Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a pharmaceutical combination of a selective 5 estrogen receptor modulator (SERM) and a growth hormone secretagogue (GHS) that stimulates bone formation, increases bone mass, decreases serum lipid levels and increases muscle mass.
• SERM selective 5 estrogen receptor modulator
• GHS growth hormone secretagogue
• the invention also relates to kits containing such combinations and the use of such combinations to treat musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass, frailty, low muscle0 mass and the like in mammals, including humans.
• this invention relates to a combination of (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)- 5,6,7,8-tetrahydronaphthalene-2-ol or 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-pyra2olo[4,3-c]pyridin-5 5-yl)-ethyl)-2-methyl-propionamide or a pharmaceutically acceptable salt thereof, kits containing such a combination and the use of such a combination to treat musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass, frailt
• Osteoporosis is a systemic skeletal disease, characterized by low bone 0 mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
• the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% 5 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 60 years, and one study estimates that there will be 4.5 million hip fractures 30 worldwide in 2050.
• Estrogen is the agent of choice in preventing osteoporosis or post menopausal bone loss in women.
• Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL's).
• Long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to either avoid this treatment or take the medication for only a short period of time.
• the risk of endometrial cancer is thought to be reduced by a concurrent use of a progesterone, there is still concern about possible increased risk of breast cancer with the use of estrogen.
• GH Growth hormone
• GH Deficiency in GH results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous GH has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
• the problem was generally solved by providing exogenous GH or by administering an agent which stimulated GH production and/or release.
• 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.
• the source of GH was the extraction of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the GH (e.g., Jacob-Creutzfeld disease).
• Jacob-Creutzfeld disease e.g., Jacob-Creutzfeld disease.
• Recently, recombinant GH has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
• GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic GH-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
• Physiologic and pharmacologic stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin 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 on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue GH releasing factor (GHRF) or an unknown endogenous GH-releasing hormone or all of these.
• L-DOPA L-3,4-dihydroxyphenylalanine
• glucagon glucagon
• vasopressin vasopressin
• insulin 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 on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known
• This invention is directed to a pharmaceutical composition
• 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 a pharmaceutically acceptable salt 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- 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 further directed to a pharmaceutical composition as recited in the immediately preceding paragraph additionally comprising a pharmaceutical carrier.
• This invention is still further directed to a composition as set forth in either of the first two paragraphs of this summary wherein said first compound is (-)-cis-6- phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-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.
• This invention is still further directed to a method, designated Method A, for treating a mammal suffering from musculo
• Method A A preferred method within Method A, designated Method B, is wherein said mammal is suffering from osteoporosis.
• Method C Another preferred method within Method A, designated Method C, is wherein said mammal is suffering from osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis.
• Method A 1 for treating a mammal suffering from musculoskeletal frailty comprising administering 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 a pharmaceutically acceptable salt thereof; and b. a second compound, said second compound being 2-amino-N-(1(R)-
• This invention is also particularly directed to a method of Method A 1 , hereinafter termed Method D, wherein the second compound is administered for a period of from about three months to about three years.
• This invention is more particularly directed to a method of Method D followed by administration of the first compound for a period of from about three months to about three years without the administration of the second compound during the period of from about three months to about three years.
• This invention is also more particularly directed to a method of Method D followed by administration of the first compound for a period greater than about three years without the administration of the second compound during the greater than about three year period.
• This invention is also directed to a method, hereinafter termed Method E, for treating a mammal suffering from musculoskeletal frailty comprising administering to said mammal a therapeutically effective amount of a composition as recited in any of the first threee paragraphs of this summary.
• a preferred method within Method E is wherein bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction is enhanced, vertebral synostosis is induced, long bone extension is enhanced, the healing rate of a bone graft or a long bone fracture is enhanced or prosthetic ingrowth is enhanced.
• This invention is also directed to a method for increasing muscle mass in a mammal comprising administering to said mammal a muscle mass increasing effective amount of a composition as recited in any of the first three paragraphs of this summary.
