WO2000078351A1

WO2000078351A1 - Osteogenesis promoters

Info

Publication number: WO2000078351A1
Application number: PCT/JP2000/003969
Authority: WO
Inventors: Kazuyuki Itoh; Kiyoko Yoshioka; Hideki Yoshikawa
Original assignee: Mitsubishi Pharma Corporation
Priority date: 1999-06-18
Filing date: 2000-06-16
Publication date: 2000-12-28
Also published as: AU5250400A

Abstract

Osteogenesis promoters which contain compounds having a Rho kinase inhibitory activity. Compounds having a Rho kinase inhibitory activity such as (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane enhance the production of bone morphogenetic protein (BMP) in mesenchymal cells. When undifferentiated mesenchymal cells are treated by these compounds, moreover, the productivity of osteopontin, which is an osteoblast differentiation marker, the alkaline phosphatase (ALP) activity and the productivity of osteocalcin are remarkably elevated. Thus, these compounds exert an effect of inducing the differentiation into osteoblasts to thereby promote osteogenesis, which makes them useful as osteogenesis promoters and/or preventives/remedies for bone diseases.

Description

Specification

Bone formation promoter

Technical field

The present invention relates to an osteogenesis promoter. More specifically, the present invention relates to an osteogenesis promoter comprising a compound having Rho kinase inhibitory activity.

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Landscape technology

In bone tissue, bone resorption and bone formation are constantly repeated in a balanced manner. Osteoblasts play a central role in bone formation, and osteoclasts play a central role in bone resorption. This balance of bone remodeling works by linking osteoclast and osteoblast cell lines. In other words, it is thought that systemic and local regulators form a complex network at each stage of bone reconstruction, act on osteoblasts and osteoclasts, and maintain bone turnover. I have.

If the balance between bone resorption and bone formation breaks down, it is thought that bone loss will occur, and osteoporosis and other bone diseases will occur.

Currently, calcium preparations, active vitamin D3 preparations, estrogen preparations, calcitonin preparations, bisphosphonates, etc. are used as prophylactic and therapeutic agents for bone diseases.Bone resorption inhibitors such as estrogen preparations, calcitonin preparations, bisphosphonate preparations are particularly used. Mainly used.

However, these bone resorption inhibitors are sometimes administered only to limited subjects or their effects may not be reliable. At present, sufficient therapeutic effects have not been obtained.

On the other hand, fluorine is a clinically usable substance that promotes bone formation. However, the safety margin of administration is narrow, and there is a problem with long-term administration. In addition, growth factors such as parathyroid hormone (PTH), osteoinductive factor (BMP), insulin-like growth factor (IGF), and fibroblast growth factor (FGF) are known as substances promoting bone formation. However, it has not yet been put to practical use.

Therefore, the emergence of low-molecular weight compounds having a bone formation promoting effect capable of directly recovering once reduced bone mass is strongly desired as an agent for treating and preventing bone diseases. As a mechanism of bone formation, undifferentiated mesenchymal cells first migrate locally. Next, the activities of the sustained release of transforming growth factor /? (TGF-3), osteoinductive factor (BMP), inulin-like growth factor (IGF), and fibroblast growth factor (FGF) released from platelets and bone Cytokines induce the differentiation of these undifferentiated mesenchymal cells into chondrocytes and osteoblasts. The differentiated osteoblast group consists of collagen, mainly type I, alkaline phosphatase (alkaline phosphatase), osteopectin (.osteonectin), osteopontin, osteopontin, bone sialoprotein, and osteocalcin. It produces extracellular matrix such as osteocalcine), induces further differentiation, and forms bone tissue (Grainger, D 丄, et al., Nature Med.1.ρ932-937 (1995)). Therefore, for bone formation, it is important to induce the differentiation of undifferentiated mesenchymal cells into osteoblasts that play a central role in bone formation.

However, these undifferentiated mesenchymal cells are derived not only from osteoblasts, but also from other bone marrow stromal cells including chondrocytes, muscle, and fat cells, which make up the skeletal system. This suggests that it is necessary to consider induction of differentiation of the mesenchymal cells into osteoblasts together with regulation of differentiation into other cell lines.

On the other hand, Rh is activated by receiving signals from various cell membrane receptors, and activated Rho activates smooth muscle contraction, cell motility, cell adhesion, cell morphology change, and cell proliferation via the actomyosin system. It has been shown to function as a molecular switch for various cellular phenomena such as It is now being clarified that Rho kinase present downstream of the Rho-mediated signal transduction pathway plays an important role in the response of Rho to the above-mentioned cellular phenomena.

In addition, undifferentiated mesenchymal cells migrate locally, and then are induced to differentiate into myotube cells, leading to formation of muscle and blood vessels. Induction of differentiation of these undifferentiated mesenchymal cells into myotube cells Has been shown to be involved in Rho (Mol. Cell Biol., 18,

1580-1589 (1998), J. Biol. Chem., 46, 30287-30294 (1998)). However, the relationship with osteogenesis is not yet clear.

On the other hand, as a compound having Rho kinase inhibitory activity, a compound represented by the following general formula (I) Has been reported (WO 98/06433). In addition, it has been reported that certain isoquinoline sulfonamide derivatives and isoquinoline derivatives also have Rho kinase inhibitory activity (WO 98/06433 and Naunyn-Schmiedeberg's Archives of Pharmacology 385 (1 ) Suppl., R219, 199 8) o

These compounds with Rho kinase inhibitory activity are widely used as antihypertensives, angina pectoris, cerebral vasospasm inhibitors, asthma, peripheral circulatory disorders, premature birth prevention, arteriosclerosis, It is useful as a cancer drug, anti-inflammatory drug, immunosuppressant drug, autoimmune disease drug, anti-AIDS drug, osteoporosis drug, retinopathy drug, brain function improving drug, contraceptive drug, gastrointestinal infection preventive drug, W098 / 06433.

In addition, compounds represented by the general formula (I) are powerful and persistent drugs for treating hypertension, angina pectoris, renal and peripheral circulatory disorders, cerebral vasospasm, etc. It is already known to be useful as a prophylactic / therapeutic agent for cardiovascular diseases such as renal and peripheral arteries, and as a therapeutic drug for asthma (Japanese Patent Application Laid-Open Nos. 62-89679 and 3-218356). JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and W095 / 28387).

In addition, the isoquinoline sulfonamide derivatives described in the above-mentioned W098 / 06433 are vasodilators, therapeutic agents for hypertension, cerebral function improving agents, anti-asthmatic agents, cardioprotective agents, platelet aggregation inhibitors, psychiatric treatments Agent, anti-inflammatory agent, agent for treating or preventing hyperviscosity syndrome, agent for treating glaucoma, agent for reducing intraocular pressure, agent for improving motor paralysis in cerebral thrombosis, agent for preventing and treating viral infections, and inhibitor of transcriptional regulator (Japanese Patent Publication No. 57-200366, Japanese Patent Application Laid-Open No. 61-227581, Japanese Patent Application Laid-Open No. 2-56617, Japanese Patent Application Laid-Open No. 4-264030, Japanese Patent Application Laid-Open No. 6-56668, 6-80 569, JP-A-6-293364, JP-A-7-41424, JP-A-7-277979, W097 / 23222, JP-A-9-227381, JP-A-10-45598 and JP-A-10-8749-1).

Furthermore, the above literature (Naunyn-Schmiedeberg's Archives of Pharmacology 385 (1) / 7 1

The isoquinoline derivative described in Suppl., R219, 1998) is known to be useful as an agent for preventing or treating brain tissue damage due to vasospasm (W097 / 28130).

However, in these prior art documents, there is no description that a compound having a Rh kinase inhibitory activity has an osteogenesis promoting effect, and no description suggesting that.

As described above, WO 98/06433 describes that a compound having a Rh kinase inhibition activity is useful as a therapeutic agent for osteoporosis. This is based on the finding that integrin activation and cell adhesion induction, which are considered to be involved in absorption, are suppressed. Therefore, there is no description in the publication that suggests that a compound having a Rh kinase inhibitory activity has a bone formation promoting effect.

Disclosure of the invention

An object of the present invention is to solve the above-mentioned problems relating to osteogenesis, especially osteogenesis in bone diseases, and an object of the present invention is to provide a useful osteogenesis promoting agent and / or a bone having an osteogenesis promoting action. To prevent and treat diseases.

The present inventors have conducted intensive studies in order to solve the above problems, and as a result, it has been found that a compound having a Rho kinase inhibitory activity enhances the production of osteoinductive factor (BMP) from mesenchymal cells, When applied to differentiated mesenchymal cells, it significantly increases the amount of osteovontin, alkaline phosphatase (ALP) activity and osteocalcin, which are osteoblast differentiation markers, that is, has an excellent bone formation promoting effect. Thus, the present invention was found to be useful as an osteogenesis promoting agent and as a prophylactic / therapeutic agent for a bone disease having an osteogenesis promoting action, thereby completing the present invention.

That is, the present invention is as follows.

(1) An osteogenesis promoter comprising a compound having Rho kinase inhibitory activity. (2) The compound having Rho kinase inhibitory activity is represented by the following general formula (I)

〇 Rb

Ra—— C II—— NI—— Rc ₍₁₎ ' (Where Ra is the formula

[In the formulas (a) and (b), R represents hydrogen, alkyl, or a substituent which may have a substituent on the ring. R represents cycloalkyl, cycloalkylalkyl, phenyl or aralkyl;

Wherein R ⁶ is hydrogen, alkyl or a formula: — NR ⁸ R ⁹ (where R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, aralkyl or phenyl.), And R ⁷ is hydrogen. , Alkyl, aralkyl, phenyl, nitro or cyano, or R ⁶ and R ⁷ are bonded to each other to further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. Represents a group forming a heterocyclic ring which may be optionally substituted.

R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.

Or R and R ¹ are bonded together with an adjacent nitrogen atom to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent. The group to be formed is shown.

R ² represents hydrogen or alkyl.

R ³ and R ⁴ are the same or different and are hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyl oxy, cyano, acyl, mercapto, alkylthio, aralkylthio, alkoxycarbonyl, alkoxycarbonyl Indicate rubbamoyl, mono-dialkyl rubamoyl or azide.

A is the formula

(Wherein, R ^{1 Q} and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^1Q and R ¹¹ are bonded to form a cyclo 1, m and n each represent 0 or an integer of 1 to 3).

In the formula (c), L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, rubamoylalkyl, phthalimidalkyl, amidino, or

O

B- -C (f) (g)

(i)

(In the formula, B represents hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, monoaminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl .

Q ¹ represents hydrogen, halogen, hydroxyl, aralkyloxy or cetylmethyl.

W represents alkylene.

Q ² represents hydrogen, halogen, a hydroxyl group or aralkyloxy.

X represents alkylene.

Q ³ represents hydrogen, halogen, hydroxyl, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-1,2,3,4,5-tetrahydropyridazine-6-yl.

Y represents a single bond, alkylene or alkenylene. ).

Further, in the formula (c), a broken line indicates a single bond or a double bond.

R ⁵ represents hydrogen, hydroxyl, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy. ]

R b represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

R c represents a nitrogen-containing heterocyclic ring which may have a substituent. ] The osteogenesis promoter according to the above (1), which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.

(3) The compound having Rho kinase inhibitory activity is represented by the following general formula (1,):

O Rb

Ra'— C—— N—— Rc P)

Where R a 'is

[In the formula, R, represents hydrogen, alkyl or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.

