must be given by injection or by a nasal spray.

Most GH deficiencies are caused by defects in GH release, not primarydefects in pituitary synthesis of GH. Therefore, an alternative strategy fornormalizing sérum GH levels is by stimulating its release from somatotrophs.Increasing GH sécrétion can be achieved by stimulating or inhibiting variousneurotransmitter Systems in the brain and hypothalamus. As a resuit, thedevelopment of synthetic GH-releasing agents to stimulate pituitary GH sécrétionare being pursued, and may hâve several advantages over expensive andinconvénient GH replacement therapy. By acting along physiologie regulatorypathways, the most désirable agents would stimulate pulsatile GH sécrétion, andexcessive levels of GH that hâve been associated with the undesirable sideeffects of exogenous GH administration would be avoided by virtue of intactnégative feedback loops.

Physiologie and pharmacologie stimulators of GH sécrétion includearginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, andinsulin induced hypoglycemia, as well as activities such as sleep and exercise,indirectly cause GH to be released from the pituitary by acting in some fashion onthe hypothalamus perhaps either to decrease somatostatin sécrétion or toincrease the sécrétion of the known secretagogue GH releasing factor (GHRF) oran unknown endogenous GH-releasing hormone or ail of these.

Commonly assigned International Patent Application Publication NumberWO97/24369, designating, inter alia, the U.S., discloses GH secretagogues of theformula -5- 011569

N

wherein the variables are defined as set forth therein. International PatentApplication Publication Number WO97/24369 is incorporated herein by reference.

Tang et al., Restoring and Maintaininq Bone in Ostéogénie Female RatSkeleton: I. Changes in Bone Mass and Structure. J. Bone Minerai Research 7 (9),p1093-1104, 1992 discloses data for the lose, restore and maintain (LRM)concept, a practical approach for reversing existing osteoporosis. The LRMconcept uses anabolic agents to restore bone mass and architecture (+ phase)and then switches to an agent with the established ability to maintain bone mass,to keep the new bone (+/- phase). The rat study utilized PGE2 and risedronate, abisphosphonate, to show that most of the new cancellous and cortical boneinduced by PGE2 can be maintained for at least 60 days after discontinuing PGE2by administering risedronate.

Shen et al., Effects of Reciprocal Treatment with Estrogen and Estrogenplus Parathyroid Hormone on Bone Structure and Strength in OvariectomizedRats, J. Clinical Investigation, 1995, 96:2331-2338 discloses data for thecombination and/or sequential use of anti-resorptive agents and anabolic agentsfor the treatment of osteoporosis.

Commonly assigned International Patent Application Publication NumberWO97/31640, designating, inter alia, the U.S., discloses the use of certain GHsecretagogues in combination with certain SERMS to treat osteoporosis.International Patent Application Publication Number W097/31640 is incorporatedherein by reference.

SUMMARY OF THE INVENTION

This invention is directed 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-ol or apharmaceutically acceptable sait thereof; and -6- 011569 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-trifluoro-ethyO^.S.SaAej-hexahydro-pyrazolopI.S-clpyridin-S-yO-ethyO^-methyl-propionamide or a pharmaceutically acceptable sait thereof. 5 This invention is further directed to a pharmaceutical composition as recited in the immediately preceding paragraph additionally comprising a pharmaceuticalcarrier.

This invention is still further directed to a composition as set forth in eitherof the first two paragraphs of this summary wherein said first compound is (-)-cis-6- 10 phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olD-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-propionamideL-tartrate. 15 This invention is still further directed to a method, designated Method A, for treating a mammal suffering from musculoskeletal frailty comprising administeringto said mammal a pharmaceutical composition as recited in any of the first threeparagraphs of this summary. A preferred method within Method A, designated Method B, is wherein said 20 mammal is suffering from osteoporosis.

Another preferred method within Method A, designated Method C, is wherein said mammal is suffering from osteotomy, childhood idiopathic bone lossor bone loss associated with periodontitis.

This invention is still further directed to a method, designated Method A1, 25 for treating a mammal suffering from musculoskeletal frailty comprisingadministering to 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 apharmaceutically acceptable sait thereof; and 30 b. a second compound, said second compound being 2-amino-N-(1(R)- (2,4-difluoro-benzyloxymethyI)-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)-ethyi)-2-methyl- propionamide or a pharmaceutically acceptable sait thereof. -7- 011569

This invention is particularty directed to a method of Method A1 wherein thefirst compound and the second compounds are administered substantiallysimultaneously.

This invention is also particularly directed to a method of Method A1, 5 hereinafter termed Method D, wherein the second compound is administered for a périod of from about three months to about three years.

