CN1301160A - Therapeutic combinations of (selective) estrogen receptor modulators (SERM) and growth hormone secretagogues (GHS) for treating musculoskeletal frailty - Google Patents
Therapeutic combinations of (selective) estrogen receptor modulators (SERM) and growth hormone secretagogues (GHS) for treating musculoskeletal frailty Download PDFInfo
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- CN1301160A CN1301160A CN99806237A CN99806237A CN1301160A CN 1301160 A CN1301160 A CN 1301160A CN 99806237 A CN99806237 A CN 99806237A CN 99806237 A CN99806237 A CN 99806237A CN 1301160 A CN1301160 A CN 1301160A
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- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 210000001875 somatotroph Anatomy 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
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
-
- 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
Abstract
This invention is directed to pharmaceutical combination compositions and methods containing (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt thereof and 2-amino-N-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3, 3a, 4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or a pharmaceutically acceptable salt thereof, methods of using such compositions and kits containing such compositions. The compositions are useful for treating musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass, frailty and low muscle mass.
Description
Background of invention
The present invention relates to stimulate bone formation, increase bone mass, blood lipid reducing level and increase the selective estrogen receptor modulators (SERM) of muscle quality and the drug combinations of growth hormone succagoga (GHS).The invention still further relates to the medicine box that contains described cooperative programs and described cooperative programs mammal, comprise treatment flesh and skeleton fragility among the people, the purposes that comprises osteoporosis, osteoporotic fracture, low bone mass, fragility, hangs down muscle quality etc.Specifically, the present invention relates to (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt and 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-cooperative programs of isobutyramide or its officinal salt, contain the medicine box of described cooperative programs and described cooperative programs mammal, comprise philtrum treatment flesh and skeleton fragility, comprise osteoporosis, osteoporotic fracture, low bone mass, fragile, the purposes of low muscle quality etc.
Osteoporosis is a kind of general skeletal diseases, it is characterized in that the degeneration of low bone mass and osseous tissue, and its consequence is the fragility increase of bone and is easy to fracture.In the U.S., this disease influence surpasses 2,500 ten thousand people and the annual fracture that causes more than 1,300,000, comprises annual 500000 spinal fractures, 250,000 Hip Fractures and 240,000 waists fracture.Hip Fracture is the most serious, has 5-20% patient dead in 1 year, and the survivor more than 50% loses behavioral competence.
The old people is taken place osteoporotic dangerous maximum, therefore, along with the aging of population, expects that this problem will significantly increase.Expect that global fracture incidence rate will increase by 3 times in following 60 years, have a research to estimate that in the year two thousand fifty, will there be 4,500,000 Hip Fractures in the whole world.
Although masculinity and femininity all is easy to take place flesh and skeleton fragility, it is bigger than the male to comprise that osteoporotic danger takes place for osteoporosis, women.After menopause, rapid bone loss can appear in women immediately.Increase can cause the other factors of osteoporotic bone loss to comprise the life style and the calcium pickup deficiency of smoking, excessive drinking, sitting formula.
Estrogen is the medicine that can be used for bone loss behind prevention of osteoporosis or the postmenopausal women.In addition, people such as Black have reported estrogen in EP 0605193A1, particularly when oral administration, can reduce plasma LDL levels and the level of useful high density lipoprotein (HDL) that raise.But secular estrin treatment can cause multiple disease, comprises that the danger of uterus carcinoma, carcinoma of endometrium and possible breast carcinoma increases, and causes many women or refuses this treatment, perhaps only short time medication.Although have teach literature the danger of carcinoma of endometrium to be reduced, but still can worry to use estrogen may increase the danger of breast carcinoma by using progesterone simultaneously.The nearest therapeutic scheme that is intended to reduce cancer risk that proposes, for example with progesterone and estrogen administering drug combinations, it is unacceptable hemorrhage to cause the patient to occur.In addition, as if progesterone and estrogen coupling can be weakened the effectiveness that estrogen reduces serum cholesterol.The side effect of the significant adverse of following in view of estrin treatment, need exploitation that serum LDL is had ideal useful influence but can not cause adverse side effect other treat osteoporotic method.
Proposed to be used for the treatment of in a large number osteoporotic selective estrogen receptor modulators recently.It is reported (osteoporosis meeting clauses and subclauses 1812/13; 16-20 day in April, 1993; 29 pages); raloxifene; 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(2-pyridine radicals ethyoxyl) benzoyl] benzo [b] thiophene; can simulate the advantageous effect of estrogen to bone and lipid; but different with estrogen is; very little [the Black of its stimulation to the uterus; L.J. etc.; raloxifene (LY139481 HCl) prevents bone loss and reduces serum cholesterol and do not cause metrauxe in ovariectomized rat; " Journal of Clinical Investigation " (J.Clin.Invest.); 1994,93:63-69 and Delmas, P.D. etc.; raloxifene is to postmenopausal women's bone mineral density; serum cholesterol concentration and endometrial influence; " New England Journal of Medicine " (New EnglandJournal of Medicine), 1997,337:1641-1647].