Or a group in which R ′ and R ¹ are bonded to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom in the ring. Is shown.

R ² represents hydrogen or alkyl.

R ³ and R ⁴ are the same or different and each represents hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyle, mercapto, alkylthio, aralkylthio, ethoxycarbonyl, alkoxycarbonyl, Indicates rubamoyl, mono-dialkyl levamoyl or azide.

A is the formula (e)

(In the formula, R ^{1 D} and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^1Q and R ¹¹ are 1, m and n each represent 0 or an integer of 1 to 3).

Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

R c represents a nitrogen-containing heterocyclic ring which may have a substituent. ]

Or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof according to the above (1) or (2).

(4) The compound having Rho kinase inhibitory activity is (+)-trans-41- (1-aminoethyl) -1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H- Pyro mouth [2,3-b] Pyridine-14-yl) 1-41 (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) 14-1 (1-aminoethyl) benzamide and (R)-(+)-N- (1H-pyro-port [2,3-b] pyridine-14-yl) -14- (1-aminoethyl) benzamide The bone formation promoting agent according to the above (1), which is a compound selected from the group consisting of and / or a pharmaceutically acceptable acid addition salt thereof.

(5): The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -1- (4-viridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid thereof. The bone formation promoter according to the above (1), which is an addition salt.

(6) The bone formation promoting agent according to any one of the above (1) to (5), which is used for preventing or treating a bone disease.

(7) The bone formation promoting agent according to the above (6), wherein the bone disease is a fracture.

(8) Including a compound having Rho kinase inhibitory activity and a pharmaceutically acceptable carrier A pharmaceutical composition for the prevention and treatment of bone diseases.

(9) The compound having a Rh kinase inhibition activity is an amide compound represented by the general formula (I), particularly, the general formula (1 ′), an isomer thereof, and / or a pharmaceutically acceptable acid addition salt thereof. The pharmaceutical composition for preventing or treating a bone disease according to the above (8), wherein

(10) The compound having Rho kinase inhibitory activity is (+)-trans-41- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1 H-Pyro mouth [2,3-b] Pyridine-1-yl) 4- (1-Aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) -1- 4- (1-Aminoethyl) benzamide and (R)-(+)-N- (1H-pyrro [2,3-b] pyridin-4-yl) 1-4- (1-aminoethyl) benzamide The pharmaceutical composition for preventing and / or treating bone diseases according to the above (8), which is a compound selected from the group consisting of: and / or a pharmaceutically acceptable acid addition salt thereof.

(11) The compound having Rho kinase inhibitory activity is (+)-trans-4_ (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid addition salt thereof. A certain pharmaceutical composition for preventing or treating a bone disease according to the above (8).

(12) The pharmaceutical composition for preventing or treating a bone disease according to any one of the above (8) to (11), wherein the bone disease is a fracture.

(13) A method for preventing and treating a bone disease, which comprises administering to a patient an effective amount of a compound having Rho kinase inhibitory activity.

(14) The compound having a Rh kinase inhibition activity is an amide compound represented by the general formula (I), particularly, the general formula (Γ), an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof. A method for preventing and treating a bone disease according to the above (13).

(15) The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H- Pyro mouth [2,3-b] Pyridine-14-yl) 1-41- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4- Pyridyl) —4- (1-aminoethyl) benzamide and (R)-(+) — N- (1H-pyro mouth [2,3-b] pyridine-14-yl) 14- (1— (13) The method for preventing or treating bone disease according to the above (13), which is a compound selected from the group consisting of aminoethyl) benzamide and / or a pharmaceutically acceptable acid addition salt thereof.

(16) The compound having a Rh kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid thereof. The method for preventing and treating bone diseases according to the above (13), which is an addition salt.

(17) The method for preventing or treating a bone disease according to any one of the above (13) to (16), wherein the bone disease is a fracture.

(18) Use of a compound having Rho kinase inhibitory activity for the manufacture of a preventive or therapeutic drug for bone disease.

(19) The compound having Rho kinase inhibitory activity is an amide compound represented by the general formula (I), particularly, the general formula (1 ′), an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof. The use according to (18) above.

(20) The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H —Pyro mouth [2,3-b] pyridine-14-yl) -14- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) —4 — (1-Aminoethyl) benzamide and (R)-(+)-N- (1H-pyrro [2,3-b] pyridin-4-yl) 1-4- (1-aminoethyl) benzamido (18) The use according to the above (18), which is a compound selected from the group consisting of amides and / or a pharmaceutically acceptable acid addition salt thereof.

(21) The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid thereof. The use according to (18), which is an addition salt.

(22) The use according to any one of (18) to (21) above, wherein the bone disease is a fracture. (23) The pharmaceutical composition for preventing or treating a bone disease according to any one of (8) to (12) above, and the pharmaceutical composition can or should be used for the prevention and treatment of a bone disease. A commercial package containing a document stating that there is.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the effect of (+)-trans-14- (1-aminoethyl) 1-1- (4-) on the differentiation of 10T1 / 2 cells and MC3T3-E1 cells into osteoblasts. Pirijiruka Rubamoiru) cyclohexane _{2 HC 1 · 1 H 2 0} ( hereinafter, illustrates the effect of Y- 27 632).

1: Shows the effect of Y-27632 on AL における activity in 10 T 1/2 cells.

2: The effect of Y—276 32 on osteocalcin production from 10 T 1/2 cells is shown.

3: Effect of 27—27632 on AL L activity in MC 3 T 3 31 cells.

Figure 2 shows the effect of Y-27632 on the differentiation of ST2 cells into osteoblasts.

1: Effect of Y-27632 on ALP activity in ST2 cells. 2: The effect of Y-2 7632 on osteocalcin production from ST2 cells is shown.

One ♦-indicates the results of culturing on a collagen-coated dish, and one □-indicates the results of culturing on a non-collagen-coated dish for 5 days.

FIG. 3 shows the effect of Y-27632 on osteobontin mRNA expression in 10 T1 / 2 cells.

a is an RNA blot image showing a change in the amount of osteobontin (OPN) mRNA.

“b” is a graph of the result of the RNA plot of “a”, and shows a relative change in the expression level (the vertical axis is an arbitrary unit). FIG. 4 shows the effect of Y-27632 on BMP-4 mRNA expression in S における 2 cells.

The results of RNA plots showing changes in BMP-4 mRNA amounts are shown relatively (vertical axis is arbitrary unit).

FIG. 5 shows the relationship between ALP activity and Rho activity in 10 T1 / 2 cells.

a is a graph showing changes in ALP activity in cells expressing active exogenous Rh in addition to endogenous R ho.

b is an immublot image showing the result of examining the expression status of endogenous Rho or active exogenous Rho in each cell using an antibody.

Detailed description of the invention

In the present invention, the osteogenesis promoting agent may be any one that activates any stage of osteogenesis as long as it has an activity to promote osteogenesis. Osteopontin, osteopontin activity using undifferentiated mesenchymal cells, osteoporosis using osteocalcin activity or osteocalcin as an index. A compound having an activity of inducing cell differentiation and promoting bone formation.

Also, osteoinductive factor (BMP) refers to a protein having BMP activity that acts on undifferentiated mesenchymal cells to differentiate them into chondrocytes and osteoblasts. For example, BMP— :! To 10 and 15 and the like.

The bone disease according to the present invention includes metabolic bone diseases including osteoporosis, fibrous ostitis, osteomalacia, pageet's disease, etc., which occur when the balance between bone resorption and bone formation in bone tissue is disrupted, and orthopedic surgery. Bone diseases such as fractures, bone defects, low back pain and osteoarthritis, and periodontal diseases in the dental field. In addition, the application of the present invention to the repair of periodontal tissue defects, the stabilization of artificial dental roots, the repair of jaw formation, the cleft palate, and the like in periodontal diseases are also included in the prevention and treatment of bone diseases of the present invention.

Rho kinase in the present invention is a cell activated by activation of Rho. N / threonine kinase. For example, ROK Hi (ROCK II: Leung, T. et al., J. Biol. Chem., 270. 29051-29054, 1995), p 160 RO CK (ROK?, ROCK— I: Ishizaki, T. et al., The EMBO J., 15 (8), 1885-1893, 1996) and other proteins with serine / threonine kinase activity.

The compound having a Rh kinase activity used as the active ingredient of the present invention may be any compound having a Rh kinase inhibitory activity. Specific examples include the amide compounds, isoquinoline sulfonamide derivatives and isoquinoline derivatives described in WO 98/06433 and WO 97/28130.

For example, as the amide compound, a compound represented by the above general formula (I), especially a compound represented by the general formula (1 ′), and as the isoquinoline sulfonic acid derivative, fasudil hydrochloride [hexahydro-one] 1- (5-isoquinolinylsulfonyl) -1H-1, 4-diazepine monohydrochloride] and the like, and the isoquinoline derivative is hexahydro-1-([4-methyl-5- (Isoquinolinyl) sulfonyl] — 1H—1,4-diazepine dihydrochloride, (S)-(+) — hexahydro—2-methyl—11-[:( 4-methyl-5-isoquinolinyl) sulfonyl] —1 H-1,4, -diazepine hydrochloride, hexahydro-7-methyl-1-[(4-methyl-5-isoquinolinyl) sulfonyl] —1H-1,4-dazebine dihydrochloride, hexahydro-5-methyl One 1— [(4— Tyl-5-isoquinolinyl) sulfonyl] 1 1H-1, 4-dazebine dihydrochloride, hexahydro-12-methyl-1 1- (; (4-methyl-15-isoquinolinyl) sulfonyl) 1 1H-1 , 4-Dazebine hydrochloride, (R)-(-1) 1-hexahydro-12-methyl-1 1-[(4-methyl-5-isoquinolinyl) sulfonyl] 1-1H-1,4-dazebine hydrochloride, R)-(+) — HexahiDraw 5-Methyl-11-((4-methyl-5-isoquinolinyl) sulfonyl] —1H—1,4-diazepine hydrochloride.

The amide compound represented by the general formula (I) is preferred, and the amide compound is particularly preferred. An amide compound represented by the general formula (1,).

In the present invention, one kind of compound having Rho kinase inhibitory activity may be contained alone or, if necessary, several kinds may be used in combination. Further, in the present invention, a compound having Rho kinase inhibitory activity and another bone resorption inhibitor and / or bone formation promoter can be used in combination.

For example, calcium preparations, vitamins D, calcitonins, bisphosphonates, estrogens sex hormones, fluorides such as sodium fluoride, parathyroid hormones (PTHs), insulin-like growth factors (IGFs), fiber Blast growth factor (FGF).

In the present specification, the definition of each symbol of the general formula (I) and the general formula (1 ′) is as follows.

R, R,, an alkyl with carbon number 1-1 0 straight-chain or branched and the alkyl in R ^1, methyl, Echiru, propyl, isopropyl building, butyl, I Sobuchiru, secondary Examples thereof include butyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Alkyl having 1 to 4 carbon atoms is preferable.

R, R ', denotes cyclopropyl Cycloalkyl in R ^1, cyclobutyl, cyclopentyl, cyclohexyl, a number 3-7 cycloalkyl carbons of heptyl and the like cyclohexylene.

R, R ', and cycloalkylalkyl in R ¹ is cycloalkyl portion is the number of 3 to 7 carbon cycloalkyl, alkyl portion is of one to six carbon atoms straight-chain or branched alkyl (Methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), which is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclopentyl Ethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbu Butyl, cyclopropylhexyl, cyclopentylhexyl, cyclohexylhexyl, cycloheptylhexyl and the like.