This invention is more particularly directed to a method of Method Dfollowed by administration of the first compound for a period of from about threemonths to about three years without the administration of the second compound 10 during the period of from about three months to about three years.

This invention is also more particularly directed to a method of Method Dfollowed by administration of the first compound for a period greater than aboutthree years without the administration of the second compound during the greaterthan about three year period. 15 This invention is also directed to a method, hereinafter termed Method E, for treating a mammal suffering from musculoskeletal frailty comprisingadministering to said mammal a therapeutically effective amount of a compositionas recited in any of the first threee paragraphe of this summary. A preferred method within Method E is-wherein bone healing following 20 facial reconstruction, maxillary reconstruction or mandibular reconstruction isenhanced, vertébral synostosis is induced, long bone extension is enhanced, thehealing rate of a bone graft or a long bone fracture is enhanced or prostheticingrowth is enhanced.

This invention is also directed to a method for increasing muscle mass in a 25 mammal comprising administering to said mammal a muscle mass increasingeffective amount of a composition as recited in any of the first three paragraphe ofthis summary.

In ail of the methods of this invention, it is particularly preferred that themammal is a human. 30 This invention is also directed to a kit comprising a treatment for a mammal suffering from musculoskeletal frailty comprising: -8- 011569 a. (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable sait thereof and apharmaceutically acceptable carrier in a first unit dosage form; b. 2-amiho-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 saitthereof and a pharmaceutically acceptable carrier in a second unit dosage form;and c. a container.

This invention is particularly directed. to a kit as described in theimmediately preceding paragraph wherein said first unit dosage form comprises (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8- tetrahydronaphthalene-2-ol D-tartrate and said second unit dosage form comprises 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,416l7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide L-tartrate.

In ail of the compositions, methods and kits of this invention, it isparticularly preferred that the D-tartrate sait of (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol is used and that the L-tartrate sait 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 used.

The phrase "condition which présents with low bone mass" refers to acondition where the level of bone mass is below the âge spécifie normal asdefined in standards by the World Health Organization "Assessment of FractureRisk and its Application to Screening for Postmenopausal Osteoporosis (1994),Report of a World Health Organization Study Group. World Health OrganizationTechnical Sériés 843". Childhood idiopathic and primary osteoporosis are alsoincluded. Included in the treatment of osteoporosis is the prévention oratténuation of long term complications such as curvature of the spine, loss ofheight, prosthetic surgery, and prévention of prostate malfunctioning. Alsoincluded is increasing the bone fracture healing rate and enhancing the rate of WO 99/65488 -9- PCT/IB99/00796 011569 successful bone grafts. Also included is periodontal disease and alveolar boneloss.

The phrase "condition which présents with low bone mass" also refers to amammal known to hâve a significantly higher than average chance of developing 5 such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the agê of 60, and persons being treated withdrugs known to cause osteoporosis as a side effect (such as glucocorticoid)).

Those skilled in the art will recognize that the term bone mass actuallyrefers to bone mass per unit area which is sometimes (although not strictly 10 correctly) referred to as bone minerai density.

The phrase “musculoskeletal frailty” refers to a condition wherein a subject has low bone mass and/or low muscle mass, and includes such diseases,disorders and conditions such as, but not limited to, conditions which présent withlow bone mass, osteoporosis, conditions which présent with low muscle mass, 15 osteotomy, childhood idiopathic bone loss, bone loss associated with periodontitis,bone healing following facial reconstruction, maxillary reconstruction, mandibularreconstruction and bone fracture. Further, musculoskeletal frailty encompassessuch conditions as interfaces between newly attached prostheses and bone whichrequire bone ingrowth. 20 The term "treating", "treat” or "treatment" as used herein includes curative, preventative (e.g., prophylactic) and palliative treatment. . The parenthetical négative or positive sign used herein in the nomenclaturedénotés the direction plane polarized light is rotated by the particular stereoisomer.

The compositions of this invention may include hydrates of the compounds 25 used therein.

The pharmaceutical compositions and methods of this invention resuit in amore rapid and higher magnitude bone mass gain than is achievable with thesame doses of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl}-5,6,7,8-tetrahydro-naphthalene-2-ol as described above alone or 2-amino-N-(1(R)-(2,4- 30 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 as described above alone. Thus, these combinations increase bone mass and decrease fracture rates to a gréater extent than is achievable through -10- 011569 use of either agent alone. Further, these combinations increase bone density andmuscle mass while at the same time reducing fat mass and total sérumcholestérol. This invention makes a significant contribution to the art by providingcompositions and methods that increase and maintain bone mass resulting in 5 prévention, retardation, and/or régression of osteoporosis and related bonedisorders.