For example the medicine of droloxifene (United States Patent (USP) 5,254,595) can reduce the dangerous of fracture and not have estrogenic side effect by the loss of prevention bone.But it is about 50% that expection uses separately estrogen and estrogen agonist that the danger of fracture is reduced, and about 50% remaining osteopenic women still has the danger of osteoporotic fracture.
The common United States Patent (USP) of transferring the possession of 5,552,412 (this patent is incorporated herein by reference) discloses the SERM chemical compound of following formula:
Variable wherein in this patent definition.
Growth hormone (GH) stimulates all tissue growths that can grow of health by the hypophysis secretion.In addition, known GH also has following basic role to the metabolic process of health:
1. in nearly all cell of health, increase proteinic synthesis rate;
2. reduce the speed of utilizing of carbohydrate in the soma;
3. increase the metabolism of free fatty and the application that fatty acid is used for energy.
The shortage of GH can cause various medical conditions.In the child, can cause the dwarf.In the adult, the consequence that acquired GH lacks comprises the violent decline of lean body mass and the increase of the total body fat that occurs together, especially in torso area.The minimizing of skeletal muscle and myocardial mass and the reduction of muscle strength cause the obvious decline of motor capacity.Bone density also can reduce.Confirmed that administration of exogenous GH can reverse many metabolism and change.Other beneficial effect of treatment comprises the reduction of LDL cholesterol and the improvement of psychologic status.
For the case of needs rising GH level, problem can be resolved by exogenous GH being provided or using the medicine that can stimulate GH to produce and/or discharge usually.Under each situation, the character of chemical compound peptide makes must pass through drug administration by injection.At first, GH obtains by extracting corpse hypophysis.Therefore, product costs an arm and a leg and exists with hypophysis source diseases associated and may infect danger (for example Jacob-Creutzfeld disease) to the GH user.Having occurred reorganization GH recently, though it no longer includes the danger of any communicate illness, but still is a kind of very expensive product, and essential by injection or nose spray delivery.
Most of GH shortage is because the defective that GH discharges causes, is not mainly to be the synthetic defective of hypophysis GH.Therefore, making the another kind of strategy of the horizontal normalization of Serum GH is to stimulate it to discharge from somatotroph.Can the GH secretion be increased by the various neurotransmitter system that stimulates or suppress in brain and the hypothalamus.Therefore, people begin exploitation and stimulate the excretory synthetic GH releasing agent of hypophysis GH, and it has many advantages compared with expensive and inconvenient GH alternative medicine.By along physiological regulation approach generation effect, optimal medicine can stimulate the GH secretion of pulsation, and can avoid the GH level relevant with the adverse side effect of exogenous GH administration excessive by complete negative feedback loop.
The excretory physiology of GH and pharmacology's stimulus object, comprise arginine, L-3, hypoglycemia and activity that 4-dihydroxyphenylalanine (L-DOPA), glucagon, vassopressin, insulin cause, for example sleep and move, can cause that indirectly GH discharges from hypophysis by acting on hypothalamus in some way, described model of action may be to reduce the secretion of somatostatin or increase known sercretogogue GH releasing factor (GHRF) or the secretion of unknown endogenous GH releasing hormone or all these.
The common International Patent Application Publication No. WO97/24369 (wherein having specified the U.S.) that transfers the possession of discloses the GH succagoga of following formula:
Variable wherein in this patent definition.International patent application no WO97/24369 is incorporated herein by reference.
Tang etc., in skeletonization female rats skeleton, restore and the maintenance bone: I. the change of bone mass and structure, " bone mineral research magazine " (J.Bone Mineral Research) 7 (9), the 1093-1104 page or leaf, 1992 disclose the data of loss, recovery and maintenance (LRM) notion (the already present osteoporotic practical approach of a kind of reverse).The LRM notion is used former bone mass of anabolica reflex and structure (+phase), uses the medicine with generally acknowledged maintenance bone mass ability then instead and keeps new bone (+/-phase).Rat studies is used PGE
2With profit match phosphonate ester (risedronate, a kind of bisphosphonates), to confirm to interrupt PGE by using sharp match phosphonate ester
2Still can make after at least 60 days by PGE
2Spongy bone and compact bone that inductive major part is new are kept.
Shen etc., add the influence of the mutual treatment of parathyroid hormone with estrogen and estrogen to ovariectomized rat bone structure and intensity, " Journal of Clinical Investigation " (J.ClinicalInvestigation), 1995,96:2331-2338 discloses associating and/or use in order anti-absorbent and anabolica are treated osteoporotic data.
