CN1220609A - Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis - Google Patents
Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis Download PDFInfo
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- CN1220609A CN1220609A CN97195144A CN97195144A CN1220609A CN 1220609 A CN1220609 A CN 1220609A CN 97195144 A CN97195144 A CN 97195144A CN 97195144 A CN97195144 A CN 97195144A CN 1220609 A CN1220609 A CN 1220609A
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- growth hormone
- osteoporosis
- bone
- medicine
- hormone component
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000009645 skeletal growth Effects 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH] (Somatotropin)
-
- 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
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
A novel method of treating or preventing the outbreak of osteoporosis in an animal, e.g. a mammal, in particular a human being, comprises cyclic administration to the individual of a growth hormone component optionally supplemented with continuous administration of a medicament having estrogenic effect and/or a medicament having gestagenic effect.
Description
The present invention relates to the treatment or the control of osteoporosis.
Osteoporosis is to be characterized as the absolute metabolic bone disease that reduces of bone amount.This more causes the generation of fracturing clinically.Osteoporosis is the subject matter of developed country.
People's skeletal growth is that the age bracket in 20-30 year just stops.Yet, by refigure, cortex and trabecular bone in life can continuous updating (referring to, for example, Parfitt, A.M. (1988), osteoporosis: etiology, diagnosis and treatment; B.L.Riggs and L.J.Melton III are compiled, Raven Press, New York).Refigure is by osteoblast or the deutero-cell of osteoblast (bone lining (lining) cell) digestion perimyelis in proper order, thus expose the mineralising bone surface cause (Chambers, T.J. (1982), J.Cell.Sci., 57,247-260).Osteoclast is replenished from the bone marrow precursor then, and with mononuclear cell, they absorb a spot of bone and therefore excavate absorption lacuna (Eriksen, E.F. wait the people, J.Bone Min.Res. (1990), 5,311-319), it is subjected to osteoblastic invasion and attack subsequently and fills lacuna with new bone.In cortical bone, the end product of this process be Haversian system (osteon) and in trabecular bone its trabecular bone osteon (Bone Structural Units, BSU or wall) seemingly.Participate in the absorption of a certain amount of bone and formation these cellularities bone many cells unit (Bone Multicellular Unit (BMU)) (ibid for Parfitt, people such as A.M.).On normal main body, the tight linking between absorption on time and the space and formation trends towards these two processes of balance, thereby the protection bone is in case loss.
It is unknown that the pathogenesis of osteoporosis remains basically.Yet, nearest histomorphometricall research (Eriksen, E.F., J.Bone Min.Res. (1990), 5,311-319) illustrated in suffering from osteoporotic patient body and reduced osteogenic activity.People such as Eriksen (Eriksen, E.F., ibid) investigate out trabecular bone refigure and found remarkable minimizing on average wall thickness in 89 osteoporosis women (66+6 year) body, this has confirmed Darby and Meunier (Calcif.Tissue Int. (1981), 33, report 199-204).The minimizing of this average thickness caused in not suffering from the main body body of osteoporosis can't see a kind of absorb and form between seriously unbalance.
All postmenopausal women more than 40% will run into mental retardation fracture (Jensen between the age in 50-70 year, people such as GF, Clin.Orthop. (1982), 166,75-79) (Bengner, people such as U, Calcif.Tissue Int. (1988) have been improved with the interior osteoporotic incidence rate of males, 42,293-296).Only can make the bone amount improve 5-10% with anti-absorption scheme treatment.Yet significantly the loss of bone amount reaches 30-50% in the osteoporosis, and optimal treatment should provide corresponding bone amount to increase.
Common known method is to use the estrin treatment menopausal women, in order that treat or prevent osteoporosis.Yet, also be known that high dose estrogenic use will strengthen carcinogenic dangerous and the bone amount is enough improved greatly.This just need comprise the estrogenic preparation of moderate, and estrogenic service efficiency has been proposed new demand.
Have now found that osteoblast has the receptor of growth hormone and insulingrowthfactor and II (IGF-I and IGF-II) (people such as Brixen, the potential using value of growth hormone in the treatment osteoporosis, Abstracts, Workshop on Growth No.5, in JIUYUE, 1992 25-26 day, Moltkes Palace, Denmark, Copenhagen).Though it is growth hormone is found the bone amount that can improve Mus and Canis familiaris L. significantly, little to people's bone amount influence.
The purpose of this invention is to provide more effective treatment or prevent the method for osteoporosis in the human body, it can guarantee to utilize estrogen more efficiently, so that the bone formation amount is higher than present obtainable level.
In first aspect, the present invention relates to the osteoporotic treatment of animal and growth hormone or have the growth hormone sample or the purposes of the chemical compound of growth hormone releasing effect and somatostatin antagonist (following be generically and collectively referred to as growth hormone component), with the compositions (below be called estrogenic component) that in treatment, bone is had anti-Absorption in similar mode in similar mode.
On the other hand, the present invention relates to increase in animal body the bone amount and prevent the osteoporosis generation and relate to growth hormone component and the purposes of estrogenic component in treatment.
Accessory rights can be expressly understood details of the present invention in requiring.
Now be surprised to find, work as growth hormone, somatostatin antagonist or growth hormone cinogenic agent (growth hormone component) are by cyclic application, and the while, when bone being had the compositions of anti-Absorption be applied to animal constantly, the loss of bone amount is stopped and finds that the bone amount is increasing.
The present invention relates to treat the method for animal osteoporosis and relevant disease such as bone deficiency disease and prevent method, this method comprises uses a certain amount of growth hormone component and estrogenic component simultaneously to animal, and the combination of two components can effectively improve the intravital bone amount of animal.
Here employed term " animal " includes, but not limited to birds, as chicken, and duck or turkey; Fish, as salmon, Squaliobarbus ourriculus or tuna; Mammal, as cattle, horse, sheep and people.By the animal treated mammal and be more preferably the people preferably, most preferably be the women, and growth hormone human growth hormone preferably.