Other features and advantages will be apparent from the spécification anddaims which describe the invention. DETAILED DESCRIPTION OF THE INVENTION10 The first compound of this invention is (-)-c/s-6-phenyl-5-[4-(2-pyrrolidin-1- yi-ethoxy)-phenylï-5,6,7,8-tetrahydro-naphthalene-2-ol, or a pharmaceuticallyacceptable sait thereof, which has the structure of Formula I:

I 15 (-)-C/s-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- naphthalene-2-ol and the pharmaceutically acceptable salts thereof are preparedas described in commonly assigned US Patent Number 5,552,412, which isreferenced above. (-)-C/s-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- 20 naphthalene-2-ol D-tartrate is prepared as set forth in the immediately precedingparagraph or, altematively, as set forth in international Patent ApplicationPublication Number WO97/16434, designating the United States and which isincorporated herein by référencé.

The second compound of this invention is 2-amino-N-(1(R)-(2,4-difluoro- 25 benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)- -11- 011569 2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamideor a pharmaceutically acceptable sait thereof, which has the structure of FormulaII:

5 II 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 the pharmaceutically acceptable salts thereofare prepared as set forth in commonly assigned International Patent Application 10 Publication Number WO97/24369, designating, inter alia, the United States, whichis referenced above. 2-Amino-N-(1 (R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-yimethyl)-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 set forth in 15 International Patent Application Publication Number WO97/24369, referencedabove. Alternative^, 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 asdescribed in Example One herein. 20 In addition, when the compounds and pharmaceutically acceptable salts thereof used in the compositions and methods of this invention form hydrates or solvatés such hydrates or solvatés are also within the scope of the invention.

The pharmaceutical combinations and methods of this invention are ail adapted to therapeutic use as agents that either activate bone turnover or prevent 25 bone résorption or increase bone formation in mammals, particulariy humans. -12- 011569

Since these functions are closely related to the development of osteoporosis andbone related disorders, these combinations, by virtue of their action on bone,prevent, arrest, regress or reverse osteoporosis.

The utility of the compositions and methods of the présent invention asmedical agents in the treatment of musculoskeletal frailty (e.g., conditions whichprésent with low bone mass or low muscle mass including osteoporosis) inmammals (e.g. humans) is demonstrated by the activity of the compounds of thisinvention in conventional assays as set forth in U.S. Patent Number 5,552,412 andInternational Patent Application Publication Number WO97/24369. Furtherevidence of the utility of the instant combination is set forth in Example Two below.Such assays also provide a means whereby the activities of the compounds ofthis invention can be compared between themselves and with the activities of other known compounds. The results of these comparisons are useful fordetermining dosage levels in mammals,- including humans, for the treatment ofsuch diseases.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of the combination of this invention systemicaliy and/orlocally. These methods include oral routes, parentéral, intraduodenal routes, etc.Generally, frie compounds of this invention are administered orally, but parentéraladministration (e.g., intravenous, intramuscular, transcutaneous, subcutaneous orintrameduüary) may be utilized, for example, where oral administration isinappropriate for the instant target or where the patient is unable to ingest thedrug. The two different compounds of this invention can be co-administeredsimultaneously or sequentially in any order, or a single pharmaceuticalcomposition comprising a first compound as described above and a secondcompound as described above in a pharmaceutically acceptable carrier can beadministered.

In any event the amount and timing of compounds administered will, ofcourse, be dépendent on the subject being treated, on the severity of the affliction,on the manner of administration and on the judgment of the prescribing physician.Thus, because of patient to patient variability, the dosages given below are aguideline and the physician may titrate doses of the drug to achieve the activity(e.g., bone mass augmentation) that the physician considère appropriate for the -13- 011569 individual patient. In considering the degree of activity desired, the physician mustbalance a variety of factors such as bone mass starting level, âge of the patient,presence of preexisting disease, as well as presence of other diseases (e.g.,cardiovascular). For example, the administration of (-)-cis-6-phenyl-5-(4-(2- 5 pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol can providecardiovascular benefits, particularly for post-menopausal women. The followingparagraphe provide preferred dosage ranges for the various components of thisinvention.

An effective dosage for " (-)-c/s-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)- 10 phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol is in the range of 0.0001 to 100mg/kg/day, preferably 0.001 to 10 mg/kg/day.

An effective dosage for 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 the range 15 of 0.0001 to 100 mg/kg/day, preferably 0.01 to 5 mg/kg/day.