Aralkyl in R, R, and R ¹ has 1 to 4 carbon atoms as the alkyl moiety, and includes benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl. And phenylalkyl.

R, R ', cycloalkyl which may have a substituent on the ring at R ^1, a cycloalkyl alkyl, phenyl, and the substituents of Ararukiru is halogen (chlorine, bromine, full Uz arsenide, iodine), Alkyl (synonymous with alkyl in R, R,, R ¹ ), alkoxy (linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, shows a Kishiruokishi like secondary butoxy, tertiary butoxy, Penchiruokishi to,.), Ararukiru (H, synonymous with Ararukiru in R ,, R ^1), haloalkyl (R, alkyl as indicated in R ,, R ¹ Is substituted with 1 to 5 halogens, such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl 2, 2 shows the 3, 3, 3-pen evening Furuoropuropiru like.), Nitro, Amino, Shiano, azides, and the like.

A heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom in which R and ¹ or R ′ and R ¹ are bonded to each other; As the group that forms, a 5- to 6-membered ring or a bonded ring thereof is preferable. Specifically, 1-pyrrolidinyl, piberidino, 1-piperazinyl, morpholino, thiomorpholino, 1-imidazolyl, 2,3-dihydrothiazo For example, one-to-one and three-by-one. Examples of the substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl, haloalkyl and the like. Wherein alkyl, § La alkyl, haloalkyl R, R ', the same meaning as in the R ^1.

The alkyl in R ² has the same meaning as the alkyl in R, R ′ and R ¹ .

R ³ , R ⁴ halogen, alkyl, alkoxy, aralkyl is R, R ′, Shows in R ¹ is as defined above.

The acyl in R ³ and R ⁴ is an alkanoyl having 2 to 6 carbon atoms (such as acetyl, propionyl, butyryl, valeryl, and vivaloyl), a benzoyl, or a phenylalkanoyl group having 2 to 4 carbon atoms. Indicates phenyl (phenylacetyl, phenylpropionyl, phenylbutyryl, etc.).

The Arukiruamino in RR ^4, a Arukiruamino having an alkyl number 1 of 6 linear or branched carbon atoms in the alkyl part, Mechiruamino, E Chiruamino, propylamino, isopropylamino, Buchiruamino, isobutyl Amino, Secondary butylamino, tertiary butylamino, pentylamino, hexylamino, etc.

The acylamino in R ³ and R ⁴ is an acylamino having 2 to 6 carbon atoms such as alkanol, benzoyl, or alkanol having an alkanoyl moiety having 2 to 4 carbon atoms, such as acetylamino. , Propionylamino, butyrylamino, phenyl, "relylamino, bivaloylamino, benzoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino and the like.

The alkylthio represented by R ³ and R ⁴ is an alkylthio having a linear or branched alkyl having 1 to 6 carbon atoms in the alkyl portion, and is methylthio, ethylthio, propylthio, isopropylthio, butylthio. , Isobutylthio, secondary butylthio, tertiary butylthio, pentylthio, hexylthio and the like.

The aralkyloxy represented by R ³ and R ⁴ has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl part thereof, and is benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, 3 — Phenylpropyloxy, 4-phenylbutyloxy and the like are shown.

The aralkylthio in RR ⁴ has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl portion thereof, and includes benzylthio, 1-phenylethylthio, 2-phenylphenylthio, 3-phenylpropylthio, 4—Fueni And rubutylthio.

The alkoxycarbonyl in R ³ and R ⁴ has a straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms in the alkoxy moiety, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Examples include sopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The mono'dialkyl carbamoyl represented by R ³ and R ⁴ is a carbamoyl mono- or di-substituted by an alkyl having 1 to 4 carbon atoms, such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, and getylcarbamoyl. Propyl carbamoyl, dipropyl carbamoyl, butyl carbamoyl, dibutyl carbamoyl and the like.

The alkoxy in R ⁵ R, R ', the same meaning as alkoxy at R ^1. The alkoxycarbonyl O alkoxy in R ^5, be one having a number 1-6 straight-chain or branched alkoxy carbon alkoxy part, main Tokishikaru Boniruokishi, ethoxycarbonyl O alkoxy, propoxycarbonyl O alkoxy , Isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, secondary butoxycarbonyloxy, tertiary butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy, etc. Shown.

The Arca Noi Ruo carboxymethyl at R ^5, be one having from 2 to 6 § Rukanoiru carbon number Arukanoiru section shows Asechiruokishi, propionyl Ruo carboxy, butyl Riruokishi, Bareriruokishi, the Bibaroiruokishi like.

The aralkyloxycarbonyloxy in R ⁵ has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl portion thereof, and is a benzyloxycarbonyloxy, an 11-phenylethyloxy. Carbonyloxy, 2-phenyl-2-ethylcarbonyloxy, 3-phenylpropyloxycarbonyl And 4-phenylbutyroxycarbonyloxy and the like.

The alkyl in R ⁶ has the same meaning as the alkyl in R, R ′ and R ¹ . Alkyl at R ⁸ and R ⁹ has the same meaning as alkyl at R, R, and R ^1, and aralkyl at R ⁸ and R ^g has the same meaning as aralkyl at R, R, and R ¹ .

Alkyl in R ⁷ is R, R,, have the same meaning as alkyl at R ^1, Ararukiru the definitive in R ⁷ is, R, R, is synonymous with Ararukiru in R ^1.

A group in which R ⁶ and R ⁷ are bonded to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent is imidazole 1- Yl, thiazole-2-yl, oxazole-2-yl, imidazoline-2-yl, 3,4,5,6-tetrahydropyridine-1-yl, 3,4,5,6-tetrahydrobilimidine 1-2-yl, 1,3-oxazoline-12-yl, 1,3-thiazoline-2-yl or halogen, alkyl, alkoxy, haloalkyl, nitro, amino, phenyl, aralkyl, etc. Benzoimidazole-2-yl, benzothiazol-1-yl, benzoxazol-2-yl and the like which may be used. Here, halogen, alkyl, alkoxy, Haroa alkyl, and Ararukiru R, R ', the same meaning as in the R ^1.

Examples of the substituent on the nitrogen atom which may have a substituent include aralkyl, aralkyl, haloalkyl and the like. Wherein alkyl, Araru kill, and haloalkyl R, R ', the same meaning as in the R ^1.

The hydroxyalkyl represented by R ^{1 Q} and R ¹¹ is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms substituted with 1 to 3 hydroxy, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like.

Alkyl in R ^10, R ^{1 1} is R, have the same meaning as alkyl at R ,, R ^1, haloalkyl of R ¹ R ^{1 1,} alkoxycarbonyl R, R,, synonymous with those shown in had us to R ¹ Yes, aralkyl in R ^{1 ()} , R ¹¹ is synonymous with aralkyl in R, R ', R ¹ . The cycloalkyl formed by the combination of R ¹ \ R ¹¹ is also the same as the cycloalkyl in R, R,, and R ¹ .

Alkyl in L is R, R ', the same meaning as alkyl at R ^1.

The aminoalkyl in L is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms which is substituted by amino, such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminoalkyl. Aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and the like.

The mono-dialkylaminoalkyl in L is an aminoalkyl which is mono- or di-substituted by alkyl having 1 to 4 carbon atoms, such as methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, acetylaminomethyl, and propylaminomethyl. Examples include nomethyl, dipropylaminomethyl, butylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 2-getylaminoethyl and the like.

L-rubamoylalkyl in L is a straight- or branched-chain alkyl having 1 to 6 carbon atoms, which is substituted with l-rubamoyl, for example, l-rubamoylmethyl, 2--lumbamoylethyl, 1-lumbamoylethyl , 3-power rubamoyl propyl, 4 -power rubamoyl butyl, 5-power lubamoyl pentyl, 6-power rubamoyl hexyl and the like.

The fluorimidalkyl in L is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms which is substituted by phthalimid. For example, phthalimidomethyl, 2-fluorimidethyl, 1- Fluorimidethyl, 3-phthalimidopropyl, 4-phthalimidbutyl, 5-phthalimidopentyl, 6-phthalimidhexyl and the like.

, R, R alkyl in B, and the same meaning as alkyl at R ^1.

Alkoxy at B is R, R ', the same meaning as alkoxy at R ^1. Ararukiru in B is R, R ', the same meaning as Ararukiru in R ^1.

Aralkyloxy in B is synonymous with aralkyloxy in R ³ and R ⁴ o Aminoalkyl in B has the same meaning as aminoalkyl in L.

The hydroxyalkyl for B is the same as the hydroxyalkyl for R ^{1 Q} and R ¹¹ .

The alkanoyloxyalkyl in B is a straight-chain or branched alkyl having 1 to 6 carbons substituted by an alkanoyloxy having an alkanoyl moiety having 2 to 6 carbons. Acetyloxymethyl, propionyloxymethyl, ptyryloxymethyl, valeryloxymethyl, bivaloyloxymethyl, acetyloxoxetil, propionyloxyxetil, butyryloxethyl, valeryloxyxetil, vivaloyloxy Shechill and the like.

The alkoxycarbonylalkyl in B is a straight-chain or branched-chain alkyl having 1 to 6 carbons substituted by an alkoxycarbonyl having an alkoxy moiety having 1 to 6 carbons. Methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, secondary butoxycarbonylmethyl, tertiary butoxycarbonylmethyl, pentyloxycarbonylmethyl, to Xyloxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxycarbonylethyl, isopropoxycarbonylyl, butoxycarbonylethyl, isobutoxycarbonylethyl, secondary butoxy Aryloxycarbonyl E chill, tertiary butoxycarbonyl E chill, Penchiruo alkoxycarbonyl E chill, hexyl O butoxycarbonyl E chill like to.

Halogen in the QQ \ Q ³ is R, R,, Ru halogen synonymous der in R ^1. The aralkyloxy in QQ ² is synonymous with the aralkyloxy in R ³ and R ⁴ .

The alkoxy in Q ³ has the same meaning as the alkoxy in R, R ′ and R ¹ . The alkylene in W, X and Y is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like. The alkenylene in Y is a linear or branched alkenylene having 2 to 6 carbon atoms, such as vinylene, propenylene, butenylene, pentenylene and the like.

The alkyl in Rb R, R ', the same meaning as alkyl at R ^1.

The Ararukiru in Rb R, R ', the same meaning as Ararukiru in R ^1. The aminoalkyl for Rb has the same meaning as the aminoalkyl for L.

The mono-dialkylaminoalkyl for Rb has the same meaning as the mono-dialkylaminoalkyl for L.