In this article, the term " simultaneously " that aspect the using of growth hormone component and estrogenic component, uses be two kinds of medicines of expression use by this way so that: any time, both can both obtain with enough amounts so that benefit of the present invention to be provided for they.This is not to infer these two kinds of medicines must use simultaneously exactly, and for example by injecting two kinds of medicines exactly simultaneously, but two kinds of medicines are for the mode administration with any practicality of being enough to obtain optimum efficiency.
As previously discussed, now fully aware of is, says on the best meaning that growth hormone component is used in a periodic manner, this be meant use growth hormone component during with do not use growth hormone component during replace mutually, this will further make an explanation in this article.Estrogenic component is used preferred every day.
A kind of can using and another kind can for example, be taken with tablet form by Orally administered in the middle of two kinds of medicines by injection.In addition, what it is contemplated that is, each medicine can be used by injection separately, use with the application form of part usefulness, and nasal administration, or use with the form of tablet.Yet growth hormone is preferably used by injection at present.What also should be susceptible to is that growth hormone is used with slow release preparaton form.
According to a preferred aspect of the present invention, estrogen is continued to use in therapeutic process, and growth hormone is used at interval with certain hour.A method for optimizing of using comprises uses estrogen every day and at about 2 days-about 28 days, preferably approximately 2 days-about 14 days, more preferably about 3 days-about 10 days, especially about 3 days-about 7 days during in and with between during using two of growth hormone about 1 the week-about 26 weeks, preferably approximately 3 the week-about 26 weeks, more preferably about 6 the week-about 12 weeks, even more preferably about 6 the week-about 10 weeks, the interval in especially about 8 weeks comes the cyclic application growth hormone.Amount with the 0.001mg-10mg/kg body weight/day is used estrogenic component.When the estrogenic component of being used was estradiol, total dosage of every day was the about 4mg of about 0.5mg-, preferably approximately the about 2mg of 1mg-.If use another kind of estrogen, then use the amount that bone is had same anti-assimilation effect.When comprising progestogen in scheme, then it can be a SH 420, according to scheduled plan every day with the about 2.0mg of about 0.1mg-, preferably approximately the amount of the about 2.0mg of 0.25mg-is used.If use another kind of estrogen, then use the amount that is equal to.
" estrogen " is believed to comprise any preparation that contains estrogenic chemicals in this article, this class material is natural human estrogen such as estrone, 17-and estradiol or derivatives thereof (resolving into natural estrogen in vivo) for example, urinate the natural premarin of preparation from horse, or do not have the artificial estrogen such as the dienestrol of steroid class formation." estrogen " can also be selected from the therapeutic agent (NSERT) of non-steroid class estrogen guiding as centchroman (Centchroman), Le Womeiluo former times sweet smell (Levormeloxifene), raloxifene (Raloxifene), droloxifene (Droloxifene), tamoxifen (Tamoxifene), relevant chemical compound on idoxifene (Idoxifene) or analog or its structure, as at WO96/21656, WO95/10513, US patent 5,280,040, WO96/09040, EP0693488, WO95/34557, EP0617030, WO93/10741, US patent 5,254,568, EP0683170, EP0659413, EP0652006, disclosed chemical compound among EP0652007 and the EP0674903, it is for reference that the content of these documents is introduced into this paper.Containing estrogen compound can be used as " estrogen " as the compositions of unique medicine activity component or the compositions that also contains progestogen except that estrogen reagent and uses.
In this article, " growth hormone " can be the growth hormone in any source, as fowl, cattle, horse, people, sheep, pig, salmon, Squaliobarbus ourriculus or tuna growth hormone, and preferred cattle, people or pig growth hormone, the human growth hormone is most preferred.According to growth hormone used in the present invention can be the spontaneous growth hormone of separating from natural origin, for example in a conventional manner by extracting the growth hormone that hypophysis obtains, or by recombinant technique such as E.B.Jensen and S.Carlsen at biotechnology and biological engineering (Biotech and Bioeng.), 36, the growth hormone that the technology of describing among the 1-11 (1990) is produced.Growth hormone also can be the clipped form of growth hormone, and wherein one or more amino acid residues lack; Its analog, wherein the one or more amino acid residues in the natural molecule are replaced by another amino acid residue (preferred natural amino acid residue), as long as this replacements does not have any side effect such as antigenicity or the activity of reduction greatly; Or derivatives thereof for example has N-or C-end and extends, as Met-hGH.Preferred growth hormone is human growth hormone (hGH).
Chemical compound with growth hormone sample or growth hormone releasing effect can be, for example, growth hormone releasing hormone (GHRH), the less oligopeptide or the polypeptide of one class of somatotropin releasing factor or stimulating growth hormone release in vivo, as the short chain growth hormone-releasing peptide, or somatomedin such as IGF-I or IGF-II, and somatostatin antagonist.
Proper growth hormone sercretogogue other example be at WO94/13696, WO94/19367, WO95/14666, WO94/11012, WO96/15148, WO95/34311, WO95/13069, disclosed chemical compound among WO93/04081 and the WO97/07117, it is for reference that the content of these documents is introduced into this paper.
For purpose of the present invention, the expression phrase " increases the bone amount " and is used to refer to a kind of like this state: wherein absorption and the balance between the formation at bone is offset to forming direction, so that stop the loss of bone amount at least.
Treatment suffer from obvious osteoporosis-[these symptoms for example can be the compression fracture of spine osteoporosis disease and at least one vertebra or in neck of femur or lumbar spine obviously bone mineral nitrogen density reduce]-postclimacteric people's recommended doses scheme, for example can be in 2 years every day with a slice Kliogest (Novo Nordisk A/S, Bagsvaerd, Denmark; Each sheet Kliogest comprises the estradiol of 2mg and the SH 420 of 1mg) and every day subcutaneous injection dosage be the 0.01-1IU/kg body weight/day, preferred 0.1-0.2IU/kg body weight/day, the more preferably Norditropin biosynthesis growth hormone (B-hGH of 0.2IU/kg body weight/day (specific activity of GH is 3IU/mg), Novo NordiskA/S, Bagsvaerd, Denmark), somatostatin antagonist or GH sercretogogue or growth hormone component, they were at about 2 days-about 28 days, preferably approximately 2 days-about 14 days, more preferably about 3 days-about 10 days, especially about 3 days-about 7 days during in discharge the GH of fixed amount, and have between during using two of growth hormone about 1 the week-about 26 weeks, preferably approximately 3 the week-about 26 weeks, more preferably about 6 the week-about 12 weeks, even more preferably about 6 the week-about 10 weeks, the interval in especially about 8 weeks.Injection can be used conventional syringe or use pen device (pen device) as Nordiject pen device (Novo Nordisk A/S, Bagsvaerd, Denmark).Estrogen preferably includes the preparation of the mixture of estrogen and progestogen.For the women who does not have the uterus, preferably only use estrogen.