Where the tartrate sait or other pharmaceutically acceptable sait of eitherof the above compounds is used in this invention, the skilled person will be able tocalculate effective dosage amounts by calculating the molecular weight of the saitform and performing simple stoichiometric ratios. 20 The compounds of the présent invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds orpharmaceutically acceptable salts thereof of this invention together with apharmaceutically acceptable carrier or diluent. Thus, the compounds andpharmaceutically acceptable salts thereof of this invention can be administered 25 separately or together in any conventional oral, parentéral or transdermal dosageform. When administered separately, the administration of the other compound orpharmaceutically acceptable sait thereof of the invention follows.

For oral administration a pharmaceutical composition can take the form ofsolutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets 30 containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. -14- 011569

Additionally, lubricating agents such as magnésium stéarate, sodium lauryl sulfateand talc are often useful for tabletting purposes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatin capsules; preferredmatériels in this connection also include lactose or milk sugar as well as high 5 molecular weight polyethylene glycols. When aqueous suspensions and/or élixirsare desired for oral administration, the compounds or pharmaceutically acceptablesalts thereof of this invention can be combined with various sweetening agents,flavoring agents, coloring agents, emulsifying agents and/or suspending agents,as well as such diluents as water, éthanol, propylene glycol, glycerin and various 10 like combinations thereof.

For purposes of parentéral administration, solutions in sesame or peanut oilor in aqueous propylene glycol can be employed, as well as stérile aqueoussolutions of the corresponding water-soluble salts. Such aqueous solutions maybe suitably buffered, if necessary, and the liquid diluent first rendered isotonie with 15 sufficient saline or glucose. These aqueous solutions are especially suitable forintravenous, intramuscular, subeutaneous and intraperitoneal injection purposes.In this connection, the stérile aqueous media employed are ail readily obtainableby standard techniques well-known to those skilled in the art.

For purposes of transdermal (e.g.,topical) administration, dilute stérile, 20 aqueous or partially aqueous solutions (usually in about 0.1% to 5%concentration), otherwise similar to the above parentéral solutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of each active ingrédient are known, or will be apparent in light of thisdisclosure, to those skilled in this art. For examples, see Remington's 25 Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., 19th Edition(1990).

Pharmaceutical compositions according to the invention may contain 0.1%-95% of a combination of the compounds or pharmaceutically acceptable saltsthereof of this invention, preferably 1%-70%. In any event, the composition or 30 formulation to be administered will contain a quantity of the compounds or pharmaceutically acceptable salts thereof of the invention in an amount effective to treat the disease/condition of the subject being treated. -15- 011569

Since the présent invention relates to treatment with a combination of thetwo active ingrédients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form. The kitincludes two separate pharmaceutical compositions: (-)-cis-6-phenyl-5-(4-(2- 5 pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or apharmaceutically acceptable sait 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)-2,3,3a14,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamideor a pharmaceutically acceptable sait thereof. The kit includes a container for 10 containing the separate compositions such as a divided bottle or a divided foilpacket, however, the separate compositions may also be contained within a single,undivided container. Typically the kit includes directions for the administration ofthe separate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosage forms (e.g., 15 oral and parentéral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired by theprescribing physicien.

An example of such a kit is a so-called biister pack. Blister packs are wellknown in the packaging industry and are being widely used for the packaging of 20 pharmaceutical unit dosage forms (tabiets, capsules, and the like). Blister packsgenerally çonsist of a sheet of relatively stiff material covered with a foil of apreferably transparent plastic material. During the packaging process recessesare formed in the plastic foil. The recesses hâve the size and shape of the tabietsor capsules to be packed. Next, the tabiets or capsules are placed in the recesses 25 and the sheet of relatively stiff material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesses were formed.As a resuit, the tabiets or capsules are sealed in the recesses between the plasticfoil and the sheet. Preferably the strength of the sheet is such that the tabiets orcapsules can be removed from the blister pack by manually applying pressure on 30 the recesses whereby an opening is formed in the sheet at the place of the recess.

The tablet or capsule can then be removed via said opening.

It is désirable to provide a memory aid on a card insert, e.g., in the form of numbers next to the tabiets or capsules whereby the numbers correspond with the -16- 011569 days of the regimen which the tablets or capsules so specified should be ingested.Another example of such a memory aid is a calendar printed on the card e.g., asfollows "First Week, Monday, Tuesday, ...etc.... Second Week, Monday,Tuesday,..." etc. Other variations of memory aids will be readily apparent. A "daily 5 dose" can be a single tablet or capsule or several pills or capsules to be taken ona given day. Also a daily dose of SERM can consist of one tablet or capsule whilea daily dose of a GH secretagogue can consist of several tablets or capsules. Thememory aid should reflect this.

