KR20000016204A - Growth hormone component and bone anti-absorptive agent in cyclic (coherence) treatment of osteoporosis - Google Patents

Abstract

PURPOSE: Provided are a novel growth hormone component and bone anti-absorptive agent in cyclic treatment of osteoporosis. CONSTITUTION: The 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

Growth Hormone Components and Anti-absorbing Drugs of Bone in Periodic (Linked) Treatment of Osteoporosis

Osteoporosis is a metabolic bone disease characterized by an absolute decrease in bone volume. This causes clinically increased sensitivity to fractures. Osteoporosis is a serious problem in developed countries.

Growth of the human skeletal skeleton stops at 20-30 years. However, both the cortex and fiber are born throughout life by a process called remodeling (eg Parfitt, AM (1988) in Osteoporosis: etiology, diagnosis and management; BL Riggs, and LJ Melton 5, eds., Raven Press, New York ). Remodeling sequence breaks down the endothelium membrane and is thereby initiated by osteoblasts or osteoblast-derived cells (endothelium cells of bone) (Chambers, TJ (1982), J. Cell. Sci., 57, 247-). 260).

Osteoclasts are then supplemented from bone marrow precursors with monocytes and they are later infiltrated by osteoblasts refilling the river with new bone (Eriksen, EF et al., J. Bone Min. Res. (1990). ), 5, 311-319) to reabsorb fine amounts of bone. Cells that participate in uptake and construction of one proton of bone constitute the multicellular unit (BMU) of bone (Parfitt, A. M. et al., Ibid). In normal patients, the tight coupling between absorption and composition in both time and space tends to balance the two processes, thereby protecting bone loss.

The pathogenesis of osteoporosis is still largely unknown. However, recent histomorphologic studies (Eriksen, E.F., J. Bone Min. Res. (1990), 5, 311-319) have shown reduced osteoblast activity in patients with osteoporosis. Eriksen et. al. (Eriksen, EFibid) investigated fibrous bone remodeling in 89 osteoporotic women (66 5 6 years old) and found a significant reduction in mean wall thickness, confirming earlier reports by Darby and Meunier (Calcif). Tissue Int. (1981), 33, 199-204). This reduction in average thickness results in a significant imbalance between absorption and composition that is not found in patients without osteoporosis.

More than 40% of all postmenopausal women suffer from low-energy fractures between 50 and 70 years old (Jensen, GF et al., Clin. Orthop. (1982), 166, 75-79) and the frequency of osteoporosis in men is increasing ( Bengner, U. et al., Calcif.Tissue Int. (1988), 42, 293-296).

With anti-absorption regimens, treatment can only provide 5-10% of bone volume. However, because bone loss in clinical osteoporosis reaches 30-50%, optimal treatment should provide an increase in the corresponding fraction of bone volume.

Methods of treating menopausal women with estrogen to treat or prevent osteoporosis are commonly known. However, administration of large amounts of estrogen increases the risk of cancer and does not provide an increase in bone volume of a sufficiently large amount. This was called a formulation consisting of a reduced amount of estrogen to increase its efficiency in using estrogen.

It is known that osteoblasts have receptors for growth hormone and insulin growth factors I and II (IGF-I and IGF-II) (Brixen et al., Potential Use of Growth Hormone in the Treatment of Osteoporosis, in Abstracts, Workshop on Growth No. 5, September 25-26, 1992, Moltkes Palace, Copenhagen, Denmark). Although growth hormone is known to significantly increase bone volume in rats and dogs, it does not appear to significantly affect human bone volume.

It is an object of the present invention to provide a more efficient method of treating or preventing the occurrence of osteoporosis in humans which ensures the use of more effective estrogens to increase the bone constituents beyond the extent obtainable here.

The present invention relates to the treatment or prevention of osteoporosis.

In a first aspect, the present invention is directed to a growth inhibitory hormone antagonist (hereinafter also collectively referred to collectively as a growth hormone component) and a composition having an anti-absorbing effect on bone in treatment (generally referred to as an estrogen component). ), Of course, relates to the use of growth hormone analogs or growth hormones or compounds having a growth hormone release effect and to the treatment of osteoporosis in animals.

In another aspect, the present invention relates to the use of growth hormone components and estrogen components in preventing the development of osteoporosis and increasing and treating bone volume in animals.

Further details of the invention will appear in the appended claims.

When growth hormone, growth inhibitory hormone antagonists, or growth hormone secretagogues (growth hormone components) are administered periodically and simultaneously with compositions that have anti-absorbing properties on bone, the loss of bone volume stops and bone An increase in volume is shown.

The present invention provides a method for preventing the occurrence of osteoporosis and related diseases such as osteopenia in an animal consisting of simultaneously administering to the animal a combined effective amount of a growth hormone component and an estrogen component to increase bone volume in the animal. Of course, it is about treatment.

The term "animal" as used in this context is not limited to birds such as chickens, ducks or turkeys, fish such as salmon, trout or tuna and mammals such as cows, horses, sheep and humans. The test animal is preferably a mammal and more preferably a human, most preferably a female and the growth hormone is preferably a human growth hormone.

In the present context, the term "simultaneously" used in connection with the administration of the growth hormone component and the estrogen component, at any time, both refers to two drug administrations in a manner that is available in appropriate amounts to provide the benefit of the present invention. I mean. This did not mean that the two drugs were administered at the same time, for example, as if two drugs were injected at the same time, but rather two drugs were intended to provide a practical way of making optimal use of it.

As noted above, it has been demonstrated that growth hormone components are administered in a periodic manner, meaning that the growth hormone component is not administered and alternately administered periods as optimally refined in the art. The estrogen component is preferably administered daily.

One of the agents is administered by injection and the other is orally administered, for example in the form of a tablet. Alternatively, it may be contemplated that each agent is administered separately, either by injection in the form of a patch for topical application or in the form of a tablet. However, current growth hormone is preferably administered by injection. Growth hormone can also be thought of as being used in sustained release formulations.

According to a preferred aspect of the present invention, estrogen is given during the treatment period in which growth hormone is given periodically. Preferred methods of administration range from about 1 week to about 26 weeks, preferably from about 3 weeks to 26 weeks, more preferably from about 6 weeks to about 12 weeks, even more preferably from about 6 weeks to the period between which growth hormone is administered. Estrogen for a period of about 10 weeks, especially about 8 weeks, about 2 days to about 28 days, preferably about 2 days to 14 days, more preferably 3 days to 10 days, especially about 3 days to about 7 days Daily administration and periodic administration of growth hormone. The estrogen component is administered in an amount of 10 mg from 0.001 mg / kg body weight daily. If other estrogens are used, a dose is given that has an equivalent anti-absorbing effect on the bone. When progesterone is included in therapy, it is the number of norethisterone acetate that is dosed from about 0.1 mg to about 2.0 mg per day, preferably from about 0.25 mg to about 2.0 mg per schedule. have. If equivalent estrogens are used, equivalent amounts are given.

In this context, "estrogen" refers to estrogen substances such as natural human estrogens, such as estrone, 17-B-estradiol and estradiol or its derivatives that are cleaved in vivo to form natural estrogens, natural horse estrogens produced in horse urine Or any formulation comprising synthetic estrogens without steroid structure such as diesterol. "Esterogens" are incorporated herein by reference, for example WO 96/21656, WO 95/10513, US Patent 5,280,040, WO 96/09040, EP 0693488, WO 05/21656, WO 95/10513 , US Patents 5,280,040, WO 96/09040, EP 0693488, WO 95/34557, EP 0617030, WO 93/10741, US Patents 5,254,568, EP 0683170, EP 0659413, EP 0652006, EP 0652007 and EP 0674903 Structurally related compounds or Centchroman, Levormeloxifene, Raloxifene, Droxoxene, Tamoxifene, Tamoxifene, Idoxifene, or analogues thereof The same can also be selected from the group of nonsteroidal estrogen induced therapeutic agents (NSERTs). "Estrogen" is used in a composition comprising an estrogen compound as the only pharmaceutically active ingredient or composition that further comprises progesterone in the estrogen drug.

In this context, "growth hormone" refers to any source such as algae, cattle, horses, sheep, pigs, salmon, trout, or tuna growth hormones, preferably bovine, human or pig growth hormones, most preferably human growth hormones. It is a growth hormone. The growth hormone used according to the present invention may be, for example, a natural growth hormone isolated from a natural source by extracting the pituitary gland by conventional methods, or, for example, E.B. Jensen and S. Carlsen in Biotech and Bioeng. It is a growth hormone produced by recombinant technology as described in 36, 1-11 (1990). Growth hormone is also a form of truncated growth hormone that has one or more amino acid termini deleted; Substitution is that one or more amino acid residues in a natural molecule do not have any side effects such as antigenic or essentially reduced activity or its derivatives with N- or C-terminal extensions such as, for example, Met-hGH, other amino acids Analogs thereof substituted by residues, preferably natural amino acid residues. Preferred growth hormone is human growth hormone (hGH).