According to another aspect of the present invention, the human growth hormone is used to make and a kind ofly treats osteoporotic medicine by using simultaneously with estrogen.
According to another aspect of the present invention, the human growth hormone is used to make a kind of by use the medicine that prevents that osteoporosis from taking place simultaneously with estrogen.
Further specify the present invention in the following embodiments, but these embodiment to limit scope of the present invention anything but.
Embodiment 1
Suffer from after the menopause in about 62 years old of obvious osteoporosis elderly woman in the time in 1 year every day oral Kliogest tablet and per 8 weeks subcutaneous injection Norditropin growth hormone in 7 days time.Take 1 tablet of Kliogest tablet incessantly every day.When using Norditropin , employed dosage is 0.2 IU/kg body weight/day in 7 days time.Confirm osteoporosis with radioactive method.This women does not suffer from loose any other osteopathia in addition of deossification.She has normal glucose metabolism function and does not suffer from noninsulindependent diabetes.She does not abuse drinks or medicine and does not have the vaginal hemorrhage of unknown cause of disease and never suffer from thromboembolism during estrin treatment.
Before the begin treatment and after treating in 6 months and 12 months, analyze bone mineral nitrogen density in lumbar spine (L2-L4) and neck of femur by quantitative digital formula radiography technology.After the treatment of 6 months and 12 months, improve 3% and 15% respectively in spinal column os in os mineral nitrogen density, with baseline Comparatively speaking.After 6 months and 12 months, the bone mineral nitrogen density of lumbar spine (is pressed g/cm at estrogen and growth hormone combined therapy
2Meter) brings up to 0.631 and 0.703 respectively from 0.611.
Compare with baseline, in the bone mineral nitrogen density raising 11.4% of 12 months treatment back necks of femur.The bone mineral nitrogen density of lumbar spine (is pressed g/cm
2Meter) then brings up to 0.774 from 0.688.
Embodiment 2
57 women's (45-75 year) that suffer from postmenopausal osteoporosis (BMD＞2SD subaverage and spinal fracture and/or Colles' fracture) are divided into the placebo Control Study that four branches carry out randomized, double-blind.
Four branch design:
GH+Kliogest
GH+ placebo (Placebo)
Placebo+Kliogest
Placebo+placebo.
Kliogest uses with oral form every day in 12 months.During treatment in 12 months per 2 months in 7 days time evening with 0.2IU/mg/ days dosage subcutaneous injection GH.
The result of the percent change of BMD shows after treatment in 12 months, with regard to the effect of BMD spinal column, accepts the patient (average percentage improves 9.5%) of Kliogest and GH combined treatment, is higher than the patient (on average improving 6.8%) who only uses estrin treatment.
For accept GH add placebo or only the patient of placebo do not observe beneficial effect.To the effect of BMD hip shown with spinal column in much at one dosage-response relation, the patient who accepts combined treatment has bigger raising than the patient who only accepts estrogen or GH on effect.
Three following embodiment have illustrated preferred GH sercretogogue.
Embodiment 3:(2E) 5-amino-5-methyl oneself-2-olefin(e) acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl) carbamoyl)-2-(2-naphthyl) ethyl) amide hydrochloride:
3-hydroxyl-1,1-dimethyl propylene aminocarbamic acid tertiary butyl ester:
Steps A: under 0 ℃, with ethyl chloroformate (1.10ml, 11.5mmol) be added drop-wise to uncle 3--butoxy carbonyl amino-3 Methylbutanoic acid (2.50g, 11.5mmol) and triethylamine (1.92ml is 13.8mmol) in the solution of oxolane (10ml).Solution is stirred 40 minutes under 0 ℃.Formed precipitate is filtered off and washs with oxolane (20ml).Liquid is cooled to 0 ℃ immediately.Drip the 2M lithium borohydride at oxolane (14.4ml, 28.8mmol) solution in.Solution is stirred 2 hours under 0 ℃, then, be warmed up to room temperature through 4 hours.It is cooled to 0 ℃.The careful methanol (5ml) that adds.Add 1N hydrochloric acid (100ml).Solution is used ethyl acetate extraction (2 * 100ml, 3 * 50ml).The organic layer that merges is with saturated sodium bicarbonate solution (100ml) washing and through dried over mgso.Solvent removed in vacuo.Crude product separates at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel (110g) with ethyl acetate/heptane 1: 2 and obtains 1.84g3-hydroxyl-1,1-dimethyl propylene aminocarbamic acid tertiary butyl ester.
