JP4618548B2 - Bone loss disease treatment - Google Patents

Description

The present invention relates to a therapeutic agent for bone loss diseases containing an EP ₄ agonist as an active ingredient.
More specifically, treatment of bone loss diseases such as primary osteoporosis, secondary osteoporosis, cancer bone metastasis, hypercalcemia, Paget's disease, bone defect, osteonecrosis and the like containing EP ₄ agonist as an active ingredient and And / or preventive agent, as well as bone formation after fracture, bone formation after bone grafting, bone formation after artificial joint surgery, bone formation after spinal fusion, and other bone formation after bone reconstruction, etc. Relates to accelerators.

  Bone repeats the cycle in about 120 to 150 days, including bone resorption by osteoclasts, bone formation by osteoblasts and resting phase (referred to as remodeling). In healthy adults, bone resorption and bone formation are tightly controlled, and total bone mass changes little. However, in a bone mass reduction disease, the balance between the two is lost, resulting in a decrease in bone mass and deterioration of bone tissue. The decrease in bone mass is 20 to 30%, and it becomes easy to break the bone. This causes bedriddenness, body deformation, and death depending on the fracture site such as a hip fracture.

Osteoporosis is a representative bone loss disease. Osteoporosis is a systemic disease whose main symptoms are bone mass loss and bone tissue deterioration.
There are various possible causes of osteoporosis, but the most common cause is hormonal imbalance after aging, especially women's menopause, so the current treatment is mainly administered with estrogen, vitamin D and calcitonin. Yes. However, administration of hormones has a risk of causing cancer (particularly breast cancer, uterine cancer, etc.) and cannot be said to be a safe treatment method.

In addition, bisphosphonate is being administered as a second-generation therapeutic agent, but there is a problem that rebound occurs when the administration is interrupted.
In addition, although any method can delay the progression of osteoporosis, it is difficult to regenerate the bone once reduced.

On the other hand, prostaglandin E ₂ (abbreviated as PGE ₂ ) is known as a metabolite in the arachidonic acid cascade, and its actions are cytoprotective, uterine contraction, analgesic, gastrointestinal peristalsis. It is known to have various functions such as exercise promotion, arousal action, gastric acid secretion inhibitory action, blood pressure lowering action, diuretic action and the like.

PGE ₂ is said to be involved in bone resorption (J. Dent Res., 59 (10), 1635 (1980); Non-patent document 1, Nature, 266 , 6455 (1977); Non-patent document 2 ).
Also, patent applications have been filed in which PGE ₁ and PGE ₂ have been observed to be bone tissue growth and bone mass increase macroscopically or microscopically when administered orally or intravenously in dogs. The amount of PG is 1000 μg / kg / day, which is a considerable amount, and it is unclear whether it plays an essential role. In addition, considering the dose, it may be a practical drug.

In recent studies, it has been found that PGE ₂ receptors have subtypes with different roles. There are roughly four subtypes known at the present time, which are called EP ₁ , EP ₂ , EP ₃ , and EP ₄ (Negishi M. et al, J. Lipid Mediators Cell Signaling, 12 , 379-391 (1995); Non-Patent Document 3). By investigating these roles, it became possible to obtain drugs with fewer side effects by finding compounds that do not bind to other subtype receptors.

Recently, EP ₂ agonists are useful for osteoporosis (WO 98/279769; Patent Document 1), and EP ₄ antagonists are useful for high bone resorption (UK Patent No. 2330307); Patent applications with Patent Document 2) have also been seen.
Further, the compound represented by the general formula (IA) is described in European Patent Application Publication No. 855389 (Patent Document 3) as being useful as an EP ₄ receptor binding agent. This application, compounds of the formula (IA) is, there is a description that is useful for the treatment and prevention of bone dysplasia, which of the EP ₄ agonist or antagonist, to bone formation, what There is no description or suggestion of whether it will work.

Thus, although there is a suggestion that PGE ₂ or PGE ₁ is involved in bone metabolism and of which subtypes are actually involved, specifically, which subtype of antagonist or agonist is useful It was in a chaotic state, confused by various theories.

J. et al. Dent Res. 1980, 59 (10), 1635. Nature, 1977, 266, 6455. J. et al. LipidMediators CellSignaling, 1995, Vol. 12, pages 379-391. International Publication No. 98/279769 Pamphlet British Patent No. 2330307 European Patent Application No. 855389

  The present inventors synthesized various compounds that selectively bind to each PGE subtype in order to find a compound having an osteogenesis promoting action as a therapeutic agent for bone mass-lowering diseases. Investigation was repeated in order to find the compound which has.

As a result, conventionally, EP ₄ antagonists are useful in bone loss diseases because they inhibit bone resorption, and EP ₄ agonists are thought to be probably not useful because they increase bone resorption and decrease bone mass. However, surprisingly, the inventors have obtained knowledge that EP ₄ agonists increase bone mass and bone density at a low dose, and have completed the present invention.
In addition, it has been confirmed by experiments that the compounds represented by the following formulas (IA) to (IJ), which are typical EP ₄ agonists, have EP ₄ agonist activity.

The present invention relates to a therapeutic and / or prophylactic agent for bone loss diseases comprising an EP ₄ agonist as an active ingredient.
According to the present invention, it has been confirmed for the first time that an EP ₄ agonist has an effect of increasing bone mass, increasing bone density, and promoting bone formation.