The common International Patent Application Publication No. WO97/31640 (wherein having specified the U.S.) that transfers the possession of discloses some GH succagoga and osteoporotic purposes is treated in some SERMS coupling.International Patent Application Publication No. WO97/31640 is incorporated herein by reference.
Summary of the invention
The present invention relates to pharmaceutical composition, described compositions contains:
A. first kind of chemical compound, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt; With
B. second kind of chemical compound, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or its officinal salt.
The invention still further relates to the pharmaceutical composition described in the preceding paragraph that also contains pharmaceutical carrier.
The invention still further relates to any one section described pharmaceutical composition in preceding two sections of this summary of the invention, wherein, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol D-tartrate, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-l (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide L-tartrate.
The invention still further relates to the method (being appointed as method A) that the mammal that suffers from flesh and skeleton fragility is treated, this method comprises, any one section described pharmaceutical composition in first three section of described this summary of the invention of administration.
Among the method A, a kind of preferable methods (being appointed as method B) is that mammal wherein suffers from osteoporosis.
Among the method A, another kind of preferable methods (being appointed as method C) is that mammal wherein suffers from sacrotomy, the loss of child Te Fa bone or the bone loss relevant with periodontitis.
The invention still further relates to the method that the mammal that suffers from flesh and skeleton fragility is treated and (be appointed as method A
1), this method comprises, to described administration:
A. first kind of chemical compound, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt; With
B. second kind of chemical compound, described second kind of chemical compound is 2-amino-N-(1 (R)-(2,4-two fluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a (R)-pyridine-2-ylmethyl)-2-(2,2, the 2-trifluoroethyl)-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-ethyl)-2-methyl propanamide or its officinal salt.
The invention particularly relates to method A
1Method, first kind of chemical compound wherein and second kind of chemical compound are gone up administration simultaneously substantially.
The present invention also is particularly related to method A
1Method (hereinafter referred to as method D), about 3 months of second kind of compound administration wherein is to about 3 years time.
The invention particularly relates to the method for method D, use about 3 months of first kind of chemical compound subsequently, do not use second kind of chemical compound in during about 3 years at about 3 months to about 3 years time.
The invention particularly relates to the method for method D, use first kind of chemical compound subsequently and surpass about 3 years time, in during about 3 years, do not using second kind of chemical compound.
The invention still further relates to the method (hereinafter referred to as method E) of the described disease of treatment in the mammal that suffers from flesh and skeleton fragility, this method comprises, any one section described pharmaceutical composition in first three section of this summary of the invention of described administration treatment effective dose.
Among the method E, preferable methods is to strengthen the knitting after face's reconstruction, upper jaw bone reconstruction or mandibular bone are rebuild; Induce the synosteosis of vertebra; Strengthen the elongation of long bone; Improve the healing speed of bone graft or long bone fracture or the inside growth of enhancing prosthese.The method that is more preferably comprises, to described administration:
A. first kind of chemical compound, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt; With
B. second kind of chemical compound, described second kind of chemical compound is 2-amino-N-(1 (R)-(2,4-two fluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a (R)-pyridine-2-ylmethyl)-2-(2,2, the 2-trifluoroethyl)-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-ethyl)-2-methyl propanamide or its officinal salt.
The invention still further relates in mammal the method that increases muscle quality, this method comprises, increases any one section described pharmaceutical composition in first three section of this summary of the invention of effective dose to described administration muscle quality.The method that is more preferably comprises, to described administration:
A. first kind of chemical compound, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt; With
B. second kind of chemical compound, described second kind of chemical compound is 2-amino-N-(1 (R)-(2,4-two fluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a (R)-pyridine-2-ylmethyl)-2-(2,2, the 2-trifluoroethyl)-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-ethyl)-2-methyl propanamide or its officinal salt.
In all methods of the present invention, preferred especially described mammal is the people.
The invention still further relates to and be used for medicine box that the mammal that suffers from flesh and skeleton fragility is treated, described medicine box contains:
A. (-) of the treatment effective dose in first unit dosage form-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt and pharmaceutically useful carrier;
B. the 2-amino-N-of the treatment effective dose in second unit dosage form (2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or its officinal salt and pharmaceutically useful carrier; With
C. container.
The invention particularly relates at the medicine box described in the preceding paragraph, wherein, described first unit dosage form contains (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol D-tartrate, described second unit dosage form contains 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide L-tartrate.
In all compositionss of the present invention, method and medicine box, especially preferably use (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7, the D-tartrate of 8-naphthane-2-alcohol and 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-the L-tartrate of isobutyramide.