In another spécifie embodiment of the invention a dispenser designed to 10 dispense the daily doses one at a time in the order of their intended use isprovided. Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such a memory-aidis a mechanical counter which indicates the number of daily doses that has beendispensed. Another example of such a memory-aid is a battery-powered micro- 15 chip memory coupled with a liquid crystal readout, or audible reminder signalwhich, for example, reads out the date that the last daily dose has been takenand/or reminds one when the next dose is to be taken.

Example 1 2- Amino-N-{1-(2,4-difluoro-benzvloxvmethvD-2-oxo-2-i3-oxo-3a-pyridin-2-vlmethvl- 20 2-(2.2.2-trifluoro-ethyn-2,3,3a.4.e,7-hexahvdro-pvrazolof4.3-c1pvridin-5-vn-ethvn-2- methvl-propionamide L-(+) tartrate A. 4-Qxo-3-pyridin-2-vlmethvl-piperidine-1,3-dicarboxvlic acid 1-ferf-butyl ester 3- ethvl ester

To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-ferf-butyl ester 3- 25 ethyl ester (10.34 g, 38.2 mmol) in DMF (40 mL) at about 0 °C was added picolylchloride hydrochloride (5.7 g, 34.7 mmol), potassium carbonate (14.4 g, 104.1mmol) and potassium iodide (5.76 g, 34.7 mmol). After stirring at about 0 °C forabout 2 hours, the ice bath was removed and DABCO (973 mg, 8.68 mmol) wasadded. The reaction mixture was stirred for about 30 min. and poured into a 30 mixture of water and IPE. The organic layer was separated and washed with saturated aqueous NaHCO3 and saturated aqueous NaCI, dried over Na2SO4 and concentrated in vacuo, The crude residue was crystallized from hexanes to give a white solid (8.19 g, yield 65%). 1H-NMR (CDCfe) δ 1.17 (t, 3H), 1.48 ( s, 9H), 1.55 -17- 011569 (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 (br s, 1 H), 7.17(d, 1 H), 7.54 (m, 1 H), 8.40 (s, 1 H). B. 3-Oxo-3a-pyridin-2-ylmethvl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro- pvrazolor4,3-c1pyridine-5-carboxvlic acid terf-butyl ester 5 A 70% aqueous solution of CF3CH2NHNH2 (325 mL, 1.986 mol) (obtained from Aldrich) was extracted with toluene (3 x 1200 mL). To a solution of theproduct made according to step A (600 g, 1.655 mol) in toluene (900 mL) was firstadded the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethylhydrazine, followed by acetic acid (121.4 g, 1.986 mol). The reaction mixture was 10 heated at about 70 °C for about 2 hours , then another toluene extraction of 70%aqueous 2,2,2-trifluoroethyl hydrazine (50 g) was added. The reaction mixturewas heated at about 80 °C for about 3.5 hours, cooled to room température anddiluted with saturated aqueous NaHCC>3 (2 L). The toluene layer was separatedand washed with saturated aqueous NaCI, dried over Na2SO4 and concentrated in 15 vacuo to give an oil (754.8 g). Crystallization from methanol/water afforded thedesired product as a white solid (609.5 g). ’H-NMR (CDCl3) δ 1.50 (s, 9H), 2.53 (d,1H), 2.70 (br s, 2H), 2.88 (br s, 1H), 3.31 (m, 2H), 3.97 (m, 1H), 4.19 (m, 1H), 4.46(br s, 1H), 4.63 (br s, 1H), 7.06 (m, 2H), 7.51(m, 1H), 8.34 (m, 1H). C. 3a-Pyridin-2-vlmethvl-2-(2.2.2-trifluoroethvD-2,3a.4,5,6,7-hexahvdro- 20 pyrazolof4,3-clpyridin-3-one

Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to a solutionof the product from step B (10 g, 24.2 mmol) in CH2CI2 (100 mL) over about 30minutes. The reaction mixture was stirred for about 1 hour, then cooled to about 0°C, and then triethylamine (Ï8.6 mL, 133.1 mmol) was added through an addition 25 funnel. The mixture was allowed to warm to room température over about 1 hour,diluted with additional CH2CI2 and washed with saturated aqueous NaCI, driedover Na2SO4l filtered and concentrated in vacuo to afford the product as a whitesolid (7.2 g). 1H-NMR (CDCI3) 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, 1 H). 8.37 (d, 1H). 30 D. 3a-Pvridin-2-vlmethyl-2-(2.2,2-trifluoroethvl)-2,3a,4,5,6,7-hexahvdro-pyrazolof4,3-c1pyridin-3-one (D)-tartrate