The bone mass reduction disease referred to in the present invention refers to a disease in which a bone mass reduction accompanied by symptoms such as bone density reduction and bone tissue degradation occurs. Examples of bone loss diseases include:
1) Primary osteoporosis (eg, primary osteoporosis associated with aging, primary osteoporosis associated with menopause, primary osteoporosis associated with ovariectomy, etc.),
2) Secondary osteoporosis (eg, associated with glucocorticoid-induced osteoporosis, hyperthyroid osteoporosis, fixation-induced osteoporosis, heparin-induced osteoporosis, immunosuppression-induced osteoporosis, osteoporosis due to renal failure, inflammatory osteoporosis, Cushing syndrome Osteoporosis, rheumatic osteoporosis, etc.),
3) Bone diseases such as cancer bone metastasis, hypercalcemia, Paget's disease, bone defect (alveolar bone defect, mandible bone defect, childhood sudden bone defect, etc.), osteonecrosis and the like.

  In addition to treating the above diseases, the present invention provides bone formation after bone surgery (eg, bone formation after fracture, bone formation after bone transplantation, bone formation after artificial joint surgery, bone formation after spinal fusion surgery) , Other bone formation after bone reconstruction, etc.), and bone transplantation alternative therapy.

The EP ₄ agonist in the present invention specifically binds to a subtype EP ₄ receptor among PGE ₂ receptors, and binds to or hardly binds to other subtypes EP ₁ , EP ₂ , EP _{3 and the} like. And all compounds having agonistic action.
Therefore, not known EP ₄ agonist only at the moment are those containing also EP ₄ agonist newly discovered future, also, not only the compounds have PG skeleton, EP ₄ agonist which does not have a PG skeleton Can also achieve the object of the present invention.

Since these compounds bind selectively to EP _4, there is no pain caused by EP ₁ , uterine relaxation thought to be caused by EP ₂ , uterine contraction considered to be caused by EP ₃ , etc. It is a drug that has no effect.
The EP ₄ agonist has a strong bone formation promoting action, as will be apparent from experiments shown later, and is therefore useful for the above-mentioned bone loss diseases including osteoporosis.

（式中、Ｒ^1Aは、ヒドロキシ、Ｃ１〜４アルキルオキシ、またはＮＲ^6AＲ^7A基（基中、Ｒ^6AおよびＲ^7Aは、独立して水素原子またはＣ１〜４アルキル基を表わす。）を表わし、
Ｒ^2Aは、水素原子またはヒドロキシを表わし、
Ｒ^3Aは、
（i）Ｃ１〜８アルキル、Ｃ２〜８アルケニル、またはＣ２〜８アルキニル基、
（ii）フェニルまたはＣ３〜７シクロアルキル基、
（iii）フェニルまたはＣ３〜７シクロアルキル基で置換されているＣ１〜８アルキル、Ｃ２〜８アルケニル、またはＣ２〜８アルキニル基（ただし、Ｒ^2Aが水素原子である場合、（i）および（ii）のアルキル、アルケニル、アルキニル基は一つのヒドロキシで置換されていてもよい。）を表わし、
記号

は二重結合または単結合であることを表わす。ただし、平衡混合物である８−エピ体を含む。）で示される化合物、 Preferred embodiments of the compounds used in the present invention include, for example, the following general formula (IA)

(In the formula, R ^1A represents hydroxy, C1-4 alkyloxy, or NR ^6A R ^7A group (wherein R ^6A and R ^7A independently represent a hydrogen atom or a C1-4 alkyl group). ,
R ^2A represents a hydrogen atom or hydroxy,
R ^3A is
(I) a C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl group,
(Ii) phenyl or a C3-7 cycloalkyl group,
(Iii) phenyl or C3~7 cycloalkyl C1~8 alkyl substituted with a group, C2-8 alkenyl or C2-8 alkynyl group, (provided that when R ^2A is a hydrogen atom, (i) and (ii ) Represents an alkyl, alkenyl, alkynyl group which may be substituted with one hydroxy),
symbol

Represents a double bond or a single bond. However, the 8-epi body which is an equilibrium mixture is included. ), A compound represented by