The nitrogen-containing heterocyclic ring represented by Rc is, when monocyclic, pyridine, pyrimidine, pyridazine, triazine, pyrazole, or triazole, and when condensed ring, virolobilizine (1H-pyromouth [2,3-b] pyridine , 1H-pyro mouth [3,2-b] pyridine, 1H-pyro mouth [3,4-1b] pyridine, etc.), virazolobiridine (1H-pyrazo mouth [3,4-1b] pyridine, 1H —Pyrazo mouth [4,3—b] pyridine, etc.), imidazoviridine (1H-imidazo [4,5—b] pyridine, etc.), pyro-mouth virimidine (1H-pyro-mouth [2,3_d] pyrimidine, 1 H-Pyro mouth [3,2-d] bilimidine, 1 H-Pyro mouth [3,4-d] Birimidine, etc.), Birazolopyrimidine (1H-Birazolo [3,4-d] Pyrimidine, Pyrazo mouth [ 1,5—a] birimidine, 1 H—pyrazo mouth [4,3—d] pyrimidi ), Imidazovirimidine (imidazo [1,2—a] pyrimidine, 1H-imidazo [4,5—d] pyrimidine, etc.), pilotriatriazine (pyromouth [1,2-a] _l, 3, 5-Triazine, Pyro mouth [2,1-f] -11,2,4-triazine, etc.), Pyrazolo mouth triazine (Vilazolo [1,5-a] -11,3,5-triazine, etc.), Triazolopyridine (1H-1,2,3-triazolo [4,5-b] pyridine etc.), triazolopyrimidine (1,2,4-triazolo [1,5-a] bilimidine, 1,2,4-triazolo [ 4,3—a] pyrimidine, 1H—1,2,3-triazolo [4,5—d] pyrimidine, etc.), cinnoline, quinazoline, quinoline, bilidopyridazine (pyrid [2,3-c] pyridazine, etc.) , Pyridovirazine (pyrid [2,3-b] pyrazine, etc.) Pyridopyrimidine (pyrido [2, 3- d] Birimijin, pyrido [3, 2-d] pyrimidine Pyrimidine (pyrimido [4,5-d] pyrimidine, pyrimido [5,4-d] pyrimidine, etc.), pyrazinovirimidine (virazino [2,3-d] pyrimidine, etc.), naphthyridine (1,8-naphthyridine, etc.), tetrazolopyrimidine (tetrazolo [1,5-a] pyrimidine, etc.), chenoviridine (thieno [2,3-b] pyridine, etc.), chenobilimidine (thieno [2,3-d]) Pyrimidine), thiazoloviridine (thiazolo [4,5-b] pyridine, thiazolo [5,4-b] pyridine, etc.), thiazolopyrimidine (thiazolo [4,5-d] pyrimidine, thiazolo [5,4-] d] virimidine, etc.), oxazolo pyridine (oxazolo [4, 5-b] pyridine, oxazolo [5, 4-b] pyridine, etc.), oxazolopyrimidine (oxo) Zoguchi [4,5-d] pyrimidine, oxazolo [5,4-d] pyrimidine, etc.), floviridine (furo [2,3-b] pyridine, furo [3,2-b] pyridine, etc.), Flopyrimidine ( Fluoro [2,3-d] pyrimidine, Fluoro [3,2-d] pyrimidine, etc.), 2,3-Dihydropyrro pyridine (2,3-dihydro-1H-pyrro [2,3-b] pyridine , 2,3-dihydro- 1H-pyro mouth [3,2-b] pyridine, etc.), 2,3-dihydrovirolopyrimidine (2,3-dihydro-1H-pyro mouth [2,3—d] pyrimidine , 2,3-dihydro-1H-pyrro [3,2-d] pyrimidine, etc.), 5,6,7,8-tetrahydropyrido [2,3-d] pyrimidine, 5,6,7,8 —Tetrahydro-1,8-naphthyridine, 5,6,7,8-tetrahydroquinoline, etc. When forming an aromatic ring to be added, the carbon atom in the ring may be carbonyl, for example, 2,3-dihydro-2-pyroxypyridine, 2,3-dihydro-1,2,3-dioxopyrropyridine , 7,8-dihydro-7-oxo-1,8_naphthyridine, 5,6,7,8-tetrahydro-17-oxo-1,1,8-naphthyridine and the like.

In addition, these rings may be halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, amino, alkylamino, cyano, formyl, acyl, aminoalkyl, mono- or dialkylaminoalkyl, azide, carboxy, alkoxycarbonyl, alkavamoyl, monoalkyl · Dialkyl Lubamoyl, Alkoxy Al It may be substituted by a substituent such as kill (methoxymethyl, methoxyl, methoxypropyl, ethoxymethyl, ethoxyl, ethoxypropyl, etc.) or hydrazino which may have a substituent.

Examples of the substituent of the human Dorajino be substituted, alkyl, Ararukiru, nitro, force Shiano etc., alkyl, Ararukiru is R, R ', alkyl in R ^1, Ararukiru synonymous For example, methylhydrazino, ethylhydrazino, benzylhydrazino and the like are exemplified.

Specific examples of the compound represented by the formula (I) include the following compounds.

(1) 4- (2-pyridylcarbamoyl) piperidine

(2) 1-benzyloxycarbonyl 4 _ (4 _ pyridylcarbamoyl) piperidine

(3) 1 Benzoyl 4- (4-pyridylcarbamoyl) piperidine

(4) 1 _ propyl 1 4— (4-pyridinole rubamoyl) piperidine

(5) 1- [3- (2- (2-Chenylmethyl) phenoxy) -1-2-hydroxypropyl] 141- (4-pyridylcarbamoyl) piperidine

(6) 4- (4-pyridylcarbamoyl) piperidine

(7) 1-benzyl-1-41- (4-pyridinorecanoleno moinole) 1-1,2,5,6-tetrahydropyridine

(8) 3- (4-pyridylcarbamoyl) piperidine

(9) 1 Benzyl 3- (4-pyridylcarbamoyl) piperidine

(1 0) 1- (2- (4-benzyloxyphenoxy) ethyl) 4- (N- (2-pyridyl) -1-N-benzylcarbamoyl) pyridine

(1 1) 1-forminole 4- (4-pyridylcarbamoyl) piperidine

(1 2) 4- (3-pyridylcarbamoyl) piperidine

(1 3) 1-Isopropyl-1- (4-Pyridylcarbamoyl) piperidine

(14) 1-Methyl-4_ (4-Pyridylcarbamoyl) piperidine

twenty four

Corrected form (Rule 91) (1 5 1 _ hexyl 4-one (4-pyridylcarbamoyl) piperidine

(1 6 1-benzyl-1 4- (4-pyridylcarbamoyl) piperidine

(1 7 1-(2-phenylethyl) 1-4-(4-pyridylcarbamoyl) pyridine

(1 8 1— (2- (4-Methoxyphenyl) ethyl) 4- (4 pyridylcarbamoyl) piperidine

(1 9 1- (2- (4-Methoxyphenyl) ethyl) 4- (2-Pyridylcarbamoyl) piperidine

(20 1-(2-(4-chlorophenyl) ethyl) 1-4-(4-pyridylcarbamoyl) piperidine

(2 1) 1-diphenylmethyl _ 4-— (2-pyridylcarbamoyl) piperidine

(22) 1— [2— (4— (5-methyl-1-oxo-1,2,3,4,5-tetrahydropyridazin-1-yl) phenyl) ethyl] 1-4— (2-pyridyl Carbamoyl) piperidine

(23) 1-(4-(4,5-dihydro-1-furyl) phenyl) 1-41 (4-pyridylcarbamoyl) piperidine

(24 1-(2-ditrophenyl) 1-4-(4-pyridylcarbamoyl) pyridine

(25 1-(2-aminophenyl) 1-41 (4-pyridylcarbamoyl) pyridine

(26) 1-nicotinol 4- (4-pyridylcarbamoyl) piperidine

(27) 1-Isonicotinoyl 4- _ (4-pyridylcarbamoyl) piperidine

(28) 1— (3,4,5—trimethoxybenzoyl) 1-4— (4—pyridylcarbamoyl) biperidine

(29 1-Acetyl-1-4- (4-pyridylcarbamoyl) piperidine

(30 1-(3-(4-fluorobenzoyl) propyl) 1-4-(4-pyridylcarbamoyl) biperidine (3 1) 1— (3— (4-fluorobenzoyl) propyl) -4-1 (2-pyridylcarbamoyl) piperidine

(32) 1- (1- (4-hydroxybenzoyl) ethyl) 1-4- (2-pyridylcarbamoyl) piperidine

(33) 1— (1— (4-Benzyloxybenzoyl) etinole) 4- (2-Pyridylcarbamoyl) piperidine

(34) 1— (2 -— (4-hydroxyphenoxy) ethyl) 1 4— (2-pyridinole rubamoyl) piperidine

(35) 1— (4- (4-phenolic) 4-hydroxybutynole) 4- (4-pyridylcarbamoyl) piperidine

(36) 1— (1-Methyl-1-2-—4-Hydroxyphenethyl) 2-Hydroxyethyl) 1-41- (2-Pyridylcanolevamoyl) Piperidine

(3 7) 1-Cinnamyl-4-1 (2-pyridylcarbamoyl) piperidine (38) 1- (2-Hydroxy-3-phenoxypropyl) 1-4- (4-Pyridinol carbamoyl) piperidine

(3 9) 1— (2—Hydroxy 3—Phenoxypropyl) 1-4— (3—Pyridinole rubamoyl) Piperidine

(40) 1- (2-hydroxy-3-phenoxypropyl) -4-1 (2-pyridinole rubamoyl) piperidine

(4 1) 1— (2-phenylethyl) _4— [N_ (2-pyridyl) -1-N— (2- (N, N-dimethylamino) ethyl) rubamoyl] piperidine

(42) 1 Benzyloxycarbone 4 _ (2-pyridylcarbamoyl) piperidine

(43) 1— (3—Frozen mouth) Canolebamoinole 4— (4—Pyridinolecanoleva moyl) Piperidine

(44) 4— [N— (2-pyridyl) 1 N— (2— (N, N-dimethylamino) etinole) canolebamoyl] piperidine

26

Corrected form (Rule 91) (45) 1-Methyl_4-I- (4-pyridylcarbamoyl) — 1,2,5,6-tetrahydropyridine

(46) 1-nicotinol 3- (4-pyridylcarbamoyl) piperidine

(47) 1-2-(4-benzoyl) ethyl 4- 1-(4- pyridyl pyruvamoyl) piperidine

(48) 1- (6-methyl-2-imidazo [1,2, -a] pyridine-3- (carbonyl) -14- (4-pyridylcarbamoyl) piperidine

(49) 1- (4-nitrobenzyl) 1-4- (4-pyridylcarbamoyl) piperidine

(5 0) 1-Hexyl-1- (4-pyridylcarbamoyl) piperidine

(51) 1 _ Benzyloxycarbonyl 4- (2-chloro-1-41-pyridylcarbamoyl) piperidine

(5 2) 4— (2-chloro-1-4-pyridylcarbamoyl) piperidine

(5 3) 1— (2 _Black mouth nicotinol)

Bipyridine

(54) 3-(2 _ 1-4-pyridylcarbamoyl) piperidine

(5 5) 1— (4 phthalimidoptyl) 1 4— (4—piri

Piperidine

(5 6) 1— (3,5-ditert-butyl-1-hydroxyhydroxynamamoyl) —4— (4 _pyridylcarbamoyl) piperidine

(57) 1-Potassium rubamoyl methyl _ 4- (4-pyridylcarbamoyl) piberidine

(58) 1-benzyloxycarbonyl _ 4- (5-nitro-2-pyridylcarbamoyl) piperidine

(5 9) 4-(5-Nitro_2-pyridylcarbamoyl) piperidine

(60) trans-1-4-benzyloxycarboxamide methyl-111- (4-pyridylcarbamoyl) cyclohexane (61) Trans-1-aminomethyl-1_ (4-pyridylcarbamoyl) cyclohexane