The phrase disease of bone mass " exist low " is meant that the bone mass level is lower than the WHO standard " assessment of fracture risk and to the application (1994) of screening postmenopausal osteoporosis, the report of World Health Organization's research group.World Health Organization's technology series 843 " in the disease of defined given age normal value.In child Te Fa and primary osteoporosis are also included within.Osteoporotic treatment comprises prevention or alleviates long-term complications such as rachiocamposis, height reduce, prosthesis, and prevention prostate malfunction.Comprise the quickening of union of fracture speed and the raising of bone transplanting succeed rate in addition.Comprise the loss of periodontal and alveolar bone in addition.
The phrase disease of bone mass " exist low " also comprises the above-mentioned disease of known generation, comprise that osteoporotic chance is apparently higher than the mammal of meansigma methods (for example, postmenopausal women, age treat the male more than 60 years old, with the known medicine (for example glucocorticoid) that causes the osteoporosis side effect people).
It will be understood by those skilled in the art that term " bone mass " in fact is meant the bone mass of per unit area, sometimes (although very incorrect) also inorganic matter density of phalanges.
Phrase " flesh and skeleton fragility " is meant that there is the disease of low bone mass and/or low muscle quality in the patient, comprise (but being not limited only to) following disease and disease, for example, exist disease, osteoporosis, the disease of the low muscle quality of existence, sacrotomy, the loss of child Te Fa bone, bone loss, the face relevant of low bone mass to rebuild with periodontitis, upper jaw bone is rebuild, mandibular bone is rebuild and fracture after knitting.In addition, flesh also comprises the new prosthese that is connected with the skeleton fragility and needs situations such as interface between the ingrown bone of bone.
Term used herein " treatment " comprises healing, prevents (for example preventative) and the treatment of alleviating property.
Used bracket negative or positive symbol is meant that specific stereoisomer makes the direction of linearly polarized light rotation in the name of this paper.
Compositions of the present invention can contain the hydrate of chemical compound used herein.
Pharmaceutical composition of the present invention and method can produce above-mentioned (-)-suitable-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl than independent use same dose]-5,6,7,8-naphthane-2-alcohol or above-mentioned 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-bone mass that isobutyramide is rapider and higher increases.In addition, these cooperative programs can reduce fat mass and total serum cholesterol in bone density improving and muscle quality.Therefore, these cooperative programs degree of increasing bone mass and reducing fracture rates is bigger when using any medicine separately.The present invention can increase and keep bone mass to prevent, delay and/or the compositions and the method for disappear osteoporosis and related bone disease have been made significant contribution to prior art by providing.
According to describing description of the present invention and claim, its its feature and advantage will be conspicuous.
Detailed Description Of The Invention
First kind of chemical compound of the present invention is (-)-suitable-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol or its officinal salt, it has the structure of following formula I:
(-)-suitable-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol and officinal salt thereof prepare according to the description in the United States Patent (USP) 5,552,412 of common transfer cited above.
(-)-suitable-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7, the 8-naphthane-2-alcohol D-tartrate is according to the preparation of the description in the last period or according to the preparation of the description among the International Patent Application Publication No. WO97/16434 (having specified the U.S.), this patent application is incorporated herein by reference.
Second kind of chemical compound of the present invention is 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide or its officinal salt, it has the structure of following formula II:
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide and officinal salt thereof can be according to the preparations of the description among the International Patent Application Publication No. WO97/24369 of common transfer, and this patent application is incorporated herein by reference.
In addition, when compound or pharmaceutically acceptable salt thereof of the present invention formed hydrate or solvate, they also within the scope of the invention.
Drug combinations of the present invention and method all are suitable for therapeutic use, activate renewal or the absorption of prevention bone or the formation of increase bone of bone in mammal, particularly people as medicine.Because the generation of these functions and osteoporosis and bone photo related disorders is closely related, therefore, these cooperative programs can prevent, stop, disappear the effect of bone owing to it or reverse osteoporosis.
The compositions and methods of the invention (are for example treated flesh and skeleton fragility as medicine in mammal (for example people), the disease that has low bone mass or low muscle quality, comprise osteoporosis) purposes can by chemical compound of the present invention at United States Patent (USP) 5,552,412 and International Patent Application Publication No. WO97/24369 in activity in the conventional analysis described confirm.Other evidence of the purposes of these cooperative programs is as described in following examples 1.Described analysis also provide with The compounds of this invention active mutually relatively and the method that compares with the activity of other known compound.These results relatively can be used for determining mammal, comprise the dosage level for the treatment of described disease among the people.
Chemical compound of the present invention can carry out administration with the chemical compound whole body of cooperative programs of the present invention and/or the method for localized delivery by any.These methods comprise oral route, parenteral, intraduodenal route etc.Chemical compound of the present invention is usually by oral administration, but can adopt parenteral (for example, in intravenous, intramuscular, percutaneous, the subcutaneous or marrow), for example, and when oral administration is unsuitable for urgent purpose or when the patient can not swallow medicine.Two kinds of different chemical compounds of the present invention can be simultaneously or with any order co-administered in turn, perhaps can administration contains the single medicine compositions of above-mentioned first kind of chemical compound and above-mentioned second kind of chemical compound and pharmaceutically suitable carrier.