In a dry and nitrogen purged 5 L round bottom flask equipped with amechanical stirrer, D-(-) tartaric acid (129 g, 0.86 mol). was. added to the -18- 011569 compound made according to step C (243 g, 0.78 mol) in acetone/water (9:1,2430 mL) at about 17 °C. The mixture was stirred at room température ovemight,filtered, the solid was collected and washed with cold acetone and dried undervacuum. The product was obtained as a yellow solid (284 g, yield 78.8%). 5 E. 2-ferf-Butoxvcarbonvlamino-3-(2,4-difluoro-benzyloxv)-propionic acid

To a solution of N-Boc-(D)-serine (452 g, 2.2026 mol) in a mixture of THF (7 L) and DMF (3 L) at about 0 °C was added potassium fert-butoxide solution(515.8 g, 4.5963 mol). The réaction mixture was stirred at about 0 °C for about 30min., then 2,4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After 10 warming to room température, the reaction mixture was concentrated in vacuo toremove the THF. Partitioned the reaction mixture between 4.5 L H2O and 4.5 LIPE. Separated the layers and adjusted the pH of the aqueous layer with 1 N HClto about 3. The aqueous layer was extracted twice with 4 L each of IPE. Theorganic solution was dried over Na2SO4, and concentrated in vacuo to yield a 15 yellow waxy solid (518.0 g, yield: 70.9 %). 1H-NMR (CDCI3) δ 1.44 (s, 9H), 3.73 (m,1H), 3.94 (d, 1H-K 4.44 (br s, 1H), 4.54 (s, 2H), 5.34 (m, 1H), 6.78 (m, 1H), 6.84 (m,1H), 7.30 (m, 1H). F. 2-Amino-3-(2,4-difluoro-benzyloxy)-propionic acid, methanesulfonic acid sait

20 To a solution of the product from step E (1.19 g, 3.59 mmol) in CH2CI2/ IPE (1:1, 12 mL) was added methanesulfonic acid (1.72 g, 17.95 mmol) through asyringe over about 10 minutes. A solid immediately precipitated out of solution.After about 1 hour, the solid was filtered and washed with a CH2CI2/IPE mixture(1:1) to afford 939 mg of product (yieid 80 %). 25 G. 2-(2-fert-Butoxvcarbonylamino-2-methyl-propionvlamino)-3-(2.4-difluoro-benzvloxy)-oropionic acid

To a solution of the product from step F (520 mg, 1.46 mmol) in THF/water(4:1, 10 mL) was added 2-ferf-butoxycarbonylamino-2-methyl-propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (438 mg, 1.46 mmol) and triethylamine (369 mg, 3.65 30 mmol). The reaction mixture was stirred at room température for. about 1 hour andquenched with a 10% aqueous citric acid solution (10 mL). After about 15 min.,ethyl acetate (50 mL) was added and the organic layer was separated and washedwith saturated aqueous NaCI, dried over Na2SO4 and concentrated in vacuo to -19- 011569 give a foam (534.1 mg, yield 88 %). ’H-NMR (CD3OD): δ 1.38 (br s, 15H), 3.77 (d,1H), 3.92 (d, 1H), 4.52 (m, 3H), 6.92 (m, 1K), 7.41 (m, 1H), 7.58 (d, 1H). H. (1 -(1 -(2,4-Difluoro-benzvloxvmethyl)-2-oxo-2-l3-oxo-3a-pyridin-2-vlmethvl- 2-(2.2,2-trifluoro-ethvD-2.3,3a,4,6.7-hexahvdro-pvrazolor4.3-c1pvridin-5-vn- 5 ethvlcarbamovQ-1-methvl-ethyl)-carbamic acid terf-butyl ester (a) .To the compound made according to step D (517 g, 1.12 mol) wasadded at about -6 °C to ethyl acetate (5170 mL) in a dry and nitrogen purged 12 Lround bottom flask equipped with a mechanical stirrer. The solution was cooled toabout -40 °C, then triethylamine (398 mL, 2.86 mol) was added over about 45 10 minutes. The reaction mixture was stirred for about 90 min. at a températurebetween about -50 °C and about -40 °C, filtered into a 22 L round bottom flaskpurged with nitrogen and washed with ethyl acetate (2068 mL, pre-cooled to about-50 °C) to give the free base as a white solid. (b) The compound made according to step G (425 g, 1.02 mol ) was added 15 at about -30 °C to an ethyl acetate solution containing the product from step H(a), triethylamine (654 mL, 4.69 mol) and PPAA (1-propanephosphonic acid cyclicanhydride) (50% in ethyl acetate, 916 mL, 1.53 mol). The reaction mixture wasstirred for about 1 hour, washed with water and saturated aqueous NaCI, driedover Na2SO4 and concentrated in vacuo to give the product as an oil (636 g, yield: 20 87.8%). I. 2-Amino-N~f1-(2,4-difluoro-benzvloxvmethvl)-2-oxo-2-r3-oxo-3a-pvridin-2- vlmethvl-2-(2.2,2-trifluoro-ethvl)-2.3,3a.4,6,7-hexahvdro-pyrazoloî4,3-c)pvridin-5- vn-ethyl)-2-methvl-propionamide