(62) trans-4-Formamidomethyl-1- (4-pyridylcarbamoyl) cyclohexane

(63) trans-1-dimethylaminoamino-1- (4-pyridylcarbamoyl) cyclohexane

(64) N-benzylidene-trans- (4-pyridylcarbamoyl) cyclohexylmethylamine

(65) trans-1-Benzylaminomethyl _1-1 (4-pyri

Le) cyclohexane

(66) trans-1-isopropylaminomethyl _1- (4-pyri

Moyl) cyclohexane

(67) trans-1-nicotinoylaminomethyl-11- (4-pyridylcarbamoyl) cyclohexane

(68) trans-4-cyclohexylaminomethyl-11- (4-pyridylcarbamoyl) cyclohexane

(6 9) trans-4-benzyloxycarboxamide 1 _ (4-pyridylcarbamoyl) cyclohexane

(70) trans-1-Amino-1- (4-pyridylcarbamoyl) cyclohexane

(71) Trans-4- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane

(72) trans-41-aminomethyl-cis-2-methyl-1- (4-pyridyl dylvamoyl) cyclohexane

(73) (+) — trans 1-4-(1-benzyloxycarboxamidopropyl) 1-1-cyclohexanecarboxylic acid

(74) (+) — trans-4- (1-benzyloxycarboxamidopropyl) -1-(4-pyridylcarbamoyl) cyclohexane

(75) (-)-trans-4-1 (1-benzyloxycarboxamidopropyl) -1- (4-pyridylcarbamoyl) cyclohexane

(76) (+) —trans-4_ (1-aminopropyl) 1 1 _ (4-pyridyl-powerbamoyl) cyclohexane

(77) (1) 1-trans-1 4- (1-aminopropyl) 1 1- (4-pyridyl carbamoyl) cyclohexane

(78) (-)-Trans-1- (1-benzyloxycarboxamidoethyl)-1- (4-pyridylcarbamoyl) cyclohexane

(79) (+) —trans-4-1 (1-benzyloxycarboxamidoethyl)-1-(4-pyridylcarbamoyl) cyclohexane

(80) (+) -trans-4- (1-aminoethyl) 1 1- (4-pyridylcarbamoyl) cyclohexane

(8 1) (1) 1-trans 4- (1-aminoethyl) 1- (4-pyridylcarbamoyl) cyclohexane

(82) trans-1- (4-chlorobenzene) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane

(83) trans-4-Aminomethyl-1- (2-pyridylcarbamoyl) cyclohexane

(84) trans-4-benzyloxycarboxamide methyl-1- (2-pyridylcarbamoyl) cyclohexane

(85) trans-1-Methylaminomethyl-1- (4-pyridylcarbamoyl) cyclohexane

(86) trans-1- (N-benzyl-1-N-methylamino) methyl-1- (4-pyridylcarbamoyl) cyclohexane

(87) trans-4-Aminomethyl-1- (3-pyridylcarbamoyl) cyclohexane (88) trans-4-Aminomethyl-1-11 [(3-hydroxy-2-pyridyl) caprolbumoyl] cyclohexane

(89) trans-4-benzyloxycarboxamide methyl-1- (3-pyridylcarbamoyl) cyclohexane

(90) trans-4_benzyloxycarboxamidomethyl-1-((3-benzyloxy-2-pyridyl) caprolvamoyl) cyclohexane

(91) Trans-4-Fuyluminidmethyl-1- (4-pyridylcarbamoyl) cyclohexane

(92) trans-4-benzyloxycarboxamidomethyl_1- (3-methyl-14-pyridylcarbamoyl) cyclohexane

(93) trans-1-aminomethyl-1-(3-methyl-1-pyridylcarbamoyl) cyclohexane

(94) 4- (trans-1-benzyloxycarboxamidomethylcyclohexylcarbonyl) amino-2,6-dimethylviridine-N-oxide

(95) 4- (trans-1-aminomethylcyclohexylcarbonyl) amino- 2, 6-dimethylviridine-N-oxide

(96) trans-4-Aminomethyl-1- (2-methyl-14-pyridylcarbamoyl) cyclohexane

(97) Trans-1- (1-benzyloxycarboxamidoethyl) -1- (4-pyridylcarbamoyl) cyclohexane

(98) trans-1- (1-amino-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane

(99) trans-1 4- (2-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane

(100) trans-4-1 (2-amino-1-methylethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane

(10 1) trans-1- (1-aminopropyl) -1- (4-pyridylcarba Moyl) cyclohexane

(102) Trans-4-aminomethyl-1-trans-1-methyl_1- (4-pyridylcarbamoyl) cyclohexane

(103) trans-4-benzylaminomethyl-cis-1-methyl-2- (4-pyridylcarbamoyl) cyclohexane

(104) trans-1- (1-benzyloxycarboxamido 1-methylethyl) _1- (4-pyridylcarbamoyl) cyclohexane

(105) trans-1- 4-benzyloxycarboxamide methyl 1 _ (N-methyl-4-pyridylcarbamoyl) cyclohexane

(106) trans-41- (1-acetoamide_1-methylethyl) -111- (4-pyridylcarbamoyl) cyclohexane

(107) trans-N- (6-amino-14-pyrimidyl) 1-4-aminomethylcyclohexanecarboxamide

(108) trans-N- (1H-pyrro [2,3-b] pyridin-4-yl) — 4-aminomethylcyclohexanecarboxamide

(109) (+) — trans-N-(1 H-pyro-mouth [2,3-b] pyridine-14-yl) 14-1 (1-aminoethyl) cyclohexanecarboxamide

(1 10) trans-N- (1H-pyro-mouth [2,3-b] pyridine-14-yl)-4- (1-amino-1-methylethyl) cyclohexanecarboxamide

(1 1 1) trans-N- (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) —4-aminomethylcyclohexanecarboxamide

(1 12) (+) —trans _N_ (1 H—pyrazo-mouth [3,4-1b] pyridine-14-yl) 1-4- (1-aminoethyl) cyclohexanecarboxamide

(1 13) trans-N- (1H-pyrazo-mouth [3,4_b] pyridine-14-yl) -4--4- (1-amino-1-methylethyl) cyclohexanecarboxamide

(1 14) (+) —trans-N— (2-amino-1-4-pyridyl) 1-4 — (1-aminoethyl) cyclohexanecarboxamide (1 15) trans-N- (1H_pyrazo-mouth [3,4-d] pyrimidine-14-yl) 1-4-aminomethylcyclohexanecarboxamide

(1 1 6) (+) — trans-N- (1 H—birazolo [3,4-d] pyrimidine — 4-yl) —4— (1-aminoethyl) cyclohexanecarboxamide (1 17) Trans-N- (1H-pyrazo-mouth [3,4_d] pyrimidine-14-yl) -14- (1-amino-1-methylethyl) cyclohexanecarboxamide

(1 18) trans-N- (4-pyrimidinyl) 1-4-aminomethylcyclohexanecarboxamide

(1 19) trans-N- (3-amino-14-pyridyl) -14-aminomethylcyclohexanecarboxamide

(1 20) trans-N_ (7H-imidazo [4,5-d] pyrimidine-1-6-yl) -1-4-aminomethylcyclohexanecarboxamide

(12 1) trans _N_ (3 H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl) _4-monoaminomethylcyclohexanecarboxamide

(122) trans-N- (1-benzyl-1H-pyrazo-mouth [3,4-b] pyridin-14-yl) -14-aminomethylcyclohexanecarboxamide

(123) trans-N- (1H-5-pyrazolyl) 1,4-aminomethylcyclohexanecarboxamide

(124) trans-N- (1H-birazolo [3,4-b] pyridine-4-41)-4-aminomethylcyclohexanecarboxamide

(125) trans-N- (4-pyridazinyl) -14-aminomethylcyclohexanecarboxamide

(126) trans-N- (7H-pyrro [2,3-d] pyrimidine-14-yl) -14-aminomethylcyclohexanecarboxamide

(127) trans-N- (2-amino-14-pyridyl) -14-aminomethylcyclohexanecarboxamide

(128) Trans-N- (thieno [2,3-d] pyrimidine-1-yl) 1-4 —Aminomethylcyclohexanecarboxamide

(129) trans-N- (5-methyl-1,2,4-triazolo [1,5-a] pyrimidine-17-yl) -14-aminomethylcyclohexanecarboxamide

(1 30) trans-N- (3-cyano-5-methylpyrazo-mouth [1,5_a] pyrimidine-17-yl) _4-monoaminomethylcyclohexanecarboxamide

(1 3 1) trans-N— (1 H—pyrazo-mouth [3,4-b] pyridine-1-41) — 4-— (1-amino-1-methylethyl) cyclohexanecarboxamide

(1 32) trans-N- (2- (1-pyrrolidinyl) _4-pyridyl) -14-aminomethylcyclohexanecarboxamide

(133) trans-N- (2,6-diamino-14-pyrimidyl) 1-4-aminomethylcyclohexanecarboxamide

(134) (+) —trans-N— (7-methyl-1,8-naphthyridine-14-yl) 1-4- (1-aminoethyl) cyclohexanecarboxamide

(135) trans-N-(1-benzyloxymethylpyro-[2, 3-b] pyridin-1-4-yl)-1-4-aminomethylcyclohexanecarboxamide

(136) (+)-trans-N-(1-methylpyro-mouth [2, 3-b] pyridine-4-yl) 14-(1-aminoethyl) cyclohexanecarboxamide

(137) trans-N-benzyl-N-(2-benzylamino-4-pyridyl)-41-(1-amino-1-methylethyl) cyclohexanecarboxamide

(138) trans-N- (2-azido-4-pyridyl) -14-aminomethylcyclohexanecarboxamide

(139) trans-N- (2,3-dihydro-1H-pyrro [2,3-b] pyridine-1-41) 1-4-aminomethylcyclohexanecarboxamide

(140) trans-N- (2,3-dihydro-1H-pyrro [2,3-b] pyridine-14-yl) 14- (1-amino-1-methylethyl) cyclohexane power lipoxamide

(14 1-1) trans-N- (2-carboxy- 1 -pyridyl) 1-4 -aminomethyl Tylcyclohexanecarboxamide

(14 1-2) (R) _ (+) — trans-N— (3-promo 1 H—pyro-port [2,3 _b] pyridine-14-yl) 1-4- (1-aminoethyl) cyclo Hexancarboxamide

(142) trans-N-(1 H-pyro-mouth [2,3 _b] pyridine-41-yl)-4 _guanidinomethylcyclohexanecarboxamide

(143) trans-N- (1H-birazolo [3,4-b] pyridine-41-yl) -4--4-guanidinomethylcyclohexanecarboxamide

(144) trans-N- (4-pyridyl) _4-guanidinomethylcyclohexancarboxamide

(145) trans-N-(1-methyl virolo [2,3-b] pyridine-14-yl) 14-1 (guanidinomethyl) cyclohexanecarboxamide

(146) trans-N-(1 H-pyro-mouth [2, 3-b] pyridine-1-4-yl)-4-(2-imidazoline-1-2-yl) aminomethylcyclohexanecarboxamide

(147) trans-N- (1-benzyloxymethylpyrro [2,3-b] pyridin-1 4-yl) 1-4-guanidinomethylcyclohexanecarboxamide

(148) trans-N-(2-amino-14-pyridyl) 14-guanidinomethylcyclohexanecarboxamide

(149) trans-N-(1-benzyloxymethyl-1 H-pyro-mouth [2, 3-b] pyridine-14-yl) 14-(2-imidazoline-12-yl) aminomethylcyclo Xancarboxamide

(150) trans-N-(1 H-virolo [2,3-b] pyridine-14-yl)-41-(3-benzylguanidinomethyl) cyclohexanecarboxamide