（式中、Ｒ^1Bは、ヒドロキシ、Ｃ１〜６アルキルオキシ、またはＮＲ^6BＲ^7B基（基中、Ｒ^6BおよびＲ^7Bは独立して、水素原子またはＣ１〜６アルキルを表わす。）を表わし、
Ｒ^2Bは水素原子またはヒドロキシを表わし、
Ｒ^3Bは単結合またはＣ１〜６アルキレンを表わし、
Ｒ^4Bは、
（i）１〜３個のＣ１〜６アルキルオキシまたはハロゲン原子で置換されているＣ１〜８アルキル、Ｃ２〜８アルケニル、またはＣ２〜８アルキニル、
（ii）フェニルオキシまたはＣ３〜７シクロアルキルオキシ、
（iii）フリル、フリルオキシ、チエニル、チエニルオキシ、ナフチル、ナフチルオキシ、フタラニル、またはフタラニルオキシ、
（iv）１〜３個の以下の基で置換されているフェニル、フェニルオキシ、Ｃ３〜７シクロアルキル、またはＣ３〜７シクロアルキルオキシ：
Ｃ１〜６アルキル、
Ｃ２〜６アルケニル、
Ｃ２〜６アルキニル、
Ｃ１〜６アルキルオキシ、
Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキル、
Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキルオキシ、
Ｃ２〜６アルケニルオキシ−Ｃ１〜６アルキル、
１〜３個のヒドロキシで置換されているＣ１〜６アルキル、
１〜３個のハロゲン原子で置換されているＣ１〜６アルキル、
Ｃ１〜６アルキルチオ、
Ｃ１〜６アルキルチオ−Ｃ１〜６アルキル、
Ｃ１〜６アルキルチオ−Ｃ１〜６アルキルオキシ、
Ｃ２〜６アルケニルチオ−Ｃ１〜６アルキル、
Ｃ１〜６アルキルスルフォニル、
ハロゲン、
トリハロメチル、
シアノ、
ニトロ、
アミノ、
ヒドロキシ、
Ｃ３〜７シクロアルキル、
Ｃ３〜７シクロアルキルオキシ、
Ｃ３〜７シクロアルキル−Ｃ１〜６アルキル、
Ｃ３〜７シクロアルキルオキシ−Ｃ１〜６アルキル、
フェニル、
フェニルオキシ、
フェニル−Ｃ１〜６アルキル、
フェニル−Ｃ２〜６アルケニル、
フェニル−Ｃ２〜６アルキニル、
フェニルオキシ−Ｃ１〜６アルキル、
フェニルオキシ−Ｃ２〜６アルケニル、
フェニルオキシ−Ｃ２〜６アルキニル、
フリル、
フリルオキシ、
フリル−Ｃ１〜６アルキル、
フリルオキシ−Ｃ１〜６アルキル、
チエニル、
チエニルオキシ、
チエニル−Ｃ１〜６アルキル、または
チエニルオキシ−Ｃ１〜６アルキル
（上記のフェニル、フリル、チエニル、シクロアルキルは、１〜３個のＣ１〜６アルキル、Ｃ１〜６アルキルオキシ、Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキル、ニトロ、ハロゲン、トリハロメチル、アミノ、またはヒドロキシで置換されていてもよい。）；または
（v）１〜３個の以下の基で置換されているフリル、フリルオキシ、チエニル、チエニルオキシ、ナフチル、ナフチルオキシ、フタラニル、またはフタラニルオキシ：
Ｃ１〜６アルキル、
Ｃ２〜６アルケニル、
Ｃ２〜６アルキニル、
Ｃ１〜６アルキルオキシ、
Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキル、
Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキルオキシ、
Ｃ２〜６アルケニルオキシ−Ｃ１〜６アルキル、
１〜３個のヒドロキシで置換されているＣ１〜６アルキル、
１〜３個のハロゲン原子で置換されているＣ１〜６アルキル、
Ｃ１〜６アルキルチオ、
Ｃ１〜６アルキルチオ−Ｃ１〜６アルキル、
Ｃ１〜６アルキルチオ−Ｃ１〜６アルキルオキシ、
Ｃ２〜６アルケニルチオ−Ｃ１〜６アルキル、
Ｃ１〜６アルキルスルフォニル、
ハロゲン、
トリハロメチル、
シアノ、
ニトロ、
アミノ、
ヒドロキシ、
Ｃ３〜７シクロアルキル、
Ｃ３〜７シクロアルキルオキシ、
Ｃ３〜７シクロアルキル−Ｃ１〜６アルキル、
Ｃ３〜７シクロアルキルオキシ−Ｃ１〜６アルキル、
フェニル、
フェニルオキシ、
フェニル−Ｃ１〜６アルキル、
フェニル−Ｃ２〜６アルケニル、
フェニル−Ｃ２〜６アルキニル、
フェニルオキシ−Ｃ１〜６アルキル、
フェニルオキシ−Ｃ２〜６アルケニル、
フェニルオキシ−Ｃ２〜６アルキニル、
フリル、
フリルオキシ、
フリル−Ｃ１〜６アルキル、
フリルオキシ−Ｃ１〜６アルキル、
チエニル、
チエニルオキシ、
チエニル−Ｃ１〜６アルキル、または
チエニルオキシ−Ｃ１〜６アルキル
（上記のフェニル、フリル、チエニル、シクロアルキルは、１〜３個のＣ１〜６アルキル、Ｃ１〜６アルキルオキシ、Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキル、ニトロ、ハロゲン、トリハロメチル、アミノ、またはヒドロキシで置換されていてもよい。）を表わし、
Ｒ^5Bは水素原子またはＣ１〜６アルキルを表わし、
記号

は、二重結合または単結合を表わす。
ただし、Ｒ^2Bが水素原子であるとき、Ｒ^3Bが表わすＣ１〜６アルキレンは１個のヒドロキシで置換されていてもよく、平衡混合物である８−エピ体を含む。）で示される化合物、 Formula (IB)