Growth hormone analogs or compounds having growth hormone release effects include, for example, growth hormones such as growth hormone release hormone (GH), growth hormone release factor or short-chain growth hormone free peptide, or growth factors such as IGF-I or IGF-II. There will be fewer oligos or polypeptides that promote the release of. Examples of suitable growth hormone components are described in WO 95/17422, WO 95/17423, WO 96/05195, WO 96/22997. The compounds disclosed in WO 96/24587, WO 97/00894 as well as the hexaurein, R.P. Margund et al., PNAS 92 (15), 1995, p. Growth hormone (GH), IGF-I, IGF-II, PACAP, truncated GHRH, GHRP-1, GHRP-2, GHRP-6, MK-677 disclosed in 7001, examples of such compounds are for example As follows.

H-HisΨ (CH ₂ NH) D-Trp-Ala-Trp-D-Phe-Lys-NH ₂ ,

H-His-D-TrpΨ (CH ₂ NH) Ala-Trp-D-Phe-Lys-NH ₂ ,

H-His-D-Trp-AlaΨ (CH ₂ NH) Trp-D-Phe-Lys-NH ₂ ,

H-His-D-Trp-Ala-TrpΨ (CH ₂ NH) D-Phe-Lys-NH ₂ ,

H-His-D-Trp-Ala-Trp-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

HD-Ala-D-2NaI-AlaΨ (CH ₂ NH) Trp-D-Phe-Lys-NH ₂ ,

HD-Ala-D-2NaI-Ala-Trp-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

(3- (4-imidazolyl) propionyl) -D-2NaI-Ala-Trp-D-PheΨ (CH ₂ NH) Lys-OH,

(3- (4-imidazolyl) propionyl) -D-2NaI-Ala-Trp-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

(3- (4-imidazolyl) acryloyl) -D-2NaI-Ala-Trp-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

HD-Ala-D-Phe-Ala-Trp-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

(2R)-(H-D-Ala-D-Phe-Ala-Trp-NH) -3-phenylpropylamine,

(2S)-(HD-Ala-D-2NaI-AlaΨ (CH ₂ NH) Trp-D-Phe-NH) -6-aminohexanol,

HD-Ala-D-2NaI-AlaΨ (CH ₂ NH) Trp-D-Phe-NH ₂ ,

4- (HD-Ala-D-2NaI-AlaΨ (CH ₂ NH) Trp-D-Phe-NH) butylamine,

(2R)-(H-D-Ala-D-2NaI-Ala-Trp-NH) -3-phenylpropylamine,

(2R)-(H-D-Ala-D-2NaI-Ala-Trp-NH) -3-phenylpropylamino) hexylamine,

(2R)-(H-D-2NaI-Ala-N-BzI-Gly-NH) -3-phenylpropylamine,

(2R)-(H-D-Ala-D-2NaI-Ala-N-BzI-Gly-NH) -3-phenylpropylamine,

H-Aib-D-2NaI-Ala-N-BzI-Gly-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

(2S)-((3- (4-imidazolyl) propionyl) Ψ (CH ₂ NH) D-Phe-Ala-Trp-D-Phe-NH) -6-aminohexanol,

(2S)-((3- (4-imidazolyl) propionyl) -D-PheΨ (CH ₂ NH) Ala-Trp-D-Phe-NH) -6-aminohexanol,

(2S)-((3- (4-imidazolyl) propionyl) -D-Phe-AlaΨ (CH ₂ NH) Trp-D-Phe-NH) -6-aminohexanol,

(2S)-((3- (4-imidazolyl) propionyl) -D-Phe-Ala-TrpΨ (CH ₂ NH) D-Phe-NH) -6-aminohexanol,

(2S)-(2R)-((3- (4-imidazolyl) propionyl) -D-Phe-Ala-Trp-NH) -3-phenylpropylamino) -6-aminohexanol,

3-((3- (4-imidazolyl) propionyl) -D-Trp-AlaΨ (CH ₂ NH) Trp-D-Phe-NH) propylamine,

(2S)-((3- (4-imidazolyl) propionyl) -D-Phe-Ala-Trp-D-PheΨ (CH ₂ NH) NH) -6-aminohexanol,

(2S)-((3- (4-imidazolyl) propionyl) -D-Trp-AlaΨ (CH ₂ NH) Trp-D-Phe-NH) -6-aminohexanol,

3-((3- (4-imidazolyl) propionyl) -D-Trp-AlaΨ (CH ₂ NH) Trp-D-Phe-NH) propylamine,

HD-Ala-D-2NaI-Ala-N-BzI-Gly-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

H-Aib-D-2Nal-Ala-N-BzI-Gly-D-PheΨ (CH ₂ NH ₂ ),

H-Ala-HisΨ (CH ₂ NH) D-2NaI-D-Phe-Lys-NH ₂ ,

H-Ala-Ala-D-2NaI-D-Phe-Lys-NH ₂ ,

H-His-D-2NaI-D-Phe-Lys-NH ₂ ,

(3- (4-imidazolyl) propionyl) -D-2NaI-D-Phe-Lys-NH ₂ ,

HD-Lys-D-2NaI-D-Phe-Lys-NH ₂ ,

H-5Apent-His-D-2Nal-D-Phe-Lys-NH ₂ ,

HD-Ala-D-2Nal-D-Phe-Lys-NH ₂ ,

H-5Apent-D-2Nal-D-Phe-Lys-NH ₂ ,

(n-propyl) -His-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Ala-3Pyal-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Ala-Phe (4-NH ₂ ) -D-2Nal-D-Phe-Lys-NH ₂ ,

HD-Ala-His-D-2Nal-D-Phe-Lys-NH ₂ ,

(2- (4-imidazolyl) acetyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3- (4-imidazolyl) acryloyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethyl benzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminophenylacetyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(4-aminophenylacetyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminocrotonoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(4-piperidino-carboxyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

H-Ala-His-D-2Nal-D-Phe-NH ₂ ,

(H-Ala-His-D-2Nal-D-Phe-NH) hexane,

6- (H-Ala-His-D-2Nal-D-Phe-NH) hexylamine,

5- (H-Ala-His-D-2Nal-D-Phe-NH) pentylanaine,

H-Ala-His-D-2Nal-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

H-Ala-His-D-2Nal-D-Phe-Lys-OH,

(2S)-(H-Ala-His-D-2Nal-D-Phe-NH) -6-aminohexanol,

(2- (H-Ala-His-D-2Nal-D-Phe-NH) ethyl) benzene,

2- (H-Ala-HiS-D-2NaI-D-Phe-NH) ethylamine,

2- (H-Ala-His-D-2Nal-D-Phe-NH) methyl) benzylamine,

H-Ala-His-D-2Nal-D-Phe-Lys (maltosyl) -NH ₂ ,

H-Ala-His-D-2Nal-D-Phe-Phe-NH ₂ ,

H-Ala-His-D-2Nal-D-Phe-D-Phe-NH ₂ ,

H-Ala-His-D-Phe-D-Phe-Lys-NH ₂ ,

H-Ala-His-D-Trp-D-Phe-Lys-NH ₂ ,

H-His-D-2Nal-D-Trp-Lys-NH ₂ ,

H-Ala-His-D-1Nal-D-Phe-Lys-NH ₂ ,

H-Ala-Phe-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Ala-His-D-2Nal-D-Phe-Lys (maltosyl) -NH ₂ ,

(2R)-(H-Ala-His-D-2Nal-D-Phe-Lys-NH) -3-phenylpropylamine,

H-Ala-N-Me- (2-aminobenzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3- (methylaminomethyl) benzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(4- (aminomethyl) benzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

H-His-Ala-D-2Nal-D-Phe-Lys-NH ₂ ,

4- (H-Ala-His-D-2Nal-D-Phe-NH) butylamine,

3- (H-Ala-His-D-2Nal-D-Phe-NH) propylamine,

(3- (dimethylaminomethyl) benzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3-amino-3-methylbutanoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-hPhe-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl)-(CH ₂ NH) D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-D-hPhe-Lys-NH ₂ ,

(3-amino-3-methylbutanoyl) -His-D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-N-Bzl-Gly-Lys-NH ₂ ,

(2S)-(3-Aminomethylbenzoyl)-(CH ₂ NH) -D-2Nal-D-Phe-NH) -6-aminohexanol,

(2S)-((3-aminomethylbenzoyl) -D-2Nal-D-Phe-NH) -6-aminohexanol,

(3-aminomethylbenzoyl) -D-2Nal-D-Thial-Lys-NH ₂ ,

(2S)-(H-Aib-HisΨ (CH ₂ NH) -D-2Nal-D-Phe-NH) -6-aminohexanol,

(3-aminomethylbenzoyl) -D-2Nal-D-3Pyal-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-D-Phe (4-F) -Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-D-Phe (4-OMe) -Lys-NH ₂ ,