Methanesulfonic acid (258.3 mL, 3.98 mol) was added dropwise at about 25 15 °C over about 55 minutes to the product from step H (566 g, 0.796 mol) in CH2CI2 (11,320 mL) in a dry and nitrogen purged 22 L round bottom flaskequipped with a mechanical stirrer. The mixture was stirred for about 40 minutesat about 20 °C, then saturated aqueous NaHCCh (8,490 mL) was added until thepH was about 7.8. The organic layer was separated, washed with water and 30 saturated aqueous NaCI, dried over Na2SO4, and concentrated in vacuo to afford an oily product (388.8 g, yield 80%). -20- 011569 j. 2-Amino-N-{ 1-(2 .4-difluoro-benzvloxymeth vl)-2-oxo-2-f 3-oxo-3a-pyridin-2- vlmethvl-2-(2.2.2-trifluoro-ethvl)-2,3'3a.4'67-hexahvdro-pyrazotof4.3-c)pyridin-5- vn-ethviï-2-methyl-propionamide L-(+) tartrate

To a solution of the product from step I (370 g, 0.6 mol) in methanol (4,070 5 mL) in a 12 L round bottom flask equipped with a mechanical stirrer was added L-(+) tartaric acid (90 g, 0.6 mol). The reaction mixture was stirred for about 90 min.at about 22 °C, filtered and concentrated. The crude residue was diluted with ethylacetate (4,560 mL), heated at about 70 °C and slowly allowed to cool to roomtempérature over about 17 hours. The solid was filtered and dried to give white 10 crystals, mp 188-189 °C (348.46 g, yield 76%). 1H NMR (MeOH, 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), 4.13-4.06 (m, 1H), 3.78 (d, 2H),3.21 (t, 1H), 3.18-2.96 (m, 2H), 2.65-2.55 (m, 2H), 1.57 (d, 6H). MS: MH+ 611.[a]589 +22.03 (c=11.9, MeOH). 15 The following assay can be used to show that the combination and methods of this invention increases lean body mass and decreases fat body masswhereas the GH secretagogue alone would be expected to decrease fat bodymass with no change in lean body mass and the SERM alone would be expectedto increase both lean and fat body mass. Further, the combination increases bone 20 density and decreases total sérum cholestérol.

Example Two

Female S-D rats (Harlan) are sham-operated or ovariectomized (OVX) at3.5 months of âge. Drug administration starts when the rats are 9 months of âgeand 5.5 months post-surgery. The sham-operated rats receive daily gavage of 25 vehicle (10% éthanol in water), while the OVX rats receive daily gavage of vehicte,or 2-amino-N-(1 (R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifiuoro-ethyl)-213,3a,4,6,7-hexahydro-pyrazolo[4)3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide at 5 mg/kg/d alone, or (-)cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-pheny!)-5,6,7,8-tetrahydronaphthalene-2-ol at 0.1 mg/kg/d 30 alone, or co-treatment of 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2- (3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifIuoro-ethyl)-2,3,3a,4,6,7-hexahydro- pyrazolo[4,3-cÎpyridin-5-yl)-ethyl)-2-methyl-propionamide and (-)cis-6-phenyl-5-(4- (2-pyrrolidin-1-yi-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol for 4 weeks. -21- 011569

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-^1^0^-6^1)-2,3,38,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide is given 2 hours prior to(-)cis-6-phenyl-5-(4-(2-pynOlidin-1-yi-ethoxy)-phenyl)-5,6,7,8- 5 tetrahydronaphthalene-2-ol. There are 8 to 10 rats per each subgroup. Ali rats aregiven subcutaneous injections with 10 mg/kg of calcein (Sigma Chemical Co., St.Louis, MO) on 13 and 3 days before autopsy. It will be recognized by those skilledin the art that the compounds used in this assay may be administered in the formof a pharmaceutically acceptable sait and that the dosage amount can be readily 10 determined by calculation of the molecular weight of the sait form and performingsimple ratios.