1H-NMR(CDCl
3):d1.33(s,6H)；1.44(s,9H)；1.88(t,2H)；1.94(br,1H)；3.75(q,2H)；4.98(br,1H)。3-(uncle-butoxy carbonyl amino)-3-methyl butyraldehyde:
Step B: under-78 ℃, (1.22ml, (1.1ml is 12.9mmol) in the solution of dichloromethane (15ml) 17.2mmol) to add oxalyl chloride to DMSO.Mixture is stirred 15 minutes under-78 ℃.Dripped 3-hydroxyl-1,1-dimethyl propylene aminocarbamic acid tertiary butyl ester (1.75g, 8.6mmol) solution in dichloromethane (10ml) through 15 minutes.Solution stirred under-78 ℃ 15 minutes once more.The interpolation triethylamine (6.0ml, 43mmol).Solution stirred 5 minutes under-78 ℃ and is heated to room temperature.Solution extracts with dichloromethane (100ml) dilution and with 1N hydrochloric acid (100ml).Water extracts with dichloromethane (50ml).The organic layer that merges washs through dried over mgso with saturated sodium bicarbonate solution (100ml).Solvent removed in vacuo.Crude product is gone up by the column chromatography purification at silica gel (140g) with ethyl acetate/heptane (1: 3) and is obtained 1.10g 3-(uncle-butoxy carbonyl amino)-3-methyl butyraldehyde.MHz-
1H-NMR(CDCl
3):d1.39(s,6H)；1.45(s,9H)；2.85(d,2H)；4.73(br.1H)；9.80(t,1H)。
(2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-2-olefin(e) acid ethyl ester:
Step C: (1.96ml 9.8mmol) is dissolved in the oxolane (30ml) with triethyl phosphine acyl acetic acid salt.Interpolation uncle-Ding potassium oxide (1.10g, 9.8mmol).Solution at room temperature stirred 40 minutes.Add 3-(uncle-butoxy carbonyl amino)-3-methyl butyraldehyde (1.10g, 5.5mmol) solution in oxolane (6ml).Solution at room temperature stirred 75 minutes.Solution is diluted with ethyl acetate (100ml) and 1N hydrochloric acid (100ml).Separate each phase.(2 * 50ml) extract water with ethyl acetate.With organic facies usefulness saturated sodium bicarbonate solution (60ml) washing of merging and through dried over mgso.Solvent removed in vacuo.Crude product with ethyl acetate/heptane (1: 4) silica gel (90g) go up by column chromatography purify obtain 1.27g (2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-2-olefin(e) acid ethyl ester.
1H-NMR(CDCl
3):d1.30(s,6H)；1.30(t,3H)；1.46(s,9H)；2.62(d,2H)；4.27(q,2H)；4.42(br,1H)；5.88(d,1H)；6.94(td,1H)。(2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-the 2-olefin(e) acid:
Step D: with (2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-(1.233g 4.54mmol) is dissolved in the diox (20ml) 2-olefin(e) acid ethyl ester.The Lithium hydrate of interpolation solid form (0.120g, 5.00mmol).Add water (10ml) till obtaining limpid solution.Solution at room temperature stirred 16 hours.Solution with water (70ml) is diluted and (2 * 100ml) extract with t-butyl methyl ether.(3 * 70ml) extract water with 1N sodium bisulfate (pH=1) acidify and with t-butyl methyl ether.With the organic facies merging and through dried over mgso.Solvent removed in vacuo obtain 1.05g (2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-the 2-olefin(e) acid.Crude product is used to following synthesizing.
1H-NMR(DMSO?d
6):d?1.15(s,6H)；1.35(s,9H)；2.53(d,2H)；5.75(d,1H)；6.57(br,1H)；6.75(td,1H)；12.15(s,1H)。N-methyl-N-((R)-1-(methylamino formoxyl)-2-phenylethyl) carbamic acid tertiary butyl ester
Step e: with uncle N--butoxy carbonyl-N-methyl D-phenylalanine (1.22g, 4.4mmol), I-hydroxybenzotriazole hydrate (0.59g, 4.4mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.88g, 4.6mmol) be dissolved in N, in the dinethylformamide (25ml) and stirred 30 minutes.(40% solution in methanol of 0.51g 6.6mmol) and with mixture stirs a night to add methyl amine.Interpolation dichloromethane (80ml) is with water (100ml) and separate each phase.(20ml, 1N), sodium bisulfate (50ml, 10%) and water (50ml) wash organic facies with sodium hydroxide.Dry (magnesium sulfate) organic facies and solvent removed in vacuo obtain 1.39g N-methyl-N-((R) 1-(methylamino formoxyl)-2-phenylethyl) carbamic acid tertiary butyl ester.
1H-NMR(CDCl
3):d1.25,1.35(2s(br),9H)；2.73-2.94(m,7H)；3.30-3.50(m,1H)；4.68,4.90(2m,1H)；5.90,6.12(2s(br)；1H)；7.12-7.25(m,5H)。(R)-N-methyl-2-methylamino-3-Phenylpropionamide:
Step F: (1.39g 7.23mmol) is dissolved in the mixture of trifluoroacetic acid (5ml) and dichloromethane (10ml) and stirred 45 minutes with N-methyl-N-((R) 1-(methylamino formoxyl)-2-phenylethyl) carbamic acid tertiary butyl ester.Vacuum is removed volatile matter and the mixture of residue with ethyl acetate (100ml) and water (100ml) is stirred.Add sodium bicarbonate (50ml, saturated) and separate each phase.Dry (magnesium sulfate) organic facies and solvent removed in vacuo obtain 330mg (R)-N-methyl-2-methylamino-3-Phenylpropionamide.
1H-NMR (CDCl
3): d2.1 (s (br), 3H); 2.32 (s, 3H); 2.77 (dd, 1H); 2.81 (2s, 3H); 3.21 (dd, 1H); 3.32 (dd, 1H); 7.12 (s (br), 1H); 7.20-7.34 (m, 5H) .N-methyl-N-{ (1R)-1-(N-methyl-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl) carbamoyl)-2-(2-naphthyl) ethyl } the carbamic acid tertiary butyl ester
Step G: (548mg 1.66mmol) is dissolved in the dichloromethane (5ml) with (R)-uncle-butoxy carbonyl-N-methylamino-3-(2-naphthyl) propanoic acid; Add 1-hydroxyl-7-azepine benzotriazole (227mg, 1.66mmol) and N, dinethylformamide (2ml).(351mg is 1.83mmol) and with solution stirring 15 minutes to add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.Add (the R)-N-methyl-2-methylamino-3-Phenylpropionamide be dissolved in the dichloromethane (4ml) (320mg, 1.66mmol) and diisopropyl ethyl amine (0.28ml 1.66mmol) and with mixture stirs a night.Add dichloromethane (50ml) and water (100ml), sodium bisulfate (50ml, 5%) and sodium bicarbonate (50ml, saturated) washing organic facies.Dry (magnesium sulfate) organic facies and solvent removed in vacuo.Residue use ethyl acetate/dichloromethane (1: 1) carry out chromatographic isolation (silica gel, 2 * 45cm) obtain 604mg N-methyl-N{ (1R)-1-(N-methyl-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl) carbamoyl)-2-(2-naphthyl)-ethyl } the carbamic acid tertiary butyl ester.