(2-aminomethylphenylacetyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(2-aminomethylbenzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

2- (H-Aib-His-D-2Nal-D-Phe-NH)-(4-pyridyl) ethane,

H-Aib-Phe-D-2Nal-D-Phe-Lys-NH ₂ ,

2- (H-Aib-His-D-2Nal-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane,

2- (H-Aib-D-2Nal-D-Phe-NH)-(4-pyridyl) ethane,

H-Aib-HisΨ (CH ₂ NH) -D-2Nal-Phe-Lys-OH,

(3-aminomethylbenzoyl) -D-2Nal-N-Me-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-Gly-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-Ala-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-Orn-NH ₂ ,

(5-aminomethylthienyl-2-carbonyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-D-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-Dab-NH ₂ ,

H-Aib-His-D-2Nal-D-PheΨ (CH ₂ NH) -Lys-NH ₂ ,

H-Aib-His-N-Me-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-N-Me-Lys-NH ₂ ,

(3-aminomethylthienyl-2-carbonyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-N-Me-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Phe-Lys-N (Me) ₂ ,

(3R) -piperidinecarbonyl-D-2Nal-D-Phe-Lys-NH ₂ ,

(3S) -piperidinecarbonyl-D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-1Nal-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Trp-Lys-NH ₂ ,

(Furfuryl) -Aib-His-D-2Nal-D-Phe-Lys-NH ₂ ,

(2-pyridylmethyl) -Aib-His-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib- (3-aminomethylbenzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib-3Pyal-D-2Nal-D-Phe-Lys-NH ₂ ,

(3S) -piperidinecarbonyl-D-2Nal-D-Phe-Lys-NH ₂ ,

(3R) -piperidinecarbonyl-D-2Nal-D-Phe-Lys-NH ₂ ,

(2- (H-Aib-His-D-2Nal-NH) ethyl) benzene,

N, N-di (2R-hydroxypropyl)-(3-aminomethylbenzoyl) -D-2Nal-D-Phe-Lys-NH ₂ ,

(2R-hydroxypropyl) -Aib-His-D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-D-PheΨ (CH ₂ NH) Lys-NH ₂ ,

(3-aminomethylbenzoyl) -N-Me-D-2Nal-D-Phe-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-D-Phe-N-Me-Lys-NH ₂ ,

HD-Thr-His-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-N- (phenethyl) -Gly-Lys-NH ₂ ,

(3-aminomethylbenzoyl) -D-2Nal-N- (phenethyl) -Gly-Lys-NH ₂ ,

H-Hyp-His-D-2Nal-D-Phe-Lys-NH ₂ ,

H-Aib-His-N-Me-D-2Nal-N- (phenethyl) -Gly-Lys-NH ₂ ,

H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH ₂ ,

H-Aib-His-D-2Nal-D-Phey (CH ₂ N (Me)) Lys-NH ₂ ,

3- (H-Aib-His-D-2Nal-N-Me-D-Phe-NH) morpholinopropane,

2- (H-Aib-His-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane,

(3R) -piperidinecarbonyl-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH ₂ ,

3- (aminomethylbenzoyl) -D-2Nal-N-Me-D-Phe-NH) morpholinopropane,

2- (H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane,

2- (3R) -piperidinecarbonyl-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane,

2- (3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) -ethane,

3- (H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH) morpholinopropane,

3-((3R) -piperidinecarbonyl-N-Me-D-2Nal-N-Me-D-Phe-NH) morpholinopropane,

3-((3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-NH) morpholinopropane,

H-Aib-His-D-2Nal-N-Me-D-Phe-Hyp-NH ₂ ,

2-((3-aminomethylbenzoyl) -D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane,

2-((3R) piperidinecarbonyl-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane,

H-Aib-His-D-2Nal-D-Phe-Lys-NH ₂ ,

3-amino-3-methyl-N- (4-oxo-5- (2 '-(tetrazol-5-yl) biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro-1H Naphtho [2,1-b] azin-3-yl) butyramide,

3-amino-3-methyl-N- (4-oxo-5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) -thien-3-yl) Benzyl) -2,3,4,5-tetrahydro-1H-naphtho- [2,1-b] azin-3-yl) butyramide,

3-((2R) -hydroxypropylamino) -3-methyl-N- (5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) thiene- 3-yl) benzyl) -4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azin-3-yl) butyramide,

1-Aminocyclopropanecarboxylic acid (4-oxo-5- (2 '-(1H-tetrazol-5-yl) -biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro- 1H-naphtho [2,1-b] azin-3-yl] amide,

3-amino-3-methyl-N- (5-benzyl-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azin-3-yl) butyr amides

(3R) piperidine-3-carboxylic acid ((1R, 2E) -4-hydroxymethyl-1- (2-naphthyl) methyl-5-phenylpent-2-enyl) amide,

3-aminomethyl-N-((1R, 2E) -4-hydroxymethyl-1- (2-naphthyl) methyl-5-phenylpent-2-enyl) -benzamide,

Piperidine-4-carboxylic acid (1-{[3-carbamoyl- [1,2,4] oxydiazol-5-yl) -2- (2-naphthyl) ethyl] -N-methyl Carbamoyl} -2- (2-naphthyl) ethyl) amide,

5-{(1R) -1-[(2R) -2- (piperidine-4-carbonylamino) -3- (2-naphthyl) propionyl-N-methylamino] -2- (2- Naphthyl) ethyl}-[1,2,4] oxadiazole-3-carboxylic acid ethyl ester,

5- {1- [2- (3-aminomethylbenzoyl) -3- (2-naphthyl) propionyl-N-methylamino] -2- (2-naphthyl) ethyl}-[1,2,4 ] Oxadiazole-3-carboxylic acid ethyl ester,

5-[(1R) -1-[(2R) -2- (3-aminomethylbenzoylamino) -3- (2-naphthyl) propionylamino] -2-phenyl-ethyl)-[1,2, 4] oxadiazole-3-carboxylic acid ethyl ester, its trifluoroacetate,

Piperidine 4-carboxylic acid [(1R) -1-{(1R) -1- (3-methyl- [1,2,4] oxadiazol-5-yl) -2-phenylethyl-carba Moyl} -2- (2-naphthyl) ethyl] amide,

3-aminomethyl-N-[(1R) -1- (1R) -1- (3-methyl- [1,2,4] oxadiazol-5-yl) -2-phenylethylcarbamoyl}- 2- (2-naphthyl) ethyl] benzamide,

4-Amino-4-methyl-pent-2-enoic acid [(1R) -1-{(1R) -1- (3-methyl- [1,2,4] oxadiazol-5-yl) -2 -Phenyl-ethylcarbamoyl} -2- (2-naphthyl) ethyl] amide,

(3R) -piperidine 3-carboxylic acid [(1R) -1-((1R) -1- (3-methyl- [1,2,4] oxadiazol-5-yl) -2-phenyl Ethyl-carbamoyl) -2- (2-naphthyl) ethyl] amide,

3-aminomethyl-N-((1R, 2E, 4S) -4-carbamoyl-5- (2-naphthyl) -1- (2-naphthyl) methylpent-2-enyl) benzamide,

Piperidine-4-carboxylic acid ((1R, 2E, 4S) -4-carbamoyl-5- (2-naphthyl) -1- (2-naphthyl) methylpent-2-ethyl) amide,

N-((1R) -1-(((1R) -1-(((1S) -5-amino-1-dimethylcarbamoyl) pentylcarbamoyl) -2-phenylethoxy) -methyl)- 2- (2-naphthyl) ethyl) -3-aminomethylbenzamide,

N-((1R, 4S) -4-(((1S) -5-amino-1- (dimethylcarbamoyl) pentyl) carbamoyl) -1-((2-naphthyl) methyl) -2- Oxo-5-phenylpentyl) -3-aminomethylbenzamide,

N-((1R, 2R, 4S) -4-(((1S) -5-amino-1- (dimethylcarbamoyl) pentyl) carbamoyl) -2-hydroxy-1- (2-naphthyl ) Methyl-5-phenylpentyl) -3-aminomethylbenzamide,

Piperidine-3-carboxylic acid (1R, 2R, 4S) -4-(((1S) -5-amino-1- (dimethylcarbamoyl) pentyl) -carbamoyl) -2-hydroxy- 1-((2-naphthyl) methyl) -5-phenylpentyl) amide,

5-((1R) -1- (N-methyl-N-((2R) -3- (2-naphthyl) -2- (piperidin-4-yl-carbonylamino) propionyl) amino) -2- (2-naphthyl) ethyl)-[1,2,4] oxadiazole-3-carboxylic acid ethyl ester,