Before autopsy on the terminal day of the assay, ail rats underketamine/xylazine anesthésia undergo dual-energy X-ray absorptiometry (DXA,QDR-1000/W, Hologic Inc., Waltham, MA) equipped with Rat Whole Body Scan 15 software (Hologic Inc., Waltham, MA) for lean and fat body mass détermination.The rats are then autopsied and blood is obtained by cardiac puncture. Totalsérum cholestérol is determined using a high performance cholestérol colorometicassay (Boehringer Mannheim Biochemicals, Indianapolis, IN). The body weightgain is calculated as body weight at autopsy minus body weight at day 0. The 20 uterine wet weight is determined immediately at autopsy.

The right fémur from each rat is removed at autopsy and scanned using dual energy x-ray absorptiometry (DXA, QDR 1000/W, Hologic Inc., Waltham, MA)equipped with "Régional High Resolution Scan" software (Hologic Inc., Waltham,MA). The scan field size is 5.08 x 1.902 cm, resolution is 0.0254 x 0.0127 cm and 25 scan speed is 7.25 mm/second. The fémoral scan images are analyzed and totalfémoral bone area, bone minerai content, and bone minerai density aredetermined according to the method described in H. Z. Ke et al., Droloxifene, aNew Estrogen Antagonist/Agonist, Prevents Bone Loss in Ovariectomized Rats.ENDOCRINOLOGY 136,2435-2441, 1995. 30 It should be understood that the invention is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined by the following daims.

Claims (6)

1. CLAIMS .,01 1 569

   1. A pharmaceuticai composition comprising: a. a first compound, said first compound being (-)-cis-6-phenyi-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or spharmaceutically acceptable sait thereof; 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- trifiuoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyiïdin-5-yl)-ethyl)-2-methyl- propionamide or a pharmaceutically acceptable sait thereof. G
2. 2. A pharmaceuticai composition of claim 1 additionally comprising apharmaceuticai carrier.
3. 3. A pharmaceuticai composition of claim 1 wherein said firstcompound is (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8- ç tetrahydronaphthalene-2-ol D-tartrate and said second compound is 2-amino-N-(1(R)-(2,4-dÎfluoro-benzyIoxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3I3a,4,6I7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyi-propionamide L-tartrate. 20 If. Useof:- 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 apharmaceutically acceptable sait thereof; and 25 b. a second compound, said second compound being 2-amino-N-(1(R)- (2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxc-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 sait thereof. in the manufacture of a médicament for the treatment of a mammal suffering from 30 musculoskeletal frailty in a mammal.
4. 5- Use according to claim ij, wherein the musculoskeletal frailty is osteoporosis. 6· Use according to claim wherein the musculoskeletal frailty is osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis. 23 - 011569
5. 7 . Use according to claim If. wherein the musculoskeletal frailty is bonehealing following facial reconstruction, maxillary reconstruction or mandibularreconstruction; and wherein vertébral synostosis is induced, long bone extension isenhanced, the healing rate of a bone graft is enhanced, or prosthetic ingrowth is enhancedby the médicament. 3 Use according to claim wherein the musculoskeletal frailty is a bonefracture in a human. 5 Use of a compound according to claim 1 in the manufacture of amédicament for increasing muscle mass in a mammal. Ιΰ>. A kit comprising: a. (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable sait thereof and apharmaceutically acceptable carrier or diluent in a first unit dosage form; 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 a pharmaceuticallyacceptable sait thereof and a pharmaceutically acceptable carrier or diluent in asecond unit dosage form; and c. a container. If. A kit of claim 71 wherein said first unit dosage form comprises (-)-cis-6-phehyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene- 2-ol D-tartrate and said second unit dosage form comprises 2-amino-N-(1(R)-(2,4-difluorp-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a14,617-hexahydro-pyrazolo{4,3-c]pyridin-5-yl)-ethy()-2-methyl-propionamide L-tartrate.
6. 12. Use of a pharmaceutical composition of claim 1 to préparé a médicament for treating a mammal suffering from musculoskeletal frailty. 13 A use of claim /2. wherein said first compound is (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol D-tartrateand 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. 1^·. A use of claim wherein said mammal is suffering fromosteoporosis. -q- . 011569 I5" A use of daim I2. wherein said mammal is suffering fromosîeotomy, chiidhood idiopathic bone or bone loss associated wiih periodontitis. | θ. The use of ciaim I2 wherein bone healing fcüowing facialreconstruction, maxiilary reconstruction or mandibular reconstruction is treated, 5 vertébral synostosis is induced or long bone extension is enhanced, the healingrate of a bone graft is enhanced or prosthetic ingrowth is enhanced. f? The use of daim I6 wherein a bone fracture is treated in a human.I S. A use of daim {tj. wherein osteoporosis is treated in a human.