(1 5 1) trans-N- (1H-pyro-mouth [2,3-b] pyridine-14-yl) -4-1- (3-phenylguanidinomethyl) cyclohexanecarboxamide

(1 52) trans-N- (1 H-pyro mouth [2,3-b] pyridine-4-yl)

3A —4— (3-Propylguanidinomethyl) cyclohexanecarboxamide (153) trans-N— (1H-pyro-port [2,3_b] pyridine-14-yl)

-4-(3-octylguanidinomethyl) cyclohexanecarboxamide (154) trans-N- (1-benzyloxymethylpyro [2,3-b] pyridin-1-4-yl) 14 1- (2-Benzyl-1-ethylethylanidinomethyl) cyclohexancarboxamide

(155) trans-N- (1H-pyrro [2,3-b] pyridin-4-yl) -4--4- (imidazoyl-2-yl) aminomethylcyclohexanecarboxamide

(1 56) trans-N- (1H-pyrro [[2,3_b] pyridin-4-yl) -4- (thiazol-2-yl) aminomethylcyclohexanecarboxamide

(1 5 7) (R)-(+) -N- (4-pyridyl) 1-4-(1 -aminoethyl) benzamide

(1 5 8) N— (4-pyridyl) 1-4 (1-amino-1—methylethyl) benzamide

(155) N- (4-pyridyl) 1-4 aminomethyl-12-benzyloxybenzamide

(160) N- (4-pyridyl) _ 4-aminomethyl-2-ethoxybenzami K

(16 1) (R)-(-) -N- (4-pyridyl) 1 -41 (1 -aminoethyl)-3-nitro benzoamide

(1 6 2) (R) — (—) —N— (4-pyridyl) 1 3 Amino 1 4— (1-Minoethyl) Benzamide

(1 6 3) (R) — (+) _N— (4 _pyridyl) _ 4 (1—aminominethyl) — 3—chlorobenzamide

(1 64) N— (4-Pyridyl) _3-aminomethylbenzamide

(16 5) (R)-(+) -N- (1 H-Virolo [2,3-b] Pyridine-14-yl) 1-4- (1-Aminoethyl) benzamide (1 6 6) (R) 1 (+) -N- (1 H-pyrazo-mouth [3,4-b] pyridine 14-yl) -4-1- (1-aminoethyl) benzamide

(1 67) N- (1 H-pyrazo mouth [3, 4-b] pyridine_4-yl) 1-4-guanidinomethylbenzamide

(1 68) N— (4-pyridyl) 1-4-guanidinomethylbenzamide

(1 6 9) (R) — (+) —N— (4-pyridyl) 1 4— (1—Aminoethyl) — 3—Fluorobenzamide

(170) N— (4-pyridyl) 4-aminomethylbenzamide

(171) N- (4-pyridyl) 4-aminomethyl-2-hydroxybenzat-

(1 72) N- (4 -pyridyl) —4 — (2 -aminoethyl) benzamide (1 73) N— (4-pyridyl) — 4-aminomethyl-3-nitrobenzamide (174) N- (4 _Pyridyl)-3-amino-4 _Aminomethylbenzamide (175) (S)-(I) -N- (4-Ipyridyl) 14-(1-Aminoethyl) benzamide

(176) (S)-(1) 1-N-(4-pyridyl) 1 2-(1-aminoethyl) benzamide

(1 77) (R)-(+) -N- (4-pyridyl) 1-4-(1 -aminoethyl) 1-2-chlorobenzene

(178) (R)-(+)-N-(1 H_pyro-mouth [2, 3-b] pyridine-1-41-yl) 1-4- (1-(3-propylguanidino) ethyl) benzami Do

(1 79) (R)-(I) -N- (1H-pyro [2,3_b] pyridine-14-yl) 1-4- (1-aminoethyl) -13-azidobenzamide

(180) (R)-(+) -N- (4-pyridyl) 1 4— (1 amaminoethyl) — 2—two-necked benzoamide

(18 1) (R)-(I) I N-(4 -Pyridyl) I 4 _ (1 Aminoethyl)-3-Ethoxybenzamide W / 7 1

(182) (R)-(+)-N (3-1-H-Pyro-mouth [2, 3-b] Pyridine _ 4 _ yl) 1-41 (1 aminoethyl) Benzamide

(183) (R)-(+)-N (3-1-1H-Pyro-[2, 3 _b] pyridin-1-4-yl) 1-4 _ (1-aminoethyl)-1-3-Azidobenzamide ( 184) (R) — (-) 1 N (4-pyridyl) 1-41 (1 -aminoethyl) _ 3-Hydroxybenzamide

(185) N— (1 H—pyrazo mouth [3, 4-b] pyridine-14-yl) _ 4-—quanidinomethyl-3 _ nitrite vent amide

(1 86) (R) -N- (1H-Bilazolo [3,4-b] Pyridine-1-4-yl)-4-(1-Guanidinoethyl) 1-3-Trobenzamide

(187) (R) -N- (1 H_Pyrazo mouth [3,4_b] Pyridine-1 4-1yl)-4-(1-Aminoethyl) 1-2-2 Trobenzamide

(188) N- (1H-pyrazo mouth [3,4-b] pyridine-14-yl) -14-guanidinobenzamide

(189) (R) -N- (1 H-Pyrazo mouth [3,4-b] Pyridine-14-yl)-4-(1-Aminoethyl) -13-Nitrobenzamide

(1 90) (R) -N- (1H-pyrazo-mouth [3,4-b] pyridine-1-yl)-4--(1-guanidinoethyl) benzamide

(1 9 1) N— (1 H—Pyrazo mouth [3, 4-b] Pyridine-14-yl) 1-4- (1-1-Amino-2-hydroxychetyl) benzamide

(1992) N— (1H—Pyrazo mouth [3, 4-b] pyridine-41-yl) 1-4-aminomethyl-3-nitrobenzamide

(1 93) N- (1H-pyro mouth [2,3-b] pyridine-14-yl) -14-piperidinecarboxamide

(194) N-(1 H-pyrazo-mouth [3, 4-b] pyridine-14-yl) _ 4-piperidinecarboxamide

(195) N- (1H-pyrazo mouth [3,4_b] pyridine-14-yl) 1-1-1 Minoacetyl 4-piperidinecarboxamide

(1 96) N- (1-Methoxymethyl-1H-pyrazo-mouth [3,4-b] pyridine-4-yl) 1-4-piperidinecarboxamide

(197) N— (2,3-dihydro-1H-pyrro [2,3-b] pyridine_4—yl) 1,4-piperidinecarboxamide

(1 98) N— (1H—pyro mouth [2,3_b] pyridine-14-yl) 1-1- (2-phenylenyl) -14-piperidinecarboxamide

(1 9 9) N— (1H—pyro mouth [2,3-b] pyridine-14-yl) -11-amidino-1-4-piperidinecarboxamide

(200) N— (1 H—pyro mouth [2,3-b] pyridine-14-yl) 1-1- (3-phenylpropyl) -14-piperidinecarboxamide

(20 1) N- (1 H-pyrro [2,3-b] pyridin-4-yl) -11-benzylyl 4-piperidinecarboxamide

(202) N- (1H-pyrazo mouth [3,4-b] pyridine-14-yl) 1-1- (2-phenylenyl) -14-piperidinecarboxamide

(203) N- (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) 1-1- (3-phenylpropyl) _4-piperidinecarboxamide

Preferably, the compounds (80), (109), (110), (112), (115), (142), (143), (144), (145), and (153) , (157), (163), (165), (166) and (179). Further, the compound used as the compound having the Rh-kinase inhibitory activity of the present invention may be a pharmaceutically acceptable acid addition salt, which includes inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and methanesulfone. Organic acids such as acid, fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, and salicylic acid. Further, the compound having a carboxyl group may be a salt with a metal such as sodium, potassium, calcium, magnesium, and aluminum, or a salt with an amino acid such as lysine. In addition, their monohydrate, dihydrate, 1/2 hydrate, 1/3 hydrate, 1/4 hydrate, 2/3 hydrate And 3/2 hydrate are also included in the present invention.

Compounds represented by the general formula (I) are described in JP-A-62-89679, JP-A-3-218356, JP-A-5-194401, JP-A-6-411080, W095 / 28387 and It can be synthesized by the method described in W098 / 06433 and the like.

When an optical isomer, a racemate or a cis-trans isomer thereof exists in the compound having the Rh kinase inhibitory activity, all of these can be used in the present invention. The isomer can be isolated by a conventional method or can be produced by using each isomer material.

Compounds having Rh kinase inhibition activity, especially compounds represented by the general formula (I), isomers thereof and / or pharmaceutically acceptable acid addition salts thereof, include humans, Since it has an osteogenesis promoting effect on mammals such as horses, dogs, mice and rats, it is useful as an osteogenesis promoter and for the prevention and treatment of the various bone diseases mentioned above.

When a compound having Rho kinase inhibitory activity is used as a medicine, it is prepared as a general pharmaceutical preparation and administered orally or parenterally.

For example, a compound having Rho kinase inhibitory activity is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.). The resulting pharmaceutical compositions or tablets, pills, powders, granules, capsules, troches, syrups, solutions, emulsions, suspensions, injections (solutions, suspensions, etc.), suppositories, inhalants, It is formulated in a form suitable for oral or parenteral use as a preparation such as a transdermal absorbent, eye drops, or ointment.

In the case of solid preparations, additives such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, pectin, tran gum , Gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydro For example, xypropylcellulose, hydroxypropylmethylcellulose, glycerin, polyethylene glycol, sodium hydrogencarbonate, magnesium stearate, and nylon are used. Further, the tablets can be made into tablets coated with a usual coating as required, for example, sugar-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.

In the case of semi-solid preparations, animal and vegetable oils (olive oil, corn oil, castor oil, etc.), mineral oils (vaseline, white petrolatum, solid paraffin, etc.), waxes (jojoba oil, carnapa wax, beeswax, etc.), A partially or totally synthesized glycerin fatty acid ester (eg, lauric acid, myristic acid, norremic acid) is used. Examples of these commercially available products include Witebsol (manufactured by Dynamid Nobel), Pharmasol (manufactured by NOF Corporation), and the like.

When a liquid preparation is used, additives such as sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, ethyl alcohol and the like can be mentioned. In particular, for injection, a sterile aqueous solution such as physiological saline, isotonic solution, or oily solution such as sesame oil or soybean oil is used. If necessary, a suitable suspending agent such as sodium carboxymethylcellulose, a nonionic surfactant, and a solubilizing agent such as benzyl benzoate or benzyl alcohol may be used in combination. Further, in the case of eye drops, an aqueous solution or an aqueous solution is used, and particularly, a sterile aqueous solution for injection is used. Buffers (preferably borate buffer, acetate buffer, carbonate buffer, etc. to reduce irritation), isotonic agents, dissolution aids, preservatives, thickeners, chelates A variety of additives such as an agent, a ρΗ adjuster (11 is usually preferably adjusted to about 6 to 8.5) and an aromatic agent may be appropriately added.