• the mammal is a human.
• This invention is also directed to a kit comprising a treatment for a mammal suffering from musculoskeletal frailty comprising: a. (-)-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 a pharmaceutically acceptable carrier in a first unit dosage form; b.
• 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,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5- yl)-ethyl)-2-methyl-propionamide L-tartrate.
• the D-tartrate salt 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 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 is used.
• condition which presents with low bone mass refers to a condition where the level of bone mass is below the age specific normal as defined in standards by 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". Childhood idiopathic and primary osteoporosis are also included. Included in the treatment of osteoporosis is the prevention or attenuation of long term complications such as curvature of the spine, loss of height, prosthetic surgery, and prevention of prostate malfunctioning. Also included is increasing the bone fracture healing rate and enhancing the rate of successful bone grafts. Also included is periodontal disease and alveolar bone loss.
• condition which presents with low bone mass also refers to a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post- menopausal women, men over the age of 60, and persons being treated with drugs known to cause osteoporosis as a side effect (such as glucocorticoid)).
• osteoporosis e.g., post- menopausal women, men over the age of 60, and persons being treated with drugs known to cause osteoporosis as a side effect (such as glucocorticoid)).
• bone mass actually refers to bone mass per unit area which is sometimes (although not strictly correctly) referred to as bone mineral density.
• 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 present with low bone mass, osteoporosis, conditions which present with low muscle mass, osteotomy, childhood idiopathic bone loss, bone loss associated with periodontitis, bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction and bone fracture. Further, musculoskeletal frailty encompasses such conditions as interfaces between newly attached prostheses and bone which require bone ingrowth.
• treating includes curative, preventative (e.g., prophylactic) and palliative treatment.
• the parenthetical negative or positive sign used herein in the nomenclature denotes the direction plane polarized light is rotated by the particular stereoisomer.
• compositions of this invention may include hydrates of the compounds used therein.
• compositions and methods of this invention result in a more rapid and higher magnitude bone mass gain than is achievable with the same doses of (-)-c/ ' s-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6 l 7,8- tetrahydro-naphthalene-2-ol as described above alone 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 as described above alone.
• these combinations increase bone mass and decrease fracture rates to a greater extent than is achievable through use of either agent alone. Further, these combinations increase bone density and muscle mass while at the same time reducing fat mass and total serum cholesterol.
• This invention makes a significant contribution to the art by providing compositions and methods that increase and maintain bone mass resulting in prevention, retardation, and/or regression of osteoporosis and related bone disorders.
• the first compound of this invention is (-)-c/ ' s-6-phenyl-5-[4-(2-pyrrolidin-1- yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, or a pharmaceutically acceptable salt thereof, which has the structure of Formula I:
• the second 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 a pharmaceutically acceptable salt thereof, which has the structure of Formula
• the pharmaceutical combinations and methods of this invention are all adapted to therapeutic use as agents that either activate bone turnover or prevent bone resorption or increase bone formation in mammals, particularly humans. Since these functions are closely related to the development of osteoporosis and bone related disorders, these combinations, by virtue of their action on bone, prevent, arrest, regress or reverse osteoporosis.
• compositions and methods of the present invention as medical agents in the treatment of musculoskeletal frailty (e.g., conditions which present with low bone mass or low muscle mass including osteoporosis) in mammals (e.g. humans) is demonstrated by the activity of the compounds of this invention in conventional assays as set forth in U.S. Patent Number 5,552,412 and
• Such assays also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
• Administration of the compounds of this invention can be via any method which delivers a compound of the combination of this invention systemically and/or locally. These methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, transcutaneous, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate for the instant target or where the patient is unable to ingest the drug.
• the two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition comprising a first compound as described above and a second compound as described above in a pharmaceutically acceptable carrier can be administered.
• the amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
• the dosages given below are a guideline and the physician may titrate doses of the drug to achieve the activity (e.g., bone mass augmentation) that the physician considers appropriate for the individual patient.