(Wherein R ^1B represents hydroxy, C 1-6 alkyloxy, or NR ^6B R ^7B group (wherein R ^6B and R ^7B independently represent a hydrogen atom or C 1-6 alkyl);
R ^2B represents a hydrogen atom or hydroxy,
R ^3B represents a single bond or C 1-6 alkylene;
R ^4B is
(I) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl substituted with 1 to 3 C1-6 alkyloxy or halogen atoms,
(Ii) phenyloxy or C3-7 cycloalkyloxy,
(Iii) furyl, furyloxy, thienyl, thienyloxy, naphthyl, naphthyloxy, phthalanyl, or phthalanyloxy,
(Iv) phenyl, phenyloxy, C3-7 cycloalkyl, or C3-7 cycloalkyloxy substituted with 1 to 3 of the following groups:
C1-6 alkyl,
C2-6 alkenyl,
C2-6 alkynyl,
C1-6 alkyloxy,
C1-6 alkyloxy-C1-6 alkyl,
C1-6 alkyloxy-C1-6 alkyloxy,
C2-6 alkenyloxy-C1-6 alkyl,
C1-6 alkyl substituted with 1-3 hydroxy,
C1-6 alkyl substituted with 1 to 3 halogen atoms,
C1-6 alkylthio,
C1-6 alkylthio-C1-6 alkyl,
C1-6 alkylthio-C1-6 alkyloxy,
C2-6 alkenylthio-C1-6 alkyl,
C1-6 alkylsulfonyl,
halogen,
Trihalomethyl,
Cyano,
Nitro,
amino,
Hydroxy,
C3-7 cycloalkyl,
C3-7 cycloalkyloxy,
C3-7 cycloalkyl-C1-6 alkyl,
C3-7 cycloalkyloxy-C1-6 alkyl,
Phenyl,
Phenyloxy,
Phenyl-C1-6 alkyl,
Phenyl-C2-6 alkenyl,
Phenyl-C2-6 alkynyl,
Phenyloxy-C1-6 alkyl,
Phenyloxy-C2-6alkenyl,
Phenyloxy-C2-6 alkynyl,
Frills,
Furyloxy,
Furyl-C1-6 alkyl,
Furyloxy-C1-6 alkyl,
Thienyl,
Thienyloxy,
Thienyl-C1-6 alkyl, or thienyloxy-C1-6 alkyl (the above phenyl, furyl, thienyl, cycloalkyl are 1 to 3 C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxy- Optionally substituted with C1-6 alkyl, nitro, halogen, trihalomethyl, amino, or hydroxy.); Or (v) furyl, furyloxy, thienyl, substituted with 1 to 3 of the following groups: Thienyloxy, naphthyl, naphthyloxy, phthalanyl, or phthalanyloxy:
C1-6 alkyl,
C2-6 alkenyl,
C2-6 alkynyl,
C1-6 alkyloxy,
C1-6 alkyloxy-C1-6 alkyl,
C1-6 alkyloxy-C1-6 alkyloxy,
C2-6 alkenyloxy-C1-6 alkyl,
C1-6 alkyl substituted with 1-3 hydroxy,
C1-6 alkyl substituted with 1 to 3 halogen atoms,
C1-6 alkylthio,
C1-6 alkylthio-C1-6 alkyl,
C1-6 alkylthio-C1-6 alkyloxy,
C2-6 alkenylthio-C1-6 alkyl,
C1-6 alkylsulfonyl,
halogen,
Trihalomethyl,
Cyano,
Nitro,
amino,
Hydroxy,
C3-7 cycloalkyl,
C3-7 cycloalkyloxy,
C3-7 cycloalkyl-C1-6 alkyl,
C3-7 cycloalkyloxy-C1-6 alkyl,
Phenyl,
Phenyloxy,
Phenyl-C1-6 alkyl,
Phenyl-C2-6 alkenyl,
Phenyl-C2-6 alkynyl,
Phenyloxy-C1-6 alkyl,
Phenyloxy-C2-6alkenyl,
Phenyloxy-C2-6 alkynyl,
Frills,
Furyloxy,
Furyl-C1-6 alkyl,
Furyloxy-C1-6 alkyl,
Thienyl,
Thienyloxy,
Thienyl-C1-6 alkyl, or thienyloxy-C1-6 alkyl (the above phenyl, furyl, thienyl, cycloalkyl are 1 to 3 C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxy- C1-6 alkyl, nitro, halogen, trihalomethyl, amino, or hydroxy may be substituted)
R ^5B represents a hydrogen atom or C 1-6 alkyl;
symbol

Represents a double bond or a single bond.
However, when R ^<2B> is a hydrogen atom, C1-6 alkylene represented by R < ^3B > may be substituted with one hydroxy, and includes an 8-epi form that is an equilibrium mixture. ), A compound represented by

（式中、Ｒ^1Cは、ヒドロキシ、Ｃ１〜６アルキルオキシ、またはＮＲ^6CＲ^7C基（基中、Ｒ^6CおよびＲ^7Cは独立して、水素またはＣ１〜４アルキルを表わす。）を表わし、
Ｒ^2Cは、オキソ、ハロゲン、またはＯ−ＣＯＲ^8C基（基中、Ｒ^8Cは、Ｃ１〜４アルキル、フェニル、またはフェニル（Ｃ１〜４アルキル）を表わす。）を表わし、
Ｒ^3Cは、水素またはヒドロキシを表わし、
Ｒ^4CaおよびＲ^4Cbは、それぞれ独立して、水素またはＣ１〜４アルキルを表わし、
Ｒ^5Cは、以下の基で置換されているフェニル基を表わす：
（i）１〜３個の
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキル、
Ｃ２〜４アルケニルオキシ−Ｃ１〜４アルキル、
Ｃ２〜４アルキニルオキシ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキルオキシ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキル（Ｃ１〜４アルキルオキシ）−Ｃ１〜４アルキル、
フェニルオキシ−Ｃ１〜４アルキル、
フェニル−Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキル、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキル、
Ｃ２〜４アルケニルチオ−Ｃ１〜４アルキル、
Ｃ２〜４アルキニルチオ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキルチオ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキル（Ｃ１〜４アルキルチオ）−Ｃ１〜４アルキル、
フェニルチオ−Ｃ１〜４アルキル、または
フェニル−Ｃ１〜４アルキルチオ−Ｃ１〜４アルキル、
（ii）Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびＣ１〜４アルキル、
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびＣ１〜４アルキルオキシ、
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびヒドロキシ、
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびハロゲン、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびＣ１〜４アルキル、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびＣ１〜４アルキルオキシ、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびヒドロキシ、または
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびハロゲン、
（iii）ハロアルキルまたはヒドロキシ−Ｃ１〜４アルキル、または
（iv）Ｃ１〜４アルキルおよびヒドロキシ；
記号

は、単結合または二重結合を表わす。
ただし、Ｒ^2CがＯ−ＣＯＲ^8C基である場合、８−９位は二重結合を表わす。）で示される化合物、および General formula (IC)