5-((1R) -1- (N-((2R) -2- (3-aminomethylbenzoylamino) -3- (2-naphthyl) propionyl) -N-methylamino) -2- (2 -Naphthyl) ethyl)-[1,2,4] oxadiazole-3-carboxylic acid ethyl ester,

5-((1R) -1- (N-((2R) -2- (3-aminomethylbenzoylamino) -3- (2-naphthyl) propionyl) -N-methylamino) -2-phenylethyl )-[1,3,4] oxadiazole-2-carboxylic acid amide,

(2E) -5-Amino-5-methylhex-2-enoic acid {(1R) -1- [N-methyl-N-((1R) -1- (3-methyl- [1,2,4] -Oxadiazol-5-yl) -2- (2-naphthyl) -ethyl) carbamoyl] -2- (2-naphthyl) ethyl} amide,

4-Amino-4-methylpent-2-enoic acid N-[(1R) -1- {N-methyl-N-[(1R) -1- (3-methyl- [1,2,4] oxadia Sol-5-yl) -2- (2-naphthyl) ethyl] carbamoyl} -2- (2-naphthyl) ethyl] -N-methylamide,

4-Amino-4-methylpent-2-enoic acid [(1R) -1- {N-methyl-N-[(1R) -1- (3-methyl- [1,2,4] oxadiazole- 5-yl) -2- (2-naphthyl) ethyl] carbamoyl} -2- (2-naphthyl) ethyl] amide,

3-aminomenyl-N-((1R) -1- {N-[(1R) -1-(((dimethylcarbamoyl) methoxy) methyl) -2-phenylethyl] -N-methylcarbamoyl } -2- (2-naphthyl) ethyl) -N-methylbenzamide,

5-((1R) -1-(((2R) -2-(((4E) -4-amino-4-methylpent-2-enoyl) methylamino) -3- (2-naphthyl)- Propionyl) methylamino) -2-phenylethyl)-[1,3,4] -oxadiazole-2-carboxylic acid amide,

Piperidine-4-carboxylic acid N-methyl-N-{-1 [methyl-1- (3-methyl- [1,2,4] oxadiazol-5-yl) -2- (2-naph Ethyl) ethyl carbamoyl) -2- (2-naphthyl) ethyl} amide,

Piperidine-4-carboxylic acid N-{-1 [methyl-1- (3-methyl- [1,2,4] -oxadiazol-5-yl) -2 (2-naphthyl) ethylcart Barmoyl) 2- (2-naphthyl) ethyl} amide,

5- {1- [2- (Piperidine-4-carbonylamino) -3- (2-naphthyl) propionyl-N-methylamino] -2- (2-naphthyl) ethyl}-[1 , 2,4] oxadiazole-3-carboxylic acid 2-propyl ester,

5- {1- [2-piperidine-4-carbonylamino) -3- (2-naphthyl) propionyl-N-methylamino] -2- (2-naphthyl) ethyl}-[1, 2,4] oxadiazole-3-carboxylic acid, trifluoro acetate,

Piperidine-4-carboxylic acid (1-{[1-3-methylcarbamoyl- [1,2,4] oxadiazol) -5-yl) -2- (2-naphthyl) -ethyl ] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) amide,

(2E) -5-Amino-5-methylhex-2-enoic acid {1- [N- (1- (3-benzylcarbamoyl- [1,2,4] oxadiazol-5-yl)- 2-phenylethyl) -N-methyl-carbamoyl] -2- (2-naphthyl) ethyl} amide,

(2E) -5-Amino-5-methylhex-2-enoic acid N-{(1R) -1-[((1R) -1-benzyl-2,5-dihydroxypentyl) -N-methylcarbox Barmoyl] -2- (2-naphthyl) ethyl} -N-methylamide,

3-aminomethyl-N-((1R) -1- {N-[(1R) -1- (2-hydroxyethoxymethyl) -2-phenylethyl] -N-methyl-carbamoyl} -2 -(2-naphthyl) ethyl) -N-methylbenzamide,

Piperidine-4-carboxylic acid ((1R, 2E) 4-hydroxymethyl-5- (2-naphthyl) -1-((2-naphthyl) methyl) -pent-2-enyl) amide,

Piperidine-4-carboxylic acid ((1R) -2- (2-naphthyl) -1-((1R) -2- (2-naphthyl) -1- (1-phenethyl-1H-tetra Sol-5-yl) ethyl-carbamoyl) ethyl) amide,

Piperidine-4-carboxylic acid N-methyl-N-((1R9-2- (2-naphthyl) -1-((1R) 2- (2-naphthyl) -1-thio-carbamoyl Ethylcarbamoyl) ethyl) amide,

Piperidine-4-carboxylic acid ((1R) -1-((1R) -1- (4-carbamoyl-5-phenyl-1,3-thiazol-2-yl) -2- (2 -Naphthyl) ethylcarbamoyl) -2- (2-naphthyl) ethyl) amide,

(2E) -5-Amino-5-methylhex-2-enoic acid {1- [N- (1- (3-methylcarbamoyl- [1,2,4] oxadiazol-5-yl)- 2-phenylethyl) -N-methyl-carbamoyl] -2- (2-naphthyl) ethyl} amide,

(2E) -5-Amino-5-methylhex-2-enoic acid {1- [N- (1- (3-dimethylcarbamoyl- [1,2,4] oxadiazol-5-yl)- 2-phenylethyl) -N-methyl-carbamoyl] -2- (2-naphthyl) ethyl} amide,

(2E) -5-Amino-5-methyl-N-((1R) -1- (N-((1R) -1- (2-hydroxyethoxymethyl) -2-phenylethyl) -N-methyl Carbamoyl) -2- (2-naphthyl) ethyl) -N-methylhex-2-enoic acid amide,

(2E) -5-amino-5-methyl-N-((1R) -1- (N-((1R) -1- (2-hydroxy-2-methylpropoxymethyl) -2-phenylethyl) -N-methylcarbamoyl) -2- (2-naphthyl) ethyl) -N-methylhex-2-enoic acid,

1-benzyl-3- (3- (morpholin-4-yl) propyl) -1- (naphth-2-yl) methyl-thiourea, its hydrogen chloride,

1-benzyl-3- (3-dimethylaminopropyl) -1-phenyl-thiourea, or its hydrogen chloride,

2- [3- (3- (morpholin-4-yl) propyl) -1- (naphth-2-yl) methyl-thioureido] -3-phenyl-propionamide,

N- (4-aminobutyl) -2- [3-((3-amino-3-methyl) butyl) -1- (naphth-2-yl) methyl-thioureido] -3-phenyl-propion amides,

N- (4-aminobutyl) -2- (N- (naphth-2-yl) methyl-N '-(piperidin-3-yl) methyl-guanido) -3-phenyl-propionamide,

N- (4-aminobutyl) -2- [1-methyl-3- (naphth-2-yl) methyl-3- (2-piperidin-2-yl) ethyl) -thioureido-3 -(Naphth-2-yl) propionamide,

3- (3- (morpholin-4-yl) propyl) -1- (naphth-2-yl) methyl-1- [2 '-(1H-tetrazol-5-yl) -biphenyl-4- Ylmethyl] -thiourea, or its hydrochloride salt;

N-((1-carbamoyl-2-phenyl) ethyl-N-methyl-2- [3-((3-morpholin-4-yl) propyl) -thioureido] -3- (naphth -2-yl) propionamide,

3- (3- (dimethylamino) propyl) -1- (naphth-1-yl) methyl-1-phenylthiourea, or its hydrochloride salt;

1-benzyl-3- (3- (morpholin-4-yl) propyl) -1-phenylthiourea,

1,1-dibenzyl-3- (3- (morpholin-4-yl) propyl) thiourea, or hydrogen chloride thereof;

1-benzyl-3- (3- (dimethylamino) propyl) -1-((naphth-2-yl) methyl) thiourea, or its hydrochloride salt;

1-benzyl-3- (3- (morpholin-4-yl) propyl) -1- (phennet-2-yl) thiourea, or hydrogen chloride thereof;

1-benzyl-3- (3- (morpholin-4-yl) propyl) -1- (quinolin-3-yl) thiourea, or dihydrogen chloride thereof;

1-benzyl-3- (3- (morpholin-4-yl) propyl) -1- (pyridin-2-yl) thiourea, or hydrogen chloride thereof;

1-benzyl-3- (3-morpholin-4-yl) propyl) -1- (4-methoxyphenyl) thiourea, or hydrogen chloride thereof;

1-benzyl-3- (3- (morpholin-4-yl) propyl) -1- (4-([1,2,3] thiadiazol-4-yl) benzyl) thiourea, or hydrogen chloride thereof salt;

3- (3-dimethylaminopropyl) -1-((naphth-2-yl) methyl) -1-phenylthiourea, or hydrogen chloride thereof;