1H-NMR (CDCl
3): d1.05,1.31,1.56 (3s, 9H); 2.28-3.37 (7m, 13H); 5.04,5.17,5.29,5.48 (4dd, 2H); 7.05-7.79 (m, 12H). (2R)-N-methyl-2-methylamino-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl)-3-(2-naphthyl) propionic acid amide.:
Step H: with N-methyl-N-{ (1R)-1-(N-methyl-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl) carbamoyl)-2-(2-naphthyl) ethyl } carbamic acid tertiary butyl ester (600mg; 1.19mmol) trifluoroacetic acid/dichloromethane (1: 1; stirred 10 minutes 5ml), vacuum is removed volatile matter.(2 * 5ml) extractings also are dissolved in the methanol (2ml) residue, mix with sodium bicarbonate (10ml) and ethyl acetate (15ml) with ether.Organic facies separated and dry (magnesium sulfate) obtains 420mg (2R)-N-methyl-2-methylamino-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl)-3-(2-naphthyl) propionic acid amide..
1H-NMR (CDCl
3): (set point value) d1.69 (s, 3H); 2.08 (d, 3H); 2.54 (s, 3H); 2.76 (dd, 1H); 2.92 (dd, 1H), 3.12 (dd, 1H), 3.31 (dd, 1H); 3.72 (dd, 1H), 4.95 (q (br), 1H); 5.50 (dd; 1H). ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl) carbamoyl)-2-(2-naphthyl) ethyl) carbamoyl) fourth-3-thiazolinyl) carbamic acid tertiary butyl ester:
Step I: with (2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-2-olefin(e) acid (200mg, 0.82mmol), 1-hydroxyl-7-azepine benzotriazole (112mg, 0.82mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (173mg, 0.90mmol) be dissolved in dichloromethane (10ml) and N, in the mixture of dinethylformamide (1ml) and stirred 15 minutes.Add N-methyl-2-methylamino-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl)-3-(2-naphthyl) propionic acid amide. (332mg that is dissolved in the dichloromethane (5ml); 0.82mol) and diisopropyl ethyl amine (0.14ml), mixture stirs a night under nitrogen atmosphere.Mixture dilutes with dichloromethane (50ml), water (50ml), sodium bicarbonate (30ml, saturated), and sodium bisulfate (30ml, 5%) washing.Separate each phase, organic facies is through dried over mgso and vacuum evaporation.Residue carries out chromatographic isolation (silica gel; 2 * 40cm) obtain 450mg ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylamino formoxyl)-2-phenylethyl) carbamoyl)-2-(2-naphthyl) ethyl) carbamoyl) fourth-3-thiazolinyl)-carbamic acid tertiary butyl ester.
1H-NMR (CDCl
3): (set point value) d1.20,1.22,1.24,1.30,1.41,1.55 (6s, 15H), 4.30,4.40 (2s (br), 1H); 5.08,5.18,5.32,5.60,5.87 (5dd, 2H); 6.05 (dd, 1H); 6.75 (m, 1H).Step J: with ((3E)-1; 1-dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-(methylamino formoxyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl) ethyl) carbamoyl) fourth-3-thiazolinyl) (403mg 0.63mmol) stirred 10 minutes in the mixture of trifluoroacetic acid (4mL) and dichloromethane (4ml) the carbamic acid tertiary butyl ester.Vacuum is removed volatile matter, and crude product uses dichloromethane, ethanol and ammonium (25%, in water) (80/18/2) to separate in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (400g) as eluent.Isolating product is dissolved in the 3M solution of hydrochloric acid in ethyl acetate and evaporation, then, is dissolved in the dichloromethane once more and twice evaporation obtains the 140mg title compound.
1H-NMR (CDCl
3): d1.05,1.10,1.15,1.16 (4s, 6H); 2.07 (s (br); 3H); 5.12,5.32,5.40,5.60,5.91 (5dd, 2H); 6.05,6.14 (2d, 1H); 6.80 (m, 1H) HPLC:R
t=29.02 minutes (method A1) ESMS:m/z=529 (100%) (M+H)
+Embodiment 4:(2E)-5-amino-5-methyl oneself-2-olefin(e) acid N-((1R)-1-(((1R)-1-((2S)-2-hydroxypropyl carbamoyl)-2-phenylethyl)-methylamino formoxyl)-2-(2-naphthyl) ethyl)-N-methyl nitrosourea:
Prepare this chemical compound with the method that is similar to embodiment 1.In step e, substitute methyl amine with (S)-2-hydroxypropyl amine.
1H-NMR (CDCl
3) (selected peak value, the mixture of rotamer) d3.90 (m, 1H); 5.55 (dd, 1H); 5.58 (d, 1H) HPLC:R
t=29.03 minutes (method A1) PDMS:m/z=573.5 (100%) (M+H)
+Embodiment 5:(2E)-5-amino-5-methyl oneself-2-olefin(e) acid ((1R)-1-(((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl) methylamino formoxyl)-2-(2-naphthyl) ethyl) methyl nitrosourea:
(R)-2-(uncle N--butoxy carbonyl-N-methylamino)-3-(4-fluorophenyl) propanoic acid:
With uncle 2--butoxy carbonyl amino-3-(4-fluorophenyl) propanoic acid (5.0g; 17.7mmol) be dissolved in the exsiccant oxolane.Add iodomethane (8.8ml; 141mmol) and with reactant mixture be cooled to 0 ℃.Slowly add sodium hydride (2.1g; 53.0mmol) and reactant mixture at room temperature stirred 12 hours.Add ethyl acetate (50ml) and water (20ml) is added drop-wise in the reactant mixture.Vacuum is removed ethyl acetate, and residue dilutes with ether (30ml) and water (100ml).Organic facies extracts with saturated sodium bicarbonate aqueous solution (50ml).The aqueous phase that citric acid (5%) is added to merging is 3 up to pH value, and subsequently, (2 * 50ml) extractions separate each phase with ethyl acetate.The organic facies water (2 * 50ml), sodium thiosulfate solution (5%; 2 * 50ml) and water (50ml) washing and dry (magnesium sulfate).Solvent removed in vacuo also is dissolved in residue in the ether (10ml).Add dicyclohexylamine (10ml).Adding dichloromethane (30ml) and heating blends dissolves up to precipitate.Add ether (20ml) and heptane (20ml), reactant mixture is not stirred placed 12 hours.Filter reaction mixture obtains 5.7g dicyclohexyl-ammonium salts (R)-2-(uncle N--butoxy carbonyl-N-methylamino)-3-(4-fluorophenyl) propanoic acid.