Under any circumstance, the dosage of chemical compound and administration time all depend on the order of severity, administering mode and the prescriber's of the object of being treated, sufferer judgement.Therefore, because the difference between patient and the patient, the dosage that below provides only is guiding, and the doctor can change drug dose and think the activity (for example bone mass increase) that is suitable for concrete patient to reach the doctor.When considering required level of activity, the essential balance various factors of doctor, for example base level of bone mass, patient's age, the existence of existing disease and the existence of other disease (for example cardiovascular disease).For example, use (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol can produce beneficial effect to cardiovascular, particularly for postmenopausal women.Following paragraph provides the preferred dose scope of the various compositions of the present invention.
(-)-suitable-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7, the effective dose of 8-naphthane-2-alcohol in 0.0001 to 100mg/kg/ day scope, preferred 0.001 to 10mg/kg/ day.
2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-effective dose of isobutyramide in 0.0001 to 100mg/kg/ day scope, preferred 0.001 to 5mg/kg/ day.
When the tartrate of above-mentioned any one chemical compound or other officinal salt are used for when of the present invention, the molecular weight that those skilled in the art can be by calculating salt form also carries out simple stoichiometric proportion and calculates effective dose.
Chemical compound of the present invention is usually with the form administration of the pharmaceutical composition that contains at least a compound or pharmaceutically acceptable salt thereof of the present invention and pharmaceutically suitable carrier or diluent.Therefore, chemical compound of the present invention and officinal salt thereof can be with oral, the parenteral of any routine or transdermal dosage form respectively or administration simultaneously.When the difference administration, the another kind of compound or pharmaceutically acceptable salt thereof of the present invention of administration subsequently.
Being used for pharmaceutical composition for oral administration can be dosage forms such as solution, suspension, tablet, pill, capsule, powder.Tablet contains various excipient such as sodium citrate, calcium carbonate and calcium phosphate and various disintegrating agent such as starch (preferred potato starch or tapioca) and some composition silicate, also contains binding agent such as polyvinylpyrrolidone, sucrose, gelatin and arabic gum simultaneously.In addition, lubricant such as magnesium stearate, sodium lauryl sulphate and Talcum are also through being usually used in the preparation of tablet.The solid composite of similar type also can be used as the implant of soft hard gelatin capsule; Thus, preferable material also comprises lactose and high-molecular weight Polyethylene Glycol.When needs carry out oral administration with aqueous suspension and/or elixir, compound or pharmaceutically acceptable salt thereof of the present invention and various sweeting agents, correctives, coloring agent, emulsifying agent and/or suspending agent and diluent such as water, ethanol, propylene glycol, glycerol and various combining form thereof can be mixed.
Parenteral can adopt the solution in Oleum Ricini or Oleum Arachidis hypogaeae semen or aqueous propylene glycol, and the aseptic aqueous solution of corresponding water soluble salt.As needs, described aqueous solution suitably can be cushioned, liquid diluent is at first transferred to etc. with enough saline or glucose ooze.These aqueous solutions are specially adapted to intravenous, intramuscular, subcutaneous and peritoneal injection.Thus, used aseptic aqueous vehicle is easy to by well known to a person skilled in the art that conventional method obtains.
For the purpose of percutaneous (for example local) administration, prepare rare aseptic moisture or partially aqueous solution (about concentration of 0.1% to 5% usually), perhaps similar with above-mentioned parenteral solution.
The method that preparation contains the various pharmaceutical compositions of a certain amount of active component is well known by persons skilled in the art, is conspicuous according to disclosure thing to it perhaps.For example, referring to " Remington pharmaceutical science " (Remington ' s Pharmaceutical Sciences), Mack Publishing Company, Easton, Pa., the 19th edition (1990).
Pharmaceutical composition of the present invention can contain the cooperative programs of The compounds of this invention or its officinal salt of 0.1%-95%, preferred 1%-70%.Under any circumstance, compositions or the preparation that is used for administration all should contain The compounds of this invention or its officinal salt for the treatment of disease of patient to be treated/disease effective dose.
Owing to the present invention relates to use the cooperative programs of two kinds of active component of administration respectively to treat, therefore, the invention still further relates to of the form merging of two kinds of different pharmaceutical compositions with medicine box.This medicine box contains two kinds of different pharmaceutical compositions: (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt and 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or its officinal salt.This medicine box also comprises the container that is used to comprise two kinds of different components, and bottle that for example separates or the paper tinsel bag that separates still, also can be included in two kinds of different compositionss in single, the undivided container.Representational medicine box contains the description that is useful on the heterogeneity administration.When heterogeneity preferably with different dosage form (for example oral with parenteral), when carrying out administration with different dosing intervals, perhaps need be gradually during escalated dose by the prescriber when certain composition in the cooperative programs, the form of medicine box is particularly advantageous.