(Wherein R ^1C represents hydroxy, ^C 1-6 alkyloxy, or NR ^6C R ^7C group (wherein R ^6C and R ^7C independently represent hydrogen or C 1-4 alkyl);
R ^2C represents an oxo, halogen, or O—COR ^8C group (wherein R ^8C represents C1-4 alkyl, phenyl, or phenyl (C1-4 alkyl));
R ^3C represents hydrogen or hydroxy,
R ^4Ca and R ^4Cb each independently represent hydrogen or C1-4 alkyl;
R ^5C represents a phenyl group substituted with the following groups:
(I) 1 to 3 C1-4 alkyloxy-C1-4 alkyl,
C2-4alkenyloxy-C1-4alkyl,
C2-4alkynyloxy-C1-4alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl (C1-4 alkyloxy) -C1-4 alkyl,
Phenyloxy-C1-4 alkyl,
Phenyl-C1-4alkyloxy-C1-4alkyl,
C1-4alkylthio-C1-4alkyl,
C2-4alkenylthio-C1-4alkyl,
C2-4alkynylthio-C1-4alkyl,
C3-7 cycloalkylthio-C1-4alkyl,
C3-7 cycloalkyl (C1-4 alkylthio) -C1-4 alkyl,
Phenylthio-C1-4 alkyl, or phenyl-C1-4 alkylthio-C1-4 alkyl,
(Ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4alkyloxy-C1-4alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or C1-4 alkylthio-C1-4 alkyl and halogen,
(Iii) haloalkyl or hydroxy-C1-4alkyl, or (iv) C1-4alkyl and hydroxy;
symbol

Represents a single bond or a double bond.
However, when R ^2C is an O—COR ^8C group, the 8-9 position represents a double bond. ), And

（式中、Ａ^Dは、Ｃ２〜８アルキレン、Ｃ２〜８アルケニレン、Ｃ１〜４アルキレン−フェニレン、またはＣ２〜４アルケニレン−フェニレンを表わし、
Ｒ^1Dは、ヒドロキシ、Ｃ１〜６アルキルオキシ、Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキルオキシ、ＨＯ−Ｃ１〜６アルキルオキシ、またはＮＲ^6DＲ^7D基（基中、Ｒ^6DおよびＲ^7Dは独立して、水素原子またはＣ１〜４アルキルを表わす。）を表わし、
Ｒ^2Dは、オキソ、ハロゲン、またはＲ^8D−ＣＯＯ−基（基中、Ｒ^8Dは、水素原子、Ｃ１〜４アルキル、フェニル、フェニル（Ｃ１〜４アルキル）、Ｃ１〜４アルキルオキシ、ＨＯＯＣ−Ｃ１〜４アルキル、Ｃ１〜４アルキルオキシ−カルボニル−Ｃ１〜４アルキル、ＨＯＯＣ−Ｃ２〜４アルケニル、またはＣ１〜４アルキルオキシ−カルボニル−Ｃ２〜４アルケニルを表わす。）を表わし、
Ｒ^3Dは、水素原子またはヒドロキシを表わし、
Ｒ^4Dは、Ｃ１〜４アルキレンを表わし、
Ｒ^5Dは、以下の基で置換されているフェニル基を表わす：
（i）１〜３個の
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキル、
Ｃ２〜４アルケニルオキシ−Ｃ１〜４アルキル、
Ｃ２〜４アルキニルオキシ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキルオキシ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキル（Ｃ１〜４アルキルオキシ）−Ｃ１〜４アルキル、
フェニルオキシ−Ｃ１〜４アルキル、
フェニル−Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキル、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキル、
Ｃ２〜４アルケニルチオ−Ｃ１〜４アルキル、
Ｃ２〜４アルキニルチオ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキルチオ−Ｃ１〜４アルキル、
Ｃ３〜７シクロアルキル（Ｃ１〜４アルキルチオ）−Ｃ１〜４アルキル、
フェニルチオ−Ｃ１〜４アルキルまたは
フェニル−Ｃ１〜４アルキルチオ−Ｃ１〜４アルキル、
（ii）Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびＣ１〜４アルキル、
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびＣ１〜４アルキルオキシ、
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびヒドロキシ、
Ｃ１〜４アルキルオキシ−Ｃ１〜４アルキルおよびハロゲン、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびＣ１〜４アルキル、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびＣ１〜４アルキルオキシ、
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびヒドロキシ、または
Ｃ１〜４アルキルチオ−Ｃ１〜４アルキルおよびハロゲン、
（iii）ハロ−Ｃ１〜４アルキルまたはヒドロキシ−Ｃ１〜４アルキル、または
（iv）Ｃ１〜４アルキルおよびヒドロキシ；
記号

は、単結合または二重結合を表わす。
ただし、Ｒ^2Dが式Ｒ^8D−ＣＯＯ−基である場合、Ｒ^1Dは、Ｃ１〜６アルキルオキシ、Ｃ１〜６アルキルオキシ−Ｃ１〜６アルキルオキシ、またはＨＯ−Ｃ１〜６アルキルオキシを表わし、８−９位は二重結合を表わす。）で示される化合物からなるＥＰ₄アゴニストから選ばれる化合物がある。 General formula (ID)