1H-NMR (CDCl
3) (mixture of rotamer) d:1.21; 1.31 (2s, 9H); 2.75; 2.84 (2s, 3H); 2.86-3.02 (m, 1H); 3.28-3.42 (m, 1H); 4.65; 4.85 (2dd, 1H); 6.85-7.00 (m, 2H); 7.10-7.25 (m, 2H).((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl)-methyl carbamic acid tertiary butyl ester:
With (R)-2-(uncle N--butoxy carbonyl-N-methylamino)-3-(4-fluorophenyl) propanoic acid (3.00g; 10.1mmol) the dicyclohexyl ammonium salt be dissolved in the dichloromethane (30ml) and with sodium bisulfate aqueous solution (10%; 30ml) washing.Organic facies drying (magnesium sulfate) is also filtered.With I-hydroxybenzotriazole (1.40g; 10.1mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (2.0g; 10.6mmol) join in the filtrate, reactant mixture at room temperature stirred 15 minutes.The interpolation methyl amine (40%, in methanol; 0.75g; 9.17mmol) and diisopropyl ethyl amine (1.7ml; 10.1mmol) and reactant mixture at room temperature stirred 12 hours.Reactant mixture is (saturated with sodium bicarbonate aqueous solution; 50ml) with sodium bisulfate aqueous solution (10%; 50ml) washing and dry (magnesium sulfate).Solvent removed in vacuo, residue are used ethyl acetate/heptane (2: 1), and (3 * 40cm) enterprising circumstances in which people get things ready for a trip spectrum separation obtain 1.06g ((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl)-methyl carbamic acid tertiary butyl ester at silica gel as eluent.
1H-NMR(CDCl
3)d:1.29；1.37(2s,9H)；2.74(s,3H)；2.8(s,3H)；2.82-2.95(m,1H)；3.36-3.48(m,1H)；4.63；4.86(m,1H)；5.89；6.14(2s,1H)；6.9-7.0(m,2H)；7.1-7.21(m,2H)。(2R)-3-(4-fluorophenyl)-N-methyl-2-(methylamino) propionic acid amide.:
With ((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl)-methyl carbamic acid tertiary butyl ester (1.0g; 3.22mmol) be dissolved in the dichloromethane (5ml).Add trifluoroacetic acid (5ml), reactant mixture at room temperature stirred 30 minutes.In reactant mixture, add dichloromethane (30ml), the aqueous solution (pH9 of sodium bicarbonate/sodium carbonate; 30ml) and sodium bicarbonate (solid), equal till 9 up to pH value.Dry (magnesium sulfate) organic facies and vacuum evaporation obtain 0.62g (2R)-3-(4-fluorophenyl)-N-methyl-2-methylamino propionic acid amide..
1H-NMR(CDCl
3)d:1.31(s,1H)；2.29(s,3H)；2.65-2.73(m,1H)；2.82(d,3H)；3.12-3.20(m,2H)；6.96-7.02(m,2H)；7.11(s,1H)；7.14-7.20(m,2H)。((1R)-1-(((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl) methylamino formoxyl)-2-(2-naphthyl)-ethyl) methyl carbamic acid tertiary butyl ester:
With (2R)-2-(uncle-butoxy carbonyl methyl amino)-3-(2-naphthyl) propanoic acid (1.0g; 3.1mmol) be dissolved in the dichloromethane (20ml).Add 1-hydroxyl-7-azepine benzotriazole (0.43g; 3.1mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.63g; 3.3mmol), reactant mixture at room temperature stirred 15 minutes.
Add (2R)-3-(4-fluorophenyl)-N-methyl-2-(methylamino) propionic acid amide. (0.6g; 2.9mmol) and diisopropyl ethyl amine (0.54ml; 3.1mmol), reactant mixture at room temperature stirred 12 hours.Add dichloromethane (30ml), reactant mixture water (30ml), sodium bisulfate aqueous solution (10%; 30ml), sodium bicarbonate/sodium carbonate (pH9; 30ml) and water (30ml) washing and dry (magnesium sulfate).Solvent removed in vacuo; residue uses ethyl acetate/heptane (2: 1) as eluent, and (4.0 * 30cm) enterprising circumstances in which people get things ready for a trip spectrum separation obtain 1.07g ((1R)-1-(((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl) methylamino formoxyl)-2-(2-naphthyl) ethyl) methyl carbamic acid tertiary butyl ester at silica gel.
1H-NMR (CDCl
3) (the selected peak of main rotamer) d:1.34 (s, 9H); 2.23 (d, 3H); 2.76 (s, 3H); 2.87 (s, 3H); 5.70 (dd, IH); 5.95 (dd, 1H).(2R)-N-((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl)-ethyl)-N-methyl-2-methylamino-3-(2-naphthyl) propionic acid amide.:
With ((1R)-1-(((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl)-ethyl) methylamino formoxyl)-2-(2-naphthyl) ethyl) methyl carbamic acid tertiary butyl ester (1.0g; 1.92mmol) be dissolved in the dichloromethane (5ml).Add trifluoroacetic acid (5ml), reactant mixture at room temperature stirred 15 minutes.In reactant mixture, add dichloromethane (25ml), sodium bicarbonate/aqueous sodium carbonate (pH9; 25ml) and sodium bicarbonate (solid) till pH8.Dry (magnesium sulfate) organic facies and vacuum evaporation obtain 0.75g (2R)-N-((1R)-2-(4-fluorophenyl)-1-methylamino formoxyl ethyl)-N-methyl-2-methylamino-3-(2-naphthyl) propionic acid amide..