The example of described medicine box is a so-called blister packages.Blister package is that packaging industry is known, and it is widely used in the packing of pharmaceutical unit dosage forms (tablet, capsule etc.).Blister package is made up of than the thin slice of stiff materials with the relative of paper tinsel covering of preferably being made by transparent plastic material one deck usually.In packaging process, in plastic foil, form depression.Depression has tablet or capsular size and the shape that will pack.Then, place depression also at the reverse side of the paper tinsel that forms depression plastic foil to be sealed in tablet or capsule with relative thin slice than stiff materials.Consequently, tablet or capsule are sealed in the depression between plastic foil and the thin slice.The intensity of thin slice is preferably, and by exerting pressure on depression with hands and tablet or capsule can being taken out from blister package, is positioned at thin slice thus and forms an opening on the position of depression.Can take out tablet or capsule by described opening then.
A memory aid preferably is provided on the card of built-in, for example,, thereby makes numeral corresponding with the natural law that should take specified tablet or capsular therapeutic scheme with the form of the numeral by tablet or capsule.Another example of described memory aid is the calendar that is imprinted on the card, for example " first week, Monday, Tuesday ... etc.. second week, Monday, Tuesday ... " Deng.It is conspicuous that other of memory aid changes form." dosage every day " can be single tablet or the capsule of taking in specified a day, also can be a plurality of pills or capsule.Dosage every day that in addition can SERM is made up of a tablet or capsule and dosage every day of GH succagoga is made up of a plurality of tablets or capsule.Memory aid should reflect these contents.
In another specific embodiment of the present invention, providing can be with the allotter of its a predetermined use order primary distribution dosage every day.Preferably on this allotter, memory aid is housed, thereby further promotes compliance therapeutic scheme.The example of described memory aid is a mechanical counter, it can show distributed every day dosage quantity.Another example of described memory aid is to use the microwafer memorizer of battery, this microwafer memorizer is connected with the alerting signal that the liquid crystal reader maybe can be heard, for example, described alerting signal can be read the date of taking dosage every day for the last time and/or remind and when take next dosage.
Below test is used for showing that cooperative programs of the present invention and method can increase lean body mass and reduce Japanese body weight, and use the expection of GH succagoga can reduce fatty body weight and can not change lean body mass separately, using SERM then to expect separately can increase lean body mass and fatty body weight simultaneously.In addition, cooperative programs can bone density improving and reduction total serum cholesterol.
Embodiment 1
Female S-D rat (Harlan) is carried out sham-operation or ovariectomy (OVX) when 3.5 monthly ages.Begin administration when rat 9 months (performing the operation back 5.5 months).The rat of sham-operation is accepted the carrier (10% alcoholic acid aqueous solution) of tube feed every day, and the OVX rat is accepted the carrier of tube feed every day, or 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide (5mg/kg/ days, use separately), or (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol (0.1mg/kg/ days, use separately), or with 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide and (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol 4 weeks of therapeutic alliance.In the therapeutic alliance group, 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide is than (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol administration in two hours early.Each subgroup has 8-10 rat.Carrying out preceding 13 days of obduction and preceding 3 days, to the calcein of all rat skin lower injection 10mg/kg (SigmaChemical Co., St.Louis, MO).It will be understood by those skilled in the art that chemical compound used in this test can be with the form administration of officinal salt, the molecular weight that its dosage can be by calculating this salt also carries out simple proportional and converts and determine easily.
Before last day is carried out obduction in test, all rats with ketamine/xylazine anesthesia are had rat body scanning software (Hologic Inc., Waltham, MA) double energy X-ray absorptiometric analysis (DXA, QDR-1000/W, Hologic Inc., Waltham is MA) to measure lean body mass and fat body weight.Then rat is carried out obduction and passes through heart puncturing extracting blood.(Boehringer Mannheim Biochemicals, Indianapolis IN) measure the total serum cholesterol with efficient cholesterol colorimetric test.Body weight during with obduction deducts the increase that the 0th day weighing machine is calculated body weight.When obduction, measure the weight in wet base in uterus immediately.