2-phenyl-3,4-dihydro-2H-quinoline-1-carbothioic acid (3- (dimethylamino) propyl) amide, or its hydrochloride salt;

Benzyl-3,4-dihydro-2H-quinoline-1-carbothioic acid (3- (dimethylamino) propyl) amide,

1- (3-((morpholin-4-yl) propyl) thiocarbamoyl) -1,2,3,4-tetrahydro-1H-quinoline-2-carboxylic acid N- (1-carbamoyl- 2- (naphth-1-yl) ethyl) -N-methylamide,

2- (3-((morpholin-4-yl) propyl) thiocarbamoyl) -1,2,3,4-tetrahydro-1H-isoquinoline-3-carboxylic acid phenyl N- [1- ( (4-aminobutyl) carbamoyl) -2- (naphth-1-yl) ethyl] -N-methylamide; or

2-phenyl-3,4-dihydro-2H-quinoline-1-carbothioic acid (3- (morpholin-4-yl) propyl) amide, or hydrogen chloride thereof;

(R) -2-((3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me) -3-phenylpropanol, or a TFA salt thereof;

3-((3-aminomethylbenzoyl) N-Me-D-2Nal-N-Me-D-Phe-NH) -1-1N, N-dimethylaminopropane, or a TFA salt thereof;

3-(((3R) -3-piperidinecarbonyl) -N-Me-D-2Nal-N-Me-D-Phe-NH) -1-N, N-dimethylaminopropane, or TFA thereof salt,

2-(((3R) -3-piperidinecarbonyl) -N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl) ethane, or Its TFA salt,

H-Aib-His-D-2Nal-N-Me-D-Phs-Ser-NH ₂ , or a TFA salt thereof;

(3-aminomethylbenzoyl) -D-2Nal-N-Me-D-Phe-Lys-NH ₂ , or a TFA salt thereof;

(4-piperidinecarbonyl) -D-2Nal-N-Me-D-Phe-NH ₂ , or a TFA salt thereof;

((3R) -3-piperidinecarbonyl) -D-2Nal-N-Me-D-Phe-NH ₂ , or a TFA salt thereof;

(3-aminomethylbenzoyl) -D-Phe-N-Me-D-Phe-NH ₂ , or a TFA salt thereof;

(3-aminomethylbenzoyl) -N-Me-D-Phe-N-Me-D-Phe-Lys-NH ₂ , or a TFA salt thereof;

((3R) -3-piperidinecarbonyl) -N-Me-D-Phe-N-Me-D-Phe-Lys-NH ₂ , or a TFA salt thereof;

H-Aib-His-N-Me-D-Phe-N-Me-D-Phe-Lys-NH ₂ , or a TFA salt thereof;

((3R) -3-piperidinecarbonyl) -N-Me-D-2Nal-N-Me-D-Phe-NH ₂ , or TFA salt;

(2R) -2-((3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me) -3- (2-naphthyl) propanol, or a TFA salt thereof;

(3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-NH ₂ , or a TFA salt thereof;

3-((3-aminomethylbenzoyl) -N-Me-D-Phe-NH) -1-N, N-dimethylaminopropane,

H-Aib-His-N-Me-D-ZNaI-N-Me-D-Phe-NH ₂ , or a TFA salt thereof,

(3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-Lys-NH ₂ ,

H-Aib-Ala-D-2Nal-N-Me-D-Phe-Lys-NH ₂ , or a TFA salt thereof;

H-Aib-His-D-2Nal-N-Me-D-Phe-NH ₂ , or a TFA salt thereof;

2-((3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-NH) -1-morpholinoethane,

(3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-NH-Me,

3-((3-methylaminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-NH) -1-N, N-dimethylaminopropane,

(3-aminomethylbenzoyl) -N-Me-D-2Nal-N-Me-D-Phe-N-Me ₂ ,

H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH ₂ ,

3-aminomethylbenzoyl-N-Me-D-2Nal-N-Me-D-Phe-NH-CH ₃ , or a TFA salt thereof;

3-methylaminomethylbenzoyl-N-Me-D-2Nal-N-Me-D-Phe-NH-CH ₃ , or a TFA salt thereof;

H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NHMe, or hydrochloride thereof; And

Piperidine-4-carboxylic acid-N-((1R) -1- (N- (1R) -2- (4-iodinephenyl) -1- (methylcarbamoyl) ethyl) -N-methylcar Barmoyl) -2- (2-naphthyl) ethyl) -N-methylamide,

(2E) 5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl)- 2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide, or its hydrochloride salt;

(2E) -5-Amino-5-methylhex-2-enoic acid N-(((1R) -1-(((1R) -1-((2S) -2-hydroxypropylcarbamoyl)- 2-phenylethyl) -methylcarbamoyl) -2- (2-naphthyl) ethyl) -N-methylamide, or

(2E) -5-Amino-5-methylhex-2-enoic acid ((1R) -1-(((1R) -2- (4-fluorophenyl) -1- (methylcarbamoyl) -ethyl ) Methylcarbamoyl) -2- (2-naphthyl) ethyl) methylamide.

Other examples of suitable growth hormone secretagogues include WO 94/13696, WO 94/19367, WO 95/14666, WO 94/11012, WO 96/15148, WO 95/34311, WO 95 /, the contents of which are incorporated herein by reference. 13069, WO 93/04081 and WO 97/07117.

For the purposes of the present invention, the expression "increase in bone volume" is used to refer to a condition in which the balance between absorption and composition of bone is shifted towards the composition at least to stop loss of bone volume. The proposed dosing regimen for treating postmenopausal people with expressive osteoporosis is, for example, spinal osteoporosis and compression fractures of at least one vertebrate or expressive mineral density in the lumbar spine of the femur for a period of two years. Kliogest (Novo Nordisk A / S, Bagsvaerd, Denmark; each tablet of Kliogest consists of 2 mg of estradiol and 1 mg of noethisteron acetate) and about 1 between the period of growth hormone administration From week to about 26 weeks, preferably from about 3 to about 26 weeks, more preferably from about 6 to about 12 weeks, more preferably from about 6 to about 10 weeks, especially about 8 weeks apart Setting of GH for a period from about 2 days to about 28 days, preferably from about 2 days to 14 days, more preferably from about 3 days to about 10 days, in particular from about 3 days to about 7 days. Amount of room 0.01-1 kg / day body weight of GH or GH secretion or growth inhibitory antagonists, norditropin biosynthetic human growth hormone (B-hGH, Novo Nordisk A / S, Bagsvaerd, Denmark) Daily injections of IU, preferably 0.1-0.2 IU per kg body weight per day, more preferably 0.2 IU per kg body weight per day sc Is treated. Injection is performed using a normal syringe or a pen device such as a Nordiject pen device (Novo Nordisk A / S, Bagsvaerd, Denmark). Estrogen is preferably a formulation consisting of a combination of estrogen and progesterone. It is desirable to supply only estrogen to women without a uterus.

According to another aspect of the invention, human growth hormone is used to formulate a therapeutic agent for osteoporosis by simultaneous administration with estrogen.

According to another aspect of the present invention, human growth hormone is used to prepare a medicament for preventing the development of osteoporosis, such as estrogen.

The invention is further illustrated in the following examples which are not intended to limit the scope of the invention in any aspect as claimed.

Example 1:

Approximately 62-year-old postmenopausal women with expressive osteoporosis were treated with Kliogest tablets for 1 year and subcutaneously for 7 days every 8th week with norditropin growth hormone. One Kliogest tablet was supplied daily without interruption. When Norditropin was administered over a 7 day period, the dose used was 0.2 IU / kg body weight per day. Osteoporosis has been demonstrated with radiation. Women did not develop any other bone disease other than osteoporosis. The women had normal glucose metabolism and were not familiar with diabetes dependent noninsulin. The woman did not abuse alcohol or drugs, had no vaginal bleeding of unknown etiology and never developed thromboembolism during the treatment of estrogen.

Bone mineral density of the lumbar spine and femur was assessed by quantitative radiographs before initiation and after 6 and 12 months of treatment. Bone mineral density in the lumbar spine increased by 3% and 15% after 6 and 12 months of treatment, respectively, compared to baseline. The bone mineral density of the lumbar spine increased from 0.611 to 0.631 and 0.703 at g / cm2 after 6 months and 12 months of treatment, in combination with estrogen and growth hormone.

The bone mineral density of the femur increased to 11.4% after 12 months of treatment compared to baseline. The bone mineral density of the femur increased from 0.688 to 0.744 at g / cm2.

Example 2:

In sub-menopausal postmenopausal osteoporosis (57 women (45-75 years) with BMD 5 2SD) a controlled study with a double-blind placebo randomized to four upper extremities and one spinal and / or coli fracture Was performed.

4 upper extremity design:

GH + Kliogest

GH + placebo

Placebo + Kliogest

Placebo + Placebo.