1H-NMR(CDCl
3)d:1.81(s,3H)；2.07(d,3H)；2.54(s,3H)；2.68-2.77(m,1H)；2.88-2.97(m,1H)；3.18(dd,1H)；3.27(dd,1H)；3.8(dd,1H)；4.95(s,1H)；5.43(dd,1H)；6.72(t,1H)；6.90(t,2H)；7.12(dd,2H)；7.32(d,1H)；7.42-7.50(m,2H)；7.62(s,1H)；7.70-7.83(m,2H)。(4 (((1R)-1 (((1R)-2 (4-fluorophenyl)-1-(methylamino formoxyl)-ethyl) methylamino formoxyl)-2-(2-naphthyl) ethyl) methylamino formoxyls)-1,1-dimethyl butyrate-3-thiazolinyl) carbamic acid tertiary butyl ester:
With (2E)-5-(uncle-butoxy carbonyl amino)-5-methyl oneself-2-olefin(e) acid (0.22g; 0.89mmol, according to embodiment 1 preparation) be dissolved in the dichloromethane (10ml).Add 1-hydroxyl-7-azepine benzotriazole (0.13g; 0.98mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.2g; 1.02mmol), reactant mixture at room temperature stirred 15 minutes.Add (2R)-N-((1R)-2-(4-fluorophenyl)-1-(methylamino formoxyl) ethyl)-N-methyl-2-methylamino-3-(2-naphthyl) propionic acid amide. (0.38g; 0.89mmol) and diisopropyl ethyl amine (0.17ml; 0.98mmol), reactant mixture at room temperature stirred 12 hours.Add dichloromethane (50ml) and with reactant mixture water (50ml), sodium bisulfate aqueous solution (10%; 50ml), sodium bicarbonate/aqueous sodium carbonate (pH9; 50ml) and water (50ml) washing and dry (magnesium sulfate).Solvent removed in vacuo; and residue is used ethyl acetate/heptane (2: 1), and (4 * 30cm) enterprising circumstances in which people get things ready for a trip spectrum separation obtain 0.34g (4-(((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylamino formoxyl ethyl) methylamino formoxyl)-2-(2-naphthyl)-ethyl) methylamino formoxyl)-1,1-dimethyl butyrate-3-thiazolinyl) carbamic acid tertiary butyl ester at silica gel as eluent.
1H-NMR (CDCl
3) (the selection peak of main rotamer) d:0.85 (s, 3H); 0.87 (s, 3H); 1.42 (s, 9H); 2.12 (d, 3H); 2.72 (s, 3H); 2.96 (s, 3H); 5.75 (dd, 1H); 5.92 (dd, 1H); 6.12 (dd, 1H).
With (4-(((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylamino formoxyl-ethyl) methylamino formoxyl)-2-(2-naphthyl) ethyl) methyl-carbamoyl)-1,1-dimethyl butyrate-3-thiazolinyl) carbamic acid tertiary butyl ester (0.33g; 0.51mmol) be dissolved in the dichloromethane (3ml).Add trifluoroacetic acid (3ml) and reactant mixture was at room temperature stirred 5 minutes.In reactant mixture, add dichloromethane (25ml), sodium bicarbonate/aqueous sodium carbonate (pH9; 25ml) and sodium bicarbonate (solid) till pH9.Dry (magnesium sulfate) organic facies and vacuum evaporation obtain the 0.18g title compound.
1H-NMR (CDC1
3) (the selection peak of main rotamer) d:1.15 (s, 6H); 2.14 (d, 3H); 2.73 (s, 3H); 3.09 (s, 3H); 5.23 (dd, 1H); 5.90 (dd, 1H); 6.12 (dd, 1H) .PDMS:m/z547.4 (M+H)
+HPLC:R
t=32.05 minutes
Claims (23)
1. method that prevents or treat osteoporosis and relevant disease, this method comprises that its consumption is enough to prevent significantly or reduces the osteoporosis degree and/or be enough to significantly improve bone strength to animal cyclic application growth hormone component such as growth hormone, somatostatin antagonist or the growth hormone cinogenic agent of need treatment.
2. according to the process of claim 1 wherein finishing at one-period and the interval in about 1 week to about 26 weeks of following one-period between beginning, in about 2 days-about 28 days time, use this growth hormone component.
3. according to the method for claim 2, wherein, in about 7 days time, use this growth hormone component to finish at one-period and the interval in about 6 weeks to about 12 weeks of following one-period between beginning.
4. according to the process of claim 1 wherein that animal is a mammal, people especially.
5. according to the process of claim 1 wherein that growth hormone component is the human growth hormone.
6. according to the process of claim 1 wherein except the cyclic application growth hormone component, also animal is continued to use the compositions that bone is had anti-Absorption.
7. according to the method for claim 6, wherein said composition comprises estrogen, especially estradiol.
8. according to the method for claim 6, wherein said composition comprises the chemical compound with estrogenic effect.
9. according to the method for claim 6, wherein said composition comprises and is selected from centchroman, Le Womeiluo former times sweet smell, raloxifene, droloxifene, one or more chemical compounds of tamoxifen or idoxifene.
10. according to the method for claim 6, wherein said composition comprises calcitonin.
11. according to the method for claim 6, wherein said composition comprises diphosphonate.
12. according to any one method among the claim 7-11, wherein compositions comprises the combination of estrogen and progestogen.
13. according to any one method in the aforementioned claim, wherein the dosage of growth hormone or burst size are about 0.01-1IU/kg body weight/day, especially approximately the 0.2IU/kg body weight/day.
14. according to the method for claim 6, wherein the dosage that bone is had a compositions of anti-Absorption is the 0.001-10mg/kg body weight/day, and wherein the dosage of growth hormone is about 0.01-1IU/kg body weight/day, especially approximately the 0.2IU/kg body weight/day.
15. growth hormone component is used to prevent or treat the purposes on the medicine of osteoporosis and relevant disease in manufacturing, this medicine is for cyclic application.