When obduction, take out each rat right femur and with have " local high resolution scanning " software (Hologic Inc., Waltham, double energy X-ray absorptiometer MA) (DXA, QDR-1000/W, Hologic Inc., Waltham MA) scans.The size of scanning area is 5.08 * 1.902cm, and resolution is 0.0254 * 0.0127cm, and scanning speed is 7.25mm/ second.Scanned picture to femur is analyzed, and according to H.Z.Ke etc., droloxifene, and new estrogen antagonist/agonist prevents the bone loss in OO rat, " endocrinology " (Endocrinology) 136; 2435-2441, the method for describing in 1995 is measured total femur area, content of bone mineral and bone mineral density.Result of study and discussion
Compared with the control, use 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3 separately, 3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide increases lean body mass and fat body weight simultaneously, and independent (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7 that uses, 8-naphthane-2-alcohol can reduce fat body weight, and lean body mass does not change.2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide and (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol cooperative programs can increase lean body mass and reduce fat body weight.Therefore, the cooperative programs of two kinds of chemical compounds are than using 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2 separately, 3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or independent (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6 that uses, 7,8-naphthane-2-alcohol has better health and forms distribution.
With respect to the rat of accepting placebo, observing total femur area in accepting the rat of cooperative programs has increased 5-6%.This result with accepting separately (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide and (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7, the recruitment of observed total femur area is similar in the rat of 8-naphthane-2-alcohol.Using 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a separately, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-group of isobutyramide in, the content of total femur inorganic matter has increased by 8.5%, using (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7 separately, in the group of 8-naphthane-2-alcohol, increased by 7.7%.But in the therapeutic alliance group, the content of total femur inorganic matter has increased by 12.5%, and this all obviously increases than any medicine of independent use.Also observed similar result for total femur inorganic matter density.
Using (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7 separately, in the group and therapeutic alliance group of 8-naphthane-2-alcohol, the total serum cholesterol descends.
These data show, 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide and (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7, the cooperative programs of 8-naphthane-2-alcohol have multiple advantage.These advantages comprise the increase of lean body mass and the decline of fat body weight and serum lipid.In addition, also observed the increase of bone mass.
Should be appreciated that the present invention is not limited only to specific embodiments described herein, and can carry out various changes and modification and the spirit and scope of the invention that do not exceed following claim and limited it.
Claims (29)
1. pharmaceutical composition, described compositions contains:
A. first kind of chemical compound, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt; With
B. second kind of chemical compound, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or its officinal salt.
2. the pharmaceutical composition of claim 1 also contains pharmaceutical carrier.
3. the pharmaceutical composition of claim 1, wherein, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol D-tartrate, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide L-tartrate.
4. the pharmaceutical composition of claim 1 is used for the purposes of medicine that the mammal that suffers from flesh and skeleton fragility is treated in preparation.
5. the purposes of claim 4, wherein, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol D-tartrate, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide L-tartrate.
6. the purposes of claim 4, wherein, described mammal suffers from osteoporosis.
7. the purposes of claim 4, wherein, what treated is sacrotomy, the loss of child Te Fa bone or the bone loss relevant with periodontitis.
8. the purposes of claim 4 wherein, is used for the treatment of the knitting after face's reconstruction, upper jaw bone reconstruction or mandibular bone are rebuild; Induce the synosteosis of vertebra; Strengthen the elongation of long bone; Improve the healing speed of bone graft or the inside growth of enhancing prosthese.
9. the purposes of claim 8, wherein, what treated is people's fracture.
10. the purposes of claim 6, wherein, what treated is people's osteoporosis.
11. medicine box, described medicine box contains:
A. (-) in first unit dosage form-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt and pharmaceutically useful carrier or diluent;
B. (2-(the 3a (R)-benzyl-2-methyl-3-oxo-2 of the 2-amino-N-in second unit dosage form, 3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or its officinal salt and pharmaceutically useful carrier or diluent; With
C. container.
12. the medicine box of claim 11, wherein, described first unit dosage form contains (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol D-tartrate, described second unit dosage form contains 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide L-tartrate.
13. to the method that the mammal that suffers from flesh and skeleton fragility is treated, this method comprises, to the pharmaceutical composition of described administration claim 1.
14. the method for claim 13, wherein, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol D-tartrate, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide L-tartrate.
15. the method for claim 13, wherein, described mammal suffers from osteoporosis.
16. the method for claim 13, wherein, what treated is sacrotomy, the loss of child Te Fa bone or the bone loss relevant with periodontitis.
17. the method for claim 13 wherein, is used for the treatment of the knitting after face's reconstruction, upper jaw bone reconstruction or mandibular bone are rebuild; Induce the synosteosis of vertebra; Strengthen the elongation of long bone; Improve the healing speed of bone graft or the inside growth of enhancing prosthese.
18. the method for claim 17, wherein, what treated is people's fracture.
19. the method for claim 15, wherein, what treated is people's osteoporosis.
20. to the method that the mammal that suffers from flesh and skeleton fragility is treated, this method comprises, to described administration:
A. first kind of chemical compound, described first kind of chemical compound is (-)-suitable-6-phenyl-5-(4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl)-5,6,7,8-naphthane-2-alcohol or its officinal salt; With
B. second kind of chemical compound, described second kind of chemical compound is 2-amino-N-(2-(3a (R)-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-six hydrogen pyrazolos [4,3-c] pyridine-5-yl)-1 (R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide or its officinal salt.