In the treatment of fractures, it can be administered systemically or locally by injection or other methods. As a method of local administration, a method of implanting a carrier containing the present drug close to a fracture site is more preferable. In this case, the carrier may be a natural polymer substance such as collagen-fipurin coagulate, or a polylactic acid glycolic acid. Such an artificial polymer substance that can be decomposed in a living body is used. In the case of bone or tooth transplantation in the field of orthopedic surgery, this agent can be used by coating the surface of the bone or tooth to be transplanted with an adhesive substance such as collagen paste or fibrin glue. Further, for bone and tooth transplantation, for example, artificial bones and artificial roots made of metal, ceramic, glass, and other natural or artificial inorganic materials (eg, hydroxyapatite, etc.) are used. In that case, it is also useful to configure the central part with a dense material, the surface part with a porous material such as hydroxyapatite, etc., and impregnate the drug into the porous part. . It is also useful to make the surface of the artificial bone made of a denser material denser and to carry the drug on the surface.

The amount of the compound having Rh kinase inhibition activity, which is an active ingredient in these preparations, is 0.1 to 100% by weight of the preparation, and suitably 1 to 50% by weight. The dosage may vary depending on the patient's condition, weight, age, etc., but in the case of oral administration, it is usually about 1 to 50 Omg per adult per day, and it may be administered once or in several divided doses. Is preferred.

Example

Hereinafter, the present invention will be described more specifically with reference to formulation examples and pharmacological actions, but the present invention is not limited thereto.

Hereinafter, the method for preparing the pharmaceutical preparation of the present invention will be described with reference to pharmaceutical preparation examples.

In the following formulation examples and experimental examples, a compound having Rho kinase inhibitory activity, (+)-trans-4- (1-1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane 2 HC 1 · 1 H ₂ 0 (also referred to as Y-27632) was used. Further, the compound used in the present invention is also referred to as the compound of the present invention for convenience. Formulation example 1: Tablet

Compound of the present invention (Y_27632) 100 mg

Lactose 500 mg

Corn starch 200 mg

Microcrystalline cellulose 297 mg

Polyvinylpyrrolidone Κ 30 500 mg

Talc 50 mg

Magnesium stearate ― 0 3

1 20.0 mg

The compound of the present invention (Y-27632), lactose, corn starch and crystalline cellulose were mixed, kneaded with polyvinylpyrrolidone-30 size liquid, and granulated through a 20 mesh sieve. After drying at 50 ° C for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and a tablet having a diameter of 12 Omg was prepared using a 7 mm diameter punch.

Formulation example 2: Forcepsel

Compound of the present invention (Y-27632) 100 mg

Lactose 70 0 mg

Starch sorghum starch 35 0 mg

Polyvinyl pyrrolidone K 30 20 mg

Talc 2 7 mg

Magnesium stearate 0 3 mg

1 20.0 mg

The compound of the present invention (Y_27632), lactose and corn starch are mixed, kneaded using polyvinylpyrrolidone K30 size liquid, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, the mixture is passed through a 24 mesh sieve, talc and magnesium stearate are mixed, and the mixture is filled into hard capsules (No. 4) to produce 120 mg capsules. Formulation example 3: Injection

Compound of the present invention (Y-27632) 5. Omg

Sodium chloride 18.Omg

Total amount of distilled water for injection 2.Oml

Sodium chloride is dissolved in about 80 parts of distilled water for injection, and then the compound of the present invention (Y

-Add 27632) and dissolve to make the total amount (100 parts). After filtration using a membrane filter (0.2 μm), the mixture was filled in a 2 ml 1 ampoule and sterilized at 115 ° C. for 30 minutes to prepare a 2 ml injection.

Hereinafter, the pharmacological action of the medicament of the present invention will be described with reference to experimental examples.

Experimental Example 1: Induction of differentiation of undifferentiated mesenchymal cells into osteoblasts

(experimental method)

Using mouse undifferentiated mesenchymal cells (10T1 / 2 cells, MC3T3-E1 cells and ST2 cells), the activity of AL-lipophosphatase (ALP) as an indicator of osteoblast differentiation And the amount of osteocalcin production was measured. 10 T 1/2 cells (supplied from RI KEN CE LLBANK (RCB0247)) were prepared in Basal Medium Eagle + 10% FCS supplemented with Y-27632 (0, 3, 5, 10, 20, 30〃M). 5% C0 ₂ presence and incubated 37 ° C, 72 hours. After cultivation, the ALP activity contained in the cells (mostly bound to the cell membrane) was measured by the p-nitrophenyl phosphate substrate method (alkaline phospha B-test ヮ), and the amount of osteocalcin in the culture supernatant was further reduced. It was measured by the RIA method (Biotec). MC 3 T 3- E 1 cells (sale from RI KEN CELL BANK (RCB 1 126 )) is also attached to, 5% C ◦ ₂ presence in MEM alpha medium + 1 0% FCS containing a Y- 27632, 37 ° C After culturing for 72 hours, ALP activity was measured in the same manner. Moreover, ST for 2 cells (sale from RI KEN CEL LBANK (RCB 02 24 )), MEM alpha medium + 1 5% C 0 2 presence in 0% FCS containing Y- 27632, 37 ° C, 5 days after culture Similarly, the ALP activity and the amount of osteocalcin were measured. In addition, it has been reported that ST 2 cells undergo bone differentiation in response to type-1 collagen (Eri Otsuka et. Al., Am. J. Physiol., 277 C132, 1999) and the same method using type-1 collagen-coated dishes (Celltight C-1, Sumitomo Bakelite Co. Japan). Was performed, and the combined effect with collagen was also examined. (Experimental result)

In 10 T 1-2 cells, the addition of Y-27632 increased ALP activity (Figure 1-1) and osteocalcin production (Figure 1-2). Furthermore, addition of Y-27632 also increased ALP activity in MC 3 T 3 -E1 cells (FIGS. 1-3). The addition of Y-27632 also increased ALP activity (Fig. 2-1) and osteocalcin production (Fig. 2-2) in ST2 cells. The effect of increasing the ALP activity and osteocalcin production of Y-27632 was more prominent when using a collagen-coated dish. In all these experiments, the greatest increase was observed when 10 μM of Y-27632.

Experimental Example 2: Effects on osteopontin and BMP-4 gene expression levels in undifferentiated mesenchymal cells

(experimental method)

Y-27632 (10〃M) is applied to 10 T 1/2 cells, and the mRNA amount of osteobontin, which is strongly expressed at the early stage of osteoblast differentiation, is measured by RNA plotting over 1 to 4 days. (K. Yoshioka et. Al., J. Biol. Chem., 273 (9), 5146, 1998). Similarly, ST-2 cells were treated with 10-M Y-27632, and the mRNA level of BMP-4, one of the osteoinductive factors, was measured over a period of 1 to 3 days by the RNA blot method. .

(Experimental result)

When 10〃M Y-27632 was added to mouse 10 T 1/2 cells, the expression of osteopontin mRNA (normalized by GAPDH mRNA) increased one day after the addition of Y-27632. And then attenuated over time (Figure 3). On the other hand, when 10 μM Y-27632 was added to mouse ST2 cells, BMP-4 m As for the amount of RNA, the expression level was significantly increased as compared with the case where Y_27632 was not added, and increased over time (FIG. 4).

Experimental Example 3: Inhibition of differentiation of Rho-expressing mesenchymal cells into osteoblasts

(experimental method)

The active Rho (Va1_Rho) expression vector is transfected into 10 T1 / 2 cells by a method using ribofectamine to express exogenous active Rh. / 2 cells (hereinafter also referred to as Rho-expressing 10T1 / 2 cells) were prepared (Itoh, K., et al., Nature Med. Feb; 5 (2): p221-225 (1999)). 5% C◦ ₂ presence in each cell similarly Basal Medium Eagle + 1 0% FCS in Experimental Example 1, after incubation 37 ° C, 48 hours, was studied the change of ALP activity by the expression of the activated Rho . The expression of active Rho was confirmed by the Western-producing method (immunoblotting) using a Rho antibody, and the ALP activity was measured in the same manner as in Experimental Example 1. As a control, cells expressing only one vector were used (mock).

(Experimental result)

Rho-expressing 10T1 / 2 cells have lower ALP activity than normal mesenchymal cells (which do not express activated Rho), and increased Rho activity suppresses differentiation into osteoblasts. Wax was shown (column V in Fig. 5). Therefore, it is presumed that suppression of Rho activity by a compound having Rho kinase inhibitory activity (Y-27632) promotes differentiation induction into osteoblasts and promotes bone formation.

Industrial application Based on the above formulation examples and experimental examples or other pharmacological experiments, compounds with Rho kinase inhibitory activity increase the production of osteoinductive factor (BMP) in mesenchymal cells, and Acts on osteoblasts by acting on leaf cells to significantly increase osteobontin production, alkaline phosphatase (ALP) activity and osteocalcin production, which are differentiation markers for osteoblasts. It has an excellent osteogenesis promoting action by having a differentiation induction action of Useful as a preventive and remedy for the disease.

Therefore, a compound having Rho kinase inhibitory activity can be used for osteoporosis, fibrous osteomyelitis, osteomalacia, etc. which occur when the balance between bone resorption and bone formation in bone tissue is disrupted due to the above-mentioned bone formation promoting action. Prevention of metabolic bone diseases including pagenit disease, bone fractures in the orthopedic field, bone defects such as bone loss, low back pain and osteoarthritis, and bone diseases such as periodontal disease in the dental field · It is useful as a treatment, and at the same time, is expected to be applied to repair of periodontal tissue defects in periodontal disease, stabilization of artificial dental roots, repair of chin ridge formation, and cleft palate. This application is based on a patent application No. 1723230 filed in Japan, filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. An osteogenesis promoter comprising a compound having Rho kinase inhibitory activity ₍

2. The compound having Rho kinase inhibitory activity is represented by the following general formula (I)

0 Rb

Ra- -C- -N- -Rc (I)

(Where Ra is the formula

c

[In the formulas (a) and (b), R represents hydrogen, alkyl, or a cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which may have a substituent on the ring;

(Wherein, R ⁶ is hydrogen, alkyl or a formula: NR ⁸ R ⁹ (where R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, aralkyl or phenyl).) R ⁷ is hydrogen Represents an alkyl, aralkyl, phenyl, nitro or cyano, or: ^fi and R ⁷ are bonded to each other to further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. Represents a group forming a heterocyclic ring which may be optionally substituted. R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.

Or R and R ¹ represent a group which, together with an adjacent nitrogen atom, forms a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent. .

R ² represents hydrogen or alkyl.

RR ⁴ may be the same or different and may be hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyl, cyano, acysyl, mercapto, alkylthio, aralkylthio, alkoxy, alkoxycarbonyl, alkavamoyl , Mono ■ Indicates dialkyl rubamoyl or azide.

A is the formula

(e)

(In the formula, R ^{1 ()} and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^{1 (}} and R ¹¹ are 1, m, and n each represent 0 or an integer of 1 to 3.).

In the formula (c), L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, fulvamoylalkyl, phthalimidalkyl, amidino, or B- ■ (g)

(Wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, monoaminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl Show.

Q ¹ represents hydrogen, halogen, hydroxyl, aralkyloxy or cetylmethyl.

W represents alkylene.

Q ² represents hydrogen, halogen, a hydroxyl group or aralkyloxy.

X represents alkylene.

Q ³ represents hydrogen, halogen, hydroxyl, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-13-oxo-1,2,3,4,5-tetrahydropyridazine-16-yl.

Y represents a single bond, alkylene or alkenylene. ).

R ⁵ represents hydrogen, a hydroxyl group, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy. ]

R b represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

R c represents a nitrogen-containing heterocyclic ring which may have a substituent. Amide compound represented by the formula (I), its isomer and / or its pharmaceutically acceptable acid addition salt. The osteogenesis promoter according to claim 1.