Kliogest was administered in a spherical form every day for 12 months in the form of a bulb. GH is 0.2 IU / mg per day at s.c. in the evening for 7 days every 2 months for a 12 month treatment period. Injection.

The outcome of the percent change after 12 months of treatment was that the BMD vertebral effect was greater in patients receiving Kliogest and GH mixed treatment with an average percent increase of 9.5% than patients treated with estrogen with an average percent increase of 6.8%.

No beneficial effect was observed in patients receiving a combination of GH and placebo or only placebo.

The effects of BMD buttock showed exactly the same dose-response relationship as a large increase in the spine of patients treated with the combination when compared to treatment with only estrogen or GH alone.

The following three examples illustrate preferred GH secretagogues.

Example 3:

(2E) 5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R) -1- (N-methyl-N-((1R) -1- (methyl-carbamoyl) 2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide hydrochloric acid:

3-hydroxy-1,1-dimethylpropylcarbamate tert-butyl ester:

Step A: At 0 ° C., 2-tert-butoxycarbonylamino-3-methyl butyrate (2.50 g, 11.5 mmol) and triethyl ether chloroformate (1.10 mL, 11.5 mmol) in tetrahydrofuran (10 mL) To the solution of ethylamine (1.92 mL, 13.8 mmol) was added dropwise. The solution was stirred at 0 ° C. for 40 minutes. The precipitate formed was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 ° C. To tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise a 2M solution of boron hydride. The solution was stirred at 0 ° C. for 2 hours and then warmed up to room temperature. It cooled to 0 ° C. over 4 hours. Methanol (5 mL) was added carefully. 1N hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2x 100 mL, 3X 50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and dried over excess magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate / heptane 1: 2 to yield 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamate tert-butyl ester.

¹ H-NMR (CDCl ₃ ): d 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94 (br, 1H); 3.75 (q, 2H); 4.98 (br, 1H).

3- (tert-butoxycarbonylamino) -3-methylbutanal:

Step B: DMSO (1.22 mL, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 mL, 12.9 mmol) in dichloromethane (15 mL) at −78 ° C. The mixture was stirred at -78 ° C for 15 minutes. A solution of 3-hydroxy-1,1-dimethylpropylcarbamate tert-butyl ester (1.75 g, 8.6 mmol) in dichloromethane (10 mL) was added dropwise over 15 minutes. The solution was stirred for another 15 minutes at -78 ° C. Triethylamine (6.0 mL, 43 mmol) was added. The solution was stirred at −78 ° C. for 5 minutes and warmed up to room temperature. The solution was diluted with dichloromethane (100 mL) and extracted with 1N hydrochloric acid (100 mL). The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and dried over excess magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate / heptane (1: 3) to yield 1.10 g of 3- (tert-butoxycarbonylamino) -3-methylbutanal.

MHz- ¹ H-NMR (CDCl ₃ ): d 1.39 (s, 6H); 1.45 (s, 9H); 2.85 (d, 2H); 4.73 (br. 1H); 9.80 (t, 1H).

Ethyl (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoate:

Step C: Triethylphosphono acetate (1.96 mL, 9.8 mmol) was dissolved in tetrahydrofuran (30 mL). Tert-butoxide potassium (1.10 g, 9.8 mmol) was added. The solution was stirred at room temperature for 40 minutes. To tetrahydrofuran (6 mL) was added a solution of 3- (tert-butoxycarbonylamino) -3-methylbutanal (1.10 g, 5.5 mmol). The solution was stirred at room temperature for 75 minutes. It was diluted with ethyl acetate (100 mL) and 1N hydrochloric acid (100 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (60 mL) and dried excess magnesium sulfate. The solvent was removed in vacuo. The crude product was silica (90 g) with ethyl acetate / heptane (1: 4) to yield 1.27 g of ethyl (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoic acid. Purified by column chromatography on the column.

¹ H-NMR (CDCl 3): d 1.30 (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- (tert-butoxycarbonylamino) -5-methylhex-2-enoic acid:

Step D: Ethyl (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoate (1.233 g, 4.54 mmol) was dissolved in dioxane (20 mL). Solid of lithium hydroxide (0.120 g, 5.00 mmol) was added. Water (10 mL) was added until the solution became clear. The solution was stirred at rt for 16 h. The solution was diluted with water (70 mL) and extracted with tert-butyl methyl ether (2x 100 mL). The aqueous phase was acidified with 1N sodium hydrogen sulfate solution (pH = 1) and extracted with tert-butylmethylether (3 x 70 mL).

The organic phase was mixed and dried over excess magnesium sulfate. The solvent was removed in vacuo to yield 1.05 g of (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoic acid. The crude product was used to further synthesize.

¹ H-NMR (DMSO d6): 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- (methylcarbamoyl) -2-phenylethyl) carbamate tert-butyl ester:

Step E: N-tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.22 g, 4.4 mmol), 1-hydroxybenzotriazole hydrate (0.59 g, 4.4 mmol) and 1-ethyl-3- ( 3-dimethyl-aminopropyl) carbodiimide hydrochloric acid (0.88 g, 4.6 mmol) was dissolved in N, N-dimethylformamide (25 mL) and stirred for 30 minutes. Methylamine (0.51 g of 40% solution in methanol, 6.6 mmol) was added and the mixture was stirred overnight. Methylene chloride (80 mL) and water (100 mL) were added and the phases were separated. The organic phase was washed with sodium hydroxide (20 mL, 1 N), sodium hydrogen sulfate (50 mL, 10%) and water (50 mL). The organic phase was dried (magnesium sulfate) and the solvent was vacuumed to yield 1.39 g of N-methyl-N-((R) 1- (methylcarbamoyl) -2-phenylethyl) carbamate tert-butyl ester Removed.

¹ H-NMR (CDCl ₃ ): d 1.25, 1.35 (2 s (br), 9H); 2.73-2.94 (m, 7 H); 3.30-3.50 (m, 1 H); 4.68, 4.90 (2 m, 1H); 5.90, 6.12 (2 s (br); 1H); 7.12-7.25 (m, 5H).

(R) -N-methyl-2-methylamino-3-phenylpropionamide:

Step F: N-methyl-N-((R) 1- (methylcarbamoyl) -2-phenylethyl) carbamate tert-butyl ester (1.39 g, 7.23 mmol) tripuluroacetate (5 mL) and chloride It was dissolved in a mixture of methylene (10 mL) and stirred for 45 minutes. The volatiles were removed in vacuo and the residue was stirred with a mixture of ethyl acetate (100 mL) and water (100 mL). Sodium bicarbonate (50 mL, saturated) was added and the phases were separated. The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to yield 330 mg of (R) -N-methyl-2-methylamino-3-phenylpropionamide.

¹ H-NMR (CDCl ₃ ): d 2.1 (s (br), 3H); 2.32 (s, 3H); 2.77 (dd, 1H); 2.81 (2 s, 3H); 3.21 (dd, 1H); 3.32 (dd, 1H); 7.12 (s (br), 1H); 7.72-7.34 (m, 5H).

N-methyl-N- (1R) -1- (N-methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) carbamate tert-butyl ester:

Step G: (R) -tert-butoxycarbonyl-N-methylamino-3- (2-naphthyl) propionic acid (548 mg, 1.66 mmol) was dissolved in methylene chloride (5 mL) (5 mL); 1-hydroxy-7-azabenzotriazole (227 mg, 1.66 mmol) was added together with N, N-dimethylformamide (2 mL). 1-ethyl-3- (3-dimethylaminopropyl) carboamide hydrochloric acid (351 mg, 1.83 mmol) was added and the solution stirred for 15 minutes. (R) -N-methyl-2-methylamino-3-phenylpropynamide (320 mg, 1.66 mmol) was dissolved in methylene chloride (4 mL) and diisopropylethylamine (0.28 mL, 1.66 mmol) was added. And the mixture was stirred overnight. Methylene chloride (50 mL) was added and the organic phase was washed with water (100 mL), sodium hydrogen sulfate (50 mL, 5%) and sodium hydrogen carbonate (50 mL, saturated). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue is N-methyl-N- (1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2 Chromatography with ethyl acetate / methylene chloride (1: 1) to yield 604 mg of -naphthyl) -ethyl) carbamate tert-butyl ester (silica, 2 x 45 cm).

¹ H-NMR (CDCl ₃ ): d 1.05, 1.31, 1.56 (3 s, 9H); 2.28-3.37 (multiple m, 13H); 5.04,5.17,5.29,5.48 (4 dd, 2H); 7.05 -7.79 (m, 12 H).