• the physician must balance a variety of factors such as bone mass starting level, age of the patient, presence of preexisting disease, as well as presence of other diseases (e.g., cardiovascular).
• the administration of (-)-cis-6-phenyl-5-(4-(2- pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol can provide cardiovascular benefits, particularly for post-menopausal women.
• the following paragraphs provide preferred dosage ranges for the various components of this invention.
• An effective dosage for (-)-c/ ' s-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol is in the range of 0.0001 to 100 mg/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 of 0.0001 to 100 mg/kg/day, preferably 0.01 to 5 mg/kg/day.
• the skilled person will be able to calculate effective dosage amounts by calculating the molecular weight of the salt form and performing simple stoichiometric ratios.
• the compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds or pharmaceutically acceptable salts thereof of this invention together with a pharmaceutically acceptable carrier or diluent.
• the compounds and pharmaceutically acceptable salts thereof of this invention can be administered separately or together in any conventional oral, parenteral or transdermal dosage form.
• the administration of the other compound or pharmaceutically acceptable salt thereof of the invention follows.
• a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
• Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are 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.
• binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
• compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• the compounds or pharmaceutically acceptable salts 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, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
• aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
• aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
• the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
• aqueous or partially aqueous solutions are prepared.
• compositions according to the invention may contain 0.1%- 95% of a combination of the compounds or pharmaceutically acceptable salts thereof of this invention, preferably 1%-70%.
• the composition or 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. Since the present invention relates to treatment with a combination of the two active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form.
• the kit includes two separate pharmaceutical compositions: (-)-cis-6-phenyl-5-(4-(2- pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt thereof and 2-amino-N-(1(R)-(2,4-difluoro- benzyioxymethyl)-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.
• the kit includes a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container.
• the kit includes directions for the administration of the separate components.
• the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
• Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
• the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
• the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on 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.
• a memory aid on a card insert e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
• a memory aid is a calendar printed on the card e.g., as follows "First Week, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday, etc.
• a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
• a daily dose of SERM can consist of one tablet or capsule while a daily dose of a GH secretagogue can consist of several tablets or capsules. The memory aid should reflect this.
• a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided.
• the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
• a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
• a battery-powered micro- chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
• step A 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 the anhydrous 2,2,2-trifluoroethyl hydrazine, followed by acetic acid (121.4 g, 1.986 mol). The reaction mixture was 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 mixture was heated at about 80 °C for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHCO 3 (2 L).
• Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to a solution of the product from step B (10 g, 24.2 mmol) in CH 2 CI 2 (100 mL) over about 30 minutes.
• the reaction mixture was stirred for about 1 hour, then cooled to about 0 °C, and then triethylamine (18.6 mL, 133.1 mmol) was added through an addition funnel.
• the mixture was allowed to warm to room temperature over about 1 hour, diluted with additional CH 2 CI 2 and washed with saturated aqueous NaCI, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford the product as a white solid (7.2 g).
• step D To the compound made according to step D (517 g, 1.12 mol) was added at about -6 °C to ethyl acetate (5170 mL) in a dry and nitrogen purged 12 L round bottom flask equipped with a mechanical stirrer. The solution was cooled to about -40 °C, then triethylamine (398 mL, 2.86 mol) was added over about 45 minutes. The reaction mixture was stirred for about 90 min.
• step G The compound made according to step G (425 g, 1.02 mol ) was added 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 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 NaCI, dried over Na 2 SO 4 and concentrated in vacuo to give the product as an oil (636 g, yield: 87.8%).
• Methanesulfonic acid (258.3 mL, 3.98 mol) was added dropwise at about 15 °C over about 55 minutes to the product from step H (566 g, 0.796 mol) in CH 2 CI 2 (11 ,320 mL) in a dry and nitrogen purged 22 L round bottom flask equipped with a mechanical stirrer. The mixture was stirred for about 40 minutes at about 20 °C, then saturated aqueous NaHCO 3 (8,490 mL) was added until the pH was about 7.8. The organic layer was separated, washed with water and saturated aqueous NaCI, dried over Na 2 SO 4 , and concentrated in vacuo to afford an oily product (388.8 g, yield 80%). J.