3. The compound having Rho kinase inhibitory activity is represented by the following general formula (1 ′)

O Rb

Ra'ichi C- -N- -Rc ()

Where R a 'is

[In the formula, R ′ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.

Or a group in which R ′ and R ¹ are bonded to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom. Is shown.

R ² represents hydrogen or alkyl.

RR ⁴ may be the same or different and may be hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkylquiloxy, cyano, acyle, mercapto, alkylthio, aralkylthio, alkoxy, alkoxycarbonyl, alkamoyl, Indicates mono- or di-alkyl rubamoyl or azide. A is the formula

(Wherein, R ^lf) and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ¹⁰ and R ¹¹ are combined to form a cycloalkyl group. 1, m and n each represent 0 or an integer of 1 to 3. ).

Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

3. The bone formation promoting agent according to claim 1, which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.

4. The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H- Pyro mouth [2,3-b] pyridine-4-yl) 1-4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) -14- (1-Aminoethyl) benzamide and (R)-(+)-N- (1H-pyrro [2,3-b] pyridin-4-yl) -14- (1-aminoethyl) benzamide 2. The bone formation promoting agent according to claim 1, which is a compound selected from the group consisting of and / or a pharmaceutically acceptable acid addition salt thereof.

5. The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane and / or its pharmaceutically acceptable acid addition. 2. The bone formation promoting agent according to claim 1, which is a salt.

6. The bone formation promoting agent according to any one of claims 1 to 5, which is used for prevention and treatment of a bone disease.

7. The bone formation promoting agent according to claim 6, wherein the bone disease is a fracture.

8. A pharmaceutical composition for preventing or treating bone disease, comprising a compound having Rho kinase inhibitory activity and a pharmaceutically acceptable carrier.

9. A compound having Rho kinase inhibitory activity is represented by the following general formula (I)

0 Rb

Ra- -C- -N- -Rc (I)

(Where Ra is the formula

c

(Wherein, R ^fi is hydrogen, alkyl or formula:. _NR ⁸ R ⁹ (wherein, R ^8, R ⁹ represents hydrogen, alkyl, a) shows a Ararukiru or phenyl same or different, R ⁷ is hydrogen, Represents alkyl, aralkyl, phenyl, nitro, or cyano, or R ^f; and R ⁷ are bonded to each other to further contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent in the ring. And a group forming a heterocyclic ring which may be represented by: You.

R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on 璟.

Or, R and R ¹ represent a group which forms a heterocyclic ring which may further contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom together with an adjacent nitrogen atom. .

R ² represents hydrogen or alkyl.

R ³ and R ⁴ are the same or different and are hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyl oxy, cyano, acyl, mercapto, alkylthio, aralkylthio, alkoxycarbonyl, alkoxycarbonyl ,, Or mono-dialkyl levamoyl or azide.

A is the formula

(Wherein, R i and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^{1 G} and R ¹¹ are bonded to form a cycloalkyl 1, m and n each represent 0 or an integer of 1 to 3.)).

In the formula (c), L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, rubamoylalkyl, phthalimidalkyl, amidino, or O

B- ■ C (g)

(In the formula, B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, monoaminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or Indicates imidazopyridyl.

Q ¹ represents hydrogen, halogen, hydroxyl, aralkyloxy or cetylmethyl.

W represents alkylene.

Q ² represents hydrogen, halogen, a hydroxyl group or aralkyloxy.

X represents alkylene.

Q ³ represents hydrogen, halogen, hydroxyl, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-13-oxo_2,3,4,5-tetrahydropyridazine-6-yl.

Y represents a single bond, alkylene or alkenylene. ).

R b represents hydrogen, alkyl, aralkyl, aminoalkyl or monodialkylaminoalkyl.

R c represents a nitrogen-containing heterocyclic ring which may have a substituent. Amide compound represented by the formula (I), its isomer and / or its pharmaceutically acceptable acid addition salt. 9. A pharmaceutical composition for preventing or treating a bone disease according to item 8.

10. The compound having Rho kinase inhibitory activity is represented by the following general formula (1 ′)

0 Rb

Ra * ichi C- -N- -Rc ()

Where R a 'is

R ² represents hydrogen or alkyl.

R ³ and R ⁴ are the same or different and are hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyl oxy, cyano, acyl, mercapto, alkylthio, aralkylthio, alkoxycarbonyl, alkoxycarbonyl Indicate rubbamoyl, mono-dialkyl rubamoyl or azide. A is the formula

(Wherein R It ^} and R ′ ¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^1Q and R ¹¹ are 1, m, and n each represent 0 or an integer of 1 to 3).

Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

10. The pharmaceutical composition for preventing or treating bone diseases according to claim 8 or 9, which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.

1 1. The compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H) —Pyro mouth [2,3_b] pyridine-14-yl) -14- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) —4— (1-aminoethyl) benzamide and (R)-(+)-N- (1H-pyrro [2,3-b] pyridin-4-yl) 1-4- (1-aminoethyl) benzamide 9. The pharmaceutical composition for preventing or treating a bone disease according to claim 8, which is a compound selected from the group consisting of and / or a pharmaceutically acceptable acid addition salt thereof.

1 2. The compound having Rh 0 kinase inhibitory activity is (+)-trans-41- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid addition thereof. 9. The pharmaceutical composition for preventing or treating a bone disease according to claim 8, which is a salt.

13. The pharmaceutical composition for preventing or treating a bone disease according to any one of claims 8 to 12, wherein the bone disease is a fracture.

14. A method for preventing or treating a bone disease, which comprises administering to a patient an effective amount of a compound having Rho kinase inhibitory activity.

1 5. The compound having Rho kinase inhibitory activity is represented by the following general formula (I)

〇 Rb

Ra—— C- -N- -Rc (I)

(Where Ra is the formula

c

(Wherein, R ⁶ is hydrogen, alkyl or formula:. _NR ⁸ R ⁹ (wherein, R ^8, R ⁹ represents hydrogen, alkyl, a) shows a Ararukiru or phenyl same or different, R ⁷ is hydrogen, Represents alkyl, aralkyl, phenyl, nitro or cyano. Alternatively, R ⁶ and R ⁷ represent a group which forms a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. ).

R ² represents hydrogen or alkyl.

A is the formula

(Wherein, R ^{1 Q} and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^1Q and R ¹¹ are 1, m, and n each represent 0 or an integer of 1 to 3.).

In the formula (c), L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, dirubamoylalkyl, phthalimidalkyl, amidino, or O

B-C (g)

(Wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylcarbonylalkyl, thioaminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazo Indicates pyridyl.

Q ¹ represents hydrogen, halogen, hydroxyl, aralkyloxy or cetylmethyl.

W represents alkylene.

Q ² represents hydrogen, halogen, a hydroxyl group or aralkyloxy.

X represents alkylene.

Y represents a single bond, alkylene or alkenylene. ).

R b represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

An amide compound represented by the formula: 15. The method for preventing and treating a bone disease according to claim 14, which is an acid addition salt.

16. The compound having Rho kinase inhibitory activity is represented by the following general formula (1 ′)

〇 Rb

Ra'ichi C- -N- -Rc (Γ)

Where R a 'is

R ² represents hydrogen or alkyl.

A is the formula

(Wherein, R ¹⁰ and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^{1 Q} and R ^{] 1} are bonded to form a cycloalkyl 1, m and n each represent 0 or an integer of 1 to 3.)).

Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

16. The method for preventing or treating a bone disease according to claim 14 or 15, which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.

17. Compounds with Rh kinase inhibition activity include (+)-trans-41- (1-aminoethyl) -1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H) —Pyro mouth [2,3-b] pyridine-14-yl) -14- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) -14 — (1-Aminoethyl) benzamide and (R)-(+) — N- (1H-pyro-mouth [2,3-b] pyridin-4-yl) 1-4- (1-aminoethyl) benzamido 15. The method for preventing and treating a bone disease according to claim 14, which is a compound selected from the group consisting of steroids and / or a pharmaceutically acceptable acid addition salt thereof.

18. A compound having an inhibitory activity on Rh kinase is (+)-trans-4-1- (1-aminoethyl) -1- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid addition salt thereof. 15. The method for preventing and treating a bone disease according to claim 14, wherein the method comprises:

19. The method for preventing or treating a bone disease according to any one of claims 14 to 18, wherein the bone disease is a fracture.

20. Compounds with Rho kinase inhibitory activity for the manufacture of drugs for the prevention and treatment of bone diseases Use of things.

2 1. The compound having Rho kinase inhibitory activity is represented by the following general formula (I)

〇 Rb

Ra ^ C- -N- -Rc (I)

(Where Ra is the formula

c

(Wherein R ^fi is hydrogen, alkyl or a formula: NR ⁸ R ⁹ (where R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, aralkyl or phenyl).) R ⁷ is hydrogen , Alkyl, aralkyl, phenyl, nitro or cyano, or R ^fi and R ⁷ are bonded to each other and further contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent in the ring. Represents a group forming a heterocyclic ring which may be optionally substituted.

R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring. Or, R and R ¹ represent a group which forms a heterocyclic ring which may further contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom together with an adjacent nitrogen atom. .

R ² represents hydrogen or alkyl.

A is the formula

(In the formula, R ^lt5 and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^1Q and R ¹¹ are bonded to form a cyclo 1, m, and n each represent 0 or an integer of 1 to 3).

In the formula (c), L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, fulvamoylalkyl, phthalimidalkyl, amidino, or

(g)

(i)

Q ¹ represents hydrogen, halogen, hydroxyl, aralkyloxy or cetylmethyl.

W represents alkylene.

Q ² represents hydrogen, halogen, a hydroxyl group or aralkyloxy.

X represents alkylene.

Y represents a single bond, alkylene or alkenylene. ).

R b represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.

R c represents a nitrogen-containing heterocyclic ring which may have a substituent. ] 20. The use according to claim 20, which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.

22. The compound having Rho kinase inhibitory activity is represented by the following general formula (1,):

0 Rb

Ra'— C—— N—— Rc () where R a 'is a formula

R ² represents hydrogen or alkyl.

RR ⁴ may be the same or different and may be hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyl, cyano, acryl, mercapto, alkylthio, aralkylthio, Represents ruboxyl, alkoxycarbonyl, rubamoyl, mono-dialkyl rubamoyl or azide.

A is the formula

(Wherein R ′ ^Q and R ¹¹ are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R ^1D and R ¹¹ are 1, m, and n each represent 0 or an integer of 1 to 3.).

Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or monodialkylaminoalkyl.

20. The use according to claim 20, which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.

23.: The compound with ho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N_ (1H— Pyro mouth [2,3-b] pyridine-14-yl) _4 _ (1 aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) -14- ( 1-Aminoethyl) benzamide and (R)-(+)-N- (1H-pyro mouth [2,3-b] pyridine-14-yl) 4- (1-aminoethyl) benzamide 21. The use according to claim 20, which is a compound selected from the group consisting of and / or a pharmaceutically acceptable acid addition salt thereof.

24. Compound having Rho kinase inhibitory activity is (+)-trans-4_ (1-aminoethyl) -1- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid addition salt thereof 21. The use according to claim 20, wherein

25. The use according to any of claims 20 to 24, wherein the bone disease is a fracture.

26. A pharmaceutical composition for the prevention and treatment of bone disease according to any one of claims 8 to 13, and that the pharmaceutical composition can or should be used for the prevention and treatment of bone disease. Commercial package containing documents stating