(2R) -N-methyl-2-methylamino-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) -3- (2-naphthyl) propionamide:

Step H: N-methyl-N- (1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2 -Naphthyl) ethyl) carbamate tert-butyl ester (600 mg, 1.19 mmol) was stirred for 10 minutes in trifluuroacetic acid / methylene chloride (1: 1,5 mL) and dissolved in methanol (2 mL) It was mixed with sodium bicarbonate (10 mL) and ethyl acetate (15 mL). The organic phase was separated and (2R) -N-methyl-2-methylamino-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) -3- (2-naphthyl) propionamide 420 Dry to produce mg (magnesium sulfate).

¹ H-NMR (CDCl ₃ ): (optional) d 1.69 (s, 3H); 2.54 (s, 3H); 2.76 (dd, 1H); 2.92 (dd, 1H), 3.12 (dd, 1H), 3.31 (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- (methylcarbamoyl) -2-) Phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) carbamoyl) but-3-enyl) carbamate tert-butyl ester:

Step I: (2E) -5- (tert-butyloxycarbonylamino) -5-methylhex-2-enoic acid (200 mg, 0.82 mmol), 1-hydroxy-7-azabenzotriazole (112 mg , 0.82 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloric acid (173 mg, 0.90 mmol) in a mixture of methylene chloride (10 mL) and N, N-dimethylformamide (1 mL) Dissolved in and stirred for 15 minutes. N-methyl-2-methylamino-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) -3- (2-naphthyl) propionamide (332 mg, 0.82 mol) is chlorinated Dissolved in methylene (5 mL) and diisopropylethylamine (0.14 mL) was added and the mixture was stirred under nitrogen overnight. The mixture was diluted with methylene chloride (50 mL) and washed with water (50 mL), sodium bicarbonate (30 mL, saturated), sodium bisulfate (30 mL, 5%). The phases were separated and the organic phase was dried over magnesium sulfate and evaporated in vacuo.

The residue is ((3E) -1,1-dimethyl-4- (N-methyl-N-((1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl)-) 2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) carbamoyl) but-3-enyl) -carbamate tert-butyl ester to produce 450 mg (silica, 2 x 40 cm).

¹ H-NMR (CDCl ₃ ): (optional) d 1.20, 1.22, 1.24, 1.30, 1.41, 1.55 (6 s, 15 H), 4.30, 4.40, (2 s (br), 1H); 5.08 , 5.18, 5.32, 5.60, 5.87 (5 dd, 2H); 6.05 (dd, 1H); 6.75 (m, 1H).

Step J: ((3E) -1,1-dimethyl-4- (methyl-((1R) -1- (methyl-((1R) -1- (methylcarbamoyl) -2-phenylethyl) -carr Barmoyl) -2- (2-naphthyl) ethyl) carbamoyl) but-3-enyl) carbamate tert-butyl ester (403 mg, 0.63 mmol) was added to trifluroacetate (4 mL) for 10 minutes. And a mixture of methylene chloride (4 mL). The volatiles were removed in vacuo and the crude product was chromatographed on silica (400 g) using a mixture of methylene chloride, ethanol and ammonia (25% in water) (80/18/2) as eluent. The isolated product was dissolved in 3M hydrochloric acid in ethyl acetate and evaporated, then redissolved in methylene chloride and evaporated twice to yield 140 mg of the title compound.

¹ H-NMR (CDCl ₃ ): d 1.05, 1.10, 1.15, 1.16 (4 s, 6H); 2.07 (s (br); 3H); 5.12, 5.32, 5.40, 5.60, 5.91 (5 dd, 2H ); 6.05, 6.14 (2 d, 1H); 6.80 (m, 1H)

HPLC: Rf = 29.02 min (Method A1)

ESMS: m / z = 529 (100%) (M + H)

Example 4:

(2E) -5-Amino-5-methylhex-2-enoic acid N-((1R) -1-(((1R) -1-((2S) -2-hydroxypropylcarbamoyl) -2 -Phenylethyl) -methylcarbamoyl) -2- (2-naphthyl) ethyl) -N-methylamide:

The compound was prepared analogously to Example 1. (s) -2-hydroxypropylamine was replaced with methylamine in step E.

¹ H-NMR (CDCl ₃ ) (selective peak, mixture of rotamers) d 3.90 (m, 1H); 5.55 (dd, 1H); 5.58 (d, 1H)

HPLC: Rt = 29.03 min (Method A1)

PDMS: m / z = 573.5 (100%) (M + H)

Example 5:

(2E) -5-Amino-5-methylhex-2-enoic acid ((1R) -1-(((1R) -2- (4-pullophenyl) -1- (methylcarbamoyl) ethyl) Methylcarbamoyl) -2- (2-naphthyl) ethyl) methylamide:

(R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (4-pullophenyl) propionic acid:

2-tert-butoxycarbonylamino-3- (4-pullophenyl) propionic acid (5.0 g; 17.7 mmol) was dissolved in dried tetrahydrofuran. Iodine methane (8.8 mL; 141 mmol) was added and the reaction mixture was cooled to 0 ° C. Sodium hydride (2.1 g; 53.0 mmol) was added slowly and the reaction mixture was stirred at rt for 12 h. Ethyl acetate (50 mL) was added and water (20 mL) was added dropwise to the reaction mixture. Ethyl acetate was removed in vacuo and the residue was diluted with diethyl ether (30 mL) and water (100 mL). The organic phase was extracted with a saturated aqueous solution of sodium bicarbonate (50 mL). Citric acid (5%) was added to the combined aqueous phase until pH 3 which was then extracted with ethyl acetate (2 × 50 mL) and the phases separated. The organic phase was washed with an aqueous solution of water (2 x 50 mL), sodium thiosulfate (5%; 2 x 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue dissolved in diethyl ether (10 mL). Dicyclohexylamine (10 mL) was added.

Methylene chloride (30 mL) was added and the mixture was heated until the precipitate dissolved. Diethyl ether (20 mL) and heptane (20 mL) were added and the reaction mixture was left for 12 hours without stirring. The reaction mixture was filtered to produce (R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (4-pullophenyl) propionic acid as dicyclohexyl ammonia salt.

¹ H-NMR (CDCl ₃ ) (mixture of rotamers) d: 1.21; 1.31 (2 s, 9H); 2.75; 2.84 (2 s, 3H); 2.86-3.02 (m, 1H); 3.28-3.42 (m, 1H); 4.65; 4.85 (2 dd, 1H); 6.85-7.00 (m, 2H); 7.10-7.25 (m, 2H).

((1R) -2- (4-Plulophenyl) -1- (methylcarbamoyl) ethyl) -methylcarbamate tert-butyl ester.

(R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (4-pulrophenyl) propionic acid (3.00 g; 10.1 mmol) was dissolved in methylene chloride (30 mL) and sulfuric acid Wash with an aqueous solution of sodium hydrogen (10%; 30 mL). The organic phase was dried (magnesium sulfate) and filtered. 1-hydroxybenzotriazole (1.40 g; 10.1 mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloric acid (2.0 g; 10.6 mmol) were added to the filtrate and the reaction mixture was at room temperature. Stir for 15 minutes.

Methylamine (40% in methanol; 9.17 mmol) and diisopropylethylamine (1.7 mL; 10.1 mmol) were added and the reaction mixture was stirred at rt for 12 h. The reaction mixture was washed with an aqueous solution of sodium bicarbonate (saturated; 50 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was eluent to yield 1.06 g of ((1R) -2- (4-fluorophenyl) -1- (methylcarbamoyl) ethyl) -methylcarbamate tert-butyl ester And chromatographed on silica (3 x 40 cm) with ethyl acetate / heptane (2: 1).

¹ H-NMR (CDCl ₃ ) d: 1.29; 1.37 (2 s, 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); 6.9-7.0 (m, 2H); 7.1-7.21 (m, 2H).

(2R) -3- (4-Plulophenyl) -N-methyl-2- (methylamino) propion-amide:

((1R) -2- (4-Plulophenyl) -1- (methylcarbamoyl) ethyl) -methylcarbamate tert-butyl ester (1.0 g; 3.22 mmol) dissolved in methylene chloride (5 mL) It became. Tripulo acetate (5 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. Methylene chloride (30 mL), an aqueous solution of sodium bicarbonate / sodium carbonate (pH9; 30 mL) and sodium bicarbonate (solid) were added to the reaction mixture until pH9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to yield 0.62 g of (2R) -3- (4-pullophenyl) -N-methyl-2-methylaminopropionamide.

¹ H-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); 7.71 (s, 1H); 7.14-7.20 (m, 2H).

((1R) -1-(((1R) -2- (4-Plulophenyl) -1- (methylcarbamoyl) ethyl) methylcarbamoyl) -2- (2-naphthyl) ethyl) methyl Carbamate Tert-Butyl Ester:

(2R) -2- (tert-butoxycarbonylmethylamino) -3- (2-naphthyl) propionic acid (1.0 g; 3.1 mmol) was dissolved in methylene chloride (20 mL). 1-hydroxy-7-azabenzotriazole (0.43 g; 3.1 mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloric acid (0.63 g; 3.3 mmol) were added and the reaction mixture was room temperature. Stir at 15 min.