• the following assay can be used to show that the combination and methods of this invention increases lean body mass and decreases fat body mass whereas the GH secretagogue alone would be expected to decrease fat body mass with no change in lean body mass and the SERM alone would be expected to increase both lean and fat body mass. Further, the combination increases bone density and decreases total serum cholesterol.
• Example Two Female S-D rats (Harlan) are sham-operated or ovariectomized (OVX) at 3.5 months of age. Drug administration starts when the rats are 9 months of age and 5.5 months post-surgery.
• the sham-operated rats receive daily gavage of vehicle (10% ethanol in water), while the OVX rats receive daily gavage of 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/d alone, or (-)cis-6-phenyl-5-(4-(2- pyrrolidin-1-yl-
• the right femur 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 "Regional 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 scan speed is 7.25 mm/second.
• the femoral scan images are analyzed and total femoral bone area, bone mineral content, and bone mineral density are determined according to the method described in H. Z.

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• 1999
  • 1999-05-03 JP JP2000554368A patent/JP2002518328A/ja active Pending
  • 1999-05-03 CA CA002335112A patent/CA2335112A1/en not_active Abandoned
  • 1999-05-03 PL PL99345064A patent/PL345064A1/xx unknown
  • 1999-05-03 WO PCT/IB1999/000796 patent/WO1999065488A1/en not_active Application Discontinuation
  • 1999-05-03 KR KR1020007014140A patent/KR20010052817A/ko not_active Application Discontinuation
  • 1999-05-03 OA OA1200000346A patent/OA11569A/en unknown
  • 1999-05-03 SK SK1890-2000A patent/SK18902000A3/sk unknown
  • 1999-05-03 BR BR9911357-0A patent/BR9911357A/pt not_active Application Discontinuation
  • 1999-05-03 AU AU33420/99A patent/AU3342099A/en not_active Abandoned
  • 1999-05-03 IL IL13958799A patent/IL139587A0/xx unknown
  • 1999-05-03 EP EP99914723A patent/EP1085867A1/en not_active Withdrawn
  • 1999-05-03 CN CN99807381A patent/CN1305378A/zh active Pending
  • 1999-05-03 ID IDW20002604A patent/ID26726A/id unknown
  • 1999-05-03 HU HU0102395A patent/HUP0102395A2/hu unknown
  • 1999-05-03 EA EA200001189A patent/EA200001189A1/ru unknown
  • 1999-05-07 PA PA19998472101A patent/PA8472101A1/es unknown
  • 1999-06-10 AP APAP/P/1999/001581A patent/AP9901581A0/en unknown
  • 1999-06-11 PE PE1999000522A patent/PE20000633A1/es not_active Application Discontinuation
  • 1999-06-11 UY UY25557A patent/UY25557A1/es not_active Application Discontinuation
  • 1999-06-14 GT GT199900083A patent/GT199900083A/es unknown
  • 1999-06-15 AR ARP990102847A patent/AR018868A1/es not_active Application Discontinuation
  • 1999-06-15 ZA ZA9903973A patent/ZA993973B/xx unknown
  • 1999-06-15 TN TNTNSN99118A patent/TNSN99118A1/fr unknown
  • 1999-06-15 MA MA25622A patent/MA26648A1/fr unknown
  • 1999-06-16 CO CO99037624A patent/CO5070586A1/es unknown
• 2000
  • 2000-11-24 IS IS5727A patent/IS5727A/is unknown
  • 2000-12-14 NO NO20006381A patent/NO20006381L/no not_active Application Discontinuation
  • 2000-12-14 HR HR20000857A patent/HRP20000857A2/hr not_active Application Discontinuation
• 2001
  • 2001-01-08 BG BG105128A patent/BG105128A/xx unknown

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