(In the formula, ^AD represents C2-8 alkylene, C2-8 alkenylene, C1-4 alkylene-phenylene, or C2-4 alkenylene-phenylene,
R ^1D is hydroxy, C 1-6 alkyloxy, C 1-6 alkyloxy-C 1-6 alkyloxy, HO—C 1-6 alkyloxy, or NR ^6D R ^7D group (in which R ^6D and R ^7D are independently Represents a hydrogen atom or C1-4 alkyl),
R ^2D is an oxo, halogen, or R ^8D —COO— group (wherein R ^8D is a hydrogen atom, C1-4 alkyl, phenyl, phenyl (C1-4 alkyl), C1-4 alkyloxy, HOOC-C1 Represents -4 alkyl, C1-4 alkyloxy-carbonyl-C1-4 alkyl, HOOC-C2-4 alkenyl, or C1-4 alkyloxy-carbonyl-C2-4 alkenyl).
R ^3D represents a hydrogen atom or hydroxy,
R ^4D represents C 1-4 alkylene,
R ^5D represents a phenyl group substituted with the following groups:
(I) 1 to 3 C1-4 alkyloxy-C1-4 alkyl,
C2-4alkenyloxy-C1-4alkyl,
C2-4alkynyloxy-C1-4alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl (C1-4 alkyloxy) -C1-4 alkyl,
Phenyloxy-C1-4 alkyl,
Phenyl-C1-4alkyloxy-C1-4alkyl,
C1-4alkylthio-C1-4alkyl,
C2-4alkenylthio-C1-4alkyl,
C2-4alkynylthio-C1-4alkyl,
C3-7 cycloalkylthio-C1-4alkyl,
C3-7 cycloalkyl (C1-4 alkylthio) -C1-4 alkyl,
Phenylthio-C1-4 alkyl or phenyl-C1-4 alkylthio-C1-4 alkyl,
(Ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4alkyloxy-C1-4alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or C1-4 alkylthio-C1-4 alkyl and halogen,
(Iii) halo-C1-4 alkyl or hydroxy-C1-4 alkyl, or (iv) C1-4 alkyl and hydroxy;
symbol

Represents a single bond or a double bond.
Provided that when R ^2D is a group of the formula R ^8D —COO—, R ^1D represents C 1-6 alkyloxy, C 1-6 alkyloxy-C 1-6 alkyloxy, or HO—C 1-6 alkyloxy; The -9 position represents a double bond. There is a compound selected from EP ₄ agonists consisting of compounds represented by

Examples of EP ₄ agonists that are more preferred embodiments of the compounds used in the present invention include the following compounds (note that the description in parentheses below each formula is an example of the specification of the patent publication describing the compound) Number.)

（WO00/03980号、実施例３）、
式（ＩＦ）

（EP985663号、実施例２）、
式（ＩＧ）

（PCT/JP99/04934号、実施例８−６）、
式（ＩＨ）

（PCT/JP99/04934号、実施例２）
および式（ＩＪ）

（PCT/JP99/04934号、実施例２−１１）
で示されるプロスタグランジン誘導体、そのアルキルエステル、その非毒性塩およびそれらのシクロデキストリン包接化合物である。 For example, the formula (IE)

(WO00 / 03980, Example 3),
Formula (IF)

(EP985663, Example 2),
Formula (IG)

(PCT / JP99 / 04934, Example 8-6),
Formula (IH)

(PCT / JP99 / 04934, Example 2)
And formula (IJ)

(PCT / JP99 / 04934, Example 2-11)
A prostaglandin derivative, an alkyl ester thereof, a non-toxic salt thereof, and a cyclodextrin inclusion compound thereof.

[ester]
The present compounds represented by the formulas (IA) to (IJ) can be converted to esters by a known method. By using the ester form, stability and absorbability are increased, so that it is more useful as a pharmaceutical product. Alkyl esters are preferred, C1-4 alkyl esters are more preferred, and methyl esters are most preferred.

[salt]
The present compounds represented by the formulas (IA) to (IJ) are converted into the corresponding salts by a known method. The salt is preferably non-toxic and water-soluble. Suitable salts include alkali metal (potassium, sodium, etc.) salts, alkaline earth metal (calcium, magnesium, etc.) salts, ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). , Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine and the like. In addition, the present compounds represented by the formulas (IA) to (IJ) can be converted into hydrates by a known method.

[Inclusion compound]
The present compounds represented by the formulas (IA) to (IJ) and esters thereof are described in GB1,351,238 or GB1,419,221 using α-, β-, γ-cyclodextrin, or a mixture thereof. By using the described method, it can be converted into a cyclodextrin inclusion compound. By converting to a cyclodextrin inclusion compound, stability is increased and water solubility is increased, which is advantageous when used as a drug.

[Production method of the present compound]
The compounds represented by the general formulas (IA) to (IJ) are described together with their production methods in the following applications.
Compound represented by general formula (IA): European Patent Application Publication No. 855389 Compound represented by General Formula (IB): European Patent Application Publication No. 985663 Compound represented by General Formula (IC): International Publication No. 00/03980 Compound represented by general formula (ID) No .: International patent application PCT / JP99 / 04934 Compound represented by formula (IE): Compound represented by International Publication No. 00/03980 formula (IF): European Patent Application Publication No. Compound represented by Formula (IG) of 985663: International Patent Application PCT / JP99 / 04934 Compound represented by Formula (IH): Compound represented by International Patent Application PCT / JP99 / 04934 Formula (IJ): International Patent Application PCT / JP99 / 04934

[toxicity]
The toxicity of the present compound represented by the formula (IE) is sufficiently low and confirmed to be sufficiently safe for use as a pharmaceutical product. For example, the maximum tolerated dose of the methyl ester of the present compound represented by formula (IE) was 30 mg / kg animal body weight or more by intravenous administration to rats.

  EXAMPLES Hereinafter, although a reference example and an Example demonstrate this invention in detail, this invention is not limited to these.