(2R) -3- (4-pullophenyl) -N-methyl-2- (methylamino) propionamide (0.6 g; 2.9 mmol) and diisopropylethylamine (0.54 mL; 3.1 mmol) were added and the reaction The mixture was stirred at rt for 12 h. Methylene chloride (30 mL) was added and the reaction mixture was poured into water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), sodium bicarbonate / sodium carbonate (pH 9; 30 mL) and water (30 mL). Washed with aqueous solution and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was taken from ((1R) -1-(((1R0-2- (4-pullophenyl) -1- (methylcarbamoyl) ethyl) methylcarbamoyl) -2- ( Chromatography on silica (4.0 x 30 cm) was performed with ethyl acetate / heptane (2: 1) as eluent to yield 1.07 g of 2-naphthyl) ethyl) methylcarbamate tert-butyl ester.

¹ H-NMR (CDCl ₃ ) (selected peak for major rotamers) d: 1.34 (s, 9H); 2.23 (d, 3H); 2.76 (s, 3H); 2.87 (s, 3H); 5.70 (dd , 1H); 5.95 (dd, 1H).

(2R) -N-((1R) -2- (4-Plulophenyl) -1- (methylcarbamoyl) -ethyl) -N-methyl-2-methylamino-3- (2-naphthyl) Propionamide:

((1R) -1-(((1R) -2- (4-Plulophenyl) -1- (methylcarbamoyl) -ethyl) methylcarbamoyl) -2- (2-naphthyl) ethyl) Methylcarbamate tert-butyl ester (1.0 g; 1.92 mmol) was dissolved in methylene chloride (5 mL). Tripulo acetate (5 mL) was added and the reaction mixture was stirred at room temperature for 15 minutes. Methylene chloride (25 mL), an aqueous solution of sodium bicarbonate (pH 9; 25 mL) and sodium bicarbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) (2R) -N-((1R) -2- (4-pullophenyl) -1-methylcarbamoylethyl) -N-methyl-2-methylamino-3- ( Evaporation under vacuum to yield 0.75 g of 2-naphthyl) propionamide.

¹ H-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); 6.72 (t, 1H); 6.90 (t, 2H); 7.12 (dd, 2H); 7.32 ( d, 1H); 7.42-7.50 (m, 2H); 7.82 (s, 1H); 7.70-7.83 (m, 2H).

(4 (((1R) -1 (((1R) -2 (4-Plulophenyl) -1- (methylcarbamoyl) -ethyl) methylcarbamoyl) -2- (2-naphthyl) ethyl ) Methylcarbamoyl) -1,1-dimethylbut-3-enyl) carbamate tert-butyl ester:

(2E) -5- (tert-butyloxycarbonylamino) -5-methylhex-2-enoic acid (0.22 g; 0.89 mmol, as prepared in Example 1) was dissolved in methylene chloride (10 mL) It became. 1-hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloric acid (0.2 g; 1.02 mmol) were added and the reaction mixture was room temperature. Stir at 15 min.

(2R) -N-((1R) -2- (4-pullophenyl) -1- (methylcarbamoyl) ethyl) -N-methyl-2-methylamino-3- (2-naphthyl) propion Amide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred at rt for 12 h.

Methylene chloride (50 mL) was added and the reaction mixture was water (50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), sodium bicarbonate / sodium carbonate (pH 9; 50 mL) and water (50 mL) Washed and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was (4-(((1R) -1-(((1R) -2- (4-pullophenyl) -1-methylcarbamoylethyl) methylcarbamoyl)- Ethyl acetate / heptane (2: 2) as eluent to yield 0.34 g of 2- (2-naphthyl) -ethyl) methylcarbamoyl) -1,1-dimethylbut-3-enyl) carbamate tert-butyl ester Chromatography on silica (4 x 30 cm) with 1).

¹ H-NMR (CDCl ₃ ) (selected peak for major rotamers) 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).

(4-(((1R) -1-(((1R) -2- (4-pullophenyl) -1-methylcarbamoyl-ethyl) methylcarbamoyl) -2 (2-naphthyl) ethyl ) Methylcarbamoyl) -1,1-dimethylbut-3-enyl) carbamate tert-butyl ester.

¹ H-NMR (CDCl ₃ ) (selected peaks for major rotamers) 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).

(4-(((1R) -1-(((1R) -2- (4-Plulophenyl) -1-methylcarbamoyl-ethyl) methylcarbamoyl) -2- (2-naphthyl) Ethyl) methyl-carbamoyl) -1,1-dimethylbut-3-enyl) carbamate tert-butyl ester (0.33 g; 0.51 mmol) was dissolved in methylene chloride (3 mL). Tripulo acetate (3 mL) was added and the reaction mixture was stirred at room temperature for 5 minutes. Methylene chloride (25 mL), an aqueous solution of sodium bicarbonate / sodium carbonate (pH 9; 25 mL) and sodium bicarbonate (solid) were added to the reaction mixture until pH 9 was reached. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to yield 0.18 g of the title compound.

¹ H-NMR (CDCl ₃ ) (selected peak for major rotamers) 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); 6.22 (dd, 1H).

PDMS: m / z 547.4 (M + H) ⁺

HPLC: Rt = 32.05 min

Claims (23)

Growth hormone components, such as growth hormone, growth inhibitory antagonists or growth hormone secretagogues, sufficient to substantially prevent or reduce the extent of osteoporosis and / or substantially increase bone strength, to prevent or treat osteoporosis and related diseases. A method for preventing or treating osteoporosis and related diseases consisting of periodic administration to an animal in need thereof. The method of claim 1, wherein the growth hormone component is administered for a period from about 2 days to about 28 days at an interval from the end of the period from about 1 week to about 26 weeks until the beginning of the next period. The method of claim 2, wherein the growth hormone component is administered for a period of about 7 days at an interval from the beginning of one period to the beginning of the next period of about 6 weeks to about 12 weeks. A method according to claim 1, wherein the animal is a mammal, in particular a human. The method of claim 1, wherein the growth hormone component is human growth hormone. The method of claim 1, wherein the composition having anti-absorbing action on the bone is continuously administered to the animal in addition to the periodic administration of the growth hormone component. 7. A method according to claim 6, wherein the composition consists of estrogens, in particular estradiol. 7. The method of claim 6, wherein said composition consists of a compound having an estrogen effect. 7. The method of claim 6, wherein the composition consists of one or more compounds selected from the group consisting of centchromes, levormeloxyphenes, raloxifenes, droroxifene, tamoxifen or idoxifen. 7. The method of claim 6, wherein said composition consists of calcitonin. 7. The method of claim 6, wherein said composition consists of bisphosphonates. 12. The method according to any one of claims 7 to 11, wherein the composition consists of a combination of estrogen and progesterone. The method of any one of the preceding claims, wherein the dosage or release of growth hormone is in the range of about 0.01-1 IU per kg body weight per day, in particular about 0.2 IU per kg body weight per day. The method of claim 6, wherein the dosage of the composition having anti-absorbing action on the bone is in the range from 0.001 to 10 mg / kg body weight per day and the dose of growth hormone is about 0.01-1 IU / kg body weight per day, In particular in the range of about 0.2 IU per kg body weight per day. Use of growth hormone components for the preparation of a medicament for the prevention and treatment of osteoporosis and related diseases whose purpose is periodic administration. Use of a growth hormone component, characterized in that the formulation of a medicament for the prevention or treatment of osteoporosis and related diseases is packaged with instructions for its periodic administration. Growth hormone or growth hormone component together with a composition having an anti-absorbing effect on bone for the preparation of a medicament for the prevention or treatment of osteoporosis and related diseases for the periodic administration of the growth hormone component and the continuous administration of the anti-absorption composition The use of. Growing together with a composition having anti-absorbing action on bone, characterized in that it is for the purpose of formulating a medicament for the purpose of preventing or treating osteoporosis and related diseases packed with instructions for the periodic administration of growth hormone components with continuous administration of the anti-absorbing composition. Use of hormonal ingredients. Use of growth hormone, characterized in that the formulation of a medicament for the prevention or treatment of osteoporosis and related diseases is packaged with instructions for the periodic administration of the growth hormone component with continuous administration of the anti-absorption composition. Use of a composition having an anti-absorbing effect on bone for the preparation of a medicament for the prevention and treatment of osteoporosis and related diseases for the purpose of periodic administration of growth hormone components simultaneously with continuous administration over several hours. A product comprising a compound having an anti-absorbing effect on bone and a growth hormone component in a combination formulation for simultaneous, separate or continuous use in preventing or treating osteoporosis. 10. The method of claim 9, wherein the composition consists of levormeloxyphene or a structurally related compound thereof. 10. The method of claim 9, wherein the composition consists of levormeloxyphene.