21. the method for claim 20, wherein, first kind of chemical compound and second kind of chemical compound are gone up administration simultaneously substantially.
22. the method for claim 20, wherein, about 3 months of second kind of compound administration is to about 3 years time.
23. the method for claim 22 is used about 3 months of first kind of chemical compound subsequently to about 3 years time, does not use second kind of chemical compound at about 3 months in during about 3 years.
24. the method for claim 22 is used first kind of chemical compound subsequently and is surpassed about 3 years time, is not using second kind of chemical compound in during about 3 years.
25. the method for claim 20, wherein, described mammal suffers from osteoporosis.
26. the method for claim 20, wherein, described mammal suffers from sacrotomy, the loss of child Te Fa bone or the bone loss relevant with periodontitis.
27. the method for claim 20 wherein, is used for the treatment of the knitting after face's reconstruction, upper jaw bone reconstruction or mandibular bone are rebuild; Induce the synosteosis of vertebra; Strengthen the elongation of long bone; Improve the healing speed of bone graft or the inside growth of enhancing prosthese.
28. the method for claim 27, wherein, what treated is people's fracture.
29. increase the method for muscle quality in having the mammal that needs, this method comprises, increases the compositions of the claim 1 of effective dose to described administration muscle quality.
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| ES2274854T3 (en) | 2000-05-08 | 2007-06-01 | Pfizer Products Inc. | ENZYMATIC RESOLUTION OF SELECTIVE MODULATORS OF THE STROGEN RECEIVER. |
| IL145106A0 (en) * | 2000-08-30 | 2002-06-30 | Pfizer Prod Inc | Intermittent administration of a geowth hormone secretagogue |
| CA2420535A1 (en) * | 2000-08-30 | 2002-03-07 | Mary Tanya Am Ende | Sustained release formulations for growth hormone secretagogues |
| WO2006024931A2 (en) * | 2004-08-31 | 2006-03-09 | Pfizer Products Inc. | Therapeutic combinations comprising a selective estrogen receptor modulator and a selective androgen receptor modulator |
| CU23558A1 (en) | 2006-02-28 | 2010-07-20 | Ct Ingenieria Genetica Biotech | COMPOUNDS ANALOG TO THE PEPTIDIC SECRETAGOGS OF THE GROWTH HORMONE |
| EP2644618B1 (en) | 2007-02-09 | 2016-08-17 | Ocera Therapeutics, Inc. | tether intermediates for the synthesis of macrocyclic ghrelin receptor modulators |
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| TW432073B (en) * | 1995-12-28 | 2001-05-01 | Pfizer | Pyrazolopyridine compounds |
| HN1996000101A (en) * | 1996-02-28 | 1997-06-26 | Inc Pfizer | COMBINED THERAPY FOR OSTEOPOROSIS |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101111512B (en) * | 2004-06-18 | 2013-05-01 | 特兰齐姆制药公司 | Methods of using macrocyclic modulators of the ghrelin receptor |
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| AU4054799A (en) | 2000-01-05 |
| BR9911324A (en) | 2001-04-03 |
| TR200003544T2 (en) | 2001-04-20 |
| OA11505A (en) | 2004-05-07 |
| CA2335134A1 (en) | 1999-12-23 |
| AR018869A1 (en) | 2001-12-12 |
| PL344981A1 (en) | 2001-11-19 |
| CO5070587A1 (en) | 2001-08-28 |
| NO20006312L (en) | 2000-12-12 |
| EP1087764A1 (en) | 2001-04-04 |
| PE20000646A1 (en) | 2000-08-05 |
| SK18912000A3 (en) | 2001-10-08 |
| ID27599A (en) | 2001-04-12 |
| ZA993975B (en) | 2000-12-15 |
| IS5691A (en) | 2000-10-27 |
| HUP0102505A3 (en) | 2002-12-28 |
| PA8475901A1 (en) | 2000-05-24 |
| EA200001186A1 (en) | 2001-06-25 |
| AP9901582A0 (en) | 1999-06-30 |
| GT199900087A (en) | 2000-12-07 |
| JP2002518326A (en) | 2002-06-25 |
| MA26652A1 (en) | 2004-12-20 |
| WO1999065486A1 (en) | 1999-12-23 |
| HUP0102505A2 (en) | 2001-11-28 |
| IL138630A0 (en) | 2001-10-31 |
| NO20006312D0 (en) | 2000-12-12 |
| KR20010052852A (en) | 2001-06-25 |
| BG105041A (en) | 2001-08-31 |
| HRP20000859A2 (en) | 2001-04-30 |
| HN1999000097A (en) | 1999-11-03 |
| TNSN99124A1 (en) | 2005-11-10 |
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