Example 1: Bone formation promoting action Three to six beagle / CSK dogs of 6 months of age were used per group.
(11α, 15α, 13E) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester ( Α-cyclodextrin inclusion compound of (methyl ester of the compound represented by formula (IE)) (active ingredient content in α-cyclodextrin inclusion compound, 25% w / w),
(11α, 15α, 13E) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-3,7-dithiaprost-13-enoic acid (formula (The compound represented by (IF)),
(9β, 11α, 15α, 5Z, 13E) -9-Chloro-11,15-dihydroxy-16- (3-ethoxymethylphenyl) -17,18,19,20-tetranorprost-5,13-dienoic acid (Compound represented by formula (IG)),
(11α, 15α, 13E) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranorprost-13-enoic acid (formula (IH)) Methyl ester of the compound represented), and
(11α, 15α, 5Z, 13E) -9-oxo-11,15-dihydroxy-16- (3-ethoxymethylphenyl) -17,18,19,20-tetranorprost-5,13-dienoic acid (formula (Compound represented by (IJ)),
Was dissolved in physiological saline and continuously administered for 24 hours a day for 4 weeks so that the effective doses were 2, 5, 10 and 25 μg / kg / day. Administration was performed from the femoral vein using an indwelling catheter, and the administration rate was 0.2 ml / kg / hour. An equal amount of physiological saline was administered to the control group. After completion of dosing, each group of animals was sacrificed and necropsied.

(1) Measurement of bone area After fixing the excised femur with 10% buffered formalin solution, it is cut from the pulley groove at the center of 25 mm and with a width of 10 mm perpendicular to the bone axis, and the surface close to the end of the bone at a constant distance. The images were taken with a camera, loaded into a computer, and the bone area was measured by image analysis. The results are shown in Table 1 below.

Discussion:
The present compound represented by the formula (IE) increased the bone area 2.8-fold over the untreated group at a dose of 10 μg / kg / day or more. In particular, at a dose of 25 μg / kg / day, a bone area increase of 7 times or more of the untreated group was observed.
The compounds of formula (IF), (IH) and (IJ) also increased bone area 2.8-5.3 fold over the untreated group at a dose of 5 μg / kg / day. In addition, the compound represented by the formula (IG) also showed a bone area increase 4.2 times that of the untreated group at a dose of 25 μg / kg / day.

(2) Measurement of bone density After taking a X-ray image of the 1 cm wide sample used in (1) from the side, the sample was taken into a computer and the radiation dose per unit area in an area of a certain width was measured to obtain the bone density. (Microfocus X-ray magnification imaging system μFX-1000 (Fuji Film)). The results are shown in Table 2.

Discussion:
The compound of formula (IE) showed a 1.5- and 1.7-fold improvement in bone density over the untreated group at doses of 10 and 25 μg / kg / day, respectively. From these results, it was confirmed that the present compound, which is an EP ₄ agonist, significantly increased the bone area and the bone density at 10 μg / kg / day or more, and has a bone formation promoting action.

Example 2 Measurement of EP ₄ Agonist Activity It was confirmed by the following experiment that the compounds represented by formulas (IA) to (IJ) bind to EP ₄ and exhibit agonist activity.
Using CHO cells expressing the EP ₄ receptor, the agonist activity of the present compounds represented by the formulas (IA) to (IJ) was measured (see FEBS Letters 364 , 339 (1995) and modified in part. Done). As a result, all the compounds were confirmed to increase cAMP and to be EP ₄ agonists.

Example 3: Bone formation promoting action Experimental method:
Eleven week old SD female rats (average 271 g) were used in groups of 8 rats. Under anesthesia with pentobarbital, the flank of the rat was incised, and the ovaries were removed and sutured. The sham group was only incised and sutured, and no ovariectomy was performed.
From the 6th day after the excision surgery, (11α, 15α, 13E) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost Α-cyclodextrin inclusion compound of 13-enoic acid / methyl ester (methyl ester of the compound represented by formula (IE)) (active ingredient content in α-cyclodextrin inclusion compound, 25% w / w) 30 μg / 5 ml / kg dissolved in physiological saline was subcutaneously administered to the back of the neck 3 times a day for 2 months every 8 hours. Saline was administered to the control group and the sham group. After completion of the study, each animal group was sacrificed and necropsied. The bone density in the sea surface bone region of the left femur was measured using a peripheral bone bone density measuring device (XCT-960A, Norland / Stratec). The results are shown in the table below.

Discussion:
As is apparent from Table 3, the present compound-administered group significantly increased bone density compared to the control group (non-administered group).

[Application to pharmaceutical products]
Since the EP ₄ agonist used in the present invention has an osteogenesis promoting action, it is useful for the treatment and / or prevention of bone loss diseases. Here, the bone mass reduction disease refers to a disease in which a decrease in bone mass accompanied by symptoms such as a decrease in bone density and deterioration of bone tissue occurs.
1) Primary osteoporosis (eg, primary osteoporosis associated with aging, primary osteoporosis associated with menopause, primary osteoporosis associated with ovariectomy, etc.),
2) Secondary osteoporosis (eg, associated with glucocorticoid-induced osteoporosis, hyperthyroid osteoporosis, fixation-induced osteoporosis, heparin-induced osteoporosis, immunosuppression-induced osteoporosis, osteoporosis due to renal failure, inflammatory osteoporosis, Cushing syndrome Osteoporosis, rheumatic osteoporosis, etc.),
3) Bone diseases such as cancer bone metastasis, hypercalcemia, Paget's disease, bone defect (alveolar bone defect, mandible bone defect, childhood sudden bone defect, etc.), osteonecrosis and the like.

  In addition to the treatment of the above-mentioned diseases, the present invention also provides bone formation after bone surgery (for example, bone formation after fracture, bone formation after bone transplantation, bone formation after artificial joint surgery, post-spine fixation) It includes bone formation, other bone formation after bone reconstruction, etc.), and bone transplantation alternative therapy.

In order to use the EP ₄ agonist, its ester, its non-toxic salt, and their cyclodextrin inclusion compound used in the present invention for the above purpose, it is usually administered topically, orally or parenterally. . Prodrugs have advantages such as loss of irritation, better absorption, and better stability.