16. growth hormone component is used to prevent or treat the purposes on the medicine of osteoporosis and relevant disease in manufacturing, this drug packages is relevant for the explanation of cyclic application.
17. growth hormone or growth hormone component are used to prevent or treat purposes on the medicine of osteoporosis and relevant disease with the compositions that bone is had anti-Absorption in manufacturing, this medicine is for cyclic application growth hormone component and continue to use anti-absorbing composition.
18. growth hormone component is used to prevent or treat purposes on the medicine of osteoporosis and relevant disease with the compositions that bone is had anti-Absorption in manufacturing, this drug packages is relevant for cyclic application growth hormone component and the explanation that continues to use anti-absorbing composition.
19. growth hormone is used to prevent or treat the purposes on the medicine of osteoporosis and relevant disease in manufacturing, this drug packages is relevant for cyclic application growth hormone component and the explanation that continues to use anti-absorbing composition.
20. the compositions that bone is had an anti-Absorption is used to prevent or treat the purposes on the medicine of osteoporosis and relevant disease in manufacturing, this medicine is for continue to use and follow cyclic application growth hormone component in a period of time.
21. contain a) growth hormone component and b) bone is had anti-Absorption chemical compound a kind of as bonded preparation by simultaneously, separately or the product that uses in order and prevent or treat osteoporosis.
22. according to the method for claim 9, wherein said composition comprises the chemical compound of Le Womeiluo former times sweet smell or its structurally associated.
23. according to the method for claim 9, wherein said composition comprises Le Womeiluo former times sweet smell.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0623/96 | 1996-05-31 | ||
| DK62396 | 1996-05-31 |
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ID=8095682
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97195144A Pending CN1220609A (en) | 1996-05-31 | 1997-05-29 | Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis |
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| Country | Link |
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| EP (1) | EP0907374A1 (en) |
| JP (1) | JP2000512274A (en) |
| KR (1) | KR20000016204A (en) |
| CN (1) | CN1220609A (en) |
| AU (1) | AU3025997A (en) |
| BR (1) | BR9709499A (en) |
| CA (1) | CA2257174A1 (en) |
| CZ (1) | CZ383298A3 (en) |
| HU (1) | HUP9904049A3 (en) |
| IL (1) | IL126983A0 (en) |
| NO (1) | NO985573L (en) |
| PL (1) | PL330239A1 (en) |
| WO (1) | WO1997046252A1 (en) |
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| HN1996000101A (en) | 1996-02-28 | 1997-06-26 | Inc Pfizer | COMBINED THERAPY FOR OSTEOPOROSIS |
| GB2324726A (en) * | 1997-05-01 | 1998-11-04 | Merck & Co Inc | Combination Therapy for the Treatment of Osteoporosis |
| US6784158B1 (en) | 1998-06-09 | 2004-08-31 | Novo Nordisk A/S | Method for preparing a compound with growth hormone releasing properties |
| WO1999064456A1 (en) * | 1998-06-09 | 1999-12-16 | Novo Nordisk A/S | A method for preparing a compound with growth hormone releasing properties |
| JP2001031635A (en) * | 1999-07-14 | 2001-02-06 | Ajinomoto Co Inc | Production of optically active n-protected-n-methyl- phenylalanine derivative |
| ATE446758T1 (en) | 2000-05-31 | 2009-11-15 | Pfizer Prod Inc | USE OF GROWTH HORMONE SECRETAGOGENES TO PROMOTE DIGESTIVE MOTILITY |
| US7476653B2 (en) | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
| CU23558A1 (en) | 2006-02-28 | 2010-07-20 | Ct Ingenieria Genetica Biotech | COMPOUNDS ANALOG TO THE PEPTIDIC SECRETAGOGS OF THE GROWTH HORMONE |
| CN101657436A (en) | 2007-02-09 | 2010-02-24 | 特兰齐姆制药公司 | Macrocyclic ghrelin receptor modulators and using method thereof |
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| NZ236618A (en) * | 1990-01-03 | 1997-06-24 | Ciba Geigy Ag | Treating and preventing osteoporosis using insulin-like growth factor i (igf i) in conjunction with a bone antiresorptive active compound |
| CA2096350C (en) * | 1990-11-26 | 2001-10-16 | Robert R. Recker | Treatment for osteoporosis using growth hormone release factor (grf) in combination with parathyroid hormone (pth) |
| KR960705575A (en) * | 1993-10-19 | 1996-11-08 | 도나 엘. 폴락 | Combination of bisphosphonates and growth hormone secretagogues (bisphosphonates and growth hormone secretagogues) |
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1997
- 1997-05-29 JP JP10500108A patent/JP2000512274A/en active Pending
- 1997-05-29 IL IL12698397A patent/IL126983A0/en unknown
- 1997-05-29 CN CN97195144A patent/CN1220609A/en active Pending
- 1997-05-29 CA CA002257174A patent/CA2257174A1/en not_active Abandoned
- 1997-05-29 CZ CZ983832A patent/CZ383298A3/en unknown
- 1997-05-29 EP EP97924934A patent/EP0907374A1/en not_active Withdrawn
- 1997-05-29 HU HU9904049A patent/HUP9904049A3/en unknown
- 1997-05-29 KR KR1019980709772A patent/KR20000016204A/en not_active Application Discontinuation
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| NO985573L (en) | 1999-01-29 |
| WO1997046252A1 (en) | 1997-12-11 |
| PL330239A1 (en) | 1999-05-10 |
| CZ383298A3 (en) | 1999-07-14 |
| HUP9904049A2 (en) | 2000-04-28 |
| HUP9904049A3 (en) | 2000-07-28 |
| IL126983A0 (en) | 1999-09-22 |
| JP2000512274A (en) | 2000-09-19 |
| EP0907374A1 (en) | 1999-04-14 |
| CA2257174A1 (en) | 1997-12-11 |
| KR20000016204A (en) | 2000-03-25 |
| BR9709499A (en) | 1999-08-10 |
| AU3025997A (en) | 1998-01-05 |
| NO985573D0 (en) | 1998-11-27 |
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