  The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 μg to 100 mg per adult. Or a parenteral administration (preferably transdermal administration, subcutaneous administration, intravenous administration) once to several times a day in the range of 0.1 μg to 10 mg, preferably in the range of 0.2 mg to 5 mg. )

  Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, or administration may be necessary beyond the range.

  When administering this compound, solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations such as ointments, patches for application to the skin, suppositories Used as an agent.

Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.
Capsules include hard capsules and soft capsules.
In such solid compositions, one or more active substances are present in at least one inert diluent such as lactose, mannitol, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminate metasilicate.

  The composition is prepared according to conventional methods with additives other than inert diluents such as lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, solubilizing agents such as glutamic acid or aspartic acid. You may contain. Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylcellulose phthalate, etc., if necessary, or may be coated with two or more layers. . Also included are capsules of absorbable substances such as gelatin.

  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg purified water, ethanol). In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.

  Other compositions for oral administration include sprays containing one or more active substances and formulated by methods known per se. In addition to the inert diluent, this composition contains a stabilizer that provides isotonicity with a stabilizer such as sodium bisulfite, and an isotonic agent such as sodium chloride, sodium citrate or citric acid. May be. The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

  The injection for parenteral administration according to the present invention includes sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (registered trademark). Such a composition may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents (for example, glutamic acid and aspartic acid). These are sterilized by filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water for injection or sterile for injection before use.

Other compositions for parenteral administration include liquids for external use, ointments, coatings, patches, suppositories and the like that contain one or more active substances and are formulated in a conventional manner.
In addition to a base such as white petrolatum, the ointment may contain a pH adjuster, a surfactant, an antiseptic, an emulsifier, a dispersant, a stabilizer, a solubilizing agent, and the like.

Formulation Example 1: Lyophilized formulation The following components were mixed by a conventional method, then the solution was sterilized by a conventional method, filled into vials in 1 ml increments, lyophilized by a conventional method, and 0.2 mg of active ingredient in one vial. 100 containing injections were obtained.
(11α, 15α, 13E) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester・ Α-Cyclodextrin ・ ・ ・ 80mg
(Content 20 mg)
・ Man knit: 5g
・ Distilled water: 100ml

Formulation Example 2: Ointment The following components were mixed in a conventional manner and filled into a tube at a rate of 10 g to obtain 100 ointments containing 0.2 mg of active ingredient per gram.
(11α, 15α, 13E) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester・ Α-Cyclodextrin ・ ・ ・ 800mg
(Content 200mg)
・ White petrolatum ・ ・ ・ 1kg

Claims (9)

General formula (IC)

(Wherein R ^1C represents hydroxy or ^C 1-6 alkyloxy,
R ^2C represents oxo,
R ^3C represents hydrogen or hydroxy,
R ^4Ca and R ^4Cb each independently represent hydrogen or C1-4 alkyl;
R ^5C represents a phenyl group substituted with the following groups:
(I) 1-3 pieces
C1-4 alkyloxy-C1-4 alkyl,
C2-4alkenyloxy-C1-4alkyl,
C2-4alkynyloxy-C1-4alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl (C1-4 alkyloxy) -C1-4 alkyl,
Phenyloxy-C1-4 alkyl,
Phenyl-C1-4alkyloxy-C1-4alkyl,
C1-4alkylthio-C1-4alkyl,
C2-4alkenylthio-C1-4alkyl,
C2-4alkynylthio-C1-4alkyl,
C3-7 cycloalkylthio-C1-4alkyl,
C3-7 cycloalkyl (C1-4 alkylthio) -C1-4 alkyl,
Phenylthio-C1-4 alkyl, or
Phenyl-C1-4alkylthio-C1-4alkyl,
(Ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4alkyloxy-C1-4alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or
C1-4alkylthio-C1-4alkyl and halogen,
(Iii) haloalkyl or hydroxy-C1-4alkyl, or
(Iv) C1-4 alkyl and hydroxy;
symbol

Represents a single bond or a double bond. )
A therapeutic and / or prophylactic agent for bone loss diseases comprising as an active ingredient a compound selected from the group of compounds represented by formula (I) or a non-toxic salt thereof .   The therapeutic and / or prophylactic agent according to claim 1, wherein the bone loss disease is primary osteoporosis.   The therapeutic and / or prophylactic agent according to claim 2, wherein the primary osteoporosis is primary osteoporosis associated with aging, primary osteoporosis associated with menopause, or primary osteoporosis associated with ovariectomy.   The therapeutic and / or prophylactic agent according to claim 1, wherein the bone loss disease is secondary osteoporosis.   Secondary osteoporosis is glucocorticoid-induced osteoporosis, hyperthyroid osteoporosis, fixation-induced osteoporosis, heparin-induced osteoporosis, immunosuppression-induced osteoporosis, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis associated with Cushing syndrome, or The therapeutic and / or prophylactic agent according to claim 4, which is rheumatic osteoporosis.   The therapeutic and / or prophylactic agent according to claim 1, wherein the bone loss disease is cancer bone metastasis, hypercalcemia, Paget's disease, bone defect, or osteonecrosis.   The therapeutic and / or prophylactic agent according to claim 1 or 6, wherein the bone loss disease is an alveolar bone defect, a mandible bone defect, or a childhood sudden bone defect.   Treatment of bone loss disease is bone formation after fracture, bone formation after bone transplantation, bone formation after artificial joint surgery, bone formation after spinal fusion, bone formation after bone reconstruction, and bone graft replacement therapy The therapeutic agent according to claim 1. The compound represented by the general formula (IC) is
(11α, 15α, 13E) -9- oxo -11,15- dihydroxy-16- (3-methoxymethyl-phenyl) tetranor-5-Chiapurosuto 13-enoic acid, its non-toxic salt or treatment and / or prophylactic agent according to claim 1 which is a methyl ester.